Therapeutic Effect of Calcimimetics on Osteoclast–Osteoblast Crosslink in Chronic Kidney Disease and Mineral Bone Disease

Abstract

We have previously demonstrated calcimimetics optimize the balance between osteoclastic bone resorption and osteoblastic mineralization through upregulating Wingless and int-1 (Wnt) signaling pathways in the mouse and cell model. Nonetheless, definitive human data are unavailable concerning therapeutic effects of Cinacalcet on chronic kidney disease and mineral bone disease (CKD-MBD) and osteoclast–osteoblast interaction. We aim to investigate whether Cinacalcet therapy improves bone mineral density (BMD) through optimizing osteocytic homeostasis in a human model. Hemodialysis patients with persistently high intact parathyroid hormone (iPTH) levels > 300 pg/mL for more than 3 months were included and received fixed dose Cinacalcet (25 mg/day, orally) for 6 months. Bone markers presenting osteoclast–osteoblast communication were evaluated at baseline, the 3rd and the 6th month. Eighty percent of study patients were responding to Cinacalcet treatment, capable of improving BMD, T score and Z score (16.4%, 20.7% and 11.1%, respectively). A significant correlation between BMD improvement and iPTH changes was noted (r = −0.26, p < 0.01). Nonetheless, baseline lower iPTH level was associated with better responsiveness to Cinacalcet therapy. Sclerostin, an inhibitor of canonical Wnt/β-catenin signaling, was decreased from 127.3 ± 102.3 pg/mL to 57.9 ± 33.6 pg/mL. Furthermore, Wnt-10b/Wnt 16 expressions were increased from 12.4 ± 24.2/166.6 ± 73.3 pg/mL to 33.8 ± 2.1/217.3 ± 62.6 pg/mL. Notably, procollagen type I amino-terminal propeptide (PINP), a marker of bone formation and osteoblastic activity, was increased from baseline 0.9 ± 0.4 pg/mL to 91.4 ± 42.3 pg/mL. In contrast, tartrate-resistant acid phosphatase isoform 5b (TRACP-5b), a marker of osteoclast activity, was decreased from baseline 16.5 ± 0.4 mIU/mL to 7.7 ± 2.2 mIU/mL. Moreover, C-reactive protein levels were suppressed from 2.5 ± 0.6 to 0.8 ± 0.5 mg/L, suggesting the systemic inflammatory burden may be benefited after optimizing the parathyroid–bone axis. In conclusion, beyond iPTH suppression, our human model suggests Cinacalcet intensifies BMD through inhibiting sclerostin expression and upregulating Wnt-10b/Wnt 16 signaling that activates osteoblastic bone formation and inhibits osteoclastic bone resorption and inflammation. From the perspective of translation to humans, this research trial brings a meaningful insight into the osteoblast–osteoclast homeostasis in Cinacalcet therapy for CKD-MBD.

Effect of Denosumab on Bone Health, Vascular Calcification, and Health-Related Quality of Life in Hemodialysis Patients with Osteoporosis: A Prospective Observational Study

“…The authors noted an inverse correlation between serum alkaline phosphatase level and coronary artery calcium (CAC) score, suggesting that the selective cessation of osteoclasts, along with intact osteoblast function and a high bone turnover rate, might create a reverse calcium paradox. This could lead to regressed ectopic calcification, stabilized vascular calcification, and increased bone mass [ 30 , 31 ]. However, our 2-year study found no significant changes in CAC.…”

Translational Medicine in Uremic Vascular Calcification: Scavenging ROS Attenuates p-Cresyl Sulfate-Activated Caspase-1, NLRP3 Inflammasome and Eicosanoid Inflammation in Human Arterial Smooth Muscle Cells

“…In the past decades, CKD-MBD therapies focused mainly on mineral-PTH hormone-vitamin D axis, such that UVC-associated mortality remains at the top of leading causes in CKD population. Hung et al reported that CKD patients with secondary hyperparathyroidism increased expression of sclerostin that inhibits Wnt 10b/Wnt 16 signaling pathway, leading to activating osteoclastic bone resorption (tartrate-resistant acid phosphatase isoform 5b) and inactivating osteoblastic bone formation (procollagen type I propeptides), bone inflammation and low bone density, and ultimately adverse clinical events [ 25 ]. In light of this, PCS-driven UVC remains intractable.…”

Circulating p-Cresyl Sulfate, Non-Hepatic Alkaline Phosphatase and Risk of Bone Fracture Events in Chronic Kidney Disease-Mineral Bone Disease

“…Chronic kidney disease-mineral bone disorder (CKD-MBD) is an intricate systemic complication in CKD patients with abnormal mineral and bone metabolism, typically manifested by dysregulated circulating levels of calcium and phosphorus, intact parathyroid hormone (iPTH), vitamin D, impaired skeletal health and vascular or ectopic soft tissue calcification [ 1 ]. Patients with later stages of CKD are doomed to suffer from lower bone mineral density, leading to strikingly higher risk of bone fracture (BF) and subsequent morbidity and mortality [ 2 ]. As CKD declines, failing renal clearance results in retention of organic compounds and anorganic substances (e.g., phosphate), also referred to as uremic solutes [ 3 , 4 ].…”