Osteoporosis

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Hence, in the Fracture Study in OSTEOPOROSIS Postmenopausal Women with Osteoporosis (FRAME) trial, which included 7,180 post‑ menopausal women with osteoporosis, 1 year Romosozumab to rebuild the of treatment with romosozumab increased spine and hip bone mineral density (BMD) from baseline by 13.3% and 6.8%, respec‑ foundations of bone strength tively8. As this treatment was followed by 1 year of denosumab therapy, the cumulative Serge L. Ferrari gains in BMD at spine and hip over 2 years Biologic agents targeting key proteins involved in bone homeostasis are reached 17.6% and 8.8%, respectively, which would be equivalent to approximately 7 years revolutionizing the management of osteoporosis. New clinical data of treatment with denosumab alone9. In the support the use of these novel therapies to rapidly increase bone mass and FRAME trial, romosozumab reduced the risk decrease the risk of fractures. of vertebral fractures by 73% and of clinical fractures by 36% within 12 months compared Refers to Saag, K. G. et al. Romosozumab or alendronate for fracture prevention in women with osteoporosis. with placebo. Although the relative reduction N. Engl. J. Med. 377, 1417–1427 (2017). in the risk of non-vertebral fractures (25%) did not reach statistical significance in the overall population, this finding could be explained Insights into the mechanisms of bone resorp‑ and the RANKL inhibitor denosumab3. by the lower than expected rate of non- tion and bone formation have led to the Alternatively, the parathyroid hormone (PTH) vertebral fracture in a large subgroup of the development of biologic therapies that target analogue teriparatide and, more recently, cohort (individuals from the Latin America proteins involved in these processes, such as the PTH-related protein analogue abalopa‑ region). Indeed, when further analyses were receptor activator of nuclear factor‑κB ligand ratide have been used to exert bone-forming conducted in individuals recruited outside of (RANKL, also known as TNFSF11) and scle‑ effects with a concomitant increase in bone Latin America, a significant 42% reduction in rostin, that are transforming the treatment of turnover of variable magnitude (greater with non-vertebral fractures was observed in this osteoporosis. The seminal role of sclerostin in teriparatide than with abaloparatide)4. By high-risk population within 12 months8. Such a the control of bone homeostasis was revealed contrast, targeting sclerostin with a mono reduction in non-vertebral fractures seemed to when mutations in the gene encoding this clonal antibody, romosozumab, potently be greater than that observed in trials of other protein, SOST, were found to cause sclero stimulates bone formation, primarily through anti-resorptive drugs, including zoledronic steosis, a generalized skeletal disorder char‑ modelling-based mechanisms5, while simulta‑ acid and denosumab. acterized by bone overgrowth and extremely neously reducing bone resorption (FIG. 1). This The superior efficacy of romosozumab high bone mass. The results of a clinical trial unique mechanism of action has resulted in over an anti-resorptive agent in patients at comparing an anti-sclerostin monoclonal prominent increases in bone mass6, and high risk of fracture has now been demon‑ antibody with a long-established therapy for in trabecular and cortical bone volume strated directly in the Active-Controlled osteoporosis reinforce the clinical potential of and strength, in animal models as well as in Fracture Study in Postmenopausal Women targeting sclerostin1. humans, and compares favourably with ter‑ with Osteoporosis at High Risk (ARCH) trial, Bone formation occurs through two dis‑ iparatide7. However, these studies have also which included 4,093 postmenopausal women tinct mechanisms, namely bone remodelling, shown that the bone-forming effects of romo‑ with severe osteoporosis (that is, with prev‑ in which osteoblast-mediated bone formation sozumab are attenuated over time, whereas alent vertebral fractures)1. Study participants depends on prior osteoclast activity and bone its anti-resorptive effects persist6. The mech‑ were randomly allocated to receive romo‑ resorption, and bone modelling, in which bone anisms underlying this attenuation are not sozumab or alendronate for 1 year, followed formation is initiated directly by osteoblasts fully understood, but most likely involve bone by open-label treatment of all patients with on quiescent bone surfaces. Besides being mechanostatic responses that trigger the over‑ alendronate for up to 2 years. Compared involved during bone growth, the latter pro‑ expression of counter-regulatory molecules, with alendronate, romosozumab increased cess is stimulated mainly by mechanical forces such as Dickkopf-related protein 1, which BMD by approximately 2.5‑fold at the spine exerted on the skeleton, which inhibit scleros‑ inhibit Wnt signalling and ultimately osteo‑ and 2‑fold at the hip in year 1, and vertebral tin expression by osteocytes, thereby activat‑ blast differentiation2. Together with its rapid fracture risk was 37% lower at year 1 and 48% ing the Wnt–β‑catenin signalling pathway and prominent effects on bone mass gain, this lower at year 2. At study completion (median in osteoblasts2. early attenuation phenomenon explains why exposure 33 months), the differences between To date, osteoporosis therapy has primar‑ romosozumab was used for only 1 year in the the group initially treated with romosozumab ily targeted osteoclasts to inhibit bone remod‑ clinical trials, before transitioning to another and the group treated with alendronate alone elling, as is the case with bisphosphonates therapy. reached –27% for clinical fractures, –19% for

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Bone lining osteoporosis, namely denosumab and romo‑ Osteoid Osteoblast cell New mineralized bone sozumab. If romosozumab becomes available Calciﬁed bone matrix in clinical practice, sequential approaches using these monoclonal antibodies should Bone Osteoclast modelling enable a much larger number of patients to quickly regain bone mass and strength, to the point that a cure for osteoporosis could be foreseen for the majority of patients.

Serge L. Ferrari Bone Romosozumab Osteocyte remodelling Service and Laboratory of Bone Diseases, Geneva Abaloparatide University Hospital, 1205 Geneva, Switzerland. [email protected] Teriparatide doi:10.1038/nrrheum.2018.5 Published online 25 Jan 2018

| 1. Saag, K. G. et al. Romosozumab or alendronate for Fig. 1 Differential effects of bone-forming agents on bone surfaces.Nature Teriparatide Reviews | andRheumatology abalopa- fracture prevention in women with osteoporosis. ratide act primarily by activating bone formation coupled to bone resorption at remodelling sur- N. Engl. J. Med. 377, 1417–1427 (2017). faces, and to a lesser extent by activating quiescent bone-forming cells at modelling surfaces. 2. Ke, H. Z., Richards, W. G., Li, X. & Ominsky, M. S. Sclerostin and Dickkopf‑1 as therapeutic targets in Romosozumab acts primarily by activating modelling-based bone formation while inhibiting bone bone diseases. Endocr. Rev. 33, 747–783 (2012). resorption at remodelling surfaces. 3. Baron, R., Ferrari, S. & Russell, R. G. Denosumab and bisphosphonates: different mechanisms of action and effects. Bone 48, 677–692 (2011). 4. Miller, P. D. et al. Effect of abaloparatide versus non-vertebral fractures and –38% for hip frac‑ older population at high cardiovascular risk; placebo on new vertebral fractures in postmenopausal tures. It is worth mentioning that in a simi‑ to the protective effects of alendronate in this women with osteoporosis: a randomized clinical trial. JAMA 316, 722–733 (2016). lar high-risk population, alendronate alone population, as suggested by some, but not all, 5. Ominsky, M. S. et al. Sustained modeling-based bone reduced vertebral fractures by 47% and clin‑ previous analyses of alendronate effects on the formation during adulthood in cynomolgus monkeys may 10 contribute to continuous BMD gains with denosumab. ical fractures by 28% versus placebo, empha‑ cardiovascular system ; or to chance alone. J. Bone Miner. Res. 30, 1280–1289 (2015). sizing that novel therapeutic approaches Notably, in some animal models sclerostin 6. McClung, M. R. et al. Romosozumab in postmenopausal women with low bone mineral starting with romosozumab would provide a seems to be expressed in the vasculature and density. N. Engl. J. Med. 370, 412–420 (2014). true improvement over the already efficacious in relation to arterial calcifications. To elu‑ 7. Langdahl, B. L. et al. Romosozumab (sclerostin monoclonal antibody) versus teriparatide in current standard of care. cidate whether or not sclerostin inhibition postmenopausal women with osteoporosis Although the findings of the ARCH trial might lead to the progression or precipitation transitioning from oral bisphosphonate therapy: a randomised, open-label, phase 3 trial. Lancet 390, confirm the potential benefits of a sclerostin- of vascular disease is therefore important, 1585–1594 (2017). neutralizing antibody in patients at high particularly because sclerostin inhibitors, by 8. Cosman, F., Crittenden, D. B. & Grauer, A. Romosozumab treatment in postmenopausal risk of fracture, they also produced some their unique mechanism of action, provide osteoporosis. N. Engl. J. Med. 376, 396–397 unexpected observations, namely a higher a new hope to eventually treat bone fragil‑ (2017). 9. Bone, H. G. et al. 10 years of denosumab treatment in number of adjudicated severe cardiovascu‑ ity in patients with diabetes mellitus and/or postmenopausal women with osteoporosis: results lar events in the romosozumab group than chronic renal failure who also have a high from the phase 3 randomised FREEDOM trial and open-label extension. Lancet Diabetes Endocrinol. 5, in the alendronate group (50 versus 38 at cardiovascular risk. 513–523 (2017). 1 12 months) . Considering the small between- To conclude, the two major discoveries in 10. Kranenburg, G. et al. Bisphosphonates for cardiovascular risk reduction: a systematic review group difference and the fact that no such bone biology of the past 20 years, namely the and meta-analysis. Atherosclerosis 252, 106–115 risk was observed in the previous (and larger) essential role of RANKL in stimulating bone (2016). placebo-controlled FRAME trial, it remains resorption and that of sclerostin in inhibit‑ Competing interests unclear whether this apparent adverse event is ing bone formation, have led in turn to the The author declares that he has received research funding related to the use of sclerostin inhibition in an development of the first two biologics to treat and consultancy fees from Amgen, MSD and UCB.