LAUSR

Although numerous strategies are available in the clinic to improve bone density and decrease risk of fractures by inhibiting osteoclasts number and action, few anabolic treatment options remain. The currently approved anabolic therapies, teriparatide, abaloparatide, and romosozumab, are available in injectable formulations only. Because the recommended duration of treatment is limited to 2 years for the parathyroid hormone and parathyroid hormone–related peptide analogs and 1 year for the anti-sclerostin antibody, strategies are being developed to inhibit bone loss after therapy discontinuation because, in the absence of antiresorptive treatment, gains in bone density are progressively lost. In addition, romosozumab was found to be associated with increased cardiovascular risks in the phase 3 trial, and was approved only for high-risk osteoporosis. Therefore, novel anabolic treatment approaches are needed. Vitamin D and its analogues have been used in combination with calcium to improve skeletal health by decreasing bone resorption in the setting of hypovitaminosis D and hypocalcemia; however, their use has been limited by the risk of hypercalcemia, hypercalciuria, nephrocalcinosis, and nephrolithiasis. For example, the vitamin D analog, 1α,25-dihydroxy2β-(3-hydroxypropoxy) vitamin D3 (ED-71) was shown to increase bonemass in postmenopausal women in a randomized, placebo control trial in Japan. Unfortunately, treatment with ED-71 was associated with hypercalcemia, in spite of its suppression of bone resorption in rats and in osteoporotic patients, likely through increased intestinal absorption of calcium. Hypercalcemia and hypercalciuria were common in the patients receiving the higher ED-71 dosage, making the clinical use of this agent particularly problematic in areas where dietary calcium intake is higher than that in Japan, including in the United States. The identification of a small but significant anabolic effect of 1,25-dihydroxyvitamin D3 independent of endogenous parathyroid hormone using genetically altered murine models opened the door to the development of vitamin D analogues with anabolic actions in bone. The DeLuca laboratory initially modified the structure of 1,25-dihydroxyvitamin D3, developing 2-methylene-19-nor-(20S)-1,25(OH)2D3 (2DM), an analog with strong anabolic activity but also high bone resorption induction. Although 2DM increased bone mass in ovariectomized rats, in postmenopausal women it increased bone turnover but not bone mineral density, likely due to a marked increase in bone resorption. 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. WR-51 was shown to bind less efficiently to the vitamin D receptor in comparison to 1,25-dihydroxyvitamin D3 and 2MD. However, it was at least 200 times more active than 1,25-dihydroxyvitamin D3 and equal to 2MD in supporting osteoblastic mineralization in culture. To test in vivo bone resorption, rats were made vitamin D–deficient and then placed on a nocalcium diet, so that calcium changesmeasured could be primarily attributed to bone resorption activity. In this key in vivo assay, WT-51, even at high doses, produced a very small calcium increase, compared to high calcium changes induced by 1,25-dihydroxyvitamin D3 and 2MD treatment. In ovariectomized female rats, in vivo administration of WT-51 increased BV/TV in lumbar spine and femur. Bone turnover markers were tested and found to support the premise that the action of WT-51 on the skeleton occurs primarily through anabolic effects, because bone resorption was not increased but rather decreased compared to the ovariectomized controls. This was in contrast to the effects of 2MD on the skeleton, which included increase in bone resorption and calcium mobilization, limiting its anabolic effects but also leading to hypercalcemia. In addition to bone volume, bone strength was tested in this model by three-point bending and found to be significantly increased by WT-51 treatment. WT-51, compared to 2MD, had the added advantage of a stronger effect on cortical bone, which may also have superior implications for bone strength in patients. Notably, at the highest dose after WT-51, there was a significant increase in serum and urinary calcium, suggesting some contribution of WT-51 to calcium mobilization. However, the serum and urinary calcium levels remained in the normal range. The study did not include a histomorphometric analysis of bone, and the authors did not