Estrogen deficiency induces bone loss by increasing bone resorption, in part, through upregulation of receptor activator of nuclear factor κB ligand (RANKL). RANKL is secreted by osteoblasts and osteocytes, but more recently also bone marrow (pre-)adipocytes have been shown to express RANKL. Estrogen deficiency increases bone marrow adipose tissue (BMAT). The aim of this study was to determine the effect of ovariectomy on RANKL protein expression by bone marrow adipocytes in C3H/HeJ mice. 14 weeks old, female C3H/HeJ mice (n=20) were randomized to sham surgery (Sham) or ovariectomy (OVX). After 4 weeks animals were euthanized. BMAT volume fraction (Ad.V/Ma.V) was quantified by polyoxometalate-based contrast enhanced nanoCT. The percentage of RANKL positive bone marrow adipocytes (RANKL.Pos.N.Ad/N.Ad) and the percentage of RANKL positive osteoblasts covering the bone surface (RANKL.Pos.B.Pm/B.Pm) were quantified in the distal metaphysis of immunohistochemically stained sections of the left femora. The effects of OVX were analyzed by Student's t-test or Mann-Whitney U test. RANKL was detected in osteoblasts, osteocytes and bone marrow adipocytes. OVX significantly increased mean RANKL.Pos.N.Ad/N.Ad (mean±SD: Sham: 42±18%; OVX: 62±14%; P = 0.029), as well as Ad.V/Ma.V (median (IQR): Sham: 1.4 (4.9)%; OVX: 7.2 (7.3)%: P = 0.008), compared to sham surgery. We show that ovariectomy increased both the percentage of RANKL positive bone marrow adipocytes and the total BMAT volume fraction in C3H/HeJ mice. This way RANKL produced by bone marrow adipocytes could be an important contributor to ovariectomy induced bone loss in C3H/HeJ mice.

This review focuses on providing physicians with insights into the complex relationship between bone marrow adipose tissue (BMAT) and bone health, in the context of weight loss through caloric restriction or metabolic and bariatric surgery (MBS), in people living with obesity (PwO). We summarize the complex relationship between BMAT and bone health, provide an overview of noninvasive imaging techniques to quantify human BMAT, and discuss clinical studies measuring BMAT in PwO before and after weight loss. The relationship between BMAT and bone is subject to variations based on factors such as age, sex, menopausal status, skeletal sites, nutritional status, and metabolic conditions. The Bone Marrow Adiposity Society (BMAS) recommends standardizing imaging protocols to increase comparability across studies and sites, they have identified both water–fat imaging (WFI) and spectroscopy (¹H-MRS) as accepted standards for in vivo quantification of BMAT. Clinical studies measuring BMAT in PwO are limited and have shown contradictory results. However, BMAT tends to be higher in patients with the highest visceral adiposity, and inverse associations between BMAT and bone mineral density (BMD) have been consistently found in PwO. Furthermore, BMAT levels tend to decrease after caloric restriction-induced weight loss. Although weight loss was associated with overall fat loss, a reduction in BMAT did not always follow the changes in fat volume in other tissues. The effects of MBS on BMAT are not consistent among the studies, which is at least partly related to the differences in the study population, skeletal site, and duration of the follow-up. Overall, gastric bypass appears to decrease BMAT, particularly in patients with diabetes and postmenopausal women, whereas sleeve gastrectomy appears to increase BMAT. More research is necessary to evaluate changes in BMAT and its connection to bone metabolism, either in PwO or in cases of weight loss through caloric restriction or MBS, to better understand the role of BMAT in this context and determine the local or systemic factors involved.

Bone marrow adipose tissue (BMAT) increases after menopause, and increased BMAT is associated with osteoporosis and prevalent vertebral fractures. Peroxisome proliferator-activated receptor-γ (PPARγ) activation promotes adipogenesis and inhibits osteoblastogenesis; therefore, PPARγ is a potential contributor to the postmenopausal increase in BMAT and decrease in bone mass. The aim of this study is to determine if PPARγ inhibition can prevent ovariectomy-induced BMAT increase and bone loss in C3H/HeJ mice. Fourteen-week-old female C3H/HeJ mice ( n = 40) were allocated to four intervention groups: sham surgery (Sham) or ovariectomy (OVX; isoflurane anesthesia) with either vehicle (Veh) or PPARγ antagonist administration (GW9662; 1 mg·kg⁻¹·day⁻¹, daily intraperitoneal injections) for 3 wk. We measured BMAT volume, adipocyte size, adipocyte number. and bone structural parameters in the proximal metaphysis of the tibia using polyoxometalate-based contrast enhanced-nanocomputed topogaphy. Bone turnover was measured in the contralateral tibia using histomorphometry. The effects of surgery and treatment were analyzed by two-way ANOVA. OVX increased the BMAT volume fraction (Sham + Veh: 2.9 ± 2.7% vs. OVX + Veh: 8.1 ± 5.0%: P < 0.001), average adipocyte diameter (Sham + Veh: 19.3 ± 2.6 μm vs. OVX + Veh: 23.1 ± 3.4 μm: P = 0.001), and adipocyte number (Sham + Veh: 584 ± 337cells/μm³ vs. OVX + Veh: 824 ± 113cells/μm³: P = 0.03), while OVX decreased bone volume fraction (Sham + Veh: 15.5 ± 2.8% vs. OVX + Veh: 7.7 ± 1.9%; P < 0.001). GW9662 had no effect on BMAT, bone structural parameters, or bone turnover. In conclusion, ovariectomy increased BMAT and decreased bone volume in C3H/HeJ mice. The PPARγ antagonist GW9662 had no effect on BMAT or bone volume in C3H/HeJ mice, suggesting that BMAT accumulation is regulated independently of PPARγ in C3H/HeJ mice.

Objectives This study aimed to determine the effect of bariatric surgery‐induced weight loss on bone marrow adipose tissue (BMAT) and bone mineral density (BMD) in postmenopausal, nondiabetic women. Methods A total of 14 postmenopausal, nondiabetic women with obesity who were scheduled for laparoscopic Roux‐en‐Y gastric bypass surgery (RYGB) were included in this study. Vertebral bone marrow fat signal fraction was determined by quantitative chemical shift magnetic resonance imaging, and vertebral volumetric BMD (vBMD) was determined by quantitative computed tomography before surgery and 3 and 12 months after surgery. Data were analyzed by linear mixed model. Results Body weight [mean (SD)] decreased after surgery from 108 (13) kg at baseline to 89 (12) kg at 3 months and 74 (11) kg at 12 months (P < 0.001). BMAT decreased after surgery from 51% (8%) at baseline to 50% (8%) at 3 months and 46% (7%) at 12 months (P = 0.004). vBMD decreased after surgery from 101 (26) mg/cm³ at baseline to 94 (28) mg/cm³ at 3 months (P = 0.003) and 94 (28) mg/cm³ at 12 months (P = 0.035). Changes in BMAT and vBMD were not correlated (ρ = −0.10 and P = 0.75). Calcium and vitamin D concentrations did not change after surgery. Conclusions RYGB decreases both BMAT (after 12 months) and vBMD (both after 3 months and 12 months) in postmenopausal, nondiabetic women. Changes in BMAT and vBMD were not correlated. These findings suggest that BMAT does not contribute to bone loss following RYGB.