Original Full Length ArticleThe association of race/ethnicity and risk of atypical femur fracture among older women receiving oral bisphosphonate therapy
Introduction
The occurrence of low energy femoral diaphysis fractures among long-term bisphosphonate (BP) users is now well defined [1] and recognized world-wide [1], [2], [3], [4], [5]. While the precise mechanism by which chronic BP exposure increases the risk of atypical femur fracture (AFF) is not fully understood, a current hypothesis involves changes in cortical bone material properties caused by prolonged suppression of bone remodeling and impairment of micro-crack repair, with development of stress fractures that can progress to completed fracture [6]. Both treatment duration [2], [3], [4] and recent BP exposure [3] appear strongly related to AFF risk. However, the overall rare occurrence of AFF events among the vast numbers of women receiving oral BP drugs each year indicates there may be additional contributing factors.
Some of the larger AFF case series have come from Asian countries, including Singapore [7], Korea [8] and Japan [9]. In several U.S. epidemiologic studies, Asians were overrepresented and contributed 17–50% of identified AFF cases [2], [10], [11], compared to a much lower proportion of Asians among women with proximal femur or non-atypical diaphyseal femur fracture (2–5%) or those receiving BPs without fracture [10], [11]. Recent data from northern California were notable for an increase in diaphyseal femur fracture rates, greatest among Asian women, many of whom received recent BP therapy [12]. These findings suggest there are important racial/ethnic disparities in BP-related AFF, although the extent to which they reflect differences in drug exposure or comorbidity is unknown.
In the present study, we examined the relative risk of AFF for Asian women compared to women of white race following initiation of BP therapy and explored potential factors contributing to this disparity. We hypothesized that Asian women have a substantially higher risk of AFF, independent of age, comorbidity, duration and recency of BP exposure.
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Study population
The source population included female members age ≥ 50 years within Kaiser Permanente Northern California (KPNC), a large, integrated healthcare delivery system serving > 3 million members. Using pharmacy databases, we identified women who initiated oral BP therapy with alendronate, risedronate or ibandronate during 1/1/2002–12/31/2007. Women without health plan membership one year prior and at least 3 years following BP initiation and those receiving intravenous BP prior to or during the study
Results
During 2002–2007, 49,658 KPNC female members age ≥ 50 years old initiated oral BP therapy and had ≥ 3 years of follow-up. Of these, 1268 (2.6%) received intravenous BP and were subsequently excluded. The final study cohort included 48,390 women, mean age 69.5 ± 10.0 years; 65.3% were white, 17.1% Asian and the remaining 17.6% were comprised of Hispanic (9.5%), black (4.1%) or other/unknown (4.0%) race/ethnicity. Women were followed for a median duration of 7.7 years (interquartile range 5.9–9.3 years),
Discussion
Our analyses, conducted within a large multiethnic cohort of women initiating BP therapy, demonstrate that Asians are at substantially higher risk of AFF when compared to women of white race. This association was not substantially modified by putative clinical risk factors and remained after adjusting for differences in BP exposure. Dell and colleagues examined 2007–2011 data from Kaiser Permanente Southern California and identified 142 (137 women) AFF cases, where 49% were Asian [2]. This
Conflict of interest
Joan Lo has received prior research funding from Amgen Inc. and current funding from Sanofi. Rita Hui and Malini Chandra have received prior research funding from Amgen Inc. Bruce Ettinger has previously received payments for serving as an expert witness in litigation involving Fosamax. Christopher Grimsrud, Romain Neugebauer, Joel Gonzalez, Amer Budayr and Gene Lau declare that they have no conflicts of interest to disclose.
Acknowledgment
The authors would like to acknowledge Drs. Patricia Zheng and Maureen Baur for their assistance with data collection. This study was supported by a grant from the Kaiser Permanente Community Benefit Program and in part by a grant from the National Institutes of Health, 1R01AG047230-01 A1. The opinions expressed in this publication are solely the responsibility of the authors and do not represent the official views of Kaiser Permanente or the National Institutes of Health.
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