Elsevier

Bone

Volume 85, April 2016, Pages 142-147
Bone

Original Full Length Article
The association of race/ethnicity and risk of atypical femur fracture among older women receiving oral bisphosphonate therapy

https://doi.org/10.1016/j.bone.2016.01.002Get rights and content

Highlights

  • Among a large cohort of women initiating bisphosphonate therapy, the rate of atypical femur fracture was 64.2 per 100,000 person years among Asian women compared to 7.6 per 100,000 person years among white women.

  • Adjusting for differences in age and bisphosphonate exposure, the relative risk of atypical femur fracture was more than 6-fold higher among Asian compared to white women.

  • These findings underscore the need to further examine the association of bisphosphonate duration and atypical femur fracture risk in women of Asian race, as well as differences by Asian subgroup.

Abstract

Purpose

Several epidemiologic studies suggest that compared to white women, Asians have a greater propensity to suffer an atypical femur fracture (AFF) while taking bisphosphonate therapy. This study examines the relative risk of AFF following bisphosphonate initiation for Asian compared to white women.

Methods

Using data from a large integrated northern California healthcare delivery system, we examined diaphyseal femur fracture outcomes among women age  50 years old who initiated oral bisphosphonate therapy during 2002–2007. An AFF was defined by the 2013 American Society of Bone and Mineral Research Task Force criteria. The risk of radiographically-confirmed AFF was examined for Asian compared to white women, adjusting for differences in bisphosphonate exposure and other potential risk factors.

Results

Among 48,390 women (65.3% white, 17.1% Asian) who newly initiated bisphosphonate therapy and were followed for a median of 7.7 years, 68 women experienced an AFF. The rate of AFF was 18.7 per 100,000 person-years overall and eight-fold higher among Asian compared to white women (64.2 versus 7.6 per 100,000 person-years). Asians were also more likely to have longer bisphosphonate treatment duration compared to whites (median 3.8 versus 2.7 years). The age-adjusted relative hazard for AFF was 8.5 (95% confidence interval 4.9–14.9) comparing Asian to white women, and was only modestly reduced to 6.6 (3.7–11.5) after adjusting for bisphosphonate duration and current use.

Conclusions

Our study confirms marked racial disparity in AFF risk that should be further investigated, particularly the mechanisms accounting for this difference. These findings also underscore the need to further examine the association of bisphosphonate duration and AFF in women of Asian race, as well as differential risk across Asian subgroups. In the interim, counseling of Asian women about osteoporosis drug continuation should include consideration of their potentially higher AFF risk.

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.

Section snippets

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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