Role and mechanism of action of sclerostin in bone

Delgado‐Calle, Jesús; Sato, Amy Y.; Bellido, Teresita

doi:10.1016/j.bone.2016.10.007

Cited by 350 publications

(318 citation statements)

References 129 publications

(177 reference statements)

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“…A so‐called self‐regulatory mechanism with long‐term administration of Scl‐Ab has been suggested . The self‐regulatory mechanism invoked to limit bone formation in response to Scl‐Ab is not fully understood.…”

Section: Discussionmentioning

confidence: 99%

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

116

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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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Section: Discussionmentioning

confidence: 99%

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

116

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“…Insulin and its signaling pathway are important for osteoblastic differentiation, collagen synthesis, and signaling pathway [23]. We previously showed that elevated serum sclerostin levels were associated with prevalent vertebral fractures in T2DM patients independently of BMD and bone turnover markers [24].…”

Section: Insulin and Insulin-like Growth Factor-imentioning

confidence: 98%

Interaction between bone and glucose metabolism [Review]

Kanazawa

2017

Endocr J

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Abstract.Accumulating evidence has shown that bone and glucose metabolism are closely associated with each other. Since the risk of osteoporotic fractures is increased in patients with diabetes mellitus (DM), osteoporosis is recently recognized as one of diabetic complications, called DM-induced bone fragility. Previous studies showed that collagen cross-links of advanced glycation end products (AGEs) and dysfunctions of osteoblast and osteocyte are involved in DMinduced bone fragility. Circulating levels of AGEs and homocysteine are increased in patients with DM, and they directly impair the functions of osteoblast and osteocyte, resulting in decreased bone formation and bone remodeling. On the other hand, bone is recently recognized as an endocrine organ. Previous studies based on in vitro and animal studies showed that osteocalcin, which is specifically expressed in osteoblasts and secreted into the circulation, may regulate glucose homeostasis. Although several clinical studies reported the relationship between osteocalcin and glucose metabolism, further large-scale and intervention studies are necessary to confirm the beneficial effects of osteocalcin on glucose metabolism in human. It has been shown that adenosine monophosphate-activated protein kinase (AMPK), an intracellular energy sensor, is involved in bone metabolism. Adiponectin and metformin stimulate osteocalcin expression and the differentiation of osteoblasts via AMPK activation. Also, AMPK activation protects against oxidative stress-induced apoptosis of osteocytes. These findings suggest that AMPK in osteoblasts and osteocytes may be a therapeutic target for DM-induced bone fragility.

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“…Sclerostin was identified by studying the loss‐of‐function mutation in patients with the rare genetic disorder Sclerosteosis . Sclerosteosis is characterized by extremely high bone mass throughout the skeleton, tall stature, and enlarged jaws …”

Section: Introductionmentioning

confidence: 99%