As the largest sesamoid bone in the human body, the patella acts as a fulcrum to enhance the biomechanical advantage of the quadriceps in extension.¹ It is subject to a variety of forces while improving distribution of forces along the extensor mechanism.² With sufficient force, the patella can be dislocated. Acute patellar dislocations are the most common knee injury, encompassing 2% to 3% of all knee injuries³ and occurring in 5.8 per 100,000 individuals.^4-5 These injuries are associated with acute trauma, frequently from sports and physical activities, occurring while in terminal extension with an axial-valgus stress on the knee during rotation.⁶

With acute patellar dislocations, patients are usually in significant discomfort. Often, the patella may spontaneously reduce; if not, closed reduction is usually successful with pressure applied anteromedially on the lateral patellar margin, while simultaneously attempting gentle extension of the leg.⁷ Closed reduction is almost universally successful, and there have only been case reports of irreducible, mainly fixed vertical axis patellar dislocations.^8-11 No reports in the literature have described subacute patellar dislocations because of their rarity. Patients present immediately after dislocation, spontaneously reduce, or have a painless, chronically dislocated patella.

We present a case of an elderly man with dementia and a subacute fixed irreducible patellar dislocation, which was reduced using a technique not described in the literature. The patient and the patient’s guardian provided written informed consent for print and electronic publication of this case report.

Case Report

A 68-year-old nonambulatory man with a history of dementia and stroke presented to the emergency department with complaints of left knee pain and his knee locked in flexion. The patient’s knee had been in that fixed hyperflexed position for at least 10 days after he sustained a twisting injury to his knee while attempting to get out of bed. At baseline, the patient was mostly bedbound and could walk minimally with maximum support, but, given his dementia, he would often attempt to ambulate by himself. After the injury, the patient did not complain of much pain at rest, but attempts at his group home to straighten his leg had caused severe pain. As a result, the patient was brought to the emergency department to be evaluated for fractures. 

Physical examination in the emergency department revealed atrophy of the lower extremity musculature and a left knee fixed at 120º in flexion. The skin was intact, and there was minimal effusion of the knee joint. The patella was noted to be laterally subluxated and tender to palpation over the lateral and medial facets. He was neurovascularly intact distally and had painless range of motion of his hips. His contralateral right knee had full range of motion with good patellar tracking.

Radiographs of the patient’s knee confirmed a lateral dislocation of the patella (Figures 1A-1C). After oral and intravenous administration of pain medication, a reduction was attempted without success. Next, an intra-articular knee injection of 10 mL of 1% lidocaine was given. After waiting 15 minutes, another reduction was tried. While the pain control was sufficient, the reduction was again unsuccessful. The knee was insufflated with 120 mL of sterile saline and reduction attempted again. By extending the knee and applying a medially directed force to the patella, reduction was successful. The patient was placed into a knee immobilizer and postreduction radiographs were taken (Figures 2A, 2B). Saline was extracted from the knee. The patient was admitted to the hospital where repeat examination of his knees during the next week revealed markedly less pain. The patient was lost to follow-up.

Discussion

Our patient presumably had a low-energy mechanism of injury, resulting in an undiagnosed patellar dislocation with delayed treatment. This subacute patellar dislocation was irreducible using the standard techniques. Alternatively, insufflation of the joint with saline provided the necessary impetus to allow for successful patellar reduction. The history of the patient reveals clues about the mechanism of injury. It is likely that the patient’s nonambulatory status resulted in a weak vastus medialis muscle that placed the patella at risk for dislocation. While the exact mechanism of dislocation is unknown, the patella was unable to be reduced spontaneously because our patient’s knee was maintained in a state of flexion secondary to pain and muscle contraction. The combination of weak quadriceps musculature, increased Q angle, and forced hyperflexion of the knee prevented closed reduction of the patella.

Fixed, irreducible patellar dislocations are rare and discussed infrequently in the literature.^9,11-12 Reported mechanisms are mostly high energy, including blows during athletics and impacts from motor vehicle collisions.^9,13 Vertical axis rotation, as first described by Cooper,¹⁴ is commonly implicated in irreducible patellar dislocations. This occurs when the patella internally rotates 180º on its vertical axis, associated with a large tear of the medial retinaculum but intact quadriceps tendon. The patella is fixed over the lateral femoral condyle with the articular surface pointing anterolaterally. Despite adequate sedation and analgesia, these are notoriously difficult to close-reduce and may necessitate open reduction.³ Our patient, while having a fixed dislocation, did not have a vertical axis component and, therefore, was amenable to our closed reduction attempt.

Our first reduction attempts were unsuccessful, likely because the patient continued to be tense, firing his quadriceps. Even after injecting the knee with lidocaine and eliminating the pain component, the patella was still impinging on the lateral femoral condyle (Figure 3A). By insufflating the knee with saline, we were able to increase the distance from the patella to the trochlea (Figure 3B). This is comparable to a knee arthroscopy, in which joint fluid pressure allows passage of arthroscopic instruments into the patellofemoral joint. We postulate that the farther the patella is anterior to the trochlea, the higher the likelihood that the patella can be reduced to its anatomic position. 

Insufflation of the knee with sterile saline is a novel technique that involves minimal risk compared with the alternatives. Sometimes, for closed reduction to be successful, individuals need to be consciously sedated to relax their muscles and eliminate pain. While conscious sedation is generally considered low risk, complications have been noted, including hypotension, apnea, and retrograde amnesia.¹⁵ Manual closed reduction may also cause additional chondral damage when the medial patellar facet contacts the lateral femoral trochlea. When closed reduction of the patella fails, open reduction is required; this inherently includes all the risks of surgery, such as bleeding, infection, neurovascular injury, and wound complications.  

Our insufflation technique does not require sedation and is minimally invasive. The saline creates space and provides lubrication to allow for easier manipulation of the patella. This theoretically protects the cartilage as the patella passes over the lateral trochlea. In addition to the intended effect of providing more space and lubrication for the reduction of the patella, insufflation of the joint may also relax the vastus musculature.¹⁶ In their study, Torry and colleagues¹⁶ injected 13 knees with 20 mL sterile saline and noted reduction in electromyography readings in the vastus medialis and lateralis muscles. This inhibition of vastus musculature may provide enough relaxation to aid in the successful reduction of the patella.

Our study is limited by our sample size of 1. Because acute patellar dislocations are often easily reduced, our technical trick is not frequently used. Additionally, while we were able to monitor his progress during his inpatient stay, our patient was lost to follow-up after his discharge from the hospital.

 If successful, the insufflation technique eliminates the need for urgent open reduction in the operating room. As a result, we recommend attempting closed reduction using insufflation of the knee with sterile saline for irreducible patellar dislocations before proceeding with open reduction.

Conclusion

Saline insufflation of the knee can be safely and easily performed to aid in the reduction of subacute, difficult patellar dislocations.

As the largest sesamoid bone in the human body, the patella acts as a fulcrum to enhance the biomechanical advantage of the quadriceps in extension.¹ It is subject to a variety of forces while improving distribution of forces along the extensor mechanism.² With sufficient force, the patella can be dislocated. Acute patellar dislocations are the most common knee injury, encompassing 2% to 3% of all knee injuries³ and occurring in 5.8 per 100,000 individuals.^4-5 These injuries are associated with acute trauma, frequently from sports and physical activities, occurring while in terminal extension with an axial-valgus stress on the knee during rotation.⁶

With acute patellar dislocations, patients are usually in significant discomfort. Often, the patella may spontaneously reduce; if not, closed reduction is usually successful with pressure applied anteromedially on the lateral patellar margin, while simultaneously attempting gentle extension of the leg.⁷ Closed reduction is almost universally successful, and there have only been case reports of irreducible, mainly fixed vertical axis patellar dislocations.^8-11 No reports in the literature have described subacute patellar dislocations because of their rarity. Patients present immediately after dislocation, spontaneously reduce, or have a painless, chronically dislocated patella.

We present a case of an elderly man with dementia and a subacute fixed irreducible patellar dislocation, which was reduced using a technique not described in the literature. The patient and the patient’s guardian provided written informed consent for print and electronic publication of this case report.

Case Report

A 68-year-old nonambulatory man with a history of dementia and stroke presented to the emergency department with complaints of left knee pain and his knee locked in flexion. The patient’s knee had been in that fixed hyperflexed position for at least 10 days after he sustained a twisting injury to his knee while attempting to get out of bed. At baseline, the patient was mostly bedbound and could walk minimally with maximum support, but, given his dementia, he would often attempt to ambulate by himself. After the injury, the patient did not complain of much pain at rest, but attempts at his group home to straighten his leg had caused severe pain. As a result, the patient was brought to the emergency department to be evaluated for fractures. 

Physical examination in the emergency department revealed atrophy of the lower extremity musculature and a left knee fixed at 120º in flexion. The skin was intact, and there was minimal effusion of the knee joint. The patella was noted to be laterally subluxated and tender to palpation over the lateral and medial facets. He was neurovascularly intact distally and had painless range of motion of his hips. His contralateral right knee had full range of motion with good patellar tracking.

Radiographs of the patient’s knee confirmed a lateral dislocation of the patella (Figures 1A-1C). After oral and intravenous administration of pain medication, a reduction was attempted without success. Next, an intra-articular knee injection of 10 mL of 1% lidocaine was given. After waiting 15 minutes, another reduction was tried. While the pain control was sufficient, the reduction was again unsuccessful. The knee was insufflated with 120 mL of sterile saline and reduction attempted again. By extending the knee and applying a medially directed force to the patella, reduction was successful. The patient was placed into a knee immobilizer and postreduction radiographs were taken (Figures 2A, 2B). Saline was extracted from the knee. The patient was admitted to the hospital where repeat examination of his knees during the next week revealed markedly less pain. The patient was lost to follow-up.

Discussion

Our patient presumably had a low-energy mechanism of injury, resulting in an undiagnosed patellar dislocation with delayed treatment. This subacute patellar dislocation was irreducible using the standard techniques. Alternatively, insufflation of the joint with saline provided the necessary impetus to allow for successful patellar reduction. The history of the patient reveals clues about the mechanism of injury. It is likely that the patient’s nonambulatory status resulted in a weak vastus medialis muscle that placed the patella at risk for dislocation. While the exact mechanism of dislocation is unknown, the patella was unable to be reduced spontaneously because our patient’s knee was maintained in a state of flexion secondary to pain and muscle contraction. The combination of weak quadriceps musculature, increased Q angle, and forced hyperflexion of the knee prevented closed reduction of the patella.

Fixed, irreducible patellar dislocations are rare and discussed infrequently in the literature.^9,11-12 Reported mechanisms are mostly high energy, including blows during athletics and impacts from motor vehicle collisions.^9,13 Vertical axis rotation, as first described by Cooper,¹⁴ is commonly implicated in irreducible patellar dislocations. This occurs when the patella internally rotates 180º on its vertical axis, associated with a large tear of the medial retinaculum but intact quadriceps tendon. The patella is fixed over the lateral femoral condyle with the articular surface pointing anterolaterally. Despite adequate sedation and analgesia, these are notoriously difficult to close-reduce and may necessitate open reduction.³ Our patient, while having a fixed dislocation, did not have a vertical axis component and, therefore, was amenable to our closed reduction attempt.

Our first reduction attempts were unsuccessful, likely because the patient continued to be tense, firing his quadriceps. Even after injecting the knee with lidocaine and eliminating the pain component, the patella was still impinging on the lateral femoral condyle (Figure 3A). By insufflating the knee with saline, we were able to increase the distance from the patella to the trochlea (Figure 3B). This is comparable to a knee arthroscopy, in which joint fluid pressure allows passage of arthroscopic instruments into the patellofemoral joint. We postulate that the farther the patella is anterior to the trochlea, the higher the likelihood that the patella can be reduced to its anatomic position. 

Insufflation of the knee with sterile saline is a novel technique that involves minimal risk compared with the alternatives. Sometimes, for closed reduction to be successful, individuals need to be consciously sedated to relax their muscles and eliminate pain. While conscious sedation is generally considered low risk, complications have been noted, including hypotension, apnea, and retrograde amnesia.¹⁵ Manual closed reduction may also cause additional chondral damage when the medial patellar facet contacts the lateral femoral trochlea. When closed reduction of the patella fails, open reduction is required; this inherently includes all the risks of surgery, such as bleeding, infection, neurovascular injury, and wound complications.  

Our insufflation technique does not require sedation and is minimally invasive. The saline creates space and provides lubrication to allow for easier manipulation of the patella. This theoretically protects the cartilage as the patella passes over the lateral trochlea. In addition to the intended effect of providing more space and lubrication for the reduction of the patella, insufflation of the joint may also relax the vastus musculature.¹⁶ In their study, Torry and colleagues¹⁶ injected 13 knees with 20 mL sterile saline and noted reduction in electromyography readings in the vastus medialis and lateralis muscles. This inhibition of vastus musculature may provide enough relaxation to aid in the successful reduction of the patella.

Our study is limited by our sample size of 1. Because acute patellar dislocations are often easily reduced, our technical trick is not frequently used. Additionally, while we were able to monitor his progress during his inpatient stay, our patient was lost to follow-up after his discharge from the hospital.

 If successful, the insufflation technique eliminates the need for urgent open reduction in the operating room. As a result, we recommend attempting closed reduction using insufflation of the knee with sterile saline for irreducible patellar dislocations before proceeding with open reduction.

Conclusion

Saline insufflation of the knee can be safely and easily performed to aid in the reduction of subacute, difficult patellar dislocations.

As the largest sesamoid bone in the human body, the patella acts as a fulcrum to enhance the biomechanical advantage of the quadriceps in extension.¹ It is subject to a variety of forces while improving distribution of forces along the extensor mechanism.² With sufficient force, the patella can be dislocated. Acute patellar dislocations are the most common knee injury, encompassing 2% to 3% of all knee injuries³ and occurring in 5.8 per 100,000 individuals.^4-5 These injuries are associated with acute trauma, frequently from sports and physical activities, occurring while in terminal extension with an axial-valgus stress on the knee during rotation.⁶

With acute patellar dislocations, patients are usually in significant discomfort. Often, the patella may spontaneously reduce; if not, closed reduction is usually successful with pressure applied anteromedially on the lateral patellar margin, while simultaneously attempting gentle extension of the leg.⁷ Closed reduction is almost universally successful, and there have only been case reports of irreducible, mainly fixed vertical axis patellar dislocations.^8-11 No reports in the literature have described subacute patellar dislocations because of their rarity. Patients present immediately after dislocation, spontaneously reduce, or have a painless, chronically dislocated patella.

We present a case of an elderly man with dementia and a subacute fixed irreducible patellar dislocation, which was reduced using a technique not described in the literature. The patient and the patient’s guardian provided written informed consent for print and electronic publication of this case report.

Case Report

A 68-year-old nonambulatory man with a history of dementia and stroke presented to the emergency department with complaints of left knee pain and his knee locked in flexion. The patient’s knee had been in that fixed hyperflexed position for at least 10 days after he sustained a twisting injury to his knee while attempting to get out of bed. At baseline, the patient was mostly bedbound and could walk minimally with maximum support, but, given his dementia, he would often attempt to ambulate by himself. After the injury, the patient did not complain of much pain at rest, but attempts at his group home to straighten his leg had caused severe pain. As a result, the patient was brought to the emergency department to be evaluated for fractures. 

Physical examination in the emergency department revealed atrophy of the lower extremity musculature and a left knee fixed at 120º in flexion. The skin was intact, and there was minimal effusion of the knee joint. The patella was noted to be laterally subluxated and tender to palpation over the lateral and medial facets. He was neurovascularly intact distally and had painless range of motion of his hips. His contralateral right knee had full range of motion with good patellar tracking.

Radiographs of the patient’s knee confirmed a lateral dislocation of the patella (Figures 1A-1C). After oral and intravenous administration of pain medication, a reduction was attempted without success. Next, an intra-articular knee injection of 10 mL of 1% lidocaine was given. After waiting 15 minutes, another reduction was tried. While the pain control was sufficient, the reduction was again unsuccessful. The knee was insufflated with 120 mL of sterile saline and reduction attempted again. By extending the knee and applying a medially directed force to the patella, reduction was successful. The patient was placed into a knee immobilizer and postreduction radiographs were taken (Figures 2A, 2B). Saline was extracted from the knee. The patient was admitted to the hospital where repeat examination of his knees during the next week revealed markedly less pain. The patient was lost to follow-up.

Discussion

Our patient presumably had a low-energy mechanism of injury, resulting in an undiagnosed patellar dislocation with delayed treatment. This subacute patellar dislocation was irreducible using the standard techniques. Alternatively, insufflation of the joint with saline provided the necessary impetus to allow for successful patellar reduction. The history of the patient reveals clues about the mechanism of injury. It is likely that the patient’s nonambulatory status resulted in a weak vastus medialis muscle that placed the patella at risk for dislocation. While the exact mechanism of dislocation is unknown, the patella was unable to be reduced spontaneously because our patient’s knee was maintained in a state of flexion secondary to pain and muscle contraction. The combination of weak quadriceps musculature, increased Q angle, and forced hyperflexion of the knee prevented closed reduction of the patella.

Fixed, irreducible patellar dislocations are rare and discussed infrequently in the literature.^9,11-12 Reported mechanisms are mostly high energy, including blows during athletics and impacts from motor vehicle collisions.^9,13 Vertical axis rotation, as first described by Cooper,¹⁴ is commonly implicated in irreducible patellar dislocations. This occurs when the patella internally rotates 180º on its vertical axis, associated with a large tear of the medial retinaculum but intact quadriceps tendon. The patella is fixed over the lateral femoral condyle with the articular surface pointing anterolaterally. Despite adequate sedation and analgesia, these are notoriously difficult to close-reduce and may necessitate open reduction.³ Our patient, while having a fixed dislocation, did not have a vertical axis component and, therefore, was amenable to our closed reduction attempt.

Our first reduction attempts were unsuccessful, likely because the patient continued to be tense, firing his quadriceps. Even after injecting the knee with lidocaine and eliminating the pain component, the patella was still impinging on the lateral femoral condyle (Figure 3A). By insufflating the knee with saline, we were able to increase the distance from the patella to the trochlea (Figure 3B). This is comparable to a knee arthroscopy, in which joint fluid pressure allows passage of arthroscopic instruments into the patellofemoral joint. We postulate that the farther the patella is anterior to the trochlea, the higher the likelihood that the patella can be reduced to its anatomic position. 

Insufflation of the knee with sterile saline is a novel technique that involves minimal risk compared with the alternatives. Sometimes, for closed reduction to be successful, individuals need to be consciously sedated to relax their muscles and eliminate pain. While conscious sedation is generally considered low risk, complications have been noted, including hypotension, apnea, and retrograde amnesia.¹⁵ Manual closed reduction may also cause additional chondral damage when the medial patellar facet contacts the lateral femoral trochlea. When closed reduction of the patella fails, open reduction is required; this inherently includes all the risks of surgery, such as bleeding, infection, neurovascular injury, and wound complications.  

Our insufflation technique does not require sedation and is minimally invasive. The saline creates space and provides lubrication to allow for easier manipulation of the patella. This theoretically protects the cartilage as the patella passes over the lateral trochlea. In addition to the intended effect of providing more space and lubrication for the reduction of the patella, insufflation of the joint may also relax the vastus musculature.¹⁶ In their study, Torry and colleagues¹⁶ injected 13 knees with 20 mL sterile saline and noted reduction in electromyography readings in the vastus medialis and lateralis muscles. This inhibition of vastus musculature may provide enough relaxation to aid in the successful reduction of the patella.

Our study is limited by our sample size of 1. Because acute patellar dislocations are often easily reduced, our technical trick is not frequently used. Additionally, while we were able to monitor his progress during his inpatient stay, our patient was lost to follow-up after his discharge from the hospital.

 If successful, the insufflation technique eliminates the need for urgent open reduction in the operating room. As a result, we recommend attempting closed reduction using insufflation of the knee with sterile saline for irreducible patellar dislocations before proceeding with open reduction.

Conclusion

Saline insufflation of the knee can be safely and easily performed to aid in the reduction of subacute, difficult patellar dislocations.

The incidence of hip fractures decreased between 1995 and 2005, but these injuries continue to occur in large numbers. Between 1986 and 2005, the mean annual number of hip fractures was 957.3/100,000, and the majority of these occurred in patients 75 to 84 years old.¹ Investigators have described total hip arthroplasty (THA) performed after initial surgical treatment in patients who developed osteoarthritis (OA) of the hip secondary to a fracture.^2-7 Only 1 of these studies compared these patients with a control group of patients who had THA for primary hip OA.² No study included both previous proximal femur and acetabular fractures.

Postfracture OA may occur when there is residual articular incongruity after fracture or osteonecrosis of the femoral head. THA is commonly used to treat OA when more conservative treatments have failed.⁶ Other indications for conversion to THA include femoral neck nonunion, significant leg-length discrepancy, and femoral head damage caused by previous internal fixation.⁴

Given these conditions and previous study findings, THA performed in patients with previous hip fracture fixation is potentially more complicated than THA for primary OA. We therefore conducted a study to evaluate differences in sociodemographic factors, surgical details, and outcomes between patients who had THA for posttraumatic OA and patients who had THA for primary OA.

Materials and Methods

After obtaining institutional review board approval and patient consent, we used a prospective database to follow 3844 patients who had THA performed for OA by 1 of 17 different surgeons at a single center over an 8-year period. Patients who had THA for secondary causes of hip OA, developmental hip dysplasia, or inflammatory processes were excluded. Of the remaining 1199 patients, 62 (5.2%) had THA for posttraumatic OA after previous acetabular or proximal femur fracture fixation (Figures 1, 2) (no THA was performed at time of initial fracture treatment), and 1137 had THA for primary OA and served as the control group.

We collected data on age, sex, fracture location, reason for THA, time between open reduction and internal fixation (ORIF) and THA, type of components, cement use, leg-length discrepancy, intraoperative complications, blood loss, operating room time, and postoperative complications. All patients were aseptic at time of THA. All posttraumatic OA patients had previous hardware removed; the extent of hardware removal was dictated by the exposure required for prosthesis implantation. These patients were contacted, and clinical follow-up was assessed with modified Harris Hip Score (HHS).⁸ HHS was determined by Dr. Khurana. Statistical analysis was performed with Student t test and Pearson χ² test using PASW Statistics 18 (SPSS, Chicago, Illinois).

The 62 posttraumatic OA patients had 63 fractures, 41 of the proximal femur (femoral neck and intertrochanteric; 65%) and 22 acetabular (35%). This group consisted of 33 females and 29 males. Their mean age at time of THA surgery was 58 years (range, 31-90 years). Mean age of the control patients was 59.4 years (range, 18-95 years). There were 35 right hips and 27 left hips in the posttrauma group. Mean body mass index (BMI) was 28.4 for the posttrauma group and 28.9 for the control group. There were no differences in age (P = .451), sex (P = .674), or BMI (P = .592) between the 2 groups (Table 1).

All 62 posttraumatic OA patients had complete hospital data, and 32 (52%) of the 62 underwent long-term follow-up (mean, 4.3 years; range, 4 months–10.5 years). At time of attempted contact (mean, 6.79 years after THA), 7 patients were deceased; cause of death was an unrelated medical condition (1) or unknown (6). The rest of the patients did not respond to multiple telephone and mail summons. Primary reasons for conversion to THA included OA (34 patients, 54%), development of osteonecrosis (12 patients, 19%), and nonunion (12 patients, 19%). The rest of the patients had fixation failure. The mechanisms of injury were motor vehicle accidents (30 patients), falls (20), and other causes (15).

Results

Thirty-two (52%) of the posttraumatic OA patients had a preoperative leg-length discrepancy. For these patients, mean time between initial fracture fixation and conversion to THA was 74 months (range, 1-480 months). Four patients required grafting with cancellous autogenous bone graft or allograft chips to fill a bony defect. Mean acetabular component diameter was 54 mm. Nineteen patients had acetabular fixation supplemented with screws. (Screw supplementation data were not recorded for control patients.) Three patients (4.7%) with an acetabular fracture had heterotopic bone removed at time of THA. Two patients underwent neurolysis of the sciatic nerve at time of surgery for preexisting nerve palsy.

Mean postoperative hemoglobin was 109 g/L in the posttraumatic OA group and 121 g/L in the control group (P <. 001). Mean postoperative hematocrit was 0.327 and 0.367, respectively (P < .001). Mean amount of Cell Saver (Haemonetics) used by patients was 176.2 and 72.9 mL, respectively (P < .001). Posttrauma patients lost a mean of 360 mL of blood more than control patients did (P < .001) and were transfused a mean of 1.59 units of blood, compared with 0.85 unit in the controls (P < .001). Patients with acetabular fractures required a mean of only 0.65 unit of transfused blood. Mean operating room time was 240.5 minutes for posttrauma patients and 135.6 minutes for control patients (P < .001). In the posttrauma group, mean size of the head of the femoral component was 29 mm (head size was not recorded for the control group). Posttrauma patients had 18 (29%) hybrid cemented hip replacements (femoral component only) and 44 uncemented hip replacements. Data on femoral stem size and type were not reported for either group.

Twenty-four posttrauma patients (39%) had a total of 63 perioperative complications, and 131 control patients (11.5%) had a total of 160 complications (P < .001). Complications in posttrauma patients with proximal femur fractures included excess bleeding (5 patients), in-hospital dislocations (2), and postoperative infections (4: 2 superficial wound infections, 1 implant infection requiring explant, 1 Clostridium difficile infection); in patients with acetabular fractures, there was only 1 dislocation (no infections). The posttraumatic OA group did not develop any symptomatic venous thromboembolic complications. One patient developed a sciatic nerve palsy after surgery. Of the 3 patients who sustained dislocations, 2 were treated with closed reduction and maintenance of implants, and 1 with revision THA. Complications in the control group included 3 infections, 4 dislocations, and 12 cases of extensive blood loss (Table 2).

In patients with long-term follow-up, mean postoperative modified HHS was 81.33 (range, 34.1-100.1). Twelve patients had an excellent score (>90), 10 a good score (80-89), 4 a fair score (70-79), and 6 a poor score (<70). Mean HHS was 84.2 for the 16 patients with a femoral head or neck fracture, 77.7 for the 6 patients with an intertrochanteric fracture, and 84.3 for the 9 patients with an acetabular fracture. Nine patients reported using a cane, 3 required walkers, 2 required wheelchairs, and 18 did not require any walking support. Four (12.5%) of the 32 patients required THA revision a mean of 3.5 years (range, 2 months–8 years) after initial arthroplasty. Reasons for revision were infections (2 patients), multiple dislocations (1), and dissociation of acetabular lining (1) (Table 3). Two of the patients who underwent THA revision had a cemented femoral stem, and 2 did not have any cemented implants. Additional details of the femoral stem components were not available for either group.

Discussion

Patients who develop posttraumatic OA of the hip have limited options. THA has emerged as an excellent option in cases of failed repair of fractures about the hip joint. The results of the present study are consistent with earlier findings of the effectiveness of THA in salvaging posttraumatic hips.^2-7 THA for patients with posttraumatic arthritis of the hip after acetabular or proximal femur fracture is longer and more complicated than THA for primary OA, and there is significantly more blood loss. In addition, the rate of early failure appears to be higher.⁹

In this study, mean amount of blood transfused for patients with previous acetabular fracture was 0.65 unit, much less than the mean of 3.5 units noted by Weber and colleagues.⁶ In their study, complications associated with THA were increased in patients with posttraumatic OA from acetabular fractures. The authors attributed these complications to scarring from previous surgery, retained hardware, heterotopic bone, and residual osseous deformity and deficiency. Our results support their conclusion. Operating times were longer, as well as blood loss and the need for blood transfusions and other blood products were increased in the patients with posttraumatic OA, as compared with patients with primary OA. Fifteen percent of patients with an acetabular fracture had undergone removal of heterotopic bone at time of surgery—similar to the rate of 18% noted in the Weber study.⁶

Our results showed that the rate of revision THA was also higher than in patients with primary THA within the general population—reported to be about 4%.⁹ The higher rate may be the result of the additional surgeries performed on patients with fractures, or hardware retention increasing the infection risk over the years. Our revision rate of 12.5% was similar to the 19% found by Ranawat and colleagues⁷ in their study.

A majority of the patients in our study had favorable long-term HHS. Mean overall HHS was 83, slightly better than the 79 reported by Srivastav and colleagues.⁴ We found that patients with intertrochanteric fractures ultimately had worse outcome scores than patients with acetabular or femoral neck fractures. These results are consistent with findings reported by Mehlhoff and colleagues⁵ in a study comparing patients with femoral neck and intertrochanteric fractures. Mean HHS for the intertrochanteric fracture patients in our study was 77.7, comparable to the mean of 78 reported by Mehlhoff and colleagues.⁵ Mean HHS for the femoral neck or head fractures in our study was 84.2, similar to the mean of 81 they noted. Patients with a previous acetabular fracture in our study had a mean HHS of 84.3, consistent with the 84 reported by Ranawat and colleagues⁷ for patients who had initially undergone ORIF for acetabular fracture. Mean HHS in our study (83) was slightly less than the 88.5 reported by Shi and colleagues¹⁰ in their study of primary THAs.

Few studies have been conducted exclusively on one type of hip fracture (acetabular) or another (proximal femur), and all except 1 did not perform a comparison. Tabsh and colleagues² compared similar cohorts but focused solely on patients with previous proximal femur fractures. The present study included a control group and both acetabular and proximal femur fractures, which allowed us to compare patients with and without previous fracture fixation and to consider the 2 different fracture types and see if they affected outcomes.

The strengths of this study include the large control group and the relatively short data-collection period. The shorter period decreased the influence of improvements in implants on patient outcomes. In addition, the control group was our own population, as we did not compare our cohort of patients with previous internal fixation and patients who had primary THAs in other studies, aside from comparisons for revision rates and HHS.

Although the ultimate long-term follow-up rate for patients with previous internal fixation was 50%, our sample size was still larger than that in most reported studies. Another weakness of our study was the large number of surgeons (17), representing an array of techniques, approaches, and surgical experience. All these factors could have influenced patient outcomes and operative data. In addition, data on revision rates and HHS were not available for our control group, so we could not directly compare these outcomes with those of the posttraumatic group. However, we used previously reported data on revision rates and HHS in primary THAs for comparison with the posttraumatic group.^9,10

Conclusion

In this study, THA was a viable option for patients with posttraumatic arthritis from a previous acetabular or proximal femur fracture. The outcomes, however, were less reliable than the outcomes of primary THA for degenerative arthritis, and the complication rates were higher. Surgeons should counsel patients about the complexity of the procedure as well as its ultimately favorable outcomes. Surgeons should expect additional technical difficulties in the operating room when treating this patient population.

The incidence of hip fractures decreased between 1995 and 2005, but these injuries continue to occur in large numbers. Between 1986 and 2005, the mean annual number of hip fractures was 957.3/100,000, and the majority of these occurred in patients 75 to 84 years old.¹ Investigators have described total hip arthroplasty (THA) performed after initial surgical treatment in patients who developed osteoarthritis (OA) of the hip secondary to a fracture.^2-7 Only 1 of these studies compared these patients with a control group of patients who had THA for primary hip OA.² No study included both previous proximal femur and acetabular fractures.

Postfracture OA may occur when there is residual articular incongruity after fracture or osteonecrosis of the femoral head. THA is commonly used to treat OA when more conservative treatments have failed.⁶ Other indications for conversion to THA include femoral neck nonunion, significant leg-length discrepancy, and femoral head damage caused by previous internal fixation.⁴

Given these conditions and previous study findings, THA performed in patients with previous hip fracture fixation is potentially more complicated than THA for primary OA. We therefore conducted a study to evaluate differences in sociodemographic factors, surgical details, and outcomes between patients who had THA for posttraumatic OA and patients who had THA for primary OA.

Materials and Methods

After obtaining institutional review board approval and patient consent, we used a prospective database to follow 3844 patients who had THA performed for OA by 1 of 17 different surgeons at a single center over an 8-year period. Patients who had THA for secondary causes of hip OA, developmental hip dysplasia, or inflammatory processes were excluded. Of the remaining 1199 patients, 62 (5.2%) had THA for posttraumatic OA after previous acetabular or proximal femur fracture fixation (Figures 1, 2) (no THA was performed at time of initial fracture treatment), and 1137 had THA for primary OA and served as the control group.

We collected data on age, sex, fracture location, reason for THA, time between open reduction and internal fixation (ORIF) and THA, type of components, cement use, leg-length discrepancy, intraoperative complications, blood loss, operating room time, and postoperative complications. All patients were aseptic at time of THA. All posttraumatic OA patients had previous hardware removed; the extent of hardware removal was dictated by the exposure required for prosthesis implantation. These patients were contacted, and clinical follow-up was assessed with modified Harris Hip Score (HHS).⁸ HHS was determined by Dr. Khurana. Statistical analysis was performed with Student t test and Pearson χ² test using PASW Statistics 18 (SPSS, Chicago, Illinois).

The 62 posttraumatic OA patients had 63 fractures, 41 of the proximal femur (femoral neck and intertrochanteric; 65%) and 22 acetabular (35%). This group consisted of 33 females and 29 males. Their mean age at time of THA surgery was 58 years (range, 31-90 years). Mean age of the control patients was 59.4 years (range, 18-95 years). There were 35 right hips and 27 left hips in the posttrauma group. Mean body mass index (BMI) was 28.4 for the posttrauma group and 28.9 for the control group. There were no differences in age (P = .451), sex (P = .674), or BMI (P = .592) between the 2 groups (Table 1).

All 62 posttraumatic OA patients had complete hospital data, and 32 (52%) of the 62 underwent long-term follow-up (mean, 4.3 years; range, 4 months–10.5 years). At time of attempted contact (mean, 6.79 years after THA), 7 patients were deceased; cause of death was an unrelated medical condition (1) or unknown (6). The rest of the patients did not respond to multiple telephone and mail summons. Primary reasons for conversion to THA included OA (34 patients, 54%), development of osteonecrosis (12 patients, 19%), and nonunion (12 patients, 19%). The rest of the patients had fixation failure. The mechanisms of injury were motor vehicle accidents (30 patients), falls (20), and other causes (15).

Results

Thirty-two (52%) of the posttraumatic OA patients had a preoperative leg-length discrepancy. For these patients, mean time between initial fracture fixation and conversion to THA was 74 months (range, 1-480 months). Four patients required grafting with cancellous autogenous bone graft or allograft chips to fill a bony defect. Mean acetabular component diameter was 54 mm. Nineteen patients had acetabular fixation supplemented with screws. (Screw supplementation data were not recorded for control patients.) Three patients (4.7%) with an acetabular fracture had heterotopic bone removed at time of THA. Two patients underwent neurolysis of the sciatic nerve at time of surgery for preexisting nerve palsy.

Mean postoperative hemoglobin was 109 g/L in the posttraumatic OA group and 121 g/L in the control group (P <. 001). Mean postoperative hematocrit was 0.327 and 0.367, respectively (P < .001). Mean amount of Cell Saver (Haemonetics) used by patients was 176.2 and 72.9 mL, respectively (P < .001). Posttrauma patients lost a mean of 360 mL of blood more than control patients did (P < .001) and were transfused a mean of 1.59 units of blood, compared with 0.85 unit in the controls (P < .001). Patients with acetabular fractures required a mean of only 0.65 unit of transfused blood. Mean operating room time was 240.5 minutes for posttrauma patients and 135.6 minutes for control patients (P < .001). In the posttrauma group, mean size of the head of the femoral component was 29 mm (head size was not recorded for the control group). Posttrauma patients had 18 (29%) hybrid cemented hip replacements (femoral component only) and 44 uncemented hip replacements. Data on femoral stem size and type were not reported for either group.

Twenty-four posttrauma patients (39%) had a total of 63 perioperative complications, and 131 control patients (11.5%) had a total of 160 complications (P < .001). Complications in posttrauma patients with proximal femur fractures included excess bleeding (5 patients), in-hospital dislocations (2), and postoperative infections (4: 2 superficial wound infections, 1 implant infection requiring explant, 1 Clostridium difficile infection); in patients with acetabular fractures, there was only 1 dislocation (no infections). The posttraumatic OA group did not develop any symptomatic venous thromboembolic complications. One patient developed a sciatic nerve palsy after surgery. Of the 3 patients who sustained dislocations, 2 were treated with closed reduction and maintenance of implants, and 1 with revision THA. Complications in the control group included 3 infections, 4 dislocations, and 12 cases of extensive blood loss (Table 2).

In patients with long-term follow-up, mean postoperative modified HHS was 81.33 (range, 34.1-100.1). Twelve patients had an excellent score (>90), 10 a good score (80-89), 4 a fair score (70-79), and 6 a poor score (<70). Mean HHS was 84.2 for the 16 patients with a femoral head or neck fracture, 77.7 for the 6 patients with an intertrochanteric fracture, and 84.3 for the 9 patients with an acetabular fracture. Nine patients reported using a cane, 3 required walkers, 2 required wheelchairs, and 18 did not require any walking support. Four (12.5%) of the 32 patients required THA revision a mean of 3.5 years (range, 2 months–8 years) after initial arthroplasty. Reasons for revision were infections (2 patients), multiple dislocations (1), and dissociation of acetabular lining (1) (Table 3). Two of the patients who underwent THA revision had a cemented femoral stem, and 2 did not have any cemented implants. Additional details of the femoral stem components were not available for either group.

Discussion

Patients who develop posttraumatic OA of the hip have limited options. THA has emerged as an excellent option in cases of failed repair of fractures about the hip joint. The results of the present study are consistent with earlier findings of the effectiveness of THA in salvaging posttraumatic hips.^2-7 THA for patients with posttraumatic arthritis of the hip after acetabular or proximal femur fracture is longer and more complicated than THA for primary OA, and there is significantly more blood loss. In addition, the rate of early failure appears to be higher.⁹

In this study, mean amount of blood transfused for patients with previous acetabular fracture was 0.65 unit, much less than the mean of 3.5 units noted by Weber and colleagues.⁶ In their study, complications associated with THA were increased in patients with posttraumatic OA from acetabular fractures. The authors attributed these complications to scarring from previous surgery, retained hardware, heterotopic bone, and residual osseous deformity and deficiency. Our results support their conclusion. Operating times were longer, as well as blood loss and the need for blood transfusions and other blood products were increased in the patients with posttraumatic OA, as compared with patients with primary OA. Fifteen percent of patients with an acetabular fracture had undergone removal of heterotopic bone at time of surgery—similar to the rate of 18% noted in the Weber study.⁶

Our results showed that the rate of revision THA was also higher than in patients with primary THA within the general population—reported to be about 4%.⁹ The higher rate may be the result of the additional surgeries performed on patients with fractures, or hardware retention increasing the infection risk over the years. Our revision rate of 12.5% was similar to the 19% found by Ranawat and colleagues⁷ in their study.

A majority of the patients in our study had favorable long-term HHS. Mean overall HHS was 83, slightly better than the 79 reported by Srivastav and colleagues.⁴ We found that patients with intertrochanteric fractures ultimately had worse outcome scores than patients with acetabular or femoral neck fractures. These results are consistent with findings reported by Mehlhoff and colleagues⁵ in a study comparing patients with femoral neck and intertrochanteric fractures. Mean HHS for the intertrochanteric fracture patients in our study was 77.7, comparable to the mean of 78 reported by Mehlhoff and colleagues.⁵ Mean HHS for the femoral neck or head fractures in our study was 84.2, similar to the mean of 81 they noted. Patients with a previous acetabular fracture in our study had a mean HHS of 84.3, consistent with the 84 reported by Ranawat and colleagues⁷ for patients who had initially undergone ORIF for acetabular fracture. Mean HHS in our study (83) was slightly less than the 88.5 reported by Shi and colleagues¹⁰ in their study of primary THAs.

Few studies have been conducted exclusively on one type of hip fracture (acetabular) or another (proximal femur), and all except 1 did not perform a comparison. Tabsh and colleagues² compared similar cohorts but focused solely on patients with previous proximal femur fractures. The present study included a control group and both acetabular and proximal femur fractures, which allowed us to compare patients with and without previous fracture fixation and to consider the 2 different fracture types and see if they affected outcomes.

The strengths of this study include the large control group and the relatively short data-collection period. The shorter period decreased the influence of improvements in implants on patient outcomes. In addition, the control group was our own population, as we did not compare our cohort of patients with previous internal fixation and patients who had primary THAs in other studies, aside from comparisons for revision rates and HHS.

Although the ultimate long-term follow-up rate for patients with previous internal fixation was 50%, our sample size was still larger than that in most reported studies. Another weakness of our study was the large number of surgeons (17), representing an array of techniques, approaches, and surgical experience. All these factors could have influenced patient outcomes and operative data. In addition, data on revision rates and HHS were not available for our control group, so we could not directly compare these outcomes with those of the posttraumatic group. However, we used previously reported data on revision rates and HHS in primary THAs for comparison with the posttraumatic group.^9,10

Conclusion

In this study, THA was a viable option for patients with posttraumatic arthritis from a previous acetabular or proximal femur fracture. The outcomes, however, were less reliable than the outcomes of primary THA for degenerative arthritis, and the complication rates were higher. Surgeons should counsel patients about the complexity of the procedure as well as its ultimately favorable outcomes. Surgeons should expect additional technical difficulties in the operating room when treating this patient population.

The incidence of hip fractures decreased between 1995 and 2005, but these injuries continue to occur in large numbers. Between 1986 and 2005, the mean annual number of hip fractures was 957.3/100,000, and the majority of these occurred in patients 75 to 84 years old.¹ Investigators have described total hip arthroplasty (THA) performed after initial surgical treatment in patients who developed osteoarthritis (OA) of the hip secondary to a fracture.^2-7 Only 1 of these studies compared these patients with a control group of patients who had THA for primary hip OA.² No study included both previous proximal femur and acetabular fractures.

Postfracture OA may occur when there is residual articular incongruity after fracture or osteonecrosis of the femoral head. THA is commonly used to treat OA when more conservative treatments have failed.⁶ Other indications for conversion to THA include femoral neck nonunion, significant leg-length discrepancy, and femoral head damage caused by previous internal fixation.⁴

Given these conditions and previous study findings, THA performed in patients with previous hip fracture fixation is potentially more complicated than THA for primary OA. We therefore conducted a study to evaluate differences in sociodemographic factors, surgical details, and outcomes between patients who had THA for posttraumatic OA and patients who had THA for primary OA.

Materials and Methods

After obtaining institutional review board approval and patient consent, we used a prospective database to follow 3844 patients who had THA performed for OA by 1 of 17 different surgeons at a single center over an 8-year period. Patients who had THA for secondary causes of hip OA, developmental hip dysplasia, or inflammatory processes were excluded. Of the remaining 1199 patients, 62 (5.2%) had THA for posttraumatic OA after previous acetabular or proximal femur fracture fixation (Figures 1, 2) (no THA was performed at time of initial fracture treatment), and 1137 had THA for primary OA and served as the control group.

We collected data on age, sex, fracture location, reason for THA, time between open reduction and internal fixation (ORIF) and THA, type of components, cement use, leg-length discrepancy, intraoperative complications, blood loss, operating room time, and postoperative complications. All patients were aseptic at time of THA. All posttraumatic OA patients had previous hardware removed; the extent of hardware removal was dictated by the exposure required for prosthesis implantation. These patients were contacted, and clinical follow-up was assessed with modified Harris Hip Score (HHS).⁸ HHS was determined by Dr. Khurana. Statistical analysis was performed with Student t test and Pearson χ² test using PASW Statistics 18 (SPSS, Chicago, Illinois).

The 62 posttraumatic OA patients had 63 fractures, 41 of the proximal femur (femoral neck and intertrochanteric; 65%) and 22 acetabular (35%). This group consisted of 33 females and 29 males. Their mean age at time of THA surgery was 58 years (range, 31-90 years). Mean age of the control patients was 59.4 years (range, 18-95 years). There were 35 right hips and 27 left hips in the posttrauma group. Mean body mass index (BMI) was 28.4 for the posttrauma group and 28.9 for the control group. There were no differences in age (P = .451), sex (P = .674), or BMI (P = .592) between the 2 groups (Table 1).

All 62 posttraumatic OA patients had complete hospital data, and 32 (52%) of the 62 underwent long-term follow-up (mean, 4.3 years; range, 4 months–10.5 years). At time of attempted contact (mean, 6.79 years after THA), 7 patients were deceased; cause of death was an unrelated medical condition (1) or unknown (6). The rest of the patients did not respond to multiple telephone and mail summons. Primary reasons for conversion to THA included OA (34 patients, 54%), development of osteonecrosis (12 patients, 19%), and nonunion (12 patients, 19%). The rest of the patients had fixation failure. The mechanisms of injury were motor vehicle accidents (30 patients), falls (20), and other causes (15).

Results

Thirty-two (52%) of the posttraumatic OA patients had a preoperative leg-length discrepancy. For these patients, mean time between initial fracture fixation and conversion to THA was 74 months (range, 1-480 months). Four patients required grafting with cancellous autogenous bone graft or allograft chips to fill a bony defect. Mean acetabular component diameter was 54 mm. Nineteen patients had acetabular fixation supplemented with screws. (Screw supplementation data were not recorded for control patients.) Three patients (4.7%) with an acetabular fracture had heterotopic bone removed at time of THA. Two patients underwent neurolysis of the sciatic nerve at time of surgery for preexisting nerve palsy.

Mean postoperative hemoglobin was 109 g/L in the posttraumatic OA group and 121 g/L in the control group (P <. 001). Mean postoperative hematocrit was 0.327 and 0.367, respectively (P < .001). Mean amount of Cell Saver (Haemonetics) used by patients was 176.2 and 72.9 mL, respectively (P < .001). Posttrauma patients lost a mean of 360 mL of blood more than control patients did (P < .001) and were transfused a mean of 1.59 units of blood, compared with 0.85 unit in the controls (P < .001). Patients with acetabular fractures required a mean of only 0.65 unit of transfused blood. Mean operating room time was 240.5 minutes for posttrauma patients and 135.6 minutes for control patients (P < .001). In the posttrauma group, mean size of the head of the femoral component was 29 mm (head size was not recorded for the control group). Posttrauma patients had 18 (29%) hybrid cemented hip replacements (femoral component only) and 44 uncemented hip replacements. Data on femoral stem size and type were not reported for either group.

Twenty-four posttrauma patients (39%) had a total of 63 perioperative complications, and 131 control patients (11.5%) had a total of 160 complications (P < .001). Complications in posttrauma patients with proximal femur fractures included excess bleeding (5 patients), in-hospital dislocations (2), and postoperative infections (4: 2 superficial wound infections, 1 implant infection requiring explant, 1 Clostridium difficile infection); in patients with acetabular fractures, there was only 1 dislocation (no infections). The posttraumatic OA group did not develop any symptomatic venous thromboembolic complications. One patient developed a sciatic nerve palsy after surgery. Of the 3 patients who sustained dislocations, 2 were treated with closed reduction and maintenance of implants, and 1 with revision THA. Complications in the control group included 3 infections, 4 dislocations, and 12 cases of extensive blood loss (Table 2).

In patients with long-term follow-up, mean postoperative modified HHS was 81.33 (range, 34.1-100.1). Twelve patients had an excellent score (>90), 10 a good score (80-89), 4 a fair score (70-79), and 6 a poor score (<70). Mean HHS was 84.2 for the 16 patients with a femoral head or neck fracture, 77.7 for the 6 patients with an intertrochanteric fracture, and 84.3 for the 9 patients with an acetabular fracture. Nine patients reported using a cane, 3 required walkers, 2 required wheelchairs, and 18 did not require any walking support. Four (12.5%) of the 32 patients required THA revision a mean of 3.5 years (range, 2 months–8 years) after initial arthroplasty. Reasons for revision were infections (2 patients), multiple dislocations (1), and dissociation of acetabular lining (1) (Table 3). Two of the patients who underwent THA revision had a cemented femoral stem, and 2 did not have any cemented implants. Additional details of the femoral stem components were not available for either group.

Discussion

Patients who develop posttraumatic OA of the hip have limited options. THA has emerged as an excellent option in cases of failed repair of fractures about the hip joint. The results of the present study are consistent with earlier findings of the effectiveness of THA in salvaging posttraumatic hips.^2-7 THA for patients with posttraumatic arthritis of the hip after acetabular or proximal femur fracture is longer and more complicated than THA for primary OA, and there is significantly more blood loss. In addition, the rate of early failure appears to be higher.⁹

In this study, mean amount of blood transfused for patients with previous acetabular fracture was 0.65 unit, much less than the mean of 3.5 units noted by Weber and colleagues.⁶ In their study, complications associated with THA were increased in patients with posttraumatic OA from acetabular fractures. The authors attributed these complications to scarring from previous surgery, retained hardware, heterotopic bone, and residual osseous deformity and deficiency. Our results support their conclusion. Operating times were longer, as well as blood loss and the need for blood transfusions and other blood products were increased in the patients with posttraumatic OA, as compared with patients with primary OA. Fifteen percent of patients with an acetabular fracture had undergone removal of heterotopic bone at time of surgery—similar to the rate of 18% noted in the Weber study.⁶

Our results showed that the rate of revision THA was also higher than in patients with primary THA within the general population—reported to be about 4%.⁹ The higher rate may be the result of the additional surgeries performed on patients with fractures, or hardware retention increasing the infection risk over the years. Our revision rate of 12.5% was similar to the 19% found by Ranawat and colleagues⁷ in their study.

A majority of the patients in our study had favorable long-term HHS. Mean overall HHS was 83, slightly better than the 79 reported by Srivastav and colleagues.⁴ We found that patients with intertrochanteric fractures ultimately had worse outcome scores than patients with acetabular or femoral neck fractures. These results are consistent with findings reported by Mehlhoff and colleagues⁵ in a study comparing patients with femoral neck and intertrochanteric fractures. Mean HHS for the intertrochanteric fracture patients in our study was 77.7, comparable to the mean of 78 reported by Mehlhoff and colleagues.⁵ Mean HHS for the femoral neck or head fractures in our study was 84.2, similar to the mean of 81 they noted. Patients with a previous acetabular fracture in our study had a mean HHS of 84.3, consistent with the 84 reported by Ranawat and colleagues⁷ for patients who had initially undergone ORIF for acetabular fracture. Mean HHS in our study (83) was slightly less than the 88.5 reported by Shi and colleagues¹⁰ in their study of primary THAs.

Few studies have been conducted exclusively on one type of hip fracture (acetabular) or another (proximal femur), and all except 1 did not perform a comparison. Tabsh and colleagues² compared similar cohorts but focused solely on patients with previous proximal femur fractures. The present study included a control group and both acetabular and proximal femur fractures, which allowed us to compare patients with and without previous fracture fixation and to consider the 2 different fracture types and see if they affected outcomes.

The strengths of this study include the large control group and the relatively short data-collection period. The shorter period decreased the influence of improvements in implants on patient outcomes. In addition, the control group was our own population, as we did not compare our cohort of patients with previous internal fixation and patients who had primary THAs in other studies, aside from comparisons for revision rates and HHS.

Although the ultimate long-term follow-up rate for patients with previous internal fixation was 50%, our sample size was still larger than that in most reported studies. Another weakness of our study was the large number of surgeons (17), representing an array of techniques, approaches, and surgical experience. All these factors could have influenced patient outcomes and operative data. In addition, data on revision rates and HHS were not available for our control group, so we could not directly compare these outcomes with those of the posttraumatic group. However, we used previously reported data on revision rates and HHS in primary THAs for comparison with the posttraumatic group.^9,10

Conclusion

In this study, THA was a viable option for patients with posttraumatic arthritis from a previous acetabular or proximal femur fracture. The outcomes, however, were less reliable than the outcomes of primary THA for degenerative arthritis, and the complication rates were higher. Surgeons should counsel patients about the complexity of the procedure as well as its ultimately favorable outcomes. Surgeons should expect additional technical difficulties in the operating room when treating this patient population.

L-ascorbic acid, more commonly know as vitamin C, is an essential micronutrient used in numerous metabolic pathways. It functions physiologically as a water-soluble antioxidant by virtue of its high reducing power, playing a key role in the function of leukocytes, protein metabolism, and production of neurotransmitters.^1-3 Vitamin C also contributes to musculoskeletal health through biosynthesis of carnitine and collagen⁴ and enhancement of intestinal absorption of dietary iron⁵ from plants and vegetables. Unlike most animals, humans are unable to synthesize this essential vitamin and therefore require intake from natural dietary sources or supplements.⁶ The ability of vitamin C to prevent or treat disease has been an area of research interest since the vitamin was identified and isolated by Szent-Györgyi in the 1930s.^7-16 Research in orthopedic surgery has focused on the effects of vitamin C on fracture healing, its potential use in preventing complex regional pain syndrome (CRPS), and its role in the pathophysiology of osteoarthritis. In this article, we review the basics of vitamin C metabolism and summarize the evidence surrounding the role of vitamin C supplementation in orthopedics.

Sources and Metabolism

Vitamin C is found naturally in many fruits and vegetables (Table 1) and is a common fortification in cereals, juices, and multivitamins. Daily recommended intake (Table 2) depends on age and smoking status. Absorption occurs in the distal small intestine, with blood plasma vitamin C concentrations reflecting dietary intake. Pharmacokinetic studies have shown that vitamin C concentrations are tightly regulated through absorption, tissue accumulation, and renal resorption, with plasma concentrations rarely exceeding 100 μmol/L without additional supplementation.¹⁷ Although the usual dietary doses of 100 mg/d (adult) are almost completely absorbed, producing a plasma concentration of 60 μmol/L, higher intake results in an increasingly smaller fraction absorbed.^1,18 Intake of more than 1000 mg/d results in less than 50% absorption¹⁹ (unmetabolized vitamin C is excreted in stool and urine¹). Even at higher doses, vitamin C has low toxicity³; the most common complaints are diarrhea, nausea, and abdominal cramps caused by the osmotic effect of unabsorbed vitamin C in the gastrointestinal tract.¹

Vitamin C Deficiency

The relationship between vitamin C deficiency and the development of scurvy has been documented for centuries. Symptoms are described in the ancient Egyptian, Greek, and Roman literature.²⁰ Ascorbic acid is essential for normal collagen function, as it is a required cofactor for enzymatic transfer of hydroxyl groups to select proline and lysine residues during procollagen formation. Hydroxylysine contributes to the intermolecular cross-links in collagen, and hydroxyproline stabilizes the triple-helix structure of collagen.²¹ Insufficient vitamin C during this process results in collagen that is non-cross-linked, nonhelical, structurally unstable, and weak.²¹ Clinical manifestations of scurvy stem from an underlying impairment of collagen production causing a systemic decrease in connective tissue integrity, capillary fragility, poor wound healing, fatigue, myalgias, arthritis, and even death.²² Vitamin C deficiency has also been implicated as a cause of diffuse bleeding in surgical patients with normal coagulation parameters secondary to capillary fragility.²³ In the United States, the 2003–2004 National Health and Nutrition Examination Survey (NHANES) measured serum vitamin C concentrations in 7277 noninstitutionalized patients 6 years old or older.²⁴ Age-adjusted incidence of subnormal serum vitamin C levels (<28 μmol/L) was 19.6%, and incidence of frank vitamin C deficiency (<11.4 μmol/L) was 7.1%. Reported rates of vitamin C deficiency in hospitalized patients are much higher, with 47% to 60% having subnormal values (<28 μmol/L) and 17% to 19% being vitamin C–deficient (<11.4 μmol/L).^22,25 Identified risk factors for hypovitaminosis C include advanced age, obesity, low socioeconomic status, unemployment, male sex, and concomitant alcohol and tobacco consumption.^22,24,25

Fracture Healing and Prevention

The effects of vitamin C deficiency on bone healing have been studied with animal models as early as the 1940s.^26,27 Early experiments using guinea pigs demonstrated failure of bone graft incorporation, delayed collagen maturation, and decreased collagen and callus formation in scorbutic animals compared with controls that received vitamin C supplementation.^26,27 Based on his work with guinea pigs, Bourne²⁶ reported in 1942 that vitamin C deficiency significantly inhibited the reparative process in damaged bone and that patients with fractures should receive vitamin C supplementation. Building on this early research, Yilmaz and colleagues²⁸ found faster histologic healing for tibia fractures in a rat model for animals that received a single injection of vitamin C 0.5 mg/kg compared with a nonscorbutic control group, and Sarisözen and colleagues²⁹ showed significantly accelerated histologic bone formation and mineralization at the fracture site for rats that received vitamin C supplementation. Moreover, Kipp and colleagues³⁰ found that scorbutic guinea pigs had lower bone mineral density (BMD), decreased bone mineral content, and impaired collagen synthesis of articular cartilage and tendons compared with nondeficient controls.

Besides promoting bone formation, vitamin C improves the mechanical strength of callus formation. Alcantara-Martos and colleagues³¹ used an osteogenic disorder Shionogi (ODS) rat model to examine the effects of vitamin C intake on femoral fracture healing. This particular animal model is unable to produce its own vitamin C. The groups with lower serum vitamin C levels demonstrated lower mechanical resistance of the fracture callus to torsional loads 5 weeks after fracture. Moreover, the group that received vitamin C supplementation showed higher histologic grade of callus formation and demonstrated faster healing rates. The authors suggested that subclinical vitamin C deficiency can delay fracture healing and that vitamin C supplementation in nondeficient patients would improve bone healing.

Other research has demonstrated a link between vitamin C and mesenchymal cell differentiation. Mohan and colleagues³² used an sfx mouse model to show that vitamin C deficiency results in decreased bone formation secondary to impaired osteoblast differentiation, diminished bone density, and development of spontaneous fractures. The authors indicated that not only is vitamin C essential for maintenance of differentiated functions of osteoblasts, but deficiency during early active growth may affect peak BMD levels in humans. Additional studies have demonstrated the role of vitamin C in endochondral bone formation through both induction of osteoblast differentiation and modulation of gene expression in hypertrophic chondrocytes.^33-36 Chronic vitamin C deficiency has been found to depress osteoblast function and differentiation of chondrocytes.³⁷ More recently, Kim and colleagues³⁸ examined the effect of vitamin C insufficiency in Gulo-deficient mice, which are unable to synthesize ascorbic acid. Ascorbic acid insufficiency over 4 weeks led to decreased plasma levels of osteocalcin and bone formation in vivo as well as significantly diminished metaphyseal trabecular bone. Despite all the evidence demonstrating the importance of vitamin C in bone formation and maintenance, many of the underlying processes in this relationship have yet to be determined.

Bone Mineral Density

Several observational studies have found a positive association between vitamin C intake and BMD in postmenopausal women. In a retrospective, cross-sectional study by Hall and Greendale,³⁹ a positive association was found between vitamin C intake and BMD of the femoral neck in 775 participants in the Postmenopausal Estrogen/Progestin Interventions trial. After calcium intake, physical activity level, smoking, estrogen use, age, and body mass index were adjusted for, each 100-mg increase in dietary vitamin C was associated with a 0.017 g/cm² increase in BMD. Wang and colleagues⁴⁰ found a positive association between dietary vitamin C intake and femoral neck BMD in a retrospective analysis of 125 postmenopausal Mexican American women. Other observational studies have reported that decreased intake of vitamin C is associated with osteoporosis⁴¹ and increased rates of BMD loss⁴² and that supplementation with vitamin C may suppress bone resorption in postmenopausal women.⁴³

The results of these studies contrast with the findings of Leveille and colleagues,⁴⁴ who examined the relationship between dietary vitamin C and hip BMD in 1892 postmenopausal women. Although the authors found that women (age, 55-64 years) using vitamin C supplements for more than 10 years had an average BMD 6.7% higher than that of nonusers, they did not find any association between dietary vitamin C intake and BMD. Moreover, NHANES III also found inconsistent associations between vitamin C and BMD among 13,080 adults surveyed in the United States.⁴⁵ Although for premenopausal women dietary ascorbic acid was associated with increased BMD, for postmenopausal women with a history of smoking and estrogen replacement, it was actually associated with lower BMD values. For other subgroups in the study, the relationship was also inconsistent or nonlinear.

The exact mechanism by which ascorbic acid contributes to BMD is not fully delineated. However, it likely is related to the known role of vitamin C in collagen formation, bone matrix development, osteoblast differentiation, and its antioxidant effects limiting bone resorption.^44,46

Hip Fractures

Besides demonstrating positive effects of vitamin C on bone healing and BMD, epidemiologic studies have found evidence of a protective effect of vitamin C on hip fracture risk. In a study of the Swedish Mammography cohort, 66,651 women (age, 40-76 years) were prospectively followed.⁴⁷ The authors found that the odds ratio (OR) for hip fractures among smokers with a low intake of vitamin E (median intake, ≤6.2 mg/d) was 3.0 (95% CI, 1.6-5.4) and for vitamin C (median intake, ≤67 mg/d) was 3.0 (95% CI, 1.6-5.6). Moreover, in smokers with a low intake of both vitamins E and C, OR increased to 4.9 (95% CI, 2.2-11.0). In addition, the Utah Study of Nutrition and Bone Health matched 1215 cases of hip fractures in patients who had ever smoked (age, >50 years) with 1349 controls and found that vitamin C intake above 159 mg/d had a significant protective effect on the incidence of hip fracture; however, a graded relationship was not observed.⁴⁸ Despite the inconsistencies in the NHANES III study regarding the relationship between vitamin C and BMD, Simon and Hudes⁴⁵ found that serum vitamin C was associated with lower risk for self-reported fracture in postmenopausal women who had ever smoked and had a history of estrogen therapy (OR, 0.51; 95% CI, 0.36-0.70). Finally, Sahni and colleagues⁴⁹ followed 958 Framingham cohort men and women (mean age, 75 years) over 17 years and found that those in the highest tertile of total vitamin C intake (median, 313 mg/d) had significantly fewer hip fractures and nonvertebral fractures compared with those in the lowest tertile of intake (median, 94 mg/d). Dietary vitamin C intake was not associated with fracture risk in this study.

Complex Regional Pain Syndrome

Type 1 CRPS is a debilitating condition characterized by severe pain, swelling, and vasomotor instability. It is commonly precipitated by an injury or surgery to an extremity and is a dreaded sequelae in orthopedics,⁵⁰ with incidence rates of 10% to 22% in wrist fractures^51-53 and 10% after foot and ankle surgery.⁵⁴ Although the pathophysiology of CRPS remains unknown, dysregulation and increased permeability of the vasculature caused by free radicals are thought to play an important role.⁵⁵ In dermal burns, high doses of vitamin C therapy slowed progression of vascular permeability and therefore reduced extravascular leakage of fluids and protein.^56,57 The ability of vitamin C to prevent CRPS has been studied in only a handful of trials.

In a double-blind trial, Zollinger and colleagues⁵¹ randomized 127 conservatively treated distal radius fractures to receive either vitamin C 500 mg or placebo daily for 50 days starting on day of injury. Incidence of CRPS (using the diagnostic criteria proposed by Veldman and colleagues⁵⁸) at 1-year follow-up was 22% in the placebo group and 7% in the vitamin C group (95% CI for difference, 2%-26%). Complaints while wearing the cast and fracture type increased the risk for developing CRPS. This initial study was followed up by a prospective, randomized, double-blind multicenter trial by the same authors,⁵² who had 416 patients with 427 wrist fractures receive either placebo or vitamin C 200 mg/d, 500 mg/d, or 1500 mg/d for 50 days. This follow-up study included both operative (11%) and nonoperative (89%) distal radius fractures. Incidence of CRPS was 10.1% in the placebo group and 2.4% in the vitamin C group (P < .002). Although there was an appreciable drop in the relative risk (RR) of developing CRPS between the vitamin C 200-mg/d and 500-mg/d groups (0.41-0.17), there was no additional benefit in the 1500-mg/d group. Pooling the data for these 2 randomized trials showed that the overall RR for developing CRPS was lower with vitamin C supplementation (RR, 0.28; 95% CI, 0.14-0.56; P = .0003).⁵⁹

Results of the 2 trials by Zollinger and colleagues^51,52 have been met with several concerns.^60-62 As a corollary to the unclear etiology of CRPS, several different sets of diagnostic criteria exist, and the criteria are somewhat subjective and imprecise. Although both trials used the Veldman criteria,⁵⁸ the incidence of CRPS in the placebo group dropped unexpectedly between trials, from 22% to 10.1%, and the results may have been different had other criteria been used. Moreover, the idea that toxic oxygen radicals have a role in CRPS and that vitamin C can scavenge these radicals is based on limited data.⁶¹ In the absence of a clear pathophysiologic explanation, some surgeons have been reluctant to treat patients with vitamin C supplementation.

Cazeneuve and colleagues⁵³ also studied the effect of vitamin C supplementation on CRPS in patients with distal radius fractures treated with reduction and intrafocal pinning. Group 1 consisted of 100 patients (treated from 1995 to 1998) who did not receive vitamin C supplementation, and group 2 consisted of 95 patients (treated from 1998 to 2002) who received vitamin C 1000 mg/d for 45 days starting on day of fracture. Patients were followed for up to 90 days after surgery. Incidence of CRPS type 1 was 10% in the untreated group and 2.1% in the group that received vitamin C supplementation.

Vitamin C prophylaxis for CRPS has also been studied in foot and ankle surgery. Besse and colleagues⁵⁴ prospectively compared 2 chronologically successive groups that received (235 feet) or did not receive (185 feet) vitamin C 1000-mg/d supplementation for 45 days. Incidence of CRPS type 1 as diagnosed with International Association for the Study of Pain (IASP) criteria dropped from 9.6% to 1.7% with vitamin C supplementation. In a case series, Zollinger and colleagues⁶³ examined CRPS type 1 rates after performing cementless total trapeziometacarpal semiconstrained joint prosthesis implantations for trapeziometacarpal arthritis. Forty implantations were performed in 34 patients. All patients received vitamin C 500 mg/d for CRPS prevention starting 2 days before surgery for 50 days. There were no cases of CRPS in the postoperative period, according to Veldman or IASP criteria. Although the results of the studies by Cazeneuve and colleagues⁵³ and Besse and colleagues⁵⁴ agree with those of the distal radius fracture trials by Zollinger and colleagues,^51,52 the quasi-experimental design and the lack of blinding and randomization temper the conclusions that can be drawn because of the risk for significant bias.

In a recent systematic review examining the effectiveness of vitamin C supplementation in preventing CRPS in trauma and surgery in the extremities, Shibuya and colleagues⁶⁴ concluded that taking at least 500 mg of vitamin C daily for 45 to 50 days after injury or surgery may help decrease the incidence of CRPS after a traumatic event.

Osteoarthritis

Damage caused by free radicals has long been thought to play an important role in osteoarthritis (OA).^65-67 A cross-sectional study in knee OA found that amounts of joint fluid antioxidants were lower in patients with severe arthritis than in those with intact cartilage, further implicating free radicals in the pathophysiology of OA.⁶⁸ Use of vitamin C for prophylaxis against development or progression of OA is therefore a hot research topic. Thus far, animal studies have had mixed results—several showing a chondroprotective effect of vitamin C^69,70 and others finding either no effect or even a positive association with the development of arthritis.⁷¹

The literature on human subjects, chiefly observational studies, is just as controversial. Wang and colleagues⁴⁰ found vitamin C intake associated with both a 50% risk reduction of bone marrow lesions on magnetic resonance imaging over a 10-year interval (OR, 0.5; 95% CI, 0.29-0.87) and inversely associated with the tibial plateau bone area. Similarly, the Clearwater Osteoarthritis Study, which followed 1023 patients (age, >40 years), showed that participants who took vitamin C supplements were 11% less likely to develop radiographic evidence of OA (RR, 0.89; 95% CI, 0.85-0.93).⁷² Nonetheless, other studies have failed to show such associations⁷³ or have demonstrated the opposite effect. Chaganti and colleagues⁷⁴ analyzed levels of vitamins C and E in the Multicenter Osteoarthritis Study (MOST) cohort of 3026 men and women (age, 50-79 years) and found higher vitamin levels were not protective against incidence of radiographic whole-knee OA and may even have been associated with increased risk.

Conclusion

Vitamin C is an essential micronutrient and a powerful water-soluble antioxidant in numerous biochemical pathways that influence bone health. It has been implicated in the biology of fracture healing, and vitamin C supplementation has been proposed as prophylaxis against hip fractures based on observational data. Results of 2 high-quality double-blind randomized trials support use of vitamin C as prophylaxis against CRPS in wrist fractures treated conservatively and operatively; the evidence for foot and ankle surgery is weaker. Use of vitamin C in OA prevention has tremendous potential, though animal and human study results are controversial. Heterogeneous results and lack of prospective trials preclude any recommendation at this time.

L-ascorbic acid, more commonly know as vitamin C, is an essential micronutrient used in numerous metabolic pathways. It functions physiologically as a water-soluble antioxidant by virtue of its high reducing power, playing a key role in the function of leukocytes, protein metabolism, and production of neurotransmitters.^1-3 Vitamin C also contributes to musculoskeletal health through biosynthesis of carnitine and collagen⁴ and enhancement of intestinal absorption of dietary iron⁵ from plants and vegetables. Unlike most animals, humans are unable to synthesize this essential vitamin and therefore require intake from natural dietary sources or supplements.⁶ The ability of vitamin C to prevent or treat disease has been an area of research interest since the vitamin was identified and isolated by Szent-Györgyi in the 1930s.^7-16 Research in orthopedic surgery has focused on the effects of vitamin C on fracture healing, its potential use in preventing complex regional pain syndrome (CRPS), and its role in the pathophysiology of osteoarthritis. In this article, we review the basics of vitamin C metabolism and summarize the evidence surrounding the role of vitamin C supplementation in orthopedics.

Sources and Metabolism

Vitamin C is found naturally in many fruits and vegetables (Table 1) and is a common fortification in cereals, juices, and multivitamins. Daily recommended intake (Table 2) depends on age and smoking status. Absorption occurs in the distal small intestine, with blood plasma vitamin C concentrations reflecting dietary intake. Pharmacokinetic studies have shown that vitamin C concentrations are tightly regulated through absorption, tissue accumulation, and renal resorption, with plasma concentrations rarely exceeding 100 μmol/L without additional supplementation.¹⁷ Although the usual dietary doses of 100 mg/d (adult) are almost completely absorbed, producing a plasma concentration of 60 μmol/L, higher intake results in an increasingly smaller fraction absorbed.^1,18 Intake of more than 1000 mg/d results in less than 50% absorption¹⁹ (unmetabolized vitamin C is excreted in stool and urine¹). Even at higher doses, vitamin C has low toxicity³; the most common complaints are diarrhea, nausea, and abdominal cramps caused by the osmotic effect of unabsorbed vitamin C in the gastrointestinal tract.¹

Vitamin C Deficiency

The relationship between vitamin C deficiency and the development of scurvy has been documented for centuries. Symptoms are described in the ancient Egyptian, Greek, and Roman literature.²⁰ Ascorbic acid is essential for normal collagen function, as it is a required cofactor for enzymatic transfer of hydroxyl groups to select proline and lysine residues during procollagen formation. Hydroxylysine contributes to the intermolecular cross-links in collagen, and hydroxyproline stabilizes the triple-helix structure of collagen.²¹ Insufficient vitamin C during this process results in collagen that is non-cross-linked, nonhelical, structurally unstable, and weak.²¹ Clinical manifestations of scurvy stem from an underlying impairment of collagen production causing a systemic decrease in connective tissue integrity, capillary fragility, poor wound healing, fatigue, myalgias, arthritis, and even death.²² Vitamin C deficiency has also been implicated as a cause of diffuse bleeding in surgical patients with normal coagulation parameters secondary to capillary fragility.²³ In the United States, the 2003–2004 National Health and Nutrition Examination Survey (NHANES) measured serum vitamin C concentrations in 7277 noninstitutionalized patients 6 years old or older.²⁴ Age-adjusted incidence of subnormal serum vitamin C levels (<28 μmol/L) was 19.6%, and incidence of frank vitamin C deficiency (<11.4 μmol/L) was 7.1%. Reported rates of vitamin C deficiency in hospitalized patients are much higher, with 47% to 60% having subnormal values (<28 μmol/L) and 17% to 19% being vitamin C–deficient (<11.4 μmol/L).^22,25 Identified risk factors for hypovitaminosis C include advanced age, obesity, low socioeconomic status, unemployment, male sex, and concomitant alcohol and tobacco consumption.^22,24,25

Fracture Healing and Prevention

The effects of vitamin C deficiency on bone healing have been studied with animal models as early as the 1940s.^26,27 Early experiments using guinea pigs demonstrated failure of bone graft incorporation, delayed collagen maturation, and decreased collagen and callus formation in scorbutic animals compared with controls that received vitamin C supplementation.^26,27 Based on his work with guinea pigs, Bourne²⁶ reported in 1942 that vitamin C deficiency significantly inhibited the reparative process in damaged bone and that patients with fractures should receive vitamin C supplementation. Building on this early research, Yilmaz and colleagues²⁸ found faster histologic healing for tibia fractures in a rat model for animals that received a single injection of vitamin C 0.5 mg/kg compared with a nonscorbutic control group, and Sarisözen and colleagues²⁹ showed significantly accelerated histologic bone formation and mineralization at the fracture site for rats that received vitamin C supplementation. Moreover, Kipp and colleagues³⁰ found that scorbutic guinea pigs had lower bone mineral density (BMD), decreased bone mineral content, and impaired collagen synthesis of articular cartilage and tendons compared with nondeficient controls.

Besides promoting bone formation, vitamin C improves the mechanical strength of callus formation. Alcantara-Martos and colleagues³¹ used an osteogenic disorder Shionogi (ODS) rat model to examine the effects of vitamin C intake on femoral fracture healing. This particular animal model is unable to produce its own vitamin C. The groups with lower serum vitamin C levels demonstrated lower mechanical resistance of the fracture callus to torsional loads 5 weeks after fracture. Moreover, the group that received vitamin C supplementation showed higher histologic grade of callus formation and demonstrated faster healing rates. The authors suggested that subclinical vitamin C deficiency can delay fracture healing and that vitamin C supplementation in nondeficient patients would improve bone healing.

Other research has demonstrated a link between vitamin C and mesenchymal cell differentiation. Mohan and colleagues³² used an sfx mouse model to show that vitamin C deficiency results in decreased bone formation secondary to impaired osteoblast differentiation, diminished bone density, and development of spontaneous fractures. The authors indicated that not only is vitamin C essential for maintenance of differentiated functions of osteoblasts, but deficiency during early active growth may affect peak BMD levels in humans. Additional studies have demonstrated the role of vitamin C in endochondral bone formation through both induction of osteoblast differentiation and modulation of gene expression in hypertrophic chondrocytes.^33-36 Chronic vitamin C deficiency has been found to depress osteoblast function and differentiation of chondrocytes.³⁷ More recently, Kim and colleagues³⁸ examined the effect of vitamin C insufficiency in Gulo-deficient mice, which are unable to synthesize ascorbic acid. Ascorbic acid insufficiency over 4 weeks led to decreased plasma levels of osteocalcin and bone formation in vivo as well as significantly diminished metaphyseal trabecular bone. Despite all the evidence demonstrating the importance of vitamin C in bone formation and maintenance, many of the underlying processes in this relationship have yet to be determined.

Bone Mineral Density

Several observational studies have found a positive association between vitamin C intake and BMD in postmenopausal women. In a retrospective, cross-sectional study by Hall and Greendale,³⁹ a positive association was found between vitamin C intake and BMD of the femoral neck in 775 participants in the Postmenopausal Estrogen/Progestin Interventions trial. After calcium intake, physical activity level, smoking, estrogen use, age, and body mass index were adjusted for, each 100-mg increase in dietary vitamin C was associated with a 0.017 g/cm² increase in BMD. Wang and colleagues⁴⁰ found a positive association between dietary vitamin C intake and femoral neck BMD in a retrospective analysis of 125 postmenopausal Mexican American women. Other observational studies have reported that decreased intake of vitamin C is associated with osteoporosis⁴¹ and increased rates of BMD loss⁴² and that supplementation with vitamin C may suppress bone resorption in postmenopausal women.⁴³

The results of these studies contrast with the findings of Leveille and colleagues,⁴⁴ who examined the relationship between dietary vitamin C and hip BMD in 1892 postmenopausal women. Although the authors found that women (age, 55-64 years) using vitamin C supplements for more than 10 years had an average BMD 6.7% higher than that of nonusers, they did not find any association between dietary vitamin C intake and BMD. Moreover, NHANES III also found inconsistent associations between vitamin C and BMD among 13,080 adults surveyed in the United States.⁴⁵ Although for premenopausal women dietary ascorbic acid was associated with increased BMD, for postmenopausal women with a history of smoking and estrogen replacement, it was actually associated with lower BMD values. For other subgroups in the study, the relationship was also inconsistent or nonlinear.

The exact mechanism by which ascorbic acid contributes to BMD is not fully delineated. However, it likely is related to the known role of vitamin C in collagen formation, bone matrix development, osteoblast differentiation, and its antioxidant effects limiting bone resorption.^44,46

Hip Fractures

Besides demonstrating positive effects of vitamin C on bone healing and BMD, epidemiologic studies have found evidence of a protective effect of vitamin C on hip fracture risk. In a study of the Swedish Mammography cohort, 66,651 women (age, 40-76 years) were prospectively followed.⁴⁷ The authors found that the odds ratio (OR) for hip fractures among smokers with a low intake of vitamin E (median intake, ≤6.2 mg/d) was 3.0 (95% CI, 1.6-5.4) and for vitamin C (median intake, ≤67 mg/d) was 3.0 (95% CI, 1.6-5.6). Moreover, in smokers with a low intake of both vitamins E and C, OR increased to 4.9 (95% CI, 2.2-11.0). In addition, the Utah Study of Nutrition and Bone Health matched 1215 cases of hip fractures in patients who had ever smoked (age, >50 years) with 1349 controls and found that vitamin C intake above 159 mg/d had a significant protective effect on the incidence of hip fracture; however, a graded relationship was not observed.⁴⁸ Despite the inconsistencies in the NHANES III study regarding the relationship between vitamin C and BMD, Simon and Hudes⁴⁵ found that serum vitamin C was associated with lower risk for self-reported fracture in postmenopausal women who had ever smoked and had a history of estrogen therapy (OR, 0.51; 95% CI, 0.36-0.70). Finally, Sahni and colleagues⁴⁹ followed 958 Framingham cohort men and women (mean age, 75 years) over 17 years and found that those in the highest tertile of total vitamin C intake (median, 313 mg/d) had significantly fewer hip fractures and nonvertebral fractures compared with those in the lowest tertile of intake (median, 94 mg/d). Dietary vitamin C intake was not associated with fracture risk in this study.

Complex Regional Pain Syndrome

Type 1 CRPS is a debilitating condition characterized by severe pain, swelling, and vasomotor instability. It is commonly precipitated by an injury or surgery to an extremity and is a dreaded sequelae in orthopedics,⁵⁰ with incidence rates of 10% to 22% in wrist fractures^51-53 and 10% after foot and ankle surgery.⁵⁴ Although the pathophysiology of CRPS remains unknown, dysregulation and increased permeability of the vasculature caused by free radicals are thought to play an important role.⁵⁵ In dermal burns, high doses of vitamin C therapy slowed progression of vascular permeability and therefore reduced extravascular leakage of fluids and protein.^56,57 The ability of vitamin C to prevent CRPS has been studied in only a handful of trials.

In a double-blind trial, Zollinger and colleagues⁵¹ randomized 127 conservatively treated distal radius fractures to receive either vitamin C 500 mg or placebo daily for 50 days starting on day of injury. Incidence of CRPS (using the diagnostic criteria proposed by Veldman and colleagues⁵⁸) at 1-year follow-up was 22% in the placebo group and 7% in the vitamin C group (95% CI for difference, 2%-26%). Complaints while wearing the cast and fracture type increased the risk for developing CRPS. This initial study was followed up by a prospective, randomized, double-blind multicenter trial by the same authors,⁵² who had 416 patients with 427 wrist fractures receive either placebo or vitamin C 200 mg/d, 500 mg/d, or 1500 mg/d for 50 days. This follow-up study included both operative (11%) and nonoperative (89%) distal radius fractures. Incidence of CRPS was 10.1% in the placebo group and 2.4% in the vitamin C group (P < .002). Although there was an appreciable drop in the relative risk (RR) of developing CRPS between the vitamin C 200-mg/d and 500-mg/d groups (0.41-0.17), there was no additional benefit in the 1500-mg/d group. Pooling the data for these 2 randomized trials showed that the overall RR for developing CRPS was lower with vitamin C supplementation (RR, 0.28; 95% CI, 0.14-0.56; P = .0003).⁵⁹

Results of the 2 trials by Zollinger and colleagues^51,52 have been met with several concerns.^60-62 As a corollary to the unclear etiology of CRPS, several different sets of diagnostic criteria exist, and the criteria are somewhat subjective and imprecise. Although both trials used the Veldman criteria,⁵⁸ the incidence of CRPS in the placebo group dropped unexpectedly between trials, from 22% to 10.1%, and the results may have been different had other criteria been used. Moreover, the idea that toxic oxygen radicals have a role in CRPS and that vitamin C can scavenge these radicals is based on limited data.⁶¹ In the absence of a clear pathophysiologic explanation, some surgeons have been reluctant to treat patients with vitamin C supplementation.

Cazeneuve and colleagues⁵³ also studied the effect of vitamin C supplementation on CRPS in patients with distal radius fractures treated with reduction and intrafocal pinning. Group 1 consisted of 100 patients (treated from 1995 to 1998) who did not receive vitamin C supplementation, and group 2 consisted of 95 patients (treated from 1998 to 2002) who received vitamin C 1000 mg/d for 45 days starting on day of fracture. Patients were followed for up to 90 days after surgery. Incidence of CRPS type 1 was 10% in the untreated group and 2.1% in the group that received vitamin C supplementation.

Vitamin C prophylaxis for CRPS has also been studied in foot and ankle surgery. Besse and colleagues⁵⁴ prospectively compared 2 chronologically successive groups that received (235 feet) or did not receive (185 feet) vitamin C 1000-mg/d supplementation for 45 days. Incidence of CRPS type 1 as diagnosed with International Association for the Study of Pain (IASP) criteria dropped from 9.6% to 1.7% with vitamin C supplementation. In a case series, Zollinger and colleagues⁶³ examined CRPS type 1 rates after performing cementless total trapeziometacarpal semiconstrained joint prosthesis implantations for trapeziometacarpal arthritis. Forty implantations were performed in 34 patients. All patients received vitamin C 500 mg/d for CRPS prevention starting 2 days before surgery for 50 days. There were no cases of CRPS in the postoperative period, according to Veldman or IASP criteria. Although the results of the studies by Cazeneuve and colleagues⁵³ and Besse and colleagues⁵⁴ agree with those of the distal radius fracture trials by Zollinger and colleagues,^51,52 the quasi-experimental design and the lack of blinding and randomization temper the conclusions that can be drawn because of the risk for significant bias.

In a recent systematic review examining the effectiveness of vitamin C supplementation in preventing CRPS in trauma and surgery in the extremities, Shibuya and colleagues⁶⁴ concluded that taking at least 500 mg of vitamin C daily for 45 to 50 days after injury or surgery may help decrease the incidence of CRPS after a traumatic event.

Osteoarthritis

Damage caused by free radicals has long been thought to play an important role in osteoarthritis (OA).^65-67 A cross-sectional study in knee OA found that amounts of joint fluid antioxidants were lower in patients with severe arthritis than in those with intact cartilage, further implicating free radicals in the pathophysiology of OA.⁶⁸ Use of vitamin C for prophylaxis against development or progression of OA is therefore a hot research topic. Thus far, animal studies have had mixed results—several showing a chondroprotective effect of vitamin C^69,70 and others finding either no effect or even a positive association with the development of arthritis.⁷¹

The literature on human subjects, chiefly observational studies, is just as controversial. Wang and colleagues⁴⁰ found vitamin C intake associated with both a 50% risk reduction of bone marrow lesions on magnetic resonance imaging over a 10-year interval (OR, 0.5; 95% CI, 0.29-0.87) and inversely associated with the tibial plateau bone area. Similarly, the Clearwater Osteoarthritis Study, which followed 1023 patients (age, >40 years), showed that participants who took vitamin C supplements were 11% less likely to develop radiographic evidence of OA (RR, 0.89; 95% CI, 0.85-0.93).⁷² Nonetheless, other studies have failed to show such associations⁷³ or have demonstrated the opposite effect. Chaganti and colleagues⁷⁴ analyzed levels of vitamins C and E in the Multicenter Osteoarthritis Study (MOST) cohort of 3026 men and women (age, 50-79 years) and found higher vitamin levels were not protective against incidence of radiographic whole-knee OA and may even have been associated with increased risk.

Conclusion

Vitamin C is an essential micronutrient and a powerful water-soluble antioxidant in numerous biochemical pathways that influence bone health. It has been implicated in the biology of fracture healing, and vitamin C supplementation has been proposed as prophylaxis against hip fractures based on observational data. Results of 2 high-quality double-blind randomized trials support use of vitamin C as prophylaxis against CRPS in wrist fractures treated conservatively and operatively; the evidence for foot and ankle surgery is weaker. Use of vitamin C in OA prevention has tremendous potential, though animal and human study results are controversial. Heterogeneous results and lack of prospective trials preclude any recommendation at this time.

L-ascorbic acid, more commonly know as vitamin C, is an essential micronutrient used in numerous metabolic pathways. It functions physiologically as a water-soluble antioxidant by virtue of its high reducing power, playing a key role in the function of leukocytes, protein metabolism, and production of neurotransmitters.^1-3 Vitamin C also contributes to musculoskeletal health through biosynthesis of carnitine and collagen⁴ and enhancement of intestinal absorption of dietary iron⁵ from plants and vegetables. Unlike most animals, humans are unable to synthesize this essential vitamin and therefore require intake from natural dietary sources or supplements.⁶ The ability of vitamin C to prevent or treat disease has been an area of research interest since the vitamin was identified and isolated by Szent-Györgyi in the 1930s.^7-16 Research in orthopedic surgery has focused on the effects of vitamin C on fracture healing, its potential use in preventing complex regional pain syndrome (CRPS), and its role in the pathophysiology of osteoarthritis. In this article, we review the basics of vitamin C metabolism and summarize the evidence surrounding the role of vitamin C supplementation in orthopedics.

Sources and Metabolism

Vitamin C is found naturally in many fruits and vegetables (Table 1) and is a common fortification in cereals, juices, and multivitamins. Daily recommended intake (Table 2) depends on age and smoking status. Absorption occurs in the distal small intestine, with blood plasma vitamin C concentrations reflecting dietary intake. Pharmacokinetic studies have shown that vitamin C concentrations are tightly regulated through absorption, tissue accumulation, and renal resorption, with plasma concentrations rarely exceeding 100 μmol/L without additional supplementation.¹⁷ Although the usual dietary doses of 100 mg/d (adult) are almost completely absorbed, producing a plasma concentration of 60 μmol/L, higher intake results in an increasingly smaller fraction absorbed.^1,18 Intake of more than 1000 mg/d results in less than 50% absorption¹⁹ (unmetabolized vitamin C is excreted in stool and urine¹). Even at higher doses, vitamin C has low toxicity³; the most common complaints are diarrhea, nausea, and abdominal cramps caused by the osmotic effect of unabsorbed vitamin C in the gastrointestinal tract.¹

Vitamin C Deficiency

The relationship between vitamin C deficiency and the development of scurvy has been documented for centuries. Symptoms are described in the ancient Egyptian, Greek, and Roman literature.²⁰ Ascorbic acid is essential for normal collagen function, as it is a required cofactor for enzymatic transfer of hydroxyl groups to select proline and lysine residues during procollagen formation. Hydroxylysine contributes to the intermolecular cross-links in collagen, and hydroxyproline stabilizes the triple-helix structure of collagen.²¹ Insufficient vitamin C during this process results in collagen that is non-cross-linked, nonhelical, structurally unstable, and weak.²¹ Clinical manifestations of scurvy stem from an underlying impairment of collagen production causing a systemic decrease in connective tissue integrity, capillary fragility, poor wound healing, fatigue, myalgias, arthritis, and even death.²² Vitamin C deficiency has also been implicated as a cause of diffuse bleeding in surgical patients with normal coagulation parameters secondary to capillary fragility.²³ In the United States, the 2003–2004 National Health and Nutrition Examination Survey (NHANES) measured serum vitamin C concentrations in 7277 noninstitutionalized patients 6 years old or older.²⁴ Age-adjusted incidence of subnormal serum vitamin C levels (<28 μmol/L) was 19.6%, and incidence of frank vitamin C deficiency (<11.4 μmol/L) was 7.1%. Reported rates of vitamin C deficiency in hospitalized patients are much higher, with 47% to 60% having subnormal values (<28 μmol/L) and 17% to 19% being vitamin C–deficient (<11.4 μmol/L).^22,25 Identified risk factors for hypovitaminosis C include advanced age, obesity, low socioeconomic status, unemployment, male sex, and concomitant alcohol and tobacco consumption.^22,24,25

Fracture Healing and Prevention

The effects of vitamin C deficiency on bone healing have been studied with animal models as early as the 1940s.^26,27 Early experiments using guinea pigs demonstrated failure of bone graft incorporation, delayed collagen maturation, and decreased collagen and callus formation in scorbutic animals compared with controls that received vitamin C supplementation.^26,27 Based on his work with guinea pigs, Bourne²⁶ reported in 1942 that vitamin C deficiency significantly inhibited the reparative process in damaged bone and that patients with fractures should receive vitamin C supplementation. Building on this early research, Yilmaz and colleagues²⁸ found faster histologic healing for tibia fractures in a rat model for animals that received a single injection of vitamin C 0.5 mg/kg compared with a nonscorbutic control group, and Sarisözen and colleagues²⁹ showed significantly accelerated histologic bone formation and mineralization at the fracture site for rats that received vitamin C supplementation. Moreover, Kipp and colleagues³⁰ found that scorbutic guinea pigs had lower bone mineral density (BMD), decreased bone mineral content, and impaired collagen synthesis of articular cartilage and tendons compared with nondeficient controls.

Besides promoting bone formation, vitamin C improves the mechanical strength of callus formation. Alcantara-Martos and colleagues³¹ used an osteogenic disorder Shionogi (ODS) rat model to examine the effects of vitamin C intake on femoral fracture healing. This particular animal model is unable to produce its own vitamin C. The groups with lower serum vitamin C levels demonstrated lower mechanical resistance of the fracture callus to torsional loads 5 weeks after fracture. Moreover, the group that received vitamin C supplementation showed higher histologic grade of callus formation and demonstrated faster healing rates. The authors suggested that subclinical vitamin C deficiency can delay fracture healing and that vitamin C supplementation in nondeficient patients would improve bone healing.

Other research has demonstrated a link between vitamin C and mesenchymal cell differentiation. Mohan and colleagues³² used an sfx mouse model to show that vitamin C deficiency results in decreased bone formation secondary to impaired osteoblast differentiation, diminished bone density, and development of spontaneous fractures. The authors indicated that not only is vitamin C essential for maintenance of differentiated functions of osteoblasts, but deficiency during early active growth may affect peak BMD levels in humans. Additional studies have demonstrated the role of vitamin C in endochondral bone formation through both induction of osteoblast differentiation and modulation of gene expression in hypertrophic chondrocytes.^33-36 Chronic vitamin C deficiency has been found to depress osteoblast function and differentiation of chondrocytes.³⁷ More recently, Kim and colleagues³⁸ examined the effect of vitamin C insufficiency in Gulo-deficient mice, which are unable to synthesize ascorbic acid. Ascorbic acid insufficiency over 4 weeks led to decreased plasma levels of osteocalcin and bone formation in vivo as well as significantly diminished metaphyseal trabecular bone. Despite all the evidence demonstrating the importance of vitamin C in bone formation and maintenance, many of the underlying processes in this relationship have yet to be determined.

Bone Mineral Density

Several observational studies have found a positive association between vitamin C intake and BMD in postmenopausal women. In a retrospective, cross-sectional study by Hall and Greendale,³⁹ a positive association was found between vitamin C intake and BMD of the femoral neck in 775 participants in the Postmenopausal Estrogen/Progestin Interventions trial. After calcium intake, physical activity level, smoking, estrogen use, age, and body mass index were adjusted for, each 100-mg increase in dietary vitamin C was associated with a 0.017 g/cm² increase in BMD. Wang and colleagues⁴⁰ found a positive association between dietary vitamin C intake and femoral neck BMD in a retrospective analysis of 125 postmenopausal Mexican American women. Other observational studies have reported that decreased intake of vitamin C is associated with osteoporosis⁴¹ and increased rates of BMD loss⁴² and that supplementation with vitamin C may suppress bone resorption in postmenopausal women.⁴³

The results of these studies contrast with the findings of Leveille and colleagues,⁴⁴ who examined the relationship between dietary vitamin C and hip BMD in 1892 postmenopausal women. Although the authors found that women (age, 55-64 years) using vitamin C supplements for more than 10 years had an average BMD 6.7% higher than that of nonusers, they did not find any association between dietary vitamin C intake and BMD. Moreover, NHANES III also found inconsistent associations between vitamin C and BMD among 13,080 adults surveyed in the United States.⁴⁵ Although for premenopausal women dietary ascorbic acid was associated with increased BMD, for postmenopausal women with a history of smoking and estrogen replacement, it was actually associated with lower BMD values. For other subgroups in the study, the relationship was also inconsistent or nonlinear.

The exact mechanism by which ascorbic acid contributes to BMD is not fully delineated. However, it likely is related to the known role of vitamin C in collagen formation, bone matrix development, osteoblast differentiation, and its antioxidant effects limiting bone resorption.^44,46

Hip Fractures

Besides demonstrating positive effects of vitamin C on bone healing and BMD, epidemiologic studies have found evidence of a protective effect of vitamin C on hip fracture risk. In a study of the Swedish Mammography cohort, 66,651 women (age, 40-76 years) were prospectively followed.⁴⁷ The authors found that the odds ratio (OR) for hip fractures among smokers with a low intake of vitamin E (median intake, ≤6.2 mg/d) was 3.0 (95% CI, 1.6-5.4) and for vitamin C (median intake, ≤67 mg/d) was 3.0 (95% CI, 1.6-5.6). Moreover, in smokers with a low intake of both vitamins E and C, OR increased to 4.9 (95% CI, 2.2-11.0). In addition, the Utah Study of Nutrition and Bone Health matched 1215 cases of hip fractures in patients who had ever smoked (age, >50 years) with 1349 controls and found that vitamin C intake above 159 mg/d had a significant protective effect on the incidence of hip fracture; however, a graded relationship was not observed.⁴⁸ Despite the inconsistencies in the NHANES III study regarding the relationship between vitamin C and BMD, Simon and Hudes⁴⁵ found that serum vitamin C was associated with lower risk for self-reported fracture in postmenopausal women who had ever smoked and had a history of estrogen therapy (OR, 0.51; 95% CI, 0.36-0.70). Finally, Sahni and colleagues⁴⁹ followed 958 Framingham cohort men and women (mean age, 75 years) over 17 years and found that those in the highest tertile of total vitamin C intake (median, 313 mg/d) had significantly fewer hip fractures and nonvertebral fractures compared with those in the lowest tertile of intake (median, 94 mg/d). Dietary vitamin C intake was not associated with fracture risk in this study.

Complex Regional Pain Syndrome

Type 1 CRPS is a debilitating condition characterized by severe pain, swelling, and vasomotor instability. It is commonly precipitated by an injury or surgery to an extremity and is a dreaded sequelae in orthopedics,⁵⁰ with incidence rates of 10% to 22% in wrist fractures^51-53 and 10% after foot and ankle surgery.⁵⁴ Although the pathophysiology of CRPS remains unknown, dysregulation and increased permeability of the vasculature caused by free radicals are thought to play an important role.⁵⁵ In dermal burns, high doses of vitamin C therapy slowed progression of vascular permeability and therefore reduced extravascular leakage of fluids and protein.^56,57 The ability of vitamin C to prevent CRPS has been studied in only a handful of trials.

In a double-blind trial, Zollinger and colleagues⁵¹ randomized 127 conservatively treated distal radius fractures to receive either vitamin C 500 mg or placebo daily for 50 days starting on day of injury. Incidence of CRPS (using the diagnostic criteria proposed by Veldman and colleagues⁵⁸) at 1-year follow-up was 22% in the placebo group and 7% in the vitamin C group (95% CI for difference, 2%-26%). Complaints while wearing the cast and fracture type increased the risk for developing CRPS. This initial study was followed up by a prospective, randomized, double-blind multicenter trial by the same authors,⁵² who had 416 patients with 427 wrist fractures receive either placebo or vitamin C 200 mg/d, 500 mg/d, or 1500 mg/d for 50 days. This follow-up study included both operative (11%) and nonoperative (89%) distal radius fractures. Incidence of CRPS was 10.1% in the placebo group and 2.4% in the vitamin C group (P < .002). Although there was an appreciable drop in the relative risk (RR) of developing CRPS between the vitamin C 200-mg/d and 500-mg/d groups (0.41-0.17), there was no additional benefit in the 1500-mg/d group. Pooling the data for these 2 randomized trials showed that the overall RR for developing CRPS was lower with vitamin C supplementation (RR, 0.28; 95% CI, 0.14-0.56; P = .0003).⁵⁹

Results of the 2 trials by Zollinger and colleagues^51,52 have been met with several concerns.^60-62 As a corollary to the unclear etiology of CRPS, several different sets of diagnostic criteria exist, and the criteria are somewhat subjective and imprecise. Although both trials used the Veldman criteria,⁵⁸ the incidence of CRPS in the placebo group dropped unexpectedly between trials, from 22% to 10.1%, and the results may have been different had other criteria been used. Moreover, the idea that toxic oxygen radicals have a role in CRPS and that vitamin C can scavenge these radicals is based on limited data.⁶¹ In the absence of a clear pathophysiologic explanation, some surgeons have been reluctant to treat patients with vitamin C supplementation.

Cazeneuve and colleagues⁵³ also studied the effect of vitamin C supplementation on CRPS in patients with distal radius fractures treated with reduction and intrafocal pinning. Group 1 consisted of 100 patients (treated from 1995 to 1998) who did not receive vitamin C supplementation, and group 2 consisted of 95 patients (treated from 1998 to 2002) who received vitamin C 1000 mg/d for 45 days starting on day of fracture. Patients were followed for up to 90 days after surgery. Incidence of CRPS type 1 was 10% in the untreated group and 2.1% in the group that received vitamin C supplementation.

Vitamin C prophylaxis for CRPS has also been studied in foot and ankle surgery. Besse and colleagues⁵⁴ prospectively compared 2 chronologically successive groups that received (235 feet) or did not receive (185 feet) vitamin C 1000-mg/d supplementation for 45 days. Incidence of CRPS type 1 as diagnosed with International Association for the Study of Pain (IASP) criteria dropped from 9.6% to 1.7% with vitamin C supplementation. In a case series, Zollinger and colleagues⁶³ examined CRPS type 1 rates after performing cementless total trapeziometacarpal semiconstrained joint prosthesis implantations for trapeziometacarpal arthritis. Forty implantations were performed in 34 patients. All patients received vitamin C 500 mg/d for CRPS prevention starting 2 days before surgery for 50 days. There were no cases of CRPS in the postoperative period, according to Veldman or IASP criteria. Although the results of the studies by Cazeneuve and colleagues⁵³ and Besse and colleagues⁵⁴ agree with those of the distal radius fracture trials by Zollinger and colleagues,^51,52 the quasi-experimental design and the lack of blinding and randomization temper the conclusions that can be drawn because of the risk for significant bias.

In a recent systematic review examining the effectiveness of vitamin C supplementation in preventing CRPS in trauma and surgery in the extremities, Shibuya and colleagues⁶⁴ concluded that taking at least 500 mg of vitamin C daily for 45 to 50 days after injury or surgery may help decrease the incidence of CRPS after a traumatic event.

Osteoarthritis

Damage caused by free radicals has long been thought to play an important role in osteoarthritis (OA).^65-67 A cross-sectional study in knee OA found that amounts of joint fluid antioxidants were lower in patients with severe arthritis than in those with intact cartilage, further implicating free radicals in the pathophysiology of OA.⁶⁸ Use of vitamin C for prophylaxis against development or progression of OA is therefore a hot research topic. Thus far, animal studies have had mixed results—several showing a chondroprotective effect of vitamin C^69,70 and others finding either no effect or even a positive association with the development of arthritis.⁷¹

The literature on human subjects, chiefly observational studies, is just as controversial. Wang and colleagues⁴⁰ found vitamin C intake associated with both a 50% risk reduction of bone marrow lesions on magnetic resonance imaging over a 10-year interval (OR, 0.5; 95% CI, 0.29-0.87) and inversely associated with the tibial plateau bone area. Similarly, the Clearwater Osteoarthritis Study, which followed 1023 patients (age, >40 years), showed that participants who took vitamin C supplements were 11% less likely to develop radiographic evidence of OA (RR, 0.89; 95% CI, 0.85-0.93).⁷² Nonetheless, other studies have failed to show such associations⁷³ or have demonstrated the opposite effect. Chaganti and colleagues⁷⁴ analyzed levels of vitamins C and E in the Multicenter Osteoarthritis Study (MOST) cohort of 3026 men and women (age, 50-79 years) and found higher vitamin levels were not protective against incidence of radiographic whole-knee OA and may even have been associated with increased risk.

Conclusion

Vitamin C is an essential micronutrient and a powerful water-soluble antioxidant in numerous biochemical pathways that influence bone health. It has been implicated in the biology of fracture healing, and vitamin C supplementation has been proposed as prophylaxis against hip fractures based on observational data. Results of 2 high-quality double-blind randomized trials support use of vitamin C as prophylaxis against CRPS in wrist fractures treated conservatively and operatively; the evidence for foot and ankle surgery is weaker. Use of vitamin C in OA prevention has tremendous potential, though animal and human study results are controversial. Heterogeneous results and lack of prospective trials preclude any recommendation at this time.

PARIS – A novel method of quantifying the risks of major bleeding and stent thrombosis may guide decisions about the duration of dual-antiplatelet therapy in stent recipients, according to Dr. Francesco Costa.

It’s a two-pronged approach that relies upon a CRUSADE bleeding risk score greater than 40 as a red flag cautioning against 24 months of dual-antiplatelet therapy (DAPT) in favor of 6 months, while also taking into consideration the anatomic location of an individual’s coronary artery disease as a guide to ischemic risk, such as stent thrombosis, Dr. Costa said at the annual congress of the European Association of Percutaneous Cardiovascular Interventions.

A patient with at least 30% luminal narrowing of the left main coronary artery and/or the proximal LAD (left anterior descending) artery is at markedly reduced risk of stent thrombosis with a DAPT regimen of 24 months rather than 6 months, according to Dr. Costa of Erasmus University in Rotterdam, the Netherlands. These findings were borne out in a retrospective analysis of data from the previously published PRODIGY trial, in which 2,013 patients undergoing percutaneous coronary intervention were randomized to receive a first- or second-generation drug-eluting stent or a bare metal stent, and then further randomized to 6 or 24 months of DAPT (Circulation 2012;125:2015-26).

As these findings about how to guide DAPT duration come from an exploratory retrospective analysis, Dr. Costa stressed, they must be considered hypothesis generating. A definitive prospective randomized trial is warranted to confirm the hypothesis. Such a trial is sorely needed, the cardiologist added.

“International guidelines suggest tailoring DAPT duration according to a patient’s ischemic and bleeding risks. However, currently a reproducible method of weighing these risks has not yet been proposed,” he said. “I think if we put 10 different [physicians] in front of a patient and asked them to define that patient’s bleeding risk, almost everyone would have a different idea.”

The PRODIGY-tested approach, while not ideal, is a definite step forward, according to Dr. Costa.

He and his coworkers evaluated three different bleeding risk scoring systems – HAS-BLED, ACUITY, and CRUSADE – before concluding that a CRUSADE score greater than 40 was superior as a predictor of major bleeding in the PRODIGY population.

Roughly 16% of participants in this all-comers study had a CRUSADE score above 40. A 24-month course of DAPT in this group was associated with a 2.7-fold increased risk of major bleeding events, compared with a 6-month course. The number-needed-to-harm with a 24-month course of DAPT was 17, compared with a number-needed-to-harm of 67 in an unselected population. In contrast, there was no significant increase in major bleeding risk with 24 months of DAPT in patients with a CRUSADE score of 40 or less.

Patients with a CRUSADE score greater than 40 also had a sharply increased need for RBC transfusion if they were on 24 months of DAPT.

The investigators chose 30% luminal narrowing of the left main or proximal LAD coronary arteries as their cutpoint for increased risk of ischemic events during follow-up because they consider it a good marker for more diffuse atherosclerotic disease.

PRODIGY participants with luminal narrowing at either location were 55% less likely to experience stent thrombosis with 24 months of DAPT than with 6.

Dr. Andreas Baumbach said the DAPT decision-making aid presented by Dr. Costa is just what interventional cardiologists have been looking for.

“We’re always talking about patients at high bleeding risk and high ischemic risk, but we haven’t really had a tool to identify those other than our clinical judgment, thinking that high bleeding risk comes with age and renal impairment. So to have a score that’s almost validated for this purpose is really important,” according to Dr. Baumbach, professor of interventional cardiology at the University of Bristol (England).

This analysis was conducted without external funding. Dr. Costa reported having no relevant financial conflicts.

[email protected]

PARIS – A novel method of quantifying the risks of major bleeding and stent thrombosis may guide decisions about the duration of dual-antiplatelet therapy in stent recipients, according to Dr. Francesco Costa.

It’s a two-pronged approach that relies upon a CRUSADE bleeding risk score greater than 40 as a red flag cautioning against 24 months of dual-antiplatelet therapy (DAPT) in favor of 6 months, while also taking into consideration the anatomic location of an individual’s coronary artery disease as a guide to ischemic risk, such as stent thrombosis, Dr. Costa said at the annual congress of the European Association of Percutaneous Cardiovascular Interventions.

A patient with at least 30% luminal narrowing of the left main coronary artery and/or the proximal LAD (left anterior descending) artery is at markedly reduced risk of stent thrombosis with a DAPT regimen of 24 months rather than 6 months, according to Dr. Costa of Erasmus University in Rotterdam, the Netherlands. These findings were borne out in a retrospective analysis of data from the previously published PRODIGY trial, in which 2,013 patients undergoing percutaneous coronary intervention were randomized to receive a first- or second-generation drug-eluting stent or a bare metal stent, and then further randomized to 6 or 24 months of DAPT (Circulation 2012;125:2015-26).

As these findings about how to guide DAPT duration come from an exploratory retrospective analysis, Dr. Costa stressed, they must be considered hypothesis generating. A definitive prospective randomized trial is warranted to confirm the hypothesis. Such a trial is sorely needed, the cardiologist added.

“International guidelines suggest tailoring DAPT duration according to a patient’s ischemic and bleeding risks. However, currently a reproducible method of weighing these risks has not yet been proposed,” he said. “I think if we put 10 different [physicians] in front of a patient and asked them to define that patient’s bleeding risk, almost everyone would have a different idea.”

The PRODIGY-tested approach, while not ideal, is a definite step forward, according to Dr. Costa.

He and his coworkers evaluated three different bleeding risk scoring systems – HAS-BLED, ACUITY, and CRUSADE – before concluding that a CRUSADE score greater than 40 was superior as a predictor of major bleeding in the PRODIGY population.

Roughly 16% of participants in this all-comers study had a CRUSADE score above 40. A 24-month course of DAPT in this group was associated with a 2.7-fold increased risk of major bleeding events, compared with a 6-month course. The number-needed-to-harm with a 24-month course of DAPT was 17, compared with a number-needed-to-harm of 67 in an unselected population. In contrast, there was no significant increase in major bleeding risk with 24 months of DAPT in patients with a CRUSADE score of 40 or less.

Patients with a CRUSADE score greater than 40 also had a sharply increased need for RBC transfusion if they were on 24 months of DAPT.

The investigators chose 30% luminal narrowing of the left main or proximal LAD coronary arteries as their cutpoint for increased risk of ischemic events during follow-up because they consider it a good marker for more diffuse atherosclerotic disease.

PRODIGY participants with luminal narrowing at either location were 55% less likely to experience stent thrombosis with 24 months of DAPT than with 6.

Dr. Andreas Baumbach said the DAPT decision-making aid presented by Dr. Costa is just what interventional cardiologists have been looking for.

“We’re always talking about patients at high bleeding risk and high ischemic risk, but we haven’t really had a tool to identify those other than our clinical judgment, thinking that high bleeding risk comes with age and renal impairment. So to have a score that’s almost validated for this purpose is really important,” according to Dr. Baumbach, professor of interventional cardiology at the University of Bristol (England).

This analysis was conducted without external funding. Dr. Costa reported having no relevant financial conflicts.

[email protected]

PARIS – A novel method of quantifying the risks of major bleeding and stent thrombosis may guide decisions about the duration of dual-antiplatelet therapy in stent recipients, according to Dr. Francesco Costa.

It’s a two-pronged approach that relies upon a CRUSADE bleeding risk score greater than 40 as a red flag cautioning against 24 months of dual-antiplatelet therapy (DAPT) in favor of 6 months, while also taking into consideration the anatomic location of an individual’s coronary artery disease as a guide to ischemic risk, such as stent thrombosis, Dr. Costa said at the annual congress of the European Association of Percutaneous Cardiovascular Interventions.

A patient with at least 30% luminal narrowing of the left main coronary artery and/or the proximal LAD (left anterior descending) artery is at markedly reduced risk of stent thrombosis with a DAPT regimen of 24 months rather than 6 months, according to Dr. Costa of Erasmus University in Rotterdam, the Netherlands. These findings were borne out in a retrospective analysis of data from the previously published PRODIGY trial, in which 2,013 patients undergoing percutaneous coronary intervention were randomized to receive a first- or second-generation drug-eluting stent or a bare metal stent, and then further randomized to 6 or 24 months of DAPT (Circulation 2012;125:2015-26).

As these findings about how to guide DAPT duration come from an exploratory retrospective analysis, Dr. Costa stressed, they must be considered hypothesis generating. A definitive prospective randomized trial is warranted to confirm the hypothesis. Such a trial is sorely needed, the cardiologist added.

“International guidelines suggest tailoring DAPT duration according to a patient’s ischemic and bleeding risks. However, currently a reproducible method of weighing these risks has not yet been proposed,” he said. “I think if we put 10 different [physicians] in front of a patient and asked them to define that patient’s bleeding risk, almost everyone would have a different idea.”

The PRODIGY-tested approach, while not ideal, is a definite step forward, according to Dr. Costa.

He and his coworkers evaluated three different bleeding risk scoring systems – HAS-BLED, ACUITY, and CRUSADE – before concluding that a CRUSADE score greater than 40 was superior as a predictor of major bleeding in the PRODIGY population.

Roughly 16% of participants in this all-comers study had a CRUSADE score above 40. A 24-month course of DAPT in this group was associated with a 2.7-fold increased risk of major bleeding events, compared with a 6-month course. The number-needed-to-harm with a 24-month course of DAPT was 17, compared with a number-needed-to-harm of 67 in an unselected population. In contrast, there was no significant increase in major bleeding risk with 24 months of DAPT in patients with a CRUSADE score of 40 or less.

Patients with a CRUSADE score greater than 40 also had a sharply increased need for RBC transfusion if they were on 24 months of DAPT.

The investigators chose 30% luminal narrowing of the left main or proximal LAD coronary arteries as their cutpoint for increased risk of ischemic events during follow-up because they consider it a good marker for more diffuse atherosclerotic disease.

PRODIGY participants with luminal narrowing at either location were 55% less likely to experience stent thrombosis with 24 months of DAPT than with 6.

Dr. Andreas Baumbach said the DAPT decision-making aid presented by Dr. Costa is just what interventional cardiologists have been looking for.

“We’re always talking about patients at high bleeding risk and high ischemic risk, but we haven’t really had a tool to identify those other than our clinical judgment, thinking that high bleeding risk comes with age and renal impairment. So to have a score that’s almost validated for this purpose is really important,” according to Dr. Baumbach, professor of interventional cardiology at the University of Bristol (England).

This analysis was conducted without external funding. Dr. Costa reported having no relevant financial conflicts.

[email protected]

Medicare, the government-run health insurance program for elderly and disabled Americans, paid physicians $90 billion in 2013, up 17% from $77 billion in 2012, U.S. healthcare officials reported earlier this month.

Physician payments accounted for less than one-fifth of Medicare's 2013 net outlays of $492 billion, which rose from $466 billion in 2012. Payments to hospitals for the top 100 inpatient stays cost Medicare $62 billion in 2013, while the rest went for drugs, privately run Medicare Advantage plans, and other program costs.

The single-greatest hospital expense was to replace knees, hips, and other joints in 446,148 operations, with $6.6 billion paid to hospitals.

The second-greatest hospital payment, $5.6 billion, went for 398,004 cases of septicemia, or blood poisoning, often a sign of poor inpatient care. TH

—Reuters Health

Medicare, the government-run health insurance program for elderly and disabled Americans, paid physicians $90 billion in 2013, up 17% from $77 billion in 2012, U.S. healthcare officials reported earlier this month.

Physician payments accounted for less than one-fifth of Medicare's 2013 net outlays of $492 billion, which rose from $466 billion in 2012. Payments to hospitals for the top 100 inpatient stays cost Medicare $62 billion in 2013, while the rest went for drugs, privately run Medicare Advantage plans, and other program costs.

The single-greatest hospital expense was to replace knees, hips, and other joints in 446,148 operations, with $6.6 billion paid to hospitals.

The second-greatest hospital payment, $5.6 billion, went for 398,004 cases of septicemia, or blood poisoning, often a sign of poor inpatient care. TH

—Reuters Health

Medicare, the government-run health insurance program for elderly and disabled Americans, paid physicians $90 billion in 2013, up 17% from $77 billion in 2012, U.S. healthcare officials reported earlier this month.

Physician payments accounted for less than one-fifth of Medicare's 2013 net outlays of $492 billion, which rose from $466 billion in 2012. Payments to hospitals for the top 100 inpatient stays cost Medicare $62 billion in 2013, while the rest went for drugs, privately run Medicare Advantage plans, and other program costs.

The single-greatest hospital expense was to replace knees, hips, and other joints in 446,148 operations, with $6.6 billion paid to hospitals.

The second-greatest hospital payment, $5.6 billion, went for 398,004 cases of septicemia, or blood poisoning, often a sign of poor inpatient care. TH

—Reuters Health

CHICAGO – Combining ibrutinib with standard chemoimmunotherapy extended progression-free survival in patients with relapsed chronic lymphocytic leukemia (CLL), according to interim results from the HELIOS trial.

In fact, while median progression-free survival was approximately 13 months in the placebo arm, the median progression-free survival had not been reached yet in the study’s ibrutinib arm, explained lead study author Dr. Asher Chanan-Khan.

“I believe that ibrutinib has now become the backbone of treatment of patients with relapsed CLL,” said Dr. Chanan-Khan, professor of medicine at the Mayo Clinic in Jacksonville, Fla.

In a video interview at the annual meeting of the American Society of Clinical Oncology, Dr. Chanan-Khan discussed ibrutinib’s significant impact on the risk of progression and death, even in the presence of factors associated with aggressive disease or poor outcome.

[email protected]

CHICAGO – Combining ibrutinib with standard chemoimmunotherapy extended progression-free survival in patients with relapsed chronic lymphocytic leukemia (CLL), according to interim results from the HELIOS trial.

In fact, while median progression-free survival was approximately 13 months in the placebo arm, the median progression-free survival had not been reached yet in the study’s ibrutinib arm, explained lead study author Dr. Asher Chanan-Khan.

“I believe that ibrutinib has now become the backbone of treatment of patients with relapsed CLL,” said Dr. Chanan-Khan, professor of medicine at the Mayo Clinic in Jacksonville, Fla.

In a video interview at the annual meeting of the American Society of Clinical Oncology, Dr. Chanan-Khan discussed ibrutinib’s significant impact on the risk of progression and death, even in the presence of factors associated with aggressive disease or poor outcome.

[email protected]

CHICAGO – Combining ibrutinib with standard chemoimmunotherapy extended progression-free survival in patients with relapsed chronic lymphocytic leukemia (CLL), according to interim results from the HELIOS trial.

In fact, while median progression-free survival was approximately 13 months in the placebo arm, the median progression-free survival had not been reached yet in the study’s ibrutinib arm, explained lead study author Dr. Asher Chanan-Khan.

“I believe that ibrutinib has now become the backbone of treatment of patients with relapsed CLL,” said Dr. Chanan-Khan, professor of medicine at the Mayo Clinic in Jacksonville, Fla.

In a video interview at the annual meeting of the American Society of Clinical Oncology, Dr. Chanan-Khan discussed ibrutinib’s significant impact on the risk of progression and death, even in the presence of factors associated with aggressive disease or poor outcome.

[email protected]

Messe Wien, site of EHA 2015

VIENNA—Researchers say they have found a way to unsickle red blood cells (RBCs), at least in vitro.

Using pegylated carboxyhemoglobin bovine gas transfer, the team restored sickled RBCs to a more normal, rounder shape in as little as 5 minutes.

Ronald Jubin, PhD, of Prolong Pharmaceuticals, the company developing carboxyhemoglobin, described this process at the 20th Congress of the European Hematology Association (abstract S140).

Pegylated carboxyhemoglobin bovine (Sanguinate [SG]) was designed to reduce vasoconstriction, counteract inflammatory responses, and deliver oxygen to hypoxic cells by releasing carbon monoxide.

The investigators contend that using SG early in a vasooclusive crisis (VOC) can limit the crisis and reduce pain severity.

They evaluated SG treatment using RBCs from healthy volunteers and patients with sickle cell disease (SCD).

The researchers monitored carboxyhemoglobin and oxyhemoglobin levels and analyzed patient samples using light microscopy and image capture flow cytometry. In this manner, they were able to visualize and quantify the effects of SG treatment on reversing the sickling of RBCs.

The investigators found that SG rapidly transferred its carbon monoxide component to oxygenated RBCs along with oxygen loading of SG.

“SG restored more normal RBC shape in as little as 5 minutes,” Dr Jubin said.

SG was also able to continually facilitate gas transfer through multiple exposure events and limited inflammatory marker expression in SCD blood samples.

The researchers concluded that SG can serve as an active gas transport agent, providing either carbon monoxide or oxygen to sickled RBCs. They also noted that image capture flow cytometry allowed for a quantitative measurement of decreased sickling and may provide a way to monitor SG treatment effects on SCD patients in future studies.

Dr Jubin said phase 1 safety trials of SG have been completed, and phase 2 trials are in development for VOC, SCD leg ulcers, delayed cerebral ischemia, prevention of delayed kidney graft function, and pulmonary hypertension in beta-thalassemia.

SG was recently awarded orphan drug status by the US Food and Drug Administration.

Orphan designation provides the company developing a drug with certain benefits and incentives, including a 7-year period of marketing exclusivity upon regulatory approval, potential tax credits for certain activities, eligibility for orphan drug grants, and the waiver of certain administrative fees.

Messe Wien, site of EHA 2015

VIENNA—Researchers say they have found a way to unsickle red blood cells (RBCs), at least in vitro.

Using pegylated carboxyhemoglobin bovine gas transfer, the team restored sickled RBCs to a more normal, rounder shape in as little as 5 minutes.

Ronald Jubin, PhD, of Prolong Pharmaceuticals, the company developing carboxyhemoglobin, described this process at the 20th Congress of the European Hematology Association (abstract S140).

Pegylated carboxyhemoglobin bovine (Sanguinate [SG]) was designed to reduce vasoconstriction, counteract inflammatory responses, and deliver oxygen to hypoxic cells by releasing carbon monoxide.

The investigators contend that using SG early in a vasooclusive crisis (VOC) can limit the crisis and reduce pain severity.

They evaluated SG treatment using RBCs from healthy volunteers and patients with sickle cell disease (SCD).

The researchers monitored carboxyhemoglobin and oxyhemoglobin levels and analyzed patient samples using light microscopy and image capture flow cytometry. In this manner, they were able to visualize and quantify the effects of SG treatment on reversing the sickling of RBCs.

The investigators found that SG rapidly transferred its carbon monoxide component to oxygenated RBCs along with oxygen loading of SG.

“SG restored more normal RBC shape in as little as 5 minutes,” Dr Jubin said.

SG was also able to continually facilitate gas transfer through multiple exposure events and limited inflammatory marker expression in SCD blood samples.

The researchers concluded that SG can serve as an active gas transport agent, providing either carbon monoxide or oxygen to sickled RBCs. They also noted that image capture flow cytometry allowed for a quantitative measurement of decreased sickling and may provide a way to monitor SG treatment effects on SCD patients in future studies.

Dr Jubin said phase 1 safety trials of SG have been completed, and phase 2 trials are in development for VOC, SCD leg ulcers, delayed cerebral ischemia, prevention of delayed kidney graft function, and pulmonary hypertension in beta-thalassemia.

SG was recently awarded orphan drug status by the US Food and Drug Administration.

Orphan designation provides the company developing a drug with certain benefits and incentives, including a 7-year period of marketing exclusivity upon regulatory approval, potential tax credits for certain activities, eligibility for orphan drug grants, and the waiver of certain administrative fees.

Messe Wien, site of EHA 2015

VIENNA—Researchers say they have found a way to unsickle red blood cells (RBCs), at least in vitro.

Using pegylated carboxyhemoglobin bovine gas transfer, the team restored sickled RBCs to a more normal, rounder shape in as little as 5 minutes.

Ronald Jubin, PhD, of Prolong Pharmaceuticals, the company developing carboxyhemoglobin, described this process at the 20th Congress of the European Hematology Association (abstract S140).

Pegylated carboxyhemoglobin bovine (Sanguinate [SG]) was designed to reduce vasoconstriction, counteract inflammatory responses, and deliver oxygen to hypoxic cells by releasing carbon monoxide.

The investigators contend that using SG early in a vasooclusive crisis (VOC) can limit the crisis and reduce pain severity.

They evaluated SG treatment using RBCs from healthy volunteers and patients with sickle cell disease (SCD).

The researchers monitored carboxyhemoglobin and oxyhemoglobin levels and analyzed patient samples using light microscopy and image capture flow cytometry. In this manner, they were able to visualize and quantify the effects of SG treatment on reversing the sickling of RBCs.

The investigators found that SG rapidly transferred its carbon monoxide component to oxygenated RBCs along with oxygen loading of SG.

“SG restored more normal RBC shape in as little as 5 minutes,” Dr Jubin said.

SG was also able to continually facilitate gas transfer through multiple exposure events and limited inflammatory marker expression in SCD blood samples.

The researchers concluded that SG can serve as an active gas transport agent, providing either carbon monoxide or oxygen to sickled RBCs. They also noted that image capture flow cytometry allowed for a quantitative measurement of decreased sickling and may provide a way to monitor SG treatment effects on SCD patients in future studies.

Dr Jubin said phase 1 safety trials of SG have been completed, and phase 2 trials are in development for VOC, SCD leg ulcers, delayed cerebral ischemia, prevention of delayed kidney graft function, and pulmonary hypertension in beta-thalassemia.

SG was recently awarded orphan drug status by the US Food and Drug Administration.

Orphan designation provides the company developing a drug with certain benefits and incentives, including a 7-year period of marketing exclusivity upon regulatory approval, potential tax credits for certain activities, eligibility for orphan drug grants, and the waiver of certain administrative fees.

Micrograph showing MM

VIENNA—Combination therapy consisting of the HDAC6 inhibitor ricolinostat, pomalidomide, and dexamethasone can provide a clinical benefit for patients with relapsed and refractory multiple myeloma (MM), according to a researchers.

In a phase 1b/2 trial, the triplet produced an overall response rate (ORR) of 29% and a clinical benefit rate of 50%.

The most common treatment-related adverse events were fatigue, diarrhea, and neutropenia.

“As a physician, it is encouraging to see patients whose multiple myeloma has progressed while receiving standard-of-care therapy achieve clinical benefit with the combination of ricolinostat, [pomalidomide], and dexamethasone,” said study investigator Noopur Raje, MD, of the Massachusetts General Hospital Cancer Center in Boston.

Dr Raje and her colleagues presented results with this combination at the 20th Congress of the European Hematology Association (abstract P279*). The research was sponsored by Acetylon Pharmaceuticals, Inc., the company developing ricolinostat.

The phase 1b portion of this trial was a 3+3 design in which ricolinostat (160 mg) was given once daily (QD) or twice daily (BID) along with pomalidomide (4 mg) for 21 days of a 28-day cycle with dexamethasone (40 mg) on days 1, 8, 15, and 22. Seven patients were treated in the phase 1b portion, with 3 at 160 mg QD and 4 at 160 mg BID.

In the ongoing phase 2 portion of the study, 32 patients were enrolled as of April 27, 2015, and 28 of these patients were evaluable for response. Nineteen of the patients received ricolinostat at 160 mg QD, and 9 received the drug at 160 mg BID.

The median age for all 39 patients was 68 (range, 48-80), and they had received a median of 3 prior therapies (range, 2-5). Seventy-four percent of patients were refractory to lenalidomide, 59% to bortezomib, and 38% to both drugs.

Treatment results

At a median follow-up of 12 weeks, the ORR among the 28 evaluable phase 2 patients was 29%. Clinical benefit, defined as minimal response or greater, was 50%.

Three patients had a very good partial response, 5 had a partial response, 6 had a minimal response, 5 had stable disease, 3 progressed, and 6 had an unconfirmed response at the time of data cutoff.

All 7 patients in the phase 1b portion of the study had discontinued treatment due to progressive disease.

Of the 28 evaluable patients in the phase 2 portion, 57% (n=16) remained on the study after a median of 3 months on therapy. The other 43% discontinued treatment due to progressive disease (n=6), a non-fatal adverse event (n=3), patient decision (n=2), or investigator decision (n=1).

The researchers said the optimal dose and schedule for ricolinostat in combination with pomalidomide and dexamethasone was 160 mg QD on days 1-21 of a 28-day cycle. Patients treated at this dose experienced no dose-limiting toxicities. At 160 mg BID, some clinically relevant grade 2 diarrhea was observed.

In all 39 patients, the common treatment-emergent adverse events were fatigue (41%), diarrhea (38%), neutropenia (36%), anemia (31%), a decrease in platelet count (26%), constipation (21%), hypertension (18%), hyponatremia (18%), upper respiratory tract infection (15%), and a decrease in white cell count (15%).

Grade 3 and 4 adverse events, apart from neutropenia (26%), were uncommon (occurring in 8% of patients or fewer).

Grade 3/4 adverse events considered possibly related to ricolinostat included neutropenia (n=5), diarrhea (n=3), bronchitis (n=1), anemia (n=1), chronic cardiac failure (n=1), leukopenia (n=1), lymphopenia (n=1), pneumonia (n=1), increased alanine aminotransferase (n=1), fatigue (n=1), thrombocytopenia (n=1), and renal failure (n=1).

“This all-oral combination has been very well-tolerated,” Dr Raje said, “making it potentially suitable for treatment of a broad range of patients, including older patients, patients for whom a non-oral drug regimen is limiting, and potentially as a part of an all-oral maintenance regimen.”

*Information in the abstract differs from that presented at the meeting.

Micrograph showing MM

VIENNA—Combination therapy consisting of the HDAC6 inhibitor ricolinostat, pomalidomide, and dexamethasone can provide a clinical benefit for patients with relapsed and refractory multiple myeloma (MM), according to a researchers.

In a phase 1b/2 trial, the triplet produced an overall response rate (ORR) of 29% and a clinical benefit rate of 50%.

The most common treatment-related adverse events were fatigue, diarrhea, and neutropenia.

“As a physician, it is encouraging to see patients whose multiple myeloma has progressed while receiving standard-of-care therapy achieve clinical benefit with the combination of ricolinostat, [pomalidomide], and dexamethasone,” said study investigator Noopur Raje, MD, of the Massachusetts General Hospital Cancer Center in Boston.

Dr Raje and her colleagues presented results with this combination at the 20th Congress of the European Hematology Association (abstract P279*). The research was sponsored by Acetylon Pharmaceuticals, Inc., the company developing ricolinostat.

The phase 1b portion of this trial was a 3+3 design in which ricolinostat (160 mg) was given once daily (QD) or twice daily (BID) along with pomalidomide (4 mg) for 21 days of a 28-day cycle with dexamethasone (40 mg) on days 1, 8, 15, and 22. Seven patients were treated in the phase 1b portion, with 3 at 160 mg QD and 4 at 160 mg BID.

In the ongoing phase 2 portion of the study, 32 patients were enrolled as of April 27, 2015, and 28 of these patients were evaluable for response. Nineteen of the patients received ricolinostat at 160 mg QD, and 9 received the drug at 160 mg BID.

The median age for all 39 patients was 68 (range, 48-80), and they had received a median of 3 prior therapies (range, 2-5). Seventy-four percent of patients were refractory to lenalidomide, 59% to bortezomib, and 38% to both drugs.

Treatment results

At a median follow-up of 12 weeks, the ORR among the 28 evaluable phase 2 patients was 29%. Clinical benefit, defined as minimal response or greater, was 50%.

Three patients had a very good partial response, 5 had a partial response, 6 had a minimal response, 5 had stable disease, 3 progressed, and 6 had an unconfirmed response at the time of data cutoff.

All 7 patients in the phase 1b portion of the study had discontinued treatment due to progressive disease.

Of the 28 evaluable patients in the phase 2 portion, 57% (n=16) remained on the study after a median of 3 months on therapy. The other 43% discontinued treatment due to progressive disease (n=6), a non-fatal adverse event (n=3), patient decision (n=2), or investigator decision (n=1).

The researchers said the optimal dose and schedule for ricolinostat in combination with pomalidomide and dexamethasone was 160 mg QD on days 1-21 of a 28-day cycle. Patients treated at this dose experienced no dose-limiting toxicities. At 160 mg BID, some clinically relevant grade 2 diarrhea was observed.

In all 39 patients, the common treatment-emergent adverse events were fatigue (41%), diarrhea (38%), neutropenia (36%), anemia (31%), a decrease in platelet count (26%), constipation (21%), hypertension (18%), hyponatremia (18%), upper respiratory tract infection (15%), and a decrease in white cell count (15%).

Grade 3 and 4 adverse events, apart from neutropenia (26%), were uncommon (occurring in 8% of patients or fewer).

Grade 3/4 adverse events considered possibly related to ricolinostat included neutropenia (n=5), diarrhea (n=3), bronchitis (n=1), anemia (n=1), chronic cardiac failure (n=1), leukopenia (n=1), lymphopenia (n=1), pneumonia (n=1), increased alanine aminotransferase (n=1), fatigue (n=1), thrombocytopenia (n=1), and renal failure (n=1).

“This all-oral combination has been very well-tolerated,” Dr Raje said, “making it potentially suitable for treatment of a broad range of patients, including older patients, patients for whom a non-oral drug regimen is limiting, and potentially as a part of an all-oral maintenance regimen.”

*Information in the abstract differs from that presented at the meeting.

Micrograph showing MM

VIENNA—Combination therapy consisting of the HDAC6 inhibitor ricolinostat, pomalidomide, and dexamethasone can provide a clinical benefit for patients with relapsed and refractory multiple myeloma (MM), according to a researchers.

In a phase 1b/2 trial, the triplet produced an overall response rate (ORR) of 29% and a clinical benefit rate of 50%.

The most common treatment-related adverse events were fatigue, diarrhea, and neutropenia.

“As a physician, it is encouraging to see patients whose multiple myeloma has progressed while receiving standard-of-care therapy achieve clinical benefit with the combination of ricolinostat, [pomalidomide], and dexamethasone,” said study investigator Noopur Raje, MD, of the Massachusetts General Hospital Cancer Center in Boston.

Dr Raje and her colleagues presented results with this combination at the 20th Congress of the European Hematology Association (abstract P279*). The research was sponsored by Acetylon Pharmaceuticals, Inc., the company developing ricolinostat.

The phase 1b portion of this trial was a 3+3 design in which ricolinostat (160 mg) was given once daily (QD) or twice daily (BID) along with pomalidomide (4 mg) for 21 days of a 28-day cycle with dexamethasone (40 mg) on days 1, 8, 15, and 22. Seven patients were treated in the phase 1b portion, with 3 at 160 mg QD and 4 at 160 mg BID.

In the ongoing phase 2 portion of the study, 32 patients were enrolled as of April 27, 2015, and 28 of these patients were evaluable for response. Nineteen of the patients received ricolinostat at 160 mg QD, and 9 received the drug at 160 mg BID.

The median age for all 39 patients was 68 (range, 48-80), and they had received a median of 3 prior therapies (range, 2-5). Seventy-four percent of patients were refractory to lenalidomide, 59% to bortezomib, and 38% to both drugs.

Treatment results

At a median follow-up of 12 weeks, the ORR among the 28 evaluable phase 2 patients was 29%. Clinical benefit, defined as minimal response or greater, was 50%.

Three patients had a very good partial response, 5 had a partial response, 6 had a minimal response, 5 had stable disease, 3 progressed, and 6 had an unconfirmed response at the time of data cutoff.

All 7 patients in the phase 1b portion of the study had discontinued treatment due to progressive disease.

Of the 28 evaluable patients in the phase 2 portion, 57% (n=16) remained on the study after a median of 3 months on therapy. The other 43% discontinued treatment due to progressive disease (n=6), a non-fatal adverse event (n=3), patient decision (n=2), or investigator decision (n=1).

The researchers said the optimal dose and schedule for ricolinostat in combination with pomalidomide and dexamethasone was 160 mg QD on days 1-21 of a 28-day cycle. Patients treated at this dose experienced no dose-limiting toxicities. At 160 mg BID, some clinically relevant grade 2 diarrhea was observed.

In all 39 patients, the common treatment-emergent adverse events were fatigue (41%), diarrhea (38%), neutropenia (36%), anemia (31%), a decrease in platelet count (26%), constipation (21%), hypertension (18%), hyponatremia (18%), upper respiratory tract infection (15%), and a decrease in white cell count (15%).

Grade 3 and 4 adverse events, apart from neutropenia (26%), were uncommon (occurring in 8% of patients or fewer).

Grade 3/4 adverse events considered possibly related to ricolinostat included neutropenia (n=5), diarrhea (n=3), bronchitis (n=1), anemia (n=1), chronic cardiac failure (n=1), leukopenia (n=1), lymphopenia (n=1), pneumonia (n=1), increased alanine aminotransferase (n=1), fatigue (n=1), thrombocytopenia (n=1), and renal failure (n=1).

“This all-oral combination has been very well-tolerated,” Dr Raje said, “making it potentially suitable for treatment of a broad range of patients, including older patients, patients for whom a non-oral drug regimen is limiting, and potentially as a part of an all-oral maintenance regimen.”

*Information in the abstract differs from that presented at the meeting.

Micrograph showing CLL

VIENNA—Results of the COMPLEMENT 2 trial indicate that adding ofatumumab to treatment with fludarabine and cyclophosphamide (OFC) can improve some outcome measures in patients with relapsed chronic lymphocytic leukemia (CLL), when compared to fludarabine and cyclophosphamide alone (FC).

Patients who received OFC had a significantly higher overall response rate and longer median progression-free survival than patients who received FC.

On the other hand, there was no significant difference between the treatment arms with regard to response duration or overall survival. And there were more grade 3 or higher adverse events (AEs) in the 3-drug arm than the 2-drug arm.

“There are limited treatment options for patients who have stopped responding to current CLL treatments, which happens in many patients with this disease over time,” said study investigator Tadeusz Robak, MD, PhD, of the Medical University of Lodz and Copernicus Memorial Hospital in Lodz, Poland.

“These data showed that the addition of ofatumumab to fludarabine and cyclophosphamide extended the amount of time before a patient’s CLL progressed, and further add to the body of evidence supporting the potential use of ofatumumab for these patients.”

The data were presented at the 20th Congress of the European Hematology Association (abstract LB219). The study was sponsored by GlaxoSmithKline and Genmab, which were previously co-developing ofatumumab. The drug is now an asset of Novartis AG.

Efficacy data

COMPLEMENT 2 is a phase 3 trial of 365 patients with relapsed CLL. Patients were randomized 1:1 to receive treatment with up to 6 cycles of OFC or FC. Baseline characteristics were well-balanced between the treatment arms.

The overall response rate was higher in the OFC arm than the FC arm—84% and 68%, respectively (P=0.0003)—as was the complete response rate—27% and 7%, respectively.

However, there was no significant difference in time to response or response duration. The median duration of response was 29.6 months in the OFC arm and 24.9 months in the FC arm (P=0.0878). And the median time to response was 0.99 months in both arms (P=0.449).

Still, patients in the OFC arm experienced a 54% improvement in progression-free survival. The median progression-free survival was 28.9 months in the OFC arm and 18.8 months in the FC arm (P=0.0032). And time to progression was 42.1 months and 26.8 months, respectively (P=0.0036).

But there was no significant difference in overall survival or time to next cancer treatment between the arms. The median overall survival was 56.4 months in the OFC arm and 45.8 months in the FC arm (P=0.1410). The median time to next therapy was 48.13 months and 40.08 months, respectively (P=0.0735).

Safety data

The rate of treatment-related AEs was 93% in the OFC arm and 85% in the FC arm. The rate of grade 3 or higher AEs was 74% and 69%, respectively.

The most common treatment-related AEs occurring in the OFC and FC arms, respectively, were neutropenia (58% vs 41%), thrombocytopenia (26% vs 32%), anemia (15% vs 26%), nausea (19% in both), leukopenia (14% vs 6%), vomiting (7% vs 10%), pyrexia (10% vs 3%), rash (10% vs 2%), fatigue (6% vs 4%), and pneumonia (6% vs 4%).

Treatment-related infections occurred in 20% of patients in the OFC arm and 15% in the FC arm. Infusion reactions occurred in 60% and 28% of patients, respectively.

Micrograph showing CLL

VIENNA—Results of the COMPLEMENT 2 trial indicate that adding ofatumumab to treatment with fludarabine and cyclophosphamide (OFC) can improve some outcome measures in patients with relapsed chronic lymphocytic leukemia (CLL), when compared to fludarabine and cyclophosphamide alone (FC).

Patients who received OFC had a significantly higher overall response rate and longer median progression-free survival than patients who received FC.

On the other hand, there was no significant difference between the treatment arms with regard to response duration or overall survival. And there were more grade 3 or higher adverse events (AEs) in the 3-drug arm than the 2-drug arm.

“There are limited treatment options for patients who have stopped responding to current CLL treatments, which happens in many patients with this disease over time,” said study investigator Tadeusz Robak, MD, PhD, of the Medical University of Lodz and Copernicus Memorial Hospital in Lodz, Poland.

“These data showed that the addition of ofatumumab to fludarabine and cyclophosphamide extended the amount of time before a patient’s CLL progressed, and further add to the body of evidence supporting the potential use of ofatumumab for these patients.”

The data were presented at the 20th Congress of the European Hematology Association (abstract LB219). The study was sponsored by GlaxoSmithKline and Genmab, which were previously co-developing ofatumumab. The drug is now an asset of Novartis AG.

Efficacy data

COMPLEMENT 2 is a phase 3 trial of 365 patients with relapsed CLL. Patients were randomized 1:1 to receive treatment with up to 6 cycles of OFC or FC. Baseline characteristics were well-balanced between the treatment arms.

The overall response rate was higher in the OFC arm than the FC arm—84% and 68%, respectively (P=0.0003)—as was the complete response rate—27% and 7%, respectively.

However, there was no significant difference in time to response or response duration. The median duration of response was 29.6 months in the OFC arm and 24.9 months in the FC arm (P=0.0878). And the median time to response was 0.99 months in both arms (P=0.449).

Still, patients in the OFC arm experienced a 54% improvement in progression-free survival. The median progression-free survival was 28.9 months in the OFC arm and 18.8 months in the FC arm (P=0.0032). And time to progression was 42.1 months and 26.8 months, respectively (P=0.0036).

But there was no significant difference in overall survival or time to next cancer treatment between the arms. The median overall survival was 56.4 months in the OFC arm and 45.8 months in the FC arm (P=0.1410). The median time to next therapy was 48.13 months and 40.08 months, respectively (P=0.0735).

Safety data

The rate of treatment-related AEs was 93% in the OFC arm and 85% in the FC arm. The rate of grade 3 or higher AEs was 74% and 69%, respectively.

The most common treatment-related AEs occurring in the OFC and FC arms, respectively, were neutropenia (58% vs 41%), thrombocytopenia (26% vs 32%), anemia (15% vs 26%), nausea (19% in both), leukopenia (14% vs 6%), vomiting (7% vs 10%), pyrexia (10% vs 3%), rash (10% vs 2%), fatigue (6% vs 4%), and pneumonia (6% vs 4%).

Treatment-related infections occurred in 20% of patients in the OFC arm and 15% in the FC arm. Infusion reactions occurred in 60% and 28% of patients, respectively.

Micrograph showing CLL

VIENNA—Results of the COMPLEMENT 2 trial indicate that adding ofatumumab to treatment with fludarabine and cyclophosphamide (OFC) can improve some outcome measures in patients with relapsed chronic lymphocytic leukemia (CLL), when compared to fludarabine and cyclophosphamide alone (FC).

Patients who received OFC had a significantly higher overall response rate and longer median progression-free survival than patients who received FC.

On the other hand, there was no significant difference between the treatment arms with regard to response duration or overall survival. And there were more grade 3 or higher adverse events (AEs) in the 3-drug arm than the 2-drug arm.

“There are limited treatment options for patients who have stopped responding to current CLL treatments, which happens in many patients with this disease over time,” said study investigator Tadeusz Robak, MD, PhD, of the Medical University of Lodz and Copernicus Memorial Hospital in Lodz, Poland.

“These data showed that the addition of ofatumumab to fludarabine and cyclophosphamide extended the amount of time before a patient’s CLL progressed, and further add to the body of evidence supporting the potential use of ofatumumab for these patients.”

The data were presented at the 20th Congress of the European Hematology Association (abstract LB219). The study was sponsored by GlaxoSmithKline and Genmab, which were previously co-developing ofatumumab. The drug is now an asset of Novartis AG.

Efficacy data

COMPLEMENT 2 is a phase 3 trial of 365 patients with relapsed CLL. Patients were randomized 1:1 to receive treatment with up to 6 cycles of OFC or FC. Baseline characteristics were well-balanced between the treatment arms.

The overall response rate was higher in the OFC arm than the FC arm—84% and 68%, respectively (P=0.0003)—as was the complete response rate—27% and 7%, respectively.

However, there was no significant difference in time to response or response duration. The median duration of response was 29.6 months in the OFC arm and 24.9 months in the FC arm (P=0.0878). And the median time to response was 0.99 months in both arms (P=0.449).

Still, patients in the OFC arm experienced a 54% improvement in progression-free survival. The median progression-free survival was 28.9 months in the OFC arm and 18.8 months in the FC arm (P=0.0032). And time to progression was 42.1 months and 26.8 months, respectively (P=0.0036).

But there was no significant difference in overall survival or time to next cancer treatment between the arms. The median overall survival was 56.4 months in the OFC arm and 45.8 months in the FC arm (P=0.1410). The median time to next therapy was 48.13 months and 40.08 months, respectively (P=0.0735).

Safety data

The rate of treatment-related AEs was 93% in the OFC arm and 85% in the FC arm. The rate of grade 3 or higher AEs was 74% and 69%, respectively.

The most common treatment-related AEs occurring in the OFC and FC arms, respectively, were neutropenia (58% vs 41%), thrombocytopenia (26% vs 32%), anemia (15% vs 26%), nausea (19% in both), leukopenia (14% vs 6%), vomiting (7% vs 10%), pyrexia (10% vs 3%), rash (10% vs 2%), fatigue (6% vs 4%), and pneumonia (6% vs 4%).

Treatment-related infections occurred in 20% of patients in the OFC arm and 15% in the FC arm. Infusion reactions occurred in 60% and 28% of patients, respectively.

Thrombus

Image by Andre E.X. Brown

Splanchnic venous thrombosis (SVT) may be an indicator of undiagnosed cancer, according to research published in Blood.

The study showed that patients with SVT had a particularly high incidence of myeloproliferative neoplasms (MPNs), liver cancer, and pancreatic cancer.

The presence of SVT also appeared to predict poorer survival in patients with liver and pancreatic cancers. The researchers were unable to calculate the impact of SVT on survival in MPN patients.

“As we learn more about the association between many types of thromboses and cancer, we also want to better understand these more rare clots and how they can perhaps signal a hidden cancer,” said study author Kirstine K. Søgaard, MD, of Aarhus University Hospital in Aarhus, Denmark.

“In this case, we had access to comprehensive data that we believed could provide insights useful to clinicians caring for patients with this condition.”

Dr Søgaard and her colleagues analyzed the medical discharge diagnoses of more than 1191 Danish patients diagnosed with SVT from 1994 to 2011. The researchers followed the patients for a median of 1.6 years, calculating their risk of having a subsequent cancer diagnosis compared to the expected risk in the general population in Denmark.

In all, 183 SVT patients were diagnosed with cancer, for an overall standardized incidence ratio (SIR) of 4.2. More than half of the cancers (n=95) were identified within 3 months of SVT diagnosis. The 3-month absolute risk of cancer was 8%, and the absolute risk at 5 years was 14.8%.

During the first 3 months of follow-up, the SIR for cancer among SVT patients was 33. The SIR fell to 2.7 between 3 and 12 months, then to 2.1 past the 1-year mark.

SIRs were highest for liver and pancreatic cancers and MPNs. The overall SIRs were 138, 21, and 133, respectively.

For MPNs, the SIR was 764 in the first 3 months of SVT diagnosis, 119 from 3 to 12 months, and 88 after the 12-month mark. For liver cancer, the SIR was 1805 in the first 3 months, 92 from 3 to 12 months, and 7.4 after the 12-month mark. For pancreatic cancer, the SIR was 256 in the first 3 months, 0 from 3 to 12 months, and 4 after the 12-month mark.

The researchers also found an excess risk of lymphoma, leukemia, and myelodysplastic syndromes in the first 3 months after SVT diagnosis. After that, the risk did not differ from that of the general population.

Patients with liver or pancreatic cancer had a poor outcome regardless of SVT, but patients with SVT and these cancers had markedly worse 3-month survival outcomes than cancer patients without SVT—44% vs 55% for patients with liver cancer and 33% vs 53% for patients with pancreatic cancer.

Patients with MPNs had a much better prognosis, regardless of SVT. And because so few MPN patients died, the researchers did not analyze the impact of SVT on relative mortality.

“This study is the first to demonstrate, in a large population, that patients who develop splanchnic venous thrombosis are likely to be diagnosed with cancer within a relatively short time period,” Dr Søgaard said. “As we continue to learn more about patients who suffer from these blood clots, it will be important to examine the pros and cons of screening for these hidden cancers.”

Thrombus

Image by Andre E.X. Brown

Splanchnic venous thrombosis (SVT) may be an indicator of undiagnosed cancer, according to research published in Blood.

The study showed that patients with SVT had a particularly high incidence of myeloproliferative neoplasms (MPNs), liver cancer, and pancreatic cancer.

The presence of SVT also appeared to predict poorer survival in patients with liver and pancreatic cancers. The researchers were unable to calculate the impact of SVT on survival in MPN patients.

“As we learn more about the association between many types of thromboses and cancer, we also want to better understand these more rare clots and how they can perhaps signal a hidden cancer,” said study author Kirstine K. Søgaard, MD, of Aarhus University Hospital in Aarhus, Denmark.

“In this case, we had access to comprehensive data that we believed could provide insights useful to clinicians caring for patients with this condition.”

Dr Søgaard and her colleagues analyzed the medical discharge diagnoses of more than 1191 Danish patients diagnosed with SVT from 1994 to 2011. The researchers followed the patients for a median of 1.6 years, calculating their risk of having a subsequent cancer diagnosis compared to the expected risk in the general population in Denmark.

In all, 183 SVT patients were diagnosed with cancer, for an overall standardized incidence ratio (SIR) of 4.2. More than half of the cancers (n=95) were identified within 3 months of SVT diagnosis. The 3-month absolute risk of cancer was 8%, and the absolute risk at 5 years was 14.8%.

During the first 3 months of follow-up, the SIR for cancer among SVT patients was 33. The SIR fell to 2.7 between 3 and 12 months, then to 2.1 past the 1-year mark.

SIRs were highest for liver and pancreatic cancers and MPNs. The overall SIRs were 138, 21, and 133, respectively.

For MPNs, the SIR was 764 in the first 3 months of SVT diagnosis, 119 from 3 to 12 months, and 88 after the 12-month mark. For liver cancer, the SIR was 1805 in the first 3 months, 92 from 3 to 12 months, and 7.4 after the 12-month mark. For pancreatic cancer, the SIR was 256 in the first 3 months, 0 from 3 to 12 months, and 4 after the 12-month mark.

The researchers also found an excess risk of lymphoma, leukemia, and myelodysplastic syndromes in the first 3 months after SVT diagnosis. After that, the risk did not differ from that of the general population.

Patients with liver or pancreatic cancer had a poor outcome regardless of SVT, but patients with SVT and these cancers had markedly worse 3-month survival outcomes than cancer patients without SVT—44% vs 55% for patients with liver cancer and 33% vs 53% for patients with pancreatic cancer.

Patients with MPNs had a much better prognosis, regardless of SVT. And because so few MPN patients died, the researchers did not analyze the impact of SVT on relative mortality.

“This study is the first to demonstrate, in a large population, that patients who develop splanchnic venous thrombosis are likely to be diagnosed with cancer within a relatively short time period,” Dr Søgaard said. “As we continue to learn more about patients who suffer from these blood clots, it will be important to examine the pros and cons of screening for these hidden cancers.”

Thrombus

Image by Andre E.X. Brown

Splanchnic venous thrombosis (SVT) may be an indicator of undiagnosed cancer, according to research published in Blood.

The study showed that patients with SVT had a particularly high incidence of myeloproliferative neoplasms (MPNs), liver cancer, and pancreatic cancer.

The presence of SVT also appeared to predict poorer survival in patients with liver and pancreatic cancers. The researchers were unable to calculate the impact of SVT on survival in MPN patients.

“As we learn more about the association between many types of thromboses and cancer, we also want to better understand these more rare clots and how they can perhaps signal a hidden cancer,” said study author Kirstine K. Søgaard, MD, of Aarhus University Hospital in Aarhus, Denmark.

“In this case, we had access to comprehensive data that we believed could provide insights useful to clinicians caring for patients with this condition.”

Dr Søgaard and her colleagues analyzed the medical discharge diagnoses of more than 1191 Danish patients diagnosed with SVT from 1994 to 2011. The researchers followed the patients for a median of 1.6 years, calculating their risk of having a subsequent cancer diagnosis compared to the expected risk in the general population in Denmark.

In all, 183 SVT patients were diagnosed with cancer, for an overall standardized incidence ratio (SIR) of 4.2. More than half of the cancers (n=95) were identified within 3 months of SVT diagnosis. The 3-month absolute risk of cancer was 8%, and the absolute risk at 5 years was 14.8%.

During the first 3 months of follow-up, the SIR for cancer among SVT patients was 33. The SIR fell to 2.7 between 3 and 12 months, then to 2.1 past the 1-year mark.

SIRs were highest for liver and pancreatic cancers and MPNs. The overall SIRs were 138, 21, and 133, respectively.

For MPNs, the SIR was 764 in the first 3 months of SVT diagnosis, 119 from 3 to 12 months, and 88 after the 12-month mark. For liver cancer, the SIR was 1805 in the first 3 months, 92 from 3 to 12 months, and 7.4 after the 12-month mark. For pancreatic cancer, the SIR was 256 in the first 3 months, 0 from 3 to 12 months, and 4 after the 12-month mark.

The researchers also found an excess risk of lymphoma, leukemia, and myelodysplastic syndromes in the first 3 months after SVT diagnosis. After that, the risk did not differ from that of the general population.

Patients with liver or pancreatic cancer had a poor outcome regardless of SVT, but patients with SVT and these cancers had markedly worse 3-month survival outcomes than cancer patients without SVT—44% vs 55% for patients with liver cancer and 33% vs 53% for patients with pancreatic cancer.

Patients with MPNs had a much better prognosis, regardless of SVT. And because so few MPN patients died, the researchers did not analyze the impact of SVT on relative mortality.

“This study is the first to demonstrate, in a large population, that patients who develop splanchnic venous thrombosis are likely to be diagnosed with cancer within a relatively short time period,” Dr Søgaard said. “As we continue to learn more about patients who suffer from these blood clots, it will be important to examine the pros and cons of screening for these hidden cancers.”