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1.  Maternal Vitamin D Status and Offspring Bone Fractures: Prospective Study over Two Decades in Aarhus City, Denmark 
PLoS ONE  2014;9(12):e114334.
Background
Studies investigating the association between maternal vitamin D status and offspring bone mass measured by dual-energy X-ray absorptiometry (DXA) during childhood have shown conflicting results.
Purpose
We used occurrence of bone fractures up to the age of 18 as a measure reflecting offspring bone mass and related that to maternal vitamin D status.
Methods
The Danish Fetal Origins 1988 Cohort recruited 965 pregnant women during 1988–89 at their 30th gestation week antenatal midwife visit. A blood sample was drawn and serum was stored, which later was analyzed for the concentration of 25-hydroxyvitamin D (25(OH)D) by the liquid chromatography coupled with a tandem mass spectrometric method (LC-MS/MS). Outcome was diagnosis of first time bone fractures extracted from the Danish National Patient Register.
Results
Vitamin D status was available for 850 women. The median (5th–95th percentile) 25(OH)D was 76.2 (23.0–152.1) nmol/l. During follow up 294 children were registered with at least one bone fracture diagnosis. Multivariable Cox regression models using age as the underlying time scale indicated no overall association between maternal vitamin D status and first time bone fractures. However, there was a significantly increased hazard ratio (HR) during childhood for those who had maternal blood drawn in Dec/Jan/Feb compared with Jun/Jul/Aug (HR: 1.75, 95%CI: 1.11–2.74). Adjustment for vitamin D status strengthened this association (1.82, 1.12–2.97), which indicated a potential seasonal impact on offspring fractures independent of maternal vitamin D status. In a sensitivity analysis we found a borderline significant inverse association between continuous concentrations of 25(OH)D and offspring forearm fractures (P = 0.054).
Conclusion
Overall, our results did not substantiate an association between maternal vitamin D status and offspring bone fractures. Further studies on this subject are needed, but the study populations must be large enough to allow for subdivision of fractures.
doi:10.1371/journal.pone.0114334
PMCID: PMC4256222  PMID: 25474409
2.  New strategies for osteoporosis patients previously managed with strontium ranelate 
The aim of this article is to describe potential alternatives to patients no longer eligible for management with strontium ranelate for osteoporosis according to the recommendations by the European Medicines Agency. A systematic search of Pubmed was done for papers on fracture efficacy of various treatments for osteoporosis, and potential harms especially in terms of cardiovascular events and stroke. The results showed that drugs more efficacious in terms of relative risk reduction of fractures than strontium ranelate were alendronate, risedronate, zoledronate, and denosumab. Raloxifene, as for strontium, may be associated with an increased risk of deep venous thromboembolism and fatal stroke. In terms of cardiovascular events special attention may be given to calcium supplements. Thus, patients at risk of stroke and ischemic cardiac events such as acute myocardial infarction should not use strontium ranelate. Ideally more efficacious drugs in terms of fracture reduction should be used such as alendronate, risedronate, zoledronate or denosumab. Raloxifene may pose a special problem as this too may be associated with an increased risk of fatal strokes. Other less-potent drugs in terms of fracture reduction should only be used if no alternatives are available (ibandronate, pamidronate, clodronate). Parathyroid hormone or analogs may be used for a limited time interval in specially selected patients and needs to be followed up with antiresorptive treatment to prevent loss of the bone gained. However, it should be remembered that no head-to-head comparison studies exist.
doi:10.1177/1759720X14552070
PMCID: PMC4239150  PMID: 25435924
alendronate; bisphosphonate; cardiovascular; denosumab; raloxifene; stroke; strontium ranelate; teriparatide
3.  Gastrointestinal Events with Clopidogrel: A Nationwide Population-Based Cohort Study 
ABSTRACT
BACKGROUND
Clopidogrel prevents cardiovascular events, but has been linked with adverse gastrointestinal (GI) complications, particularly bleeding events.
OBJECTIVE
We aimed to investigate the risk of adverse GI events in patients treated with clopidogrel.
DESIGN
A nationwide population-based cohort study based on linkage of three administrative registries in Denmark.
PARTICIPANTS
All individuals who redeemed at least one prescription of clopidogrel from 1996 to 2008 were included as exposed subjects (n = 77,503). For each exposed subject, three matched controls were randomly selected from the background population (n = 232,510).
ANALYSES
Follow-up began on January 1, 1996, and was censored on December 31, 2007, or if patients emigrated or died. The study endpoint was the occurrence of any gastritis, GI ulcer or bleeding. Analyses were adjusted for comorbidity and medication.
RESULTS
Regardless of dose, adjusted odds ratios associating clopidogrel use with the study endpoint were statistically significant and followed a dose–response pattern. The crude absolute risk of GI events were: never users: 2.2 %; <0.1 defined daily dose (DDD) of clopidogrel per day: 7.1 %; 0.1–0.39 DDD: 6.0 %; 0.4–0.79 DDD: 5.7 %; ≥0.80 DDD: 4.4 %. Adjusted odds ratios were: <0.1 DDD: 1.34, 95 % CI: 1.26–1.42; 0.1–0.39 DDD: 1.58, 95 % CI: 1.48–1.68; 0.4–0.79 DDD: 1.91, 95 % CI: 1.77–2.06; ≥0.80 DDD: 1.77, 95 % CI: 1.66–1.89, all p-values < 0.01. Depending on the dose, numbers needed to harm ranged from 58 to 33 patients receiving 12 months of clopidogrel treatment.
CONCLUSIONS
The well-known cardioprotective effect of clopidogrel must be carefully weighed against an increased risk of GI events.
doi:10.1007/s11606-012-2208-0
PMCID: PMC3614150  PMID: 22948933
clopidogrel; coronary artery disease; gastritis; gastrointestinal hemorrhage; stomach ulcer
4.  Diabetes and Osteoporosis – Cause for Concern? 
doi:10.3389/fendo.2014.00053
PMCID: PMC3997044  PMID: 24795695
diabetes; osteoporosis; bone quality; bone; endocrinology and bone metabolism
5.  Fractures in users of antidepressants and anxiolytics and sedatives Effects of age and dose 
Aim
To study the effects of age and dose of selective serotonin reuptake inhibitors (SSRI), trycyclic antidepressants (TCA) and anxiolytics/sedatives on fracture risk.
Subjects and methods
Case control study. From the Danish National Health Service, we identified 124,655 fracture cases and 373,962 age- and gender-matched controls. Crude odds ratios (OR) were estimated, and propensity score adjustment was used to minimize confounding by indication.
Results
A higher risk of fractures was associated with an increasing dose of anxiolytics and sedatives; the highest excess risk was present in the age stratum below 40 years of age (p<0.01), and thereafter the excess risk of fractures declined with age. For SSRI, a growing excess risk of fractures was seen with both increasing dose and age. Regarding TCA, no particular trend with age was present. However, an increasing risk of fractures was associated with increasing TCA dose in the age group above 60 years. Finally, for other antidepressants no particular trend with age or dose was observed. In our data, a hospital diagnosis of depression or manic-depression was associated with fewer fractures.
Conclusion
Caution should be shown upon prescription of SSRI to older subjects. A hospital diagnosis of depression or manic-depression and thus potentially more severe disease was not a risk factor for fractures.
doi:10.1007/s00198-012-2043-5
PMCID: PMC3658008  PMID: 22669469
Selective serotonin reuptake inhibitors; tricyclic antidepressants; antidepressant; fracture
6.  Fracture prevention in postmenopausal women 
Clinical Evidence  2011;2011:1109.
Introduction
The lifetime risk of fracture in white women is 20% for the spine, 15% for the wrist, and 18% for the hip, with an exponential increase in risk beyond the age of 50 years.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of bisphosphonates to prevent fractures in postmenopausal women? What are the effects of pharmacological treatments other than bisphosphonates to prevent fractures in postmenopausal women? What are the effects of non-pharmacological treatments to prevent fractures in postmenopausal women? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 2010 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 71 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: alendronate, calcium, calcium plus vitamin D, clodronate, denosumab, etidronate, exercise, hip protectors, hormone replacement therapy, ibandronate, multifactorial non-pharmacological interventions, pamidronate, parathyroid hormone, raloxifene, risedronate, strontium ranelate, vitamin D, vitamin D analogues, and zoledronate.dfsg
Key Points
The lifetime risk of fracture in white women is 20% for the spine, 15% for the wrist, and 18% for the hip, with an exponential increase in risk beyond the age of 50 years. About 13% of people die in the year after a hip fracture, and most survivors lose some or all of their previous independence.
Alendronate, risedronate, zoledronate, denosumab, and parathyroid hormone reduce vertebral and non-vertebral fractures compared with placebo. Etidronate, ibandronate, pamidronate, and raloxifene reduce vertebral fractures, but have not been shown to reduce non-vertebral fractures.Raloxifene protects against breast cancer, but increases venous thromboembolic events and stroke compared with placebo. Strontium ranelate reduces vertebral and, to some extent, non-vertebral fractures. Clodronate may reduce non-vertebral fractures at 3 years, but its effects on rate of vertebral fracture are unclear.
CAUTION: Hormone replacement therapy may reduce fractures, but it increases the risk of breast cancer and cardiovascular events. The risks of adverse effects of treatment are thought to outweigh the beneficial effects of hormone replacement therapy in prevention of fractures.
Combined calcium plus vitamin D or vitamin D analogues alone may reduce vertebral and non-vertebral fractures, but trials have given inconclusive results. Monotherapy with calcium or vitamin D has not been shown to reduce fractures, and calcium alone may potentially be associated with an increased risk of cardiovascular adverse effects.
We don't know whether multifactorial non-pharmacological interventions including environmental manipulation or regular exercise reduce the risk of fractures. Hip protectors may reduce the risk of hip fractures in nursing-home residents, but compliance tends to be low.
Calcitonin was included in an earlier version of this review. However, in light of a drug alert (http://www.ema.europa.eu/ema/) it was removed from this version because of new harms data. It will be covered in the next update of this review when these new harms data can be incorporated.
PMCID: PMC3217780  PMID: 21542947
7.  No effect of season of birth on risk of type 1 diabetes, cancer, schizophrenia and ischemic heart disease, while some variations may be seen for pneumonia and multiple sclerosis 
Dermato-endocrinology  2013;5(2):309-316.
Background: The risk of type 1 diabetes (T1DM), infections, cancer, schizophrenia and multiple sclerosis (MS) has been associated with environmental factors including vitamin D status.
Materials and Methods: Data were obtained from all children born in Denmark in 1940 (n = 72,839), 1977 (n = 89,570), and 1996 (n = 74,015). Information on contacts to hospitals (1977–2009) was obtained from the National Hospital Discharge Register. The main exposure variable was season of birth as a proxy variable for vitamin D status (summer: April–September and winter: October–March).
Results: No associations between season of birth and risk of MS were seen in the 1940 cohort or the 1996 cohort. In the 1977 cohort, there was a borderline statistically significant decreased risk of MS in those born during wintertime compared with those born during summertime (HR = 0.70, 95% CI: 0.47–1.04, p = 0.07). There were no significant differences within the groups regarding season and risk of T1DM at any age, T1DM before 10 y, infection, any type of cancer, schizophrenia and myocardial infarction. In the 1977 cohort the risk of pneumonia was significantly lower among those born in the summer compared with the winter at any age (HR 0.91, 95% CI 0.85–0.97, p < 0.01) and at age < 10 y (HR 0.90, 95% CI 0.84–0.97, p < 0.01).
Conclusion: MS and pneumonia in young subjects may be related to season of birth and thus maternal vitamin D exposure. Low sunlight exposure in the winter time leading to low vitamin D levels during pregnancy may be a potential explanation.
doi:10.4161/derm.22779
PMCID: PMC3772919  PMID: 24194971
Vitamin D and Multiple Sclerosis; type 1 Diabetes; cancer; schizophrenia; pneumonia; myocardial infarction
8.  A simple score for estimating the long-term risk of fracture in patients with multiple sclerosis 
Neurology  2012;79(9):922-928.
Objective:
To derive a simple score for estimating the long-term risk of osteoporotic and hip fracture in individual patients with MS.
Methods:
Using the UK General Practice Research Database linked to the National Hospital Registry (1997–2008), we identified patients with incident MS (n = 5,494). They were matched 1:6 by year of birth, sex, and practice with patients without MS (control subjects). Cox proportional hazards models were used to calculate the long-term risk of osteoporotic and hip fracture. We fitted the regression model with general and specific risk factors, and the final Cox model was converted into integer risk scores.
Results:
In comparison with the FRAX calculator, our risk score contains several new risk factors that have been linked with fracture, which include MS, use of antidepressants, use of anticonvulsants, history of falling, and history of fatigue. We estimated the 5- and 10-year risks of osteoporotic and hip fracture in relation to the risk score. The C-statistic was moderate (0.67) for the prediction of osteoporotic fracture and excellent (0.89) for the prediction of hip fracture.
Conclusion:
This is the first clinical risk score for fracture risk estimation involving MS as a risk factor.
doi:10.1212/WNL.0b013e318266faae
PMCID: PMC3425841  PMID: 22895583
9.  A health economic analysis of osteoporotic fractures: who carries the burden? 
Archives of Osteoporosis  2013;8(1-2):126.
Summary
This is a cost-of-illness study of osteoporotic fractures in Denmark estimating the incremental societal cost associated with osteoporotic fractures, with both direct cost and productivity cost. This study includes cost regarding hospitals, general practices, the patients, the municipalities and regions. The total cost of osteoporotic fractures in Denmark was estimated at EUR 1.563 billion.
Purpose
The aim of this study is to estimate the societal burden imposed by osteoporotic fractures in Denmark. In contrast to prior studies, this study will present a comprehensive model for the cost of osteoporotic fractures regarding hospitals, general practices, the municipalities, the regions and the patients.
Methods
This cost-of-illness study applied an incidence-based bottom-up approach from a societal perspective, including both direct costs and productivity costs. The study focused on incremental cost associated with osteoporotic fractures using a Markov model. Danish citizens ≥50 years with an osteoporotic fracture between 2001 and 2010 were studied.
Results
The total cost of osteoporotic fractures in Denmark was estimated to EUR 1.563 billion in 2011, at EUR 628 million and EUR 936 million for men and women, respectively. The most expensive fracture for both genders was first hip fracture. The municipalities carried the majority of the costs, with 55–57 % of incremental lifetime cost.
Conclusions
This study showed that the incremental societal burden of osteoporotic fractures is an important health problem. Medical costs of the osteoporotic fractures were substantial cost for the health care sector, but were by far exceeded by the cost for the municipality in terms of social services and rehabilitation.
Electronic supplementary material
The online version of this article (doi:10.1007/s11657-013-0126-3) contains supplementary material, which is available to authorized users.
doi:10.1007/s11657-013-0126-3
PMCID: PMC3880482  PMID: 23420317
Costs and cost analysis; Osteoporosis; Fractures; Bone; Markov; Denmark
10.  Clinical risk factors for osteoporosis are common among elderly people in Nuuk, Greenland 
International Journal of Circumpolar Health  2013;72:10.3402/ijch.v72i0.19596.
Background
Osteoporosis is a debilitating condition characterized by fractures, pain and premature death. Risk factors for osteoporosis predict the risk of fragility fractures.
Aim
To describe the occurrence of risk factors for osteoporosis among populations in Nuuk, the capital of Greenland.
Methods
A random sample of women born in 1934–42, 1945–47, 1956, and men born in 1956 were selected from the national civil registry. A questionnaire was sent out in Greenlandic and Danish on risk factors for osteoporosis: family history, smoking habits, alcohol intake, presence of disease, sun exposure, intake of dairy products, age at menopause (women) and number of falls. Additional questions included the frequency of back pain, previous fractures, intake of vitamin D and calcium supplements, use of anti-osteoporotic drugs, steroids and other drugs.
Results
The questionnaire was sent to 317 subjects confirmed to be living at an address in Nuuk and 181 (57.1%) responded. More young women than older women were smokers (60.6% vs. 35.0%; p=0.022) while limited sun exposure was reported by more of the old women (37.2% vs. 5.6%; p=0.003). Family history of osteoporosis was reported by 15.0%, without difference between groups. Alcohol and milk intake did not differ between groups. Premature menopause was reported by 17.9% of the women. Falls within the last year were reported by 42.4% with fewer falls in the oldest age group (21.9% vs. 50.0%; p=0.005). Frequency of fragility fractures increased with age (5.7% vs. 24.3% vs. 30.4%; p=0.02) and the risk of a fragility fracture increased with age (p=0.004; OR, 95% CI: 4.5, 1.6–12.2, reference: below 70 years), when adjusted for smoking, gender and falls. The use of anti-osteoporotic drugs was low (3.4%) while 28.8% took calcium and vitamin D supplements.
Conclusions
Age is a dominating risk factor for fragility fractures in Greenland. The use of anti-osteoporotic drugs is low in Greenland, even if osteoporotic fractures are common in old age.
doi:10.3402/ijch.v72i0.19596
PMCID: PMC3546323  PMID: 23326764
risk factors; osteoporosis; fragility fractures; Greenland Inuit; old people
11.  Risk of Fracture with Thiazolidinediones: An Individual Patient Data Meta-Analysis 
Background: The use of thiazolidinediones (TZDs) has been associated with increased fracture risks. Our aim was to estimate the risk of fracture with TZDs in three different healthcare registries, using exactly the same study design, and to perform an individual patient data meta-analysis of these three studies.
Methods: Population-based cohort studies were performed utilizing the British General Practice Research Database (GPRD), the Dutch PHARMO Record Linkage System (RLS), and the Danish National Health Registers. In all three databases, the exposed cohort consisted of all patients (aged 18+) with at least one prescription of antidiabetic (AD) medication. Cox proportional hazards models were used to estimate hazard ratios (HRs) of fracture. The total period of follow-up for each patient was divided into periods of current exposure and past exposure, with patients moving between current and past use.
Results: In all three registries, the risk of fracture was increased for women who were exposed to TZDs: HR 1.48 (1.37–1.60) in GPRD, HR 1.35 (1.15–1.58) in PHARMO, and HR 1.22 (1.03–1.44) in Denmark. Combining the data in an individual patient data meta-analysis resulted, for women, in a 1.4-fold increased risk of any fracture for current TZD users versus other AD drug users [adj. HR 1.44 (1.35–1.53)]. For men, there was no increased fracture risk [adj. HR 1.05 (0.96–1.14)]. Risks were increased for fractures of the radius/ulna, humerus, tibia/fibula, ankle, and foot, but not for hip/femur or vertebral fractures. Current TZD users with more than 25 TZD prescriptions ever before had a 1.6-fold increased risk of fracture compared with other AD drug users [HR 1.59 (1.46–1.74)].
Conclusion: In this study, we consistently found a 1.2- to 1.5-fold increased risk of fractures for women using TZDs, but not for men, across three different healthcare registries. TZD users had an increased risk for fractures of the extremities, and risks further increased for prolonged users of TZDs.
doi:10.3389/fendo.2013.00011
PMCID: PMC3582108  PMID: 23549934
thiazolidinediones; fracture; individual patient data; meta-analysis; epidemiology
12.  Risk of Fracture with Thiazolidinediones: Disease or Drugs? 
Calcified Tissue International  2012;90(6):450-457.
The use of thiazolidinediones (TZDs) has been associated with an increased fracture risk. In addition, type 2 diabetes mellitus (T2DM) has been linked with fracture. We evaluated to what extent the association between TZD use and fracture risk is related to the drug or to the underlying disease. We conducted a population-based cohort study using the Danish National Health Registers (1996–2007), which link pharmacy data to the national hospital registry. Oral antidiabetic users (n = 180,049) were matched 1:3 by year of birth and sex to nonusers. Cox proportional hazards models were used to estimate hazard ratios (HRs) of fracture. Time-dependent adjustments were made for age, comorbidity, and drug use. We created a proxy indicator for the severity of disease. The first stage was defined as current use of either a biguanide or a sulfonyluerum, the second stage as current use of a biguanide and a sulfonyluerum at the same time, the third stage as patients using TZDs, and the fourth stage as patients using insulin. The risk of osteoporotic fracture was increased 1.3-fold for stages 3 and 4 compared with controls. Risk with current TZD use (stage 3 HR = 1.27, 95 % CI 1.06–1.52) and risk with current use of insulin (stage 4 HR = 1.25, 95 % CI 1.20–1.31) were similar. In the first (HR = 1.15, 95 % CI 1.13–1.18) and second (HR = 1.00, 95 % CI 0.96–1.04) stages risks were lower. Risk of osteoporotic fracture was similar for TZD users and insulin users. When studying fracture risk with TZDs, the underlying T2DM should be taken into account.
doi:10.1007/s00223-012-9591-8
PMCID: PMC3349019  PMID: 22488176
Thiazolidinedione; Type 2 diabetes mellitus; Fracture risk; Osteoporosis
13.  Fracture prevention in postmenopausal women 
Clinical Evidence  2010;2010:1109.
Introduction
The lifetime risk of fracture in white women is 20% for the spine, 15% for the wrist, and 18% for the hip, with an exponential increase in risk beyond the age of 50 years.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of bisphosphonates to prevent fractures in postmenopausal women? What are the effects of pharmacological treatments other than bisphosphonates to prevent fractures in postmenopausal women? What are the effects of non-pharmacological treatments to prevent fractures in postmenopausal women? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 78 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: alendronate, calcitonin, calcium, calcium plus vitamin D, clodronate, etidronate, exercise, hip protectors, hormone replacement therapy, ibandronate, multifactorial non-pharmacological interventions, pamidronate, parathyroid hormone, raloxifene, risedronate, strontium ranelate, vitamin D, vitamin D analogues, and zoledronate.
Key Points
The lifetime risk of fracture in white women is 20% for the spine, 15% for the wrist, and 18% for the hip, with an exponential increase in risk beyond the age of 50 years. About 13% of people die in the year after a hip fracture, and most survivors lose some or all of their previous independence.
Alendronate, risedronate, zoledronate, and parathyroid hormone reduce vertebral and non-vertebral fractures compared with placebo. Etidronate, ibandronate, pamidronate, and raloxifene reduce vertebral fractures, but have not been shown to reduce non-vertebral fractures. Raloxifene protects against breast cancer, but increases venous thromboembolic events and stroke compared with placebo. Strontium ranelate reduces vertebral and, to some extent, non-vertebral fractures. Calcitonin may reduce vertebral fractures over 1 to 5 years, but has not been shown to reduce non-vertebral fractures. Clodronate may reduce non-vertebral fractures at 3 years, but its effects on rate of vertebral fracture are unclear.
CAUTION: Hormone replacement therapy may reduce fractures, but it increases the risk of breast cancer and cardiovascular events. The risks of adverse effects of treatment are thought to outweigh the beneficial effects of hormone replacement therapy in prevention of fractures.
Combined calcium plus vitamin D, or vitamin D analogues alone, may reduce vertebral and non-vertebral fractures, but studies have given inconclusive results. Monotherapy with calcium or vitamin D has not been shown to reduce fractures.
We don't know whether multifactorial non-pharmacological interventions including environmental manipulation, or regular exercise, reduce the risk of fractures. Hip protectors may reduce the risk of hip fractures in nursing-home residents, but compliance tends to be low.
PMCID: PMC2907603
14.  The Evidence for Efficacy of Osteoporosis Treatment in Men with Primary Osteoporosis: A Systematic Review and Meta-Analysis of Antiresorptive and Anabolic Treatment in Men 
Journal of Osteoporosis  2011;2011:259818.
Purpose. Fragility fractures in men constitute a major worldwide public health problem with a life-time risk of 13%. It cannot be directly inferred that antiosteoporotic drugs effective in women have the same effect in men. Our aim was to appraise the existing evidence for efficacy of osteoporosis treatment in men. Methods. This study was a systematic review of the published literature on the clinical efficacy of medical osteoporosis therapy in the reduction of fracture risk in men (age > 50 years). Studies included were randomised, placebo-controlled trials of men. Results. Five BMD studies of antiresorptive treatment were included. All studies showed an increase in BMD, but there was only a nonsignificant trend in the reduction of clinical fractures. Three BMD studies of anabolic treatment with teriparatide were also included. These showed a significant mean increase in spine BMD and for vertebral fractures a non-significant trend towards a reduction was seen. Conclusion. The evidence of medical osteoporosis treatment in men is scant and inconclusive due to the lack of prospective RCT studies with fracture prevention as primary end point. So far, all evidence is based on BMD increases in small RCT studies showing BMD increases comparable to those reported in postmenopausal women.
doi:10.4061/2011/259818
PMCID: PMC3138068  PMID: 21776371
15.  Vitamin D Status and Bone and Connective Tissue Turnover in Brown Bears (Ursus arctos) during Hibernation and the Active State 
PLoS ONE  2011;6(6):e21483.
Background
Extended physical inactivity causes disuse osteoporosis in humans. In contrast, brown bears (Ursus arctos) are highly immobilised for half of the year during hibernation without signs of bone loss and therefore may serve as a model for prevention of osteoporosis.
Aim
To study 25-hydroxy-vitamin D (25OHD) levels and bone turnover markers in brown bears during the hibernating state in winter and during the active state in summer. We measured vitamin D subtypes (D2 and D3), calcitropic hormones (parathyroid hormone [PTH], 1,25-dihydroxy-vitamin D [1,25(OH)2D]) and bone turnover parameters (osteocalcin, ICTP, CTX-I), PTH, serum calcium and PIIINP.
Material and Methods
We drew blood from seven immobilised wild brown bears during hibernation in February and in the same bears while active in June.
Results
Serum 25-hydroxy-cholecalciferol (25OHD3) was significantly higher in the summer than in the winter (22.8±4.6 vs. 8.8±2.1 nmol/l, two tailed p - 2p = 0.02), whereas 25-hydroxy-ergocalciferol (25OHD2) was higher in winter (54.2±8.3 vs. 18.7±1.7 nmol/l, 2p<0.01). Total serum calcium and PTH levels did not differ between winter and summer. Activated 1,25(OH)2D demonstrated a statistically insignificant trend towards higher summer levels. Osteocalcin levels were higher in summer than winter, whereas other markers of bone turnover (ICTP and CTX-I) were unchanged. Serum PIIINP, which is a marker of connective tissue and to some degree muscle turnover, was significantly higher during summer than during winter.
Conclusions
Dramatic changes were documented in the vitamin D3/D2 ratio and in markers of bone and connective tissue turnover in brown bears between hibernation and the active state. Because hibernating brown bears do not develop disuse osteoporosis, despite extensive physical inactivity we suggest that they may serve as a model for the prevention of this disease.
doi:10.1371/journal.pone.0021483
PMCID: PMC3121767  PMID: 21731765
16.  Treating postmenopausal osteoporosis in women at increased risk of fracture – critical appraisal of bazedoxifene: a review 
Several categories of drugs to treat osteoporosis exist in the form of bisphosphonates, strontium, parathyroid hormone, and selective estrogen receptor modulators (SERM). Advantages and disadvantages exist for each category as some patients may, for example, not tolerate bisphosphonates for gastrointestinal side effects, and especially in women in whom osteoporosis is frequent, several options for treatment are needed. The objectives of this review were to critically appraise the effects of bazedoxifene on risk of fractures especially in women at high risk of fractures. A systematic literature search was conducted for studies, especially randomized controlled trials with fractures as end-points. Bazedoxifene is a new member of the SERM group. The literature search identified one randomized controlled trial with fractures as end-point. This was a 3-year randomized double-blind placebo controlled trial in which 7492 postmenopausal women aged 55 to 85 years were randomly allocated to 1) bazedoxifene (20 [n = 1886] or 40 [n = 1872] mg/day); 2) raloxifene (60 mg/day, n = 1849); or 3) placebo (n = 1885). The risk of vertebral fractures decreased with both 20 (HR 0.58, 95% CI 0.38 to 0.89) and 40 (HR 0.63, 95% CI 0.42 to 0.96) mg of bazedoxifene per day compared to placebo. There was no reduction in non-vertebral fractures. A subgroup of women with a priori high risk of fractures was identified post hoc. In this subgroup there was a reduction in the risk of non-vertebral fractures with the 20 mg dose of bazedoxifene compared to placebo (HR 0.50, 95% CI 0.28 to 0.90). In the 40 mg bazedoxifene group no significant reduction in non-vertebral fractures was seen in this subgroup (HR 0.70, 95% CI 0.40 to 1.20). In general post-hoc defined subgroup analyses should be interpreted with caution. However, the results indicate that bazedoxifene may be effective in preventing vertebral fractures in postmenopausal women with osteoporosis.
PMCID: PMC2971709  PMID: 21072279
bazedoxifene; fracture; bone mineral density
17.  Loss of life years after a hip fracture 
Acta Orthopaedica  2009;80(5):525-530.
Background Patients with a hip fracture have a high mortality; however, it is not clear how large the loss of life-years is over an extended observation period.
Subjects and methods This was a cohort study involving all patients in Denmark who suffered a hip fracture between 1977 and 2001 (n = 169,145). The survival rate for these patients was compared to that for age- and sex-matched subjects without a hip fracture (n = 524,010).
Results There was a substantial degree of excess mortality, with a pronounced variation in age and sex. The absolute number of life-years lost compared to age-matched subjects without a hip fracture was larger in younger subjects than in older subjects (men aged 51–60 years lived 7.5 years less on average while men over 80 years of age lived 3 years less). Expressed as a percentage, however, older subjects had the largest relative loss of expected remaining years of life. Men ≤ 50 years of age lost 18% of their expected remaining years of life, as opposed to men > 80 years of age who lost as much as 58% of their expected remaining years of life. In women, the trend was similar but less pronounced (27% loss in women ≤ 50 years of age vs. 38% in women > 80 years of age).
Interpretation A large proportion of the estimated remaining life is lost after a hip fracture, even in younger patients. Prevention may save life years, although not all of the years lost after a hip fracture may be due to the hip fracture per se.
doi:10.3109/17453670903316835
PMCID: PMC2823336  PMID: 19916683
18.  Simvastatin Does Not Affect Vitamin D Status, but Low Vitamin D Levels Are Associated with Dyslipidemia: Results from a Randomised, Controlled Trial 
Objectives. Statin drugs act as inhibitors of the 3-hydroxy-3methylglutaryl coenzyme A (HMG-CoA) reductase enzyme early in the mevalonate pathway, thereby reducing the endogenous cholesterol synthesis. In recent studies, it has been suggested from epidemiological data that statins also may improve vitamin D status, as measured by increased plasma 25-hydroxyvitamin D (25OHD) levels. We now report the results from a randomised controlled trial on effects of simvastatin on plasma 25OHD levels. Design and Methods. We randomised 82 healthy postmenopausal women to one year of treatment with either simvastatin 40 mg/d or placebo and performed measurement at baseline and after 26 and 52 weeks of treatment. The study was completed by 77 subjects. Results. Compared with placebo, plasma levels of cholesterol and low-density lipoproteins decreased in response to treatment with simvastatin, but our study showed no effect of simvastatin on vitamin D status. However, plasma levels of triglycerides were inversely associated with tertiles of plasma 25OHD levels and changes in plasma triglycerides levels correlated inversely with seasonal changes in vitamin D status. Conclusion. Our data do not support a pharmacological effect of statins on vitamin D status, but do suggest that vitamin D may influence plasma lipid profile and thus be of importance to cardiovascular health.
doi:10.1155/2010/957174
PMCID: PMC2778175  PMID: 20016680
19.  Cohort study on effects of parathyroid surgery on multiple outcomes in primary hyperparathyroidism 
BMJ : British Medical Journal  2003;327(7414):530-534.
Objectives To assess the effects of surgery compared with conservative treatment (no surgery) for primary hyperparathyroidism.
Design Cohort study.
Setting Nationwide Danish cohort.
Participants 3213 patients, mean age 61 (SD 16) years, with a diagnosis of primary hyperparathyroidism between 1980 and 1999. 1934 (60%) underwent surgery and 1279 (40%) were treated conservatively.
Main outcome measures Occurrence of fractures, osteoporosis, kidney or urinary tract stones, acute myocardial infarction, angina pectoris, cardiac arrhythmias, arterial hypertension, heart failure, stroke, acute pancreatitis, stomach or duodenal ulcers, muscle pain, malignant diseases, psychiatric disorders, and mortality.
Results At diagnosis of primary hyperparathyroidism, patients who subsequently underwent surgery had a lower prevalence of previous fracture (odds ratio 0.64, 95% confidence interval 0.51 to 0.80), acute myocardial infarction (0.59, 0.42 to 0.83), stroke (0.57, 0.37 to 0.88), psychiatric disorders (0.54, 0.31 to 0.94), and painful muscle disorders (0.44, 0.26 to 0.76), whereas kidney stones (2.49, 1.93 to 3.23) and acute pancreatitis (2.77, 1.33 to 5.76) were more prevalent. After diagnosis, the risks of fractures (hazards ratio 0.69, 0.56 to 0.84) and gastric ulcers (0.59, 0.41 to 0.84) were lower in patients treated surgically than those treated conservatively. Events involving kidney or urinary tact stones were more prevalent in patients treated surgically than patients treated conservatively (1.87, 1.30 to 2.68). Mortality was lower in patients treated surgically (0.65, 0.57 to 0.73).
Conclusions Patients treated surgically for primary hyperparathyroidism have a lower prevalence of fractures and gastric ulcers than patients treated conservatively. The type of treatment had no effect on the occurrence of cardiovascular events.
PMCID: PMC192894  PMID: 12958111
20.  Risk of renal stone events in primary hyperparathyroidism before and after parathyroid surgery: controlled retrospective follow up study 
BMJ : British Medical Journal  2002;325(7368):807.
Aim
To study the risk of renal stone episodes and risk factors for renal stones in primary hyperparathyroidism before and after surgery.
Design
Register based, controlled retrospective follow up study.
Setting
Tertiary hospitals in Denmark.
Participants
674 consecutive patients with surgically verified primary hyperparathyroidism. Each patient was compared with three age- and sex-matched controls randomly drawn from the background population. Hospital admissions for renal stone disease were compared between patients and controls. Risk factors for renal stones among patients were assessed.
Main outcome measures
Number of renal stone episodes; comparison of hospital admissions for renal stones in patients and controls; assessment of risk factors for renal stones.
Results
Relative risk of a stone episode was 40 (95% confidence interval 31 to 53) before surgery and 16 (12 to 23) after surgery. Risk was increased 10 years before surgery, and became normal more than 10 years after surgery. Stone-free survival 20 years after surgery was 90.4% in patients and 98.7% in controls (risk difference 8.3%, 4.8% to 11.7%). Patients with preoperative stones had 27 times the risk of postoperative stone incidents than controls. Before surgery, males had more stone episodes than females and younger patients had more stone episodes than older patients. Neither parathyroid pathology, weight of removed tissue, plasma calcium levels, nor skeletal pathology (fractures) influenced the risk of renal stones. After surgery, younger age, preoperative stones and ureteral strictures were significant risk factors for stones.
Conclusions
The risk of renal stones is increased in primary hyperparathyroidism and decreases after surgery. The risk profile is normal 10 years after surgery. Preoperative stone events increase the risk of postoperative stones. Stone formers and non-stone formers had the same risk of skeletal complications.
What is already known on this topicPatients with primary hyperparathyroidism have an increased risk of renal stone eventsThe extent to which parathyroid surgery reduces the risk of further stones is unclearWhat this study addsThe risk of a new stone event was 8.3% higher in patients than in controls after surgeryIn patients with stone disease before operation the risk rate for a postoperative stone event was 27times that in controlsThe risk of a renal stone event was higher than the risk among controls until more than 10 years after surgery
PMCID: PMC128947  PMID: 12376441
21.  Cohort study of risk of fracture before and after surgery for primary hyperparathyroidism 
BMJ : British Medical Journal  2000;321(7261):598-602.
Objectives
To study whether fracture risk before and after surgery was increased in patients with primary hyperparathyroidism.
Design
Cohort study.
Setting
Three Danish university hospitals.
Participants
674 consecutive patients with primary hyperparathyroidism (median age 61, range 13-89 years) operated on during the period 1 January 1979 to 31 December 1997; 2021 age and sex matched controls from national patient register.
Main outcome measure
Fractures.
Results
The cases had an increased relative rate of fractures compared with the controls before surgery (1.8, 95% confidence interval 1.3 to 2.3) but not after surgery (1.0, 0.8 to 1.3). The risk of fracture was increased for the vertebrae (3.5, 1.3 to 9.7), the distal part of the lower leg and ankles (2.3, 1.2 to 4.3), and the non-distal part of the forearm (4.0, 1.5 to 10.6) before surgery but not after. The increase in risk of fracture began about 10 years before surgery. Risk peaked 5-6 years before surgery and remained raised, although at a lower level, in the five years immediately before surgery. A small increase in risk of fracture of the distal forearm emerged more than 10 years after surgery (2.9, 1.3 to 6.7).
Conclusions
Risk of fracture is increased up to 10 years before surgery in patients with primary hyperparathyroidism. The risk returns to normal after surgery.
PMCID: PMC27473  PMID: 10977834
22.  The Risk of Fracture in Patients With Multiple Sclerosis: The UK General Practice Research Database 
Journal of Bone and Mineral Research  2011;26(9):2271-2279.
Patients with multiple sclerosis (MS) may be at an increased risk of fracture owing to a greater risk of falling and decreased bone mineral density when compared with the general population. This study was designed to estimate the relative and absolute risk of fracture in patients with MS. We conducted a population-based cohort study using data from the UK General Practice Research Database linked to the National Hospital Registry (1997–2008). Incident MS patients (n = 5565) were matched 1:6 by year of birth, sex, and practice with patients without MS (controls). Cox proportional-hazards models were used to derive adjusted hazard ratios (HRs) for fracture associated with MS. Time-dependent adjustments were made for age, comorbidity, and drug use. Absolute 5- and 10-year risks of fracture were estimated for MS patients as a function of age. Compared with controls, MS patients had an almost threefold increased risk of hip fracture [HR = 2.79, 95% confidence interval (CI) 1.83–4.26] and a risk of osteoporotic fracture that was increased 1.4-fold (HR = 1.35, 95% CI 1.13–1.62). Risk was greater in patients who had been prescribed oral/intravenous glucocorticoids (GCs; HR = 1.85, 95% CI 1.14–2.98) or antidepressants (HR = 1.79, 95% CI 1.37–2.35) in the previous 6 months. Absolute fracture risks were low in younger MS patients but became substantial when patients were older than 60 years of age. It is concluded that MS is associated with an increased risk of fracture. Fracture risk assessment may be indicated in patients with MS, especially those prescribed GCs or antidepressants. © 2011 American Society for Bone and Mineral Research
doi:10.1002/jbmr.418
PMCID: PMC3193376  PMID: 21557309
MULTIPLE SCLEROSIS; FRACTURE RISK; OSTEOPOROSIS; EPIDEMIOLOGY
23.  Use of Insulin and Insulin Analogs and Risk of Cancer — Systematic Review and Meta-Analysis of Observational Studies 
Current Drug Safety  2014;8(1):333-348.
Background:
An association of insulin use and risk of cancer has been reported but evidence is conflicting and methodological issues have been identified.
Objective:
To summarize results regarding insulin use and cancer risk by a systematic review and meta-analysis of cohort and case-control studies examining risk of cancer associated with insulin use in patients with diabetes.
Data Sources:
Systematic literature search in 5 databases: PubMed, Embase, Web of Science, Scopus and Cochrane Library.
Study Eligibility Criteria (PICOS):
Population: diabetes patients. Exposure: Users of any exogenous insulin. Comparison: Diabetes patients with or without use of antidiabetic drugs. Outcome: Any incident cancer. Study Design: Cohort and case-control studies.
Results:
42 eligible studies examined risk of any cancer and 27 site-specific cancers. Results of individual studies were heterogeneous. Meta-analyses were significant for: Insulin vs No Insulin: Increased risk for pancreas, liver, kidney, stomach and respiratory cancer, decreased risk for prostate cancer. Insulin vs Non-Insulin Antidiabetics: Increased risk for any, pancreatic and colorectal cancer. Glargine vs Non-Glargine Insulin: Increased risk for breast cancer, decreased risk for colon cancer.
Limitations:
Few studies available for most cancer sites and exposure contrasts, and few assess effect of dose and duration of exposure. Methodological issues in several studies. Availability of confounders.
Conclusions:
Insulin use was associated with risk of cancer at several sites. Cautious interpretation of results is warranted as methodological issues and limitations in several of the included studies have been identified. Choice of study design may have a profound effect on estimated cancer risk.
doi:10.2174/15680266113136660067
PMCID: PMC3899599  PMID: 24215311
Cancer risk; diabetes mellitus; insulin; neoplasm; meta-analysis; systematic review.

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