Research ArticleBone

ATRAID regulates the action of nitrogen-containing bisphosphonates on bone

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Science Translational Medicine  20 May 2020:
Vol. 12, Issue 544, eaav9166
DOI: 10.1126/scitranslmed.aav9166

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Screening for side effect susceptibility

Osteoporosis is typically treated with nitrogen-containing bisphosphonates (N-BPs), which inhibit bone resorption; however, N-BPs can cause serious side effects including osteonecrosis of the jaw and fracture. To understand susceptibility to these side effects, Surface et al. investigated the role of the gene ATRAID in mediating responses to N-BPs. Atraid-deficient mice had weaker bones and did not respond to N-BP treatment in models of osteoporosis, and patients with coding variants in ATRAID taking N-BPs presented with atypical fractures and osteonecrosis of the jaw. The authors determined that ATRAID is necessary for inhibition of osteoclast function by N-BPs. Results suggest that it may be prudent to screen patients for variants in ATRAID to avoid N-BP side effects.

Abstract

Nitrogen-containing bisphosphonates (N-BPs), such as alendronate, are the most widely prescribed medications for diseases involving bone, with nearly 200 million prescriptions written annually. Recently, widespread use of N-BPs has been challenged due to the risk of rare but traumatic side effects such as atypical femoral fracture (AFF) and osteonecrosis of the jaw (ONJ). N-BPs bind to and inhibit farnesyl diphosphate synthase, resulting in defects in protein prenylation. Yet, it remains poorly understood what other cellular factors might allow N-BPs to exert their pharmacological effects. Here, we performed genome-wide studies in cells and patients to identify the poorly characterized gene, ATRAID. Loss of ATRAID function results in selective resistance to N-BP–mediated loss of cell viability and the prevention of alendronate-mediated inhibition of prenylation. ATRAID is required for alendronate inhibition of osteoclast function, and ATRAID-deficient mice have impaired therapeutic responses to alendronate in both postmenopausal and senile (old age) osteoporosis models. Last, we performed exome sequencing on patients taking N-BPs that suffered ONJ or an AFF. ATRAID is one of three genes that contain rare nonsynonymous coding variants in patients with ONJ or an AFF that is also differentially expressed in poor outcome groups of patients treated with N-BPs. We functionally validated this patient variation in ATRAID as conferring cellular hypersensitivity to N-BPs. Our work adds key insight into the mechanistic action of N-BPs and the processes that might underlie differential responsiveness to N-BPs in people.

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