This study investigated the efficacy of the two FDA-approved bone anabolic ligands of the parathyroid hormone receptor 1 (PTH1R), teriparatide or human parathyroid hormone 1–34 (PTH) and abaloparatide (ABL), to restoring skeletal health using a preclinical murine model of streptozotocin-induced T1-DM. Intermittent daily subcutaneous injections of equal molar doses (12 pmoles/g/day) of PTH (50 ng/g/day), ABL (47.5 ng/g/day), or vehicle, were administered for 28 days to 5-month-old C57Bl/6 J male mice with established T1-DM or control (C) mice. ABL was superior to PTH in increasing or restoring bone mass in control or T1-MD mice, respectively, which was associated with superior stimulation of trabecular and periosteal bone formation, upregulation of osteoclastic/osteoblastic gene expression, and increased circulating bone remodeling markers. Only ABL corrected the reduction in ultimate load, which is a measure of bone strength, induced by T1-DM, and it also increased energy to ultimate load. In addition, bones from T1-DM mice treated with PTH or ABL exhibited increased ultimate stress, a material index, compared to T1-DM mice administered with vehicle. And both PTH and ABL prevented the increased expression of the Wnt antagonist Sost/sclerostin displayed by T1-DM mice. Further, PTH and ABL increased to a similar extent the circulating bone resorption marker CTX and the bone formation marker P1NP in T1-DM after 2 weeks of treatment; however, only ABL sustained these increases after 4 weeks of treatment. We conclude that at equal molar doses, ABL is more effective than PTH in increasing bone mass and restoring the cortical and trabecular bone lost with T1-DM, due to higher and longer-lasting increases in bone remodeling.

中文翻译：

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Abaloparatide 在恢复 1 型糖尿病雄性小鼠的骨量和强度方面比特立帕肽更有效

本研究使用临床前小鼠模型研究了 FDA 批准的两种甲状旁腺激素受体 1 (PTH1R) 骨合成代谢配体特立帕肽或人甲状旁腺激素 1-34 (PTH) 和 abaloparatide (ABL) 在恢复骨骼健康方面的功效链脲佐菌素诱导的 T1-DM。每日间歇性皮下注射等摩尔剂量（12皮摩尔/克/天）的PTH（50纳克/克/天）、ABL（47.5纳克/克/天）或媒介物，持续28天至5个月。已建立 T1-DM 的老 C57Bl/6 J 雄性小鼠或对照 (C) 小鼠。 ABL 在增加或恢复对照小鼠或 T1-MD 小鼠的骨量方面分别优于 PTH，这与对小梁骨和骨膜骨形成的优异刺激、破骨细胞/成骨细胞基因表达的上调以及循环骨重塑标志物的增加有关。只有 ABL 纠正了 T1-DM 引起的极限载荷（骨强度的衡量指标）的降低，并且还增加了极限载荷的能量。此外，与接受媒介物治疗的 T1-DM 小鼠相比，接受 PTH 或 ABL 治疗的 T1-DM 小鼠的骨骼表现出增加的极限应力（材料指数）。 PTH 和 ABL 均阻止 T1-DM 小鼠表现出的 Wnt 拮抗剂 Sost/sclerostin 表达增加。此外，治疗 2 周后，T1-DM 患者的 PTH 和 ABL 循环骨吸收标志物 CTX 和骨形成标志物 P1NP 的增加程度相似；然而，只有 ABL 在治疗 4 周后维持了这些增加。我们的结论是，在等摩尔剂量下，ABL 在增加骨量和恢复 T1-DM 损失的皮质骨和骨小梁方面比 PTH 更有效，因为骨重塑的增加更高且更持久。