期刊
JOURNAL OF BONE AND MINERAL RESEARCH
卷 32, 期 1, 页码 24-33出版社
WILEY-BLACKWELL
DOI: 10.1002/jbmr.3003
关键词
ABALOPARATIDE; PTHrP; ANABOLIC AGENTS; BONE FORMATION; OSTEOPOROSIS
资金
- Radius Health
Abaloparatide is a novel 34-amino acid peptide selected to be a potent and selective activator of the parathyroid hormone receptor (PTH1R) signaling pathway with 41% homology to PTH(1-34) and 76% homology to PTHrP(1-34). A 12-month treatment study was conducted in osteopenic ovariectomized (OVX) rats to characterize the mechanisms by which abaloparatide increases bone mass. Sprague-Dawley (SD) rats were subjected to OVX or sham surgery at age 6 months and left untreated for 3 months to allow OVX-induced bone loss. Ten OVX rats were euthanized after this bone depletion period, and the remaining OVX rats received daily subcutaneous injections of vehicle (n=18) or abaloparatide at 1, 5, or 25g/kg/d (n=18/dose level) for 12 months. Sham controls (n=18) received vehicle daily. Bone densitometry and biochemical markers of bone formation and resorption were assessed longitudinally, and L-3 vertebra and tibia were collected at necropsy for histomorphometry. Abaloparatide increased biochemical bone formation markers without increasing bone resorption markers or causing hypercalcemia. Abaloparatide increased histomorphometric indices of bone formation on trabecular, endocortical, and periosteal surfaces without increasing osteoclasts or eroded surfaces. Abaloparatide induced substantial increases in trabecular bone volume and density and improvements in trabecular microarchitecture. Abaloparatide stimulated periosteal expansion and endocortical bone apposition at the tibial diaphysis, leading to marked increases in cortical bone volume and density. Whole-body bone mineral density (BMD) remained stable in OVX-Vehicle controls while increasing 25% after 12 months of abaloparatide (25g/kg). Histomorphometry and biomarker data suggest that gains in cortical and trabecular bone mass were attributable to selective anabolic effects of abaloparatide, without evidence for stimulated bone resorption. (c) 2016 American Society for Bone and Mineral Research.
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