Reduce Fracture Incidence Research Articles

Change in the use of hormone replacement therapy and the incidence of fracture in Oslo

Fracture incidence in Oslo decreased from the 1970s to the 1990s in younger postmenopausal women, but not in older women or in men. Concurrently, hormone replacement therapy increased considerably. Using data from the Oslo Health Study, we estimated that roughly half the decline might be attributed hormone replacement therapy. Between the late 1970s and the late 1990s, the incidence of hip fracture and distal forearm fracture decreased in younger postmenopausal women in Oslo, but not in elderly women or in men. The purpose of this report is to evaluate whether the decreased incidence was coherent with trends in use of hormone replacement therapy (HRT). Data on estrogens were collected from official drug statistics, data on fractures from published studies and data on bone mineral density (BMD) from the Oslo Health Study. The sale of all estrogens increased 22 times from 1979 to 1999, and the sub-category estradiol combined with progestin increased 35 times. In the corresponding period the incidence of distal forearm fracture in women aged 50-64 years decreased by 33% and hip fracture by 39%. Based on differences in BMD between users and non-users of HRT, we estimated that up to half of this decline might be due to HRT. The reduction in fracture incidence in postmenopausal women in Oslo occurred in a period with a substantial increase in the use of HRT. Future surveillance will reveal whether the last years' decline in use of HRT will be translated into increasing fracture rates.

Combination anabolic and antiresorptive therapy for osteoporosis: Opening the anabolic window

Antiresorptive agents for osteoporosis are a cornerstone of therapy, but anabolic drugs have recently increased our options. By stimulating bone formation, anabolic agents reduce fracture incidence by improving bone qualities in addition to increasing bone mass. The only anabolic agent currently approved for osteoporosis by the US Food and Drug Administration, teriparatide (recombinant human parathyroid hormone ), has emerged as a major approach to selected patients with osteoporosis. Recombinant human parathyroid hormone (1-84) is also available in Europe. Teriparatide increases bone density and bone turnover, improves microarchitecture, and changes bone size. The incidence of vertebral and nonvertebral fractures is reduced. A current concept in the mechanism of teriparatide action is related to its effect to stimulate processes associated with bone formation before it stimulates processes associated with bone resorption. This sequence of events has led to the concept of the anabolic window, the period of time when teriparatide is maximally anabolic. Newer approaches to the use of teriparatide alone and in combination with antiresorptive agents have led to ways in which the anabolic window can be expanded.

Challenges in Science and Academic-Industry Interactions

Challenges in Science and Academic-Industry Interactions

Bisphosphonate antifracture efficacy

All bisphosphonates available for the treatment of postmenopausal osteoporosis reduce bone turnover, increase bone mineral density (BMD) and thereby reduce fracture incidence. Incident vertebral fractures are a key efficacy endpoint in bisphosphonate trials. They are less influenced by extrinsic factors (e.g., falls) than non-vertebral fractures and are highly predictive for future vertebral and non-vertebral fractures. The registration studies for daily oral alendronate, risedronate and ibandronate all demonstrated substantial reductions in vertebral fracture risk vs. placebo in postmenopausal women with established osteoporosis: 44% and 47% for daily alendronate, 41% and 49% for daily risedronate and 62% and 50% for daily and intermittent ibandronate, respectively. The effect of bisphosphonate treatment on non-vertebral fractures in these trials was variable, and highlights the difference in nature and incidence of non-vertebral fractures compared with vertebral fractures. Daily risedronate demonstrated a 39% reduction in non-vertebral fracture risk in the overall study population ( P = 0.02 vs. placebo), but failed to achieve a significant effect in a second study. Alendronate and ibandronate did not show a significant effect in the overall populations of their respective trials, however, in high-risk patients (femoral neck BMD < − 2.5), daily alendronate achieved a risk reduction of 36% on all clinical fractures. Also in high-risk subgroups, daily ibandronate showed 69% ( P = 0.012 vs. placebo) and 60% ( P = 0.037 vs. placebo) reductions in non-vertebral fracture risk (femoral neck BMD < − 3.0 or lumbar spine BMD < − 2.5 plus a history of clinical fracture in the past 5 years, respectively). Less frequent dosing regimens, which may improve patient compliance with treatment, have become standard in the management of postmenopausal osteoporosis. To establish the efficacy of a new regimen of a daily drug with proven antifracture efficacy, a bridging study is commonly used with surrogate endpoints of antifracture efficacy such as BMD and bone turnover markers. MOBILE (Monthly Oral iBandronate In LadiEs; a bridging study) confirmed that monthly oral ibandronate is non-inferior and even superior to daily oral ibandronate for gains in lumbar spine BMD (primary endpoint) and total hip BMD. These gains in BMD suggest that at least equivalent antifracture efficacy may be expected from this regimen in women with postmenopausal osteoporosis.

Changes in bone density under treatment with parathyroid hormone

Introduction: A new treatment approach for osteoporosis is the intermittent application of the biochemically active part of the parathyroid hormone, teriparatide (hPTH 1–34). Several studies provide evidence that under treatment with teriparatide an increase in bone density and a decrease in fracture incidence is achieved. This paper should reveal just how effective the treatment with teriparatide is in increasing bone density and reducing fracture incidence for those patients who despite treatment with bisphosphonate suffer a progression of the osteoporosis, or for those who due to serious side-effects are forced to abandon the bisphosphonate treatment.

L-Amino acid-sensing by calcium-sensing receptors: A molecular link between protein and calcium metabolism

Dietary protein intake has a major, positive influence on bone health including improved bone mineral density and reductions in fracture-incidence, however, the molecular origins of these effects are unclear. Herein we consider how the release of amino acids from dietary protein appears to provide molecular signals in the gastrointestinal tract as well as the portal and systemic blood and demonstrate how one, broad-spectrum, amino acid sensor, the extracellular calcium-sensing receptor, responds to these signals in endogenous tissues including the parathyroid, gut and kidney.

Anabolic Therapy for Osteoporosis

Antiresorptive agents for osteoporosis are a cornerstone of therapy, but anabolic drugs have recently increased our options. By directly stimulating bone formation, anabolic agents reduce fracture incidence by improving bone qualities as well as increasing bone mass. The anabolic agent currently approved for osteoporosis, teriparatide (recombinant human parathyroid hormone[1-34]), has emerged as a major approach for selected patients with osteoporosis. Parathyroid hormone(1-84) is also available in Europe. Teriparatide increases bone density and bone turnover, improves microarchitecture and changes bone size. The incidence of vertebral and nonvertebral fractures is reduced. A current concept in the mechanism of teriparatide action is related to its effect of stimulating processes associated with bone formation before processes associated with bone resorption. This sequence of events has led to the concept of the anabolic window, the period of time when teriparatide is maximally anabolic. Newer approaches to the use of teriparatide alone and in combination with antiresorptive agents has led to ways in which the anabolic window can be expanded.

Clodronate Reduces the Incidence of Fractures in Community-Dwelling Elderly Women Unselected for Osteoporosis: Results of a Double-Blind, Placebo-Controlled Randomized Study

A 3-year prospective, randomized, placebo-controlled trial of oral clodronate 800 mg showed that the incidence of clinical fractures was decreased by 20% in 5596 elderly women unselected for osteoporosis. The effect occurred in the absence of systematic calcium and vitamin D supplementation and was observed across a wide range of BMDs. To date, most studies with bisphosphonates have reported on their use in individuals selected to be at high risk for fracture usually by the presence of low BMD or a prior fragility fracture, usually of the spine. We wished to determine the effect of the bisphosphonate, clodronate, on the rate of fractures in women > or =75 years of age living in the community. Women > or =75 years of age living in the general community in South Yorkshire and North Derbyshire, identified from general practice registers, were recruited by letter of invitation to a randomized, double-blind, controlled trial of 800 mg oral clodronate (Bonefos) or matching placebo daily over 3 years. The main outcomes were the incidences of hip and any clinical fracture. Of the 5579 elderly women included in the intention-to-treat analysis of efficacy, 114 had a new hip fracture during the 3-year treatment phase: 56 (2.0%) women in the clodronate group and 58 (2.1%) women in the placebo group (hazard ration [HR], 1.02; 95% CI, 0.71-1.47). Clodronate did, however, decrease the incidence of any clinical fracture by 20% (264 women [9.5%] versus 337 [12.1%] in the placebo group; HR, 0.80; 95% CI, 0.68-0.94). The incidence of osteoporosis-associated nonhip fractures was also significantly decreased by 29% (5.2% versus 7.4%; HR, 0.71; 95% CI, 0.57-0.87). The ability of clodronate to reduce the risk of osteoporotic fracture was independent of baseline BMD, but the number needed-to-treat was lower in the presence of osteoporosis. Oral daily clodronate can prevent fractures without significant adverse effects in elderly women living in the general community. The effect on hip fracture risk is not significant, but an effect similar to that at other nonvertebral sites cannot be excluded. This study suggests that antiresorptive therapies can reduce fracture incidence in high-risk individuals even in the presence of a normal or osteopenic BMD.

Osteogenesis imperfecta type VI in childhood and adolescence: Effects of cyclical intravenous pamidronate treatment

Cyclical intravenous treatment with pamidronate is of clinical benefit in children with moderate to severe osteogenesis imperfecta (OI) types I, III and IV, but there is no information on the effects of this treatment on the newly described OI type VI. Here, we report on the results of 3 years of pamidronate treatment in 10 children and adolescents with OI type VI (age range 0.8 to 14.5 years, three girls). Treatment effects were compared to those of 10 patients with OI types I, III, and IV, who were matched for age and disease severity (based on height and lumbar spine areal bone mineral density). During pamidronate therapy, lumbar spine areal bone mineral density z scores increased and lumbar spine vertebral bodies improved in shape. Iliac bone histomorphometry showed a tendency to higher cortical thickness (+ 53%, P = 0.06) but the mineralization defect, a characteristic feature of OI type VI, did not change during pamidronate treatment. Annualized fracture incidence decreased from 3.1 per year before treatment to 1.4 fractures per year during treatment ( P < 0.05). Regarding mobility, the Pediatric Evaluation of Disability Inventory gross motor score increased by 42% during pamidronate treatment ( P < 0.005). Significant improvements were also found for age-related z scores of maximal isometric grip force. In comparison to the OI control group, the fracture incidence was higher and the gross motor scores were lower in OI type VI, both before and after pamidronate treatment ( P < 0.05 for each parameter). No differences were found between the groups for changes in densitometric measures and cortical thickness during pamidronate treatment. Our results suggest that 3 years of intravenous pamidronate therapy led to improvements in bone mineral mass, gross motor function, muscle force and fracture incidence in patients with OI type VI. However, the gains in mobility scores and reductions in fracture incidence during pamidronate treatment are less than in other OI types.

Bone mineral densities in the prehistoric, Viking‐Age and medieval populations of Norway

AbstractOsteoporosis is a prevalent condition in Norway, as evidenced by the fact that this country has the highest reported incidences of hip and distal forearm fractures. Because recent studies suggest a higher bone density in rural populations compared with urban ones, increased physical activity is believed to be an important factor in reducing fracture incidence. In the present investigation, 185 femoral necks from the Schreiner Collection in Oslo were measured by means of a bone‐mass scanner. The bones, anthropological specimens ranging from the Stone Age to the Middle Ages, were separated into three groups: prehistoric (n = 36), Viking Age (n = 38) and medieval (n = 111). The medieval group was further separated into urban, rural and monastic populations. The examination showed that: (a) there was no significant difference at a 5% level in average bone mineral density (BMD) between the male and female material; (b) there was no significant difference in average BMD among the prehistoric, Viking Age, and medieval periods (P = 0.151); (c) there was no significant difference in average BMD between the rural and urban medieval material; (d) there was a significant difference in average BMD only between the monastic and the rural medieval material; (e) only the medieval material showed a significantly higher average BMD than that of today (P = 0.001). These findings may indicate that factors in addition to physical activity are important for normal BMD maintenance. Copyright © 2006 John Wiley &amp; Sons, Ltd.

Anabolic skeletal therapy for osteoporosis

Antiresorptive agents for osteoporosis are a cornerstone of therapy, but anabolic drugs have recently widened our therapeutic options. By directly stimulating bone formation, anabolic agents reduce fracture incidence by improving bone qualities besides increasing bone mass. In this article, we review the role of anabolic treatment for osteoporosis. The only anabolic agent currently approved in the United States for osteoporosis, teriparatide [recombinant human parathyroid hormone(1-34)], has clearly emerged as a major approach to selected patients with osteoporosis. Teriparatide increases bone density and bone turnover, improves microarchitecture, and changes bone size. The incidence of vertebral and nonvertebral fractures is reduced. Teriparatide is approved for both postmenopausal women and men with osteoporosis who are at high risk for fracture. Other potential anabolic therapies for osteoporosis, including other forms of parathyroid hormone, strontium ranelate, growth hormone, and insulin-like growth factor-1, are also reviewed in this article.

The use of parathyroid hormone in the treatment of osteoporosis

Anabolic skeletal agents have recently broadened our therapeutic options for osteoporosis. By directly stimulating bone formation, they reduce fracture incidence by improving bone qualities in addition to increasing bone mass. Teriparatide [recombinant human parathyroid hormone(1-34)], the only anabolic agent currently approved in the United States for osteoporosis, has emerged as a major therapeutic approach to selected patients with osteoporosis. Teriparatide is approved for both postmenopausal women and men with osteoporosis who are at high risk for fracture. With the use of this anabolic agent, bone density and bone turnover increase, microarchitecture improves, and bone size is beneficially altered. The incidence of vertebral and nonvertebral fractures is reduced with teriparatide use. Combination therapy with parathyroid hormone and an antiresorptive does not appear to offer definitive advantages over the use of PTH or an antiresorptive alone, although recent ideas about combining these agents may offer new insights. In order to maintain increases in bone density acquired during PTH therapy, it is important to follow its use with an antiresorptive agent.

The relative merits of anabolics versus anti-resorptive compounds: where our targets should be, and whether we are addressing them

Currently available results from fracture trials provide evidence that the most potent anti-resorptive agents reduce vertebral and non-vertebral fractures maximally by 61% and 51%, respectively. Results from the Phase III trial with denosumab, the human monoclonal antibody, are eagerly awaited. Denosumab leads to sustained 80-90% reduction of bone resorption markers, which is below the level commonly achieved with bisphosphonates, and it will be interesting to see whether this leads to an improvement in its anti-fracture efficacy over bisphosphonates. If the majority of the anti-fracture efficacy of anti-resorptive agents results from the reduction of the remodelling space (removal of stress raisers) and the conservation of structural integrity of cancellous bone, a further decrease in bone resorption might not be desirable, especially as suppression of the residual remodelling capacity could lead to an increased risk for accumulation of microdamage. In contrast to anti-resorptive agents, the bone anabolic parathyroid hormone activates modelling drifts, which act to increase trabecular thickness and add bone predominantly on the endocortical, and to a lesser degree the periosteal, surface. Despite its anabolic nature, reduction of vertebral and non-vertebral fractures is only marginally better than those achieved with anti-resorptive agents. Ageing compromises locomotor capacity and is associated with an increased risk of falls. Perhaps it is time to shift our attendance to the age-related deterioration of muscle or neuromuscular function as a target and add this 'adjuvant therapy' to the potent anti-remodelling and bone anabolic agents available for the treatment of osteoporosis if we truly want to reduce fracture incidence beyond what is possible today.

Effects of Calcium Supplementation on Clinical Fracture and Bone Structure

Increased dietary calcium intake has been proposed as a population-based public health intervention to prevent osteoporotic fractures. We have examined whether calcium supplementation decreases clinical fracture risk in elderly women and its mechanism of action. Five-year, double-blind, placebo-controlled study of 1460 women recruited from the population and older than 70 years (mean age, 75 years) who were randomized to receive calcium carbonate, 600 mg twice per day, or identical placebo. The primary end points included clinical incident osteoporotic fractures, vertebral deformity, and adverse events ascertained in 5 years. Bone structure was also measured using dual x-ray absorptiometry of the hip and whole body, quantitative ultrasonography of the heel, and peripheral quantitative computed tomography of the distal radius. Among our patients, 16.1% sustained 1 or more clinical osteoporotic fractures. In the intention-to-treat analysis, calcium supplementation did not significantly reduce fracture risk (hazard ratio, 0.87; 95% confidence interval, 0.67-1.12). However, 830 patients (56.8%) who took 80% or more of their tablets (calcium or placebo) per year had reduced fracture incidence in the calcium compared with the placebo groups (10.2% vs 15.4%; hazard ratio, 0.66; 95% confidence interval, 0.45-0.97). Calcium-treated patients had improved quantitative ultrasonography findings of the heel, femoral neck and whole-body dual x-ray absorptiometry data, and bone strength compared with placebo-treated patients. Of the 92 000 adverse events recorded, constipation was the only event increased by the treatment (calcium group, 13.4%; placebo group, 9.1%). Supplementation with calcium carbonate tablets supplying 1200 mg/d is ineffective as a public health intervention in preventing clinical fractures in the ambulatory elderly population owing to poor long-term compliance, but it is effective in those patients who are compliant.

Anabolic Agents for Osteoporosis

Antiresorptive agents for osteoporosis are a cornerstone of therapy, but anabolic drugs have recently widened our therapeutic options. By directly stimulating bone formation, anabolic agents reduce fracture incidence by improving other bone qualities in addition to increasing bone mass. Teriparatide (human parathyroid hormone[1-34]) has clearly emerged as a major approach for selected patients with osteoporosis. Teriparatide increases bone mineral density and bone turnover, improves bone microarchitecture, and changes bone size. The incidence of vertebral and non-vertebral fractures is reduced. Teriparatide is approved in many countries throughout the world for the treatment of both postmenopausal women and men with osteoporosis who are at high risk for fracture. Another anabolic agent, strontium ranelate, may both promote bone formation and inhibit bone resorption. Clinical trials support the use of strontium ranelate as a treatment for postmenopausal osteoporosis and have shown that strontium ranelate reduces the frequency of vertebral and non-vertebral fractures. Other potential anabolic therapies for osteoporosis, including other forms of parathyroid hormone, growth hormone, and insulin-like growth factor-I, have been examined, although less data are currently available on these approaches.

Clinical risk indices, prediction of osteoporosis, and prevention of fractures: diagnostic consequences and costs

The primary aim of this study was to validate the Osteoporosis Self-Assessment Tools for Asians (OSTA) instrument in Thai women, and to evaluate its utility in terms of economic costs and fracture prediction. Femoral neck and lumbar spine BMD was measured by dual energy X-ray absorptiometry in 322 Thai women, aged 60+/-10 years (mean+/-SD; range: 45-84 years). The women were classified as having osteoporosis if their BMD T-scores were < or =-2.5. The OSTA score was calculated for each woman using her age and weight according to the formula: 0.2(weight-age). Women with OSTA scores < or =-1 and >-1 were classified as "high risk" and "low risk," respectively. The prevalence of osteoporosis was 33% by femoral neck or lumbar spine BMD. Using the OSTA score, 165 (51.2%) women were classified as high risk. The sensitivity, specificity and positive predictive value of OSTA was 82% 64% and 53%, respectively. If the OSTA score is used to identify women with high risk of fracture, and assuming that the incidence of fracture among osteoporotic and non-osteoporotic women are 2% and 1% per year, respectively, the OSTA score can identify 59% of fracture cases correctly, and 41% are expected to be missed. Furthermore, if the high-risk subjects identified by OSTA are to be treated, and if the treatment reduces fracture incidence by 50%, and assuming that the treatment cost is $1 per day, then the cost to prevent one fracture is estimated to be $48,530. Results of this study suggest that, in the Thai population, the OSTA score had high sensitivity but low specificity and low positive predictive value in the identification of osteoporotic women. Its use in the general population can result in a high false-positive rate and incur significant cost to the community.

Relationship Between Bone Morphology and Bone Quality in Male Tibias: Implications for Stress Fracture Risk

Biomechanical properties were assessed from the tibias of 17 adult males 17-46 years of age. Tissue-level mechanical properties varied with bone size. Narrower tibias were comprised of tissue that was more brittle and more prone to accumulating damage compared with tissue from wider tibias. A better understanding of the factors contributing to stress fractures is needed to identify new prevention strategies that will reduce fracture incidence. Having a narrow (i.e., more slender) tibia relative to body mass has been shown to be a major predictor of stress fracture risk and fragility in male military recruits and male athletes. The intriguing possibility that slender bones, like those shown in animal models, may be composed of more damageable material has not been considered in the human skeleton. Polar moment of inertia, section modulus, and antero-posterior (AP) and medial-lateral (ML) widths were determined for tibial diaphyses from 17 male donors 17-46 years of age. A slenderness index was defined as the inverse ratio of the section modulus to tibia length and body weight. Eight prismatic cortical bone samples were generated from each tibia, and tissue-level mechanical properties including modulus, strength, total energy, postyield strain, and tissue damageability were measured by four-point bending from monotonic (n = 4/tibia) and damage accumulation (n = 4/tibia) test methods. Partial correlation coefficients were determined between each geometrical parameter and each tissue-level mechanical property while taking age into consideration. Significant correlations were observed between tibial morphology and the mechanical properties that characterized tissue brittleness and damageability. Positive correlations were observed between measures of bone size (AP width) and measures of tissue ductility (postyield strain, total energy), and negative correlations were observed between bone size (moment of inertia, section modulus) and tissue modulus. The correlation analysis suggested that bone morphology could be used as a predictor of tissue fragility and stress fracture risk. The average mechanical properties of cortical tissue varied as a function of the overall size of the bone. Therefore, under extreme loading conditions (e.g., military training), variation in bone quality parameters related to damageability may be a contributing factor to the increased risk of stress fracture for individuals with more slender bones.

Effects of once-weekly oral alendronate on bone in children on glucocorticoid treatment

To determine the effects of once-weekly oral alendronate on indices of bone size, density and resorption in children with chronic illness being treated with glucocorticoids. Twenty-two children with chronic illness treated with prednisone were randomized to receive 1 year's treatment with either once-weekly oral placebo or alendronate (1-2 mg/kg body weight) in a double-blind study. The main outcome measures were changes in lumbar spine and femoral shaft size and volumetric density (measured by dual energy X-ray absorptiometry) and N-telopeptide excretion (a marker of bone resorption). Once-weekly alendronate was well tolerated, and there were no major adverse events. In both groups bone size and bone mineral content increased through growth. Volumetric bone density of the lumbar spine increased significantly in the alendronate group (P = 0.013), but not in the placebo group. There were no differences between the groups in growth in the cortical width of the femoral shaft, but the cross-sectional moment of inertia per unit length-a derived estimate of mechanical strength-increased significantly in the alendronate group (P = 0.014) but not in the placebo group. Urine N-telopeptide excretion was suppressed significantly in the alendronate group (P = 0.007) but not in the placebo group. Height velocity was positively correlated with changes in both lumbar spine area and the total width of the femoral shaft (P = 0.015, P = 0.026, respectively). Once-weekly oral alendronate is well tolerated, suppresses bone resorption and may improve volumetric bone density at the lumbar spine and mechanical strength of the femoral shaft in children with chronic illness taking glucocorticoids. It does not affect bone growth. Larger controlled studies are needed to determine if these changes translate into reduced fracture incidence or greater peak bone mass. This study highlights the importance of differentiating between changes in bone size and changes in volumetric bone density in assessing bone in children, and also having control subjects in intervention studies.

Nouveaux traitements de l'ostéoporose

New intermittent regimens with bisphosphonates such as oral ibandronate, and maybe annual intra-venous zoledronate, will be useful additions to the treatment of post-menopausal osteoporosis. Strontium ranelate is a new molecule that both inhibits bone resorption and stimulates bone formation, with proven efficacy to reduce fracture incidence. Teriparatide (1-34 fragment of parathyroid hormone), using daily subcutaneous injections, has also proven its efficacy to decrease vertebral and peripheral fracture risk in postmenopausal osteoporotic women. In the next five years, new SERMs and inhibitors of RANK-ligand might be new treatment options.

Fracture incidence in relation to the pattern of use of hormone therapy in postmenopausal women.

Evidence is limited on the effects of different patterns of use of postmenopausal hormone therapy on fracture incidence and particularly on the effects of ceasing use. To investigate the effect of different patterns of hormone therapy use on fracture incidence. Prospective study of 138,737 postmenopausal women aged 50 to 69 years recruited from the UK general population in 1996-1998 (the Million Women Study) and followed up for 1.9 to 3.9 years (average, 2.8 years) for fracture incidence. Adjusted relative risk (RR) for incident fracture (except fracture of the fingers, toes, and ribs) in hormone therapy users compared with never users at baseline. A total of 5197 women (3.7%) reported 1 or more fractures, 79% resulting from falls. Current users of hormone therapy at baseline had a significantly reduced incidence of fracture (RR, 0.62; 95% confidence interval [CI], 0.58-0.66; P<.001). This protection was evident soon after hormone therapy began, and the RR decreased with increasing duration of use (P =.001). Among current users at baseline the RR of fracture did not vary significantly according to whether estrogen-only, estrogen-progestin, or other types of hormones were used (RR [95% CI], 0.64 [0.58-0.71], 0.58 [0.53-0.64], and 0.67 [0.56-0.80], respectively; P =.19), nor did it vary significantly according to estrogen dose or estrogen or progestin constituents. The RR associated with current use of hormone therapy did not vary significantly according to 11 personal characteristics of study participants, including their age at menopause, body mass index, and physical activity. Past users of hormone therapy at baseline experienced no significant protection against fractures (RR, 1.07; 95% CI, 0.99-1.15); incidence rates returned to those of never-users within about a year of ceasing use. All types of hormone therapy studied confer substantial protection against fracture while they are used. This protection appears rapidly after use commences and wears off rapidly after use ceases. The older women are, the greater is their absolute reduction in fracture incidence while using hormone therapy.