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An increased risk of fractures in primary hyperparathyroidism (PHPT) has been reported in a number of relatively small studies. Performing a systematic literature search, we identified available studies and calculated common estimates by pooling results from the individual studies in a meta-analysis. Searching EMBASE and PubMed, we identified published studies reporting the risk of fractures in PHPT compared to a control group. We calculated odds ratio (OR) with 95% confidence interval (CI). A total of 804 studies were identified of which 12 studies were included. Risk of any fracture was increased compared to controls (OR 2.01; 95% CI, 1.61-2.50; I2 46%, 5 studies). Analysis of fracture risk at specific sites showed an increased risk of fracture at the forearm (OR 2.36; 95% CI, 1.64-3.38; I2 0%, 4 studies) and spine (OR 3.00; 95% CI, 1.41, 6.37, I2 88%, 9 studies). Risk estimate for hip fractures was non-significantly increased (OR 1.27; 95% CI, 0.97-1.66; I2 0%, 3 studies). Risk of vertebral fractures (VFx) was also increased if analyses were restricted to only studies with a healthy control group (OR 5.76; 95% CI, 3.86-8.60; I2 29%, 6 studies), studies including patients with mild PHPT (OR 4.22; 95% CI, 2.20-8.12; I2 57%, 4 studies) or studies including postmenopausal women (OR 8.07; 95% CI, 4.79-13.59; I2 0%, 3 studies). PHPT is associated with an increased risk of fractures. Although a number of studies are limited—it seems that the risk is increased across different skeletal sites including patients with mild PHPT and postmenopausal women. [ABSTRACT FROM AUTHOR]

Summary: Treatment of benign prostate hyperplasia with α-blockers may affect blood pressure while treatment with 5-α-reductase inhibitors may affect conversion of testosterone potentially leading to osteoporosis. In our study, neither 5-α-reductase inhibitors nor α-blockers were associated with negative effects on fractures, α-blockers perhaps being associated with a limited decrease in fractures. Introduction: The objective is to study fracture risk associated with drugs for benign prostate hyperplasia. The hypotheses were that (1) α-blockers may elevate fracture risk by causing presyncope/falls and (2) 5-α-reductase inhibitors may elevate fracture risk by lowering dihydrotestosterone. Methods: This is a nationwide case-control study using all 9,719 male fracture patients aged ≥60 years in the year 2000 as cases and drawing 29,156 age- and gender-matched controls. The main exposure was the use of the drugs mentioned above for benign prostate hyperplasia. Confounder control included social variables, contacts to hospitals and general practitioners, alcoholism and other variables. Results: For the 5-α-reductase inhibitors, no change in overall risk of fractures was seen. No change in risk of hip, spine and forearm fractures was present. For the α-blockers, a decrease in overall risk of fractures was seen, as well as a decrease in the risk of hip and spine fractures, but only at average doses >0.5 defined daily doses per day. No decrease was seen for forearm fractures. A decreasing risk of any fracture, hip fractures and spine fractures were seen with increasing dose of α-blockers, while no such association was seen for the forearm fractures. Conclusion: Neither the 5-α-reductase inhibitors nor α-blockers were associated with negative effects on fracture risk. A small trend towards a decrease in fracture risk may be present for the α-blockers. However, more research is needed to confirm if this trend is real. [ABSTRACT FROM AUTHOR]

In a cohort of 169,145 patients with a hip fracture and 524,010 controls we observed an excess mortality among patients compared to controls for as long as 20 years after the hip fracture. The main reason for the excess mortality was linked to the trauma that caused the hip fracture. Patients with a hip fracture have a significant excess mortality. However, it remains unclear if the mortality is linked to the pre-morbid conditions or to complications to the fracture. All subjects with a hip fracture in Denmark between 1977 and 2001 were compared with three age- and gender-matched subjects from the general population. A total of 169,145 fracture cases were compared to 524,010 controls. The cases had a much higher prevalence of co-morbidity than the controls. The mortality rate was twice as high in fracture cases compared with controls (HR = 2.26, 95% CI: 2.24–2.27). Adjustments for confounders only changed the excess mortality risk little. The mortality after the hip fracture was divided into two categories: an excess mortality of 19% within the first year following the fracture (relative survival = 0.81 compared to controls), and an excess mortality of 1.8% per year (relative survival 0.982) for every additional year following the fracture. The major causes of the excess mortality were due to complications to the fracture event (70.8% within the first 30 days). Patients with a hip fracture have a pronounced excess mortality risk. The major cause was linked to the fracture event and not to pre-existing co-morbidity. [ABSTRACT FROM AUTHOR]

We studied the effects of various nonmorphine pain medications as well as rheumatoid arthritis and osteoarthritis on fracture risk in a nationwide case-control study. Cases were all subjects with any fracture sustained during the year 2000 ( n = 124,655) in Denmark. 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 acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), or acetylsalicylic acid (ASA). Adjustments were made for several confounders. The effect of dose was examined by stratifying for cumulated dose (defined daily dose, DDD). For acetaminophen, a small increase in overall fracture risk was observed with use within the last year (odds ratio [OR] = 1.45, 95% confidence interval [CI] 1.41–1.49). For ASA, no increase in overall fracture risk was present with recent use. Significant heterogeneity was present for the NSAIDs; e.g., ibuprofen was associated with an increased overall fracture risk (OR = 2.09, 95% CI 2.00–2.18 for <20 DDD), while celecoxib was not (OR = 0.76, 95% CI 0.51–1.13 for <20 DDD, 2 P < 0.01 for comparison). Osteoarthritis was associated with a decreased risk of any fracture if the diagnosis had been made more than 1 year ago (OR = 0.70, 95% CI 0.67–0.72). Rheumatoid arthritis was associated with an increase in overall fracture risk if the diagnosis had been made within the last year (OR = 1.86, 95% CI 1.68–2.07). Weak analgesics may be associated with fracture risk in a varying way. The effects in most cases were small. Falls may be one reason for the increase in fracture risk with some NSAIDs. [ABSTRACT FROM AUTHOR]

We studied the effect of proton pump inhibitors, histamine H2 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 H2 antagonists, and other antacid drugs. Adjustments were made for several confounders, including diagnosis of an ulcer, nonsteroidal anti-inflammatory drug use, use of histamine H1 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 H2 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. [ABSTRACT FROM AUTHOR]

We studied the fracture risk associated with use of methotrexate, azathioprine, and cyclosporine. The study was designed as a case-control study. All patients with a fracture ( n = 124,655) in the year 2000 in Denmark served as cases. Information on fractures and confounders was retrieved from the National Hospital Discharge Register and a number of other national registers. For each case, three age- and gender-matched controls were randomly drawn from the general population ( n = 373,962). Exposure was use of the drugs and a number of covariates including other immunosuppressive drugs, corticosteroids, any cancer, Crohn’s disease, ulcerative colitis, rheumatoid arthritis, psoriasis, liver and kidney disease, prior fracture, and alcoholism. Azathioprine was associated with an increase in overall fracture risk, but besides this, none of the drugs was significantly associated with overall fracture risk or risk of hip, spine, or forearm fracture. Liver [odds ratio (OR) = 1.55, 95% confidence interval (CI) 1.42–1.69] and kidney (OR = 1.26, 95% CI 1.16–1.37) diseases were significantly associated with increased risk of fractures. Azathioprine was associated with an increase in overall fracture risk but not in the risk of spine, hip, or forearm fractures. Methotrexate and cyclosporine were not associated with fracture risk. It thus seems that the underlying disease for which the treatment is administered may be responsible for much of the increase in fracture risk rather than the drugs used to treat the disorder in question. [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]

Introduction: Discrepant results have been reported on association between treatment with lipid lowering drugs and fracture risk. Several studies have failed to demonstrate an effect of statins on bone mineral density. Therefore, the epidemiological findings of a reduced fracture risk may be due to selections bias, e.g. a healthy drug user effect. If so, the reduced fracture risk is most likely independent of type of lipid lowering drug. Aim: We assessed fracture risk in users of various lipid-lowering drugs. Methods: In a case-control design, we compared 124,655 fracture cases with 373,962 age- and gender-matched controls. We used computerized registers to assess individual drug use and related these data to individual fracture data and information on potential confounders. Results: Use of statins was associated with a reduced risk of any fracture (adj. OR 0.87; 95% CI, 0.83–0.92) and hip fractures (adj. OR 0.57; 95% CI, 0.48-0.69). Risk of hip fracture decreased with increased accumulated dose of statins. This was true in men and in women and in subjects younger and older than 65 years of age. However, fracture risk was not reduced in patients treated with pravastatin (adj. OR 1.02; 95% CI, 0.89–1.17) or non-statin lipid lowering drugs (adj. OR 0.99; 95% CI, 0.86–1.15). Conclusions: The reduced fracture risk in users of lipid lowering drugs is apparently specifically related to users of non-pravastatin statins. Our findings do not support the hypothesis of a healthy drug user effect as an explanation for the reduced fracture risk in users of statins. [ABSTRACT FROM AUTHOR]

Introduction: Our objective was to study the association between fracture risk and the use of anxiolytics and sedatives (benzodiazepines, etc.), neuroleptics and antidepressants. Subjects and methods: This was a case control study. All cases consisted of subjects who had sustained a fracture during the year 2000 ( n=124,655). For each case, three controls ( n=373,962) matched for age and gender were randomly drawn from the background population. Exposure was defined as the use of neuroleptics, antidepressants and anxiolytics/sedatives, psychiatric disease (manic depressive states, schizophrenia, other psychoses), and other confounders. The effect of dose was examined as a defined daily dose per day (DDD/day). The values referred to are confounder-adjusted. Results: For anxiolytics and sedatives, there was a small increase in overall fracture risk (OR: around 1.1) even with limited doses (<0.1 DDD/day). No dose-response relationship was observed for anxiolytics and sedatives. For neuroleptics, a limited increase in overall fracture risk was observed (OR: around 1.2 from <0.05 DDD/day with no dose-response relationship). For antidepressants, a dose-response relationship was observed for fracture risk (OR: increasing from 1.15, 95% CI: 1.11–1.19 at <0.15 DDD/day to 1.40, 95% CI: 1.35–1.46 for ≥0.75 DDD/day). The risk of fracture was higher with selective serotonin re-uptake inhibitors than with tricyclic antidepressants. Conclusions: Small increases in fracture risk were seen with the use of anxiolytics and sedatives and neuroleptics without a dose-response relationship. The increase may be linked to an increased risk of falls. For antidepressants, a dose-response relationship was found, with a higher fracture risk for selective serotonin re-uptake inhibitors. [ABSTRACT FROM AUTHOR]

The purpose of this study was to assess alterations in fracture risk in patients with hyper- and hypothyroidism, and the effects of antithyroid drugs and levothyroxine on fracture risk. The study was designed as a case–control study. All patients with a fracture ( n = 124,655) in the year 2000 in Denmark served as cases. For each case, three age- and gender-matched controls were randomly drawn from the general population ( n = 373,962). Exposure variables were a diagnosis of hyperthyroidism, hypothyroidism, ever use of antithyroid drugs, and ever use of levothyroxine. Adjustments were made for time since diagnosis, surgery for hyperthyroidism, thyroid cancer, prior fracture, alcoholism, and corticosteroid use. There was an increase in the risk of any fracture within the first 5 years after a diagnosis of hyperthyroidism, and the first 10 years after a diagnosis of hypothyroidism. Use of antithyroid drugs was associated with a significantly reduced fracture risk independently of the dose used (odds ratio [OR] 0.79–0.84, 2 P < 0.05). No effect of levothyroxine on fracture risk was present. Thyroid surgery for hyperthyroidism and thyroid cancer were not associated with fracture risk. A prior fracture, alcoholism, and corticosteroid use were significant risk factors for fractures. Fracture risk is increased at the time of diagnosis of both hyper- and hypothyroidism, and this increase seems reversible. Low-dose levothyroxine was not associated with fracture risk. The effect of antithyroid drugs may be caused by the reduction in thyroid hormone levels. [ABSTRACT FROM AUTHOR]

Lithium has been shown to inhibit bone resorption and to interact with Wnt signaling, potentially pointing to bone anabolic properties. We, therefore, studied the effects of lithium on fracture risk using a case–control study design. Cases were all subjects including children with any fracture sustained during the year 2000 ( n = 124,655). For each case, three controls ( n = 373,962) matched according to age and gender was randomly drawn from the background population. Adjustments were made for use of other psychotropic drugs (neuroleptics, antidepressants, and anxiolytics/sedatives), psychiatric disease (manic depressive states, schizophrenia, and other psychoses), and other confounders. The effect of dose was examined by stratifying for cumulated dose (DDD, defined daily dose). In the crude analysis, there was a decreasing relative risk of any fracture with increasing accumulated dose of lithium. After adjustment for psychotropic drug use, the risk of any fracture was decreased (odds ratio [OR] 0.74, 95% confidence interval [CI] 0.60–0.92 for 250–849 DDD, and OR 0.67, 95% CI 0.55–0.81 for ≥ 850 DDD of lithium). For Colles’ fractures and spine fractures, a significant decrease was seen with ≥ 850 DDD (OR 0.57, 95% CI 0.35–0.94 for Colles’ fracture and OR 0.32, 95% CI 0.11–0.95 for spine fractures). For hip fractures, a nonsignificant trend toward a decrease was seen; however, without a dose-response relationship. Adjustment for further confounders did not change the results. Lithium treatment was associated with a decreased risk of fractures potentially pointing at bone anabolic properties. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: We studied the association between fractures and type 1 and type 2 diabetes mellitus. Methods: 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. Results: 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 nonsignificant 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. Conclusions/interpretation: 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. [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]

In recent studies from Sweden and the United States, a high vitamin A intake has been associated with low bone mineral density (BMD) and increased fracture risk. In Sweden and the United States, food items such as milk and breakfast cereals are fortified with vitamin A, whereas in Denmark there is no mandatory fortification with vitamin A. In the present study, we investigated relations between vitamin A intake and BMD and fracture risk in a Danish population consuming mostly unfortified food items. Within a population-based cohort study in 2,016 perimenopausal women, associations between BMD and vitamin A intake were assessed at baseline and after 5-year follow-up. Moreover, associations between baseline vitamin A intake and 5-year changes in BMD were studied. Finally, fracture risk was assessed in relation to vitamin A intake. In our cohort, dietary retinol intake (0.53 mg/day) was lower than the intake reported in recent studies form Sweden (0.78 mg/day) and the United States (1.66 mg/day). Cross-sectional and longitudinal analyses showed no associations between intake of vitamin A and BMD of the femoral neck or lumbar spine. Neither did BMD differ between those 5% who had the highest, and those 5% who had the lowest, vitamin A intake. During the 5-year study period, 163 subjects sustained a fracture (cases). Compared to 978 controls, logistic regression analyses revealed no difference in vitamin A intake. Thus, in a Danish population, average vitamin A intake is lower than in Sweden and the United States and not associated with detrimental effects on bone. [ABSTRACT FROM AUTHOR]

AIM:: To study fracture rates and risk factors for fractures in patients with spinal cord injuries. Material and methods: A self-administered questionnaire was mailed to 646 members of the Danish Paraplegic Association and 1000 randomly selected normal controls. 438 patients (309 males, 129 females, 67.8%) and 654 controls (332 males, 322 females, 65.4%) returned the questionnaire. Median age in patients was 42, range 10–80 years, and in controls 43, range 19–93 years (2p=0.25). Results: The crude fracture rate was 2% per year in patients and 1% per year in controls (RR=2.0, P<0.001). Low-energy fractures were much more prominent in patients (19.0% of all fractures) than in controls (1.4%, P<0.001). The fracture rate did not differ before the injury but increased after the injury to a constant level from the third year and forward. Fractures of the lower extremities were more prominent in patients than controls (femurs: RR=23.4, P<0.001, lower legs: RR=5.2, P<0.001, feet/toes: RR=2.4, P=0.006) while fractures of the forearms (P<0.001) and clavicles (P=0.03) were absent among patients. Fractures were more frequent in female patients (RR=1.6, P=0.008) and in male patients with a family history of fractures (RR=2.0, P=0.004). Conclusions: Low-energy fractures especially of the lower extremities are frequent in spinal cord injury patients and especially among female patients. The forearms seem protected from fractures. [ABSTRACT FROM AUTHOR]