Denosumab Reduces Fracture Incidence in Postmenopausal Women

Denosumab reduced the incidence of new vertebral and hip fractures in postmenopausal women with osteoporosis at both higher and lower risk for fracture, in a post-hoc analysis of data from a 3-year, phase III randomized trial in the Journal of Clinical Endocrinology & Metabolism.

The monoclonal antibody denosumab (Prolia) was approved in June 2010 for treatment of postmenopausal women who have a high risk of osteoporotic fractures. In phase II and III trials, denosumab rapidly decreased bone resorption markers and increased bone mineral density at all skeletal sites, compared with placebo, wrote Dr. S. Boonen of Leuven (Belgium) University and his associates (J. Clin. Endocrinol. Metab. 2011;96 [doi:10.1210/jc.2010-2784]).

The Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial enrolled 7,808 postmenopausal women aged 60-80 years with osteoporosis to receive either a subcutaneous injection of denosumab (60 mg) or placebo along with daily calcium and vitamin D supplements every 6 months. All subjects had bone mineral density (BMD) T scores of less than –2.5 but not less than –4.0 at the lumbar spine or total hip. At 36 months, denosumab was associated with reductions of 68% in vertebral fracture and 40% in hip fracture (N. Engl. J. Med. 2009;361:756-65).

The new analysis compared high-risk and low-risk groups within the FREEDOM population. High-risk groups included women with two or more preexisting vertebral fractures of any degree of deformity, or one or more vertebral fractures of moderate or severe deformity, or both; a femoral neck BMD T score of -2.5 or less; or both multiple and/or moderate or severe vertebral deformities and a femoral neck BMD T score of –2.5 or less.

For hip fractures, the higher-risk subgroups included women who were age 75 years or older; had a femoral neck BMD T score of –2.5 or less; or were 75 years or older with a femoral neck BMD T score of –2.5 or less. Women who did not have those specified risk factors were included in the lower-risk subgroups.

Over 3 years, denosumab treatment was equally effective at reducing the risk of new vertebral fractures in women at both higher and lower risk for those types of fractures, similar to the overall FREEDOM population. Compared with placebo, denosumab reduced the incidence of vertebral fracture in the subgroups at higher risk by prevalent vertebral fracture status by 9.2% (16.6% placebo vs. 7.5% denosumab) among those at risk via baseline femoral neck BMD T score of –2.5 by 6.8% (9.9% vs. 3.1%), and among those with both risk factors by 12.3% (20.1% vs. 8.1%).

The numbers needed to treat to prevent one vertebral fracture in each of these higher-risk subgroups were 11, 15, and 12, respectively, Dr. Boonen and his associates said.

Similar results were seen for the lower-risk groups, including a 4.4% absolute risk reduction in those without prevalent vertebral fracture, 3.7% for those with BMD T score greater than –2.5, and 4.5% for those with without one or both risk factors. Subgroup results for hip fractures were also consistent with the findings from the overall FREEDOM population, with the same efficacy of denosumab consistent across patients with different levels of risk. Compared with placebo, denosumab treatment significantly reduced the incidence of hip fracture among those aged 75 years or older by 1.4% (2.3% placebo vs. 0.9% denosumab); those with a baseline femoral neck BMD T score of -2.5 or less by 1.4% (2.8% vs. 1.4%); and by 2.4% among those with both risk factors (4.1% vs. 1.7%).

"It is reassuring to see that the effect is similar across a range of fracture risk. ... The FDA-approved indication for denosumab is for ‘postmenopausal women at high risk of fracture,’ but the FREEDOM trial was not enriched with ‘women at high risk,’ " noted Dr. Nelson Watts, director of the University of Cincinnati Bone Health and Osteoporosis Center, in an interview. Risk reduction for hip fractures was low in the lower-risk subgroups because the incidence of hip fractures was low, and the difference between the denosumab and placebo groups was therefore not statistically significant. Adverse event incidences were also not statistically different between the treatment groups within any of the higher- and lower-risk subgroups, and were consistent with the adverse event incidences for the overall FREEDOM trial, the investigators said.

Overall mortality was lower – but not significantly so – among all the subgroups with denosumab. However, there was a significantly lower incidence of fatal adverse events with denosumab vs. placebo in the higher-risk group with prevalent vertebral fracture (1.8% vs. 4.9%) and in those with both prevalent vertebral fracture and low femoral neck BMD (1.6% vs. 7.1%). The difference in mortality among the higher-risk subgroups was greater than that of the lower-risk groups, they noted.

The reason for the mortality difference is unclear, Dr. Watts said. "This was not an end point in the main trail and only significant in a small subgroup of high risk patients. It’s clear that women who fracture have decreased survival, so it’s logical that preventing fracture would reduce mortality."

"Our analyses highlight the consistency of the antifracture efficacy of denosumab across subjects with differences in a variety of major risk factors for fractures at baseline. Our analyses suggests that denosumab reduces both new vertebral and hip fractures, regardless of the underlying risk and that the higher absolute fracture risk observed in the higher-risk subgroups is associated with greater absolute risk reduction. These analyses add to the evidence that denosumab is an effective option for the treatment of postmenopausal osteoporosis," Dr. Boonen and his associates concluded.

The study was funded by Amgen Inc. Dr. Boonen has received funding for serving as a trial investigator and as a member of the steering committee for Amgen, as well as consulting and lecture fees from the company. He is also senior clinical investigator of the Fund for Scientific Research in Flanders, Belgium. Four of the study’s coinvestigators are employees of Amgen, and the others disclosed relationships with Amgen and several other pharmaceutical companies. Dr. Watts is director, cofounder, and owner OsteoDynamics and holds stock and patents. He has received fees and/or honoraria from numerous drug companies including Amgen, Novartis, Warner Chilcott, Johnson & Johnson, Merck, and Takeda, Vivus, and Warner Chilcott. Through his university, he has research support from Amgen, Merck, and NPS.

Denosumab reduced the incidence of new vertebral and hip fractures in postmenopausal women with osteoporosis at both higher and lower risk for fracture, in a post-hoc analysis of data from a 3-year, phase III randomized trial in the Journal of Clinical Endocrinology & Metabolism.

The monoclonal antibody denosumab (Prolia) was approved in June 2010 for treatment of postmenopausal women who have a high risk of osteoporotic fractures. In phase II and III trials, denosumab rapidly decreased bone resorption markers and increased bone mineral density at all skeletal sites, compared with placebo, wrote Dr. S. Boonen of Leuven (Belgium) University and his associates (J. Clin. Endocrinol. Metab. 2011;96 [doi:10.1210/jc.2010-2784]).

The Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial enrolled 7,808 postmenopausal women aged 60-80 years with osteoporosis to receive either a subcutaneous injection of denosumab (60 mg) or placebo along with daily calcium and vitamin D supplements every 6 months. All subjects had bone mineral density (BMD) T scores of less than –2.5 but not less than –4.0 at the lumbar spine or total hip. At 36 months, denosumab was associated with reductions of 68% in vertebral fracture and 40% in hip fracture (N. Engl. J. Med. 2009;361:756-65).

The new analysis compared high-risk and low-risk groups within the FREEDOM population. High-risk groups included women with two or more preexisting vertebral fractures of any degree of deformity, or one or more vertebral fractures of moderate or severe deformity, or both; a femoral neck BMD T score of -2.5 or less; or both multiple and/or moderate or severe vertebral deformities and a femoral neck BMD T score of –2.5 or less.

For hip fractures, the higher-risk subgroups included women who were age 75 years or older; had a femoral neck BMD T score of –2.5 or less; or were 75 years or older with a femoral neck BMD T score of –2.5 or less. Women who did not have those specified risk factors were included in the lower-risk subgroups.

Over 3 years, denosumab treatment was equally effective at reducing the risk of new vertebral fractures in women at both higher and lower risk for those types of fractures, similar to the overall FREEDOM population. Compared with placebo, denosumab reduced the incidence of vertebral fracture in the subgroups at higher risk by prevalent vertebral fracture status by 9.2% (16.6% placebo vs. 7.5% denosumab) among those at risk via baseline femoral neck BMD T score of –2.5 by 6.8% (9.9% vs. 3.1%), and among those with both risk factors by 12.3% (20.1% vs. 8.1%).

The numbers needed to treat to prevent one vertebral fracture in each of these higher-risk subgroups were 11, 15, and 12, respectively, Dr. Boonen and his associates said.

Similar results were seen for the lower-risk groups, including a 4.4% absolute risk reduction in those without prevalent vertebral fracture, 3.7% for those with BMD T score greater than –2.5, and 4.5% for those with without one or both risk factors. Subgroup results for hip fractures were also consistent with the findings from the overall FREEDOM population, with the same efficacy of denosumab consistent across patients with different levels of risk. Compared with placebo, denosumab treatment significantly reduced the incidence of hip fracture among those aged 75 years or older by 1.4% (2.3% placebo vs. 0.9% denosumab); those with a baseline femoral neck BMD T score of -2.5 or less by 1.4% (2.8% vs. 1.4%); and by 2.4% among those with both risk factors (4.1% vs. 1.7%).

"It is reassuring to see that the effect is similar across a range of fracture risk. ... The FDA-approved indication for denosumab is for ‘postmenopausal women at high risk of fracture,’ but the FREEDOM trial was not enriched with ‘women at high risk,’ " noted Dr. Nelson Watts, director of the University of Cincinnati Bone Health and Osteoporosis Center, in an interview. Risk reduction for hip fractures was low in the lower-risk subgroups because the incidence of hip fractures was low, and the difference between the denosumab and placebo groups was therefore not statistically significant. Adverse event incidences were also not statistically different between the treatment groups within any of the higher- and lower-risk subgroups, and were consistent with the adverse event incidences for the overall FREEDOM trial, the investigators said.

Overall mortality was lower – but not significantly so – among all the subgroups with denosumab. However, there was a significantly lower incidence of fatal adverse events with denosumab vs. placebo in the higher-risk group with prevalent vertebral fracture (1.8% vs. 4.9%) and in those with both prevalent vertebral fracture and low femoral neck BMD (1.6% vs. 7.1%). The difference in mortality among the higher-risk subgroups was greater than that of the lower-risk groups, they noted.

The reason for the mortality difference is unclear, Dr. Watts said. "This was not an end point in the main trail and only significant in a small subgroup of high risk patients. It’s clear that women who fracture have decreased survival, so it’s logical that preventing fracture would reduce mortality."

"Our analyses highlight the consistency of the antifracture efficacy of denosumab across subjects with differences in a variety of major risk factors for fractures at baseline. Our analyses suggests that denosumab reduces both new vertebral and hip fractures, regardless of the underlying risk and that the higher absolute fracture risk observed in the higher-risk subgroups is associated with greater absolute risk reduction. These analyses add to the evidence that denosumab is an effective option for the treatment of postmenopausal osteoporosis," Dr. Boonen and his associates concluded.

The study was funded by Amgen Inc. Dr. Boonen has received funding for serving as a trial investigator and as a member of the steering committee for Amgen, as well as consulting and lecture fees from the company. He is also senior clinical investigator of the Fund for Scientific Research in Flanders, Belgium. Four of the study’s coinvestigators are employees of Amgen, and the others disclosed relationships with Amgen and several other pharmaceutical companies. Dr. Watts is director, cofounder, and owner OsteoDynamics and holds stock and patents. He has received fees and/or honoraria from numerous drug companies including Amgen, Novartis, Warner Chilcott, Johnson & Johnson, Merck, and Takeda, Vivus, and Warner Chilcott. Through his university, he has research support from Amgen, Merck, and NPS.

Denosumab reduced the incidence of new vertebral and hip fractures in postmenopausal women with osteoporosis at both higher and lower risk for fracture, in a post-hoc analysis of data from a 3-year, phase III randomized trial in the Journal of Clinical Endocrinology & Metabolism.

The monoclonal antibody denosumab (Prolia) was approved in June 2010 for treatment of postmenopausal women who have a high risk of osteoporotic fractures. In phase II and III trials, denosumab rapidly decreased bone resorption markers and increased bone mineral density at all skeletal sites, compared with placebo, wrote Dr. S. Boonen of Leuven (Belgium) University and his associates (J. Clin. Endocrinol. Metab. 2011;96 [doi:10.1210/jc.2010-2784]).

The Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial enrolled 7,808 postmenopausal women aged 60-80 years with osteoporosis to receive either a subcutaneous injection of denosumab (60 mg) or placebo along with daily calcium and vitamin D supplements every 6 months. All subjects had bone mineral density (BMD) T scores of less than –2.5 but not less than –4.0 at the lumbar spine or total hip. At 36 months, denosumab was associated with reductions of 68% in vertebral fracture and 40% in hip fracture (N. Engl. J. Med. 2009;361:756-65).

The new analysis compared high-risk and low-risk groups within the FREEDOM population. High-risk groups included women with two or more preexisting vertebral fractures of any degree of deformity, or one or more vertebral fractures of moderate or severe deformity, or both; a femoral neck BMD T score of -2.5 or less; or both multiple and/or moderate or severe vertebral deformities and a femoral neck BMD T score of –2.5 or less.

For hip fractures, the higher-risk subgroups included women who were age 75 years or older; had a femoral neck BMD T score of –2.5 or less; or were 75 years or older with a femoral neck BMD T score of –2.5 or less. Women who did not have those specified risk factors were included in the lower-risk subgroups.

Over 3 years, denosumab treatment was equally effective at reducing the risk of new vertebral fractures in women at both higher and lower risk for those types of fractures, similar to the overall FREEDOM population. Compared with placebo, denosumab reduced the incidence of vertebral fracture in the subgroups at higher risk by prevalent vertebral fracture status by 9.2% (16.6% placebo vs. 7.5% denosumab) among those at risk via baseline femoral neck BMD T score of –2.5 by 6.8% (9.9% vs. 3.1%), and among those with both risk factors by 12.3% (20.1% vs. 8.1%).

The numbers needed to treat to prevent one vertebral fracture in each of these higher-risk subgroups were 11, 15, and 12, respectively, Dr. Boonen and his associates said.

Similar results were seen for the lower-risk groups, including a 4.4% absolute risk reduction in those without prevalent vertebral fracture, 3.7% for those with BMD T score greater than –2.5, and 4.5% for those with without one or both risk factors. Subgroup results for hip fractures were also consistent with the findings from the overall FREEDOM population, with the same efficacy of denosumab consistent across patients with different levels of risk. Compared with placebo, denosumab treatment significantly reduced the incidence of hip fracture among those aged 75 years or older by 1.4% (2.3% placebo vs. 0.9% denosumab); those with a baseline femoral neck BMD T score of -2.5 or less by 1.4% (2.8% vs. 1.4%); and by 2.4% among those with both risk factors (4.1% vs. 1.7%).

"It is reassuring to see that the effect is similar across a range of fracture risk. ... The FDA-approved indication for denosumab is for ‘postmenopausal women at high risk of fracture,’ but the FREEDOM trial was not enriched with ‘women at high risk,’ " noted Dr. Nelson Watts, director of the University of Cincinnati Bone Health and Osteoporosis Center, in an interview. Risk reduction for hip fractures was low in the lower-risk subgroups because the incidence of hip fractures was low, and the difference between the denosumab and placebo groups was therefore not statistically significant. Adverse event incidences were also not statistically different between the treatment groups within any of the higher- and lower-risk subgroups, and were consistent with the adverse event incidences for the overall FREEDOM trial, the investigators said.

Overall mortality was lower – but not significantly so – among all the subgroups with denosumab. However, there was a significantly lower incidence of fatal adverse events with denosumab vs. placebo in the higher-risk group with prevalent vertebral fracture (1.8% vs. 4.9%) and in those with both prevalent vertebral fracture and low femoral neck BMD (1.6% vs. 7.1%). The difference in mortality among the higher-risk subgroups was greater than that of the lower-risk groups, they noted.

The reason for the mortality difference is unclear, Dr. Watts said. "This was not an end point in the main trail and only significant in a small subgroup of high risk patients. It’s clear that women who fracture have decreased survival, so it’s logical that preventing fracture would reduce mortality."

"Our analyses highlight the consistency of the antifracture efficacy of denosumab across subjects with differences in a variety of major risk factors for fractures at baseline. Our analyses suggests that denosumab reduces both new vertebral and hip fractures, regardless of the underlying risk and that the higher absolute fracture risk observed in the higher-risk subgroups is associated with greater absolute risk reduction. These analyses add to the evidence that denosumab is an effective option for the treatment of postmenopausal osteoporosis," Dr. Boonen and his associates concluded.

The study was funded by Amgen Inc. Dr. Boonen has received funding for serving as a trial investigator and as a member of the steering committee for Amgen, as well as consulting and lecture fees from the company. He is also senior clinical investigator of the Fund for Scientific Research in Flanders, Belgium. Four of the study’s coinvestigators are employees of Amgen, and the others disclosed relationships with Amgen and several other pharmaceutical companies. Dr. Watts is director, cofounder, and owner OsteoDynamics and holds stock and patents. He has received fees and/or honoraria from numerous drug companies including Amgen, Novartis, Warner Chilcott, Johnson & Johnson, Merck, and Takeda, Vivus, and Warner Chilcott. Through his university, he has research support from Amgen, Merck, and NPS.