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Examines the efficacy of calcium and cholecalciferol for the treatment of hip fractures in elderly women in Great Britain. Correlation between bone density and serum parathyroid hormone concentration; Determinants of secondary hyperparathyroidism; Risk factors for fractures.

A response by P.J. Meunier et al. to a letter to the editor about their article "The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis," in the January 29, 2004 issue is presented.

Focuses on treatment of Paget's disease of the bone. Complications of the disease; Pathology; Epidemiology; Etiology; Clinal features; Diagnosis; Drug therapy; Surgery; Recommendations.

Background: The results of meta-analyses examining the relationship between vitamin D supplementation and fracture reduction have been inconsistent. Methods: We pooled participant-level data from 11 double-blind, randomized, controlled trials of oral vitamin D supplementation (daily, weekly, or every 4 months), with or without calcium, as compared with placebo or calcium alone in persons 65 years of age or older. Primary end points were the incidence of hip and any nonvertebral fractures according to Cox regression analyses, with adjustment for age group, sex, type of dwelling, and study. Our primary aim was to compare data from quartiles of actual intake of vitamin D (including each individual participant's adherence to the treatment and supplement use outside the study protocol) in the treatment groups of all trials with data from the control groups. Results: We included 31,022 persons (mean age, 76 years; 91% women) with 1111 incident hip fractures and 3770 nonvertebral fractures. Participants who were randomly assigned to receive vitamin D, as compared with those assigned to control groups, had a nonsignificant 10% reduction in the risk of hip fracture (hazard ratio, 0.90; 95% confidence interval [CI], 0.80 to 1.01) and a 7% reduction in the risk of nonvertebral fracture (hazard ratio, 0.93; 95% CI, 0.87 to 0.99). By quartiles of actual intake, reduction in the risk of fracture was shown only at the highest intake level (median, 800 IU daily; range, 792 to 2000), with a 30% reduction in the risk of hip fracture (hazard ratio, 0.70; 95% CI, 0.58 to 0.86) and a 14% reduction in the risk of any nonvertebral fracture (hazard ratio, 0.86; 95% CI, 0.76 to 0.96). Benefits at the highest level of vitamin D intake were fairly consistent across subgroups defined by age group, type of dwelling, baseline 25-hydroxyvitamin D level, and additional calcium intake. Conclusions: High-dose vitamin D supplementation (≥800 IU daily) was somewhat favorable in the prevention of hip fracture and any nonvertebral fracture in persons 65 years of age or older. (Funded by the Swiss National Foundations and others.) [ABSTRACT FROM PUBLISHER]

Abstract: Bone mineral is a major determinant of the mechanical resistance of bones. In bone structural units (BSUs), mineralization of osteoid tissue begins with a rapid primary mineralization followed by a secondary mineralization phase, i.e., a slow and gradual maturation of the mineral component leading to complete mineralization during an unknown period. The aim of this study was to determine the chronology of secondary bone mineralization in ewes, an animal model with a remodeling activity close to humans. Eighteen ewes received different fluorescent labels every 6 months to date the “age” of each labeled BSU. The degree of mineralization of bone (DMB) and Vickers microhardness were measured in labeled BSUs, while mineralization at the crystal level was assessed by Fourier transform infrared microspectroscopy (FTIRM). During the first 6 months of mineralization, degree of mineralization and microhardness significantly increased. They then increased more slowly until at 30 months they reach their maximal values. This progression during secondary mineralization was associated with an improvement of both the maturation and the crystal perfection of the mineral part of bone matrix. Finally, secondary mineralization in BSUs is completed after a period of 30 months. This observation should be taken into account for understanding the effects of long-term treatments of bone diseases. [Copyright &y& Elsevier]

A letter to the editor is presented in response to the article "Effect of Risedronate on the Risk of Hip Fracture in Elderly Women," by M. R. McClung and colleagues in the February 1, 2001 issue of the "New England of Medical Journal."

In osteoporosis, bone fragility results from both bone loss and changes in trabecular microarchitecture, which can be quantified by bone histomorphometric parameters. Twenty human calcaneum were collected after necropsy. All measurements were performed at the same anatomical location. Bone histomorphometric parameters were measured on histological slides with an automatic image analyzer. The aims of our study were (1) to develop automatic measurements of four additional parameters reflecting trabecular network connectivity and complexity, i.e., trabecular bone pattern factor (TBPf), Euler number/tissue volume (Euler) according to the three definitions previously reported and to a fourth one established in the laboratory (Euler(strut.cavity)), marrow star volume, and interconnectivity index, and to determine their usefulness in microarchitecture characterization; and (2) to validate these parameters by evaluating their relationship with dual-energy X-ray absorptiometry and quantitative ultrasound (QUS) measurements performed on the same samples. The statistical analysis showed that TBPf and Euler(strut.cavity) appeared to be the most significant connectivity parameters, independently of bone quantity (bone mineral density, apparent density, cancellous bone volume). For QUS, after adjustment for bone quantity, only speed of sound (SOS) was significantly and negatively correlated to Euler(strut.cavity). Broadband ultrasound attenuation depends only on bone quantity. In conclusion, TBPf (a strut analysis parameter extrapolable in three dimensions) and Euler(strut.cavity) (the only bone connectivity parameter reflecting SOS) are two valid bone microarchitecture parameters. These new parameters were significantly correlated to the established trabecular structure parameters: trabecular thickness or trabecular spacing, being weakly correlated with SOS. [ABSTRACT FROM AUTHOR]

Abstract: The beneficial skeletal effects of menopausal estrogen replacement therapy (HRT) are well documented. The role of secondary mineralization of bone as a determinant of bone quality is now well established in postmenopausal women treated with bisphosphonates or SERMs. The aim of present study was to investigate the effect of conventional and high doses of estrogen on the main parameters reflecting the degree of mineralization of bone (DMB). Bone biopsies were obtained from 20 women with osteopenia or osteoporosis before and after 24 months (18 to 38 months) of conventional HRT, and from 19 women who had received high doses of estradiol (implant 100 mg every 3–6 months for 1.5–20 years). DMB parameters (mean DMB, DMB Freq. Max. and Heterogeneity Index of the individual distributions of DMB) were measured using quantitative microradiography in cortical, cancellous, and total bone and expressed as g mineral/cm3 bone. Values obtained in women before HRT were lower than those reported in pre- and postmenopausal control women. After conventional HRT, there was an increase in mean DMB (total bone) of 4.4 ± 1.9% (mean ± SEM) versus pre-treatment values (4.1 ± 2.1% in cortical bone, 4.5 ± 2.3% in cancellous bone); these differences did not reach statistical significance (P = 0.055). Results were similar for DMB Freq. Max. but Heterogeneity Index was not significantly changed. After high dose estradiol therapy, mean DMB (total bone) was 6.9 ± 1.9% higher than in untreated women (8.6 ± 2.1% in cortical bone, 6.5 ± 2.1% in cancellous bone); this difference was statistically significant (P ≤ 0.03). Results were similar for DMB Freq. Max. but once again Heterogeneity Index was not significantly modified. The increases in mean DMB were due to a shift of the curves towards high DMB with a decrease of the low DMB values, as confirmed by the absence of changes in the Heterogeneity Index. Estrogen therapy is associated with an increased degree of mineralization of bone induced by a prolongation of secondary mineralization, similar to that observed with other antiresorptive agents. However, this increase was about two-fold lower than that observed after alendronate therapy (10 mg/day/3 years) in postmenopausal osteoporotic women. [Copyright &y& Elsevier]

Objectives. – To determine the number of women in France at least 50 years of age with risk factors for osteoporosis likely to lead to bone mineral density measurement, an investigation reimbursed by the French national health insurance system in patients at risk for osteoporosis. The study was commissioned by the French health authorities.Material and methods. – Risk factors for osteoporosis were defined as recommended by the French Agency for Accreditation and Evaluation in Health (Anaes) in 2001. The study data were from nine cohort studies done in France and from the national health insurance agency for the Rhône-Alpes region of France. Risk factor prevalences in France were standardized by extrapolation according to the age distribution in France.Results. – Overall, data were collected in 123,986 women aged 50 years or older. From these data, risk factor estimates were as follows: menopause before 40 years of age, 1.5 millions women; body mass index (BMI) lower than 19 kg/m2, nearly 700,000; history of fracture, more than 2 millions; history of femoral neck fracture in the mother, more than 1 million; history of health problems potentially responsible for osteoporosis, 400,000; and history of long-term glucocorticoid therapy, 612,000. In all, 3,186,318 (30%) women were estimated to have at least one risk factor and 785,512 (7.5%) at least two risk factors.Conclusions. – Although our study sample was not representative of the population residing in France, the large sample size and diversity of data sources support the validity of our estimate of the prevalence of risk factors for osteoporosis in postmenopausal women living in France. [Copyright &y& Elsevier]

Objective: To assess the cost implications for a preventive treatment strategy for institutionalised elderly women with a combined 1200 mg/day calcium and 800 IU/day vitamin D3 supplementation in seven European countries. Design: Retrospective cost effectiveness analysis based on a prospective placebo-controlled randomised clinical trial. Data sources: Recently published cost studies in seven European countries. Clinical results from Decalyos, a 3-year placebo-controlled study in elderly institutionalised women. Trials: Decalyos study, with 36 months follow-up of 3270 mobile elderly women living in 180 nursing homes, allocated to two groups. One group received 1200 mg/day elemental calcium in the form of tricalcium phosphate together with 800 IU/day (20 μg) of cholecalciferol (vitamin D3), the other placebo. Results: In the 36 months analysis of the Decalyos study, 138 hip fractures occurred in the group of 1176 women, receiving supplementation and 184 hip fractures in the placebo group of 1127 women. The mean duration of treatment was 625.4 days. Adjusted to 1000 women, 46 hip fractures were avoided by the calcium and vitamin D3 supplementation. For all countries, the total costs in the placebo group were higher than in the group receiving supplementation, resulting in a net benefit of €79 000–711 000 per 1000 women. Conclusion: This analysis suggests that the supplementation strategy is cost saving. The results may underestimate the net benefits, as this treatment has also shown to be effective in decreasing the incidence of other non-vertebral fractures in elderly institutionalised women. [Copyright &y& Elsevier]

Background: Risedronate increases bone mineral density in elderly women, but whether it prevents hip fracture is not known. Methods: We studied 5445 women 70 to 79 years old who had osteoporosis (indicated by a T score for bone mineral density at the femoral neck that was more than 4 SD below the mean peak value in young adults [–4] or lower than –3 plus a nonskeletal risk factor for hip fracture, such as poor gait or a propensity to fall) and 3886 women at least 80 years old who had at least one nonskeletal risk factor for hip fracture or low bone mineral density at the femoral neck (T score, lower than –4 or lower than –3 plus a hip-axis length of 11.1 cm or greater). The women were randomly assigned to receive treatment with oral risedronate (2.5 or 5.0 mg daily) or placebo for three years. The primary end point was the occurrence of hip fracture. Results: Overall, the incidence of hip fracture among all the women assigned to risedronate was 2.8 percent, as compared with 3.9 percent among those assigned to placebo (relative risk, 0.7; 95 percent confidence interval, 0.6 to 0.9; P=0.02). In the group of women with osteoporosis (those 70 to 79 years old), the incidence of hip fracture among those assigned to risedronate was 1.9 percent, as compared with 3.2 percent among those assigned to placebo (relative risk, 0.6; 95 percent confidence interval, 0.4 to 0.9; P=0.009). In the group of women selected primarily on the basis of nonskeletal risk factors (those at least 80 years of age), the incidence of hip fracture was 4.2 percent among those assigned to risedronate and 5.1 percent among those assigned to placebo (P=0.35). Conclusions: Risedronate significantly reduces the risk of hip fracture among elderly women with confirmed osteoporosis but not among elderly women selected primarily on the basis of risk factors other than low bone mineral density. (N Engl J Med 2001;344:333-40.) [ABSTRACT FROM AUTHOR]

Objective: This study was undertaken to assess the effect of strontium ranelate on nonvertebral and vertebral fractures in postmenopausal women with osteoporosis in a 5-year, double-blind, placebo-controlled trial., Methods: A total of 5,091 postmenopausal women with osteoporosis were randomized to receive either strontium ranelate at 2 gm/day or placebo for 5 years. The main efficacy criterion was the incidence of nonvertebral fractures. In addition, incidence of hip fractures was assessed, by post hoc analysis, in the subset of 1,128 patients who were at high risk of fractures (age 74 years or older with lumbar spine and femoral neck bone mineral density T scores -2.4 or less). The incidence of new vertebral fractures was assessed, using the semiquantitative method described by Genant, in the 3,646 patients in whom spinal radiography (a nonmandatory procedure) was performed during the course of the study. Fracture data were analyzed using the Kaplan-Meier survival method., Results: Of the 5,091 patients, 2,714 (53%) completed the study up to 5 years. The risk of nonvertebral fracture was reduced by 15% in the strontium ranelate group compared with the placebo group (relative risk 0.85 [95% confidence interval 0.73-0.99]). The risk of hip fracture was decreased by 43% (relative risk 0.57 [95% confidence interval 0.33-0.97]), and the risk of vertebral fracture was decreased by 24% (relative risk 0.76 [95% CI 0.65-0.88]) in the strontium ranelate group. After 5 years, the safety profile of strontium ranelate remained unchanged compared with the 3-year findings., Conclusion: Our findings indicate that treatment of postmenopausal osteoporosis with strontium ranelate results in a sustained reduction in the incidence of osteoporotic nonvertebral fractures, including hip fractures, and vertebral fractures over 5 years.

Unlabelled: Strontium ranelate is a new anti-osteoporotic treatment. On bone biopsies collected from humans receiving long-term treatment over 5 yr, it has been shown that strontium ranelate has good bone safety and better results than placebo on 3D microarchitecture. Hence, these effects may explain the decreased fracture rate., Introduction: Strontium ranelate's mode of action involving dissociation of bone formation and resorption was shown in preclinical studies and could explain its antifracture efficacy in humans., Materials and Methods: One hundred forty-one transiliac bone biopsies were obtained from 133 postmenopausal osteoporotic women: 49 biopsies after 1-5 yr of 2 g/d strontium ranelate and 92 biopsies at baseline or after 1-5 yr of placebo., Results and Conclusions: Histomorphometry provided a 2D demonstration of the bone safety of strontium ranelate, with significantly higher mineral apposition rate (MAR) in cancellous bone (+9% versus control, p = 0.019) and borderline higher in cortical bone (+10%, p = 0.056). Osteoblast surfaces were significantly higher (+38% versus control, p = 0.047). 3D analysis of 3-yr biopsies with treatment (20 biopsies) and placebo (21 biopsies) using microCT showed significant changes in microarchitecture with, in the strontium ranelate group, higher cortical thickness (+18%, p = 0.008) and trabecular number (+14%, p = 0.05), and lower structure model index (-22%, p = 0.01) and trabecular separation (-16%, p = 0.04), with no change in cortical porosity. The changes in 3D microarchitecture may enhance bone biomechanical competence and explain the decreased fracture rate with strontium ranelate.

Many postmenopausal women have a calcium intake far below the recommended amount and, in addition to attempting to improve their diet, need a calcium supplement. The aim of the study was to assess the effects of the consumption of a high calcium mineral water (HCaMW) on biochemical indices of bone remodeling in postmenopausal women with low Ca intake. A 6-month randomized double-blind placebo-controlled trial was designed to assess the effects of a daily consumption of 1 liter of a HCaMW (596 mg Ca/l) on serum parathyroid hormone (PTH) and biochemical markers of bone remodeling in postmenopausal women with a dietary Ca intake lower than 700 mg/day. The placebo group drank 1 liter of a mineral water with a low calcium content (10 mg/l). One hundred eighty healthy women were recruited (mean age: 70.1+/-4.0 years); 152 completed the 6-month trial. The changes from baseline of biochemical indices after 6 months consisted of a significant 14.1% decrease of serum PTH, osteocalcin (-8.6%), bone alkaline phosphatase (-11.5%), serum (-16.3%) and urine (-13.0%) type-1 collagen C-telopeptide in the HCaMW group compared to the placebo group, where all biochemical indices increased after 6 months. The additive effect of a small vitamin D supplement (400 iu/day) was also evaluated. In women receiving vitamin D in addition to HCaMW, the decrease in bone indices was not found to be greater than in women drinking only the HCaMW. A daily supplement of 596 mg of Ca through the consumption of 1 l of HCaMW was able to lower serum PTH and the indices of bone turnover in postmenopausal women with a low Ca intake. This could contribute to the repair of calcium deficiency and to the reduction of age-related bone loss in this population.

Bone quality can be defined by the ability to resist fracture. Biomechanical testing represents a direct approach to evaluate bone quality. This quality is dependent of several determinants: intrinsic properties of bone including mineral and organic phases, amount of bone, bone architecture and bone size. These determinants are more or less linked to bone turnover, an absence or excessive one increasing bone fragility. Consequently, a minimum but not excessive level of bone turnover must be preserved in osteoporosis treatment.

Alendronate and teparatide, recombinant human PTH (1-34) are available treatment for osteoporosis in postmenopausal women. They act through opposite mechanisms of action. Alendronate reduces the remodeling of bone and thus increases secondary mineralization without any change in the amount of bone. Teriparatide, 20 micrograms/day, a bone forming agent would increase the amount of bone through two mechanisms, modeling--formation without resorption, and remodeling--resorption then formation with formation higher than resorption. Theses effects are present at the sixth month.

Deleterious effect of oral corticosteroids on bone has been well documented, whereas this remains debated for inhaled ones (ICS). Our objectives were to analyze the effects of ICS on bone mineral density, fracture risk and bone markers. We performed an exhaustive systematic research of all controlled trials potentially containing pertinent data, peer-reviewed by a dedicated WHO expert group, and comprehensive meta-analyses of the data. Inclusion criteria were ICS, and BMD/markers/fractures in asthma/chronic obstructive pulmonary diseases (COPD) and healthy patients. Analyses were performed in a conservative fashion using professional dedicated softwares and stratified by outcome, study design and ICS type. Results were expressed as standardized mean difference/effect size (ES), relative risk (RR) or odds ratio (OR), depending on study design and outcome units. Publication bias was investigated. Twenty-three trials were reviewed; 11 papers fit the inclusion criteria and were assessed for the main analysis. Quality scores for the randomized controlled trials (RCTs) were 80%, 71% for the prospective cohort studies, and 78% for the retrospective cohort and cross-sectional studies. We globally assessed ICS effects on BMD and found deleterious effects: ES=0.61 ( p=0.001) for healthy subjects, and ES=0.27 ( p<0.001) for asthma/COPD patients. For these patients, this effect was 0.21 ( p<0.01) at the lumbar spine, and 0.26 ( p<0.001) at the hip or femoral neck. A single study evaluated the impact of ICS on hip fracture and reported an increased OR of 1.6 (1.24; 2.03). Lumbar fracture rate differences did not reach the level of statistical significance: 1.87 (0.5; 6.94). Osteocalcin and PICP were decreased and ICTP, pyridinoline and deoxypyridinoline levels were not significantly affected. Budesonide (BUD) appeared to be the ICS inducing the less deleterious effects on bone, followed by beclomethasone dipropionate (BDP) and triamcinolone (TRI). Publication bias investigation provided non-significant results. In our meta-analyses, BUD at a mean daily dose (SD) of 686 microg (158 microg), BDP at 703 microg (123 microg) and TRI at 1,000 microg (282 microg) were found to affect bone mineral density and markers in patients suffering from the two major respiratory diseases. These findings could have practical implication in the long-term management of asthmatic and COPD patients.

Objectives: To evaluate the efficacy of pamidronate in protecting against fractures, increasing bone mineral density (BMD), and decreasing bone remodeling marker levels in children with osteogenesis imperFecta., Patients and Methods: Seven children (two girls and five boys; mean age, 8.5 years) were given cyclical intravenous pamidronate (Aredia) for 1 to 7 years, with a mean cycle duration of 6 months and a mean dose of 1.86 mg/kg/cycle. Four patients had type III and three type IV disease according to the Sillence classification scheme., Results: A trend toward a decrease in the fracture rate as compared to the pretreatment period was found, but the difference was not significant in this small sample (P = 0.09). Lumbar spine BMD showed a significant annual increase (+26.7%, P = 0.03) far greater than the expected mean annual increase related to growth. No significant decreases in bone remodeling markers were noted., Conclusion: Pamidronate seems useful in the treatment of osteogenesis imperfecta in children, since it increases BMD and reduces the fracture rate, in keeping with the findings from the larger series studied by Glorieux. Pamidronate is a symptomatic, noncurative treatment that does not correct the genetic abnormalities responsible for the histological bone alterations.

Background: Bisphosphonates are effective agents for the management of osteoporosis. Their low bioavailability and low potency necessitate frequent administration on an empty stomach, which may reduce compliance. Gastrointestinal intolerance limits maximal dosing. Although intermittent intravenous treatments have been used, the optimal doses and dosing interval have not been systematically explored., Methods: We studied the effects of five regimens of zoledronic acid, the most potent bisphosphonate, on bone turnover and density in 351 postmenopausal women with low bone mineral density in a one-year, randomized, double-blind, placebo-controlled trial. Women received placebo or intravenous zoledronic acid in doses of 0.25 mg, 0.5 mg, or 1 mg at three-month intervals. In addition, one group received a total annual dose of 4 mg as a single dose, and another received two doses of 2 mg each, six months apart. Lumbar-spine bone mineral density was the primary end point., Results: There were similar increases in bone mineral density in all the zoledronic acid groups to values for the spine that were 4.3 to 5.1 percent higher than those in the placebo group (P<0.001) and values for the femoral neck that were 3.1 to 3.5 percent higher than those in the placebo group (P<0.001). Biochemical markers of bone resorption were significantly suppressed throughout the study in all zoledronic acid groups. Myalgia and pyrexia occurred more commonly in the zoledronic acid groups, but treatment-related dropout rates were similar to that in the placebo group., Conclusions: Zoledronic acid infusions given at intervals of up to one year produce effects on bone turnover and bone density as great as those achieved with daily oral dosing with bisphosphonates with proven efficacy against fractures, suggesting that an annual infusion of zoledronic acid might be an effective treatment for postmenopausal osteoporosis.