[Alendronate more effective than alfacalcidol in the prevention of osteoporosis in patients with rheumatic disease who are starting glucocorticoid therapy]. / Alendroninezuur effectiever dan alfacalcidol voor preventie van osteoporose bij patiënten met een reumatische ziekte die starten met glucocorticoïdtherapie.

OBJECTIVE: To compare the effects of alendronate and alfacalcidol in the prevention ofglucocorticoid-related osteoporosis in patients with a rheumatic disease. DESIGN: Randomised, double-blind, double-placebo clinical trial (www. clinicaltrials.gov; number: NCT00138983). METHODS: A total of 201 patients with rheumatic disease who were starting glucocorticoid treatment at a daily dose that was equivalent to at least 7.5 mg of prednisone were randomised to alendronate (10 mg) and a placebo capsule ofalfacalcidol daily (n = 100) or alfacalcidol (1 microg) and a placebo tablet ofalendronate daily (n = 101) for 18 months. Primary outcome was change in lumbar spine bone mineral density at 18 months. The main secondary outcome was the incidence of morphometrically confirmed vertebral deformities. RESULTS: Overall, 163 patients completed the study. The bone mineral density of the lumbar spine increased by 2.1% (95% CI: 1.1-3.1) in the alendronate group and decreased by 1.9% (95% CI: -3.I--0.7) in the alfacalcidol group. At 18 months the mean difference in change in bone mineral density between the two groups was 4.0% (95% CI: 2.4-5-5). Three patients in the alendronate group had a new vertebral deformity, compared with 8 patients in the alfacalcidol group, including 5 symptomatic vertebral fractures in 3 patients; the hazard ratio was 0.4 (95% CI: 0.1-1.4). CONCLUSION: Alendronate was more effective than alfacalcidol in preventing glucocorticoid-induced bone loss during this 18-month trial in patients with rheumatic diseases who were starting glucocorticoid treatment.

Hip fracture prediction in elderly men and women: validation in the Rotterdam study.

The aim of our study was to validate a hip fracture risk function, composed of age and femoral neck bone mineral density (BMD). This estimate of the 1-year cumulative risk was previously developed on the basis of Dutch hip fracture incidence data and BMD in men and women. A cohort of 7046 persons (2778 men) aged 55 years and over was followed for an average of 3.8 years. The 1-year hip fracture risk estimate was calculated for each participant according to the risk function and categorized as low (<0.1%), moderate (0.1 to < 1%), or high (> or =1%). Observed first hip fracture incidence was then analyzed for each of these risk categories by age and gender. Additionally, we calculated the relative risk per standard deviation (SD) decrease in femoral neck BMD in this population. At baseline, 2360 individuals were categorized as low risk, 2567 as moderate risk, and 378 as high risk During follow-up, 110 first hip fractures were observed corresponding to an incidence rate of 4.1/1000 person-years (pyrs) (95% confidence interval 3.4-5.0). The observed incidence rate in the low risk group was 0.2/1000 pyrs (0.1-0.9), 2.7/1000 pyrs (1.8-3.9) in the moderate risk group, and 18.4/1000 pyrs (12.4-27.2) in the high risk group. Below the age of 70 years, incidence was low in all categories, and very few individuals were considered at high risk Above the age of 70 years, the observed incidence was high in the high risk group, while in the low and moderate risk groups, the incidence remained low even over 80 years of age. In women, the age-adjusted relative risk for hip fractures was 2.5 per SD decrease in femoral neck BMD (1.8-3.6), while in men this relative risk was 3.0 per SD (1.7-5.4). In conclusion, we observed a similar relation of hip fracture with femoral neck BMD in men and women and were able to predict accurately hip fracture rates over a period of almost 4 years.

Added value of bone mineral density in hip fracture risk scores.

Hip fractures constitute a major health problem. For effective prevention, high-risk groups need to be identified. The objective here was to develop hip fracture risk scores while assessing the added value of bone mineral density relative to more conventional risk indicators. We prospectively followed during 4 years a cohort of 5208 persons (2193 men) aged 55 years and over from the Rotterdam Study, a population-based cohort study conducted in the Netherlands. Risk scores for hip fracture were constructed using several conventional risk indicators requiring interview and anthropometry only, and bone mineral density. During follow-up, 50 persons (14 men) suffered hip fracture. Hip fracture risk was independently determined by age, gender, height, the use of a walking aid, cigarette smoking, and either bone mineral density or weight. We developed two risk scores, with and without bone mineral density. The observed 4-year risk ranged from 3/3389 (0.1%) to 17/169 (10.1%) for the lowest and highest category of the score including bone mineral density, respectively. For the score without bone mineral density, these risks were 8/3117 (0.3%) and 16/144 (11.1%), respectively. The area under the receiver operating characteristic curve indicating discriminatory power was 0.88 for the risk score including, and 0.83 for the score excluding, bone mineral density (p for difference = 0.04). In conclusion, risk scores with and without bone mineral density measurement can be used for hip fracture risk assessment in elderly persons. While the score with bone mineral density has a modestly better performance, the score requiring interview and anthropometry only may be especially useful in primary care settings.

Bone mineral density and mortality in elderly men and women: the Rotterdam Study.

Recent studies have shown that a low bone mineral density (BMD) is associated with a higher risk of mortality. Most studies have investigated this relationship in women only and presented their risk estimates per standard deviation change in BMD. However, when using this approach, a BMD threshold might be missed when relative risks are presented in the traditional manner. Therefore, in this study our aim was to model the relation between BMD and all-cause mortality. In the Rotterdam Study, follow-up was complete for 5819 men and women aged > or =55 years for whom BMD data were available. During an average follow-up of 5.4 years, 399 men and 317 women died. We calculated BMD Z scores using measurements performed at the femoral neck. Cox proportional hazards regression was used to fit the model. An average BMD, reflected by a Z score = 0, was used as the reference. For women, no significant relationship between BMD and overall mortality was observed. For men, however, a cubic model best fitted the relationship under study, also after adjusting for age and body mass index (BMI). The risk of mortality increased when BMD was below average. Similar results were found when separate curves were made for diabetics and nondiabetics, smokers (ever or never), and tertiles of BMI. Excluding subjects who had suffered hip fractures, or adjusting for the number of drugs used and for lower limb disability, essentially did not change results. This suggests that low BMD is not mainly due to morbidity and impaired mobility in our cohort, which makes this a less likely explanation for the observed relation with mortality. The results of our study suggest that, in men, a nonlinear relationship between BMD and mortality exists, which is independent of comorbidity, whereas, in women, no significant relationship was observed.

Fracture incidence and association with bone mineral density in elderly men and women: the Rotterdam Study.

The incidence of all non-vertebral fractures, as well as the relation to bone mineral density (BMD), was quantified in 7806 men and women from the Rotterdam Study, a prospective, population-based cohort study of men and women aged 55 years and older. In addition, the sensitivity of using a T-score at or below -2.5 for identifying subjects at risk for fractures was assessed. At baseline, between 1990 and 1993, femoral neck BMD was measured by dual energy X-ray absorptiometry (DXA). Subsequently, gender-specific T-scores were calculated using the NHANES reference population. During a mean follow-up of 6.8 years, information on incident non-vertebral fractures was gathered. In general, hip, wrist and upper humerus fractures are the most frequent fractures in both men and women. Femoral neck BMD appears to be an equally important risk factor in both genders, and is especially related to hip fractures. For all non-vertebral fractures, the age-adjusted hazard ratio (95% confidence interval) per standard deviation decrease in femoral neck BMD was 1.5 (1.4-1.6) for women and 1.4 (1.2-1.6) for men. For hip fractures, the hazard ratios were 2.1 (1.7-2.5) for women and 2.3 (1.6-3.3) for men. Only 44% of all non-vertebral fractures occurred in women with a T-score below -2.5; in men, this percentage was even lower (21%). Thus, there is a clear need for the development of more sensitive risk assessment tools, using not only BMD, but also other clinical predictors of fractures.

Bone density and risk of hip fracture in men and women: cross sectional analysis.

OBJECTIVE: To determine the relative contribution of decline in bone density to the increase in risk of hip fracture with age in men and women. DESIGN: Incidence data of hip fracture from the general population were combined with the bone density distribution in a sample from the same population and with a risk estimate of low bone density known from literature. SETTING: The Netherlands. SUBJECTS: All people with a hospital admission for a hip fracture in 1993, and bone density measured in a sample of 581.4 men and women aged 55 years and over in a district of Rotterdam. MAIN OUTCOME MEASURE: One year cumulative risk of hip fracture by age, sex, and bone density measured at the femoral neck. RESULTS: A quarter of all hip fractures occurred in men. Men reached the same incidence as women at five years older. Controlled for age, the risk of hip fracture by bone density was similar in men and women. The risk of hip fracture increased 13-fold from age 60 to 80; decrease in bone density associated with age contributed 1.9 (95% confidence interval 1.5 to 2.4) in women and 1.6 (1.3 to 1.8) in men. CONCLUSIONS: The risk of hip fracture by age and bone density is similar in men and women. The decrease in bone density associated with age makes a limited contribution to the exponential increase of the risk of hip fracture with age.

[Costs due to osteoporosis-induced fractures in The Netherlands; possibilities for cost control]. / Kosten wegens osteoporotische fracturen in Nederland; mogelijkheden voor kostenbeheersing.

OBJECTIVE: Evaluation of the medical costs of osteoporotic fractures in the Netherlands and a discussion of the possibilities of cost control. DESIGN: Cost calculation using published data combined with data from routine hospital and nursing home registration. SETTING: The Netherlands. METHODS: We estimated the total cost of osteoporosis related to fractures of the hip, forearm and vertebrae. Incidence data and data from hospital and nursing home stays were related to information about costs. The analysis was performed for men and women aged 50 and older based on data from 1993. The validity of the assumptions was tested in a sensitivity analysis. RESULTS: The direct medical cost of osteoporosis-related fractures was estimated to be over 400 million builders each year. More than one-third of this cost originated in the group aged 85 and over, while this group only represented 1.3% of the population. About 85% of the costs were caused by hip fractures. Of those costs of hip fractures 80% was due to the hospital admissions. The length of stay in the hospital was associated with discharge status (the length of stay for patients going to a nursing home was almost 8 days longer than for patients leaving for their own homes) and age (the length of stay increased by 0.3 days/year of age). The cost of the stay in a nursing home and of ambulatory care were 20% and 10%, respectively, of the total costs. CONCLUSION: In the short term, cost control is mainly possible by reducing the length of stay in the hospital. This can be done by providing better methods of discharge to suitable care facilities. The cost-effectiveness of prevention of fractures is at present unclear. Due to the duration of the treatment and the frequency of fractures at high ages, the timing of the intervention is of great importance.

Bone mineral density and fracture risk in type-2 diabetes mellitus: the Rotterdam Study.

The aim of this study was to determine the association between type-2 diabetes mellitus (DM), BMD and fractures in 6,655 men and women aged 55 years and over from the Rotterdam Study. We compared subjects with type-2 DM to subjects without DM. Additionally, subset analyses were performed, dividing subjects on the basis of the glucose tolerance test into already treated DM, newly diagnosed DM, impaired glucose tolerance (IGT) and normal glucose tolerance (NGT, reference). Femoral neck and lumbar spine BMD were measured using DEXA. Nonvertebral fracture ascertainment was performed using an automated record system involving GPs and local hospitals. Although subjects with DM had higher BMD, they had an increased nonvertebral fracture risk: hazard ratio (HR) 1.33 (1.00-1.77). In subset analysis, the increased fracture risk appeared restricted to treated DM subjects only: HR 1.69 (1.16-2.46). Subjects with IGT had a higher BMD, but contrary to treated DM, they had a lower fracture risk: HR 0.80 (0.63-1.00). In conclusion, subjects with type-2 DM and IGT both have a higher BMD. Whereas, subjects with IGT have a decreased fracture risk, subjects with DM (primarily those with already established and treated DM) had an increased fracture risk, probably due to long-term complications associated with DM.

Fractures in the elderly: epidemiology and demography.

Osteoporosis and osteoporosis-related fractures are a major source of both morbidity and cost in the elderly, the fractures that are most commonly associated with osteoporosis being those of the hip, the distal forearm and the vertebrae, although it is believed that most other fractures occurring in the elderly are also related to osteoporosis. In this review, the incidence of all types of fracture is described based on the available literature, and the foreseeable trends resulting from demographic changes are discussed. Emphasis is given to the epidemiology of hip fracture since this is the most serious consequence of osteoporosis. Hip fractures occur all over the world, most currently occurring in Western countries, mainly Europe and the USA, but it is expected that there will be a large increase in the number of hip fractures in other countries because of demographic changes. The incidence of hip fractures increases exponentially with age, resulting in a 1-year incidence of 1% in women aged 80 in Western countries. Most hip fractures occur in women, but this is again partly due to demography, because of the longer life expectancy of women. Wrist fractures occur more often in women and do not show the same increase with age as hip fractures. The incidence reaches a plateau at age 60-70. Vertebral fractures show a modest increase with age and are again more common in women than men. The incidence of all other fractures increases modestly with age

Incremental cost of medical care after hip fracture and first vertebral fracture: the Rotterdam study.

The aim of this study was to estimate the additional cost of medical care (the incremental cost) caused by incident hip and vertebral fractures, using a matched case cohort design within a longitudinal follow-up study. Incident hip fractures were recorded using the regular follow-up system of the Rotterdam Study. Incident vertebral fractures were recorded by morphometric comparison of spinal radiographs taken at intervals of 2.2 years on average. The matched control group was randomly selected from other participants of the Rotterdam Study in whom no fracture occurred during follow-up, but who were otherwise comparable at baseline. Cases were matched for age, gender, self-perceived health, ability to perform activities of daily life, living situation and general practitioner. Medical expenditure was assessed by retrieval of the general practice medical records and by recording all hospital and nursing home admissions, and all general practice and outpatient visits. Pharmaceutical consumption was recorded through the computerized records of the central pharmacy. Valid results were obtained for 44 pairs (91%) in the hip fracture and for 42 pairs (93%) in the vertebral fracture group. Cost of medical consumption in the year before the hip fracture was similar in patients and control subjects, but the incremental cost in the first year after the hip fracture was almost US$10 000. In the second year after hip fracture the incremental cost was still about $1000. Accounting for the excess mortality in hip fracture patients had little effect on cost in the first year, but cost in the second year was doubled to almost $2000. For vertebral fractures, we did not detect important acute care costs, but these fractures were associated with a yearly recurrent incremental cost of over $1000. However, almost half this difference was already present before the occurrence of the fracture, and was attributable to hospital admissions. The remainder of the incremental cost was mainly due to pharmaceutical consumption and to a lesser extent to admissions to orthopedic surgery wards. We conclude that hip fractures cause excess mortality and an important incremental cost especially during the first year, and that these could probably be avoided by prevention of hip fractures. For vertebral fractures we found no evidence of important acute care costs but we observed a yearly returning incremental cost. Part of this incremental cost, however, was pre-existing and might therefore by caused by co-morbidity.

Bone mineral density and the risk of peripheral arterial disease: the Rotterdam Study.

Low estrogen exposure throughout life is thought to result in low bone mineral density (BMD) and an increased incidence of cardiovascular disease. In the Rotterdam Study we cross-sectionally examined the relation between BMD and peripheral arterial disease (PAD), as assessed by an ankle-arm index (AAI) of <0.9 in either leg. Data on BMD and PAD were available for 5268 individuals (3053 women, 2215 men). From the BMD, Z-scores were calculated and subsequently divided into tertiles. Logistic regression analysis was used to compute odds ratios (OR) for PAD in tertiles of BMD, using the upper tertile as a reference. When adjusting for age, women with a low femoral neck BMD had a significantly increased risk of PAD (OR = 1.49, 95% CI 1.16-1.91). This could not be found for men (1.14, 0.84-1.53). The mid-tertile did not differ from the reference in either men or women. In women, additional adjustment for several potential confounders resulted in a somewhat lowered risk estimate (1.35, 1.02-1.79). In contrast, no association between lumbar spine BMD and PAD could be observed in either men or women. Our study shows an association between low femoral neck BMD and PAD in women only, an association unlikely to be causal. Estrogen deficiency may be the common denominator in osteoporosis and PAD, resulting in clustering of these two major diseases in postmenopausal women.

Longitudinal changes in ultrasound parameters of the calcaneus.

We examined with a median follow-up of 1.4 years (range 1.0-2.0 years) the rates of change per year in ultrasound parameters of the calcaneus. Speed of sound (SOS), Broadband ultrasound attenuation (BUA) and Stiffness were measured twice in 543 subjects (224 men) participating in the Rotterdam Study. SOS fell by -2.5 m/s per year in both sexes (95% CI -4.0 to -1.1 m/s per year in men and -3.6 to -1.4 m/s per year in women). Stiffness decreased by -0.62 (-1.33 to 0.09) per year in men and -0.66 (-1.24 to -0.08) per year in women. In men the rate of change in SOS and Stiffness tended to increase with age. BUA did not change significantly during follow-up in either sex. The prospectively assessed rates of loss differed considerably from those observed cross-sectionally, especially for SOS in men (cross-sectional -0.7 m/s per year, longitudinal -2.5 m/s per year). There was substantial variation between individuals both in changes per year in SOS and in changes per year in BUA. With a median follow-up time of 1.4 years, approximately 27% of the variation in the rate of change for SOS could be explained by measurement error while for BUA this was approximately 9% and for Stiffness 11%. Only a small percentage of subjects had changes larger than could be accounted for by measurement error (SOS: men 26.8%, women 21.6%; BUA: men 28.5%, women: 38.8%; Stiffness: men 32.6%, women 35.1%). The latter may limit the use of ultrasound measurements as a follow-up tool in individuals rather than in populations.

Risk factors for increased bone loss in an elderly population: the Rotterdam Study.

The association of bone loss with age, sex, and several prevalent and modifiable potential risk factors for osteoporosis was studied in 1,856 men and 2,452 women aged 55 years and over from the Rotterdam Study, a population-based cohort study in the Netherlands. The rate of change in femoral neck bone mineral density was estimated longitudinally between 1990 and 1995, after 2 years of follow-up on average. These rates, adjusted for age and body mass index, were -0.0025 (95% confidence interval -0.0038 to -0.0012) in men and -0.0045 (95% confidence interval -0.0056 to -0.0034) g/cm2/year in women (p=0.03). Bone loss accelerated with age, as seen more clearly in men than in women. Lower body mass index and cigarette smoking were associated with increased bone loss in both men and women. In men, higher calcium intake was associated with lower rates, and disability was associated with borderline significantly higher rates of bone loss (p=0.07). In women, a nonsignificant relation was observed with disability, but not with dietary calcium intake. Alcohol intake was not consistently related to the rate of bone loss in either sex. It is concluded that in elderly people the rate of bone loss is higher in women, progresses with age, and is further determined by several modifiable risk factors, particularly in men.