Whitfield James F, Morley Paul, Willick Gordon E
Institute for Biological Sciences, National Research Council of Canada, Ottawa, Ontario, Canada.
Treat Endocrinol. 2002;1(3):175-90. doi: 10.2165/00024677-200201030-00005.
The susceptibility to traumatic fracturing of osteopenic bones, and the spontaneous fracturing of osteoporotic bones by normal body movements caused by the microstructural deterioration and loss of bone, are currently treated with antiresorptive drugs, such as the bisphosphonates, calcitonin, estrogens, and selective estrogen receptor modulators. These antiresorptive agents target osteoclasts and, as their name indicates, reduce or stop bone resorption. They cannot directly stimulate bone formation, increase bone mass above normal values in ovariectomized rat models, or improve microstructure. However, there is a family of agents - the parathyroid hormone (PTH) and some of its fragments and their analogs - which directly stimulate bone growth and improve microstructure independently from impairing osteoclasts. These drugs are about to make their clinical debut in treating patients with osteoporosis and, probably not too far in the future, for accelerating fracture healing. They stimulate osteoblast accumulation and bone formation in three ways via signals from the type 1 PTH/PTH-related protein (PTHR1) receptors on proliferatively inactive preosteoblasts, osteoblasts, osteocytes and bone-lining cells. The receptor signals shut down the proliferative machinery in preosteoblasts and push their maturation to osteoblasts, cause the osteoblastic cells to make and secrete several factors that stimulate the extensive proliferation of osteoprogenitors without PTHRI receptors, stimulate the reversion of bone-lining cells to osteoblasts, and extend osteoblast lifespan and productivity by preventing them from suicidally initiating apoptosis. The first of the PTHs to reach the clinic will be teriparatide [recombinant human (h)PTH-(1-34)], which was recommended for approval in 2001 by the US Food and Drug Administration Endocrinology and Metabolic Drugs Advisory Committee for the treatment of postmenopausal osteoporosis. Teriparatide has been shown to considerably increase cancellous and cortical bone mass, improve bone microstructure, prevent fractures and thus provide benefits that cannot be provided by current antiresorptive drugs, when administered subcutaneously at a daily dose of 20 microg for no longer than 2 years to patients with osteoporosis.
骨质减少的骨骼对外伤性骨折的易感性，以及由于骨骼微观结构恶化和骨质流失导致正常身体活动引起的骨质疏松性骨骼的自发性骨折，目前采用抗吸收药物进行治疗，如双膦酸盐、降钙素、雌激素和选择性雌激素受体调节剂。这些抗吸收药物作用于破骨细胞，顾名思义，可减少或停止骨吸收。它们不能直接刺激骨形成，不能使去卵巢大鼠模型中的骨量增加到正常水平以上，也不能改善微观结构。然而，有一类药物——甲状旁腺激素（PTH）及其一些片段和类似物——能直接刺激骨生长并改善微观结构，且不影响破骨细胞。这些药物即将在治疗骨质疏松症患者中首次临床应用，而且可能在不久的将来用于加速骨折愈合。它们通过增殖静止的前成骨细胞、成骨细胞、骨细胞和骨衬细胞上的1型PTH/甲状旁腺激素相关蛋白（PTHR1）受体发出的信号，以三种方式刺激成骨细胞聚集和骨形成。受体信号关闭前成骨细胞中的增殖机制，促使其成熟为成骨细胞，使成骨细胞产生并分泌多种因子，刺激无PTHRI受体的骨祖细胞大量增殖，刺激骨衬细胞转化为成骨细胞，并通过防止成骨细胞自杀性启动凋亡来延长其寿命和提高其生产力。首个进入临床的PTH将是特立帕肽[重组人（h）PTH-（1-34）]，2001年美国食品药品监督管理局内分泌和代谢药物咨询委员会推荐其用于治疗绝经后骨质疏松症。已证明，对于骨质疏松症患者，每天皮下注射20微克特立帕肽，连续使用不超过2年，可显著增加松质骨和皮质骨量，改善骨微观结构，预防骨折，从而提供现有抗吸收药物无法提供的益处。
