Update on Bone Anabolics in Osteoporosis Treatment: Rationale, Current Status, and Perspectives
Update on Bone Anabolics in Osteoporosis Treatment: Rationale, Current Status, and Perspectives
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DOI：
10.1210/jc.2011-2332
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发表时间：
2012-02-01
影响因子：
5.8
通讯作者：
Hesse, Eric
中科院分区：
文献类型：
--
作者：
Baron, Roland;Hesse, Eric
骨质疏松症定义为继发于轻微创伤或无创伤的骨骼骨折相关的低骨矿物质密度，最常累及脊柱、髋关节和前臂。骨矿物质密度的降低是不平衡的骨重建过程的结果，骨吸收高于骨形成。骨质疏松症主要影响绝经后妇女，但也影响老年男性。这一慢性疾病给现代社会带来了相当大的医疗和社会经济负担。迄今为止，用于治疗骨质疏松症的治疗选择主要包括抗再吸收药物，特别是双膦酸盐和最近的地舒单抗，但也包括降钙素，对于女性，还包括雌激素或选择性雌激素受体调节剂。然而，这些药物具有局限性，特别是它们导致低转换状态的事实，其中骨形成随着骨重塑活性的降低而降低。在这篇综述中，我们讨论了替代类骨质疏松症药物，即骨合成代谢药物，它们的生物学，以及它们为我们的治疗设备提供的前景。我们专注于两个主要的骨合成代谢途径确定为今天：PTH，目前市场上唯一的合成代谢药物;和通过抑制内源性抑制剂sclerostin和dickkopf 1的经典Wnt信号的激活。每种方法都基于不同的分子机制，但最近的证据表明，这两种途径实际上可能会趋同，至少部分趋同。而重组人PTH治疗正在重新审视不同的配方，并试图通过钙敏感受体调节内源性PTH分泌，抗体sclerostin和dickkopf 1目前在临床试验中，可能被证明是更有效地增加骨量，可能独立于骨转换。这些合成代谢方法都有其自身的局限性和安全性问题，但骨质疏松症的有效合成代谢治疗的前景确实光明。（J Clin Endocrinol Metab 97：311-325，2012）
Osteoporosis is defined as low bone mineral density associated with skeletal fractures secondary to minimal or no trauma, most often involving the spine, the hip, and the forearm. The decrease in bone mineral density is the consequence of an unbalanced bone remodeling process, with higher bone resorption than bone formation. Osteoporosis affects predominantly postmenopausal women, but also older men. This chronic disease represents a considerable medical and socioeconomic burden for modern societies. The therapeutic options for the treatment of osteoporosis have so far comprised mostly antiresorptive drugs, in particular bisphosphonates and more recently denosumab, but also calcitonin and, for women, estrogens or selective estrogen receptor modulators. These drugs have limitations, however, in particular the fact that they lead to a low turnover state where bone formation decreases with the decrease in bone-remodeling activity. In this review, we discuss the alternative class of osteoporosis drugs, i.e. bone anabolics, their biology, and the perspectives they offer for our therapeutic armamentarium. We focus on the two main osteoanabolic pathways identified as of today: PTH, the only anabolic drug currently on the market; and activation of canonical Wnt signaling through inhibition of the endogenous inhibitors sclerostin and dickkopf1. Each approach is based on a different molecular mechanism, but most recent evidence suggests that these two pathways may actually converge, at least in part. Whereas recombinant human PTH treatment is being revisited with different formulations and attempts to regulate endogenous PTH secretion via the calcium-sensing receptor, antibodies to sclerostin and dickkopf1 are currently in clinical trials and may prove to be even more efficient at increasing bone mass, possibly independent of bone turnover. Each of these anabolic approaches has its own limitations and safety issues, but the prospects of effective anabolic therapy for osteoporosis are indeed bright. (J Clin Endocrinol Metab 97: 311-325, 2012)