Influence of glycemic control and hypoglycemia on the risk of fracture in patients with diabetes mellitus: a systematic review and meta-analysis of observational studies.

Individuals with diabetes mellitus (DM) have an increased risk of fracture. Glycemic control is crucial to the management of DM, but there are concerns pertaining to hypoglycemia development in the course of glycemic control target achievement. The extent to which glycemic control may affect the risk of fracture remains less defined. Hypoglycemia-induced falls have been suggested to contribute to an elevated risk of fracture in DM patients. In this meta-analysis of observational studies, we aimed to investigate the relative contribution of glycemic control, as measured by glycated hemoglobin (HbA1c), and hypoglycemia to the risk of fracture in DM. The PubMed and Web of Science databases were searched for relevant studies. A random-effects model was used to generate summary relative risks (RRs) and 95% confidence intervals (CIs). Both increased HbA1c levels (RR per 1% increase 1.08, 95% CI 1.03, 1.14; nstudies = 10) and hypoglycemia (RR 1.52, 95% CI 1.23, 1.88; nstudies = 8) were associated with an increased risk of fracture. The association between HbA1c levels and the risk of fracture was somewhat nonlinear, with a noticeably increased risk observed at an HbA1c level ≥ 8%. The positive associations of HbA1c levels and hypoglycemia with the risk of fracture did not reach statistical significance in the studies that adjusted for insulin use, hypoglycemia, or falls for the former and in those that adjusted for falls for the latter. In summary, both increased HbA1c levels and hypoglycemia may increase the risk of fracture in patients with DM. The positive association between HbA1c levels and the risk of fracture appears to be, in part, explained by hypoglycemia-induced falls, possibly due to insulin use. The avoidance of hypoglycemia in the course of achieving good glycemic control through the careful selection of glucose-lowering medications may contribute to fracture prevention by reducing the risk of falls related to treatment-induced hypoglycemia.

Systematic review and meta-analysis of the association between dairy consumption and the risk of hip fracture: critical interpretation of the currently available evidence.

In the present meta-analysis, reductions in the risk of hip fracture with milk consumption were only observed among American adults, but not among Scandinavian adults, possibly because milk products are more commonly fortified with vitamin D in the former population than in Scandinavian countries. The reduction in the risk of hip fracture was also observed with yogurt consumption, which is often associated with healthy lifestyles and dietary patterns that contribute to improved bone health. INTRODUCTION: Although dairy products contain bone-beneficial nutrients, the association between dairy consumption and the risk of hip fracture remains equivocal. Fueling this uncertainty, the elevated risk of hip fracture in association with milk consumption was observed in a cohort of Swedish women. A systematic review and meta-analysis of prospective cohort studies was performed to critically evaluate the association, or lack thereof, between dairy consumption (milk, yogurt, and cheese) and the risk of hip fracture. METHODS: A random effects model was used to generate the summary relative risks (RRs) with their 95% confidence intervals (CIs) for the associations of interest. RESULTS: In the meta-analysis of the highest versus lowest category of consumption, higher consumption of yogurt (RR 0.78, 95% CI 0.68, 0.90), but not milk (RR 0.86, 95% CI 0.73, 1.02) or cheese (RR 0.85, 95% CI 0.66, 1.08), was associated with a lower risk of hip fracture. For milk, the reduced risk of fracture with higher milk consumption was observed in the USA (RR 0.75, 95% CI 0.65, 0.87), but not in Scandinavian countries (RR 1.00, 95% CI 0.85, 1.17). These findings were further supported by the fact that American studies (RR 0.93, 95% CI 0.88, 0.98; per 1 glass/day), but not Scandinavian studies (RR 1.01, 95% CI 0.95, 1.07; per 1 glass/day), demonstrated a linear association between milk consumption and the risk of hip fracture. CONCLUSIONS: The cumulative evidence from prospective cohort studies reassuringly suggests that the risk of hip fracture may not be elevated among people who consume milk, yogurt, and cheese, and that a greater consumption of milk or yogurt may even be associated with a lower risk of hip fracture depending on the factors that may differ across the population of interest.

Risk of fracture with dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists, or sodium-glucose cotransporter-2 inhibitors in real-world use: systematic review and meta-analysis of observational studies.

In the present meta-analysis based on real-world data, the use of dipeptidyl peptidase-4 inhibitors (DPP-4i), glucagon-like peptide-1 receptor agonists (GLP-1ra), or sodium-glucose cotransporter-2 inhibitors (SGLT2i) was not associated with the risk of fracture. INTRODUCTION: Cumulative evidence from randomized control trials (RCTs) with limited fracture events showed that the use of DPP-4i, GLP-1ra, or SGLT2i may not affect the risk of fracture. However, additional insights from large population-based studies with routinely collected data on fracture events and an adequate amount of fracture events are necessary to draw firm conclusions. To refine and complement the results from RCTs, a systematic review and meta-analysis of observational studies were performed to investigate the association between the use of DPP-4i, GLP-1ra, or SGLT2i and the risk of fracture in real-world settings. METHODS: The PubMed and Web of Science databases were searched to identify relevant observational studies. A random-effect model was used to estimate the summary relative risks (RRs). RESULTS: The use of DPP-4i (RR 0.83, 95% CI [confidence interval] 0.60, 1.14; n = 11), GLP-1ra (RR 0.65, 95% CI 0.24, 1.74; n = 4), or SGLT2i (RR 1.02, 95% CI 0.91, 1.16; n = 4) was not associated with the risk of fracture. In general, there was a consistent lack of association between the use of DPP-4i or GLP-1ra and the risk of fracture across nearly all subgroups, except for a significantly reduced risk of hip fracture with the use of GLP-1ra (RR 0.21, 95% CI 0.04, 0.98). CONCLUSIONS: Cumulative real-world evidence does not support an association between the use of DPP-4i, GLP-1ra, or SGLT2i and the risk of fracture. Our findings, together with the cumulative evidence from RCTs, should reassure policy makers and medical practitioners that the use of these medications is unlikely to increase the risk of fracture among type 2 diabetes mellitus patients in general. Further studies need to investigate the long-term impact of these drugs on the fracture risk, particularly in high-risk populations.

Sex hormone-binding globulin and risk of fracture in older adults: systematic review and meta-analysis of observational studies.

We conducted a meta-analysis of observational study to clarify the association between sex hormone-binding globulin (SHBG) levels and the risk of fracture in older adults. We found that higher SHBG levels were associated with an increased risk of fracture in older adults. INTRODUCTION: The association between SHBG levels and the risk of fracture in older adults remains elusive. We aim to clarify this association by conducting a meta-analysis of observational studies. METHODS: PubMed and Web of Science databases were searched for relevant observational studies investigating the association between SHBG levels and the risk of fracture in older adults. The relative risks (RRs) with 95% confidence intervals (CIs) from each study were transformed into a continuous variable for each 1 µg/dL increase in SHBG and were pooled under a random-effects model. RESULTS: A total of 16 observational studies were included in the present meta-analysis. The summary RR of fracture risk associated with each 1 µg/dL increase in SHBG was 1.18 (95% CI 1.11, 1.26); no statistically significant heterogeneity was observed across studies (I2 = 0%, P = 0.67). The positive association was also evident in men (RR 1.22, 95% CI 1.12, 1.33) and women (RR 1.15, 95% CI, 1.05, 1.26). By site of fracture, higher SHBG levels were positively associated with higher risks of hip fracture (RR 1.43, 95% CI 1.23, 1.65), vertebral fracture (RR 1.31, 95% CI 1.12, 1.54), and non-vertebral fracture (RR 1.21, 95% CI 1.06, 1.38). CONCLUSIONS: The present meta-analysis suggests that higher SHBG levels predict an increased risk of fracture in older adults. Further studies should aim to elucidate the complex biological mechanisms by which SHBG may affect fracture risk.

Body fatness at a young age and risks of eight types of cancer: systematic review and meta-analysis of observational studies.

The associations between body fatness at a young age (childhood, adolescence and young adulthood; age ≤ 30 years) and diffuse large B-cell lymphoma (DLBCL), oesophageal adenocarcinoma, gastric cardia cancer, hepatocellular carcinoma, multiple myeloma, pancreatic cancer, renal cell cancer and thyroid cancer remain inconclusive. We performed a comprehensive systematic literature review and meta-analysis of observational studies to clarify the associations between body fatness at a young age and the risks of these cancers. PubMed and Web of Science databases were searched for relevant observational studies. Fifty-six articles yielded data on 27,559 cancer cases, including 3,170 DLBCL, 1,491 oesophageal adenocarcinoma, 1,103 gastric cardia cancer, 1,067 hepatocellular carcinoma, 3,090 multiple myeloma, 7,220 pancreatic cancer, 6,212 renal cell cancer and 4,206 thyroid cancer cases. Each 5 kg m-2 increase in body mass index at a young age was positively associated with DLBCL (relative risk [RR] 1.21, 95% confidence interval [CI] 1.09, 1.35), oesophageal adenocarcinoma (RR 1.88, 95% CI 1.37, 2.57), gastric cardia cancer (RR 1.59, 95% CI 1.15, 2.21), hepatocellular carcinoma (RR 1.31, 95% CI 1.13, 1.51), multiple myeloma (RR 1.23, 95% CI 1.15, 1.30), pancreatic cancer (RR 1.17, 95% CI 1.11, 1.24), renal cell cancer (RR 1.22, 95% CI 1.16, 1.28) and thyroid cancer (RR 1.12, 95% CI 1.07, 1.17). In summary, higher body fatness at a young age increases the risks of developing various types of cancer later in life. Prevention of overweight and obesity in children, adolescents and young adults should therefore be emphasized to reverse the obesity epidemic and thereby avoid further increases in the burden of cancer attributed to excess body fatness.

Body fatness at a young age, body fatness gain and risk of breast cancer: systematic review and meta-analysis of cohort studies.

Higher body fatness in adulthood has been consistently associated with an increased risk of postmenopausal breast cancer, as well as a tendency towards a lower risk of premenopausal breast cancer. However, the association between body fatness at a young age (≤30 years), body fatness gain and the risk of breast cancer is less defined. PubMed and Web of Science databases were searched to identify relevant publications. Risk estimates with 95% confidence intervals from each study were transformed into a continuous variable for each 5 kg m-2 increase in body mass index (BMI) and were pooled under a random-effects model. Each 5 kg m-2 increase in BMI was significantly associated with a 14%, 12% and 17% lower risk of breast cancer later in life among all women, premenopausal women and postmenopausal women, respectively. Significant heterogeneity and publication bias were observed. The results remained unchanged after the trim and fill method was applied to correct the bias. Each 5 kg m-2 increase in BMI from a young age until cohort entry was significantly associated with a 13% and 14% higher risk of breast cancer in all women and postmenopausal women, respectively. In summary, higher body fatness at a young age may have a protective role in the later development of breast cancer in both premenopausal and postmenopausal women. However, this potential benefit should not be overemphasized, as our findings suggest that increased body fatness gain from a young age is positively associated with postmenopausal breast cancer risk. These findings further justify the need to maintain a steady weight throughout life.

Effects of Milk Proteins Supplementation in Older Adults Undergoing Resistance Training: A Meta-Analysis of Randomized Control Trials.

BACKGROUND: Older adults experience age-related physiological changes that affect body weight and body composition. In general, nutrition and exercise have been identified as potent stimulators of protein synthesis in skeletal muscle. Milk proteins are excellent sources of all the essential amino acids and may represent an ideal protein source to promote muscle anabolism in older adults undergoing resistance training. However, several randomized control trials (RCTs) have yielded mixed results on the effects of milk proteins supplementation in combination with resistance training on body weight and composition. METHODS: PubMed, Web of Science and Cochrane databases were searched for literature that evaluated the effects of milk proteins supplementation on body weight and composition among older adults (age ≥ 60 years) undergoing resistance training up to September 2016. A random-effects model was used to calculate the pooled estimates and 95% confidence intervals (CIs) of effect sizes. RESULTS: The final analysis included 10 RCTs involving 574 participants (mean age range from 60 to 80.8 years). Overall, the combination of milk proteins supplementation and resistance training did not have significant effect on fat mass (0.30, 95% CI -0.25, 0.86 kg) or body weight (1.02, 95% CI: -0.01, 2.04 kg). However, a positive effect of milk proteins supplementation paired with resistance training on fat-free mass was observed (0.74, 95% CI 0.30, 1.17 kg). Greater fat-free mass gains were observed in studies that included more than 55 participants (0.73, 95% CI 0.30, 1.16 kg), and in studies that enrolled participants with aging-related medical conditions (1.60, 95% CI 0.92, 2.28 kg). There was no statistical evidence of publication bias among the studies. CONCLUSION: Our findings provide evidence that supplementation of milk protein, in combination with resistance training, is effective to elicit fat-free mass gain in older adults.

Central obesity and risks of pre- and postmenopausal breast cancer: a dose-response meta-analysis of prospective studies.

Epidemiologic evidence has shown inconsistent findings regarding the relationships between abdominal fatness, as measured by waist circumferences (WC) or waist-to-hip ratio (WHR), and risks of pre- and postmenopausal breast cancer (BC). A dose-response meta-analysis of prospective studies was conducted to address these issues. Potentially eligible studies were identified by searching PubMed and EMBASE databases, and by carefully reviewing the bibliographies of retrieved publications and related reviews. The summary relative risks (RRs) with 95% confidence intervals (CIs) were calculated using a random-effects model. When the most fully adjusted RRs were combined, both WC (14 studies, RR per 10-cm increase = 1.06, 95% CI: 1.04-1.09, I2 = 29.9%) and WHR (15 studies, RR per 0.1-unit increase = 1.07, 95% CI: 1.01-1.14, I2 = 52.9%) were significantly positively associated with postmenopausal BC, but neither WC (eight studies, RR per 10-cm increase = 1.05, 95% CI: 0.99-1.10, I2 = 0%) nor WHR (11 studies, RR per 0.1-unit increase = 1.07, 95% CI: 0.95-1.21, I2 = 59.7%) were associated with premenopausal BC. The WHR-postmenopausal BC association lost statistical significance after correcting publication bias (RR per 0.1-unit increase = 1.06, 95% CI: 0.99-1.13). When considering BMI-adjusted RRs, WC was associated with both pre- (five studies, RR per 10-cm increase = 1.09, 95% CI: 1.02-1.16, I2 = 0%) and postmenopausal BC (seven studies, RR per 10-cm increase = 1.05, 95% CI: 1.02-1.08, I2 = 6.3%), whereas WHR was not associated with either pre- (seven studies, RR per 0.1-unit increase = 1.12, 95% CI: 0.94-1.34, I2 = 70.9%) or postmenopausal BC (eight studies, RR per 0.1-unit increase = 1.05, 95% CI: 0.98-1.13, I2 = 57.3%). Among non-current (former or never) users of hormone replacement therapy, the summary RR per 10-cm increase of postmenopausal BC associated with WC was 1.08 (95% CI: 1.03-1.05, I2 = 69.2%, seven studies; BMI-adjusted RR = 1.05, 95% CI: 1.02-1.09, I2 = 22.8%, four studies). This meta-analysis indicates that central obesity measured by WC, but not by WHR, is associated with modestly increased risks of both pre- and postmenopausal BC independent of general obesity.