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

Abstract

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

Therapeutic Irradiation: Consequences for Bone and Bone Marrow Adipose Tissue

“…Well-studied osteoanabolic treatments are human parathyroid hormone (hPTH) and sclerostin antibody (Scl-Ab). Both of these agents stimulate bone formation, but through different modes of action (40, 41). Scl-Ab increases bone formation by inhibiting sclerostin binding to lipoprotein receptor protein (LRP) 5/6 that inhibits canonical WNT signaling and subsequently activating SSC differentiation into osteoblasts (40, 41).…”

“…Both of these agents stimulate bone formation, but through different modes of action (40, 41). Scl-Ab increases bone formation by inhibiting sclerostin binding to lipoprotein receptor protein (LRP) 5/6 that inhibits canonical WNT signaling and subsequently activating SSC differentiation into osteoblasts (40, 41). Scl-Ab also suppresses bone resorption through inhibitory effects on osteoclastogenesis regulators (41–43).…”

“…Scl-Ab increases bone formation by inhibiting sclerostin binding to lipoprotein receptor protein (LRP) 5/6 that inhibits canonical WNT signaling and subsequently activating SSC differentiation into osteoblasts (40, 41). Scl-Ab also suppresses bone resorption through inhibitory effects on osteoclastogenesis regulators (41–43). hPTH stimulates both anabolic and catabolic activities with a net gain in favor of the former, but there is evidence that hPTH anabolic capabilities are dependent on its ability to stimulate osteoclastogenesis (41, 44).…”

“…Scl-Ab also suppresses bone resorption through inhibitory effects on osteoclastogenesis regulators (41–43). hPTH stimulates both anabolic and catabolic activities with a net gain in favor of the former, but there is evidence that hPTH anabolic capabilities are dependent on its ability to stimulate osteoclastogenesis (41, 44). Not only do these osteoanabolic agents increase bone accrual, but they also decrease BMA (41).…”

MarrowQuant Across Aging and Aplasia: A Digital Pathology Workflow for Quantification of Bone Marrow Compartments in Histological Sections

“…While the BM is a particularly difficult organ for histological analysis, in part due to the soft and hard tissue that are juxtaposed, the overall analysis of its multiple components (bone, blood progenitors, adipocytes) provides important information to understand its physiopathology. Available histomorphometric analysis programs usually specialize in detecting individual components, and either require targeted staining protocols to detect specific components within the bone fraction, or use less adapted tools from the extramedullary adipose field to quantify the BMAd fraction [ (8,9,(20)(21)(22)(23)(24)(25)(26)(27); and also reviewed in (6)]. In order to reduce inter-observer variability and to quantify sections of entire murine bones rather than representative fields of view, automation and standardization of methods are key.…”