The study is convincing
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Yearly monitoring does not predict fractures after bisphosphonate cessation

Fracture risk in women who discontinue therapy with bisphosphonates can be assessed by measuring bone mineral density at the time of discontinuation, but subsequent frequent monitoring appears to have little predictive value, according to researchers.

The findings were published online May 5 in JAMA Internal Medicine (doi:10.1001/jamainternmed.2014.1232).

Dr. Douglas Bauer of the University of California, San Francisco, and his colleagues looked at data from a trial of about 1,000 postmenopausal women aged 61-86 who had been treated for 4-5 years with alendronate and were randomized to an additional 5 years of alendronate treatment or placebo.

Among the 437 women assigned to placebo, 22% (n = 94) experienced one or more fractures during follow-up. Hip and neck BMD were assessed via dual-energy x-ray absorptiometry (DXA) at baseline and at 1 and 3 years, and bone turnover markers (BTMs) were also analyzed.

Neither 1-year changes in hip DXA nor 1- or 3-year changes in BTM levels were associated with fracture risk. Only age and lower hip BMD at the time of treatment discontinuation were significantly predictive of fracture, according to Dr. Bauer and his associates.

The relative hazard ratio was 1.87 (95% confidence interval, 1.20-2.92) for fracture risk in lowest tertile of baseline hip BMD, and 1.54 (95% CI, 1.26-1.85) per 5-year increase in age.

Yearly monitoring – recommended by many experts after discontinuation of bisphosphonates – should not be considered predictive of fractures, the researchers noted. It was "somewhat surprising that short-term changes in these individual measurements are not associated with fracture risk after discontinuation," they wrote.

The researchers cautioned clinicians and patients contemplating a drug holiday after 5 years of treatment to "be aware that short-term monitoring to detect individuals at higher risk who might resume bisphosphonate therapy, or initiate another therapy, may not add to risk prediction over and above age and BMD measured at the time of discontinuation."

The study’s limitations include its relatively small number of fractures observed, reducing its statistical power, and the use of a single bisphosphonate medication, Dr. Bauer acknowledged.

The researchers received no outside funding, though their findings were derived from an analysis of the placebo group of the FLEX trial, a manufacturer-sponsored study comparing extended alendronate sodium treatment with placebo in a large cohort of women treated 5 years on alendronate (JAMA 2006;296:2927-38).

Dr. Bauer reported no conflicts of interest related to the study; other study authors disclosed financial relationships with Amgen, GlaxoSmithKline, Merck, Novartis, Nycomed, and Eli Lilly.

Body

In an era when we know much more about how to start than how to stop alendronate therapy, the results of Bauer and colleagues suggest that identification of patients at high risk of fracture after treatment discontinuation is best accomplished by BMD measurement at the time of discontinuation rather than frequent short-term monitoring with BMD or bone turnover marker measurements after treatment discontinuation.

The study is convincing because of its reliance on a clinical fracture outcome rather than surrogate measures such as rates of BMD loss or changes in bone turnover marker levels. Future studies should be longer in duration to accumulate more evidence regarding predictors of long-term fracture incidence after bisphosphonate withdrawal and to identify an outcomes-based bisphosphonate washout period for trials of sequential therapy.

Dr. Margaret L. Gourlay is in the department of family medicine at the University of North Carolina, Chapel Hill, and Dr. Kristine E. Ensrud is in the school of public health at the University of Minnesota, Minneapolis. Dr. Ensrud disclosed a consulting relationship with Merck Sharp & Dohme. Their comments were taken from an editorial (JAMA Intern. Med. 2014 May 5 [doi:10.1001/jamainternmed.2014.162]).

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Body

In an era when we know much more about how to start than how to stop alendronate therapy, the results of Bauer and colleagues suggest that identification of patients at high risk of fracture after treatment discontinuation is best accomplished by BMD measurement at the time of discontinuation rather than frequent short-term monitoring with BMD or bone turnover marker measurements after treatment discontinuation.

The study is convincing because of its reliance on a clinical fracture outcome rather than surrogate measures such as rates of BMD loss or changes in bone turnover marker levels. Future studies should be longer in duration to accumulate more evidence regarding predictors of long-term fracture incidence after bisphosphonate withdrawal and to identify an outcomes-based bisphosphonate washout period for trials of sequential therapy.

Dr. Margaret L. Gourlay is in the department of family medicine at the University of North Carolina, Chapel Hill, and Dr. Kristine E. Ensrud is in the school of public health at the University of Minnesota, Minneapolis. Dr. Ensrud disclosed a consulting relationship with Merck Sharp & Dohme. Their comments were taken from an editorial (JAMA Intern. Med. 2014 May 5 [doi:10.1001/jamainternmed.2014.162]).

Body

In an era when we know much more about how to start than how to stop alendronate therapy, the results of Bauer and colleagues suggest that identification of patients at high risk of fracture after treatment discontinuation is best accomplished by BMD measurement at the time of discontinuation rather than frequent short-term monitoring with BMD or bone turnover marker measurements after treatment discontinuation.

The study is convincing because of its reliance on a clinical fracture outcome rather than surrogate measures such as rates of BMD loss or changes in bone turnover marker levels. Future studies should be longer in duration to accumulate more evidence regarding predictors of long-term fracture incidence after bisphosphonate withdrawal and to identify an outcomes-based bisphosphonate washout period for trials of sequential therapy.

Dr. Margaret L. Gourlay is in the department of family medicine at the University of North Carolina, Chapel Hill, and Dr. Kristine E. Ensrud is in the school of public health at the University of Minnesota, Minneapolis. Dr. Ensrud disclosed a consulting relationship with Merck Sharp & Dohme. Their comments were taken from an editorial (JAMA Intern. Med. 2014 May 5 [doi:10.1001/jamainternmed.2014.162]).

Title
The study is convincing
The study is convincing

Fracture risk in women who discontinue therapy with bisphosphonates can be assessed by measuring bone mineral density at the time of discontinuation, but subsequent frequent monitoring appears to have little predictive value, according to researchers.

The findings were published online May 5 in JAMA Internal Medicine (doi:10.1001/jamainternmed.2014.1232).

Dr. Douglas Bauer of the University of California, San Francisco, and his colleagues looked at data from a trial of about 1,000 postmenopausal women aged 61-86 who had been treated for 4-5 years with alendronate and were randomized to an additional 5 years of alendronate treatment or placebo.

Among the 437 women assigned to placebo, 22% (n = 94) experienced one or more fractures during follow-up. Hip and neck BMD were assessed via dual-energy x-ray absorptiometry (DXA) at baseline and at 1 and 3 years, and bone turnover markers (BTMs) were also analyzed.

Neither 1-year changes in hip DXA nor 1- or 3-year changes in BTM levels were associated with fracture risk. Only age and lower hip BMD at the time of treatment discontinuation were significantly predictive of fracture, according to Dr. Bauer and his associates.

The relative hazard ratio was 1.87 (95% confidence interval, 1.20-2.92) for fracture risk in lowest tertile of baseline hip BMD, and 1.54 (95% CI, 1.26-1.85) per 5-year increase in age.

Yearly monitoring – recommended by many experts after discontinuation of bisphosphonates – should not be considered predictive of fractures, the researchers noted. It was "somewhat surprising that short-term changes in these individual measurements are not associated with fracture risk after discontinuation," they wrote.

The researchers cautioned clinicians and patients contemplating a drug holiday after 5 years of treatment to "be aware that short-term monitoring to detect individuals at higher risk who might resume bisphosphonate therapy, or initiate another therapy, may not add to risk prediction over and above age and BMD measured at the time of discontinuation."

The study’s limitations include its relatively small number of fractures observed, reducing its statistical power, and the use of a single bisphosphonate medication, Dr. Bauer acknowledged.

The researchers received no outside funding, though their findings were derived from an analysis of the placebo group of the FLEX trial, a manufacturer-sponsored study comparing extended alendronate sodium treatment with placebo in a large cohort of women treated 5 years on alendronate (JAMA 2006;296:2927-38).

Dr. Bauer reported no conflicts of interest related to the study; other study authors disclosed financial relationships with Amgen, GlaxoSmithKline, Merck, Novartis, Nycomed, and Eli Lilly.

Fracture risk in women who discontinue therapy with bisphosphonates can be assessed by measuring bone mineral density at the time of discontinuation, but subsequent frequent monitoring appears to have little predictive value, according to researchers.

The findings were published online May 5 in JAMA Internal Medicine (doi:10.1001/jamainternmed.2014.1232).

Dr. Douglas Bauer of the University of California, San Francisco, and his colleagues looked at data from a trial of about 1,000 postmenopausal women aged 61-86 who had been treated for 4-5 years with alendronate and were randomized to an additional 5 years of alendronate treatment or placebo.

Among the 437 women assigned to placebo, 22% (n = 94) experienced one or more fractures during follow-up. Hip and neck BMD were assessed via dual-energy x-ray absorptiometry (DXA) at baseline and at 1 and 3 years, and bone turnover markers (BTMs) were also analyzed.

Neither 1-year changes in hip DXA nor 1- or 3-year changes in BTM levels were associated with fracture risk. Only age and lower hip BMD at the time of treatment discontinuation were significantly predictive of fracture, according to Dr. Bauer and his associates.

The relative hazard ratio was 1.87 (95% confidence interval, 1.20-2.92) for fracture risk in lowest tertile of baseline hip BMD, and 1.54 (95% CI, 1.26-1.85) per 5-year increase in age.

Yearly monitoring – recommended by many experts after discontinuation of bisphosphonates – should not be considered predictive of fractures, the researchers noted. It was "somewhat surprising that short-term changes in these individual measurements are not associated with fracture risk after discontinuation," they wrote.

The researchers cautioned clinicians and patients contemplating a drug holiday after 5 years of treatment to "be aware that short-term monitoring to detect individuals at higher risk who might resume bisphosphonate therapy, or initiate another therapy, may not add to risk prediction over and above age and BMD measured at the time of discontinuation."

The study’s limitations include its relatively small number of fractures observed, reducing its statistical power, and the use of a single bisphosphonate medication, Dr. Bauer acknowledged.

The researchers received no outside funding, though their findings were derived from an analysis of the placebo group of the FLEX trial, a manufacturer-sponsored study comparing extended alendronate sodium treatment with placebo in a large cohort of women treated 5 years on alendronate (JAMA 2006;296:2927-38).

Dr. Bauer reported no conflicts of interest related to the study; other study authors disclosed financial relationships with Amgen, GlaxoSmithKline, Merck, Novartis, Nycomed, and Eli Lilly.

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Yearly monitoring does not predict fractures after bisphosphonate cessation
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Yearly monitoring does not predict fractures after bisphosphonate cessation
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Fracture risk, therapy, bisphosphonates, bone mineral density, JAMA Internal Medicine
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Fracture risk, therapy, bisphosphonates, bone mineral density, JAMA Internal Medicine
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