Fracture Risk In Type Research Articles

Genistein Treatment Increases Bone Mass in Obese Diabetic Mice

Genistein, a phytoestrogen that demonstrates bone‐protective properties, is currently being investigated as a treatment for a number of conditions that affect skeletal health, including type 2 diabetes. Type 2 diabetics have an elevated risk of developing fractures, particularly in bones of the lower limb. Type 2 diabetics also tend to be obese ‐ as many as 85% according to the World Health Organization. This study investigates the effects of genistein treatment on the properties of lower limb bones in obese, diabetic mice. Twenty mice of the ob/ob strain aged 6 weeks were randomly divided into two groups. One group received 600 mg/kg of genistein in their chow for 4 weeks. Comparisons of tibial midshafts show mice treated with genistein have significantly greater diameters and ratios of cortical bone to total tissue area (B.ar/Tt.Ar) than controls (P < 0.05). Evaluation of the proximal tibial growth plate reveals significantly decreased growth plate thickness in genistein‐treated mice, suggesting genistein affects endochondral ossification. Although these initial findings are promising, further study is needed to assess the effects of genistein on fracture risk in type 2 diabetics.

Raloxifene prevents skeletal fragility in adult female Zucker Diabetic Sprague-Dawley rats.

Fracture risk in type 2 diabetes is increased despite normal or high bone mineral density, implicating poor bone quality as a risk factor. Raloxifene improves bone material and mechanical properties independent of bone mineral density. This study aimed to determine if raloxifene prevents the negative effects of diabetes on skeletal fragility in diabetes-prone rats. Adult Zucker Diabetic Sprague-Dawley (ZDSD) female rats (20-week-old, n = 24) were fed a diabetogenic high-fat diet and were randomized to receive daily subcutaneous injections of raloxifene or vehicle for 12 weeks. Blood glucose was measured weekly and glycated hemoglobin was measured at baseline and 12 weeks. At sacrifice, femora and lumbar vertebrae were harvested for imaging and mechanical testing. Raloxifene-treated rats had a lower incidence of type 2 diabetes compared with vehicle-treated rats. In addition, raloxifene-treated rats had blood glucose levels significantly lower than both diabetic vehicle-treated rats as well as vehicle-treated rats that did not become diabetic. Femoral toughness was greater in raloxifene-treated rats compared with both diabetic and non-diabetic vehicle-treated ZDSD rats, due to greater energy absorption in the post-yield region of the stress-strain curve. Similar differences between groups were observed for the structural (extrinsic) mechanical properties of energy-to-failure, post-yield energy-to-failure, and post-yield displacement. These results show that raloxifene is beneficial in preventing the onset of diabetes and improving bone material properties in the diabetes-prone ZDSD rat. This presents unique therapeutic potential for raloxifene in preserving bone quality in diabetes as well as in diabetes prevention, if these results can be supported by future experimental and clinical studies.

High serum pentosidine but not esRAGE is associated with prevalent fractures in type 1 diabetes independent of bone mineral density and glycaemic control

Fracture risk in type 1 diabetes (T1D) is supposed to be underestimated by bone mineral density (BMD). Individuals with T1D had more prevalent fractures in a cross-sectional study. Serum levels of pentosidine, an advanced glycation end product, and poor glycaemic control were associated with prevalent fractures independent of BMD. Type 1 diabetes (T1D) is associated with increased fracture risk. Bone mineral density (BMD) underestimates the risk of fractures in some individuals. The accumulation of advanced glycation end products (AGEs) impairs bone matrix and reduces bone strength. In a cross-sectional study, 128 men and premenopausal women with T1D were evaluated. We compared traditional risk factors for fractures, BMD, parameters of bone metabolism and AGEs in individuals with and without prevalent fractures. An independent association of serum AGE levels with prevalent fractures was investigated. Individuals with prevalent fractures exhibited a longer duration of T1D, higher HbA1c and more diabetic-related complications. BMD at the femoral neck (z-score -0.76 ± 0.94 vs. -0.23 ± 1.02; p = 0.031) and total hip (z-score -0.54 ± 0.93 vs. 0.11 ± 1.11; p = 0.017) was lower in those with prevalent fractures. Individuals with fractures had higher pentosidine levels (164.1 ± 53.6 vs. 133.2 ± 40.4; p = 0.002). The levels of N-ε-(carboxymethyl)-lysine (CML) and endogenous secretory receptor for AGEs (esRAGE) did not significantly differ. Multivariate logistic regression analysis adjusted for age, BMI, family history of fractures, smoking, vitamin D deficiency, BMD at lumbar spine, femoral neck and total hip identified pentosidine levels and HbA1c as independent factors associated with prevalent fractures (odds ratio 1.02, 95% CI 1.00-1.03/pmol/ml increase of pentosidine; p = 0.008 and odds ratio 1.93, 95% CI 1.16-3.20 per percentage increase of HbA1c; p = 0.011). The pentosidine levels but not BMD are independently associated with prevalent fractures. Impaired bone quality in T1D may result from increased AGE formation.

High Bone Mineral Density and Fracture Risk in Type 2 Diabetes as Skeletal Complications of Inadequate Glucose Control

OBJECTIVEIndividuals with type 2 diabetes have increased fracture risk despite higher bone mineral density (BMD). Our aim was to examine the influence of glucose control on skeletal complications.RESEARCH DESIGN AND METHODSData of 4,135 participants of the Rotterdam Study, a prospective population-based cohort, were available (mean follow-up 12.2 years). At baseline, 420 participants with type 2 diabetes were classified by glucose control (according to HbA1c calculated from fructosamine), resulting in three comparison groups: adequately controlled diabetes (ACD; n = 203; HbA1c <7.5%), inadequately controlled diabetes (ICD; n = 217; HbA1c ≥7.5%), and no diabetes (n = 3,715). Models adjusted for sex, age, height, and weight (and femoral neck BMD) were used to test for differences in bone parameters and fracture risk (hazard ratio [HR] [95% CI]).RESULTSThe ICD group had 1.1–5.6% higher BMD, 4.6–5.6% thicker cortices, and −1.2 to −1.8% narrower femoral necks than ACD and ND, respectively. Participants with ICD had 47–62% higher fracture risk than individuals without diabetes (HR 1.47 [1.12–1.92]) and ACD (1.62 [1.09–2.40]), whereas those with ACD had a risk similar to those without diabetes (0.91 [0.67–1.23]).CONCLUSIONSPoor glycemic control in type 2 diabetes is associated with fracture risk, high BMD, and thicker femoral cortices in narrower bones. We postulate that fragility in apparently “strong” bones in ICD can result from microcrack accumulation and/or cortical porosity, reflecting impaired bone repair.

Usefulness of bone turnover markers in the evaluation of fracture risk in type 2 diabetes

Usefulness of bone turnover markers in the evaluation of fracture risk in type 2 diabetes

Response: The Association between Serum Endogenous Secretory Receptor for Advanced Glycation End Products and Vertebral Fractures in Type 2 Diabetes (Endocrinol Metab 2012;27:289-94, Cheol Ho Lee et al.)

The authors would like to thank the reviewers for their time and constructive comments concerning our manuscript. This study analyzed the relationship between vertebral fracture and endogenous secretory receptor for advanced glycation end products (esRAGE) in type 2 diabetes. We verified that patients in the lowest tertile of esRAGE had a higher risk of moderate or severe vertebral fractures than patients in the highest tertile. It is well known that type 2 diabetes patients had a higher risk of hip or vertebral fractures although they had a similar or slightly higher bone mineral density (BMD) compared to healthy individuals [1,2]. This suggests that reduced bone quality is more profoundly associated with the increase in fracture risk, rather than decreased BMD in type 2 diabetes patients. Previous studies have indicated an increase in advanced glycation end products (AGEs) due to elevated blood glucose, and a decrease in esRAGE interrupting signal transmission within the cells of AGEs, as potential causal factors for deteriorating BMD [3,4]. As we mentioned, this study has statistical limitations. Some risk factors including previous fracture history, family history of osteoporotic fracture, and BMD were not included in multiple regression analysis of the relationship between esRAGE and vertebral fractures. Previous history of fracture was excluded from the analysis since it was known in only 50% to 60% of the subjects. The major limitation of our study is the lack of BMD measurements, which is an important risk factor for vertebral fractures. In addition, small sample size makes it difficult to draw conclusions. We feel that a prospective study is needed to further investigate the effects of low esRAGE levels on the increased risk of fractures in type 2 diabetes. Thanks again for your interest and comprehensive comments in our paper.

Phalangeal quantitative ultrasound and metabolic control in pre-menopausal women with type 1 diabetes mellitus.

Several studies have reported increased fracture risk in Type 1 diabetes mellitus (T1DM). Quantitative Ultrasound (QUS) provides information on the structure and elastic properties of bone, which are important determinants of fracture risk, along with bone mineral density. To study phalangeal sites by QUS, examine bone turnover markers and analyze association between these factors with metabolic control in a population of pre-menopausal women with T1DM. Thirty-five T1DM pre-menopausal women (mean age 34.5 ± 6.8 yr) attending the Diabetic Outpatients Clinic in the Department of Internal Medicine, University of Messina, were consecutively enrolled and divided into two groups, taking into account the mean value of glycated hemoglobin in the last three years. Twenty healthy age-matched women served as controls. Phalangeal ultrasound measurements [Amplitude Dependent Speed of Sound (AD-SoS), Ultrasound Bone Profile Index (UBPI), TScore, Z-Score] were performed using a DBM Sonic Bone Profiler. Osteocalcin and deoxypyridinoline served as markers of bone formation and bone resorption, respectively. T1DM women with poor metabolic control showed lower phalangeal QUS values compared to healthy controls (p<0.01) and T1DM women with good metabolic control (p<0.05). No significant differences in QUS measurements were detected between T1DM women with good metabolic control and healthy controls. Lower bone formation and increased bone resorption, although not statistically significant, were observed in patients with poor metabolic control in comparison to patients with good metabolic control. Poor metabolic control may worsen the quality of bone in T1DM. Phalangeal QUS could be considered as a tool to screen T1DM women for osteoporosis in pre-menopausal age.

Effects of Raloxifene on Bone Metabolism in Hemodialysis Patients

Effects of Raloxifene on Bone Metabolism in Hemodialysis Patients

Fracture Incidence and Risk of Osteoporosis in Female Type 2 Diabetic Patients in Korea

BackgroundThere are no published data regarding fracture risk in type 2 diabetic patients in Korea. In this study, we compared the fracture incidence and risk of osteoporosis of type 2 diabetic female patients with those in a non-diabetic hypertensive cohort.MethodsThe incidence of fracture in a type 2 diabetic cohort was compared with that in a non-diabetic hypertensive cohort over the course of 7 years. Female type 2 diabetic and non-diabetic hypertensive patients who visited Eulji General Hospital outpatient clinic from January 2004 to April 2004 were assigned to the diabetic cohort and the non-diabetic hypertensive cohort, respectively. Surveys on fracture event, use of anti-osteoporosis medications, and bone mineral density were performed.ResultsThe number of fractures was 88 in the female diabetic cohort (n=1,268, 60.6±11.5 years) and 57 in the female non-diabetic hypertensive cohort (n=1,014, 61.4±11.7 years). The RR in the diabetic cohort was 1.38 (P=0.064; 95% confidence interval [CI], 0.98 to 1.94) when adjusted for age. Diabetic patients with microvascular complications (61.0%) showed a higher RR of 1.81 (P=0.014; 95% CI, 1.13 to 2.92) compared with those without these complications. The prevalence of osteoporosis was comparable between the groups, while use of anti-osteoporosis medication was more common in the diabetic cohort (12.8%) than in the hypertensive cohort (4.5%) (P<0.001).ConclusionIn our study, a higher fracture risk was observed in female type 2 diabetics with microvascular complications. Special concern for this risk group is warranted.

Dipeptidyl Peptidase-4 Inhibitors and Bone Fractures

OBJECTIVEThiazolidinediones and insulin are associated with a higher risk of fractures in type 2 diabetic patients. Incretin hormones increase bone density in experimental models, but the effect of dipeptidyl peptidase-4 (DPP-4) inhibitors on bone fractures has not been reported so far.RESEARCH DESIGN AND METHODSA meta-analysis was performed including all randomized clinical trials with a duration of at least 24 weeks, enrolling patients with type 2 diabetes, comparing DPP-4 inhibitors with placebo or active drugs.RESULTSTwenty-eight trials enrolling 11,880 and 9,175 patients for DPP-4 inhibitors and comparators, respectively, were included, reporting 63 fractures. DPP-4 inhibitors, compared with placebo or other treatments, were associated with a reduced risk of fractures (Mantel–Haenszel odds ratio [MH-OR] 0.60, 95% CI 0.37–0.99, P = 0.045), even after the exclusion of comparisons with thiazolidinediones or sulfonylureas (MH-OR 0.56, 0.33–0.93, P = 0.026).CONCLUSIONSThe present meta-analysis suggests that treatment with DPP-4 inhibitors could be associated with a reduced risk of bone fractures.

Osteoporosis and diabetes

Diabetes mellitus and osteoporosis are chronic diseases with an elevated and growing incidence in the elderly. Recent epidemiological studies have demonstrated an elevated risk of hip, humerus and foot fractures in elder diabetic subjects. While type 1 diabetes is generally associated with a mild reduction in bone mineral density (BMD), type 2 diabetes, more prevalent in old subjects, is frequently linked to a normal or high BMD. Studies on experimental models of diabetes have suggested an altered bone structure that may help to explain the elevated risk of fractures observed in these animals and may as well help to explain the paradox of an incremented risk of fractures in type 2 diabetic elderly in the presence of normal or elevated BMD. In addition, diabetic elderly have an increased risk of falls, consequent at least in part to a poor vision, peripheral neuropathy, and weaken muscular performance. Diabetes may affect bone tissue by different mechanisms including obesity, hyperinsulinemia, deposit of advanced glycosilation end products in collagen fibre, reduced circulating levels of IGF-1, hypercalciuria, renal function impairment, microangiopathy and chronic inflammation. A better understanding of these mechanisms may help implement the prevention of fractures in the growing population of mature diabetics.

Bone metabolism and fracture risk in type 2 diabetes mellitus [Review

Osteoporosis and type 2 diabetes mellitus (T2DM) are now prevalent in aging and westernized societies, and adversely affect the health of the elderly people by causing fractures and vascular complications, respectively. Recent experimental and clinical studies show that both disorders are etiologically related to each other through the actions of osteocalcin and adiponectin. Meta-analyses of multiple clinical studies show that hip fracture risk of T2DM patients is increased to 1.4 to 1.7-folds, although BMD of the patients is not diminished. Vertebral fracture risk of T2DM patients is also increased, and BMD is not useful for assessing its risk. These findings suggest that bone fragility in T2DM depends on bone quality deterioration rather than bone mass reduction. Thus, surrogate markers are needed to replace the insensitivity of BMD in assessing fracture risks of T2DM patients. Markers related to advanced glycation end products as well as insulin-like growth factor-I may be such candidates, because these substances were experimentally shown to modulate bone quality in DM. In practice, it is important for physicians to assess fracture risk in T2DM patients by evaluating prior VFs and fracture histories using spine X-ray and interview, respectively, until the usefulness of surrogate markers is established.

Diabetes and Its Complications and Their Relationship with Risk of Fractures in Type 1 and 2 Diabetes

This case-control study sought to assess the effects of diabetes and its complications on the risk of fractures. There were 124,655 fracture cases and 373,962 age- and sex-matched controls. The main exposure was diabetes and its complications, and the main confounders were use of insulin and oral antidiabetic agents, presence of cardiovascular disease, and use of drugs for cardiovascular disease, along with a number of other confounders. In the crude analysis, diabetes and all complications was associated with a statistically significantly increased overall risk of fractures. The increase in risk of fractures was higher in type 1 diabetes (T1D) than in type 2 diabetes (T2D). However, after adjustment for confounders, the difference between T1D and T2D disappeared, and only diabetic kidney disease in T1D retained a significantly increased risk of fractures. There was a time dependency in the risk of fractures with an early increase at <2.5 years after diagnosis. followed by a decrease to the level of the background population from 2.5 to 5 years after diagnosis, and a limited increase in T1D but not T2D at >5 years after diagnosis. We conclude that diabetes, whether T1D or T2D, seems to carry an increased risk of fractures, and complications to diabetes except for diabetic kidney disease add little to the overall risk of fracture, perhaps pointing at a common risk factor linked to the high blood glucose levels, which may weaken bone strength.

Fracture Risk in Type 2 Diabetes: Update of a Population-Based Study

We found no significant excess of fractures among Rochester, MN, residents with diabetes mellitus initially recognized in 1950-1969, but more recent studies elsewhere have documented an apparent increase in hip fracture risk. To explore potential explanations for any increase in fractures, we performed an historical cohort study among 1964 Rochester residents who first met glycemic criteria for diabetes in 1970-1994 (mean age, 61.7 +/-14.0 yr; 51% men). Fracture risk was estimated by standardized incidence ratios (SIRs), and risk factors were evaluated in Andersen-Gill time-to-fracture regression models. In 23,236 person-years of follow-up, 700 diabetic residents experienced 1369 fractures documented by medical record review. Overall fracture risk was elevated (SIR, 1.3; 95% CI, 1.2-1.4), but hip fractures were increased only in follow-up beyond 10 yr (SIR, 1.5; 95% CI, 1.1-1.9). As expected, fracture risk factors included age, prior fracture, secondary osteoporosis, and corticosteroid use, whereas higher physical activity and body mass index were protective. Additionally, fractures were increased among patients with neuropathy (hazard ratio [HR], 1.3; 95% CI, 1.1-1.6) and those on insulin (HR, 1.3; 95% CI, 1.1-1.5); risk was reduced among users of biquanides (HR, 0.7; 95% CI, 0.6-0.96), and no significant influence on fracture risk was seen with sulfonylurea or thiazolidinedione use. Thus, contrary to our earlier study, the risk of fractures overall (and hip fractures specifically) was increased among Rochester residents with diabetes, but there was no evidence that the rise was caused by greater levels of obesity or newer treatments for diabetes.

Thiazolidinedione Treatment Decreases Bone Mineral Density in Type 2 Diabetic Men

Case-control studies of patients with fractures have found that subjects with diabetes have at least a twofold higher risk of fracture than subjects without diabetes (1), with an increased risk of hip, humerus, and foot fractures in elderly diabetic subjects (2–4). Risk factors that contribute to increased fracture in diabetic subjects include number of falls (5,6), insulin use (7,8), functional disability (9–11), diabetes duration (7,12), and poor vision (7). Recent studies report that older women and African Americans have higher incidence of osteoporotic fractures (13). In addition, lower bone strength (bone mineral density [BMD]) might be expected to increase risk for the development of osteoporosis and fracture. Type 2 diabetic patients are widely prescribed drugs called thiazolidinediones, which increase insulin sensitivity via activation of peroxisome proliferator–activated receptor (PPAR)-γ receptors. However, it is not known whether thiazolidinedione use has any effect on bone mass and thereby increases risk of fracture in type 2 diabetic patients. In animal studies, thiazolidinedione treatment was associated with bone loss in a mouse model (14,15), which was explained by possible imbalance in bone from increased apoptotic death of osteogenic cells and diminished bone formation (15), and also in ovariectomized rats (16). Other investigators did not find bone loss in troglitazone-treated mice (17). There is limited information on the effect of …

Elevated Hip Fracture Risk in Type 1 Diabetic Patients

Patients with type 1 diabetes often have low bone mineral density, but epidemiological data on fracture risk are sparse and imprecise, particularly for men. In the Swedish Inpatient Register, we identified a population-based cohort of 24,605 patients (12,551 men and 12,054 women) who were hospitalized for diabetes before age 31 years during 1975 through 1998. Follow-up for hip fracture was accomplished through cross-linkage in the Inpatient Register until the end of 1998. Censoring information was obtained from the registers of Death and Migration. Using the Kaplan-Meier method, we calculated the cumulative probability of getting a hip fracture. Standardized hospitalization ratios and their 95% CIs estimated relative risks with the age-, sex-, and calendar period-matched Swedish general population as reference. In total, 70 and 51 first hip fractures were ascertained in men and women, respectively, corresponding to a cumulative probability (both sexes) of 65.8/1,000 until age 65 years. Markedly elevated risks were observed in both men and women (standardized hospitalization ratios = 7.6 [95% CI 5.9-9.6] and 9.8 [7.3-12.9], respectively), increasing with follow-up time. Ophthalmic, nephropathic, neurological, and cardiovascular complications were indicators of particularly high risks. Both male and female type 1 diabetic patients are at increased risk for hip fracture. Although optimal preventive measures still need to be defined, the co-occurrence with other diabetes complications suggests that tighter metabolic control might reduce the risk.

Diabetes Mellitus: Does it Affect Bone?

Both diabetes and fractures affect a large proportion of older adults. Recent cohort studies indicate that diabetes itself is associated with increased risk of fracture of the hip, proximal humerus, and foot. Observational studies and animal models suggest that decreased bone strength in diabetes may contribute to fracture risk but this remains a controversial issue. Type 1 diabetes is associated with modest reductions in bone mineral density (BMD) but type 2 diabetes is often characterized by elevated BMD. This paradox of higher BMD but increased fracture risk in type 2 diabetes may be explained by a combination of more frequent falls and poorer bone quality. Diabetes can impact bone through multiple pathways, some with contradictory effects, including obesity, changes in insulin levels, higher concentrations of advanced glycation end products in collagen, hypercalciuria associated with glycosuria, reduced renal function, lower insulin-like growth factor-I, microangiopathy, and inflammation. A better understanding of how diabetes metabolism and treatments affect bone would improve fracture prevention efforts in older diabetic adults.