The complex pathophysiology of bone fragility in obesity and type 2 diabetes mellitus: therapeutic targets to promote osteogenesis

Fractures associated with Type2 diabetes (T2DM) are major public health concerns in an increasingly obese and aging population. Patients with obesity or T2DM have normal or better than normal bone mineral density but at an increased risk for fractures. Hence it is crucial to understand the pathophysiology and mechanism of how T2DM and obesity result in altered bone physiology leading to increased fracture risk. Although enhanced osteoclast mediated bone resorption has been reported for these patients, the most notable observation among patients with T2DM is the reduction in bone formation from mostly dysfunction in osteoblast differentiation and survival. Studies have shown that obesity and T2DM are associated with increased adipogenesis which is most likely at the expense of reduced osteogenesis and myogenesis considering that adipocytes, osteoblasts, and myoblasts originate from the same progenitor cells. Furthermore, emerging data point to an inter-relationship between bone and metabolic homeostasis suggesting that these physiologic processes could be under the control of common regulatory pathways. Thus, this review aims to explore the complex mechanisms involved in lineage differentiation and their effect on bone pathophysiology in patients with obesity and T2DM along with an examination of potential novel pharmacological targets or a re-evaluation of existing drugs to improve bone homeostasis

Effect of Weight Loss, Exercise, or Both on Undercarboxylated Osteocalcin and Insulin Secretion in Frail, Obese Older Adults

Background. Obesity exacerbates age-related decline in glucometabolic control. Undercarboxylated osteocalcin (UcOC) regulates pancreatic insulin secretion. The long-term effect of lifestyle interventions on UcOC and insulin secretion has not been investigated. Methods. One hundred seven frail, obese older adults were randomized into the control (N=27), diet (N=26), exercise (N=26), and diet-exercise (N=28) groups for 1 year. Main outcomes included changes in UcOC and disposition index (DI). Results. UcOC increased in the diet group (36 ± 11.6%) but not in the other groups (P<0.05 between groups). Although similar increases in DI occurred in the diet-exercise and diet groups at 6 months, DI increased more in the diet-exercise group (92.4 ± 11.4%) than in the diet group (61.9 ± 15.3%) at 12 months (P<0.05). UcOC and body composition changes predicted DI variation in the diet group only (R2=0.712), while adipocytokines and physical function changes contributed to DI variation in both the diet (∆R2=0.140 and 0.107) and diet-exercise (∆R2=0.427 and 0.243) groups (P<0.05 for all). Conclusions. Diet, but not exercise or both, increases UcOC, whereas both diet and diet-exercise increase DI. UcOC accounts for DI variation only during active weight loss, while adipocytokines and physical function contribute to diet-exercise-induced DI variation, highlighting different mechanisms for lifestyle-induced improvements in insulin secretion. This trial was registered with ClinicalTrials.gov number NCT00146107

Weight loss, exercise, or both and physical function in obese older adults

BACKGROUND: Obesity exacerbates the age-related decline in physical function and causes frailty in older adults; however, the appropriate treatment for obese older adults is controversial. METHODS: In this 1-year, randomized, controlled trial, we evaluated the independent and combined effects of weight loss and exercise in 107 adults who were 65 years of age or older and obese. Participants were randomly assigned to a control group, a weightmanagement (diet) group, an exercise group, or a weight-management-plus-exercise (diet–exercise) group. The primary outcome was the change in score on the modified Physical Performance Test. Secondary outcomes included other measures of frailty, body composition, bone mineral density, specific physical functions, and quality of life. RESULTS: A total of 93 participants (87%) completed the study. In the intention-to-treat analysis, the score on the Physical Performance Test, in which higher scores indicate better physical status, increased more in the diet–exercise group than in the diet group or the exercise group (increases from baseline of 21% vs. 12% and 15%, respectively); the scores in all three of those groups increased more than the scores in the control group (in which the score increased by 1%) (P<0.001 for the between-group differences). Moreover, the peak oxygen consumption improved more in the diet–exercise group than in the diet group or the exercise group (increases of 17% vs. 10% and 8%, respectively; P<0.001); the score on the Functional Status Questionnaire, in which higher scores indicate better physical function, increased more in the diet–exercise group than in the diet group (increase of 10% vs. 4%, P<0.001). Body weight decreased by 10% in the diet group and by 9% in the diet–exercise group, but did not decrease in the exercise group or the control group (P<0.001). Lean body mass and bone mineral density at the hip decreased less in the diet–exercise group than in the diet group (reductions of 3% and 1%, respectively, in the diet–exercise group vs. reductions of 5% and 3%, respectively, in the diet group; P<0.05 for both comparisons). Strength, balance, and gait improved consistently in the diet–exercise group (P<0.05 for all comparisons). Adverse events included a small number of exercise-associated musculoskeletal injuries. CONCLUSIONS: These findings suggest that a combination of weight loss and exercise provides greater improvement in physical function than either intervention alone

Effect of aerobic or resistance exercise, or both, on intermuscular and visceral fat and physical and metabolic function in older adults with obesity while dieting

BACKGROUND: Obesity exacerbates age-related effects on body composition and physical and metabolic function. Which exercise mode is most effective in mitigating these deleterious changes in dieting older adults with obesity is unknown. METHODS: In a randomized controlled trial, we performed a head-to-head comparison of aerobic (AEX), resistance (REX), or combination (COMB) exercise during matched ~10% weight loss in 160 obese older adults. Prespecified analyses compared 6-month changes in intermuscular adipose tissue (IMAT) and visceral adipose tissue (VAT) assessed using MRI, insulin sensitivity index (ISI) by oral glucose tolerance test, physical function using Modified Physical Performance Test (PPT), VO2peak, gait speed, and knee strength by dynamometry. RESULTS: IMAT and VAT decreased more in COMB than AEX and REX groups (IMAT; -41% vs -28% and -23% and VAT: -36% vs -19% and -21%; p = .003 to .01); IMAT and VAT decreased in all groups more than control (between-group p \u3c .001). ISI increased more in COMB than AEX and REX groups (86% vs 50% and 39%; p = .005 to .03). PPT improved more in COMB than AEX and REX groups, while VO2peak improved more in COMB and AEX than REX group (all p \u3c .05). Knee strength improved more in COMB and REX than AEX group (all p \u3c .05). Changes in IMAT and VAT correlated with PPT (r = -0.28 and -0.39), VO2peak (r = -0.49 and -0.52), gait speed (r = -0.25 and -0.36), and ISI (r = -0.49 and -0.52; all p \u3c .05). CONCLUSIONS: Weight loss plus combination aerobic and resistance exercise was most effective in improving ectopic fat deposition and physical and metabolic function in older adults with obesity

Novel Adipokines and Their Role in Bone Metabolism: A Narrative Review

The growing burden of obesity and osteoporosis is a major public health concern. Emerging evidence of the role of adipokines on bone metabolism has led to the discovery of novel adipokines over the last decade. Obesity is recognized as a state of adipose tissue inflammation that adversely affects bone health. Adipokines secreted from white adipose tissue (WAT) and bone marrow adipose tissue (BMAT) exerts endocrine and paracrine effects on the survival and function of osteoblasts and osteoclasts. An increase in marrow fat is implicated in osteoporosis and, hence, it is crucial to understand the complex interplay between adipocytes and bone. The objective of this review is to summarize recent advances in our understanding of the role of different adipokines on bone metabolism. Methods: This is a comprehensive review of the literature available in PubMED and Cochrane databases, with an emphasis on the last five years using the keywords. Results: Leptin has shown some positive effects on bone metabolism; in contrast, both adiponectin and chemerin have consistently shown a negative association with BMD. No significant association was found between resistin and BMD. Novel adipokines such as visfatin, LCN-2, Nesfatin-1, RBP-4, apelin, and vaspin have shown bone-protective and osteoanabolic properties that could be translated into therapeutic targets. Conclusion: New evidence suggests the potential role of novel adipokines as biomarkers to predict osteoporosis risk, and as therapeutic targets for the treatment of osteoporosis

The rs4646 and rs12592697 Polymorphisms in CYP19A1 Are Associated with Disease Progression among Patients with Breast Cancer from Different Racial/ethnic Backgrounds.

Given the racial/ethnic disparities in breast cancer, we evaluated the association between CYP19A1 single nucleotide polymorphisms (SNPs) on disease progression in women with breast cancer from different racial/ethnic backgrounds. This is a cross-sectional analysis of data from 327 women with breast cancer in the Expanded Breast Cancer Registry program of the University of New Mexico. Stored DNA samples were analyzed for CYP19A1 SNPs using a custom designed microarray panel. Genotype-phenotype correlations were analyzed. Of the 384 SNPs, 2 were associated with clinically significant outcomes, the rs4646 and rs12592697. The T allele for the rs4646 was associated with advanced stage of the disease at the time of presentation (odds ratio OR:1.8, confidence intervals CI: 1.05-3.13, p<0.05) and a more progressive disease (OR: 2.1 CI: 1.1-4.0, p=0.04). For the rs12592697, the variant T allele was more frequent in Hispanic women and associated with a more progressive disease (OR: 2.05 CI: 1.0-4.0, p=0.04). However, further analysis according to menopausal status showed that the association between these 2 SNPs with disease progression or the stage at diagnosis are confined only to postmenopausal women. The odds ratios of disease progression among postmenopausal women carrying the T allele for the rs4646 and rs12592697 are 3.05 (1.21, 7.74, p=0.02) and 3.80 (1.24, 11.6, p=0.02), respectively. Regardless, differences in disease progression among the different genotypes for both SNPs disappeared after adjustment for treatment. In summary, the rs4646 and the rs12592697 SNPs in CYP19A1 are associated with differences in disease progression in postmenopausal women. However, treatment appears to mitigate the differences in genetic risk.ClinicalTrials.govs Identifier: NCT00322894(https://clinicaltrials.gov/ct2/show/NCT00322894?term=new+mexico+breast+cancer+registry&rank=1