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.

中文翻译：

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ATRAID 调节含氮双膦酸盐对骨骼的作用。

含氮双膦酸盐 (N-BP)，如阿仑膦酸盐，是治疗骨病最广泛使用的药物，每年开出近 2 亿张处方。最近，由于非典型股骨骨折 (AFF) 和颌骨坏死 (ONJ) 等罕见但创伤性副作用的风险，N-BP 的广泛使用受到了挑战。N-BP 结合并抑制法尼基二磷酸合酶，导致蛋白质异戊二烯化缺陷。然而，对于哪些其他细胞因素可能允许 N-BP 发挥其药理作用，人们仍然知之甚少。在这里，我们对细胞和患者进行了全基因组研究，以确定特征不明确的基因，ATRAID ATRAID 功能的丧失导致对 N-BP 介导的细胞活力丧失的选择性抗性和阿仑膦酸盐介导的异戊二烯化抑制的预防。ATRAID 是阿仑膦酸盐抑制破骨细胞功能所必需的，并且 ATRAID 缺陷小鼠在绝经后和老年（老年）骨质疏松症模型中对阿仑膦酸盐的治疗反应受损。最后，我们对服用 N-BPs 的患有 ONJ 或 AFF 的患者进行了外显子组测序。ATRAID 是三种基因之一，在 ONJ 或 AFF 患者中含有罕见的非同义编码变异，在接受 N-BPs 治疗的不良结果组中也有差异表达。我们在功能上验证了 ATRAID 中的这种患者变异，因为它赋予细胞对 N-BPs 的超敏反应。