Sclerostin Inhibition for Osteoporosis - a New Approach Carolyn B

The NEW ENGLAND JOURNAi, of MEDICINE

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Sclerostin Inhibition for Osteoporosis - A New Approach Carolyn B. Becker, M.D.

Effective new therapies are still needed for peo every 3 months at various doses; oral alendro ple with osteoporosis. ln 2002, the introduction nate at a dose of 70 mg weekly; subcutaneous of teriparatide, or recombinant parathyroid hor teriparatide at a dose of 20 µg daily; or placebo mone (PTH [1-34)), opened a promising chapter injections given monthly or every 3 months. in osteoporosis care.1 For the first time, there was Primary and secondary end points included an anabolic agent that significantly increased changes in BMD as compared with placebo, bone mineral density (BMD), reduced fracture changes in markers of bone metabolism, and risk, and restored bone architecture back to, or comparisons of the study drug with alendronate dose to, normal. However, despite an impressive and teriparatide. track record of both safety and efficacy, teripara The results were impressive. As compared tide has had a limited clinical reach as compared with baseline, BMD was significantly improved with other agents, largely owing to its require for all doses of romosozumab and at all sites ment for daily subcutaneous injection, a black-box except at the distal third of the radius, which warning about osteosarcoma in rats, and its high remained essentially unchanged. At the highest cost. Since antiresorptive therapies do not restore monthly dose of roniosozumab, increases in bone architecture and have a number of other BMD at the spine and hip were rapid and robust, limitations, finding new treatments for osteopo surpassing the BMD values with alendronate and rosis has been a high priority. teriparatide at 6 months and remaining signifi The results of the study by Mcclung et al. 2 cantly higher than the BMD values with either now reported in the Journal represent a potential comparator by the end of the trial. breakthrough in osteoporosis therapeutics. The If the changes in BMD for a presumed ana study introduces romosozumab, a humanized bolic agent were predictable, the changes in bone monoclonal antibody directed against the osteo turnover markers were not. Levels of bone-forma cyte-derived glycoprotein known as sderostin. tion markers increased rapidly after the first dose Humans with genetic deficiencies of sclerostin of romosozumab but then declined. By month 6, and mice with knockout of the sclcrostin gene the bone-formation markers were nearly back to (Sost) have high bone mass, increased bone baseline levels, despite continued administration strength, and resistance to fracture. Sclerostin of the drug. In contrast and perhaps most sur works by inhibiting the Wnt and bone morpho prising, markers of bone resorption declined in genetic protein signaling pathways that are crit the first week and remained suppressed for the ical for osteoblast proliferation and activity. By duration of the trial. inhibiting sclerostin, romosozumab should en The pattern of brief anabolic stimulation hance osteoblastic function. coupled with chronic suppression of bone resorp This phase 2 study was a randomized, placebo tion seen with romosozumab is unprecedented controlled trial that included two comparator among current therapies for osteoporosis; Potent drugs. Participants were healthy postmenopausal antiresorptive agents such as bisphosphonates women with osteopenia, randomly assigned to and denosumab suppress both bone-resorption one of eight study groups - romosozumab ad and bone-formation markers. Teriparatide in ministered subcutaneously either monthly or creases levels of bone-formation markers early

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on but, after a delay, stimulates bone-resorption number, NCT01631214) and may answer some markers as well. The so-called anabolic window of these questions. For now, more than a decade opened by teriparatide may be prematurely after the introduccion of teriparatide, we may at closed by this effect on resorption, blunting the last have a sequel to the anabolic story. bone-strengthening properties of the drug. PTH Disclosure forms provided by the author are available with the related protein, another potential anabolic agent, full te.xt of this article at NEJM.org. 3 was recently shown to act similarly to PTH. From Brigham and Women's Hospital, Boston. - Odanacatib, a cathepsin I< inhibit-Or; initially sup This article was published on January I, 2014, at NEJM .org. presses both bone-formation and bone-resorption markers, but the levels of bone-formation mark l. Neer R.M , Arnaud CD, Zanchma JR. et al. Bffect of parathy roid hormone (1·34) on fractures and bone miner.ii dtnsity in ers increase back to baseline values by 1 year. 4 pomncnopausal women with osteoporosis. N Engl J Med 2001; Can we reproduce the effect.of romosozumab 344:1434-41. on bone remodeling with existing osteoporosis 2. McC!ung MR., Grauer A, Boonen S, et al. R.omosozumab in postmenopausal women with low bone mineral density. N Engl therapies? Results from small studies suggest J Med. 001: 10.t056/Nff]Moa1305224. that perhaps we can. Combination therapy with 3. Horwitz MJ, Augustine M, Kahn L, et al. A comparison of teriparatide and potent but intermittently dosed par:ithyroid hormone-related protein (1·36) and parathyroid 5 hormone (1-34) on markers of bone turnover 3nd bone density in antiresorptive agents such as zoledronic acid or postmenopausal women: the PrOP study. J Bone Miner Res denosumab6 administered one or two times per 2013;2!1:2266-76. year shows promising results. Shorter courses of 4. Brixen K, ChapurlatR. Cheung AM. etal. !lone density. turn over, and estimated strength in postmenopausal women treated PTH followed sequentially or cyclicaily by oral with odaoacatib: a randomized trial. J Clin Bndocrinol Metab bisphosphonates may increase bone formation 2013;98:571-80. 7 8 without stimulating resorption. • $, Cosman F, Eriksen EF, R.ecknor C, ct al. Bffects ofintr avenous zoledronic acid plus subcutaneous tertparatide [rhPTH(l-34)) Many questions about romosozumab remain. in postmenopauul ostcoporosi~. J Bone Miner Res 2011;26:SOl Will changes in BMD translate into potent anti ll. fracture efficacy? Will it be safe over time? In 6. Tsai JN, Uihlein AV, Lee H, et al. Teriparatide and deno sumab, alone or combined, in women with postmcnopausal os the current study, there were no clinically sig teoporosis: the DATA study r:indomised trial. Lancet 2013;382: nificant adverse events other than injection-site 50-6. irritation. Will longer administration (>1 year) 1. Cosman F, Nieves J, Zion M, Woelfcrr L, Luckey M, Lindsay R. Daily :ind cyclic parathyroid hormone in women receiving alen cause bony complications such as cranial-nerve dron:ue. N Hugi J Med 2005;353:566-75. palsies 0·r spinal stenosis? What duration of 8. Schafer AL, Sellmeyer DB. Palernto L, et al. Six months of treatment is associated with the highest rate of parathyroid hormone (1-84) administered concurrently versus sequentially with monthly ibandronate over two yeafs: the PTH response? Why did BMD not improve at the and Jbandronate Combination Study (PICS) randomized trial. wrist? A phase 3 clinical trial of romosozumab J Clin Endotrinol Metab 2012:97:3522·9.

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