The effects of sclerostin antibody plus parathyroid hormone (1–34) on bone formation in ovariectomized rats

Wu, Jian; Cai, Xianhua; Qin, Xing-Xing; Liu, Yanxi

doi:10.1007/s00391-017-1219-1

Cited by 10 publications

(26 citation statements)

References 41 publications

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“…In contrast to Scl-Ab, hPTH substantially increases both bone anabolic (formation) and catabolic (resorption) activities, although the former is more pronounced during the first few months of therapy in humans. hPTH stimulates osteogenesis in PTH1R + osteoprogenitors [18] and increases the activity of mature osteoblasts, resulting in increased bone formation and bone mass [1,2,19]. This activation may be in part due to enhanced Wnt signaling, but other pathways are certainly operative [18,20].…”

Section: Introductionmentioning

confidence: 99%

Inverse correlation between trabecular bone volume and bone marrow adipose tissue in rats treated with osteoanabolic agents

Costa

Fairfield

Reagan

2019

Bone

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There is currently an unmet clinical need for improved treatments for skeletal diseases such as osteoporosis and cancer-induced bone disease. This is due in part to a paucity of novel targets and an incomplete understanding of the mechanisms of action for established therapies. We defined the effects of anabolic treatments on bone and the bone marrow adipocyte (BMA). Sclerostinneutralizing antibodies (Scl-Ab, romosozumab, human parathyroid hormone (hPTH, 1-34), and hPTH/hPTHrP analogues (eg. teriparatide and abaloparatide) stimulate bone formation and have been studied in clinical trials for severe osteoporosis. In this study, eight-week-old male and female rats were administered vehicle, Scl-Ab (3 mg/kg or 50 mg/kg) weekly, or hPTH (1-34) (75 μg/kg) daily for 4 or 26 weeks. Histological analyses of distal femura were performed using a novel ImageJ method for trabecular bone and bone marrow adipose tissue (BMAT). Adipocyte number, circumference, and total adipose area were compared within the tissue area (T.Ar) or the marrow area (Ma.Ar), (defined as the T.Ar minus the trabecular bone area). After 26 weeks of treatment, a significant inverse correlation between bone and tissue adiposity (total adipocyte area divided by T.Ar) were observed in males and females (p<0.0001). However, there were no significant correlations between bone and marrow adiposity (total adipocyte area divided by Ma.Ar) for either sex after 26 weeks of treatments. Scl-Ab treatments also resulted in no effect on adipocytes based on marrow adiposity for either sex after 26 weeks. However, chronic hPTH treatments significantly reduced adipocyte number and adiposity within the T.Ar and within the Ma.Ar in males. Overall, our data suggest that with long-term treatment, Scl-Abs decrease total tissue adiposity mainly by increasing trabecular bone, resulting in an overall reduction in the space in which adipocytes can reside. These findings were determined by developing and comparing two

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Section: Introductionmentioning

confidence: 99%

Inverse correlation between trabecular bone volume and bone marrow adipose tissue in rats treated with osteoanabolic agents

Costa

Fairfield

Reagan

2019

Bone

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“…In four studies [ 33 , 35 , 58 , 59 ], ovariectomy surgery was performed to induce osteopenia. In the initial sample size, 223 ovariectomized (OVX) and 153 sham-ovariectomized (Sham) rats were identified.…”

Section: Resultsmentioning

confidence: 99%

Antisclerostin Effect on Osseointegration and Bone Remodeling

Couto

Fernandes

Saavedra-Silva

et al. 2023

JCM

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Objective: This study reviewed the literature on local or systemic administration of antisclerostin, presenting results associated with osseointegration of dental/orthopedic implants and stimulation of bone remodeling. Materials and Methods: An extensive electronic search was conducted through MED-LINE/PubMed, PubMed Central, Web of Science databases and specific peer-reviewed journals to identify case reports, case series, randomized controlled trials, clinical trials and animal studies comparing either the systemic or local administration of antisclerostin and its effect in osseointegration and bone remodeling. Articles in English and with no restriction on period were included. Results: Twenty articles were selected for a full-text, and one was excluded. Finally, 19 articles were included in the study (16 animal studies and 3 randomized control trials). These studies were divided into two groups, which evaluated (i) osseointegration and (ii) bone remodeling potential. Initially 4560 humans and 1191 animals were identified. At least 1017 were excluded from the studies (981 humans and 36 animals), totaling 4724 subjects who completed (3579 humans and 1145 animals). (a) Osseointegration: 7 studies described this phenomenon; 4 reported bone-implant contact, which increased in all included studies. Similar results were found for bone mineral density, bone area/volume and bone thickness. (b) Bone remodeling: 13 studies were used for description. The studies reported an increase in BMD with sclerostin antibody treatment. A similar effect was found for bone mineral density/area/volume, trabecular bone and bone formation. Three biomarkers of bone formation were identified: bone-specific alkaline phosphatase (BSAP), osteocalcin and procollagen type 1 N-terminal Pro-peptide (P1NP); and markers for bone resorption were: serum C-telopeptide (sCTX), C-terminal telopeptides of type I collagen (CTX-1), β-isomer of C-terminal telopeptides of type I collagen (β-CTX) and tartrate-resistant acid phosphatase 5b (TRACP-5b). There were limitations: low number of human studies identified; high divergence in the model used (animal or human); the variance in the type of Scl-Ab and doses of administration; and the lack of reference quantitative values in the parameters analyzed by authors’ studies (many articles only reported qualitative information). Conclusion: Within the limitations of this review and carefully observing all data, due to the number of articles included and the heterogeneity existing, more studies must be carried out to better evaluate the action of the antisclerostin on the osseointegration of dental implants. Otherwise, these findings can accelerate and stimulate bone remodeling and neoformation.

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“…Romosozumab is a humanized monoclonal antibody against sclerostin that has been approved by the FDA to treat osteoporosis in postmenopausal women. This antibody also has activity against sclerostin in rodents (45,46). All injections were subcutaneous.…”

Section: Methodsmentioning

confidence: 99%

“…SOSTi (Romosozumab) is a humanized monoclonal antibody that binds sclerostin, preventing binding to LRP5/6 and increasing Wnt pathway activation and bone formation (43). It is FDA-approved for the treatment of osteoporosis (20,44) and has activity in rodents in addition to humans (45,46).…”

Section: Significancementioning

confidence: 99%

The effect of parathyroid hormone on osteogenesis is mediated partly by osteolectin

Zhang

Cohen

Shen

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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We previously described a new osteogenic growth factor, osteolectin/Clec11a, which is required for the maintenance of skeletal bone mass during adulthood. Osteolectin binds to Integrin α11 (Itga11), promoting Wnt pathway activation and osteogenic differentiation by leptin receptor+ (LepR+) stromal cells in the bone marrow. Parathyroid hormone (PTH) and sclerostin inhibitor (SOSTi) are bone anabolic agents that are administered to patients with osteoporosis. Here we tested whether osteolectin mediates the effects of PTH or SOSTi on bone formation. We discovered that PTH promoted Osteolectin expression by bone marrow stromal cells within hours of administration and that PTH treatment increased serum osteolectin levels in mice and humans. Osteolectin deficiency in mice attenuated Wnt pathway activation by PTH in bone marrow stromal cells and reduced the osteogenic response to PTH in vitro and in vivo. In contrast, SOSTi did not affect serum osteolectin levels and osteolectin was not required for SOSTi-induced bone formation. Combined administration of osteolectin and PTH, but not osteolectin and SOSTi, additively increased bone volume. PTH thus promotes osteolectin expression and osteolectin mediates part of the effect of PTH on bone formation.

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The effects of sclerostin antibody plus parathyroid hormone (1–34) on bone formation in ovariectomized rats

Cited by 10 publications

References 41 publications

Inverse correlation between trabecular bone volume and bone marrow adipose tissue in rats treated with osteoanabolic agents

Inverse correlation between trabecular bone volume and bone marrow adipose tissue in rats treated with osteoanabolic agents

Antisclerostin Effect on Osseointegration and Bone Remodeling

The effect of parathyroid hormone on osteogenesis is mediated partly by osteolectin

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