Multiscale effects of the calcimimetic drug, etelcalcetide on bone health of rats with secondary hyperparathyroidism induced by chronic kidney disease

被引：4

作者：

Sharma, Shivani ^{[1
,2
,3
]}

Kumar, Saroj ^{[4
]}

Tomar, Manendra Singh ^{[5
]}

Chauhan, Divya ^{[3
,6
]}

Kulkarni, Chirag ^{[1
,2
,3
]}

Rajput, Swati ^{[1
,2
,3
]}

Sadhukhan, Sreyanko ^{[1
,2
,3
]}

Porwal, Konica ^{[1
,2
]}

Guha, Rajdeep ^{[7
]}

Shrivastava, Ashutosh ^{[5
]}

Gayen, Jiaur R. ^{[3
,6
]}

Kumar, Navin ^{[4
]}

Chattopadhyay, Naibedya ^{[1
,2
,3
]}

机构：

[1] CSIR, CSIR Cent Drug Res Inst, Div Endocrinol, Lucknow 226031, Uttar Pradesh, India

[2] CSIR, CSIR Cent Drug Res Inst, Ctr Res ASTHI, Lucknow 226031, Uttar Pradesh, India

[3] Acad Sci & Innovat Res AcSIR, Ghaziabad 201002, India

[4] Indian Inst Technol Ropar, Dept Mech Engn, Rupnagar 140001, Punjab, India

[5] King Georges Med Univ, Ctr Adv Res, Fac Med, Lucknow 226003, Uttar Pradesh, India

[6] CSIR, CSIR Cent Drug Res Inst, Div Pharmaceut & Pharmacokinet, Lucknow 226031, Uttar Pradesh, India

[7] CSIR, CSIR Cent Drug Res Inst, Div Lab Anim Facil, Lucknow 226031, Uttar Pradesh, India

来源：

BONE | 2024年 / 185卷

关键词：

Etelcalcetide; Secondary hyperparathyroidism; micro-computed tomography; Histomorphometry; Bone-quality; Mechanical strength; CALCIUM-SENSING RECEPTOR; GLOMERULAR-FILTRATION-RATE; VASCULAR CALCIFICATION; PARATHYROID-HORMONE; CORTICAL BONE; STRENGTH; DIFFERENTIATION; HEMODIALYSIS; ACTIVATION; CINACALCET;

D O I：

10.1016/j.bone.2024.117126

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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.

引用

页数：14

共 70 条

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