No Link to Femur Fractures Found with Bisphosphonates
By John Gever, Senior Editor, MedPage Today
Published: March 24, 2010
Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner
Atypical femoral fractures in patients with osteoporosis were extremely rare and not significantly more common with bisphosphonates, results of a meta-analysis showed.
Among more than 14,000 patients involved in three large randomized trials, only 12 fractures of the subtrochanteric or diaphyseal femur were recorded, Dennis Black, PhD, of the University of California San Francisco, and colleagues reported online in the New England Journal of Medicine.
The investigators looked at data from the Fracture Intervention Trial (FIT) and its five-year extension, which compared alendronate (Fosamax) to placebo, and the HORIZON Pivotal Fracture Trial, which tested zoledronic acid (Reclast).
They reported the following relative risks for subtrochanteric or diaphyseal fractures associated with the specific bisphosphonate-based therapies evaluated in the trials:
* Alendronate in FIT: RR 1.03 (95% CI 0.06 to 16.46)
* Alendronate in the FIT Long-Term Extension: RR 1.33 (95% CI 0.12 to 14.67)
* Zoledronic acid in HORIZON: RR 1.50 (95% CI 0.25 to 9.00)
But Black and colleagues did not rule out the possibility of a genuine risk, despite the lack of statistical significance, because the confidence intervals were so wide.
"The study was underpowered for definitive conclusions," they wrote.
In an accompanying editorial, Elizabeth Shane, MD, of Columbia University in New York City, urged physicians with concerns about atypical femoral fractures and bisphosphonates to avoid a "rush to judgment."
She suggested that physicians "re-evaluate" patients taking bisphosphonates for long periods with bone density measurements and risk factors for fracture.
"It is reasonable to consider drug holidays with careful observation for most patients with osteoporosis who are receiving long-term therapy," she wrote, especially those with reduced markers of bone turnover.
But Shane also pointed out that other studies have found that benefits of bisphosphonate therapy continue to accrue past five years.
Black and colleagues re-examined the FIT and HORIZON trials in the wake of case reports suggesting that atypical femoral fractures are more common with bisphosphonate therapy.
The reports have prompted the FDA to begin a formal safety review, although the agency emphasized that the evidence it has seen to date does not demonstrate a genuine risk.
The main FIT study was a one-year placebo controlled study followed by three to 4.5 years of follow-up.
In the extension, participants completing the main trial were offered one year of open-label alendronate followed by a randomized, placebo-controlled extension that lasted up to five years. Overall, patients in this trial received alendronate for up to 10 years.
HORIZON tested three years of annual infusions of zoledronic acid.
In all, the three studies involved 51,287 patient-years of drug exposure.
The three groups of patients -- 6,459 in the main FIT study, 1,099 in its extension, and 7,736 in the Horizon study -- included 283 who suffered hip or femur fractures.
Black and colleagues collected data on the specifics of these fractures. They immediately excluded about half because they involved the femoral neck or subcapital sections of the femur, obviously resulted from other pathologies or high-energy impacts, or were periprosthetic.
For the remainder, x-rays and/or surgical reports were reviewed by a radiologist who determined that only 12, occurring in 10 patients, were "fractures of interest."
The overall rate of atypical fractures was therefore calculated to be 2.3 per 10,000 patient-years of observation, which Black and colleagues called "extremely low."
The lack of apparent association between bisphosphonate use and atypical femoral fractures, even in the long-term FIT extension, suggested that duration of treatment may not be a factor in whatever risk bisphosphonates pose.
But in cautioning about the limits of their data, they noted that "atypical features could not be fully assessed, since radiographs were not generally available."
The small number of events also precluded a definitive conclusion that the rate was not higher in patients treated with bisphosphonates.
In addition, the trials, except for the extension of FIT, were not long-term studies of bisphosphonate use.
Yet, on the other hand, they argued that bisphosphonates definitely do prevent other types of fractures. On the basis of the FIT and HORIZON trials, they calculated that 3,000 patient-years of treatment would prevent 71 vertebral fractures, 11 hip fractures, and 18 other types of fracture.
Black and colleagues also noted that their findings were similar to those of a Danish registry analysis reported last year.
In her editorial, Shane indicated that more research is needed -- not only to assess the true incidence of atypical femoral fractures and the association with bisphosphonates, but also on methods to detect incipient fractures and management of those that occur.
The study was funded by Merck and Novartis.
Study authors reported relationships with Merck, Novartis, Amgen, Roche, AstraZeneca, GlaxoSmithKline, Procter & Gamble, Medtronic, Nastech, Nestle, Fonterra Brands, Ono, Osteologix, Pfizer, Eli Lilly, sanofi-aventis, Tethys, Unilever, Unipath, Inverness, Ortho Clinical Diagnostics, Osi Prosidion, and Takeda. Some authors were employees of Merck and Novartis.
Shane reported research funding from Novartis, Amgen, Eli Lilly, and Merck.
Primary source: New England Journal of Medicine
Source reference:
Shane E "Evolving data about subtrochanteric fractures and bisphosphonates" N Engl J Med 2010; DOI:10.1056/NEJMe1003064.
Additional source: New England Journal of Medicine
Source reference:
Black D, et al "Bisphosphonates and fractures of the subtrochanteric or diaphyseal femur" N Engl J Med 2010; DOI:10.1056/NEJMoa1001086.
Published: March 24, 2010
Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner
Atypical femoral fractures in patients with osteoporosis were extremely rare and not significantly more common with bisphosphonates, results of a meta-analysis showed.
Among more than 14,000 patients involved in three large randomized trials, only 12 fractures of the subtrochanteric or diaphyseal femur were recorded, Dennis Black, PhD, of the University of California San Francisco, and colleagues reported online in the New England Journal of Medicine.
The investigators looked at data from the Fracture Intervention Trial (FIT) and its five-year extension, which compared alendronate (Fosamax) to placebo, and the HORIZON Pivotal Fracture Trial, which tested zoledronic acid (Reclast).
They reported the following relative risks for subtrochanteric or diaphyseal fractures associated with the specific bisphosphonate-based therapies evaluated in the trials:
* Alendronate in the FIT Long-Term Extension: RR 1.33 (95% CI 0.12 to 14.67)
* Zoledronic acid in HORIZON: RR 1.50 (95% CI 0.25 to 9.00)
But Black and colleagues did not rule out the possibility of a genuine risk, despite the lack of statistical significance, because the confidence intervals were so wide.
"The study was underpowered for definitive conclusions," they wrote.
In an accompanying editorial, Elizabeth Shane, MD, of Columbia University in New York City, urged physicians with concerns about atypical femoral fractures and bisphosphonates to avoid a "rush to judgment."
She suggested that physicians "re-evaluate" patients taking bisphosphonates for long periods with bone density measurements and risk factors for fracture.
"It is reasonable to consider drug holidays with careful observation for most patients with osteoporosis who are receiving long-term therapy," she wrote, especially those with reduced markers of bone turnover.
But Shane also pointed out that other studies have found that benefits of bisphosphonate therapy continue to accrue past five years.
Black and colleagues re-examined the FIT and HORIZON trials in the wake of case reports suggesting that atypical femoral fractures are more common with bisphosphonate therapy.
The reports have prompted the FDA to begin a formal safety review, although the agency emphasized that the evidence it has seen to date does not demonstrate a genuine risk.
The main FIT study was a one-year placebo controlled study followed by three to 4.5 years of follow-up.
In the extension, participants completing the main trial were offered one year of open-label alendronate followed by a randomized, placebo-controlled extension that lasted up to five years. Overall, patients in this trial received alendronate for up to 10 years.
HORIZON tested three years of annual infusions of zoledronic acid.
In all, the three studies involved 51,287 patient-years of drug exposure.
The three groups of patients -- 6,459 in the main FIT study, 1,099 in its extension, and 7,736 in the Horizon study -- included 283 who suffered hip or femur fractures.
Black and colleagues collected data on the specifics of these fractures. They immediately excluded about half because they involved the femoral neck or subcapital sections of the femur, obviously resulted from other pathologies or high-energy impacts, or were periprosthetic.
For the remainder, x-rays and/or surgical reports were reviewed by a radiologist who determined that only 12, occurring in 10 patients, were "fractures of interest."
The overall rate of atypical fractures was therefore calculated to be 2.3 per 10,000 patient-years of observation, which Black and colleagues called "extremely low."
The lack of apparent association between bisphosphonate use and atypical femoral fractures, even in the long-term FIT extension, suggested that duration of treatment may not be a factor in whatever risk bisphosphonates pose.
But in cautioning about the limits of their data, they noted that "atypical features could not be fully assessed, since radiographs were not generally available."
The small number of events also precluded a definitive conclusion that the rate was not higher in patients treated with bisphosphonates.
In addition, the trials, except for the extension of FIT, were not long-term studies of bisphosphonate use.
Yet, on the other hand, they argued that bisphosphonates definitely do prevent other types of fractures. On the basis of the FIT and HORIZON trials, they calculated that 3,000 patient-years of treatment would prevent 71 vertebral fractures, 11 hip fractures, and 18 other types of fracture.
Black and colleagues also noted that their findings were similar to those of a Danish registry analysis reported last year.
In her editorial, Shane indicated that more research is needed -- not only to assess the true incidence of atypical femoral fractures and the association with bisphosphonates, but also on methods to detect incipient fractures and management of those that occur.
The study was funded by Merck and Novartis.
Study authors reported relationships with Merck, Novartis, Amgen, Roche, AstraZeneca, GlaxoSmithKline, Procter & Gamble, Medtronic, Nastech, Nestle, Fonterra Brands, Ono, Osteologix, Pfizer, Eli Lilly, sanofi-aventis, Tethys, Unilever, Unipath, Inverness, Ortho Clinical Diagnostics, Osi Prosidion, and Takeda. Some authors were employees of Merck and Novartis.
Shane reported research funding from Novartis, Amgen, Eli Lilly, and Merck.
Primary source: New England Journal of Medicine
Source reference:
Shane E "Evolving data about subtrochanteric fractures and bisphosphonates" N Engl J Med 2010; DOI:10.1056/NEJMe1003064.
Additional source: New England Journal of Medicine
Source reference:
Black D, et al "Bisphosphonates and fractures of the subtrochanteric or diaphyseal femur" N Engl J Med 2010; DOI:10.1056/NEJMoa1001086.
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