Sclerostin vaccination mitigates estrogen deficiency induction of bone mass loss and microstructure deterioration

Wang, Feng Sheng; Wu, Ren‐Chin; Lain, Wei Shiung; Tsai, Tsai Chen; Chen, Yu Shan; Sun, Yan; Ke, Huei Jing; Li, Jui Chen; Hwang, Jaulang; Ko, Jih Yang

doi:10.1016/j.bone.2018.04.007

Cited by 9 publications

(9 citation statements)

References 45 publications

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“…Similar results were found in a gonad-intact aged male rat model (31), an orchiectomized rat model of male osteoporosis (22), or in female, gonad-intact cynomolgus monkeys (32). Our data were in agreement with the study revealing that sclerostin antibody treatment mitigated the estrogen deficiency-mediated deterioration of bone mass, trabecular microarchitecture, and biomechanical properties (4). Interestingly, Scl-Ab also suppressed bone resorption (22).…”

Section: Discussionsupporting

confidence: 93%

“…Sclerosteosis and van Buchem disease result in generalized high bone mass due to overactive osteoblast activity (6, 7). Subsequent studies have indicated that monoclonal antibodies to sclerostin such as romosozumab have been used in preclinical and clinical studies of osteoporosis with beneficial outcomes for bone mass and microstructure, and fractures risk reduction (4, 5, 8). Previous studies demonstrated that estrogen-deficient women had higher sclerostin serum levels (9), and high serum levels of sclerostin were associated with increased fracture risk, particularly in populations with lower bone mass (10).…”

Section: Introductionmentioning

confidence: 99%

“…Sclerostin antibody (Scl-Ab) acts to restore bone mass, trabecular microstructure and strength in ovary-intact and ovariectomized (OVX) rats (4, 5, 22–24). Ex vivo , sclerostin can induce adipogenesis in 3T3-L1 cells, mouse or human bone marrow-derived mesenchymal stromal cells.…”

Section: Introductionmentioning

confidence: 99%

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Sclerostin Antibody Mitigates Estrogen Deficiency-Inducted Marrow Lipid Accumulation Assessed by Proton MR Spectroscopy

Huang

Jiang

et al. 2019

Front. Endocrinol.

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Sclerostin knock-out mice or sclerostin antibody (Scl-Ab) treated wild-type mice displayed decreased marrow adiposity. But the effects of Scl-Ab on estrogen deficiency-induced marrow fat expansion remain elusive. In this work, 45 female New Zealand rabbits were equally divided into sham-operation, ovariectomy controls, and ovariectomy treated with Scl-Ab for 5 months. MR spectroscopy was performed to longitudinally assess marrow fat fraction at baseline conditions, 2.5 and 5 months post-operatively, respectively. We evaluated bone mineral density (BMD), bone structural parameters, serum bone biomarkers, and quantitative parameters of marrow adipocytes. Ovariectomized rabbits markedly exhibited expansion of marrow fat in a time-dependent manner, with a variation of marrow fat fraction (+17.8%) at 2.5 months relative to baseline and it was maintained until 5 months (+30.4%, all P < 0.001), which was accompanied by diminished BMD and deterioration of trabecular microstructure. Compared to sham controls, adipocyte mean diameter, adipocyte density and adipocytes area percentage was increased by 42.9, 68.3, and 108.6% in ovariectomized rabbits, respectively. Scl-Ab treatment increased serum bone formation marker and alleviated the ovariectomy escalation of serum bone resorption marker. It remarkably lessened the ovariectomy-mediated deterioration of BMD, and morphometric characteristics of trabecular bone. Marrow fat fraction was decreased significantly with Scl-Ab to levels matching that of sham-operated controls and correlated positively with reductions in adipocyte mean diameter, percentage adipocyte volume per marrow volume, and adipocyte density. Taken together, early Scl-Ab treatment reverts marrow fat expansion seen in ovariectomized rabbits in addition to having a beneficial effect on bone mass and microstructural properties.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

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Sclerostin Antibody Mitigates Estrogen Deficiency-Inducted Marrow Lipid Accumulation Assessed by Proton MR Spectroscopy

Huang

Jiang

et al. 2019

Front. Endocrinol.

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“…Estrogens regulate the production of the inhibitor of Wnt signaling, sclerostin [54]. In mice, the sclerostin-Fc vaccination reduced serum sclerostin concentrations, increased serum levels of bone formation markers, alleviated the ovariectomy-induced increase in serum resorption markers, and improved the estrogen deficiency-mediated deterioration of BMD, morphometric characteristics of trabecular bone, and mechanical strength of the femur and lumbar spine [55]. Treatment of postmenopausal women with estrogen or raloxifene reduces circulating and bone marrow plasma levels of sclerostin as well as bone sclerostin messenger RNA (mRNA) [56].…”

Section: Bone Effects Of Menopausal Hormone Therapymentioning

confidence: 99%

Update on Menopausal Hormone Therapy for Fracture Prevention

Štěpán

Hruskova

Kverka

2019

Curr Osteoporos Rep

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Purpose of Review The goal of the review is to assess the appropriateness of menopausal hormone therapy (MHT) for the primary prevention of bone loss in women at elevated risk in the early years after menopause. Recent Findings Estrogen alone or combined with progestin to protect the uterus from cancer significantly reduces the risk of osteoporosis-related fractures. MHT increases type 1 collagen production and osteoblast survival and maintains the equilibrium between bone resorption and bone formation by modulating osteoblast/osteocyte and T cell regulation of osteoclasts. Estrogens have positive effects on muscle and cartilage. Estrogen, but not antiresorptive therapies, can attenuate the inflammatory bonemicroenvironment associated with estrogen deficiency. However, already on second year of administration, MHT is associated with excess breast cancer risk, increasing steadily with duration of use. Summary MHT should be considered in women with premature estrogen deficiency and increased risk of bone loss and osteoporotic fractures. However, MHT use for the prevention of bone loss is hindered by increase in breast cancer risk even in women younger than 60 years old or who are within 10 years of menopause onset.

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“…It has been studied with regards to the treatment of osteoporosis in postmenopausal women with low bone density [ 41 ]. In addition, very recent research shows that SOST-Fc vaccination might be a therapeutic approach for preventing osteoporosis [ 42 ]. So far, it has not been established how anti-sclerostin antibodies affect vascular calcifications [ 43 ].…”

Section: Methodsmentioning

confidence: 99%

Sclerostin is an independent risk factor for all-cause mortality in kidney transplant recipients

et al. 2020

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Background Sclerostin is a hormone contributing to the bone-vascular wall cross talk and has been implicated in cardiovascular events and mortality in patients with chronic kidney disease (CKD). We analyzed the relationship between sclerostin and mortality in renal transplant recipients. Methods 600 stable renal transplant recipients (367men, 233 women) were followed for all-cause mortality for 3 years. Blood and urine samples for analysis and clinical data were collected at study entry. We performed Kaplan–Meier survival analysis and Cox regression models considering confounding factors such as age, eGFR, cold ischemia time, HbA1c, phosphate, calcium, and albumin. Optimal cut-off values for the Cox regression model were calculated based on ROC analysis. Results Sixty-five patients died during the observation period. Nonsurvivors (n = 65; sclerostin 57.31 ± 30.28 pmol/L) had higher plasma sclerostin levels than survivors (n = 535; sclerostin 47.52 ± 24.87 pmol/L) (p = 0.0036). Kaplan–Meier curve showed that baseline plasma sclerostin concentrations were associated with all-cause mortality in stable kidney transplant recipients (p = 0.0085, log-rank test). After multiple Cox regression analysis, plasma levels of sclerostin remained an independent predictor of all-cause mortality (hazard ratio, 1.011; 95% CI 1.002–1.020; p = 0.0137). Conclusions Baseline plasma sclerostin is an independent risk factor for all-cause mortality in patients after kidney transplantation.

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Sclerostin vaccination mitigates estrogen deficiency induction of bone mass loss and microstructure deterioration

Cited by 9 publications

References 45 publications

Sclerostin Antibody Mitigates Estrogen Deficiency-Inducted Marrow Lipid Accumulation Assessed by Proton MR Spectroscopy

Sclerostin Antibody Mitigates Estrogen Deficiency-Inducted Marrow Lipid Accumulation Assessed by Proton MR Spectroscopy

Update on Menopausal Hormone Therapy for Fracture Prevention

Sclerostin is an independent risk factor for all-cause mortality in kidney transplant recipients

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