Deeptha Sukumar

Bone Metabolism in Obesity and Weight Loss

Excess body weight due to obesity has traditionally been considered to have a positive effect on bone; however, more recent findings suggest that bone quality is compromised. Both obesity and caloric restriction increase fracture risk and are regulated by endocrine factors and cytokines that have direct and indirect effects on bone and calcium absorption. Weight reduction will decrease bone mass and mineral density, but this varies by the individuals age, gender, and adiposity. Dietary modifications, exercise, and medications have been shown to attenuate the bone loss associated with weight reduction. Future obesity and weight loss trials would benefit from assessment of key hormones, adipokine and gut peptides that regulate calcium absorption, and bone mineral density and quality by using sensitive techniques in high-risk populations.

Areal and Volumetric Bone Mineral Density and Geometry at Two Levels of Protein Intake During Caloric Restriction: A Randomized, Controlled Trial

Weight reduction induces bone loss by several factors, and the effect of higher protein (HP) intake during caloric restriction on bone mineral density (BMD) is not known. Previous study designs examining the longer‐term effects of HP diets have not controlled for total calcium intake between groups and have not examined the relationship between bone and endocrine changes. In this randomized, controlled study, we examined how BMD (areal and volumetric), turnover markers, and hormones [insulin‐like growth factor 1 (IGF‐1), IGF‐binding protein 3 (IGFBP‐3), 25‐hydroxyvitamin D, parathyroid hormone (PTH), and estradiol] respond to caloric restriction during a 1‐year trial using two levels of protein intake. Forty‐seven postmenopausal women (58.0 ± 4.4 years; body mass index of 32.1 ± 4.6 kg/m2) completed the 1‐year weight‐loss trial and were on a higher (HP, 24%, n = 26) or normal protein (NP, 18%, n = 21) and fat intake (28%) with controlled calcium intake of 1.2 g/d. After 1 year, subjects lost 7.0% ± 4.5% of body weight, and protein intake was 86 and 60 g/d in the HP and NP groups, respectively. HP compared with NP diet attenuated loss of BMD at the ultradistal radius, lumbar spine, and total hip and trabecular volumetric BMD and bone mineral content of the tibia. This is consistent with the higher final values of IGF‐1 and IGFBP‐3 and lower bone‐resorption marker (deoxypyridinoline) in the HP group than in the NP group (p < .05). These data show that a higher dietary protein during weight reduction increases serum IGF‐1 and attenuates total and trabecular bone loss at certain sites in postmenopausal women.

The High Serum Monocyte Chemoattractant Protein-1 in Obesity Is Influenced by High Parathyroid Hormone and Not Adiposity

CONTEXT Chronic high levels of PTH may be associated with up-regulation of proteases and cytokines. Monocyte chemoattractant protein-1 (MCP-1) is an inflammatory cytokine, produced predominantly by macrophages and endothelial cells, and is expressed in adipose tissue. More recently it has been shown that PTH administration increases MCP-1 expression in osteoblasts. OBJECTIVES Because both PTH and MCP-1 levels are higher in obesity, the goal was to determine whether the high MCP-1 occurs only in the presence of high serum PTH and is independent of adiposity and examine its relationship with bone mineral density (BMD) and turnover. DESIGN, SETTING, AND PARTICIPANTS In this case-control clinical design, 111 eligible women were categorized into four groups: leaner women [body mass index (BMI) 23 ± 2 kg/m(2)] with normal or higher PTH and obese (BMI 44 ± 7 kg/m(2)) with normal or higher PTH. RESULTS Serum MCP-1 levels were higher (P < 0.01) in the high (PTH = 74.9 ± 27.0 pg/ml, MCP-1 = 421.5 ± 157.0 pg/ml) compared with normal PTH (PTH = 32.5 ± 10.4 pg/ml, MCP-1 = 322.5 ± 97.8 pg/ml) group, independent of BMI. C-reactive protein and adiponectin were influenced only by BMI and not PTH. MCP-1 was positively associated with osteocalcin and propeptide of type 1 collagen in the leaner (r > 0.3, P < 0.05) but not the obese women and was not associated with BMD in either group. CONCLUSIONS Together these data suggest that MCP-1 is higher only in the presence of increased PTH and that adiposity alone cannot explain the higher MCP-1 levels in obesity.

Moderate weight loss in obese and overweight men preserves bone quality

BACKGROUND Weight loss (WL) negatively affects bone mineral density (BMD) in older populations and has specifically been shown in women. OBJECTIVE In this prospective controlled trial, we examined variables of bone quality and endocrine changes after intentional WL in men. DESIGN Thirty-eight overweight and obese [mean ± SD body mass index (in kg/m²): 31.9 ± 4.4; age: 58 ± 6 y] men were recruited to either WL through caloric restriction or weight maintenance (WM) for 6 mo. RESULTS There was a -7.9 ± 4.4% and +0.2 ± 1.6% change in body weight in the WL and WM groups, respectively. There was a greater increase in femoral neck and total body BMD and bone mineral content (BMC) in the WM group than in the WL group (P-interaction effect < 0.05). In contrast, there was a trend for the tibia cortical thickness and area to decrease more in the WM group than in the WL group (P ≤ 0.08). There was a decrease in the periosteal circumference in both groups over time (P < 0.01) and no statistically significant changes in trabecular bone. Circulating total, free, and bioavailable estradiol decreased in the WL group compared with the WM group, and changes were different between groups (P < 0.05). Serum total and bioavailable testosterone increased in both groups (P < 0.01). Serum 25-hydroxyvitamin D increased to a similar extent in both groups (P < 0.05). CONCLUSIONS Moderate WL in overweight and obese men did not decrease BMD at any anatomical site or alter cortical and trabecular bone and geometry. Also, despite increased BMD at some sites when maintaining excess body weight, cortical bone showed a trend in the opposite direction.

The Effect of Obesity on the Relationship Between Serum Parathyroid Hormone and 25-Hydroxyvitamin D in Women

CONTEXT Obesity is associated with lower serum concentrations of 25-hydroxyvitamin D (25OHD) and higher intact PTH. The threshold of 25OHD needed to maximally suppress intact PTH has been suggested as a marker of optimal vitamin D status. OBJECTIVE In this study, we hypothesized that whereas the obese have a higher serum PTH and lower 25OHD, suppression of serum PTH by 25OHD would be independent of body weight. DESIGN, SETTING, AND PARTICIPANTS We performed a retrospective analysis on 383 women (ages 24-75 y) with a wide range of body weights (43-185 kg) who were stabilized to 1-1.2 g calcium/d for 1 month before blood draw. Body composition, serum PTH, 25OHD, calcium, and creatinine were measured. Locally weighted regression and smoothing scatterplots were used to depict the association between serum PTH and 25OHD. A nonlinear exponential model determined the point for near maximal suppression of PTH by 25OHD. RESULTS The point for near maximal suppression of PTH by 25OHD for all women (body mass index, 31.4 ± 7.7 kg/m²) occurred at a 25OHD concentration of 21.7 ng/mL (95% confidence interval, 28-48 ng/mL). No point of maximal suppression was found for nonobese women, yet in the obese women (n = 207; body mass index, >30 kg/m²) suppression of PTH occurred at a 25OHD concentration of 11.1 ng/mL (95% confidence interval, 4.7-17.5 ng/mL). CONCLUSIONS These results suggest that if PTH is suppressed at a lower serum 25OHD in the obese compared to the entire population, the lower average 25OHD concentrations in the obese may not have the same physiological significance as in the general population.

Does bone loss begin after weight loss ends? Results 2 years after weight loss or regain in postmenopausal women

ObjectiveShort-term weight loss is accompanied by bone loss in postmenopausal women. The longer-term impact of weight loss on bone in reduced overweight/obese women compared with women who regained their weight was examined in this study using a case-control design. MethodsPostmenopausal women (N = 42; mean [SD] body mass index, 28.3 [2.8] kg/m2; mean [SD] age, 60.7 [5.5] y) were recruited 2 years after the start of a 6-month weight loss trial; those who maintained their weight (weight loss maintainer [WL-M] group) were matched to a cohort of women who regained their weight (weight loss regainer [WL-R] group). Serum hormones and bone markers were measured in a subset. Bone mineral density (BMD) at the femoral neck, trochanter, spine, radius, and total body, and soft-tissue composition were taken at baseline, 0.5 years, and 2 years. ResultsDuring weight loss, both groups lost 9.3% (3.4%) of body weight, with no significant difference between the groups. After weight loss, weight change was −0.1% (2.7%) and 6.0% (3.3%) in the WL-M (n = 22) and WL-R (n = 20) groups, respectively. After 2 years, both groups lost BMD at the femoral neck and trochanter (P ⩽ 0.01), whereas only the WL-M group reduced BMD at the 1/3 radius (P < 0.001). There was greater BMD loss at the trochanter (−6.8% [5.7%]) and 1/3 radius (−4.5% [3.3%]) in the WL-M group compared with the WL-R group after 2 years. Multiple linear regression showed that change in leg fat mass (but not trunk fat) contributed to trochanter BMD loss (P < 0.05). ConclusionsAfter 2 years, there is no BMD recovery of weight reduction–induced bone loss, irrespective of weight regain. These data suggest that the period after weight loss may be an important point in time to prevent bone loss for those who maintain weight and those who regain weight.

VITAMIN D-BINDING PROTEIN LEVELS IN FEMALE PATIENTS WITH PRIMARY HYPERPARATHYROIDISM

OBJECTIVE To determine whether low levels of vitamin D-binding protein (DBP) are related to 25-hydroxyvitamin D (25[OH]D) deficiency in female patients with primary hyperparathyroidism (PHPT). METHODS Twenty-five female patients with PHPT (serum calcium level >10.2 mg/dL and intact parathyroid hormone (iPTH) level >66 pg/mL) and 25 healthy age- and body mass index-matched female control subjects were xaminod. Serum calcium and iPTH levels were determined by commercial laboratories. Levels of 25(OH)D and 1,25-dihydroxyvitamin D (1,25[OH]₂D) were determined by radioimmunoassay, and DBP level was determined by enzyme-linked immunosorbent assay. RESULTS Serum iPTH and calcium levels were higher in PHPT patients than control subjects (P<.001). Levels of 25(OH)D, albumin, and DBP were lower in the serum of PHPT patients than control subjects (P<.01). There were no significant differences in 1,25(OH)₂D and free 25(OH)D levels between PHPT patients and control subjects. DBP level was inversely correlated with calcium (r = -0.47; P<.01) and iPTH (r = -0.31; P<.05) levels. The 25(OH)D level correlated positively with both DBP (r = 0.28; P<.05) and albumin (r = 0.44; P<.05) levels. CONCLUSION Both serum 25(OH)D and DBP levels were lower in female patients with PHPT compared with control subjects. We suggest that a low DBP level contributes to the low 25(OH)D level observed in female PHPT patients. The etiology of the decrease in DBP and its relationship to calcium, 25(OH)D, and PTH levels require further investigation.

Serum Parathyroid Hormone Responses to Vitamin D Supplementation in Overweight/Obese Adults: A Systematic Review and Meta-Analysis of Randomized Clinical Trials

Obesity is often associated with vitamin D deficiency and secondary hyperparathyroidism. Vitamin D supplementation typically leads to the reductions in serum parathyroid hormone (PTH) levels, as shown in normal weight individuals. Meanwhile, the dose of vitamin D supplementation for the suppression of PTH may differ in overweight and obese adults. We conducted a systematic review and meta-analysis of randomized controlled trials to determine the dose of vitamin D supplementation required to suppress PTH levels in overweight/obese individuals. We identified 18 studies that examined overweight or obese healthy adults who were supplemented with varying doses of vitamin D3. The primary outcomes examined were changes in PTH and serum 25-hydroxyvitamin D (25OHD) levels from baseline to post-treatment. The results of the meta-analysis showed that there was a significant treatment effect of vitamin D supplementation on PTH, total standardized mean difference (SMD) (random effects) = −0.38 (95% CI = −0.56 to −0.20), t = −4.08, p < 0.001. A significant treatment effect of vitamin D supplementation was also found on 25OHD, total SMD (random effects) = 2.27 (95% CI = 1.48 to 3.06) t = 5.62, p < 0.001. Data from available clinical trials that supplemented adults with D3 ranging from 400 IU to 5714 IU, showed that 1000 IU of vitamin D supplementation best suppressed serum PTH levels, total SMD = −0.58, while vitamin D supplementation with 4000 IU showed the greatest increase in serum 25OH levels. Vitamin D and calcium supplementation of 700 IU and 500 mg, respectively, also showed a significant treatment effect on the suppression of PTH with a total SMD = −5.30 (95% CI = −9.72 to −0.88). In conclusion, the meta analysis of available clinical trials indicates that 1000 IU vitamin D supplementation can suppress serum PTH levels, while 4000 IU of vitamin D was associated with the largest increase in serum 25OHD levels in the overweight and obese population.

Vitamin D supplementation during short-term caloric restriction in healthy overweight/obese older women: Effect on glycemic indices and serum osteocalcin levels

The effect of vitamin D supplementation and caloric restriction (CR) on glycemic indices and osteocalcin (OC) is not clear. In this randomized controlled double blind trial, we examined whether vitamin D3 supplementation at 2500 IU/d (D) or placebo has differential effects on markers of insulin sensitivity and bone turnover in overweight/obese postmenopausal women during 6 weeks of caloric restriction (weight loss; WL, n = 39) compared to weight maintenance (WM, n = 37). Seventy-six women (57 ± 6 years) completed this study and the WL groups lost 4 ± 1% of body weight. Baseline serum 25-hydroxyvitamin D (25OHD) was 24.8 ± 5.6 ng/mL at baseline; the rise was greatest in WL-D group (p < 0.05). There was an interaction between vitamin D intake and weight on serum OC, insulin, glucose and markers of insulin sensitivity (p < 0.05). The change in OC was explained by changes in serum 25OHD and insulin (model R(2) = 25.6%). Overall, vitamin D supplementation and CR influence serum osteocalcin levels and modestly favor improvements in insulin sensitivity.

Intervariability among serum intact parathyroid hormone assays : a need for standardization

The measurement of parathyroid hormone (PTH) is both common and important in the field of osteoporosis for research and clinical diagnoses. Variations in the estimation of PTH have been reported [1,2] but have not focused on the more commonly used intact PTH (1–84) assays. Because we recently found marked variability between two PTH immunoradiometric assays (IRMA) in the lab, we evaluated PTH by a variety of methods using commercially available intact PTH (1–84) assay kits. This report highlights variability in PTH assay methods obtained by using various kits and assays from different companies. The goal was to define the inconsistencies between PTH assays when values range from normal to slightly high levels.