The issue has drawn the focus of the American Society for Bone and Mineral Research (ASBMR), which appointed a task force to address it. A multidisciplinary expert group reviewed pertinent published reports of atypical femoral fracture, as well as preclinical studies, that could provide insight into its pathogenesis.
What we know about this type of fracture
Preclinical data lend biologic plausibility to a potential association between long-term bisphosphonate use and atypical femoral fracture. These data highlight the effects of bisphosphonates on:
- collagen cross-linking and maturation
- accumulation of microdamage and advanced glycation end products
- heightened mineralization, remodeling, vascularity, and angiogenesis.
The task force concluded that bisphosphonates are highly effective at reducing the risk of spinal and nonspinal fractures, including typical and common femoral neck and intertrochanteric fractures. However, there is evidence of a relationship between long-term bisphosphonate use and a specific type of subtrochanteric and femoral shaft fracture. This type of fracture is characterized by unique radiographic features:
- transverse or short oblique orientation
- absence of comminution
- cortical thickening
- stress fracture or stress reaction on the symptomatic and/or contralateral side
- delayed healing.
This type of fracture also has unique clinical features—namely, prodromal pain and bilaterality.
The apparent increase in the risk of atypical femoral fracture in patients using glucocorticoids is a concern because bisphosphonates are the mainstay of prevention of glucocorticoid-induced osteoporotic fracture.
Bone biopsies from the iliac crest or fracture site, or both, generally show reduced bone formation consistent with bisphosphonate action. Paradoxically, some patients show biopsy evidence of enhanced bone resorption. Biochemical bone-turnover markers are often normal but may be increased.
Atypical femoral fracture can occur in patients who have not been treated with bisphosphonates, and its true incidence in treated and untreated patients is unknown. However, it appears to be more common in patients who have been exposed to long-term bisphosphonates—usually for longer than 3 years (median treatment: 7 years).
It must be emphasized that this type of fracture is rare, particularly considering the millions of patients who have used bisphosphonates and the much higher incidence of typical and common femoral neck and intertrochanteric fractures in untreated patients.
Bisphosphonates are important drugs for the prevention of common osteoporotic fractures. However, atypical femoral fracture is a concern, and more information is needed to help us identify patients at risk and to guide decision-making about the optimal duration of bisphosphonate therapy.
WHAT THIS EVIDENCE MEANS FOR PRACTICE
Any discussion with the patient about bisphosphonate use should begin with a mention of the millions of women who have been treated successfully with these agents and the thousands and thousands of hip, spinal, and other nonvertebral fractures that have been prevented. Only 249 cases of atypical femoral fracture have been reported worldwide.
The patient should also be reassured that research into this phenomenon is continuing. At present, the risk-benefit ratio greatly favors use of these medications in properly selected patients at heightened risk of osteoporotic fracture.
New delayed-release bisphosphonate can be taken with food
Benhamou CL, Zanchetta JR, Kaufman JM, et al. A novel delayed-release risedronate 35 mg once-a-week formulation taken with or without breakfast: 2 year BMD data. Osteoporosis Int. 2011;22:S337-S338.
Oral bisphosphonates are poorly absorbed from the gastrointestinal (GI) tract, with bioavailability of less than 1%. Absorption is further reduced when a bisphosphonate is taken with food, beverages other than plain water, medications, or supplements. Because of this limited absorption, oral bisphosphonates must be taken at least 30 to 60 minutes before the first food, drink, or other medication of the day. Noncompliance leads to reduced bioavailability and, potentially, decreased efficacy.
A new delayed-release formulation of risedronate (Atelvia) was approved by the FDA in late 2010 and made available for prescribing earlier this year. It is designed to improve absorption of risedronate in the presence of food, allowing for administration immediately after breakfast.
Two innovations were utilized in the manufacture of this tablet. First, it has an enteric coating to deliver risedronate beyond the stomach in the small intestine, with active drug released at a pH level above 5.5. Second, it contains a chelating agent—edetate disodium (EDTA)—which binds free divalent cations, such as calcium, magnesium, and iron.
Details of the study
Benhamou and colleagues compared three regimens of risedronate:
- 35 mg weekly of the delayed-release formulation, taken at least 30 minutes before breakfast
- 35 mg weekly of the delayed-release formulation, taken 30 minutes after breakfast
- 5 mg daily of the immediate-release risedronate formulation, taken 30 minutes before breakfast.
This phase 3, randomized, double-blind, active-controlled study involved 43 centers across North America, Europe, and South America. Characteristics of women in the study included: