Division of Endocrinology and Centre for Research in ASTHI, CSIR-Central Drug Research Institute, Council of Scientific and Industrial Research, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
Department of Mechanical Engineering, Indian Institute of Technology Ropar, Rupnagar, Punjab 140001, India.
Bone. 2024 Aug;185:117126. doi: 10.1016/j.bone.2024.117126. Epub 2024 May 20.
Chronic kidney disease-induced secondary hyperparathyroidism (CKD-SHPT) heightens fracture risk through impaired mineral homeostasis and elevated levels of uremic toxins (UTs), which in turn enhance bone remodeling. Etelcalcetide (Etel), a calcium-sensing receptor (CaSR) agonist, suppresses parathyroid hormone (PTH) in hyperparathyroidism to reduce excessive bone resorption, leading to increased bone mass. However, Etel's effect on bone quality, chemical composition, and strength is not well understood. To address these gaps, we established a CKD-SHPT rat model and administered Etel at a human-equivalent dose concurrently with disease induction. The effects on bone and mineral homeostasis were compared with a CKD-SHPT (vehicle-treated group) and a control group (rats without SHPT). Compared with vehicle-treated CKD-SHPT rats, Etel treatment improved renal function, reduced circulating UT levels, improved mineral homeostasis parameters, decreased PTH levels, and prevented mineralization defects. The upregulation of mineralization-promoting genes by Etel in CKD-SHPT rats might explain its ability to prevent mineralization defects. Etel preserved both trabecular and cortical bones with attendant suppression of osteoclast function, besides increasing mineralization. Etel maintained the number of viable osteocytes to the control level, which could also contribute to its beneficial effects on bone. CKD-SHPT rats displayed increased carbonate substitution of matrix and mineral, decreased crystallinity, mineral-to-matrix ratio, and collagen maturity, and these changes were mitigated by Etel. Further, Etel treatment prevented CKD-SHPT-induced deterioration in bone strength and mechanical behavior. Based on these findings, we conclude that in CKD-SHPT rats, Etel has multiscale beneficial effects on bone that involve remodeling suppression, mineralization gene upregulation, and preservation of osteocytes.
慢性肾脏病继发甲状旁腺功能亢进症（CKD-SHPT）通过破坏矿物质稳态和升高尿毒症毒素（UTs）水平来增加骨折风险，进而增强骨重塑。钙敏感受体（CaSR）激动剂依特卡肽（Etel）抑制甲状旁腺激素（PTH）在甲状旁腺功能亢进症中的作用，减少过度的骨吸收，从而增加骨量。然而，Etel 对骨质量、化学成分和强度的影响尚不清楚。为了解决这些差距，我们建立了 CKD-SHPT 大鼠模型，并在疾病诱导的同时以人类等效剂量给予 Etel。将其对骨和矿物质稳态的影响与 CKD-SHPT（给予 vehicle 组）和对照组（无 SHPT 的大鼠）进行比较。与 vehicle 治疗的 CKD-SHPT 大鼠相比，Etel 治疗改善了肾功能，降低了循环 UT 水平，改善了矿物质稳态参数，降低了 PTH 水平，并预防了矿物质化缺陷。Etel 在 CKD-SHPT 大鼠中上调了促进矿物质化的基因，这可能解释了其预防矿物质化缺陷的能力。Etel 不仅抑制了破骨细胞的功能，还保留了小梁骨和皮质骨，增加了矿物质化。Etel 维持了存活的骨细胞数量达到对照水平，这也可能有助于其对骨骼的有益作用。CKD-SHPT 大鼠表现出基质和矿物质中碳酸盐取代增加、结晶度降低、矿物质与基质比和胶原成熟度降低，这些变化被 Etel 减轻。此外，Etel 治疗预防了 CKD-SHPT 引起的骨强度和机械性能恶化。基于这些发现，我们得出结论，在 CKD-SHPT 大鼠中，Etel 对骨骼具有多尺度的有益作用，包括抑制重塑、上调矿物质化基因和保留成骨细胞。
