Pia Eiken

Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomised trial

Objective To investigate the long term effect of hormone replacement therapy on cardiovascular outcomes in recently postmenopausal women. Design Open label, randomised controlled trial. Setting Denmark, 1990-93. Participants 1006 healthy women aged 45-58 who were recently postmenopausal or had perimenopausal symptoms in combination with recorded postmenopausal serum follicle stimulating hormone values. 502 women were randomly allocated to receive hormone replacement therapy and 504 to receive no treatment (control). Women who had undergone hysterectomy were included if they were aged 45-52 and had recorded values for postmenopausal serum follicle stimulating hormone. Interventions In the treatment group, women with an intact uterus were treated with triphasic estradiol and norethisterone acetate and women who had undergone hysterectomy received 2 mg estradiol a day. Intervention was stopped after about 11 years owing to adverse reports from other trials, but participants were followed for death, cardiovascular disease, and cancer for up to 16 years. Sensitivity analyses were carried out on women who took more than 80% of the prescribed treatment for five years. Main outcome measure The primary endpoint was a composite of death, admission to hospital for heart failure, and myocardial infarction. Results At inclusion the women on average were aged 50 and had been postmenopausal for seven months. After 10 years of intervention, 16 women in the treatment group experienced the primary composite endpoint compared with 33 in the control group (hazard ratio 0.48, 95% confidence interval 0.26 to 0.87; P=0.015) and 15 died compared with 26 (0.57, 0.30 to 1.08; P=0.084). The reduction in cardiovascular events was not associated with an increase in any cancer (36 in treated group v 39 in control group, 0.92, 0.58 to 1.45; P=0.71) or in breast cancer (10 in treated group v 17 in control group, 0.58, 0.27 to 1.27; P=0.17). The hazard ratio for deep vein thrombosis (2 in treated group v 1 in control group) was 2.01 (0.18 to 22.16) and for stroke (11 in treated group v 14 in control group) was 0.77 (0.35 to 1.70). After 16 years the reduction in the primary composite outcome was still present and not associated with an increase in any cancer. Conclusions After 10 years of randomised treatment, women receiving hormone replacement therapy early after menopause had a significantly reduced risk of mortality, heart failure, or myocardial infarction, without any apparent increase in risk of cancer, venous thromboembolism, or stroke. Trial registration ClinicalTrials.gov NCT00252408.

Subtrochanteric and Diaphyseal Femur Fractures in Patients Treated With Alendronate: A Register-Based National Cohort Study†‡

Alendronate (aln) is a potent bisphosphonate with a prolonged duration of action. Recent reports have found long‐term aln use to be common in patients with subtrochanteric or proximal diaphyseal femur fracture, raising concerns that these fractures could be a consequence of excessive suppression of bone turnover. Two national observational register‐based studies were performed: (1) cross‐sectional study (N = 11,944) comparing age distribution, exposure, and trauma mechanisms between different types of proximal femur fractures and (2) matched cohort study in patients with prior nonhip fractures (N = 5187 + 10,374), testing the hypothesis that the increase in the risk of subsequent atypical femur fractures exceeded the increase in typical hip fractures. We also sought evidence of a dose‐response relationship, where high adherence to or long‐term use of aln led to more atypical femur fractures. We found that 7% of patients with atypical fractures were aln exposed, and the same was found for typical hip fractures. In the cohort study, the HR for subtrochanteric/diaphyseal fracture with aln was 1.46 (0.91–2.35, p = 0·12) compared with 1.45 (1.21–1.74, p < 0·001) for hip fracture after adjustment for comorbidity and co‐medications. The risk was reduced by high adherence, and the ratio between hip and subtrochanteric/diaphyseal femur fractures was identical in aln‐treated patients and the control cohort even in the limited number of patients who received long‐term treatment. Subtrochanteric/diaphyseal femur fractures share the epidemiology and treatment response of classical hip fractures and are best classified as osteoporotic fractures.

Excess mortality in men compared with women following a hip fracture. National analysis of comedications, comorbidity and survival

INTRODUCTION osteoporosis is a common disease, and the incidence of osteoporotic fractures is expected to rise with the growing elderly population. Immediately following, and probably several years after a hip fracture, patients, both men and women, have a higher risk of dying compared to the general population regardless of age. The aim of this study was to assess excess mortality following hip fracture and, if possible, identify reasons for the difference between mortality for the two genders. METHODS this is a nationwide register-based cohort study presenting data from the National Hospital Discharge Register on mortality, comorbidity and medication for all Danish patients (more than 41,000 persons) experiencing a hip fracture between 1 January 1999 and 31 December 2002. Follow-up period was until 31 December 2005. RESULTS we found a substantially higher mortality among male hip fracture patients than female hip fracture patients despite men being 4 years younger at the time of fracture. Both male and female hip fracture patients were found to have an excess mortality rate compared to the general population. The cumulative mortality at 12 months among hip fracture patients compared to the general population was 37.1% (9.9%) in men and 26.4% (9.3%) in women. In the first year, the risk of death significantly increased for women with increasing age (hazard ratio, HR: 1.06, 95% confidence interval, CI: 1.06-1.07), the number of comedications (HR 1.04, 95% CI 1.03-1.05) and the presence of specific Charlson index components and medications described below. For men, age (HR 1.07, 95% CI 1.07-1.08), number of comedications (HR 1.06, 95% CI 1.04-1.07) and presence of different specific Charlson index components and medications increased the risk. Long-term survival analyses revealed that excess mortality for men compared with women remained strongly significant (HR 1.70, 95% CI 1.65-1.75, P < 0.001), even when controlled for age, fracture site, the number of medications, exposure to drug classes A, C, D, G, J, M, N, P, S and for chronic comorbidities. CONCLUSION excess mortality among male patients cannot be explained by controlling for known comorbidity and medications. Besides gender, we found higher age and multimorbidity to be related to an increased risk of dying within the first year after fracture; acute complications might be one of the explanations. This study emphasises the need for particular rigorous postoperative diagnostic evaluation and treatment of comorbid conditions in the male hip fracture patient.

Cumulative Alendronate Dose and the Long-Term Absolute Risk of Subtrochanteric and Diaphyseal Femur Fractures: A Register-Based National Cohort Analysis

CONTEXT Bisphosphonates are the mainstay of anti-osteoporotic treatment and are commonly used for a longer duration than in the placebo-controlled trials. A link to development of atypical subtrochanteric or diaphyseal fragility fractures of the femur has been proposed, and these fractures are currently the subject of a U.S. Food and Drug Administration review. OBJECTIVE Our objective was to examine the risk of subtrochanteric/diaphyseal femur fractures in long term users of alendronate. DESIGN We conducted an age- and gender-matched cohort study using national healthcare data. PATIENTS Patients were alendronate users, without previous hip fracture, who began treatment between January 1, 1996, and December 31, 2005 (n=39,567) and untreated controls, (n=158,268). MAIN OUTCOME MEASURES Subtrochanteric or diaphyseal femur fractures were evaluated. RESULTS Subtrochanteric and diaphyseal fractures occurred at a rate of 13 per 10,000 patient-years in untreated women and 31 per 10,000 patient-years in women receiving alendronate [adjusted hazard ratio (HR)=1.88; 95% confidence interval (CI)=1.62-2.17]. Rates for men were six and 31 per 10,000 patient-years, respectively (HR=3.98; 95% CI=2.62-6.05). The HR for hip fracture was 1.37 (95% CI=1.30-1.46)) in women and 2.47 (95% CI=2.07-2.95) in men. Risks of subtrochanteric/diaphyseal fracture were similar in patients who had received 9 yr of treatment (highest quartile) and patients who had stopped therapy after the equivalent of 3 months of treatment (lowest quartile). CONCLUSIONS Alendronate-treated patients are at higher risk of hip and subtrochanteric/diaphyseal fracture than matched control subjects. However, large cumulative doses of alendronate were not associated with a greater absolute risk of subtrochanteric/diaphyseal fractures than small cumulative doses, suggesting that these fractures could be due to osteoporosis rather than to alendronate.

Hormonal replacement therapy reduces forearm fracture incidence in recent postmenopausal women — results of the Danish Osteoporosis Prevention Study

OBJECTIVES To study the fracture reducing potential of hormonal replacement therapy (HRT) in recent postmenopausal women in a primary preventive scenario. METHODS Prospective controlled comprehensive cohort trial: 2016 healthy women aged 45-58 years, from three to 24 months past last menstrual bleeding were recruited from a random sample of the background population. Mean age was 50. 8+/-2.8 years, and the number of person years followed was 9335.3. There were two main study arms: a randomised arm (randomised to HRT; n=502, or not; n=504) and a non-randomised arm (on HRT; n=221, or not; n=789 by own choice). First line HRT was oral sequential oestradiol/norethisterone in women with intact uterus and oral continuous oestradiol in hysterectomised women. RESULTS After five years, a total of 156 fractures were sustained by 140 women. There were 51 forearm fractures in 51 women. By intention-to-treat analysis (n=2016), overall fracture risk was borderline statistically significantly reduced (RR=0.73, 95% CI: 0.50-1.05), and forearm fracture risk was significantly reduced (RR=0.45, 95% CI: 0.22-0.90) with HRT. Restricting the analysis to women who had adhered to their initial allocation of either HRT (n=395) or no HRT (n=977) showed a significant reduction in both the overall fracture risk (RR=0.61, 95% CI: 0.39-0.97) and the risk of forearm fractures (RR=0.24, 95% CI: 0.09-0.69). Compliance with HRT was 65% after five years. CONCLUSIONS It is possible to reduce the number of forearm fractures and possibly the total number of fractures in recent postmenopausal women by use of HRT as primary prevention.

Single nucleotide polymorphisms in the P2X7 gene are associated to fracture risk and to effect of estrogen treatment

Objectives The purinergic P2RX7 receptor (P2RX7) has been shown to play a role in the regulation of osteoblast and osteoclast activity. The aim of this study was to determine the presence of polymorphisms in exon 13 of the P2X7 gene and the association with osteoclast apoptosis in vitro and bone status in vivo. Methods A total of 1764 postmenopausal women were genotyped for three single nucleotide polymorphisms detected after sequencing of exon 13 of P2X7. Bone markers, bone mineral density of the hip and lumbar spine were determined at baseline and after 10 years, and vertebral fracture incidence after 10 years. In-vitro ATP-induced caspase-1 determinations were performed on osteoclasts from the different genotypes. Results Three polymorphisms were detected (Gln460Arg, Glu496Ala, and Ile568Asn). None of the polymorphisms was related to bone mineral density or changes in bone mineral density over 10 years in hormone replacement therapy naïve women. The Ile568Asn polymorphism was however, associated with effect of hormone replacement therapy. Furthermore, the 10-year fracture incidence was significantly associated with both the Glu496Ala and the Ile568Asn. The Glu496Ala polymorphism was closely related to ATP-induced osteoclast apoptosis in vitro, as osteoclasts from individuals homozygous for the C allele had significantly decreased apoptotic activity. Conclusion The P2X7 Glu496Ala and the Ile568Asn single nucleotide polymorphisms are associated with 10-year fracture risk in postmenopausal women and response to hormone replacement therapy treatment. Further, the Glu496Ala polymorphism is strongly influencing osteoclast apoptosis in vitro, which could contribute to increased fracture risk.

Atrial fibrillation in fracture patients treated with oral bisphosphonates

Objectives.  To determine if patients receiving oral bisphosphonates are at excess risk of atrial fibrillation (AF), stroke and myocardial infarction.

Hormone Replacement Therapy Dissociates Fat Mass and Bone Mass, and Tends to Reduce Weight Gain in Early Postmenopausal Women: A Randomized Controlled 5-Year Clinical Trial of the Danish Osteoporosis Prevention Study†

The aim of this study was to study the influence of hormone replacement therapy (HRT) on weight changes, body composition, and bone mass in early postmenopausal women in a partly randomized comprehensive cohort study design. A total of 2016 women ages 45–58 years from 3 months to 2 years past last menstrual bleeding were included. One thousand were randomly assigned to HRT or no HRT in an open trial, whereas the others were allocated according to their preferences. All were followed for 5 years for body weight, bone mass, and body composition measurements. Body weight increased less over the 5 years in women randomized to HRT (1.94 ± 4.86 kg) than in women randomized to no HRT (2.57 ± 4.63, p = 0.046). A similar pattern was seen in the group receiving HRT or not by their own choice. The smaller weight gain in women on HRT was almost entirely caused by a lesser gain in fat. The main determinant of the weight gain was a decline in physical fitness. Women opting for HRT had a significantly lower body weight at inclusion than the other participants, but the results in the self‐selected part of the study followed the pattern found in the randomized part. The change in fat mass was the strongest predictor of bone changes in untreated women, whereas the change in lean body mass was the strongest predictor when HRT was given. Body weight increases after the menopause. The gain in weight is related to a decrease in working capacity. HRT is associated with a smaller increase in fat mass after menopause. Fat gain protects against bone loss in untreated women but not in HRT‐treated women. The data suggest that womens attitudes to HRT are more positive if they have low body weight, but there is no evidence that the conclusions in this study are skewed by selection bias.

Site of osteodensitometry in perimenopausal women : Correlation and limits of agreement between anatomic regions

Because the bone mineral density (BMD) in different anatomic regions is heterogenous the number of women who fulfill the World Health Organization definition of osteopenia or osteoporosis increases with the number of regions examined. The purpose of this study was to investigate the agreement between measurements of the spine, femur, forearm, and whole body following menopause. Two thousand and five healthy, perimenopausal women, mean age 50.6 years, were studied using Hologic QDR‐1000/W and QDR‐2000 densitometers. Though the BMD of different anatomic regions were correlated (r = 0.40–0.77, p < 0.01), the variability in each patient regarding T and Z scores between regions was considerable. For example, despite a high correlation (r = 0.67, p < 0.01) and no systematic difference between the T scores for total femoral and lumbar BMD, the limits of agreement (mean difference ± 2 SD) for the comparison were −1.89 to 1.87. Femoral neck T scores were 0.5 SD lower than those of the other regions, confirming reports that the young adult reference for this measurement is disproportionally high. The prevalence of osteoporosis was 1.2% when femur total BMD was considered alone and 5.9% when lumbar and ultradistal forearm results were included. However, as many as 7.9% showed osteoporosis of the femoral neck when the Hologic T score was used, compared with 0.7% using National Health and Nutrition Examination Survey (NHANES) values. The choice of anatomic region and availability of appropriate young adult reference data has considerable impact on the apparent prevalence of osteoporosis. Given the heterogeneity between regions, a combination of spinal and femoral densitometry should be used in diagnosing osteoporosis, though this increases the prevalence of osteoporosis by 50% or more in perimenopausal women.

Proton Pump Inhibitor Use and the Antifracture Efficacy of Alendronate

BACKGROUND Proton pump inhibitors (PPIs) are widely used in elderly patients and are frequently coadministered in users of oral bisphosphonates. Biologically, PPIs could affect the absorption of calcium, vitamin B(12), and bisphosphonates and could affect the osteoclast proton pump, thus interacting with bisphosphonate antifracture efficacy. Moreover, PPIs themselves have been linked to osteoporotic fractures. METHODS Population-based, national register-based, open cohort study of 38,088 new alendronate sodium users with a mean duration of follow-up of 3.5 years. We related risk of hip fracture to recent pharmacy records of refill of prescriptions for alendronate. RESULTS For hip fractures, there was statistically significant interaction with alendronate for PPI use (P < .05). The treatment response associated with complete refill compliance to alendronate was a 39% risk reduction (hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.52-0.71; P < .001) in patients who were not PPI users, while the risk reduction in concurrent PPI users was not significant (19%; HR, 0.81; 95% CI, 0.64-1.01; P = .06). The attenuation of the risk reduction was dose and age dependent. In contrast, there was no significant impact of concurrent use of histamine H(2) receptor blockers. CONCLUSIONS Concurrent PPI use was associated with a dose-dependent loss of protection against hip fracture with alendronate in elderly patients. This is an observational study, so a formal proof of causality cannot be made, but the dose-response relationship and the lack of impact of prior PPI use provides reasonable grounds for discouraging the use of PPIs to control upper gastrointestinal tract complaints in patients treated with oral bisphosphonates.