Sclerostin deficiency in humans

Lierop, Antoon H van; Appelman‐Dijkstra, Natasha M.; Papapoulos, Socrates E.

doi:10.1016/j.bone.2016.10.010

Cited by 82 publications

(68 citation statements)

References 62 publications

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“…In patients with sclerosteosis, increased intracranial pressure can occur from reduced intracranial diameter, calvarial thickening, and jugular vein occlusion. (19) In the present study, these findings were limited to some vascular foramen occlusion, whereas intracranial volumes and shapes remained unchanged. The present findings demonstrate outcomes after a high dose for an extreme duration and suggest need for additional studies to better understand how this finding could be mitigated through a less severe treatment regimen or when Scl-Ab is combined with an antiresorptive, (58,59) possibly facilitating reduced drug exposure from both medications.…”

Section: Discussionsupporting

confidence: 46%

“…Functional nervous changes were not observed, and foramen functioning exclusively as nervous passages were not narrowed. In patients with sclerosteosis, increased intracranial pressure can occur from reduced intracranial diameter, calvarial thickening, and jugular vein occlusion . In the present study, these findings were limited to some vascular foramen occlusion, whereas intracranial volumes and shapes remained unchanged.…”

Section: Discussionsupporting

confidence: 42%

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Sclerostin Antibody–Induced Changes in Bone Mass Are Site Specific in Developing Crania

Scheiber

Barton

Khoury

et al. 2019

Journal of Bone and Mineral Research

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Sclerostin antibody (Scl‐Ab) is an anabolic bone agent that has been shown to increase bone mass in clinical trials of adult diseases of low bone mass, such as osteoporosis and osteogenesis imperfecta (OI). Its use to decrease bone fragility in pediatric OI has shown efficacy in several growing mouse models, suggesting translational potential to pediatric disorders of low bone mass. However, the effects of pharmacologic inhibition of sclerostin during periods of rapid growth and development have not yet been described with respect to the cranium, where lifelong deficiency of functioning sclerostin leads to patterns of excessive bone growth, cranial compression, and facial palsy. In the present study, we undertook dimensional and volumetric measurements in the skulls of growing Brtl/+ OI mice treated with Scl‐Ab to examine whether therapy‐induced phenotypic changes were similar to those observed clinically in patients with sclerosteosis or Van Buchem disorder. Mice treated between 3 and 14 weeks of age with high doses of Scl‐Ab show significant calvarial thickening capable of rescuing OI‐induced deficiencies in skull thickness. Other changes in cranial morphology, such as lengths and distances between anatomic landmarks, intracranial volume, and suture interdigitation, showed minimal effects of Scl‐Ab when compared with growth‐induced differences over the treatment duration. Treatment‐induced narrowing of foramina was limited to sites of vascular but not neural passage, suggesting patterns of local regulation. Together, these findings reveal a site specificity of Scl‐Ab action in the calvaria with no measurable cranial nerve impingement or brainstem compression. This differentiation from the observed outcomes of lifelong sclerostin deficiency complements reports of Scl‐Ab treatment efficacy at other skeletal sites with the prospect of minimal cranial secondary complications. © 2019 American Society for Bone and Mineral Research. © 2019 American Society for Bone and Mineral Research.

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Section: Discussionsupporting

confidence: 46%

Section: Discussionsupporting

confidence: 42%

Sclerostin Antibody–Induced Changes in Bone Mass Are Site Specific in Developing Crania

Scheiber

Barton

Khoury

et al. 2019

Journal of Bone and Mineral Research

View full text Add to dashboard Cite

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“…In addition, DKK-1 expression in bone tissue increases in SOST knockout mice and in Scl-Ab treated rats (32) similar to serum DKK-1 levels in patients with sclerosteosis. (7) A compensatory increase in expression of other ◼ 1606 CHAVASSIEUX ET AL.…”

Section: Remodeling Process At Month 12mentioning

confidence: 99%

“…Sclerostin is a protein produced by the osteocytes that inhibits bone formation by inhibiting canonical Wnt signaling . Inherited sclerostin deficiency is characterized by a high bone mass, high BMD, and a reduced fracture risk . Romosozumab (Amgen, Thousand Oaks, CA, USA and UCB Pharma, Brussels, Belgium), a bone‐forming agent, is a humanized monoclonal antibody that binds and inhibits sclerostin, thereby promoting osteoblast differentiation and activity.…”

Section: Introductionmentioning

confidence: 99%

“…(5,6) Inherited sclerostin deficiency is characterized by a high bone mass, high BMD, and a reduced fracture risk. (7) Romosozumab (Amgen, Thousand Oaks, CA, USA and UCB Pharma, Brussels, Belgium), a bone-forming agent, is a humanized monoclonal antibody that binds and inhibits sclerostin, thereby promoting osteoblast differentiation and activity. Romosozumab results in increased cortical and cancellous bone formation, mass, and strength, as reported in different animal models.…”

Section: Introductionmentioning

confidence: 99%

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Bone-Forming and Antiresorptive Effects of Romosozumab in Postmenopausal Women With Osteoporosis: Bone Histomorphometry and Microcomputed Tomography Analysis After 2 and 12 Months of Treatment

Chavassieux

Chapurlat

Portero-Muzy

et al. 2019

Journal of Bone and Mineral Research

122

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Sclerostin, a protein produced by osteocytes, inhibits bone formation. Administration of sclerostin antibody results in increased bone formation in multiple animal models. Romosozumab, a humanized sclerostin antibody, has a dual effect on bone, transiently increasing serum biochemical markers of bone formation and decreasing serum markers of bone resorption, leading to increased BMD and reduction in fracture risk in humans. We aimed to evaluate the effects of romosozumab on bone tissue. In a subset of 107 postmenopausal women with osteoporosis in the multicenter, international, randomized, double‐blind, placebo‐controlled Fracture Study in Postmenopausal Women with Osteoporosis (FRAME), transiliac bone biopsies were performed either after 2 (n = 34) or 12 (n = 73) months of treatment with 210 mg once monthly of romosozumab or placebo to evaluate histomorphometry and microcomputed tomography‐based microarchitectural endpoints. After 2 months, compared with either baseline values assessed after a quadruple fluorochrome labeling or placebo, significant increases (P < 0.05 to P < 0.001) in dynamic parameters of formation (median MS/BS: romosozumab 1.51% and 5.64%; placebo 1.60% and 2.31% at baseline and month 2, respectively) were associated with a significant decrease compared with placebo in parameters of resorption in cancellous (median ES/BS: placebo 3.4%, romosozumab 1.8%; P = 0.022) and endocortical (median ES/BS: placebo 6.3%, romosozumab 1.6%; P = 0.003) bone. At 12 months, cancellous bone formation was significantly lower (P < 0.05 to P < 0.001) in romosozumab versus placebo and the lower values for resorption endpoints seen at month 2 persisted (P < 0.001), signaling a decrease in bone turnover (P = 0.006). No significant change was observed in periosteal and endocortical bone. This resulted in an increase in bone mass and trabecular thickness with improved trabecular connectivity, without significant modification of cortical porosity at month 12. In conclusion, romosozumab produced an early and transient increase in bone formation, but a persistent decrease in bone resorption. Antiresorptive action eventually resulted in decreased bone turnover. This effect resulted in significant increases in bone mass and improved microarchitecture.© 2019 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research (ASBMR).

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Future Therapies

McClung¹

2018

Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism

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Sclerostin deficiency in humans

Cited by 82 publications

References 62 publications

Sclerostin Antibody–Induced Changes in Bone Mass Are Site Specific in Developing Crania

Sclerostin Antibody–Induced Changes in Bone Mass Are Site Specific in Developing Crania

Bone-Forming and Antiresorptive Effects of Romosozumab in Postmenopausal Women With Osteoporosis: Bone Histomorphometry and Microcomputed Tomography Analysis After 2 and 12 Months of Treatment

Future Therapies

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