The Impact of Interventional Weight Loss on Bone Marrow Adipose Tissue in People Living with Obesity and Its Connection to Bone Metabolism.

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.

Osteoporosis and Bone Marrow Adipose Tissue.

PURPOSE OF REVIEW: This review focuses on the recent findings regarding bone marrow adipose tissue (BMAT) concerning bone health. We summarize the variations in BMAT in relation to age, sex, and skeletal sites, and provide an update on noninvasive imaging techniques to quantify human BMAT. Next, we discuss the role of BMAT in patients with osteoporosis and interventions that affect BMAT. RECENT FINDINGS: There are wide individual variations with region-specific fluctuation and age- and gender-specific differences in BMAT content and composition. The Bone Marrow Adiposity Society (BMAS) recommendations aim to standardize imaging protocols to increase comparability across studies and sites. Water-fat imaging (WFI) seems an accurate and efficient alternative for spectroscopy (1H-MRS). Most studies indicate that greater BMAT is associated with lower bone mineral density (BMD) and a higher prevalence of vertebral fractures. The proton density fat fraction (PDFF) and changes in lipid composition have been associated with an increased risk of fractures independently of BMD. Therefore, PDFF and lipid composition could potentially be future imaging biomarkers for assessing fracture risk. Evidence of the inhibitory effect of osteoporosis treatments on BMAT is still limited to a few randomized controlled trials. Moreover, results from the FRAME biopsy sub-study highlight contradictory findings on the effect of the sclerostin antibody romosozumab on BMAT. Further understanding of the role(s) of BMAT will provide insight into the pathogenesis of osteoporosis and may lead to targeted preventive and therapeutic strategies.

Gender- and Age-Associated Differences in Bone Marrow Adipose Tissue and Bone Marrow Fat Unsaturation Throughout the Skeleton, Quantified Using Chemical Shift Encoding-Based Water-Fat MRI.

Bone marrow adipose tissue (BMAT) is a dynamic tissue which is associated with osteoporosis, bone metastasis, and primary bone tumors. The aim of this study is to determine region-specific variations and age- and gender-specific differences in BMAT and BMAT composition in healthy subjects. In this cross-sectional study, we included 40 healthy subjects (26 male: mean age 49 years, range 22-75 years; 14 female: mean age 50 years, range 29-71) and determined the bone marrow signal fat fraction and bone marrow unsaturation in the spine (C3-L5), pelvis, femora, and tibiae using chemical shift encoding-based water-fat imaging (WFI) with multiple gradient echoes (mGRE). Regions of interest covered the individual vertebral bodies, pelvis and proximal epimetaphysis, diaphysis, and distal epimetaphysis of the femur and tibia. The spinal fat fraction increased from cervical to lumbar vertebral bodies (mean fat fraction ( ± SD or (IQR): cervical spine 0.37 ± 0.1; thoracic spine 0.41 ± 0.08. lumbar spine 0.46 ± 0.01; p < 0.001). The femoral fat fraction increased from proximal to distal (proximal 0.78 ± 0.09; diaphysis 0.86 (0.15); distal 0.93 ± 0.02; p < 0.001), while within the tibia the fat fraction decreased from proximal to distal (proximal 0.92 ± 0.01; diaphysis 0.91 (0.02); distal 0.90 ± 0.01; p < 0.001). In female subjects, age was associated with fat fraction in the spine, pelvis, and proximal femur (ρ = 0.88 p < 0.001; ρ = 0.87 p < 0.001; ρ = 0.63 p = 0.02; ρ = 0.74 p = 0.002, respectively), while in male subjects age was only associated with spinal fat fraction (ρ = 0.40 p = 0.04). Fat fraction and unsaturation were negatively associated within the spine (r = -0.40 p = 0.01), while in the extremities fat fraction and unsaturation were positively associated (distal femur: r = 0.42 p = 0.01; proximal tibia: r = 0.47, p = 0.002; distal tibia: r = 0.35 p = 0.03), both independent of age and gender. In conclusion, we confirm the distinct, age- and gender-dependent, distribution of BMAT throughout the human skeleton and we show that, contradicting previous animal studies, bone marrow unsaturation in human subjects is highest within the axial skeleton compared to the appendicular skeleton. Furthermore, we show that BMAT unsaturation was negatively correlated with BMAT within the spine, while in the appendicular skeleton, BMAT and BMAT unsaturation were positively associated.

The Effect of Roux-en-Y Gastric Bypass on Bone Marrow Adipose Tissue and Bone Mineral Density in Postmenopausal, Nondiabetic Women.

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.

Ovariectomy increases RANKL protein expression in bone marrow adipocytes of C3H/HeJ mice.

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 bone marrow (pre)adipocytes have also 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 (OVX) on RANKL protein expression by bone marrow adipocytes in C3H/HeJ mice. Fourteen-week-old female C3H/HeJ mice (n = 20) were randomized to sham surgery (Sham) or OVX. After 4 wk animals were euthanized. BMAT volume fraction (BMAT volume/marrow volume) was quantified by polyoxometalate-based contrast-enhanced nano-computed tomography. The percentage of RANKL-positive bone marrow adipocytes (RANKL-positive bone marrow adipocytes/total adipocytes) and the percentage of RANKL-positive osteoblasts covering the bone surface (bone surface covered in RANKL-positive osteoblasts/total bone surface) were quantified in the distal metaphysis of immunohistochemically stained sections of the left femur. 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 percentage of RANKL-positive bone marrow adipocytes [mean (SD): Sham 42 (18)%; OVX 64 (12)%; P = 0.029] as well as BMAT volume/marrow volume [median (interquartile range): Sham 1.4 (4.9)%; OVX 7.2 (7.3)%; P = 0.008] compared with Sham. We show that OVX increased both the percentage of RANKL-positive bone marrow adipocytes and the total BMAT volume fraction in C3H/HeJ mice. Therefore, RANKL produced by bone marrow adipocytes could be an important contributor to OVX-induced bone loss in C3H/HeJ mice.

The effect of raloxifene on bone marrow adipose tissue and bone turnover in postmenopausal women with osteoporosis.

In patients with postmenopausal osteoporosis low bone volume is associated with high bone marrow adipose tissue (MAT). Moreover, high MAT is associated with increased fracture risk. This suggests an interaction between MAT and bone turnover, however literature remains equivocal. Estrogen treatment decreases MAT, but the effect of raloxifene, a selective estrogen receptor modulator (SERM) registered for treatment of postmenopausal osteoporosis, on MAT is not known. The aim of this study is 1] to determine the effect of raloxifene on MAT and 2] to determine the relationship between MAT and bone turnover in patients with osteoporosis. Bone biopsies from the MORE trial were analyzed. The MORE trial investigated the effects of raloxifene 60 or 120mg per day versus placebo on bone metabolism and fracture incidence in patients with postmenopausal osteoporosis. We quantified MAT in iliac crest biopsies obtained at baseline and after 2years of treatment (n=53; age 68.2±6.2years). Raloxifene did not affect the change in MAT volume after 2years compared to baseline (placebo: 1.89±10.84%, raloxifene 60mg: 6.31±7.22%, raloxifene 120mg: -0.77±10.72%), nor affected change in mean adipocyte size (placebo: 1.45 (4.45) µm, raloxifene 60mg: 1.45 (4.35) µm, raloxifene 120mg: 0.81 (5.21) µm). Adipocyte number tended to decrease after placebo treatment (-9.92 (42.88) cells/mm2) and tended to increase during raloxifene 60mg treatment (13.27 (66.14) cells/mm2) while adipocyte number remained unchanged in the raloxifene 120mg group, compared to placebo (3.06 (39.80) cells/mm2, Kruskal-Wallis p=0.055, post hoc: placebo vs raloxifene 60mg p=0.017). MAT volume and adipocyte size were negatively associated with osteoclast number at baseline (R2=0.123, p=0.006 and R2=0.098, p=0.016 respectively). Furthermore adipocyte size was negatively associated with osteoid surface (R2=0.067, p=0.049). Finally, patients with vertebral fractures had higher MAT volume (50.82 (8.80)%) and larger adipocytes (55.75 (3.14) µm) compared to patients without fractures (45.58 (12.72)% p=0.032, 52.77 (3.73) µm p=0.004 respectively). In conclusion, raloxifene did not affect marrow adipose tissue, but tended to increase adipocyte number compared to placebo. At baseline MAT volume and adipocyte size were associated with bone resorption, and adipocyte size was associated with osteoid surface, suggesting an interaction between bone marrow adipocytes and bone turnover. In addition, we found that high MAT volume and larger adipocyte size are associated with prevalent vertebral fractures in postmenopausal women with osteoporosis, indicating that adipocyte size affects bone quality independent of bone volume.

The effect of PPARγ inhibition on bone marrow adipose tissue and bone in C3H/HeJ mice.

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.