Abstract
Context
Sleeve gastrectomy (SG), the most common metabolic and bariatric surgery in adolescents, is associated with bone loss. Marrow adipose tissue (MAT) is a dynamic endocrine organ that responds to changes in nutrition and might serve as a novel biomarker for bone health. Two types of MAT have been described, which differ in anatomic location—proximal regulated MAT vs distal constitutive MAT.
Objective
To determine the effects of SG on volumetric bone mineral density (vBMD) and MAT in adolescents with obesity. We hypothesized that SG would lead to a decrease in vBMD and differential changes in MAT.
Design
12-month prospective study in 52 adolescents with moderate-to-severe obesity (38 female; mean age:17.5 ± 2.2 years; mean BMI 45.2 ± 7.0 kg/m2), comprising 26 subjects before and after SG and 26 nonsurgical controls.
Main Outcome Measures
Lumbar vBMD by quantitative computed tomography; MAT of the lumbar spine, femur and tibia by proton magnetic resonance spectroscopy; abdominal fat and thigh muscle by magnetic resonance imaging.
Results
Adolescents lost 34.1 ± 13.1 kg after SG vs 0.3 ± 8.4 kg in the control group (P < 0.001). Lumbar vBMD decreased in the SG group (P = 0.04) and this change was associated with a reduction in weight and muscle area (P < 0.05) and an increase in lumbar MAT (P = 0.0002). MAT of the femur and tibia decreased after SG vs controls (P < 0.05); however, the differences were no longer significant after controlling for change in weight.
Conclusion
SG in adolescents decreased lumbar vBMD associated with an increase in lumbar MAT and decrease in extremity MAT. This demonstrates differential changes of regulated MAT in the lumbar spine and constitutive MAT in the distal skeleton in adolescents in response to SG.
Keywords: marrow adipose tissue, proton MR spectroscopy, sleeve gastrectomy, adolescents, bone mineral density, quantitative computed tomography
The prevalence of childhood obesity has increased over the last decades with a concomitant rise in metabolic and bariatric surgery (MBS) procedures. Bariatric surgery is highly effective in treating cardiometabolic complications of obesity, such as type 2 diabetes mellitus, hypertension, and dyslipidemia (1-4). Sleeve gastrectomy is the most commonly performed MBS procedure in adolescents and adults (5), with demonstrated success in reducing weight and treating obesity-related comorbidities (6). Despite its effectiveness in reducing weight and cardiometabolic complications, studies in adults have demonstrated detrimental effects of sleeve gastrectomy on the skeleton with reduction in bone mineral density (BMD) (7-11).
Adolescence is a crucial time of bone accrual and interventions that prevent bone accrual during this critical period might have detrimental effects later in life (12). Only a few studies have examined the effects of bariatric surgery on the skeleton in adolescents (13-15), 1 in patients undergoing sleeve gastrectomy (15) and 2 after Roux-en-Y gastric bypass (13, 14); all demonstrated reductions of BMD and BMD z-score by dual-energy x-ray-absorptiometry (DXA). DXA determines areal BMD, which is susceptible to artifactual changes following extreme weight loss (16) and might overestimate bone loss following bariatric surgery. Quantitative computed tomography (QCT) measures volumetric bone mineral density (vBMD), and although vBMD by QCT measurements are also affected by overlying soft tissues, the error is smaller and more uniform than BMD assessed by DXA (17). One study in adolescents undergoing sleeve gastrectomy examined vBMD and bone microarchitecture of the peripheral skeleton (distal radius and tibia) using high-resolution computed tomography (CT) and found reductions in trabecular vBMD but increases in cortical vBMD at both sites, and no change in strength estimates (15). Of note, no study has assessed vBMD of the lumbar spine, a critical site of bone loss, in adolescents after MBS.
Skeletal integrity is determined not only by BMD but also by its microenvironment. Recent studies have identified marrow adipose tissue (MAT) as a dynamic endocrine organ that responds to nutritional challenges and that might serve as a novel biomarker for bone quality (18-21). The distribution and composition of MAT varies by age and skeletal site. At birth, bone marrow is red or hematopoietic and consists of multipotent mesenchymal stem cells. With aging, differentiation of mesenchymal stem cells into adipocytes leads to conversion of red to yellow (fatty) marrow, which is typically complete by the age of 25 (22). Two types of MAT have been described, which differ by skeletal site and composition. Regulated MAT (rMAT), which responds to environmental stimuli such as nutritional, hormonal, and weight changes, is found in the proximal skeleton and contains more saturated lipids compared with constitutive MAT (cMAT), which is comparatively more inert, and is found in distal skeletal sites and contains more unsaturated lipids (23). Studies in adults have identified unsaturated lipids within MAT as a novel imaging biomarker showing positive effects on bone health in postmenopausal women with osteoporotic fractures (24) and on bone health and metabolic risk in patients with type 2 diabetes (21).
Advances in magnetic resonance (MR) technology allow the longitudinal assessment of MAT quantity and composition noninvasively and without ionizing radiation, which is particularly important in adolescents (25, 26). Only a few studies in adults have assessed MAT quantity following MBS. In studies examining women who had undergone Roux-en-Y gastric bypass, a decrease in MAT was found in patients with type 2 diabetes (27, 28) while there was no change in patients without diabetes (7, 27, 28). Only 1 study has examined MAT following sleeve gastrectomy and found an increase in MAT content following MBS (7). No study has examined the effect of MBS on MAT in adolescents.
Therefore, the purpose of our study was to determine the effects of sleeve gastrectomy on lumbar vBMD and lumbar and extremity MAT content and composition in adolescents with moderate-to-severe obesity. We hypothesized that sleeve gastrectomy would lead to a decrease in vBMD and differential changes in MAT quantity and composition depending on skeletal site.
Materials and Methods
Our study was approved by our Institutional Review Board and compliant with Health Insurance Portability and Accountability Act regulations. Written informed consent/assent was obtained from all subjects.
Subjects
Subjects with moderate-to-severe obesity (BMI of ≥35 kg/m2) and at least 1 obesity-related comorbidity or a BMI of ≥40 kg/m2, were recruited from several tertiary care obesity treatment centers. Inclusion criteria were ages from 14 to 21 years for all subjects, and for the surgical group, a plan to undergo sleeve gastrectomy. Exclusion criteria were pregnancy, history of medical disorders known to affect bone metabolism, recent use of medication that may affect bone metabolism (other than calcium, vitamin D, or hormonal contraception), use of antipsychotic medications that cause weight gain if treated for less than 6 months or if the dose was not stable for at least 2 months prior to study enrollment, untreated thyroid dysfunction or if the subject was on a stable dose of replacement levothyroxine for less than 3 months before study enrollment, history of smoking more than 10 cigarettes per day or of substance abuse (per DSM-5), weight >200 kg (due to limitations of the magnetic resonance imaging [MRI] scanner) and contraindications to MRI, such as the presence of metallic implant or claustrophobia. The decision to undergo bariatric surgery was made by the treating physician.
Study visits were performed at baseline (prior to sleeve gastrectomy) and 12 months after sleeve gastrectomy. Control (nonsurgical) subjects were also examined at baseline and were followed for 12 months. Each participant underwent a history and physical examination, fasting blood tests, QCT, proton MR spectroscopy (1H-MRS), and MRI at baseline and 12 months. Nonsurgical controls received diet and exercise counseling throughout the study. All participants received calcium and vitamin D supplementation as previously described (15).
Quantitative computed tomography
The vBMD of the lumbar spine (L1-L2) was assessed using a 16-multidetector-row CT scanner (LightSpeed Pro, GE Healthcare, Waukesha, WI, USA). Subjects were placed supine in the CT scanner on a calibration phantom (Mindways Software, Inc., Austin, TX, USA), and helical scanning of L1-L2 was performed using the following parameters: 120kV, 100mA, slice thickness of 2.5 mm, FOV of 500 mm and table height of 144 mm.
Analysis of vBMD was performed with QCTPro software (Mindways Software, Inc., Austin, TX) as previously described (29).
Proton MR spectroscopy
Subjects underwent 1H-MRS of the first and second lumbar vertebrae (L1-L2), the femoral mid-diaphysis, and distal tibial metaphysis. All studies were performed on a 3.0 Tesla MR imaging system (Siemens Trio; Siemens Medical Systems, Erlangen, Germany) after an overnight fast. Single-voxel 1H-MRS data were acquired by using a point-resolved spatially localized spectroscopy pulse sequence without water suppression (TR/TE 3000/30, 8 acquisitions, 1024 data). For each voxel placement, automated optimization of gradient shimming was performed (19).
Fitting of all 1H-MRS data was performed using LCModel (version 6.3-0K, Stephen Provencher, Oakville, Canada). Metabolite quantification was performed using eddy current correction and water scaling. A customized fitting algorithm for bone marrow analysis provided estimates for all lipid signals combined (0.9, 1.3, 1.6, 2.3, 5.2 and 5.3 ppm). Unsaturated fatty acid estimates at 5.3 and 5.2 ppm and saturated fatty acid estimates at 1.3 ppm were quantified. Lipid resonances were scaled to unsuppressed water peak (4.7 ppm) and expressed in lipid-to-water ratios (LWR).
Magnetic resonance imaging
MRI (Siemens Trio; Siemens Medical Systems, Erlangen, Germany) was performed to determine abdominal adipose tissue depots and thigh muscle. Single slice MRI was performed at the midportion of the fourth lumbar vertebra (L4) and the mid-thigh, equidistant to the femoral head and medial femoral condyle (axial T1-weighted fast spin-echo pulse sequence, 10 mm slice thickness, 40 cm field of view, TR 300 msec, TE 12 msec, echo train of 4, 512 × 512 matrix, 1 number of acquisitions). Visceral adipose tissue (VAT) and abdominal subcutaneous adipose tissue compartments, as well as mid-thigh muscle cross-sectional areas (cm2) were determined based on offline analysis of tracings obtained using commercial software (VITRAK, Merge/eFilm, Milwaukee, WI).
All QCT, 1H-MRS, and MRI acquisitions and analyses were performed blinded to the group assignment under the supervision of a musculoskeletal radiologist with 15 years of experience (M.A.B.).
Calciotropic hormones
The following fasting blood tests were obtained: calcium, phosphate, 25(OH)vitamin D, and parathyroid hormone (PTH) (intra- and interassay coefficient of variations ≤3%) (LabCorp, Burlington, NC, USA).
Statistical analysis
Statistical analyses were performed using JMP Statistical Discovery Software (Version 12, SAS Institute, Carey, NC). Baseline characteristics and 12-month changes between the sleeve gastrectomy and control groups were compared by the Student t-test or the Wilcoxon Rank Sum test depending on the data distribution; 12-month changes within groups were assessed using paired t-tests. Multivariable analysis was used to determine differences between groups controlling for baseline weight and 12-month change in weight. Linear regression analysis was performed to determine associations between change in weight and body composition and change in lumbar spine vBMD and in MAT content and composition. Pearson correlation coefficients are reported. P < 0.05 was used to denote significance. Data are presented as mean ± standard deviation.
Results
Baseline characteristics
Subject characteristics, body composition, vBMD, and MAT in the sleeve gastrectomy and control groups are shown in Table 1. The study group included 52 subjects (mean age 17.5 ± 2.2 years, range 13 to 21 years), 38 females and 14 males, with moderate-to-severe obesity (mean BMI: 45.2 ± 7.0 kg/m2, range 35 to 64 kg/m2) who underwent sleeve gastrectomy (n = 26) or were followed without surgery (n = 26). Both groups had comparable age, calciotropic hormones, lumbar spine vBMD and lumbar, femoral and tibial MAT. The surgical group had a higher baseline weight and BMI (Table 1). Clinical characteristics have been previously reported in a subset of subjects (15), however, no QCT, MRI or 1H-MRS data have been published.
Table 1.
Baseline Characteristics
| SG (n = 26) | Controls (n = 26) | P value | |
|---|---|---|---|
| Age, years | 18.0 ± 2.1 | 17.0 ± 2.3 | 0.1 |
| Female/male, n | 19/7 | 19/7 | 1.0 |
| Weight, kg | 136.6 ± 24.3 | 119.8 ± 23.0 | 0.01 |
| BMI, kg/m2 | 47.9 ± 7.0 | 42.5 ± 6.0 | 0.005 |
| Serum calcium, mg/dLa | 9.3 ± 0.3 | 9.3 ± 0.4 | 0.8 |
| Serum 25-hydoxyvitamin D, ng/mLa | 23.9 ± 9.3 | 22.7 ± 7.4 | 0.6 |
| Serum phosphorous, mg/dLa | 3.5 ± 0.9 | 3.6 ± 0.7 | 0.7 |
| Serum parathyroid hormone, pg/mLa | 43.5 ± 15.4 | 39.8 ± 13.8 | 0.5 |
| Visceral adipose tissue, cm2 | 123 ± 46 | 102 ± 73 | 0.2 |
| Subcutaneous adipose tissue, cm2 | 744 ± 147 | 674 ± 155 | 0.1 |
| Thigh muscle, cm2 | 180 ± 34 | 177 ± 26 | 0.7 |
| QCT lumbar vBMD, mg/cm3 | 200.2 ± 39.4 | 197.5.0 ± 35.2 | 0.8 |
| QCT lumbar vBMD z-score | 0.36 ± 1.57 | 0.34 ± 1.29 | 0.9 |
| Lumbar MAT, LWR | 0.37 ± 0.17 | 0.39 ± 0.19 | 0.7 |
| Femoral diaphysis MAT, LWR | 4.89 ± 2.96 | 3.27 ± 2.41 | 0.07 |
| Distal tibial MAT, LWR | 11.39 ± 3.02 | 9.45 ± 3.37 | 0.06 |
Abbreviations: BMI, body mass index; LWR, lipid-to-water ratio; MAT, marrow adipose tissue; QCT, quantitative computed tomography; SG, sleeve gastrectomy; vBMD, volumetric bone mineral density.
a Normal ranges: serum calcium: normal range: 8.5-10.5 mg/dL; serum 25-hydoxyvitamin D (ng/mL): 20-80 ng/mL; serum phosphorous (mg/dL): 2.6-4.5 mg/dL; serum parathyroid hormone (pg/mL): 10-60 pg/mL
Effects of bariatric surgery on weight and body composition
Mean weight loss was -34.1 ± 13.1 kg in the sleeve gastrectomy group (P < 0.001) while there was no significant change in the control group. VAT, subcutaneous adipose tissue, and thigh muscle decreased significantly in the sleeve gastrectomy group (P < 0.001) but not in the control group (Table 2).
Table 2.
Effects of Bariatric Surgery on Body Composition and Calciotropic Hormones in the 12 Months After Sleeve Gastrectomy vs Nonsurgical Care (Controls)
| Variable | Treatment | Baseline | 12 months | Delta 12 months | P value within group | P value between groups 12-month change | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Weight, kg | SG | 136.6 | ± | 24.3 | 102.5 | ± | 26.6 | −34.1 | ± | 13.1 | <0.001 | <0.001 a |
| controls | 119.8 | ± | 23.0 | 120.1 | ± | 23.7 | 0.3 | ± | 8.4 | 0.4 | ||
| BMI, kg/m2 | SG | 47.9 | ± | 7.0 | 35.8 | ± | 8.7 | −12.1 | ± | 4.6 | <0.001 | <0.001 a |
| controls | 42.5 | ± | 6.0 | 42.2 | ± | 6.5 | −0.3 | ± | 3.1 | 0.9 | ||
| Visceral adipose tissue, cm2 | SG | 123 | ± | 46 | 64 | ± | 36 | −57 | ± | 34 | <0.001 | <0.001 a |
| controls | 102 | ± | 73 | 113 | ± | 61 | 11 | ± | 36 | 0.3 | ||
| Subcutaneous adipose tissue, cm2 | SG | 744 | ± | 147 | 469 | ± | 180 | −271 | ± | 144 | <0.001 | <0.001 a |
| controls | 674 | ± | 155 | 707 | ± | 171 | 23 | ± | 80 | 0.3 | ||
| Thigh muscle, cm2 | SG | 180 | ± | 34 | 151 | ± | 28 | −28 | ± | 22 | <0.001 | <0.001 a |
| controls | 177 | ± | 26 | 180 | ± | 24 | 3 | ± | 11 | 0.5 | ||
| Serum calcium, mg/dL | SG | 9.3 | ± | 0.3 | 9.3 | ± | 0.2 | −0.01 | ± | 0.3 | 0.9 | 0.4 |
| controls | 9.3 | ± | 0.4 | 9.2 | ± | 0.4 | −0.08 | ± | 0.3 | 0.2 | ||
| Serum 25(OH) vitamin D, ng/mL | SG | 23.9 | ± | 9.3 | 28.4 | ± | 12.8 | 4.2 | ± | 12.0 | 0.1 | 0.1 |
| controls | 22.7 | ± | 7.4 | 22.3 | ± | 6.0 | −1.0 | ± | 7.0 | 0.5 | ||
| Serum PTH, pg/mL | SG | 43.5 | ± | 15.4 | 37.2 | ± | 11.4 | −7.1 | ± | 16.0 | 0.2 | 0.4 |
| controls | 39.8 | ± | 13.8 | 40.1 | ± | 21.4 | −1.1 | ± | 15.0 | 0.8 | ||
| Serum phosphorus, mg/dL | SG | 3.5 | ± | 0.9 | 3.8 | ± | 0.6 | 0.30 | ± | 1.05 | 0.2 | 0.4 |
| controls | 3.6 | ± | 0.7 | 3.8 | ± | 0.5 | 0.08 | ± | 0.61 | 0.5 |
Abbreviations: BMI, body mass index; PTH, parathyroid hormone; SG, sleeve gastrectomy.
a significant after controlling for baseline weight
Effects of bariatric surgery on calciotropic hormones
Mean serum calcium, 25(OH)-vitamin D, PTH, and phosphorous did not change significantly after sleeve gastrectomy or within the control group and were within the normal range in both groups at 12 months (Table 2).
Effects of bariatric surgery on bone mineral density
Lumbar spine vBMD by QCT decreased within the sleeve gastrectomy group (P = 0.04), while there was no significant change in the control group, however, 12-month change between the groups only revealed a trend (P = 0.08).
Effects of bariatric surgery on marrow adipose tissue
In the axial skeleton, lumbar spine total MAT content and unsaturated MAT increased following sleeve gastrectomy compared with control (P ≤ 0.049), while saturated MAT increased after sleeve gastrectomy (P = 0.0007), but the change between groups only showed a trend (P = 0.07) (Table 3).
Table 3.
Effects of Bariatric Surgery on Bone Mineral Density and Marrow Adipose Tissue in the 12 Months After Sleeve Gastrectomy vs Nonsurgical Care (Controls)
| Variable | Treatment | Baseline | 12 months | Delta 12 months | P value within group | P value between groups 12-month change | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| QCT lumbar vBMD, mg/cm3 | SG | 200.2 | ± | 39.4 | 193.3 | ± | 37.5 | −6.9 | ± | 15.5 | 0.04 | 0.08 |
| controls | 197.5 | ± | 35.2 | 198.2 | ± | 33.8 | 0.7 | ± | 13.7 | 0.8 | ||
| Lumbar total MAT, LWR | SG | 0.37 | ± | 0.17 | 0.49 | ± | 0.25 | 0.11 | ± | 0.13 | 0.001 | 0.049 a |
| controls | 0.39 | ± | 0.19 | 0.42 | ± | 0.16 | 0.03 | ± | 0.12 | 0.28 | ||
| Lumbar unsaturated MAT, LWR | SG | 0.03 | ± | 0.01 | 0.04 | ± | 0.03 | 0.01 | ± | 0.03 | 0.1 | 0.02 a |
| controls | 0.03 | ± | 0.01 | 0.02 | ± | 0.01 | −0.007 | ± | 0.02 | 0.1 | ||
| Lumbar saturated MAT, LWR | SG | 0.30 | ± | 0.15 | 0.39 | ± | 0.19 | 0.09 | ± | 0.10 | 0.0007 | 0.07 |
| controls | 0.32 | ± | 0.17 | 0.34 | ± | 0.15 | 0.03 | ± | 0.10 | 0.2 | ||
| Femoral diaphyseal total MAT, LWR | SG | 4.89 | ± | 2.96 | 3.92 | ± | 2.33 | −0.90 | ± | 2.39 | 0.09 | 0.01 |
| controls | 3.27 | ± | 2.41 | 4.51 | ± | 3.13 | 1.24 | ± | 3.12 | 0.07 | ||
| Femoral diaphyseal unsaturated MAT, LWR | SG | 0.43 | ± | 0.29 | 0.30 | ± | 0.24 | −0.12 | ± | 0.21 | 0.02 | 0.09 |
| controls | 0.35 | ± | 0.42 | 0.38 | ± | 0.42 | 0.03 | ± | 0.35 | 0.7 | ||
| Femoral diaphyseal saturated MAT, LWR | SG | 3.35 | ± | 1.95 | 2.93 | ± | 1.73 | −0.38 | ± | 1.70 | 0.3 | 0.04 |
| controls | 2.40 | ± | 1.77 | 3.31 | ± | 2.28 | 0.92 | ± | 2.38 | 0.08 | ||
| Tibial total MAT, LWR | SG | 11.39 | ± | 3.02 | 10.01 | ± | 2.00 | −1.33 | ± | 2.47 | 0.04 | 0.002 a |
| controls | 9.45 | ± | 3.37 | 11.32 | ± | 2.73 | 2.11 | ± | 3.46 | 0.01 | ||
| Tibial unsaturated MAT, LWR | SG | 1.31 | ± | 0.62 | 1.45 | ± | 0.76 | 0.19 | ± | 0.87 | 0.39 | 0.7 |
| controls | 1.54 | ± | 1.03 | 1.86 | ± | 0.79 | 0.31 | ± | 0.92 | 0.14 | ||
| Tibia saturated MAT, LWR | SG | 8.82 | ± | 2.41 | 7.72 | ± | 1.65 | −1.16 | ± | 1.87 | 0.02 | 0.001 a |
| controls | 7.24 | ± | 2.56 | 8.51 | ± | 2.22 | 1.50 | ± | 2.64 | 0.02 |
Abbreviations: LWR, lipid-to-water ratio; MAT, marrow adipose tissue; QCT, quantitative computed tomography; SG, sleeve gastrectomy; vBMD, volumetric bone mineral density.
a significant after controlling for baseline weight
In the peripheral skeleton, MAT behaved differently compared with the axial skeleton. Total and saturated femoral and tibial MAT decreased following sleeve gastrectomy compared with the control group (P ≤ 0.04) while unsaturated MAT of the femur decreased within the sleeve gastrectomy group (P = 0.02) (Fig. 1). After controlling for change in weight, the differences were no longer significant (P > 0.5). In the control group, peripheral MAT increased, consistent with the physiologic conversion of hematopoietic to fatty marrow during adolescence (Table 3).
Figure 1.
Proton magnetic resonance spectroscopy (1H-MRS) of the lumbar spine and distal tibia in a 16-year-old female prior to and 12 months after sleeve gastrectomy (weight loss 45.8 kg). Marrow adipose tissue (MAT) content in lipid-to-water ratio (LWR) by 1H-MRS of L1 (A and B) increased following sleeve gastrectomy (MAT pre–sleeve gastrectomy 0.60 LWR, MAT post–sleeve gastrectomy 1.06 LWR), while MAT content of the distal tibia (C and D) decreased (MAT pre–sleeve gastrectomy 10.66 LWR, MAT post–sleeve gastrectomy 7.39 LWR). For purposes of visual comparison, the amplitudes of unsuppressed water are scaled identically.
Association between body composition, bone mineral density, and marrow adipose tissue
QCT-measured bone loss at the lumbar spine over 12 months was significantly associated with weight loss and muscle loss (P < 0.05) (Table 4). Within the axial skeleton, lumbar spine total MAT content and saturated and unsaturated MAT increased with weight loss, while unsaturated MAT increased with VAT loss (P = 0.005).
Table 4.
Pairwise Correlation of 12-Month Changes in Weight and Body Composition and 12-Month Change in BMD and MAT
| 12-month change | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| 12-month change | Spine vBMD | Lumbar total MAT | Lumbar unsat MAT | Lumbar sat MAT | Femoral total MAT | Femoral unsat MAT | Femoral sat MAT | Tibial total MAT | Tibial unsat MAT | Tibial sat MAT |
| Weight | R = 0.31, P = 0.03 | R = −0.33, P = 0.03 | R = −0.40, P = 0.009 | R = −0.32, P = 0.04 | R = 0.31, P = 0.04 | R = 0.24, P = 0.1 | R = 0.32, P = 0.03 | R = 0.46, P = 0.004 | R = 0.19, P = 0.3 | R = 0.46, P = 0.004r |
| Visceral adipose tissue | R = 0.23, P = 0.1 | R = −0.26, P = 0.1 | R = −0.43, P = 0.005 | R = −0.24, P = 0.1 | R = 0.35, P = 0.02 | R = 0.24, P = 0.1 | R = 0.32, P = 0.03 | R = 0.46, P = 0.004 | R = 0.19, P = 0.3 | R = 0.46, P = 0.003 |
| Muscle | R = 0.30, P = 0.049 | R = −0.26, P = 0.1 | R = −0.32, P = 0.04 | R = −0.23, P = 0.1 | R = 0.28, P = 0.06 | R = 0.31, P = 0.04 | R = 0.25, P = 0.1 | R = 0.45, P = 0.005 | R = 0.21, P = 0.3 | R = 0.44, P = 0.005 |
Abbreviations: MAT, marrow adipose tissue; sat, saturated; unsat, unsaturated; sat: saturated vBMD, volumetric bone mineral density.
In the peripheral skeleton, loss of weight and loss of VAT over 12 months were significantly associated with loss of total and saturated femoral and tibial MAT (P ≤ 0.04). Muscle loss was associated with loss of unsaturated MAT in the femur and total and saturated MAT in the tibia (P ≤ 0.04) (Table 4).
There was an inverse association between 12-month change in lumbar vBMD and lumbar MAT (r = −0.48; P = 0.0002), while there were no associations between lumbar vBMD and MAT composition and MAT content at peripheral skeletal sites (P > 0.1).
Discussion
Our study shows that sleeve gastrectomy in adolescents with moderate-to-severe obesity decreased lumbar vBMD associated with an increase in lumbar MAT, while extremity MAT decreased. We also demonstrate differential changes in MAT composition with an increase in unsaturated lipids of the axial skeleton (lumbar spine) and a decrease in saturated lipids of the peripheral skeleton (femur and tibia). This demonstrates differential changes of proximal (lumbar) regulated MAT and distal (extremity) constitutive MAT in adolescents in response to weight loss associated with sleeve gastrectomy.
Childhood obesity is an epidemic, and as a consequence, the use of MBS surgery to manage severe obesity in adolescents is on the rise, with sleeve gastrectomy being the most commonly performed procedure (3, 6, 30). Although sleeve gastrectomy is extremely effective in helping patients to achieve weight loss and prevent the early onset of comorbidities, our study suggests that bone loss may be a complication of such surgeries in adolescents. Our study shows for the first time a loss of vBMD of the lumbar spine, assessed by QCT, in adolescents following sleeve gastrectomy. Only few studies have examined the effects of MBS on the skeleton in adolescents (13-15), all of which have shown a reduction of areal BMD by DXA. DXA is influenced by extreme changes in soft tissues, as can be seen after MBS, which might overestimate bone loss (16). QCT, which measures vBMD can overcome some of these challenges and is less susceptible to extreme changes in body size (17). Our observed decline in lumbar vBMD supports the DXA data (13-15) and confirms that the observed reduction in areal BMD is not an artifact of the extreme changes in soft tissues. In our study, loss of lumbar spine vBMD was accompanied by a significant increase in lumbar MAT, consistent with studies in female adolescents and adults with anorexia nervosa and obesity, showing reciprocal associations between lumbar spine BMD and MAT (18, 20, 21, 31).
Only a few studies have examined the effect of bariatric surgery on MAT in adults; however, no such study has been performed in adolescents. Only 1 study in 10 adults has examined the effect of sleeve gastrectomy on total MAT content and revealed an increase in MAT of the lumbar spine and femoral diaphysis following sleeve gastrectomy (7). Our results of an increase in lumbar MAT are consistent with these results. However, we observed a decrease in femoral and tibial MAT, confirming that the effects of sleeve gastrectomy on the peripheral skeleton differ in adolescents compared with adults. These changes lost significance after controlling for change in weight, confirming that these changes are driven primarily by weight loss. Adolescence is a critical time of bone accrual and conversion of hematopoietic (red) to fatty (yellow) marrow, which has different fat content and composition (22). Recent translation research has identified 2 types of MAT which differ in skeletal site and composition. Regulated MAT is found in the proximal (axial) skeleton and contains more saturated lipids while constitutive MAT is found in the distal (peripheral) skeleton and contains more unsaturated lipids (23). We observed an increase in unsaturated lipids in the proximal skeleton (lumbar spine) and a decrease in saturated lipids in the peripheral skeleton (femur and tibia) with a decrease in unsaturated lipids in the femur. Prior studies in adults with osteoporosis and type 2 diabetes showed lower unsaturated lipids within MAT in patients with type 2 diabetes and in patients with osteoporotic fragility fractures (21, 24). The significance of our findings and how they relate to future fracture risk requires longer-term longitudinal studies. Studies in adults who had undergone MBS have shown a higher risk for any type of fracture, especially extremity fractures, while a study examining the risk of major osteoporotic fractures (proximal humerus, wrist and distal forearm, spine) found a statistically higher risk only in patients who had undergone gastric bypass (32). Our findings also support the presence of different types of MAT that behave differently in response to undernutrition. While in adults regulated MAT has originally been described as more responsive to environmental stimuli, including weight changes, constitutive MAT has been described as less responsive and more inert (23). Our findings demonstrate that both MAT depots are responsive to nutrition and weight changes in adolescence. Of note, MAT increased in the peripheral skeleton in controls, consistent with physiologic increase of MAT during adolescence. However, sleeve gastrectomy led to a disruption in this physiologic increase with changes in MAT content and composition.
Increased MAT has been found in states of chronic undernutrition (18, 25) but also in obesity (19), especially in visceral obesity (20). In our study, the amount of weight and muscle loss was associated with lumbar bone loss and concomitant increase in lumbar MAT, suggesting that subjects who lost the most weight following sleeve gastrectomy had the highest loss of BMD and the highest increase in lumbar MAT, which would support studies in anorexia nervosa patients who have high MAT content (18). In fact, we observed an inverse association between 12-month change in lumbar MAT and vBMD, supporting the hypothesis that MAT negatively affects bone health (33). We further showed an association between the amount of VAT loss and increase in lumbar MAT unsaturated lipids, suggesting that loss of cardiometabolically detrimental VAT has positive effects on MAT composition, being associated with higher unsaturated lipid content, which has been shown to have protecting effects on bone (24) and is lower in patients with type 2 diabetes (21, 24, 34). In the peripheral skeleton, weight loss and loss of VAT were significantly associated with total and saturated femoral and tibial MAT loss, showing that axial and peripheral MAT depots respond differently to nutritional challenges.
Mechanisms that impact bone after sleeve gastrectomy are multifactorial and include mechanical unloading from weight loss and loss of muscle mass, consistent with our observed correlation between the amount of weight loss and loss of muscle and decline of vBMD (35). Moreover, calcium absorption can decrease after sleeve gastrectomy (36); therefore, we supplemented calcium and vitamin D in our study, and calcium, vitamin D, phosphorous, and PTH levels remained within normal limits 12 months after sleeve gastrectomy. However, despite adequate vitamin D and calcium intake, adolescents lost bone following sleeve gastrectomy, and this may reflect alterations in gastrointestinal and neuropeptide signaling that contribute to bone loss after MBS.
The primary limitation of our study is the relatively small sample size. However, even with a limited number of subjects in each group, we were able to detect a difference in BMD and MAT content and composition 12 months after sleeve gastrectomy. We also followed our subjects only for 12 months and longer follow-up is necessary to examine how our findings translate into fracture risk. Strengths of our study include the assessments of vBMD by QCT, detailed assessment of axial and peripheral MAT content and composition using 1H-MRS, and detailed assessment of body composition by MRI.
In conclusion, sleeve gastrectomy in adolescents with obesity decreased lumbar spine vBMD associated with an increase in lumbar MAT, while extremity MAT decreased. Sleeve gastrectomy was associated with an increase in unsaturated lipids of the axial skeleton and a decrease in saturated lipids of the peripheral skeleton reflecting differential regulation of MAT types in adolescents in response to surgical weight loss. Longer-term longitudinal studies are necessary to determine how these changes translate into fracture risk.
Acknowledgments
Financial Support: This work was supported by the following grants: National Institutes of Health (NIH) NIDDK R01 DK103946-01A1 (M.M., M.A.B.), NIH K23DK110419-01 (V.S.), P30-DK040561 (V.S., F.C.S.), K24DK109940 (M.A.B.), K24 HD071843 (M.M.), L30 DK118710 (F.C.S.), NIH P30-DK057521 (V.S.).
Glossary
Abbreviations
- 1H-MRS
proton MR spectroscopy
- BMD
bone mineral density
- CT
computed tomography
- DXA
dual-energy x-ray absorptiometry
- LWR
lipid-to-water ratio
- MAT
marrow adipose tissue
- MBS
metabolic and bariatric surgery
- MR
magnetic resonance
- PTH
parathyroid hormone
- QCT
quantitative computed tomography
- SG
sleeve gastrectomy
- VAT
visceral adipose tissue
- vBMD
volumetric bone mineral density
Additional Information
Disclosure Summary: The authors do not have any conflicts of interests to disclose.
Data Availability
Restrictions apply to the availability of data generated or analyzed during this study to preserve patient confidentiality or because they were used under license. The corresponding author will on request detail the restrictions and any conditions under which access to some data may be provided.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Restrictions apply to the availability of data generated or analyzed during this study to preserve patient confidentiality or because they were used under license. The corresponding author will on request detail the restrictions and any conditions under which access to some data may be provided.