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Evolving Data about Subtrochanteric Fractures and Bisphosphonates-EDITORIAL
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NEJM March 24 2010
Elizabeth Shane, M.D.
From the Department of Medicine, Division of Endocrinology, Columbia University College of Physicians and Surgeons, New York.
Osteoporosis, a skeletal disorder characterized by reduced bone strength that predisposes to an increased risk of fracture, affects 10 to 12 million people in the United States. In 2000, there were 9 million fractures worldwide, of which 1.6 million were hip fractures. Fractures are important because of their association with an increased rate of death, substantial morbidity, enormous costs, and devastating effects on independence and quality of life.
Bisphosphonates, the major class of drugs used to treat osteoporosis,1,2 decrease osteoclast-mediated bone resorption and bone turnover markers and increase bone mineral density. They have been shown to reduce the risk of osteoporotic fracture in numerous large clinical trials.3 Because of their avid binding to bone mineral, bisphosphonates remain in the skeleton for years, and antifracture efficacy persists for some time after discontinuation.2 The four bisphosphonates in common clinical use - alendronate, risedronate, ibandronate, and zoledronate - differ according to binding affinity, potency, speed of onset, antifracture efficacy, and duration of action. All four drugs reduce the rate of vertebral fractures, and all but ibandronate reduce the rates of hip and nonvertebral fractures.3 Since alendronate was approved in the United States in 1995, bisphosphonates have been used by millions of women and men worldwide.
In general, bisphosphonates have an excellent safety profile.2 However, a number of potential side effects have been identified. Among these are cases of "atypical" fracture of the subtrochanteric and diaphyseal femoral shaft that occur with minimal or no trauma.4,5 These fractures generally affect the proximal third of the femoral shaft but may occur anywhere along the femoral diaphysis. They are usually transverse but may have a shallow, oblique configuration and may be bilateral and associated with a medial spike, cortical thickening, and prodromal symptoms, such as thigh pain. Such fractures have been reported in several case series, as summarized by Watts and Diab.2 The majority of these case reports involved patients receiving long-term alendronate therapy, sometimes together with other antiresorptive drugs, corticosteroids, or proton-pump inhibitors. It has been suggested that in some patients, prolonged administration of bisphosphonates may lead to oversuppression of bone turnover,5 which no longer permits remodeling to repair microdamage and thereby reduces bone strength.5
Although the pathogenesis of atypical femur fractures are unknown and a causal relationship with bisphosphonates has not been established, these reports represent a major concern for physicians and patients. However, it important to recognize that subtrochanteric fractures make up only 2 to 4% of all hip fractures. Atypical subtrochanteric fractures that are associated with bisphosphonate therapy are even less common.4 Epidemiologic studies suggest that femoral-shaft fractures are more likely to be caused by osteoporosis than by bisphosphonates and that the numbers of such fractures are reduced by high adherence to bisphosphonate therapy.6 In addition, on the basis of two large database studies, the overall incidence of such fractures has not increased since bisphosphonates were approved for the treatment of osteoporosis.7
In this issue of the Journal, Black et al.8 report a secondary analysis of three large, randomized clinical trials of bisphosphonates: two of oral alendronate in the Fracture Intervention Trial (FIT) and the FIT Long-Term Extension (FLEX) trial (ClinicalTrials.gov number, NCT00398931 [ClinicalTrials.gov] ) and one of zoledronate in the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) Pivotal Fracture Trial (PFT) (NCT00049829 [ClinicalTrials.gov] ). In the FIT study, women were randomly assigned to receive either alendronate or placebo for 3 to 4.5 years. In the FLEX extension, 1099 women who were originally assigned to receive alendronate in the FIT study underwent a second randomization to receive either alendronate at a daily dose of 5 mg or 10 mg or placebo. The total duration of active alendronate use was 10 years for women assigned to receive alendronate and 5 years for those assigned to receive placebo. In the HORIZON-PFT trial, 7736 women were randomly assigned to receive either 5 mg of zoledronate or placebo and were followed for 3 years.
Black et al. reviewed all 284 hip and femur fractures to identify which occurred in the femoral shaft and to assess atypia. The investigators found 12 subtrochanteric or diaphyseal fractures (4%) in 10 patients. The relative hazard ratios for these fractures in patients who were treated with alendronate versus placebo were 1.03 (95% confidence interval [CI], 0.06 to 16.46) in the FIT study and 1.33 (95% CI, 0.12 to 14.67) in the FLEX extension. The relative hazard ratio of zoledronate versus placebo was 1.50 (95% CI, 0.25 to 9.00) in the HORIZON-PFT trial. The authors concluded that there was no significant association between bisphosphonate use and the risk of subtrochanteric or diaphyseal fracture, even among women who were treated for as long as 10 years. They calculated that treating 1000 women who had osteoporosis for 3 years would prevent about 100 fractures (including about 11 hip fractures), a benefit that exceeded the risk of subtrochanteric or diaphyseal fracture, if bisphosphonate use was causal.
This new report has important strengths. The investigators evaluated studies that were randomized and placebo-controlled, involving 14,195 women and 55,000 person-years of observation. The degree of exposure to bisphosphonates is known, providing a denominator that was lacking in previous reports. The alendronate extension data that compared 5 years and 10 years of alendronate use provide some reassurance regarding reported associations between subtrochanteric or diaphyseal fracture and long-term bisphosphonate treatment.
However, several important limitations in the study by Black et al. diminish our ability to draw definitive conclusions. In most cases, radiographs were not available to evaluate features of atypia. Only a minority of women received more than 3 to 4 years of bisphosphonate treatment, and some received a lower dose of alendronate (5 mg) than is commonly prescribed. Most important, as the authors acknowledge, because of the rarity of atypical femoral fractures, the study's statistical power was extremely low, which underscores the difficulty in detecting rare complications, even in very large clinical trials. The experience with bisphosphonates highlights the importance of postmarketing surveillance studies to detect the emergence of rare side effects of drugs that are widely used for very common chronic diseases.
What are the implications of this study for clinical practice? The results provide assurance that subtrochanteric fractures are extremely rare, as compared with femoral-neck and intertrochanteric fractures.6,7 The findings also suggest that many more common and equally devastating hip fractures are prevented by bisphosphonates than are potentially caused by the drugs.
On the basis of available data, physicians should not rush to judgment and stop prescribing bisphosphonates because of concern about atypical femoral fractures. However, they should reevaluate patients who are receiving long-term bisphosphonate therapy in the context of contemporary guidelines for treatment initiation, progress while receiving therapy, current bone mineral density measurements, and risk factors for fracture.9 Although detailed recommendations are beyond the scope of this editorial, it is reasonable to consider drug holidays with careful observation for most patients with osteoporosis who are receiving long-term therapy, particularly those whose bone-turnover markers indicate substantially reduced levels. However, we must also balance evidence of persistent antifracture efficacy after discontinuation with data showing that the use of alendronate for 10 years, as compared with 5 years, was associated with significantly fewer new vertebral fractures2,3 and nonvertebral fractures in patients with a bone mineral density T score of -2.5 or below.10
Because subtrochanteric fractures are so rare, many questions remain unanswered. Research is needed to address the true incidence of such fractures, the pathogenetic importance of bisphosphonate use and other risk factors, the detection of incipient fractures, and appropriate medical and surgical management.
Disclosure forms provided by the author are available with the full text of this article at NEJM.org.
References
1. Russell RG, Watts NB, Ebetino FH, Rogers MJ. Mechanisms of action of bisphosphonates: similarities and differences and their potential influence on clinical efficacy. Osteoporos Int 2008;19:733-759. [CrossRef][Web of Science][Medline]
2. Watts NB, Diab DL. Long-term use of bisphosphosphonates in osteoporosis. J Clin Endocrinol Metab 2010 February 19 (Epub ahead of print).
3. Bilezikian JP. Efficacy of bisphosphonates in reducing fracture risk in postmenopausal osteoporosis. Am J Med 2009;122:Suppl:S14-S21. [Medline]
4. Lenart BA, Lorich DG, Lane JM. Atypical fractures of the femoral diaphysis in postmenopausal women taking alendronate. N Engl J Med 2008;358:1304-1306. [Free Full Text]
5. Odvina CV, Zerwekh JE, Rao DS, Maalouf N, Gottschalk FA, Pak CY. Severely suppressed bone turnover: a potential complication of alendronate therapy. J Clin Endocrinol Metab 2005;90:1294-1301. [Free Full Text]
6. Abrahamsen B, Eiken P, Eastell R. Subtrochanteric and diaphyseal femur fractures in patients treated with alendronate: a register-based national cohort study. J Bone Miner Res 2009;24:1095-1102. [CrossRef][Web of Science][Medline]
7. Nieves JW, Bilezikian JP, Lane JM, et al. Fragility fractures of the hip and femur: incidence and patient characteristics. Osteoporos Int 2009;21:399-408. [Web of Science][Medline]
8. Black DM, Kelly MP, Genant HK, et al. Bisphosphonates and fractures of the subtrochanteric or diaphyseal femur. N Engl J Med 2010. DOI: 10.1056/NEJMoa1001086.
9. NOF's clinician's guide to prevention and treatment of osteoporosis. Washington, DC: National Osteoporosis Foundation, 2009.
10. Schwartz AV, Bauer DC, Cummings SR, et al. Efficacy of continued alendronate for fractures in women with and without prevalent vertebral fracture: the FLEX trial. J Bone Miner Res 2010 January 8 (Epub ahead of print).
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