TNSALP Mutations in Atypical Femoral Fractures with Long-Term Bisphosphonate Use

描述(由申请人提供)：低磷症(HPP)是一种可遗传的代谢性骨骼疾病，由组织非特异性碱性磷酸酶(TNSALP)基因功能丧失突变引起，因此具有血清碱性磷酸酶水平低的特点。HPP的临床表现是骨骼基质矿化受损(导致软骨病或软骨病)，因为作为TNSALP底物的焦磷酸水平过高，抑制了矿化过程。最近，美国骨与矿物研究学会成立了一个特别工作组，调查长期使用双膦酸类药物治疗骨质疏松与非典型股骨粗隆下和骨干骨折(ASFF)的关系。由于这些骨折类似于成人低磷酸盐症中出现的假性骨折，而且双膦酸盐是焦磷酸盐的化学衍生物，他们的建议之一是对这些骨质疏松症患者的TNSALP基因进行测序，看看他们是否携带有可能使他们患上这些不寻常的、使人虚弱的骨折的TNSALP突变或多态。我们现在已经记录了这样一个案例。一位55岁的女性，在口服和静脉注射双磷酸盐治疗了四年后，同时出现了双侧无创伤性ASFF。在对她的TNSALP基因进行测序后，我们发现了一个单一突变(c.212G&gt；A，p.Arg71His)。这种缺陷可以作为单一显性轻度突变遗传，也可以在重度隐性HPP中合并第二个突变遗传。虽然患者血清ALP水平较低(26U/L，NL32~116U/L)，但从未被诊断为HPP。我们假设，要么是隐性TNSALP突变的携带者，要么是由于单个TNSALP突变而导致的轻度显性HPP(确诊或未确诊)，则易导致“骨质疏松症”患者发生ASFF。使用双磷酸盐治疗会进一步加剧骨骼疾病，导致明显的骨折。我们假设，大量使用双膦酸类药物并患有ASFF的“骨质疏松症”患者将携带TNSALP突变。因此，我们将测试正在使用双膦酸盐治疗并经历ASFF的骨质疏松症患者是否比对照组有更高的TNSALP突变或多态频率。如果我们的假设被证实，骨质疏松症患者应该进行血清TNSALP活性筛查，然后进一步检测TNSALP底物水平，可能还有TNSALP突变。有证据表明载体状态或主要HPP的患者不应使用双膦酸类药物治疗。这将减少骨质疏松症患者ASFF的发生率。

DESCRIPTION (provided by applicant): Hypophosphatasia (HPP), a heritable metabolic bone disease, is caused by loss-of-function mutations in the tissue non-specific alkaline phosphatase (TNSALP) gene, and therefore features low serum levels of alkaline phosphatase. HPP manifests clinically due to impaired mineralization of skeletal matrix (causing rickets or osteomalacia) because the excess levels of pyrophosphate, the substrate for TNSALP, inhibits the mineralization process. Recently, a task force was established by the American Society for Bone and Mineral Research to investigate the association of atypical subtrochanteric and diaphyseal femoral fractures (ASFFs) with the long-term use of bisphosphonates for osteoporosis. Because these fractures resemble pseudofractures seen in adult hypophosphatasia, and that bisphosphonates are chemical derivatives of pyrophosphate, one of their recommendations was to sequence the TNSALP gene in these osteoporosis patients to see if they are carriers of TNSALP mutations or polymorphisms that may predispose them to these unusual and debilitating fractures. We have now documented such a case. A 55 year-old woman, after treatment for four years with oral and later intravenous bisphosphonates for presumed osteoporosis, suffered simultaneous atraumatic bilateral ASFFs. After sequencing her TNSALP gene, we identified a single mutation (c.212 G>A, p.Arg71His). This defect can be inherited as a single dominant mild mutation or combined with a second mutation in severe recessive HPP. The patient had never been diagnosed with HPP, although her serum ALP was low (26 U/L, Nl 32 - 116 U/L). We hypothesize that being either a carrier of a recessive TNSALP mutation or having a mild dominant form (diagnosed or undiagnosed) of HPP due to a single TNSALP mutation predisposes "osteoporosis" patients to ASFFs. Treatment with bisphosphonates then further exacerbates skeletal disease leading to overt fracture. We hypothesize that a significant number of "osteoporosis" patients using bisphosphonates and having ASFFs will carry TNSALP mutations. Therefore, we will test whether osteoporosis patients who are using bisphosphonate therapy and experience ASFFs have a higher frequency of TNSALP mutations or polymorphisms than control groups. If our hypothesis is validated, osteoporosis patients should be screened for serum TNSALP activity, and then further tested for TNSALP substrate levels and perhaps TNSALP mutations. Those with evidence of carrier status or dominant HPP should not be treated with bisphosphonates. This will reduce the incidence of ASFFs in osteoporosis patients.