Inhibition of osteoclast differentiation by 1.25 ‐D and the calcimimetic KP2326 reveals 1.25‐D resistance in advanced CKD

ABSTRACTActive vitamin D analogs and calcimimetics are the main therapies used for treating secondary hyperparathyroidism (SHPT) in patients with chronic kidney disease (CKD). Peripheral blood mononuclear cells (PBMCs) of 19 pediatric patients with CKD1 ‐5D and 6 healthy donors (HD) were differentiated into mature osteoclasts with RANK‐L and M‐CSF. The effects of single or combined treatment with active vitamin D (1.25‐D) and/or calcimimetic KP2326 were evaluated on osteoclastic differentiation and osteoclastic‐mediated bone resorption. A lthough 1.25‐D inhibited osteoclastic differentiation, a significant resistance to 1.25‐D was observed when glomerular filtration rate (GFR) decreased. A significant albeit less important inhibitory effect of KP2326 on osteoclastic differentiation was also found both in cells derived from HD and CKD patients, through a putative activation of the Erk pathway. This inhibitory effect was not modified by CKD stage. Combinatorial treatment with 1.25‐D and KP2326 did not result in synergistic effects. Last, KP2326 significantly inhibited osteoclast‐mediated bone resorption.Both 1.25 ‐D and KP2326 inhibit osteoclastic differentiation, however to a different extent. There is a progressive resistance to 1.25‐D in advanced CKD that is not found with KP2326. KP2326 also inhibits bone resorption. Given that 1.25‐D has no effect on osteoclastic resorption activity and that calci mimetics also have direct anabolic effects on osteob...
Source: Journal of Bone and Mineral Research - Category: Orthopaedics Authors: Tags: Original Article Source Type: research