Atypical femoral fracture in patients with bone metastasis receiving denosumab therapy: a retrospective study and systematic review

Momoko Takahashi,Kentaro Sakamaki,Noriyuki Baba,Rika Kizawa,Hidetaka Kawabata,Yukinori Ozaki,Jun Masuda,Takashi Shigekawa,Yuji Miura,Taro Umezu,Haruo Iguchi,Keiichi Kinowaki,Toshimi Takano,Nobuko Tamura,Chihiro Kondoh,Yuko Tanabe

doi:10.1186/s12885-019-6236-6

Abstract

BackgroundWhile denosumab has been shown to prevent skeletal-related events in patients with bone metastasis, there is a concern that it may cause atypical femoral fracture (AFF). While AFF has been reported in patients with osteoporosis receiving denosumab, data are scarce in the context of AFF occurring in patients with bone metastasis receiving monthly denosumab therapy.MethodsTo analyze the incidence of AFF in patients with bone metastasis, we reviewed the medical records of patients who had received monthly denosumab (120 mg) treatment from May 2012 to June 2017 at any of the three participant institutions.ResultsThe study population consisted of 277 patients who had received a median of 10 doses (range, 1–79) of denosumab. Five patients were diagnosed as having AFF or symptomatic atypical femoral stress reaction (AFSR) needing surgical intervention, representing an incidence rate of 1.8% (95% confidence interval, 0.77–4.2). These patients had received 15, 45, 45, 46 or 47 doses of denosumab, respectively. Four of the patients had received prior zoledronic acid treatment. The results of our analysis suggested that long-term use of denosumab, especially for more than 3.5 years, and prior use of zoledronic acid were risk factors for the development of AFF.ConclusionsWe found the AFF events in 5 patients (1.8%) among 277 cancer patients who had received monthly denosumab (120 mg) treatment. Long-term denosumab treatment and prior zoledronic acid treatment were identified as risk factors for the development of AFF.

Highlights

While denosumab has been shown to prevent skeletal-related events in patients with bone metastasis, there is a concern that it may cause atypical femoral fracture (AFF)
Treatment with bisphosphonates (BP) and denosumab is known to reduce the frequency of skeletal-related events (SREs), such as pathologic bone fracture, spinal cord compression, need for external beam radiation or surgery to the bone, and hypercalcemia associated with cancer with bone metastasis [1,2,3,4]
The patients had received a median of 10 doses of denosumab, and 16 (5%) patients had received more than 45 doses

Summary

Introduction

While denosumab has been shown to prevent skeletal-related events in patients with bone metastasis, there is a concern that it may cause atypical femoral fracture (AFF). Treatment with bisphosphonates (BP) and denosumab is known to reduce the frequency of skeletal-related events (SREs), such as pathologic bone fracture, spinal cord compression, need for external beam radiation or surgery to the bone, and hypercalcemia associated with cancer with bone metastasis [1,2,3,4]. Localized periosteal or endosteal thickening of the lateral cortex at the fracture site, which is called “beaking” or “flaring”, is another major feature (Table 1). The pathogenesis of AFF is not fully understood, the cause of AFF is considered to be stress or insufficient fractures that accumulate due to the suppression of bone remodeling by BP or denosumab treatment. Continuous loading of femur may develop microcracks within the bone cortex and BP or denosumab inhibit the normal osteoclastic resorption of them, which may eventually lead a fracture [15]

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