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

Long-term randomized trial of intensive versus symptomatic management in Paget's disease of bone: The PRISM-EZ study

It has been suggested that normalization of bone turnover may improve clinical outcome in Paget’s disease of bone (PDB) by preventing complications such as fractures and the progression of osteoarthritis. Here we investigated the long-term effects of a treatment strategy that aimed to normalize bone turnover in PDB with that of symptomatic treatment. The study group comprised 502 subjects who were enrolled into a three-year extension of the Paget’s Disease: Randomised Trial of Intensive versus Symptomatic Management (PRISM) study. Intensive bisphosphonate therapy was continued in 270 of these subjects with the aim of normalising serum total alkaline phosphatase (ALP) concentrations using zoledronic acid as the treatment of first-choice. Symptomatic treatment was continued in 232 subjects where bisphosphonates were given only if there was bone pain thought to be caused by PDB. The primary outcome was fracture and secondary outcomes were orthopaedic procedures, quality of life and bone pain, adjusted for baseline characteristics. Serum total ALP concentrations were significantly lower in the intensive group on entry to the study and the differences between groups increased as the study progressed. There were no clinically important differences in quality of life measures or bone pain between the treatment groups. Intensive treatment was associated with a non-significant increase in fracture risk (hazard ratio =1.90, [95% confidence interval 0.91 to 3.98], p=0.087), orthopaedic procedures (1.81 [0.71 to 4.61], p=0.214), and serious adverse events (relative risk 1.28 [0.96-1.42]. We conclude that long-term intensive bisphosphonate therapy confers no clinical benefit over symptomatic therapy and is associated with a non-significant increase in the risk of fractures, orthopaedic events and serious adverse events. The results of this study suggest that in patients with established PDB, bisphosphonate therapy should focus on control of symptoms rather than suppression of bone turnover

Bisphosphonate-associated femoral fracture: implication for management

Studies carried out on individuals being treated long term with bisphosphonates have provoked considerable interest and perplexity about the effect that these drugs have on bone turnover in the long run. In fact the experiences reported by numerous researchers tend to highlight how treatment with high doses of bisphosphonates over many years, of individuals with osteoporosis complicated by or secondary to neoplastic pathologies, causes a suppression of bone turnover that over time predisposes the bone to the accumulation of micro damage that can then result in complicated fractures, as in the case described here

Spontaneous Non-Traumatic Stress Fractures in Bilateral Femoral Shafts in a Patient Treated with Bisphosphonates

Bisphosphonates are potent inhibitors of bone resorption and widely used to treat osteoporosis. Extensive studies have shown that therapy with bisphosphonates improves bone density and decreases fracture risk. However, concerns have been raised about potential over-suppression of bone turnover during long-term use of bisphosphonates, resulting in increased susceptibility to and delayed healing of non-spinal fractures. We report a patient who sustained non-traumatic stress fractures in bilateral femoral shafts with delayed healing after long-term bisphosphonate therapy. She underwent open reduction and surgical internal fixation. Although bisphosphonates effectively prevent vertebral fractures, and their safety has been tested in randomized trials, we must emphasize the need for awareness of the possibility that long-term suppression of bone turnover with bisphosphonates may eventually lead to an accumulation of fatigue-induced damage and adverse skeletal effects such as delayed fracture healing

Oral Bisphosphonates and Risk of Subtrochanteric or Diaphyseal Femur Fractures in a Population-Based Cohort

Bisphosphonates are the primary therapy for postmenopausal and glucocorticoid-induced osteoporosis. Case series suggest a potential link between prolonged use of bisphosphonates and low-energy fracture of subtrochanteric or diaphyseal femur as a consequence of oversuppression of bone resorption. Using health care utilization data, we conducted a propensity score–matched cohort study to examine the incidence rates (IRs) and risk of subtrochanteric or diaphyseal femur fractures among oral bisphosphonate users compared with raloxifene or calcitonin users. A Cox proportional hazards model evaluated the risk of these fractures associated with duration of osteoporosis treatment. A total of 104 subtrochanteric or diaphyseal femur fractures were observed among 33,815 patients. The estimated IR of subtrochanteric or diaphyseal femur fractures per 1000 person-years was 1.46 [95% confidence interval (CI) 1.11–1.88] among the bisphosphonate users and 1.43 (95% CI 1.06–1.89) among raloxifene/calcitonin users. No significant association between bisphosphonate use and subtrochanteric or diaphyseal femur fractures was found [hazard ratio (HR) = 1.03, 95% CI 0.70–1.52] compared with raloxifene/calcitonin. Even with this large study size, we had little precision in estimating the risk of subtrochanteric or diaphyseal femur fractures in patients treated with bisphosphonates for longer than 5 years (HR = 2.02, 95% CI 0.41–10.00). The occurrence of subtrochanteric or diaphyseal femur fracture was rare. There was no evidence of an increased risk of subtrochanteric or diaphyseal femur fractures in bisphosphonate users compared with raloxifene/calcitonin users. However, this study cannot exclude the possibility that long-term bisphosphonate use may increase the risk of these fractures. © 2011 American Society for Bone and Mineral Research

Short-Term Exercise Training Inconsistently Influences Basel Testosterone in Older Men: A Systematic Review and Meta-Analysis

Background The age-associated decrease in testosterone is one mechanism suggested to accelerate the aging process in males. Therefore, approaches to increase endogenous testosterone may be of benefit. The aim of this paper was to undertake a Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA)-accordant meta-analysis concerning the effect of exercise on total (TT), bioavailable (bio-T), free (free-T), and salivary (sal-T) testosterone in older males. Methods Databases were searched up to and including 20th February 2018 for the terms ‘testosterone AND exercise AND aging AND males’, ‘testosterone AND exercise AND old AND males’, ‘testosterone AND training AND aging AND males’ and ‘testosterone AND training AND old AND males’. From 1259 originally identified titles, 22 studies (randomized controlled trials; RCTs; n=9, and uncontrolled trials; UCTs; n=13) were included which had a training component, participants ≥60 years of age, and salivary or serum testosterone as an outcome measure. Meta-analyses were conducted on change to testosterone following training using standardised difference in means (SDM) and random effects models. Results The overall SDM for endurance training, resistance training, and interval training was 0.398 (95% CI = 0.034 – 0.761; P = 0.010), -0.003 (95% CI = -0.330 – 0.324; P = 0.986), and 0.283 (95% CI = 0.030 – 0.535; P = 0.028) respectively. Resistance training exhibited a qualitative effect of hormone fraction whereby free-T resulted in the greatest SDM (0.253; 95% CI = -0.043 – 0.549; P = 0.094), followed by TT (0.028; 95% CI = -0.204 – 0.260; P = 0.813), and resistance training negatively influenced bio-T (-0.373; 95% CI = -0.789 – 0.042; P = 0.078). Due to the small number of studies, subgroup analysis was not possible for endurance training and interval training studies. Conclusions Data from the present investigation suggests that resistance training does not significantly influence basal testosterone in older men. Magnitude of effect was influenced by hormone fraction, even within the same investigation. Aerobic training and interval training did result in small, significant increases in basal testosterone. The magnitude of effect is small but the existing data are encouraging and may be an avenue for further research