A Bisphosphonate With a Low Hydroxyapatite Binding Affinity Prevents Bone Loss in Mice After Ovariectomy and Reverses Rapidly With Treatment Cessation.
A Bisphosphonate With a Low Hydroxyapatite Binding Affinity Prevents Bone Loss in Mice After Ovariectomy and Reverses Rapidly With Treatment Cessation.
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DOI：
10.1002/jbm4.10476
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发表时间：
2021-04
期刊：
影响因子：
3.8
通讯作者：
Schaffler MB
中科院分区：
文献类型：
--
作者：
Coffman AA;Basta-Pljakic J;Guerra RM;Ebetino FH;Lundy MW;Majeska RJ;Schaffler MB
双膦酸盐（BP）是骨质疏松症治疗的主要药物；然而，由于过度抑制重塑而对骨骼健康的担忧仍然存在。长期的骨重塑抑制会对骨材料特性产生不利影响，导致动物体内微损伤积累和断裂韧性降低，以及患者基质矿化和非典型股骨骨折的增加。尽管通过 BP 进行“药物假期”以恢复重塑和改善骨质量似乎是合理的，但临床 BP 由于其高羟基磷灰石 (HAP) 结合亲和力，因此具有较长的功能半衰期。这实际上限制了药物假期的可逆性和有效性。具有低 HAP 亲和力和强破骨细胞抑制作用的 BP 可能提供一种替代方法；当停止给药时，它们的抗吸收作用应迅速逆转。本研究使用 NE-58025 测试了这一概念，NE-58025 是一种具有低 HAP 亲和力和中等破骨细胞抑制潜力的 BP。对年轻成年雌性 C57Bl/6 小鼠进行卵巢切除 (OVX)，并用 NE-58025、利塞膦酸盐或 PBS 载体治疗 3 个月，以测试预防长期骨质流失的有效性。评估了骨微结构、组织形态计量学和全骨力学性能。为了测试可逆性，对 OVX 小鼠进行类似治疗 3 个月，然后停止治疗，并在治疗后 3 个月内评估骨骼情况。 NE-58025 和 RIS 抑制长期 OVX 诱导的骨质流失，但 NE-58025 的抗骨吸收作用更明显。停止 NE-58025 治疗会导致小梁吸收迅速发生，破骨细胞表面在 1 个月内增加 200%，骨质流失。停止利塞膦酸盐治疗不会导致吸收指数或骨质流失增加。这些结果表明，NE-58025 可预防 OVX 引起的骨质流失，并且其作用在体内停止治疗后迅速逆转。低 HAP 亲和力 BP 可用作具有快速开启/关闭曲线的可逆抗吸收剂，这可能有助于通过长期 BP 治疗维持骨骼健康。 © 2021 作者。 JBMR Plus 由 Wiley periodicals LLC 代表美国骨与矿物研究学会出版。
Bisphosphonates (BPs) are a mainstay of osteoporosis treatment; however, concerns about bone health based on oversuppression of remodeling remain. Long‐term bone remodeling suppression adversely affects bone material properties with microdamage accumulation and reduced fracture toughness in animals and increases in matrix mineralization and atypical femur fractures in patients. Although a “drug holiday” from BPs to restore remodeling and improve bone quality seems reasonable, clinical BPs have long functional half‐lives because of their high hydroxyapatite (HAP) binding affinities. This places a practical limit on the reversibility and effectiveness of a drug holiday. BPs with low HAP affinity and strong osteoclast inhibition potentially offer an alternative approach; their antiresorptive effect should reverse rapidly when dosing is discontinued. This study tested this concept using NE‐58025, a BP with low HAP affinity and moderate osteoclast inhibition potential. Young adult female C57Bl/6 mice were ovariectomized (OVX) and treated with NE‐58025, risedronate, or PBS vehicle for 3 months to test effectiveness in preventing long‐term bone loss. Bone microarchitecture, histomorphometry, and whole‐bone mechanical properties were assessed. To test reversibility, OVX mice were similarly treated for 3 months, treatment was stopped, and bone was assessed up to 3 months post‐treatment. NE‐58025 and RIS inhibited long‐term OVX‐induced bone loss, but NE‐58025 antiresorptive effects were more pronounced. Withdrawing NE‐58025 treatment led to the rapid onset of trabecular resorption with a 200% increase in osteoclast surface and bone loss within 1 month. Cessation of risedronate treatment did not lead to increases in resorption indices or bone loss. These results show that NE‐58025 prevents OVX‐induced bone loss, and its effects reverse quickly following cessation treatment in vivo. Low‐HAP affinity BPs may have use as reversible, antiresorptive agents with a rapid on/off profile, which may be useful for maintaining bone health with long‐term BP treatment. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.