Fracture prevention by screening for high fracture risk: a systematic review and meta-analysis.

This systematic review and meta-analysis showed a significant reduction of (major) osteoporotic fractures and hip fractures after screening using fracture risk assessment and bone densitometry compared with usual care. The results indicate that screening is effective for fracture risk reduction, especially hip fractures. To perform a systematic review and meta-analysis of population screening for high fracture risk on fracture prevention compared with usual care. MEDLINE and Embase were searched for studies published until June 20th 2019. Randomized studies were selected that screened for high fracture risk using at least bone densitometry, screened in a general population, provided subsequent treatment with anti-osteoporosis medication, had a usual care group as comparator, and had at least one fracture-related outcome (all fractures, (major) osteoporotic fractures, or hip fractures). The primary assessment was the hazard ratio (HR) for fracture-related outcomes. All-cause mortality was a secondary outcome. Random-effects models were used to estimate pooled HRs. We identified 1186 potentially eligible articles and included three randomized studies: the ROSE study, the SCOOP study, and the SOS with a total number of N = 42,009 participants. Respectively, 11%, 15%, and 18% of the participants in the intervention group started medication. Meta-analysis showed a statistically significant and clinically relevant reduction of osteoporotic fractures (HR = 0.95, 95% confidence interval (CI) = 0.89-1.00), major osteoporotic fractures (HR = 0.91; 95%CI = 0.84-0.98), and hip fractures (HR = 0.80; 95%CI = 0.71-0.91), but no reduction of all fractures (HR = 0.95; 95%CI = 0.89-1.02). The pooled HR for the secondary outcome all-cause mortality was 1.04 (95% CI = 0.95-1.14). Numbers needed to screen to prevent one fracture were 247 and 272 for osteoporotic fractures and hip fractures, respectively (corresponding to 113 and 124 performed bone densitometry examinations, and 25 and 28 persons being treated). This meta-analysis showed that population screening is effective to reduce osteoporotic fractures and hip fractures. Implementation of screening in older women should be considered as serious option to prevent osteoporotic fractures, especially hip fractures.

Self-perception of fracture risk: what can it tell us?

In this study, we report that self-perception of fracture risk captures some aspect of fracture risk not currently measured using conventional fracture prediction tools and is associated with improved medication uptake. It suggests that adequate appreciation of fracture risk may be beneficial and lead to greater healthcare engagement and treatment. INTRODUCTION: This study aimed to assess how well self-perception of fracture risk, and fracture risk as estimated by the fracture prediction tool FRAX, related to fracture incidence and uptake and persistence of anti-osteoporosis medication among women participating in the Global Longitudinal study of Osteoporosis in Women (GLOW). METHODS: GLOW is an international cohort study involving 723 physician practices across 10 countries in Europe, North America and Australia. Aged ≥ 55 years, 60,393 women completed baseline questionnaires detailing medical history, including co-morbidities, fractures and self-perceived fracture risk (SPR). Annual follow-up included self-reported incident fractures and anti-osteoporosis medication (AOM) use. We calculated FRAX risk without bone mineral density measurement. RESULTS: Of the 39,241 women with at least 1 year of follow-up data, 2132 (5.4%) sustained an incident major osteoporotic fracture over 5 years of follow-up. Within each SPR category, risk of fracture increased as the FRAX categorisation of risk increased. In GLOW, only 11% of women with a lower baseline SPR were taking AOM at baseline, compared with 46% of women with a higher SPR. AOM use tended to increase in the years after a reported fracture. However, women with a lower SPR who were fractured still reported lower AOM rates than women with or without a fracture but had a higher SPR. CONCLUSIONS: These results suggest that SPR captures some aspect of fracture risk not currently measured using conventional fracture prediction tools and is also associated with improved medication uptake.

Design of the SALT Osteoporosis Study: a randomised pragmatic trial, to study a primary care screening and treatment program for the prevention of fractures in women aged 65 years or older.

BACKGROUND: Several drugs have become available for the treatment of osteoporosis. However, screening and treatment of patients with a high fracture risk is currently not recommended in the Netherlands, because the effectiveness of bone sparing drugs has not been demonstrated in the general primary care population. Here we describe the design of the SALT Osteoporosis study, which aims to examine whether the screening and treatment of older, female patients in primary care can reduce fractures, in comparison to usual care. METHODS: A randomised pragmatic trial has been designed using a stepwise approach in general care practices in the Netherlands. Women aged ≥65 years, who are not prescribed bone sparing drugs or corticosteroids are eligible for the study. First, women with at least one clinical risk factor for fractures, as determined by questionnaires, are randomly assigned to the intervention or control group. Second, women in the intervention group having a high fracture risk according to our screening program, including an adapted fracture risk assessment (FRAX) tool, combined with dual-energy x-ray absorptiometry (DXA), and instant vertebral assessment (IVA), are offered a structured treatment program. The women in the control group receive care as usual and will undergo the same screening as the intervention group at the end of the trial. The follow-up duration will be three years and the primary outcome is time to first incident fracture and the total number of fractures. DISCUSSION: The results of the current study will be very important for underpinnings of the prevention strategy of the osteoporosis guidelines. TRIAL REGISTRATION: ID NTR2430 . Registered 26 July 2010.

Disease-specific perception of fracture risk and incident fracture rates: GLOW cohort study.

UNLABELLED: Accurate patient risk perception of adverse health events promotes greater autonomy over, and motivation towards, health-related lifestyles. INTRODUCTION: We compared self-perceived fracture risk and 3-year incident fracture rates in postmenopausal women with a range of morbidities in the Global Longitudinal study of Osteoporosis in Women (GLOW). METHODS: GLOW is an international cohort study involving 723 physician practices across ten countries (Europe, North America, Australasia); 60,393 women aged ≥55 years completed baseline questionnaires detailing medical history and self-perceived fracture risk. Annual follow-up determined self-reported incident fractures. RESULTS: In total 2,945/43,832 (6.8%) sustained an incident fracture over 3 years. All morbidities were associated with increased fracture rates, particularly Parkinson's disease (hazard ratio [HR]; 95% confidence interval [CI], 3.89; 2.78-5.44), multiple sclerosis (2.70; 1.90-3.83), cerebrovascular events (2.02; 1.67-2.46), and rheumatoid arthritis (2.15; 1.53-3.04) (all p < 0.001). Most individuals perceived their fracture risk as similar to (46%) or lower than (36%) women of the same age. While increased self-perceived fracture risk was strongly associated with incident fracture rates, only 29% experiencing a fracture perceived their risk as increased. Under-appreciation of fracture risk occurred for all morbidities, including neurological disease, where women with low self-perceived fracture risk had a fracture HR 2.39 (CI 1.74-3.29) compared with women without morbidities. CONCLUSIONS: Postmenopausal women with morbidities tend to under-appreciate their risk, including in the context of neurological diseases, where fracture rates were highest in this cohort. This has important implications for health education, particularly among women with Parkinson's disease, multiple sclerosis, or cerebrovascular disease.

Non-hip, non-spine fractures drive healthcare utilization following a fracture: the Global Longitudinal Study of Osteoporosis in Women (GLOW).

UNLABELLED: We evaluated healthcare utilization associated with treating fracture types in >51,000 women aged ≥55 years. Over the course of 1 year, there were five times more non-hip, non-spine fractures than hip or spine fractures, resulting in twice as many days of hospitalization and rehabilitation/nursing home care for non-hip, non-spine fractures. INTRODUCTION: The purpose of this study is to evaluate medical healthcare utilization associated with treating several types of fractures in women ≥55 years from various geographic regions. METHODS: Information from the Global Longitudinal Study of Osteoporosis in Women (GLOW) was collected via self-administered patient questionnaires at baseline and year 1 (n = 51,491). Self-reported clinically recognized low-trauma fractures at year 1 were classified as incident spine, hip, wrist/hand, arm/shoulder, pelvis, rib, leg, and other fractures. Healthcare utilization data were self-reported and included whether the fracture was treated at a doctor's office/clinic or at a hospital. Patients were asked if they had undergone surgery or been treated at a rehabilitation center or nursing home. RESULTS: During 1-year follow-up, there were 195 spine, 134 hip, and 1,654 non-hip, non-spine fractures. Clinical vertebral fractures resulted in 617 days of hospitalization and 512 days of rehabilitation/nursing home care; hip fractures accounted for 1,306 days of hospitalization and 1,650 days of rehabilitation/nursing home care. Non-hip, non-spine fractures resulted in 3,805 days in hospital and 5,186 days of rehabilitation/nursing home care. CONCLUSIONS: While hip and vertebral fractures are well recognized for their associated increase in health resource utilization, non-hip, non-spine fractures, by virtue of their 5-fold greater number, require significantly more healthcare resources.

Regional and age-related variations in the proportions of hip fractures and major fractures among postmenopausal women: the Global Longitudinal Study of Osteoporosis in Women.

UNLABELLED: We examined variations in proportions of hip fractures and major fractures among postmenopausal women using the Global Longitudinal Study of Osteoporosis in Women (GLOW). The proportion of major fractures that were hip fractures varied with age and region, whereas variations in the proportion of fractures that were major fractures appeared modest. INTRODUCTION: In many countries, the World Health Organization fracture risk assessment tool calculates the probability of major fractures by assuming a uniform age-associated proportion of major fractures that are hip fractures in different countries. We further explored this assumption, using data from the GLOW. METHODS: GLOW is an observational population-based study of 60,393 non-institutionalized women aged ≥55 years who had visited practices within the previous 2 years. Main outcome measures were self-reported prevalent fractures after the age of 45 years and incident fractures during the 2 years of follow-up. RESULTS: The adjusted proportion of prevalent and incident major fractures after the age of 45 years that were hip fractures was higher in North America (16%, 17%) than in northern (13%, 12%) and southern Europe (10%, 10%), respectively. The proportion of incident major fractures that were hip fractures increased more than five-fold with age, from 6.6% among 55-59-year-olds to 34% among those aged ≥85 years. Regional and age-associated variations in the proportion of all incident fractures that were major fractures were less marked, not exceeding 16% and 28%, respectively. CONCLUSIONS: The data suggest that there may be regional differences in the proportion of major fractures that are hip fractures in postmenopausal women. In contrast, the regional and age-related variations in the proportion of fractures that are major fractures appear to be modest. However, because of the limited number of fractures in our sample, further studies are necessary to confirm these findings.

Burden of non-hip, non-vertebral fractures on quality of life in postmenopausal women: the Global Longitudinal study of Osteoporosis in Women (GLOW).

UNLABELLED: Among 50,461 postmenopausal women, 1,822 fractures occurred (57% minor non-hip, non-vertebral [NHNV], 26% major NHNV, 10% spine, 7% hip) over 1 year. Spine fractures had the greatest detrimental effect on EQ-5D, followed by major NHNV and hip fractures. Decreases in physical function and health status were greatest for spine or hip fractures. INTRODUCTION: There is growing evidence that NHNV fractures result in substantial morbidity and healthcare costs. The aim of this prospective study was to assess the effect of these NHNV fractures on quality of life. METHODS: We analyzed the 1-year incidences of hip, spine, major NHNV (pelvis/leg, shoulder/arm) and minor NHNV (wrist/hand, ankle/foot, rib/clavicle) fractures among women from the Global Longitudinal study of Osteoporosis in Women (GLOW). Health-related quality of life (HRQL) was analyzed using the EuroQol EQ-5D tool and the SF-36 health survey. RESULTS: Among 50,461 women analyzed, there were 1,822 fractures (57% minor NHNV, 26% major NHNV, 10% spine, 7% hip) over 1 year. Spine fractures had the greatest detrimental effect on EQ-5D summary scores, followed by major NHNV and hip fractures. The number of women with mobility problems increased most for those with major NHNV and spine fractures (both +8%); spine fractures were associated with the largest increases in problems with self care (+11%), activities (+14%), and pain/discomfort (+12%). Decreases in physical function and health status were greatest for those with spine or hip fractures. Multivariable modeling found that EQ-5D reduction was greatest for spine fractures, followed by hip and major/minor NHNV. Statistically significant reductions in SF-36 physical function were found for spine fractures, and were borderline significant for major NHNV fractures. CONCLUSION: This prospective study shows that NHNV fractures have a detrimental effect on HRQL. Efforts to optimize the care of osteoporosis patients should include the prevention of NHNV fractures.

Adherence and profile of non-persistence in patients treated for osteoporosis--a large-scale, long-term retrospective study in The Netherlands.

SUMMARY: We analyzed 12-month compliance for all ten oral osteoporosis drugs in the Netherlands by medication possession ratio (MPR ≥ 80%) in 105,506 patients, and persistence in 8,626 starters indicated high MPR (91%), low persistence (43%), and no restart in 78% of the stoppers after 18 months. INTRODUCTION: We studied compliance and persistence for all available oral osteoporosis medications on a national scale in the Netherlands. METHODS: We analyzed the IMS Health's longitudinal prescription database, which represents 73% of all pharmacies in the Netherlands. Twelve-month compliance was measured by medication possession ratio (MPR) in a cross-sectional cohort of 105,506 patients who received at least three prescriptions. Twelve-month persistence (no gap in refills for >6 months) was measured in all 8,626 consecutive patients starting therapy, with a further follow-up in non-persistent patients during an additional 18 months for evaluation of switching, restart, or definitive stopping oral medication. Multivariate logistic regression analysis was used to analyze the odds ratios (ORs) with 95% confidence intervals (CI) of characteristics of non-persistence. RESULTS: MPR of ≥80% was found in 91% of patients. Persistence was 43% (range, 29-52%). Persistence was related to age >60 years (ORs, 1.41 to 1.64), pharmacy outside very dense urban area (ORs, 1.39 to 1.44), additional use of calcium and/or vitamin D supplementation (OR, 1.26 and CI, 1.13, 1.39) and use of glucocorticoids (OR, 0.65 and CI, 0.59, 0.72) or cardiovascular medication (OR, 0.88 and CI, 0.79, 0.97). Of non-persistent patients, 22% restarted within 18 months with oral osteoporosis drugs. CONCLUSIONS: One-year compliance for all available oral osteoporosis medications was high, but 1-year persistence was low. Most stoppers did not restart or switch during an additional 18-month follow-up. These data indicate a major failure to adequately treat patients at high risk for fractures in daily practice.

Failure to perceive increased risk of fracture in women 55 years and older: the Global Longitudinal Study of Osteoporosis in Women (GLOW).

UNLABELLED: We compared self-perception of fracture risk with actual risk among 60,393 postmenopausal women aged ≥55 years, using data from the Global Longitudinal Study of Osteoporosis in Women (GLOW). Most postmenopausal women with risk factors failed to appreciate their actual risk for fracture. Improved education about osteoporosis risk factors is needed. INTRODUCTION: This study seeks to compare self-perception of fracture risk with actual risk among postmenopausal women using data from GLOW. METHODS: GLOW is an international, observational, cohort study involving 723 physician practices in 17 sites in ten countries in Europe, North America, and Australia. Participants included 60,393 women ≥55 years attended by their physician during the previous 24 months. The sample was enriched so that two thirds were ≥65 years. Baseline surveys were mailed October 2006 to February 2008. Main outcome measures were self-perception of fracture risk in women with elevated risk vs women of the same age and frequency of risk factors for fragility fracture. RESULTS: In the overall study population, 19% (10,951/58,434) of women rated their risk of fracture as a little/much higher than that of women of the same age; 46% (27,138/58,434) said it was similar; 35% (20,345/58,434) believed it to be a little/much lower. Among women whose actual risk was increased based on the presence of any one of seven risk factors for fracture, the proportion who recognized their increased risk ranged from 19% for smokers to 39% for current users of glucocorticoid medication. Only 33% (4,185/12,612) of those with ≥2 risk factors perceived themselves as being at higher risk. Among women reporting a diagnosis of osteopenia or osteoporosis, only 25% and 43%, respectively, thought their risk was increased. CONCLUSION: In this international, observational study, most postmenopausal women with risk factors failed to appreciate their actual risk for fracture.

Spine radiographs to improve the identification of women at high risk for fractures.

SUMMARY: In women older than 60 years with clinical risk factors for osteoporosis but without osteoporosis based on bone mineral density (T-score >or= -2.5), a systematic survey with X-rays of the spine identified previously unknown vertebral deformities in 21% of women. INTRODUCTION: This study determines the prevalence of vertebral deformities in elderly women with clinical risk factors for osteoporosis but with BMD values above the threshold for osteoporosis (T-score >or= -2.5). METHODS: Bisphosphonate naïve women older than 60 years attending 35 general practices in the Netherlands with >or=2 clinical risk factors for osteoporosis were invited for BMD measurement (DXA). In women with T-score >or= -2.5 at both spine and the hips, lateral radiographs of the thoracic and lumbar spine were performed. RESULTS: Of 631 women with a DXA measurement, 187 (30%) had osteoporosis (T-score < -2.5 at the spine or the hip). Of the remaining 444 women with T-score >or= -2.5 at both spine and hip, 387 had additional spine radiographs, of whom 80 (21%) had at least one vertebral deformity. CONCLUSION: In elderly women with clinical risk factors for osteoporosis but BMD T-score >or= -2.5, addition of spine radiographs identified vertebral deformities in 21% (95% CI: 17-25). Since these women are at risk of future fractures, antiosteoporotic treatment should be considered.

The Global Longitudinal Study of Osteoporosis in Women (GLOW): rationale and study design.

SUMMARY: The Global Longitudinal study of Osteoporosis in Women (GLOW) is a prospective cohort study involving 723 physicians and 60,393 women subjects >or=55 years. The data will provide insights into the management of fracture risk in older women over 5 years, patient experience with prevention and treatment, and distribution of risk among older women on an international basis. INTRODUCTION: Data from cohort studies describing the distribution of osteoporosis-related fractures and risk factors are not directly comparable and do not compare regional differences in patterns of patient management and fracture outcomes. METHODS: The GLOW is a prospective, multinational, observational cohort study. Practices typical of each region were identified through primary care networks organized for administrative, research, or educational purposes. Noninstitutionalized patients visiting each practice within the previous 2 years were eligible. Self-administered questionnaires were mailed, with 2:1 oversampling of women >or=65 years. Follow-up questionnaires will be sent at 12-month intervals for 5 years. RESULTS: A total of 723 physicians at 17 sites in ten countries agreed to participate. Baseline surveys were mailed (October 2006 to February 2008) to 140,416 subjects. After the exclusion of 3,265 women who were ineligible or had died, 60,393 agreed to participate. CONCLUSIONS: GLOW will provide contemporary information on patterns of management of fracture risk in older women over a 5-year period. The collection of data in a similar manner in ten countries will permit comparisons of patient experience with prevention and treatment and provide insights into the distribution of risk among older women on an international basis.

Generation of Fibrodysplasia ossificans progressiva and control integration free iPSC lines from periodontal ligament fibroblasts.

Fibrodysplasia ossificans progressiva (FOP) is a very rare devastating heterotopic ossification disorder, classically caused by a heterozygous single point mutation (c.617G>A) in the ACVR1gene, encoding the Bone morphogenetic protein (BMP) type I receptor, also termed activin receptor-like kinase (ALK)2. FOP patients develop heterotopic ossification episodically in response to inflammatory insults, thereby compromising tissue sampling and the development of in vitro surrogate models for FOP. Here we describe the generation and characterization of a control and a classical FOP induced pluripotent stem cell (iPSC) line derived from periodontal ligament fibroblast cells using Sendai virus vectors.

Oxybutynin: dry days for patients with hyperhidrosis.

We report the case of a 56-year-old postmenopausal woman who was referred to our Endocrinology Outpatient Clinic because of severe hyperhidrosis. She had a four-year history of excessive sweating of her face and upper body. On presentation no sweating could be documented. Physical examination was also unremarkable. It appeared that five days earlier her general practitioner had prescribed oxybutynin for urge incontinence and this accidentally cured her hyperhidrosis. She was diagnosed with idiopathic hyperhidrosis. We advised her to continue the oxybutynin and six months later, she was still symptom-free. Oral anticholinergic drugs are known to be effective for hyperhidrosis, but only anecdotal reports on oxybutynin can be found in the literature. Oxybutynin is not approved for hyperhidrosis, explaining the unfamiliarity with this medicine. This case shows that oxybutynin can be a very effective and simple treatment with only mild side effects. Therefore, oxybutynin merits consideration in patients with idiopathic hyperhidrosis. This report includes a concise review of the causes and treatment options of hyperhidrosis.

[Teriparatide: an anabolic drug for the treatment of patients with osteoporosis]. / Teriparatide: een anabool geneesmiddel voor de behandeling van patiënten met osteoporose.

The management of osteoporosis has been dominated by the use of antiresorptive agents, such as bisphosphonates and raloxifene, which have been shown to effectively reduce the risk of osteoporotic fractures. Teriparatide, a recombinant human parathyroid hormone, has recently become available. It has an altogether different action. Teriparatide is an anabolic agent that primarily stimulates bone formation. This leads to an increase in bone volume and the bone structure and microarchitecture is restored by an increase in trabecular thickness and an increase in the number of connections between trabeculae. Clinically relevant studies on teriparatide in postmenopausal women and in men have shown that it significantly lowers the risk of fracture. Teriparatide should not be combined with bisphosphonates. There are no clear recommendations on the order of treatment with teriparatide and bisphosphonates. The high costs ofteriparatide have slowed the trajectory from registration to reimbursement in the Netherlands. Since 1 February 2005 teriparatide may be prescribed for postmenopausal women with serious osteoporosis i.e. with a minimum of 1 osteoporotic fracture who (a) despite treatment with bisphosphonates or raloxifene after 2 prolapsed vertebrae once again have 1 or more fractures (inadequate response); (b) can tolerate neither bisphosphonates nor raloxifene; (c) are prescribed the drug by their treating medical specialist.

Risk factors determining active urinary stone formation in patients with urolithiasis.

AIMS: The goal of clinical and metabolic evaluation of patients with urinary stones is to identify patients at high risk for recurrent stone formation and as such, to allow the practitioner to suggest preventive therapies. However, knowledge about risk factors for active stone formation in patients with urolithiasis is limited. This study was initiated to assess the significance of several metabolic and clinical parameters for the determination of the risk of active stone formation. METHODS: Study in 320 consecutive outpatients referred to our clinic for metabolic analysis. Clinical and metabolic parameters were determined by standardized procedures of questionnaires, serum biochemical profiles and urinalysis. RESULTS: In 21.5% of 284 patients with complete data stone formation was active. Hypercalciuria, hypocitraturia and urinary tract infections had odds ratios for active stone formation above 2.5, whereas the odds ratio of a positive family history was 0.38. Hyperuricosuria, hyperoxaluria and a low urinary volume did not influence the risk for active stone formation. CONCLUSION: The risk profile for active stone formation differs from the risk profile for urolithiasis in general. Metabolic evaluation and determination of those risk factors in patients with urolithiasis might improve the estimation of the risk of future stone formation.

Vitamin D status in urinary calcium stone formation.

Serum vitamin D metabolites were measured in 160 normocalcemic urinary calcium stone formers and in 217 control subjects. No difference in concentrations of 25-hydroxy-vitamin D (25[OH]D), 24,25-dihydroxyvitamin D (24,25[OH]2D), and 1,25-dihydroxyvitamin D (1,25[OH]2D) was found between stone formers and control subjects. Values for 25(OH)D and 24,25(OH)2D were higher in hypercalciuric stone formers than in normocalciuric stone formers independent of seasonal fluctuation. No difference in concentration of serum 1,25(OH)2D was found between hypercalciuric and normocalciuric stone formers. No correlations were present between the serum concentrations of the measured vitamin D metabolites and of measures of calcium and phosphate metabolism. These findings suggest no major pathophysiologic role of the main vitamin D metabolites in urinary calcium stone formation.

The effect of cross-gender hormonal treatment on bone metabolism in male-to-female transsexuals.

A deficiency of sex hormones leads in both sexes to increased bone loss, and hormonal substitution can prevent this. The effect of the change of hormonal environment on bone metabolism in transsexuals is unknown. Transilial bone biopsies were obtained from 23 male-to-female transsexuals (mean age +/- SD, 38.0 +/- 11.7 years) after estrogen (ethinylestradiol, 100 micrograms/day) and antiandrogen treatment (cyproterone acetate, 100 mg/day) for 8-41 months. Histomorphometric data were compared with those from 11 healthy men (39.6 +/- 9.4 years). There was no difference in bone volume, bone surface, or trabecular thickness between transsexuals and controls. Eroded surface and osteoclast number were not different between the groups. The osteoid volume, surface, and thickness were significantly lower in the transsexuals than in the controls. The mineral apposition rate and adjusted apposition rate were normal, but mineralizing surface and bone formation rate were suppressed in the transsexuals compared with data reported from the literature. The results indicate that antiandrogen and estrogen treatment in male-to-female transsexuals may suppress bone turnover and is not associated with bone loss.

Long-term effect of calcium supplementation on bone loss in perimenopausal women.

We observed in a controlled 2 year longitudinal trial in 248 perimenopausal women that a daily calcium supplement of either 1000 or 2000 mg Ca2+ significantly reduced lumbar bone loss and bone turnover in the first year of calcium supplementation. In the second supplementation year the rate of lumbar bone loss in the treated subjects was not significantly different from that in the control group, although two of the three biochemical parameters of bone turnover remained decreased throughout the study. To quantify further the long-term effect of calcium supplementation, we extended the study for another year in 214 women. In the women of the control group who were menstruating until the last year of the trial, the mean change in lumbar bone mineral density after 3 years was -3.2% of the initial value versus 1.6% in the calcium-supplemented groups (p < 0.01). The decrease in lumbar bone loss in these supplemented premenopausal and early perimenopausal women remained statistically significant in the second and third years of supplementation. In the women who stopped menstruating before or during the study, the long-term reduction in lumbar bone loss was not significant (mean difference between control and treatment groups < 0.6% points after 3 years). The decrease in metacarpal cortical thickness (MCT) in the treated subjects during 3 years was on average -3.0% of the initial value in the control versus -2.0% in the supplemented subjects (P < 0.01). The effect of calcium supplementation on MCT was not significantly related to the menopausal status of the subjects.(ABSTRACT TRUNCATED AT 250 WORDS)