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Inverse correlation between trabecular bone volume and bone marrow adipose tissue in rats treated with osteoanabolic
Samantha Costa1, Heather Fairfield1, Michaela R Reagan1
1Maine Medical Center Research Institute, Scarborough, ME, USA; University of Maine Graduate School of Biomedical Science and Engineering, Orono, ME, USA; Tufts University School of Medicine, Boston, MA, USA.
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.
Insights
Sclerostin-neutralizing antibodies (Scl-Ab) and human parathyroid hormone (hPTH) treatments impact bone marrow adiposity differently. Long-term Scl-Ab reduces adiposity by increasing bone, while hPTH directly decreases adipocytes in males.
Area of Science:
- Bone Biology and Disease
- Endocrinology
- Skeletal Therapeutics
Background:
- Unmet clinical need exists for improved treatments for skeletal diseases like osteoporosis and cancer-induced bone disease.
- Novel therapeutic targets and mechanisms of action for established therapies are incompletely understood.
- Anabolic treatments, including sclerostin-neutralizing antibodies (Scl-Ab) and human parathyroid hormone (hPTH), show promise for stimulating bone formation.
Purpose of the Study:
- To define the effects of anabolic treatments (Scl-Ab and hPTH) on bone and bone marrow adipocytes (BMA).
- To compare two methods for assessing marrow adiposity: within total tissue area (T.Ar) and within marrow area (Ma.Ar).
Main Methods:
- Male and female rats received vehicle, Scl-Ab (3 or 50 mg/kg weekly), or hPTH (75 μg/kg daily) for 4 or 26 weeks.
- Histological analyses of distal femurs were performed using a novel ImageJ method.
- Adipocyte number, circumference, and total adipose area were quantified within T.Ar and Ma.Ar.
Main Results:
- After 26 weeks, a significant inverse correlation between bone and total tissue adiposity (in T.Ar) was observed in both sexes (p < 0.0001).
- Scl-Ab treatments showed no significant effect on adipocytes based on marrow adiposity (in Ma.Ar) after 26 weeks.
- Chronic hPTH treatment significantly reduced adipocyte number and adiposity within both T.Ar and Ma.Ar in males.
Conclusions:
- Long-term Scl-Ab treatment decreases total tissue adiposity primarily by increasing trabecular bone, reducing available space for adipocytes.
- hPTH treatment directly reduces adipocyte number and adiposity, particularly in males.
- The choice of adiposity measurement (T.Ar vs. Ma.Ar) is critical and should be considered based on study relevance.
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