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). Sclerostin-neutralizing antibodies (Scl-Ab), romosozumab, human parathyroid hormone (hPTH, 1-34), and hPTH/hPTHrP analogues (e.g. 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 different methods of assessment of the marrow cavity, defined to either include or exclude trabecular bone. Thus, researchers should consider which adiposity measurement is more informative and relevant for their studies. Overall, our findings should help design improved therapies or combination treatments to target a potential new contributor to bone diseases: the bone marrow adipocyte.