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1 誗新药房誗 特立帕肽 ( 重组人甲状旁腺素 1 鄄 34) 在骨质疏松治疗中的应用 骆天红摇 Julie Michelle Blair 摇 Sebastian Sorsaburu 摇摇揖提要铱摇特立帕肽是一种注射用人重组甲状旁腺素, 已在全球范围内被批准用于治疗骨质疏松症, 在 2011 年进入中国 临床前研究显示, 通过不同于包括双膦酸盐 选择性雌激素受体调节剂 ( selective estrogen receptor modulators,serms) 降钙素和雌激素在内的其他抗骨吸收药物的独特作用机制, 特立帕肽可起到促进骨形成的作用 在男性和绝经后妇女中进行的临床试验已证实特立帕肽有成骨作用, 并可降低骨折风险, 升高骨转换标志物 ( 包括血清骨钙素和 I 型前胶原 N 末端肽 [ procollagen type I N 鄄 terminal propeptide,pinp] 骨密度[bone mineral density,bmd]) 及改善骨质量 最近, 在亚裔人群中进行的临床试验也已得出相似结论, 并证实与目前的抗骨吸收药物相比, 特立帕肽可提高骨标志物和骨密度 揖关键词铱摇骨标志物 ; 骨密度 ; 骨质量 ; 骨折 ; 骨质疏松 ; 特立帕肽 Teriparatide (recombinant human parathyroid hormone 1 鄄 34) for the treatment of osteoporosis: a review 摇 LUO Tian 鄄 hong, Julie Michelle Blair, Sebastian Sorsaburu. * Medical Department, Lilly Suzhou Pharmaceutical Co. Ltd. Shanghai Branch, Shanghai , China 揖 Summary 铱摇 Teriparatide is an injectable recombinant human parathyroid hormone(1 鄄 34) [rhpth(1 鄄 34)], which has been approved for the treatment of osteoporosis worldwide, including China since In pre 鄄 clinical studies, teriparatide was shown to exhibit anabolic effects on bone with a unique mechanism of action that is distinct from that of antiresorptive agents, including bisphosphonates, selective estrogen receptor modulators ( SERMs), calcitonin, and estrogen. This bone 鄄 building effect has been supported by clinical trials in men and postmenopausal women, with reductions in fracture risk, and increases in bone turnover markers, including serum osteocalcin and procollagen type I N 鄄 terminal propeptide ( PINP), and bone mineral density ( BMD), and improvements in bone quality. Recent studies in Asian patient populations show similar results and support the findings for bone markers and BMD when compared with current antiresorptive medications. 揖 Key words 铱摇 Bone markers; Bone mineral density; Bone quality; Fracture; Osteoporosis; Teriparatide 摇摇近年来, 在亚洲, 骨质疏松对公共健康的挑战正与 日俱增 : 预计到 2050 年, 髋骨骨折的人数将上升到 [1], 其中仅因髋部骨折即可造成 20% 患者死 亡和 50% 患者丧失功能 [2], 所以目前迫切需要能够减 少骨折风险的有效治疗手段 虽然目前有多种治疗手段 [ 如 denosumab 选择性 雌激素受体调节剂 ( SERMs) 激素替代治疗 降钙素 和雷奈酸锶 ], 但是双膦酸盐是最常见的治疗骨质疏 松的药物 这一类抑制骨吸收药物通过抑制破骨细胞 对骨的重吸收, 从而起到预防骨质流失和延缓骨质破 坏进程的作用, 最终改善骨密度和降低骨折风险 虽 然有研究表明, 抗骨吸收药物可有效延缓骨密度流失 和稳定骨量, 并减少骨折风险, 但是中止该治疗将重新 DOI: / cma. j. issn 鄄 作者单位 : 礼来苏州制药有限公司上海分公司 ( 骆天红 ); 澳大利亚悉尼, 礼来澳大利亚控股有限公司, 安进澳大利亚有限公司 (Julie Michelle Blair); 美国印第安纳波利斯, 美国礼来公司 ( Sebastian Sorsaburu) 激活骨吸收 而且, 长期使用双膦酸盐会导致因长期抑制骨代谢所致的微损伤积聚和骨强度下降所致的不 [3 鄄良反应, 如下颚骨坏死 非典型股骨骨折等 5] 此外, 此类药物无法重建流失的骨质 [6] 因此, 我们需要一种能够重建骨质, 而不是仅能够延缓或中止骨质流失的药物 一 全长型甲状旁腺素及其 N 末端片段的合成代谢作用全长型甲状旁腺素 (full 鄄 length parathyroid hormone, PTH)(1 鄄 84) 和他的活性片段 PTH(1 鄄 34) 可通过与在成骨细胞表面表达的 G 蛋白偶联 PTH 鄄 1 受体相互作用, 从而激活 camp 依赖的蛋白激酶 A 及钙依赖的蛋白激酶 C 信号通路并调节成骨细胞功能 PTH 还可激活 MAK 激酶及磷脂酶 A 及 D 信号通路 另外还有多种机制调控 PTH 信号传导, 如调控 PTH 受体内吞, 与输入蛋白 (importin) 的结合, 核转位等 [7] 在啮齿类动物中进行的临床前研究表明,PTH 的疗效呈剂量依赖和给药方式依赖 ( 即间歇给药对持续给药 ): 高剂量 增录 12b 鄄 1

2 PTH 持续给药可导致分解代谢, 低剂量间歇给药可导 致单纯的合成代谢 [8] PTH 的骨合成代谢作用可通 过抑制成骨细胞凋亡 [9] 激活骨衬细胞和增强成骨细 [10] 胞分化来介导 这一作用最终可使成骨细胞活性 和数量的增加, 从而激活骨转换代谢, 增加骨小梁和骨 膜表面的骨质沉积 [11] 持续 PTH 给药可导致分解代 谢的激活 (PTH 常见的生理作用 ) 然而, 间歇低剂量 给药可导致单纯的合成代谢, 这一成骨效应先于破骨 细胞的激活 所谓的 合成代谢窗冶 (anabolic window) 是指骨形成作用大于骨吸收作用 [7,12], 从而为治疗骨 质疏松提供了机会 PTH (1 鄄 84) 治疗绝经后骨质疏 松妇女的临床试验表明, 间歇给药可提高骨密度, 并减 少骨折发生的风险 [13 鄄 15] 在相似人群中进行的研究 表明,PTH(1 鄄 34) 活性片段间歇给药亦可迅速促进骨 形成 [16], 并提高骨密度 [17,18], 降低骨折风险 [19] PTH (1 鄄 34) 间歇给药治疗男性骨质疏松也可提高骨密度 以上结果均提示,PTH 间歇给药的骨合成代谢作用与 患者性别及 PTH 片段长短无关 特立帕肽 ( 重组 DNA 来源的甲状旁腺素 ) [rhpth (1 鄄 34)] 是首个促进骨合成代谢类药物, 在全球 64 个 国家被批准用于治疗男性和绝经后妇女的骨质疏松 2011 年 3 月 16 日, 特立帕肽在中国被批准用于存在 高度骨折风险的绝经后骨质疏松妇女的治疗 本文综 述了特立帕肽治疗男性和绝经后骨质疏松妇女的临床 研究数据 二 绝经后妇女的骨质疏松 1. 骨折风险 : 研究表明,PTH 可预防 阻断及部分 逆转动物及人体的骨丢失, 动物研究还显示 PTH 可同 时增加骨量和骨强度, 提示在人体中也可能有预防骨 折的作用 [20,21] 在一项安慰剂对照 双盲 多中心的 骨折预防试验 ( Fracture Prevention Trial, FPT) 中, 共 名已发生过骨折且未接受抗骨吸收药物治疗的 绝经后妇女随机分组, 分别接受安慰剂 特立帕肽 20 滋 g / d 或特立帕肽 40 滋 g / d 的治疗 ( 平均年龄 69 ~ 71 岁, 平均绝经年限 21 ~ 24 年 ) 结果显示, 与安慰剂相 比, 特立帕肽 20 滋 g / d 和特立帕肽 40 滋 g / d 可分别降低 65% 和 69% 的椎体骨折风险 [22], 以及降低 53% 和 54% 的新发非椎体骨折的风险, 并分别增加 9% 和 13% 的腰椎骨密度以及 3% 和 6% 的股骨颈骨密度 当用脊柱畸形指数进行评估时, 接受特立帕肽治疗的 患者新发骨折的数量和严重度下降, 且可减少与基线 骨折数量及严重度相关的新发骨折风险 [23] FPT 的 亚组分析显示, 安慰剂组患者的新发骨折风险随既往 骨折次数和严重程度的增加而升高, 但是特立帕肽组 患者则未发现此相关性 [24] 而且, 特立帕肽组中相对 骨折风险的降低与年龄大小 [25] 骨密度基线值 已有 椎体骨折 [26] [27] [28] 治疗前骨转换率或肾功能状态无 关 此外, 在 FPT 中, 停止特立帕肽治疗后, 椎体骨折 风险的下降可持续至少 18 个月 [29], 非椎体骨折风险 的下降可持续至少 30 个月 [30] 在另一项随机双盲试 验 ( 共 146 名绝经后妇女, 平均年龄 65 ~ 66 岁 ) 中, 与 阿仑膦酸钠相比, 特立帕肽可增加腰椎的骨密度 (12. 2% 对 5. 6%, P<0. 001), 并降低非椎体骨折风险 (4. 1% 对 13. 7%, P = ) [31] 2. 骨密度和骨代谢标志物 : 一项包含 FPT 和两项 与阿仑膦酸钠进行的头对头比较临床试验的 meta 分 析显示, 超过 90% 接受特立帕肽治疗的绝经后妇女, 其骨密度较基线时增加幅度至少达到 3% [32] 在亚裔人群 ( 包括中国 日本和其他亚洲国家 ) 中 进行的临床试验得出了类似的结果, 接受特立帕肽治 疗的绝经后骨质疏松妇女的骨密度显著增加 这 5 项 临床试验 (1 项为安慰剂对照 [33],4 项为降钙素对 照 [34 鄄 37], 试验人数为 63 ~ 327 人, 疗程均为 6 个月, 平 均年龄 66 ~ 72, 平均绝经年限 18 ~ 22 年 ), 由于这些 试验疗程过短, 因此无法进行骨折风险的评估 但是, 与安慰剂或降钙素相比, 在 6 个月的治疗期内, 特立帕 肽组患者的腰椎骨密度提高, 骨形成标志物水平迅速 升高 与此结果类似, 最近一项历时 2 年的在日本完 成的研究 ( 共 207 名绝经后妇女, 中位年龄 70 岁 ) 同 样得到骨密度和骨转换标志物水平升高的结果 [38] 接受特立帕肽治疗后, 可使患者早期骨形成标志物升 高, 这与随后骨密度或骨折风险的变化程度相关 [39] 接受治疗后的第 1 个月和第 3 个月, 骨形成标志物玉 型前胶原蛋白 C 末端肽 ( procollagen type I C 鄄 terminal peptide, PICP ) 与玉型前胶原蛋白 N 末端肽 (procollagen type I N 鄄 terminal peptide, PINP) 水平升高 均可作为 18 个月时腰椎骨密度增加的预测因子 (0. 65 和 0. 61; P<0. 05) [40] 早期骨形成标志物的升高还 与骨微结构的改善相关 [41] 最近的一项桥接试验报 告比较了三项疗程为 12 个月的日本人群中的研究与 FPT 研究, 结果显示, 接受特立帕肽治疗的患者骨密度 和骨代谢标志物的改善与 FPT 患者人群相似, 另外, 降低骨折风险也相近 [42] 特立帕肽与双膦酸盐的头对头对比研究提示, 这 两种药物可通过不同的作用机制来增加骨密度 [43,44] 由此促进了两类不同药物序贯疗法的探索性研究 但 这些研究结果不完全一致 在一项研究中, 接受阿仑 膦酸钠治疗后再给予特立帕肽会降低患者骨密度的增 幅 [45] 通过对骨密度的增幅与骨代谢标志物水平的 评估, 发现阿伦膦酸钠较利塞膦酸钠更明显抑制特立 增录 12b 鄄 2

3 帕肽的疗效, 可见双膦酸盐的这一效应与其种类有关 [46] 然而另一项研究结果则显示, 特立帕肽对骨密度和骨形成标志物的升高作用在不同双膦酸盐类药物之间并无差异 [47] 相反, 关于特立帕肽治疗结束后是否需要再用其他抗骨质疏松治疗, 目前较为一致地认为在给予特立帕肽后再给予二膦酸盐或其他抗吸收药 [48 鄄物可维持先前特立帕肽的疗效 50] 3. 骨质量 : 虽然骨密度可作为特立帕肽治疗后椎骨骨折风险下降的预测因子, 但研究显示接近 70% 的骨折风险下降是骨强度增加的结果 [51] 对 FPT 亚组患者进行髂骨活检的骨组织形态学检测和微型 CT 扫描的随访分析后发现, 特立帕肽治疗组患者的骨微结构 ( 包括骨小梁 骨皮质厚度和骨小梁连接性 ) 明显改善 [52] 对部分患者进行活检分析结果发现, 特立帕肽治疗可使骨基质的矿化 骨矿物质的结晶和胶原交联比例明显降低 [53], 增强骨骼稳定性和骨皮质厚度, 并且增加股骨颈和股骨粗隆区域骨轴向和抗弯曲的强度 [54] 特立帕肽治疗可增加骨构建和骨重建骨单位的成骨活性 [55], 增强远端桡骨干的机械强度 [56] 对髂骨间嵴活检的 DXA(dual X 鄄 ray absorptiometry) 测定显示, 接受特立帕肽或阿仑膦酸钠治疗可增加骨密度 ; 而且, 与阿仑膦酸钠相比, 特立帕肽可提高患者的骨形成组织形态学指数 [43], 并增加椎体的强度 [57] 4. 背痛 : 椎体骨折相关的背痛可影响骨质疏松患者的生活质量 特立帕肽疗程与非椎体骨折和背痛发生率的改善相关 ( 与安慰剂相比, 特立帕肽 20 滋 g / d 分别减少 7. 3% 和 8. 3% ) [58] 最近一项 meta 分析显示, 与阿仑膦酸钠 激素替代治疗或安慰剂治疗相比, 特立帕肽可降低新发背痛或背痛加重的发生率 [59] 另一项 meta 分析显示, 特立帕肽组患者的背痛缓解可持续 30 个月 [60] 观察性研究 [ 包括欧洲复泰奥观察性研究 (EFOS) 在内 ] 结果显示, 在接受特立帕肽治疗期间和治疗中止后的 18 个月内, 患者背痛和骨折风险明显下降 [61] 总之, 这些研究证实, 就临床疗效和生活质量而言, 特立帕肽是治疗绝经后妇女骨质疏松的有效药物, 其疗效与患者年龄和疾病严重程度无关 除了骨密度之外, 这部分患者的疗效还可通过骨标志物水平来进行监测 三 男性骨质疏松 PTH(1 鄄 34) 不仅可用于治疗绝经后的骨质疏松妇女, 还可用于男性骨质疏松的治疗 与安慰剂相比, PTH(1 鄄 34) 400 IU / d 治疗男性特发性骨质疏松, 在 18 个月时可使患者腰椎骨密度增加 13. 5%, 且血清骨特异性碱性磷酸酶和骨钙素可持续升高约 6 个月 [62] 在部分男性患者中,PTH(1 鄄 34) 的作用至少有一部分是通过其增强患者的骨微结构和增加骨小梁体积的效应来介导的 [63] 在 PTH(1 鄄 34) 治疗中止后, 与不接受任何治疗的患者相比, 使用双膦酸盐患者的骨密度仍可持续升高 [64] ; 但是, 另外一项研究表明, 与女性患者相比, 男性患者在特立帕肽治疗结束后并非一定需要用抗骨吸收药物维持 [65] 另一项临床试验对比了 40 滋 g / d PTH(1 鄄 34) 与 10 mg / d 阿仑膦酸钠或两者联合治疗男性骨质疏松的疗效, 结果显示 PTH(1 鄄 34) 单药治疗组患者的血清碱性磷酸酶与腰椎和股骨颈骨密度的升高明显高于其他两组的患者 [66] 与之相似, 与阿仑膦酸钠单药治疗组和联合治疗组患者相比, PTH (1 鄄 34) 单药治疗组患者骨代谢标志物水平明显较高 [67] 总之, 这些结果均证实阿仑膦酸钠可抑制 PTH (1 鄄 34) 的合成代谢作用 一项在男性骨质疏松患者中进行的大型随机试验显示, 与安慰剂相比, 特立帕肽 20 滋 g / d 或 40 滋 g / d 可提高患者腰椎和股骨颈的骨密度 [68] 随后的安全性分析显示, 在治疗中止后的 30 个月内, 特立帕肽 20 滋 g / d 组或 40 滋 g / d 组患者椎体骨折的发生率明显较低 ( 分别为 5. 4% 和 6. 0%, 安慰剂组 11. 7% ); 与安慰剂组相比, 虽然未显示统计学差异 (P = 0. 07), 但两组特立帕肽患者的新发椎体骨折的风险可下降约 51% [69] 总之, 这些结果均提示, 与绝经后骨质疏松女性类似, 特立帕肽同样可用于治疗男性骨质疏松 四 糖皮质激素所致骨质疏松 ( glucocorticoid 鄄 induced osteoporosis, GIO) 长期使用糖皮质激素可导致严重的骨质疏松症, 患者在开始治疗的 3 ~ 6 个月内出现迅速的骨丢失, 开始治疗的 6 个月内骨折风险明显增加 [70] 糖皮质激素通过干扰成骨细胞的生成, 诱导成骨细胞凋亡从而发挥其抑制骨形成的作用 [71,72] 这一抗成骨细胞活性的作用可增加骨折的发生率, 而且该发生率与糖皮质激素剂量呈正相关 [73] 美国风湿病学会推荐双膦酸盐做为 GIO 的首选治疗 [74] 但是, 双膦酸盐类药物并非针对 GIO 抑制骨合成代谢的病理机制, 而特立帕肽通过促进骨形成的作用机制能更有效地针对 GIO 的病理机制 有关 PTH(1 鄄 34) 治疗 GIO 的研究最初是在接受糖皮质激素和雌激素替代治疗的 GIO 绝经后妇女中进行的 与安慰剂组相比, 接受 12 个月的治疗后, PTH 组患者腰椎骨密度明显增高 (11% 对 0%, P < ) [75], 且这一差异可在中止治疗后维持 12 个月 [76] 腰椎骨密度的增高至少部分是由椎体横截面面积增加所致 [77] 一项大型头对头 双盲临床试验 增录 12b 鄄 3

4 中, 研究者对比了特立帕肽 20 滋 g / d 与阿仑膦酸钠 10 mg / d 治疗男性和绝经后妇女的 GIO 的疗效 此项研究中患者腰椎骨密度获得了明显改善, 在治疗的第 6 个月时, 特立帕肽组患者增高了 7. 2%, 阿仑膦酸钠组增高了 3. 4% (P<0. 001) [78] 虽然两组患者的非椎体骨折发生率相似 (5. 6% 对 3. 7%, P = 0. 36), 但特立帕肽组患者椎体骨折的发生率 (0. 6% ) 较阿仑膦酸钠组 (6. 1% ) 更低 (P = ) 且上述疗效与患者的绝经状态或性别无关 [79] 持续治疗至 36 个月时, 与阿仑膦酸钠组相比, 特立帕肽组患者腰椎 ( 11. 0% 对 5. 3% ) 全髋 (5. 2% 对 2. 7% ) 和股骨颈 (6. 3% 对 3. 4% ) 的骨密度增高更明显, 椎体骨折的发生率更低 (1. 7% 对 7. 7% ) [80] 在这一研究结束时, 特立帕肽组与阿仑膦酸钠组相比有更多患者发生血钙升高 [78,80] 亚组分析显示, 特立帕肽组患者血清骨形成标志物 ( 骨钙素和 PINP) 分别升高了 92% 和 108%, 阿仑膦酸钠组患者分别降低 40% 和 53% [81] 事后分析显示, 与基线值相比, 治疗 1 个月和 6 个月时特立帕肽组患者骨标志物的变化幅度与治疗 18 个月时骨密度改善相关 [82] 在另一项针对此 36 个月研究的回顾性分析中, 当患者按照糖皮质激素剂量进行分层后, 低剂量糖皮质激素患者腰椎骨密度的增高更为明显 [83] 总之, 与双膦酸盐相比, 在骨形成 骨密度增高程度和椎体骨折风险下降方面, 接受特立帕肽治疗患者的疗效更为显著 结合特立帕肽治疗的安全性数据, 特立帕肽是安全 有效的 GIO 治疗药物 五 安全性特立帕肽并不适用于骨 Paget 病 不明原因碱性磷酸酶升高 甲状旁腺亢进 高钙血症 骨营养不良性肾病 骨放疗史 骨骺开放 ( 儿童和青年 ) 原发骨肿瘤和肿瘤骨转移的患者 当有肾结石和 ( 或 ) 痛风史的患者接受特立帕肽治疗时, 建议密切随访 [49,84] 在临床试验中, 接受特立帕肽治疗后的不良反应发生率较低 与安慰剂相比, 在接受特立帕肽治疗的初期, 患者轻度腿部抽筋和一过性眩晕的发生率略高 [22] 与安慰剂组患者相比, 接受特立帕肽治疗患者可有血钙和尿酸升高 [22,85] 但与 PTH(1 鄄 84) 治疗相比, 上述不良反应较后者轻 [13], 这可能是由于特立帕肽可被快速吸收和清除, 仅有 4 h 药物暴露时间 [86] 其他不良反应包括恶心 头痛 轻度的过敏反应和给药部位反应 由于 45% 接受高剂量特立帕肽的大鼠发生了骨肉瘤, 因此一项特立帕肽治疗绝经后骨质疏松女性的关键研究被提前中止了 [87] 在特立帕肽产品说明书中, 加黑框警示了发生骨肉瘤的风险, 而且相关厂家推 出了一项 10 年的上市后产品监察项目 自从 2002 年 特立帕肽上市以来, 在全球接近 名接受特立 帕肽治疗的患者中, 仅报道了两例患者发生骨肉 瘤 [88,89] 虽然并不能排除这两位患者的骨肉瘤与接 受特立帕肽治疗相关, 但是在超过六十岁的男性和女 性中, 每年骨肉瘤的发病率为 1 / [88] 由于接 受特立帕肽治疗患者骨肉瘤发病率与总体人群相似, 目前特立帕肽治疗与骨肉瘤的相关性并无定论 六 未来治疗方向 骨折愈合 目前一些最新的研究开始探索特立帕肽促进骨折 愈合的疗效 在啮齿类动物 兔子和灵长类动物中进 行的临床前研究显示, 特立帕肽可刺激软痂 硬痂和新 骨的生成, 增加骨痂面积和改善力学特性, 最终加速骨 折愈合 [90 鄄 92] 在人类中的数据尚十分有限, 部分研究 报道特立帕肽可促进股骨颈骨折的愈合, 如一项在意 大利的临床研究显示 24 名用髓内钉作内固定治疗的 股骨颈骨折的女性患者 [ 年龄 (62 ~ 94 岁 )], 根据有 无椎体压缩性骨折 ( vertebral compression fracture, VCF) 分成两组, 其中 14 例有 VCF 的患者给予每天 PTH 20 滋 g 皮下注射, 这些患者下地行走时间显著早 于对照组, 同时伴有显著的疼痛减轻和生活质量改 善 [93], 其他研究还显示特立帕肽可促进骨皮质的愈 [94] 合和非愈合性骨折的愈合 [95] 特立帕肽独特的促进骨合成代谢作用使其有别于 抑制骨吸收药物的作用机制 通过刺激成骨细胞的活 性, 延长其存活时间, 特立帕肽在减少骨质疏松患者骨 折风险 增加其骨密度和骨代谢标志物水平以及改善 骨质量方面疗效显著 最近, 中华医学会骨质疏松和骨矿盐疾病分会发 布的指南 (2011) 推荐特立帕肽作为具有成骨作用的 抗骨质疏松药物 [96] 美国食品药品监管局推荐, 存在 高骨折风险的男性和绝经后妇女骨质疏松以及 GIO 患者 ( 高骨折风险定义为既往发生过骨质疏松性骨折 或抑制骨吸收治疗无效或不能耐受的患者 ) 一生中接 受特立帕肽治疗不可超过 24 个月 必需注意, 在中止 治疗后, 特立帕肽所致的部分骨密度改善可能会丢 失 [30] ; 但是, 通过接受后续的抑制骨吸收治疗, 这种骨 密度改善可持续得到巩固 [48 鄄 50] 总之, 特立帕肽的疗效以及安全性 治疗依从性和 持续性以及已有的生活质量改善的数据显示, 特立帕 肽可作为伴有骨质疏松性骨折风险的亚洲严重骨质疏 松患者的有效治疗选择 参摇考摇文摇献 [1] Mithal A, Dhingra V, Lau E. The Asian audit. Epidemiology, costs and burden of osteoporosis in Asia International Osteoporosis 增录 12b 鄄 4

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