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Diabetes affects bone metabolism. The hypothesis was that type 1 (T1D) and type 2 (T2D) affects BMD and fracture risk differently. Pubmed, Embase, and Web of Science were searched using the terms \"diabetes\", \"fracture\", and \"bone mineral\". Hip fracture risk was increased in T1D (RR = 6.94, 95% CI: 3.25-14.78, five studies) and T2D (1.38, 95% CI: 1.25-1.53, eight studies) compared to subjects without diabetes. The increase in relative hip fracture risk was significantly higher in T1D than in T2D. BMD Z-score was decreased in the spine (mean +/- SEM -0.22 +/- 0.01) and hip (-0.37 +/- 0.16) in T1D and increased in the spine (0.41 +/- 0.01) and hip (0.27 +/- 0.01) in T2D. A meta-regression showed that body mass index (BMI) was a major determinant for BMD in both the spine and hip. Glycated haemoglobin (HbA1C) was not linked to BMD. The increase in fracture risk was higher and BMD lower in patients with complications to diabetes. Hip fracture risk is increased in both T1D and T2D, whereas BMD is increased in T2D and decreased in T1D. A common factor such as complications may explain the increase in fracture risk, whereas BMI may ameliorate the increase in fracture risk in T2D.

Summary This study examined whether markers of bone turnover differ between individuals with and without diabetes. Bone markers showed heterogeneity between studies and were discrepant for markers of bone creation and markers of bone degradation. Bone markers may be of lesser value in diabetes due to heterogeneity. Introduction The aim of this meta-analysis was to compare existing literature regarding changes in bone markers among diabetics compared to healthy controls. To exclude that blood glucose levels among diabetes patients could influence the assays used for determining bone turnover markers, a methodological study was performed. Methods Medline at Pubmed Embase, Cinahl, Svemed+, Cochrane library, and Bibliotek.dk was searched in August 2012. The studies should examine biochemical bone turnover among diabetes patients in comparison to controls in an observational design. In the methodological study, fasting blood samples were drawn from two individuals. Glucose was added to the blood samples in different concentrations and OC, CTX, and procollagen type 1 amino terminal propeptide were measured after 0, 1, 2, and 3 h. Results Twenty-two papers fulfilled the criteria for the meta-analysis. From the pooled data in the meta-analysis, the bone markers osteocalcin (OC) (−1.15 ng/ml [−1.78,-0.52]) and C-terminal cross-linked telopeptide (CTX) (−0.14 ng/ml [−0.22, −0.05]) were significantly lower among diabetes patients than non-diabetes patients, however other markers did not differ. All markers displayed very high heterogeneity by I2 statistics. In the methodological study, the addition of glucose did not significantly change the bone markers neither by level of glucose nor with increasing incubation time. Conclusion The dissociative pattern of biochemical bone markers of bone formation and bone resorption present in diabetes patients is thus not caused by glucose per se but may be modulated by unknown factors associated with diabetes mellitus.

SummaryPeople with diabetes have an increased risk of fractures, and in this study, the effect of hypoglycaemia and insulin on this risk was investigated. Type 1 diabetes and hypoglycaemia did increase the fracture risk, and prevention of hypoglycaemia is thus an important focus area in the prevention of fractures.IntroductionStudies have shown that type 1 diabetes (T1D) and type 2 diabetes (T2D) are associated with increased risk of fractures. Especially, subjects with T1D have an increased risk of fractures. The purpose of this study was to investigate the association of T1D, hypoglycaemia and insulin on fracture risk.MethodsA cohort study with T1D subjects (n = 19,896) and T2D subjects (n = 312,188) matched with subjects from the general populated (n = 996,252) and a nested case-control study with T1D subjects with fracture (n = 895) as cases and T1D subjects without (n = 2685) as controls were conducted based on subjects from the Danish National Patient Registry (DNPR).ResultsT1D (HR = 2.47, 95% CI 2.37 to 2.59), age (HR = 1.05, 95% CI 1.05 to 1.05), previous fracture (HR = 1.95, 95% CI 1.92 to 1.99) and being female (HR = 2.06, 95% CI 2.04 to 2.09) increased the risk of fractures. Also, T2D (HR = 1.14, 95% CI 1.11 to 1.18) increased the risk of proximal upper arm and shoulder fractures. T1D (HR = 2.41, 95% CI 2.20 to 2.65) increased the risk of hip and femoral region fractures. Hypoglycaemia (OR = 1.58, 95% CI 1.27 to 1.97) increased the risk of fractures, whereas insulin use did not change the risk.ConclusionsHypoglycaemic episodes are associated with increased fracture risk, and the frequency of hypoglycaemic episodes leading to hospital admission was above 16% for T1D subjects. Prevention of hypoglycaemia is thus an important focus area in the prevention of fractures.

Summary The incidence of hip fractures in Denmark declined by about 20% from 1997 to 2006 in both men and women aged 60 and over. The decrease in hip fracture rates was much too large to be explained by the extent of anti-osteoporotic medication used in the country. Introduction The purpose of this study is to clarify (1) if hip fracture rates decline in Denmark despite low treatment rates and (2) if changes in age-specific rates could be explained by anti-osteoporotic medications. Methods National registers were used to obtain incidence rates for hip fractures in men and women aged 60+ and aggregated national data on number of users of anti-osteoporotic medications for 1997-2006. The potential contribution of anti-osteoporotic treatment to prevented hip fractures was estimated. Results Incidence rates declined by 20% in men and 22% in women. Use of specific anti-osteoporotic medications had increased from 1.8% in 60+-year-old women and 0.2% in 60+-year-old men to 7.3% and 1.3%, respectively. The decrease risk in men was nearly the same as in women, despite a six times lower treatment prevalence. The number of prevented hip fractures that could be attributed to therapy was 1.3% in men and 3.7% in women. Conclusions The decrease in hip fractures is much too large to be explained by the extent of anti-osteoporotic medication. Interestingly, the decrease in fracture rates also applied to men, despite much lower treatment rates. Potential explanations include smoking habits, obesity, national home visit programmes, improved general health and vitamin D supplementation.

Alendronate (ALN) and risedronate (RIS) are ideal as first-choice therapy options in the treatment of postmenopausal osteoporosis. What to do for patients who do not respond adequately to bisphosphonates has not been conclusively determined, but transitioning to other therapies should be considered. The aim of this article is to describe potential alternatives for patients switching from ALN or RIS to other therapies for osteoporosis. A systematic search of PubMed was conducted to find papers that evaluate the effects of switching therapies on fractures, bone mineral density (BMD), or bone turnover markers. Results from 11 studies that prospectively assessed treatment after ALN or RIS in women with postmenopausal osteoporosis were reviewed. All studies are of short duration (all 24 months or less) and assess the topic of transitioning therapy from ALN or RIS. None of the studies had the statistical power to assess fracture-reduction efficacy. Transitioning from ALN to zoledronic acid maintains therapeutic effects for 12 months. Switching to strontium ranelate, denosumab, or teriparatide causes further increases in BMD. Specifically, transitioning to teriparatide could be used for a limited time for select patients but needs to be followed up with anti-resorptive treatment to prevent a loss of the bone gained. There are only few studies—of short duration—that assess the topic of transitioning therapy from ALN or RIS, although this is a very frequent occurrence in clinical practice. This is especially true if the patient has not reached his/her therapy goal. Further long-term studies are needed.

SummarySome studies indicate potential beneficial effects of metformin on body composition and bone. This trial compared metformin + insulin vs placebo + insulin. Metformin treatment had a small but positive effect on bone quality in the peripheral skeleton, reduced weight gain, and resulted in a more beneficial body composition compared with placebo in insulin-treated patients with type 2 diabetes.IntroductionGlucose-lowering medications affect body composition. We assessed the long-term effects of metformin compared with placebo on whole body bone and body composition measures in patients with type 2 diabetes mellitus.MethodsThis was a sub-study of the Copenhagen Insulin and Metformin Therapy trial, which was a double-blinded randomized placebo-controlled trial assessing 18-month treatment with metformin compared with placebo, in combination with different insulin regimens in patients with type 2 diabetes mellitus (T2DM). The sub-study evaluates the effects on bone mineral content (BMC), density (BMD), and body composition from whole body dual-energy X-ray absorptiometry (DXA) scans which were assessed at baseline and after 18 months.ResultsMetformin had a small, but positive, (p < 0.05) effect on subtotal, appendicular, and legs BMC and BMD compared with placebo. After adjustment for sex, age, vitamin D, smoking, BMI, T2DM duration, HbA1c, and insulin dose, the effects on appendicular BMC and BMD persisted (p < 0.05 for both). The changes in appendicular BMC and BMD corresponded approximately to a 0.7% and 0.5% increase in the metformin group and 0.4% and 0.4% decrease in the placebo group, respectively. These effects were mostly driven by an increase in BMC and BMD in the legs and a loss of BMC and BMD in the arms. During 18 months, all participants increased in weight, fat mass (FM), FM%, and lean mass (LM), but decreased in LM%. The metformin group increased less in weight (subtotal weight (weight-head) − 2.4 [− 3.5, − 1.4] kg, p value < 0.001) and FM (− 1.5 [− 2.3, − 0.8] kg, p value < 0.001) and decreased less in LM% (0.6 [0.2, 1.1] %, p value < 0.001) compared with the placebo group.ConclusionMetformin treatment had a small positive effect on BMC and BMD in the peripheral skeleton and reduced weight gain compared with placebo in insulin-treated patients with T2DM.

Summary Pain medication has been associated with fractures. We found higher weight in paracetamol and non-steroidal anti-inflammatory drugs (NSAID) users and lower vitamin D levels in opioid and acetylsalicylic acid users. None of the pain medications influenced bone mineral density or loss. NSAID were associated with an increased fracture risk. Introduction To study the effects of use of paracetamol, non-steroidal anti-inflammatory drugs (NSAID), acetylsalicylic acid (ASA), and opioids on bone mineral density (BMD) and risk of fractures. Methods Two-thousand sixteen perimenopausal women followed for 10 years as part of a partly randomised comprehensive cohort study on hormone therapy (HT). BMD was measured at baseline and after 10 years by DXA (Hologic). Results Paracetamol users were heavier (70.4 ± 13.4 vs. 67.7 ± 11.9 kg, 2 p  < 0.01) than non-users. NSAID users were heavier (71.6 ± 15.6 vs. 67.8 ± 11.9 kg, 2 p  = 0.04) than non-users. ASA users had lower 25-hydroxy-vitamin D (25OHD) levels (21.9 ± 9.3 vs. 25.3 ± 12.4 ng/ml, 2 p  < 0.01) than non-users. Opioid users had lower 25OHD (21.4 ± 8.4 vs. 25.2 ± 12.3 ng/ml) and lower intake of vitamin D (2.2 ± 1.1 vs. 3.1 ± 3.0 μg/day, 2 p  < 0.01) than non-users. Despite these differences, no baseline differences were present in spine, hip, forearm or whole body BMD. Over 10 years, no differences were present in BMD alterations except a small trend towards a higher BMD gain in the spine in users of paracetamol, NSAID, ASA, and opioids compared to non-exposed. After adjustment, NSAID exposed sustained more fractures (HR = 1.44, 95% CI 1.07–1.93) than non-users. For users of paracetamol and opioids, a non-significant trend towards more fractures was present after adjustment. For ASA users, no excess risk of fractures was present. Conclusion Significant differences exist between subjects exposed to pain medications and non-users. Despite an absence of an effect over time on BMD, users of NSAID experienced more fractures than expected. The reasons for this have to be explored in further studies.

SummarySome antihyperglycemic medications have been found to affect bone metabolism. We assessed the long-term effects of metformin compared with placebo on bone mineral density (BMD) and trabecular bone score (TBS) in patients with type 2 diabetes. Metformin had no significant effect on BMD in the spine and hip or TBS compared with a placebo.IntroductionPatients with type 2 diabetes mellitus (T2DM) have an increased risk of fractures despite a high bone mass. Some antihyperglycemic medications have been found to affect bone metabolism. We assessed the long-term effects of metformin compared with placebo on bone mineral density (BMD) and trabecular bone score (TBS).MethodsThis was a sub-study of a multicenter, randomized, 18-month placebo-controlled, double-blinded trial with metformin vs. placebo in combination with different insulin regimens (the Copenhagen Insulin and Metformin Therapy trial) in patients with T2DM. BMD in the spine and hip and TBS in the spine were assessed by dual-energy X-ray absorptiometry at baseline and after 18 months follow-up.ResultsFour hundred seven patients were included in this sub-study. There were no between-group differences in BMD or TBS. From baseline to 18 months, TBS decreased significantly in both groups (metformin group, − 0.041 [− 0.055, − 0.027]; placebo group − 0.046 [− 0.058, − 0.034]; both p < 0.001). BMD in the spine and total hip did not change significantly from baseline to 18 months. After adjustments for gender, age, vitamin D, smoking, BMI, duration of T2DM, HbA1c, and insulin dose, the TBS between-group differences increased but remained non-significant. HbA1c was negatively associated with TBS (p = 0.009) as was longer duration of diabetes, with the femoral neck BMD (p = 0.003). Body mass index had a positive effect on the hip and femoral neck BMD (p < 0.001, p = 0.045, respectively).ConclusionsEighteen months of treatment with metformin had no significant effect on BMD in the spine and hip or TBS in patients with T2DM compared with a placebo. TBS decreased significantly in both groups.Trial registrationClinicalTrials.gov (NCT00657943)

We studied the effect of proton pump inhibitors, histamine H(2) receptor antagonists, and other types of antacid drugs on fracture risk. All cases were subjects with any fracture sustained during the year 2000 (n = 124,655). For each case, three controls (n = 373,962) matched on age and gender were randomly drawn from the background population. The primary exposure variables were use of proton pump inhibitors, histamine H(2) antagonists, and other antacid drugs. Adjustments were made for several confounders, including diagnosis of an ulcer, nonsteroidal anti-inflammatory drug use, use of histamine H(1) antagonists, stomach resection, previous fracture, and use of corticosteroids. The effect of dose was examined by stratifying for cumulated dose (defined daily dose). Use of proton pump inhibitors was associated with an increase in fracture risk for use within the last year [odds ratio (OR) = 1.18, 95% confidence interval (CI) 1.12-1.43 for overall fracture risk; OR = 1.45, 95% CI 1.28-1.65 for hip fractures; and OR = 1.60, 95% CI 1.25-2.04 for spine fractures). Histamine H(2) antagonists were associated with a decreased fracture risk if they had been used within the last year (OR = 0.88, 95% CI 0.82-0.95 for any fracture, OR = 0.69, 95% CI 0.57-0.84 for hip fractures). Other antacids were not associated with overall fracture risk but were associated with hip and spine fractures. Proton pump inhibitors appeared to be associated with a limited increase in fracture risk, in contrast to histamine H( 2 ) antagonists, which seemed to be associated with a small decrease in fracture risk. In all cases, the changes in risk estimates were small and the clinical significance was limited.

We studied the association between fractures and type 1 and type 2 diabetes mellitus. In this case-control study, all subjects diagnosed with a fracture (n=124,655) in Denmark served as cases, and for each case three control subjects (n=373,962) matched for sex and age were retrieved from the general population. Type 1 and type 2 diabetes were associated with an increased risk (1) of any fracture (odds ratio [OR]=1.3, 95% CI: 1.2-1.5 for type 1 diabetes and 1.2, 95% CI: 1.1-1.3 for type 2 diabetes after adjustment for confounders) and (2) of hip fractures (OR=1.7, 95% CI: 1.3-2.2 for type 1 diabetes, and 1.4, 95% CI: 1.2-1.6 for type 2 diabetes). Furthermore, type 2 diabetes was associated with a significant increase in forearm fractures (OR=1.2, 95% CI: 1.0-1.5), and type 1 diabetes was associated with an increased risk of spine fractures (OR=2.5, 95% CI: 1.3-4.6), whereas type 2 diabetes was not. Use of metformin and sulphonylureas was associated with a significantly decreased risk of any fracture, whereas a non-significant trend towards decreased risk of any fracture was associated with the use of insulin. Except for a decrease in hip fractures with use of sulphonylureas, no change in fracture risk in the hip, spine or forearm was associated with the use of insulin or oral antidiabetic drugs. Type 1 and type 2 diabetes are associated with an increased risk of any fracture and hip fractures. The use of drugs to control diabetes may reduce the association between diabetes and fractures.