Sclerostin inhibition: a novel therapeutic approach in the treatment of osteoporosis

Figures & data

Figure 1 Wnt signaling pathways and the biology of sclerostin.

Notes: (A) Canonical Wnt signaling: in the absence of sclerostin, Wnt binds to LRP 5/6 and its co-receptor, frizzled. This results in phosphorylation of the cytoplasmic tail of LRP 5/6, which allows axin to bind the receptor complex Axin binding leads to inhibition of GSK-3β, which normally functions to target β-catenin for degradation. Therefore, cytoplasmic levels of β-catenin increase and are translocated to the nucleus, where they bind to DNA binding proteins and activate target gene promoters. This results in osteoblast differentiation, proliferation and survival and hence, increased bone formation. (B and C) Loss-of-function of LRP5 and Wnt prevent canonical Wnt signaling: Loss-of-function of LRP5 and Wnt prevent formation of the active Wnt-LRP 5/6-frizzled complex and prevent Wnt signaling. The cytoplasmic tail of LRP 5/6 remains unphosphorylated. Therefore, axin does not bind the receptor complex. GSK-3β activity is uninhibited and therefore leads to phosphorylation of β-catenin, targeting it for degradation. Cytoplasmic levels of β-catenin decrease. Therefore, there is less translocation of the protein to the nucleus. Target gene promoters of the Wnt signaling pathway are not activated. This results in decreased bone formation and increased bone resorption and hence, skeletal fragility and fractures. (D) Inhibition of canonical Wnt signaling by sclerostin: sclerostin is secreted by osteocytes. It binds to LRP 5/6, which prevents Wnt from binding to LRP 5/6 and its co-receptor, frizzled. Therefore, Wnt signaling is inhibited. Through the mechanisms described above (B and C), this results in decreased bone formation and increased bone resorption.

Figure 2 Clinical effects of sclerosteosis and van Buchem disease.

Notes: (A) Sclerosteosis: facial features of a patient with sclerosteosis including a high forehead and large protruding chin. Reprinted from: The American Journal of Human Genetics, 64(6), Balemans W, van Den ende J, Freire Paes-Alves A, et al. Localization of the gene for sclerosteosis to the van Buchem disease-gene region on chromosome 17q12-q21. 1661–1669, Copyright © 1999; with permission from Elsevier.⁶⁶ (B) van Buchem disease: X-rays show the generalized sclerosis seen in van Buchem patients. The picture to the left is a lateral view of the elbow showing diffuse diaphyseal sclerosis with a thickened cortex. The picture in the center and to the right are anteroposterior and lateral views of the skull which show extensive sclerosis of the calvarium and the skull base, enlargement of the mandible, and obliteration of the paranasal and mastoid air spaces. Reprinted from The American Journal of Human Genetics. 62(2). van Hul W, Balemans W, van Hul E, et al. van Buchem disease (hyperostosis corticalis generalisata) maps to chromosome 17q12-q21. 391–399. Copyright © 1998; with permission from Elsevier.²⁸

Figure 3 The effect of sclerostin inhibition on Wnt signaling.

Notes: Sclerostin is secreted by the osteocyte. Romosozumab, a humanized MAb against sclerostin, binds circulating sclerostin. This prevents binding of sclerostin to LRP 5/6. Therefore, Wnt is able to bind LRP 5/6 and its co-receptor, frizzled. This activates the Wnt signaling pathway, which eventually leads to osteoblast differentiation, proliferation and survival and, hence, increased bone formation.
Abbreviation: MAb, monoclonal antibody.

Table 1 Summary of Phase I and II studies of romosozumab

Clinical trial number	Study name	Number of participants	Study population	Treatment arms	Primary endpoint	Completion date (actual or expected)
NCT01059435	A first in-human study evaluating AMG 785 in healthy men and postmenopausal women	74	Healthy males and postmenopausal females, ages 45–59 years	Postmenopausal women: one dose of romosozumab: 0.1, 0.3, 1, 3, 5 or 10 mg/kg SC; or 1 or 5 mg/kg IV or placebo SC or IV Men: one dose of romosozumab: 1 or 5 mg/kg SC or IV or placebo SC or IV	Number of subjects who experience clinically significant changes in vital signs, physical exam, laboratory tests, and ECGs; develop anti-AMG 785 antibodies; report treatment-emergent adverse events up to 85 days after drug administration	August 2008
NCT01825785	A multiple dose study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of AMG 785	48	Healthy males and postmenopausal females with low BMD (not osteoporosis), ages 45–80 years	Romosozumab or placebo 1 mg/kg SC every 2 weeks ×6 doses; Romosozumab or placebo 3 mg/kg every 4 weeks ×3 doses; Romosozumab or placebo 2 mg/kg every 2 weeks ×6 doses; Romosozumab or placebo 2 mg/kg every 4 weeks ×3 doses	Number (percentage) of subjects who experience clinically significant changes in vital signs, physical exam, laboratory tests, and ECGs; develop anti-AMG 785 antibodies; report treatment-emergent adverse events up to 169 days after initial drug administration	July 2009
NCT01101061	A single-dose study evaluating AMG 785 in healthy postmenopausal Japanese women	31	Postmenopausal Japanese women, ages 45–70 years	Single-dose of romosozumab 1 mg/kg, 3 mg/kg or 5 mg/kg or single dose of placebo	Number (percentage) of subjects who experience clinically significant changes in vital signs, physical exam, laboratory tests, and ECGs; develop anti-AMG 785 antibodies; report treatment-emergent adverse events up to 85 days after drug administration	November 2010
NCT00950950	A study to evaluate the effect of AMG 785 on bone quality of the forearm in postmenopausal women with low bone mass	24	Postmenopausal women with low BMD (not osteoporosis), ages 55–80 years	Romosozumab or placebo 3 mg/kg SC every 4 weeks for 3 months	Polar cross-sectional moment of inertia at the distal radius assessed by pQCT at screening and on days 29, 57, 85, 127, and 169	December 2010
NCT00907296	Study of AMG 785 in tibial diaphyseal fractures status post intramedullary nailing	402	Skeletally mature adults with a unilateral closed or Gustilo type I or II open tibial fracture and fracture fixation with intramedullary nailing, ages 18–85 years	Two, three or four doses of romosozumab 70 mg, romosozumab 140 mg, or romosozumab 210 mg or four doses of placebo	Time to radiographic healing for the romosozumab versus placebo groups, followed for 24 weeks	September 2012
NCT01588509	Transition from Alendronate to AMG 785	60	Postmenopausal women with low BMD (T-score ≤−2.0 and ≥−4.0) taking alendronate for ≥ 1 year, ages 55–85 years	Three doses of romosozumab dose one or dose two	Change from baseline in lumbar spine BMD at day 85	January 2013
NCT01081678	Study to assess fracture healing with sclerostin antibod	332	Males and females with low energy intertrochanteric or femoral neck fracture with internal fixation of fracture with screw or nail	Four doses of romosozumab 70 mg, 140 mg or 210 mg or four doses of placebo	Functional healing measured by mean value for the timed-up-and-go test over weeks 6 to 20 for the romosozumab vs placebo groups	January 2013
NCT01833754	Study of romosozumab (AMG 785) administered to healthy subjects and subjects with stage 4 renal impairment or stage 5 renal impairment requiring hemodialysis	24	Healthy subjects with eGFR ≥80, subjects with stage 4 renal impairment and subjects on dialysis	Single dose of romosozumab	Incidence of adverse events, results of safety monitoring (labs, vital signs, ECG), incidence of anti-romosozumab antibodies at 85 days	April 2014
NCT01992159	Study with AMG 785 to treat Japanese women with postmenopausal osteoporosis	252	Postmenopausal Japanese women with osteoporosis, ages 55–85 years	Romosozumab (three treatment arms, doses unknown) or placebo SC for 12 months (frequency unknown)	Changes from baseline in lumbar spine BMD at 12 months	January 2015
NCT00896532	Phase II study of AMG 785 in postmenopausal women with low bone mineral density	419	Postmenopausal women with low BMD (T-score between −2.0 and −3.5), ages 55–85 years	a) Romosozumab 70 mg, 140 mg, or 210 mg or placebo every month b) Teriparatide 20 mcg daily c) Romosozumab 140 mg or 210 mg or placebo every 3 months d) Alendronate 70 mg every week e) Denosumab 60 mg or placebo every 6 months f) Zoledronic acid 5 mg IV annually	Percentage change from baseline at month 12 in BMD at the lumbar spine for the individual romosozumab groups and pooled placebo arms	April 2016

Abbreviations: BMD, bone mineral density; SC, subcutaneously; IV, intravenously; ECG, electrocardiogram; pQCT, peripheral quantitative computed tomography; eGFR, estimated glomerular filtration rate.

Table 2 Summary of Phase III studies of romosozumab in osteoporosis*

Clinical trial number	Study name	Number of participants	Study population	Treatment arms	Primary endpoint	Expected completion date
01575834	Registrational study with AMG 785 to treat postmenopausal osteoporosis (FRAME)	7,180	Women with postmenopausal osteoporosis, ages 55–90 years	Romosozumab SC (dose unknown) or placebo SC for 12 months followed by open-label denosumab for 24 months	Incidence of vertebral fracture at 12 months and 24 months	December 2016
01631214	Study to determine the efficacy and safety of romosozumab in the treatment of postmenopausal women with osteoporosis	4,000	Women with postmenopausal osteoporosis with high risk of fracture (defined as a T-score at the hip of ≤−2.5 and a vertebral fracture or T-score at the hip of ≤−2.0 and a recent hip fracture or two vertebral fractures), ages 55–90 years	a) Romosozumab SC (dose unknown) and placebo alendronate for 12 months b) Alendronate and placebo romosozumab SC for 12 months → Both followed by open-label alendronate for 12 months	Incidence of clinical fracture and new vertebral fracture over 24 months	March 2017
01796301	An open-label study to evaluate the effect of treatment with AMG 785 or teriparatide in postmenopausal women (STRUCTURE)	436	Postmenopausal women with osteoporosis previously treated with a bisphosphonate for at least 3 years, ages 60–90 years	Romosozumab SC (dose unknown) or teriparatide SC for 12 months	Percentage change from baseline in BMD at the total hip at month 12	June 2015
02016716	A randomized Phase III study to evaluate two different formulations of romosozumab in postmenopausal women with osteoporosis	294	Postmenopausal women with osteoporosis at high risk of fractures (defined as T-score between −2.5 and −3.5 at the lumbar spine, total hip or femoral neck and a history of fragility fracture or at least two other risk factors), ages 55–90 years	Romosozumab formulation A romosozumab formulation B, placebo formulation A, or placebo formulation B (doses unknown)	Percentage change from baseline in BMD at the lumbar spine at 6 months	December 2014
02186171	A double-blind study to compare the safety and efficacy of romosozumab (AMG 785) versus placebo in men with osteoporosis (BRIDGE)	225	Men with osteoporosis, ages 55–90 years	Romosozumab SC (dose unknown) or placebo SC for 12 months	Percentage change from baseline in BMD at the lumbar spine at 12 months	December 2016

Note

* Reference: ClinicalTrials.gov.

Abbreviations: BMD, bone mineral density; SC, subcutaneously.

BalemansWVan Den EndeJFreire Paes-AlvesALocalization of the gene for sclerosteosis to the van Buchem disease-gene region on chromosome 17q12-q21Am J Hum Genet19996461661166910330353

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Van HulWBalemansWVan HulEVan Buchem disease (hyperostosis corticalis generalisata) maps to chromosome 17q12-q21Am J Hum Genet19986223913999463328

 PubMed Web of Science ®Google Scholar