Abstract
BackgroundBisphosphonate (BP) therapy has been associated with atypical femur fracture (AFF). However, the threshold of treatment duration leading to increased AFF risk is unclear. In a retrospective cohort of older women initiating BP, we compared the AFF risk associated with treatment for at least three years to the risk associated with treatment less than three years.MethodsWe used observational data from a large population of female members of an integrated healthcare system who initiated oral BP during 2002–2014. Women were retrospectively followed for incident AFF confirmed by radiologic adjudication. Demographic data, pharmacologic exposures, comorbidity, bone density, and fracture history were ascertained from electronic health records. Inverse probability weighting was used to estimate risk differences comparing the cumulative incidence (risk) of AFF if women discontinued BP within three years to the cumulative incidence of AFF if women continued BP for three or more years, adjusting for potential time-dependent confounding by the aforementioned factors.ResultsAmong 87,820 women age 45–84 years who initiated BP (mean age 68.6, median T-score − 2.6, 14% with prior major osteoporotic fracture), 16,180 continued BP for three or more years. Forty-six confirmed AFFs occurred during follow-up in the two groups. AFF-free survival was greater for BP treatment < 3 years compared to treatment ≥3 years (p = 0.004 comparing areas under survival curves). At five years, the risk of AFF was 27 per 100,000 (95% confidence interval, CI: 8–46) if women received BP treatment < 3 years and 120 per 100,000 (95% CI: 56–183) if women received BP treatment ≥3 years (risk difference 93 per 100,000, 95% CI: 30–160). By ten years, the risks were 27 (95% CI: 8–46) and 363 (95% CI: 132–593) per 100,000 for BP treatment < 3 and ≥ 3 years, respectively (risk difference 336 per 100,000, 95% CI: 110–570).ConclusionsBisphosphonate treatment for 3 or more years was associated with greater risk of AFF than treatment for less than 3 years. Although AFFs are uncommon among BP-treated women, this increased risk should be considered when counseling women about long-term BP use. Future studies should further characterize the dose-response relationship between BP duration and incident AFF and identify patients at highest risk.
Highlights
Bisphosphonate (BP) therapy has been associated with atypical femur fracture (AFF)
Following early case reports of non-traumatic subtrochanteric and femoral shaft fractures observed in postmenopausal women with prolonged BP exposure [2, 3], the definition of AFF evolved to encompass specific radiographic imaging criteria that include a primarily transverse fracture occurring in the femoral diaphysis, with minimal or no comminution, and the presence of localized periosteal or endosteal thickening of the lateral cortex [1, 4, 5]
We excluded women with any of the following within 2 years before BP initiation: diagnosed metastatic cancer beyond lymph nodes (ICD-9 197.x-199.0), multiple myeloma (ICD-9 203.0x), Paget’s disease of the bone (ICD-9 731.0), osteogenesis imperfecta (ICD9 756.51), hypophosphatasia (ICD-9 275.3), and primary hyperparathyroidism (ICD-9 252.01); receipt of teriparatide or denosumab; advanced kidney disease defined by outpatient estimated glomerular filtration rate < 30 mL/min/1.73 m2 calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation [12] or by prior receipt of chronic dialysis or renal transplantation
Summary
Bisphosphonate (BP) therapy has been associated with atypical femur fracture (AFF). the threshold of treatment duration leading to increased AFF risk is unclear. Atypical femur fractures (AFF) are an uncommon complication of oral bisphosphonate (BP) therapy [1], one of the first line therapies for osteoporosis and fracture prevention These distinctive fractures do not appear to be related to osteoporotic bone fragility and may happen in the absence of a fall or apparent trauma. A post-hoc analysis of three randomized placebo-controlled clinical trials of women exposed to BP therapy for 3–5 and up to 10 years did not observe an association of BP treatment with diaphyseal femur fracture risk [9]; of 14,195 subjects, only 3600 had been exposed to BP longer than 3 years and the radiographs in most cases were not examined [9]. In the absence of randomized trials designed to examine AFF risk, which are not possible due to the size and length of time required to study this adverse outcome, the question remains as to the time-point during BP treatment where AFF risk increases
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