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BackgroundType 2 diabetes mellitus (T2D) is associated with an increased fracture risk. There is little evidence for the effects of glucagon-like peptide 1 receptor agonists (GLP-1RA) on fracture risk in T2D. We aimed to investigate the risk of major osteoporotic fractures (MOF) for treatment with GLP-1RA compared to dipeptidyl peptidase 4 inhibitors (DPP-4i) as add-on therapies to metformin.MethodsWe conducted a population-based cohort study using Danish national health registries. Diagnoses were obtained from discharge diagnosis codes (ICD-10 and ICD-8-system) from the Danish National Patient Registry, and all redeemed drug prescriptions were obtained from the Danish National Prescription Registry (ATC classification system). Subjects treated with metformin in combination with either GLP-1RA or DPP-4i were enrolled from 2007 to 2018. Subjects were propensity-score matched 1:1 based on age, sex, and index date. MOF were defined as hip, vertebral, humerus, or forearm fractures. A Cox proportional hazards model was utilized to estimate hazard rate ratios (HR) for MOF, and survival curves were plotted using the Kaplan-Meier estimator. In addition, Aalen’s Additive Hazards model was applied to examine additive rather than relative hazard effects while allowing time-varying effects.ResultsIn total, 42,816 individuals treated with either combination were identified and included. After matching, 32,266 individuals were included in the main analysis (16,133 in each group). Median follow-up times were 642 days and 529 days in the GLP-1RA and DPP-4i group, respectively. We found a crude HR of 0.89 [0.76–1.05] for MOF with GLP-1RA compared to DPP-4i. In the fully adjusted model, we obtained an unaltered HR of 0.86 [0.73–1.03]. For the case of hip fracture, we found a crude HR of 0.68 [0.49–0.96] and a similar adjusted HR. Fracture risk was lower in the GLP-1RA group when examining higher daily doses of the medications, when allowing follow-up to continue after medication change, and when examining hip fractures, specifically. Additional subgroup- and sensitivity analyses yielded results similar to the main analysis.ConclusionIn our primary analysis, we did not observe a significantly different risk of MOF between treatment with GLP-1RA and DPP-4i. We conclude that GLP-1RA are safe in terms of fracture.

BackgroundType 2 diabetes mellitus (T2D) is associated with an increased fracture risk. It is debated whether sodium-glucose cotransporter 2 (SGLT2) inhibitors influence fracture risk in T2D. We aimed to investigate the risk of major osteoporotic fractures (MOF) with SGLT2 inhibitors compared to glucagon-like peptide 1 (GLP-1) receptor agonists when used as add-on therapies to metformin.MethodsWe conducted a population-based cohort study using Danish national health registries. Diagnoses were obtained from discharge diagnosis codes (ICD-10 and ICD-8-system) from the Danish National Patient Registry, and all redeemed drug prescriptions were obtained from the Danish National Prescription Registry (ATC classification system). Subjects treated with metformin in combination with either SGLT2 inhibitors or GLP-1 receptor agonists were identified and enrolled from 2012 to 2018. Subjects were then propensity-score matched 1:1 based on age, sex, and index date. Major osteoporotic fractures (MOF) were defined as hip, vertebral, humerus, or forearm fractures. A Cox proportional hazards model was utilized to estimate hazard rate ratios (HR) for MOF, and survival curves were plotted using the Kaplan-Meier estimator.ResultsIn total, 27,543 individuals treated with either combination were identified and included. After matching, 18,390 individuals were included in the main analysis (9,190 in each group). Median follow-up times were 355 [interquartile range (IQR) 126-780] and 372 [IQR 136-766] days in the SGLT2 inhibitor and GLP-1 receptor agonist group, respectively. We found a crude HR of 0.77 [95% CI 0.56-1.04] for MOF with SGLT2 inhibitors compared to GLP-1 receptor agonists. In the fully adjusted model, we obtained an unaltered HR of 0.77 [95% CI 0.56-1.05]. Results were similar across subgroup- and sensitivity analyses.ConclusionThese results suggest that SGLT2 inhibitors have no effect on fracture risk when compared to GLP-1 receptor agonists. This is in line with results from previous studies.

ObjectivePatients with diabetes mellitus have an increased risk of fractures; however, the underlying mechanism is largely unknown. We aimed to investigate whether the risk of major osteoporotic fractures in diabetes patients differs between subjects initiated with alendronate and denosumab, respectively.Methods and Research DesignWe conducted a retrospective nationwide cohort study through access to all discharge diagnoses (ICD-10 system) from the National Danish Patient Registry along with all redeemed drug prescriptions (ATC classification system) from the Health Service Prescription Registry. We identified all subjects with a diabetes diagnosis between 2000 and 2018 and collected data on the first new prescription of anti-osteoporotic treatment between 2011 and 2018. Exposure was defined as either alendronate or denosumab treatment initiated after diabetes diagnosis. Outcome information was collected by identification of all major osteoporotic fracture (MOF) diagnoses, i.e., hip, spine, forearm, and humerus, from exposure until 2018 or censoring by emigration or death. The risk of fracture was calculated as hazard ratios (HR) using multiply adjusted Cox proportional models with death as a competing risk.ResultsWe included 8,745 subjects initiated with either alendronate (n = 8,255) or denosumab (n = 490). The cohort consisted of subjects with a mean age of 73.62 (SD ± 9.27) years, primarily females (69%) and suffering mainly from type 2 diabetes (98.22%) with a median diabetes duration at baseline of 5.45 years (IQR 2.41–9.19). Those in the denosumab group were older (mean 75.60 [SD ± 9.72] versus 73.51 [SD ± 9.23] years), had a higher proportion of women (81% versus 68%, RR 1.18 [95% CI 1.13–1.24], and were more comorbid (mean CCI 2.68 [95% CI 2.47–2.88] versus 1.98 [95% CI 1.93–2.02]) compared to alendronate initiators. In addition, denosumab users had a higher prevalence of previous fractures (64% versus 46%, RR 1.38 [95% CI 1.28–1.48]). The adjusted HR for any MOF after treatment initiation with denosumab was 0.89 (95% CI 0.78–1.02) compared to initiation with alendronate.ConclusionThe risk of incident MOF among subjects with diabetes was similar between those initially treated with alendronate and denosumab. These findings indicate that the two treatment strategies are equally effective in preventing osteoporotic fractures in subjects with diabetes.

Background: Stroke is a leading cause of mortality and morbidity. It is associated with excessive bone loss and risk of fracture in stroke patients is high. The P2Y12R antagonist and platelet inhibitor, clopidogrel, is widely used for secondary prevention after a stroke. However, recent studies have shown that clopidogrel has negative effects on bone and that long-term clopidogrel use is associated with increased fracture risk. The purpose of the current study was therefore to investigate the association of clopidogrel treatment with risk of fractures in stroke and TIA patients.Methods: The study was a cohort study including all subjects who were prescribed clopidogrel between 1996 and 2008 in Denmark (n = 77,503). Age- and gender matched controls (n = 232,510) were randomly selected from the background population. The study end-points were occurrence of stroke or TIA and occurrence of fracture. Clopidogrel use was primary exposure.Results: Ischemic stroke increased risk of fracture by 50% while haemorrhagic stroke and TIA increased the risk by 30%. However, after adjusting for multiple confounders only patients with ischemic stroke and haemorrhagic stroke had increased fracture risk. Clopidogrel use was not associated with increased fracture risk in subjects with ischaemic stroke or TIA. In contrast, after adjusting for multiple confounders clopidogrel treatment was associated with a 10–35% reduced risk of fracture.Conclusion: Patients with stroke have increased risk of osteoporotic fractures, but clopidogrel treatment does not increase fracture risk. In contrast, patients less adherent to the treatment have lower risk of fractures than non-users and patients with high adherence. However, based on the increased risk in stroke patients, clinicians should consider evaluation of bone status of these patients.

Introduction: Vitamin K functions as a co-factor in the post-translational carboxylation of several bone proteins, including osteocalcin. Aim: The aim of this study was to investigate the relationship between vitamin K1 intake and bone mineral density (BMD) and fracture risk in a perimenopausal Danish population. Design: The study was performed within the Danish Osteoporosis Prevention Study (DOPS), including a population-based cohort of 2,016 perimenopausal women. During the study approximately 50% of the women received hormone replacement therapy (HRT). Associations between vitamin K1 intake and BMD were assessed at baseline and after 5-years of follow-up (cross-sectional design).Moreover, associations between vitamin K1 intake and 5-year and 10-year changes in BMD were studied (follow-up design). Finally, fracture risk was assessed in relation to vitamin K1 intake (nested case-control design). Results: In our cohort, dietary vitamin K1 intake (60 μg/day) was close to the daily intake recommended by the Food and Agriculture Organization (FAO). Cross-sectional and longitudinal analyses showed no associations between intake of vitamin K1 and BMD of the femoral neck or lumbar spine. Neither did BMD differ between those 5%that had the highest vitamin K1 intake and those 5% that had the lowest. During the 10-years of follow-up, 360 subjects sustained a fracture (cases). In a comparison between the cases and 1,440 controls, logistic regression analyses revealed no difference in vitamin K1 intake between cases and controls. Conclusion: In a group of perimenopausal and early postmenopausal women, vitamin K1 intake was not associated with effects on BMD or fracture risk. [ABSTRACT FROM AUTHOR]

Objectives. To study the effect of morphine and opiates on fracture risk. Design. Case–control study. Setting. Nationwide register-based study. Subjects. Cases were all 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 morphine and opiates. Morphine and other opiates had been used by 10 015 (8.0%) of the case subjects and 12 108 (3.2%) of the controls. Adjustments were made for several confounders including prior fracture, and use of weak analgesics [nonsteroidal anti-inflammatory drugs, acetylsalicylic acid (ASA) and acetaminophene]. The effect of dose was examined by stratifying for cumulated dose (defined daily dose). Main outcome measure. Fracture. Results. Morphine (1.47, 95% CI 1.37–1.58), fentanyl (2.23, 95% CI 1.89–2.64), methadone (1.39, 95% CI 1.05–1.83), oxycodone (1.36, 95% CI 1.08–1.69), nicomorphine (1.57, 95% CI 1.38–1.78), ketobemidone (1.07, 95% CI 1.02–1.13), tramadol (1.54, 95% CI 1.49–1.58) and codeine (1.16, 95% CI 1.12–1.20) were all associated with an increase in overall fracture risk. No increase was present for buprenorphine (0.86, 95% CI 0.79–0.95), pethidine (0.98, 95% CI 0.89–1.08), dextropropoxiphene (1.02, 95% CI 0.90–1.16), and combinations of ASA and codeine (0.94, 95% CI 0.88–1.01). Conclusions. An increased fracture risk is seen in users of morphine and opiates. The reason for this may be related to the risk of falls due to central nervous system effects such as dizziness. [ABSTRACT FROM AUTHOR]

Background. Loop diuretics (LD) increase renal calcium excretion. Discrepant results on associations between LD and fracture risk have been reported. Objective. To assess the fracture risk in users of LD. Design and subjects. A population-based pharmaco-epidemiological case–control design with fracture in year 2000 as outcome and use of LD during the previous 5 years as exposure variable. We used nationwide computerized registers to assess individual use of LD and related these data to individual fracture data and information on potential confounders. We compared 64 699 cases aged 40 years or more who sustained a fracture during year 2000 with 194 111 age- and gender-matched controls. Results. A total of 44 001 subjects used LD. Ever use of LD was associated with a crude 51% (OR 1.51; 95% CI 1.48–1.55) increased risk of any fracture and a 72% (OR 1.72; 95% CI 1.64–1.81) increased risk of hip fracture. The risk estimates were reduced after confounder adjustment, i.e. adjusted risk of any fracture was increased by 4% (OR 1.04; 95% CI 1.01–1.07) and risk of hip fracture by 16% (OR 1.16; 95% CI 1.10–1.23). In current users, a tendency towards a decreased fracture risk with increased dose was observed, whereas in former users risk of fracture increased with increased dose. Use of furosemide was associated with higher risk estimates than use of bumetanide. Conclusion. Treatment with LD affects fracture risk. Special attention should be paid to patients in whom treatment with LD is initiated or stopped, as they may be at an increased risk of fracture. [ABSTRACT FROM AUTHOR]

This meta-analysis assesses the effects of epilepsy on fracture risk and changes in bone mineral density (BMD) in patients with epilepsy. A search of PubMed was conducted using the key words epilepsy, fracture, and bone mineral. A weighted estimate of relative risk of fractures and changes in BMD ( Z-score) was calculated. From the changes in BMD, expected increase in relative fracture risk was calculated. A total of 11 studies on fracture risk and 12 studies on BMD were retrieved. The relative risk of any fracture was increased (2.2, 95% CI: 1.9–2.5, five studies), as was the risk of hip (5.3, 3.2–8.8, six studies), forearm (1.7, 1.2–2.3, six studies), and spine fractures (6.2, 2.5–15.5, three studies). A large proportion of fractures (35%) seemed related to seizures. Spine (mean ± SEM: −0.38 ± 0.06) and hip (−0.56 ± 0.06) BMD Z-scores were significantly decreased, hip more than spine ( 2 P < 0.05). The expected increases in relative risk of any fracture from BMD Z-scores were 1.2–1.3, and significantly lower than observed (2 P < 0.05). The deficit in BMD in patients with epilepsy is too small to explain the observed increase in fracture risk. The remainder of the increase in fracture risk may be linked to seizures. [ABSTRACT FROM AUTHOR]

Vestergaard P, Rejnmark L, Mosekilde L (Aarhus University Hospital, Aarhus, Denmark). Fracture risk associated with systemic and topical corticosteroids.J Intern Med2005;257: 374–384.To study the fracture risk associated with the use of corticosteroids in any formulation and administration.Case–control study.Community-based study in Denmark.Cases were all 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. Adjustments were made for concurrent diseases (lung diseases, rheumatic disorders), use of other drugs (inhaled bronchodilators), contacts to hospitals and general practitioners, and social variables.An increased risk of any fracture, hip, spine, and forearm fractures was present with use of more than 2.5 mg of prednisolone or equivalent orally per day. For inhaled corticosteroids a limited increase in the risk of any fracture was present in users of more than 7.5 mg prednisolone equivalents per day (equivalent to 1875 μg of budesonide per day). However, no increase in the risk of hip, spine or forearm fractures was present in users of inhaled corticosteroids. For other topical corticosteroids (dermal, rectal, nasal, local application in the mouth, the eyes or the ears) no increase in fracture risk could be demonstrated even at high doses after adjustment for confounders.Ingestion of more than 2.5 mg of oral prednisolone equivalents per day is associated with an increase in fracture risk. No increase is associated with inhaled corticosteroids except at daily dosages above 7.5 mg of prednisolone equivalents. No increase in fracture risk is associated with other forms of topical corticosteroids. [ABSTRACT FROM AUTHOR]

Vestergaard P, Olsen ML, Paaske Johnsen S, Rejnmark L, Toft Sørensen H, Mosekilde L (Aarhus University Hospital, Denmark; and Aarhus and Aalborg University Hospitals; Aarhus, Denmark). Corticosteroid use and risk of hip fracture: a population-based case–control study in Denmark. J Intern Med 2003; 254: 486–493. Corticosteroids (CS) are used in a wide range of conditions but have several possible adverse effects including an increased risk of osteoporotic fractures. To examine the association between cumulative CS dose and risk of hip fracture. Population-based case–control design. A total of 6660 subjects with hip fracture and 33 272 age-matched population controls were identified using the County Hospital Discharge Registry in North Jutland County, Denmark and the Danish Central Personal Registry, respectively. Data on redeemed prescriptions for CS within the last 5 years before the index date were retrieved from a population-based prescription database, and recalculated to prednisolone equivalents. Cases and controls were categorized according to cumulative CS dose: (i) no use; (ii) <130 mg (e.g. equivalent to 30 mg of prednisolone for 4 days given for an acute exacerbation of asthma); (iii) 130–499 mg (e.g. equivalent to a short course of prednisolone of 450 mg for acute asthma); (iv) 500–1499 mg (e.g. equivalent to 7.5 mg prednisolone daily for 6 months or 800 μg day−1 of inhaled budesonide for 1 year); and (v) ≥1500 mg (e.g. equivalent to >4.1 mg day−1 for 1 year, a long-term high dose). Data were analysed using conditional logistic regression adjusted for potential confounders including gender, redeemed prescriptions for hormone replacement therapy, antiosteoporotic, anxiolytic, antipsychotic and antidepressant drugs. Compared with never users, an increased risk of hip fracture was found for CS users, with increasing cumulative doses of any type of CS use during the preceding 5 years [adjusted odds ratio (OR) = 0.96, 95% confidence interval (CI) = 0.89–1.04] for <130 mg prednisolone; OR = 1.17 (CI = 1.01–1.35) for 130–499 mg; OR = 1.36 (CI = 1.19–1.56) for 500–1499 mg; and OR = 1.65 (CI = 1.43–1.92) for ≥1500 mg. An increased risk was also found when the study population was stratified according to gender, age and type of CS (systemic or topical). Even a limited daily dose of CS (more than an average dose of approximately 71 μg prednisolone per day) was associated with an increased risk of hip fracture. [ABSTRACT FROM AUTHOR]

Abstract: Use of antidepressant medications that act on the serotonin system has been linked to detrimental impacts on bone mineral density (BMD), and to osteoporosis. This article reviews current evidence for such effects, and identifies themes for future research. Serotonin receptors are found in all major types of bone cell (osteoblasts, osteocytes, and osteoclasts), indicating an important role of the neuroendocrine system in bone. Observational studies indicate a complex relationship between depression, antidepressants, and fracture. First, the presence of depression itself increases fracture risk, in relation with decreased BMD and an increase in falls. A range of aspects of depression may operate, including behavioral factors (e.g., smoking and nutrition), biological changes, and confounders (e.g., comorbidities and concomitant medications). A substantial proportion of depressed patients receive antidepressants, mostly selective serotonin reuptake inhibitors (SSRIs). Some of these have been linked to decreased BMD (SSRIs) and increased fracture risk (SSRIs and tricyclic agents). Current use of SSRIs and tricyclics increases fracture risk by as much as twofold versus nonusers, even after adjustment for potential confounders. While there is a dose–response relationship for SSRIs, the effect does not appear to be homogeneous across the whole class of drugs and may be linked to affinity for the serotonin transporter system. The increase in risk is the greatest in the early stages of treatment, with a dramatic increase after initiation, reaching a peak within 1month for tricyclics and 8months for SSRIs. Treatment-associated increased risk diminishes towards baseline in the year following discontinuation. The body of evidence suggests that SSRIs should be considered in the list of medications that are risk factors for osteoporotic fractures. [Copyright &y& Elsevier]