Nonclinical cardiovascular safety evaluation of romosozumab, an inhibitor of sclerostin for the treatment of osteoporosis in postmenopausal women at high risk of fracture

Turk, James R.; Deaton, Aimée M.; Yin, Jun; Stolina, Marina; Felx, Melanie; Boyd, Gabrielle; Bienvenu, Jean-Guy; Varela, Aurore; Guillot, Martin; Holdsworth, Gill; Wolfreys, Alison; Dwyer, Denise; Kumar, Shailendra; Koning, Emily M. de; Qu, Yusheng; Engwall, Michael; Locher, Kathrin; Ward, Lucas D.; Glaus, Charles; He, Yudong; Boyce, Rogely

doi:10.1016/j.yrtph.2020.104697

Cited by 33 publications

(40 citation statements)

References 63 publications

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“…Nonetheless, whilst these variants were associated with increased BMD and other musculoskeletal and anthropometric phenotypes, there was still no evidence of an association between the two trans variants assessed and cardiovascular risk. The data presented here are consistent with the complete nonclinical cardiovascular evaluation of romosozumab, where no functional morphologic or transcriptional effects on the cardiovascular system were observed in animal models in the presence or absence of atherosclerosis (15).…”

Section: Discussionsupporting

confidence: 88%

Genetic and atherosclerotic plaque immunohistochemical analyses do not associate reduced sclerostin expression with cardiovascular events

Holdsworth

Staley

Hall

et al. 2020

Preprint

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The sclerostin antibody romosozumab increases bone formation and decreases bone resorption, leading to increased bone mass, bone mineral density and bone strength, and reduced fracture risk. In a clinical study versus alendronate in postmenopausal women (ARCH), an imbalance in adjudicated serious cardiovascular (CV) events driven by an increase in myocardial infarction (MI) and stroke was observed.To investigate whether inhibition of sclerostin in atherosclerotic plaques may have contributed to this imbalance, sclerostin was immunostained in human plaques to determine whether it was detected in regions relevant to plaque stability. Additionally, genetic variants associated with lifelong reduced sclerostin expression were explored for associations with phenotypes including those related to bone physiology and CV risk factors/events in a population-based phenome-wide association study (PheWAS).Sclerostin expression was absent (67%) or reduced in atherosclerotic plaques and when present was in deeper regions of the plaque/wall and not in areas considered relevant to plaque stability (fibrous cap and endothelium). Natural genetic modulation of sclerostin by variants with a significant positive effect on bone physiology showed no association with lifetime risk of MI or stroke. These data do not support a causal association between sclerostin inhibition and increased risk of serious cardiovascular events.

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Section: Discussionsupporting

confidence: 88%

Genetic and atherosclerotic plaque immunohistochemical analyses do not associate reduced sclerostin expression with cardiovascular events

Holdsworth

Staley

Hall

et al. 2020

Preprint

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show abstract

“…In line with these findings, SOST down-regulation was reported in human AS plaques compared with aorta (77) and SOST expression in the aorta is reduced in rabbit and mouse models of atherosclerosis (16,78) .…”

Section: Discussionsupporting

confidence: 77%

“…The objective of this part of the study was to investigate the extent and location of sclerostin expression in human AS plaques, however, confirmation of the presence of a protein does not inform on its function in that location. In preclinical studies, transcriptomic analysis indicated that sclerostin inhibition did not affect Wnt pathways in the vasculature in the presence or absence of atherosclerosis (16) .…”

Section: Discussionmentioning

confidence: 99%

“…Since excess sclerostin has been reported to be protective against atheroprogression and inflammation in an ApoE mouse model (9) , it has also been hypothesised that a reduction in sclerostin could be associated with an increased risk of atheroprogression. However, a recently published study found no association between sclerostin inhibition and atheroprogression when reduction in sclerostin was directly assessed in two ApoE mouse models using different methods of inducing atheroprogression (16) . In the recent ARCH phase III comparator clinical trial of the sclerostin antibody romosozumab or alendronate in women with post-menopausal osteoporosis, a numerical imbalance in positively adjudicated serious cardiovascular adverse events was observed during the first 12 months of the study (50 patients (2.5%) in the romosozumab group vs. 38 patients (1.9%) in the control alendronate group) (17) , which was driven by a greater number of myocardial infarction and stroke events.…”

Section: Introductionmentioning

confidence: 97%

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Sclerostin Downregulation Globally by Naturally Occurring Genetic Variants, or Locally in Atherosclerotic Plaques, Does Not Associate With Cardiovascular Events in Humans

Holdsworth

Staley

Hall

et al. 2020

Journal of Bone and Mineral Research

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Inhibition of sclerostin increases bone formation and decreases bone resorption, leading to increased bone mass, bone mineral density and bone strength, and reduced fracture risk. In a clinical study of the sclerostin antibody romosozumab versus alendronate in postmenopausal women (ARCH), an imbalance in adjudicated serious cardiovascular (CV) adverse events driven by an increase in myocardial infarction (MI) and stroke was observed. To explore whether there was a potential mechanistic plausibility that sclerostin expression, or its inhibition, in atherosclerotic (AS) plaques may have contributed to this imbalance, sclerostin was immunostained in human plaques to determine whether it was detected in regions relevant to plaque stability in 94 carotid and 50 femoral AS plaques surgically collected from older female patients (mean age 69.6 ±10.4 years), sclerostin staining was absent in most plaques (67%) and when detected, it was of reduced intensity compared with normal aorta, and was located in deeper regions of the plaque/wall but was not observed in areas considered relevant to plaque stability (fibrous cap and endothelium). Additionally, genetic variants associated with lifelong reduced sclerostin expression were explored for associations with phenotypes including those related to bone physiology and CV risk factors/events in a population-based phenome-wide association study (PheWAS). Natural genetic modulation of sclerostin by variants with a significant positive effect on bone physiology showed no association with lifetime risk of MI or stroke. These data do not support a causal association between the presence of sclerostin, or its inhibition, in the vasculature and increased risk of serious cardiovascular events.

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“…The beneficial effects of these two agents against osteoporosis have been reported in a number of studies (47)(48)(49)(50). Although the effect of romosozumab on cardiovascular events including VC is controversial (45,51), baicalin has been reported to relax VSMCs (52), ameliorate atherosclerosis (53), prevent trans-differentiation of VSMCs (54) and inhibit vascular remodeling (55), via which baicalin may ameliorate VC. These results suggested that inhibition of sclerostin may exert beneficial effects on both VC and osteoporosis.…”

Section: Discussionmentioning

confidence: 99%

Shuxuetong injection simultaneously ameliorates dexamethasone‑driven vascular calcification and osteoporosis

Liu

et al. 2021

Exp Ther Med

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Nonclinical cardiovascular safety evaluation of romosozumab, an inhibitor of sclerostin for the treatment of osteoporosis in postmenopausal women at high risk of fracture

Cited by 33 publications

References 63 publications

Genetic and atherosclerotic plaque immunohistochemical analyses do not associate reduced sclerostin expression with cardiovascular events

Genetic and atherosclerotic plaque immunohistochemical analyses do not associate reduced sclerostin expression with cardiovascular events

Sclerostin Downregulation Globally by Naturally Occurring Genetic Variants, or Locally in Atherosclerotic Plaques, Does Not Associate With Cardiovascular Events in Humans

Shuxuetong injection simultaneously ameliorates dexamethasone‑driven vascular calcification and osteoporosis

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