A New 1,25 Dihydroxy Vitamin D Analog with Strong Bone Anabolic Activity in OVX Rats with Little or no Bone Resorptive Activity

Abstract

A new 1α,25‐dihydroxy vitamin D3 analog (2‐methylene‐22(E)‐(24R)‐22‐dehydro‐1α,24,25‐trihydroxy‐19‐norvitamin D3 or WT‐51) has been tested as a possible therapeutic for osteoporosis. It is 1/10th as active as 1,25(OH)2D3 in binding affinity for the vitamin D receptor but is at least 200 times more active than 1,25(OH)2D3 and equal to that of 2MD (2‐methylene‐19‐nor‐(20S)‐1α,25(OH)2D3, an analog previously tested in postmenopausal women), in supporting bone formation by isolated osteoblasts in culture. However, in contrast to 2MD, it is virtually inactive on bone resorption in vivo. WT‐51 markedly increased bone mass (lumbar and femur) in ovariectomized (OVX) female rats. Further, bone strength tested by the three‐point bending system is significantly increased by WT‐51. Thus, WT‐51 is an attractive candidate for the treatment of postmenopausal osteoporosis. © 2019 American Society for Bone and Mineral Research.

Improved in vivo Experimental Screening Identifies an Anabolic Analog of 1,25 Dihydroxyvitamin D3 With Minimal Bone Resorption Activity

“…In this double‐blind, placebo‐controlled trial, there was also a significant increase in urinary calcium in patients treated with both doses of 2MD tested, suggesting the need for vitamin D analogs with anabolic action but limited or no activity on bone resorption. In the article in this issue by Plum and colleagues, the authors present work testing a new 1,25‐dihydroxyvitamin D3 analog ((2‐methylene‐22(E)‐(24R)‐22‐dehydro‐1,24,25‐trihydroxy‐19‐norvitamin D3, mercifully abbreviated as WT‐51) that could represent a major advance in therapeutic options for the treatment of osteoporosis by increasing bone mass without enhancing bone resorption. In this work, WT‐51 was selected based on its effective interaction with the nuclear vitamin D receptor, strong anabolic activity in osteoblastic cells in vitro, and, most importantly, limited bone resorption activity in vivo.…”

“…Will WT‐51 be a viable anabolic agent in patients? Plum and colleagues argue that, for the studies with 2MD, the rat model was not predictive of the human result because it is skewed to test modeling rather than remodeling of bone, and therefore it is less susceptible to the bone resorptive actions of any agent. In humans, where bone remodeling is at play, the contributions of analog action on bone resorption would be amplified, resulting in loss of a net bone mass increase.…”