Incidence Of Nonvertebral Fractures Research Articles

The -1997 G/T and Sp1 Polymorphisms in the Collagen Type I alpha1 (COLIA1) Gene in Relation to Changes in Femoral Neck Bone Mineral Density and the Risk of Fracture in the Elderly: The Rotterdam Study

The COLIA1 Sp1 polymorphism has been associated with bone mineral density (BMD) and fracture. A promoter polymorphism, -1997 G/T, also has been associated with BMD. In this study, we examined whether these polymorphisms alone and in the form of haplotypes influence bone parameters and fracture risk in a large population-based cohort of elderly Caucasians. We determined the COLIA1 -1997 G/T (promoter) and Sp1 G/T (intron) polymorphisms in 6,280 individuals and inferred haplotypes. Femoral neck BMD and BMD change were compared across COLIA1 genotypes at baseline and follow-up (mean 6.5 years). We also investigated the relationship between the COLIA1 polymorphisms and incident nonvertebral fractures, which were recorded during a mean follow-up period of 7.4 years. Vertebral fractures were assessed by radiographs on 3,456 genotyped individuals. Femoral neck BMD measured at baseline was 3.8% lower in women carrying two copies of the T-Sp1 allele (P for trend = 0.03). No genotype dependent differences in BMD loss were observed. In women homozygous for the T allele of the Sp1 polymorphism, the risk of fragility fracture increased 2.3 times (95% confidence interval 1.4–3.9, P = 0.001). No such association was observed with the promoter polymorphism. In men, no association with either the Sp1 or the -1997 G/T promoter polymorphism was seen with BMD or fracture. High linkage disequilibrium (LD; D′ = 0.99, r2 = 0.03) exists between the two studied polymorphisms. We observed three haplotypes in our population: haplotype 1 (Gpromoter–Gintron) frequency (f) = 69%, haplotype 2 (Gpromoter–Tintron) f = 17.6%, and haplotype 3 (Tpromoter–Gintron) f = 13.4%. Haplotype 2 was associated with a 2.1-fold increased risk of fragility fracture in women (95% confidence interval 1.2–3.7, P = 0.001). We confirm that the COLIA1 Sp1 polymorphism influences BMD and the risk of fracture in postmenopausal Caucasian women. In contrast, we found no independent effect of the -1997 G/T promoter polymorphism on BMD or fracture.

Associations between the metabolic syndrome and bone health in older men and women: the Rancho Bernardo Study

We examined the associations of metabolic syndrome (MS) with BMD, osteoporosis, and osteoporotic fractures in 417 men and 671 women from the Rancho Bernardo Study. After adjusting for BMI, MS was associated with lower, not higher BMD. Incidence of osteoporotic non-vertebral fractures was higher in participants with MS. MS may be another risk factor for osteoporotic fractures. The metabolic syndrome (MS) is a cluster of risk factors, including abdominal obesity, high glucose, triglycerides, hypertension and low HDL levels, associated with cardiovascular disease morbidity. The association between components of the MS and bone mineral density (BMD) has been researched, but results are contradictory. We used multivariate regression models to examine the cross-sectional associations of MS defined by NCEP-ATP III criteria with BMD and osteoporosis, and the longitudinal association of MS with fractures in 420 men and 676 women from the Rancho Bernardo Study. Prevalence of MS at baseline was 23.5% in men and 18.2% in women. In age-adjusted analyses, men and women with MS had higher BMD at total hip when compared to those without MS (p < 0.001 and p = 0.01, respectively). Men but not women with MS also had higher BMD at femoral neck (p = 0.05). After adjusting for BMI, these associations were reversed, such that MS was associated with lower and not higher BMD. Incidence of osteoporotic non-vertebral fractures was higher in participants with MS. MS may be another risk factor for osteoporotic fractures. The association of MS with higher BMD was explained by the higher BMI in those with MS.

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.

Relationship between change in femoral neck bone mineral density and hip fracture incidence during treatment with strontium ranelate

ABSTRACTObjective: Strontium ranelate (SR) increases bone mineral density (BMD) in postmenopausal osteoporotic women and reduces vertebral and non-vertebral fracture incidence. Hip fracture reduction has also been observed during 3-year treatment with SR in osteoporotic women at high risk of hip fracture. The objective of this study is to analyse the association between BMD changes and hip fracture incidence during treatment with SR.Material and methods: In this post-hoc analysis, 465 women aged over 74 years with low BMD at the femoral neck (T-score ≤ –2.4 according to NHANES normative values) were selected from the population of a recently published study (the Treatment of Peripheral Osteoporosis Study – TROPOS). BMD was assessed at the femoral neck at baseline and after a follow-up of 3 years. Hip fractures were reported by study investigators.Results: After adjusting for age, body mass index, femoral neck BMD at baseline and number of prevalent vertebral fractures, we found that for each 1% increase in femoral neck BMD observed after 3 years, the risk to experience a hip fracture after 3 years decreased by 7% (95% CI: 1–14%) ( p = 0.04). In patients experiencing a hip fracture over 3 years of treatment with SR, femoral neck BMD increased by (mean [SE]) 3.41 (1.02)% compared to 7.23 (0.81)% in patients without hip fracture ( p = 0.02).Conclusion: In this post-hoc analysis of women undergoing 3 years of SR treatment, an increase in femoral neck BMD is associated with a decrease in hip fracture incidence.

Monthly dosing with risedronate 50 mg on three consecutive days a month compared with daily dosing with risedronate 5 mg: a 6-month pilot study

ABSTRACTObjective: Risedronate 5 mg daily significantly reduces the incidence of vertebral and non-vertebral osteoporotic fractures in postmenopausal women. We compared the efficacy and tolerability of risedronate 50 mg administered on 3 consecutive days per month, with and without a loading dose, with those of risedronate 5 mg daily in a randomized, double-blind study.Methods: Subjects were postmenopausal women 65–80 years old with low bone mineral density (BMD) (T-score ≤ –2). Subjects received risedronate 5 mg daily for 6 months (n = 48), risedronate 150 mg (50-mg doses on 3 consecutive days) monthly for 6 months (n = 50), or a loading dose of risedronate 15 mg daily for 1 month followed by 150 mg (50-mg doses on 3 consecutive days) monthly for 5 months (n = 52).Results: Within 1 week, statistically significant reductions in urine N-telopeptide, the primary efficacy measure, were observed in all three groups. After 6 months, the least squares (LS) mean differences (95% confidence intervals [CI]) from the change in the 5 mg daily group (–39.88) were –3.54% (–15.71; 8.64) for the 150 mg monthly and –2.02% (–14.13;10.10) for the loading dose + 150 mg monthly groups. Mean percent changes in serum alpha-C-telopeptide, bone-specific alkaline phosphatase, and BMD, secondary efficacy measures, after 6 months were also similar for the three groups. The LS mean differences (95% CI) from the mean percent change in BMD in the 5 mg daily group (3.22%) were 0.20 (–1.15; 1.55) for the 150 mg monthly and –0.58 (–1.93; 0.76) for the loading dose + 150 mg monthly groups. The safety profile of the monthly regimens was similar to that of the 5 mg daily regimen and consistent with product labeling.Conclusions: A monthly regimen of risedronate 50 mg on 3 consecutive days per month was similar to risedronate 5 mg daily with respect to its effect in suppressing bone turnover and increasing BMD and its safety profile in women with postmenopausal osteoporosis. This study was not powered to be a confirmatory trial for non-inferiority; therefore, additional study is needed.

Fractures and avascular necrosis before and after orthotopic liver transplantation

With early posttransplant bone loss, orthotopic liver transplantation (OLT) recipients experience a high rate of fracturing and some avascular necrosis (AVN), but little is known about the incidence of and predictive factors for these skeletal complications. We studied 360 consecutive patients who underwent transplantation for primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) and assessed both vertebral and nonvertebral (rib, pelvic, and femur) fractures in a protocolized fashion. Before OLT, 20% of the patients had experienced fracturing, and 1.4% of the patients had experienced AVN. Following OLT, there was a sharp increase in fracturing, with a 30% cumulative incidence of fractures at 1 year and 46% at 8 years after transplantation. In contrast to previous studies, there was a similar incidence of posttransplant vertebral and nonvertebral fractures. The greatest risk factors for posttransplant fracturing were pretransplant fracturing and the severity of osteopenia and posttransplant glucocorticoids. Nine percent of the liver recipients experienced AVN after OLT, and this correlated with pretransplant and posttransplant lipid metabolism, bone disease (bone mineral density and fracturing), and posttransplant glucocorticoids. A novel association between cholestasis and AVN was also identified, the mechanism for which is not known. Fortunately, recent years have seen an increase in the bone mass of liver recipients and, along with this, less fracturing and less AVN. Nonetheless, 25% of patients undergoing OLT for chronic cholestatic liver disease still develop de novo fractures after OLT; this situation demands an ongoing search for effective therapeutic agents for these patients.

Estrogen Receptor β (ESR2) Polymorphisms in Interaction With Estrogen Receptor α (ESR1) and Insulin-Like Growth Factor I (IGF1) Variants Influence the Risk of Fracture in Postmenopausal Women

In this large population-based cohort study, variants in ESR2 were associated with increased risk of vertebral and incident fragility fracture in postmenopausal women. Interaction of ESR2 with ESR1 and IGF1 was determined and revealed a deleterious genetic combination that enhances the risk of osteoporotic fracture. Osteoporosis is a complex disease with strong genetic influence, but the genes involved are ill-defined. We examined estrogen receptor beta (ESR2) polymorphisms in interaction with estrogen receptor alpha (ESR1) and insulin-like growth factor I (IGF1) variants in relation to the risk of osteoporotic fracture, BMD, and bone geometry. In the Rotterdam study, a prospective population-based cohort of elderly white individuals, we studied six single nucleotide polymorphisms (SNPs) in ESR2 (n = 6343, 60% women). We analyzed the genetic variants in the form of haplotypes reconstructed by a statistical method. Results refer to the most frequent ESR2 haplotype 1 estimated from two SNPs in intron 2 and the 3'-untranslated region (UTR). Outcomes included vertebral and incident nonvertebral fractures, BMD, and hip structural analysis (HSA). We also studied the interaction with (the most frequent) ESR1 haplotype 1 estimated from the PvuII and XbaI polymorphisms and an IGF1 promoter CA-repeat. Compared with ESR2 haplotype 1 noncarriers, female homozygous carriers had a 1.8- and 1.4-fold increased risk of vertebral and fragility fractures. HSA showed that ESR2 haplotype 1 homozygote women had 2.6% thinner cortices, 1.0% increased neck width, and 4.3% higher bone instability (buckling ratios). For testing the gene interaction, we assumed a recessive model of ESR2 haplotype 1. Female homozygous carriers of ESR2 haplotype 1 and noncarriers of ESR1 haplotype 1 had a 3.5- and 1.8-fold increased risk of vertebral and fragility fractures (p(interaction) = 0.10). Such effects and interactions were stronger in women homozygous for the IGF1 192-bp allele, with 9.3-fold increased risk (p(interaction) = 0.002) for vertebral and 4.0-fold increased risk (p(interaction) = 0.01) for fragility fractures. Multilocus interaction analyses of fracture endured correction for multiple testing using Monte-Carlo simulations (p(interaction) = 0.02 for vertebral and p(interaction) = 0.03 for fragility fractures). Similar patterns of interaction were observed for BMD, cortical thickness, bone strength (section modulus), and instability (buckling ratio). In men, no such effects were observed. Variants of ESR2 alone and in interaction with ESR1 and IGF1 influence the risk of fracture in postmenopausal women. These findings reinforce the polygenic and complex character of osteoporosis.

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.

Knee pain, knee osteoarthritis, and the risk of fracture

Patients with osteoarthritis (OA) have increased bone mineral density; however, the association between knee OA and fracture is controversial. Few data exist on the association between knee pain and fracture. We examined the association of knee OA and knee pain with fracture and falls in elderly men and women. The study group comprised 6,641 men and women ages > or =75 years who participated in a 3-year randomized controlled trial of intramuscular vitamin D therapy. Patients completed a questionnaire about knee pain and OA. Fracture and fall data were collected prospectively every 6 months. Knee pain prevalence and a clinician diagnosis of knee OA were 35.2% and 6.8%, respectively. A total of 436 incident nonvertebral fractures were reported, and 3,992 patients sustained a fall. Prevalent knee pain was associated with an increased risk of falls (hazard ratio [HR] 1.26, 95% confidence interval [95% CI] 1.17-1.36) and hip fracture (HR 2.0, 95% CI 1.18-3.37). Increasing severity of knee pain was associated with a greater risk of falls and hip fracture. Clinician diagnosis of knee OA was associated with an increased risk of nonvertebral fractures (HR 1.61, 95% CI 1.09-2.36). The increased risk of fracture was not substantially reduced by adjusting for falls, but was attenuated by adjustment for the use of walking aids. Patients with a clinical diagnosis of knee OA and with knee pain have an increased risk of nonvertebral and hip fracture. This is not explained by the increased risk of falls, but is more likely to be due to the severity of falls sustained. Knee pain and OA should be regarded as independent risk factors for fracture.

Postmenopausal osteoporosis. What have we learned since the introduction of bisphosphonates?

Over the past 12 years bisphosphonates have become a mainstay of treatment for postmenopausal osteoporosis. As a class, bisphosphonates significantly suppress bone turnover and increase BMD at the lumbar spine and other site through their direct inhibitory effects on osteoclasts. Alendronate and risedronate reduce the incidence of clinical vertebral and non-vertebral fractures. Etidronate and both oral and intravenous ibandronate reduce the incidence of clinical vertebral fractures, but data from primary analyses for reduction in non-vertebral fractures are currently less robust. Intravenous administration of zoledronate is under late-stage investigation for use in postmenopausal osteoporosis. Combinations of alendronate with estrogen or raloxifene provide a greater reduction in bone turnover markers and greater increases in BMD, but fracture risk reduction has not been determined. Overall, bisphosphonates are well tolerated. The most common side effects of oral bisphosphonates are upper gastrointestinal symptoms. Newer safety concerns about the use of bisphosphonates include osteonecrosis of the jaw and oversuppression of bone turnover. The optimal duration of bisphosphonate treatment has not been clearly established.

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.

Strontium ranelate: vertebral and non-vertebral fracture risk reduction

Fractures are common at the spine and hip, but at least half the morbidity and mortality of fractures in the community come from fractures that involve other sites. Over half of all fractures arise in individuals without osteoporosis, whereas the highest risk group for fractures are individuals over 80 years of age. Reducing the burden of fractures should thus include an assessment of drug efficacy against all fractures in a wide range of individuals. For vertebral fractures, in the phase III Spinal Osteoporosis Therapeutic Intervention study of 1649 postmenopausal women with osteoporosis, 2 g strontium ranelate a day produced a risk reduction of 49% in the first year and 41% during 3 years. In the TReatment Of Peripheral OSteoporosis study, which was designed to examine the effect of strontium ranelate on non-vertebral fractures, of the 5091 patients, 3640 had spine X-rays. The vertebral fracture risk reduction was 45% at one year and 39% over 3 years. In a preplanned pooling of the above two studies, 1170 patients had vertebral osteopenia. Strontium ranelate reduced the risk of vertebral fracture in 3 years by 40% in these patients. In 409 patients with lumbar or femoral neck osteopenia, strontium ranelate reduced the risk of vertebral fractures by 62% over 3 years. In the pre-planned pooling of data from the two studies, in 1488 women aged between 80 and 100 years (mean age 84 +/- 3 years), the risk of vertebral fractures was reduced in one year by 59% and by 32% over 3 years. For non-vertebral fractures, in the TReatment Of Peripheral OSteoporosis study, treatment for 3 years reduced the fracture risk by 16%, and by 19% for major fragility fractures. In a post-hoc analysis of 1977 women at high risk of hip fracture (aged > or = 74 years and with a femoral neck bone mineral density T-score < or = -2.4) the hip fracture risk was reduced by 36%. In patients aged 80 and over in the pre-planned pooling of data from the two studies, the risk of an incident non-vertebral fracture was reduced by 41% in the first year and by 31% over 3 years. Strontium ranelate, a new anti-osteoporosis agent, has a broad range of antifracture efficacy.

Safety and Efficacy of Teriparatide in Elderly Women with Established Osteoporosis: Bone Anabolic Therapy from a Geriatric Perspective

To assess the safety and efficacy of teriparatide in patients aged 75 and older and compare these findings with those of women younger than 75 using data from the Fracture Prevention Trial (FPT). The FPT was a randomized, multicenter, double-blind, placebo-controlled study. The FPT multicenter international study. Postmenopausal women aged 42 to 86 were randomized to placebo (N=544) or teriparatide 20 mug (N=541) by daily self-injection for a median of 19 months. Patients received daily oral supplements of 1,000 mg calcium and 400 to 1,200 IU vitamin D. For this analysis, subgroups were defined according to patient age younger than 75 (N=841) and 75 and older (N=244). The effects of teriparatide on bone mineral density (BMD) of the lumbar spine and femoral neck; the incidence of new vertebral and new nonvertebral fragility fractures; bone turnover markers, including bone-specific alkaline phosphatase; and urinary deoxypyridinoline corrected for creatinine clearance, as well as the safety of teriparatide, were investigated. There were no significant treatment-by-age interactions for the bone turnover markers, femoral neck BMD, vertebral fractures, nonvertebral fragility fractures, height loss, hyperuricemia, or hypercalcemia. A significant treatment-by-age interaction for lumbar spine BMD (P=.08) was due to an increase in BMD observed in the placebo group aged 75 and older. There were no treatment-by-age interactions for important treatment-emergent adverse events (TEAEs), including back pain, nausea, leg cramps, and dizziness. The most important TEAEs in women aged 80 and older (23 patients from the placebo group and 25 patients from the teriparatide group) were also reviewed; no unexpected TEAEs were found in the patients treated with teriparatide. These results indicate that the clinical effects of teriparatide were consistent in the older and younger women. Age does not affect the safety and efficacy of teriparatide in postmenopausal women with osteoporosis.

RETRACTED ARTICLE: Comparison of the effect of alendronate on lumbar bone mineral density and bone turnover in men and postmenopausal women with osteoporosis

The purpose of the present study was to compare the effect of alendronate treatment on lumbar bone mineral density (BMD) and bone turnover in men and postmenopausal women with osteoporosis. Sixty men with primary or secondary osteoporosis and 318 women with postmenopausal osteoporosis were treated with alendronate. The primary end points were lumbar BMD and urinary cross-linked N-terminal telopeptides of type I collagen (NTX) and serum alkaline phosphatase (ALP) levels. The secondary end point was the incidence of vertebral and nonvertebral fractures. Forty-seven (78.3%) men and 254 (79.9%) women who could complete the 12-month trial were analyzed. The mean ages of men and postmenopausal women were 69.1 and 70.4 years, respectively. Both men and postmenopausal women showed higher levels of urinary NTX as compared with normal range of premenopausal women. Alendronate treatment decreased urinary NTX level by 39.2% in men and 45.4% in postmenopausal women at 3 months and serum ALP level by 17.8 and 21.0%, respectively, at 12 months. Following reduction in bone turnover markers, lumbar BMD increased 5.8 and 7.6% in men and postmenopausal women, respectively, at 12 months. Reduction in urinary NTX level and increase in lumbar BMD were smaller in men than in postmenopausal women. The incidence of vertebral and nonvertebral fractures was 10.6 and 8.5%, respectively, in men and 8.3 and 7.5%, respectively, in postmenopausal women, with no significant difference in these incidences between them. These results suggested that alendronate treatment effectively increased lumbar BMD from baseline in men with primary or secondary osteoporosis following reduction in bone turnover, although its efficacy did not appear to be greater than in postmenopausal women with osteoporosis.

Beyond daily dosing: Clinical experience

Osteoporosis has had a significant public health impact, with many sufferers experiencing fractures. Such fractures lead to increased disability, mortality and reduced quality of life, all of which raise healthcare costs. Oral bisphosphonates are associated with significant antifracture efficacy and have therefore become the mainstay of treatment for postmenopausal osteoporosis. Poor therapeutic adherence with daily bisphosphonates has been improved by the introduction of weekly regimens, although adherence levels remain suboptimal. Bisphosphonate regimens with dosing intervals beyond a week have therefore been developed to address this issue. Oral ibandronate, a potent nitrogen-containing bisphosphonate, has been studied using daily and intermittent regimens (between-dose interval >2 months). The initial phase II 2-year study confirmed the feasibility of the intermittent regimen, providing increases in lumbar spine bone mineral density (BMD) superior to placebo ( P < 0.01) and equivalent to the daily regimen (5.64% vs. 5.54%, respectively). BONE (Oral i Bandronate Osteoporosis vertebral fracture trial in North America and Europe), a large phase III 3-year study was subsequently initiated, including 2946 women with postmenopausal osteoporosis and testing both a daily as well as an intermittent regimen with a dose-free interval of more than 2 months. Significant vertebral antifracture efficacy (the primary study endpoint) was demonstrated with daily (2.5 mg) and intermittent (20 mg every other day for 12 doses every 3 months) ibandronate in comparison with placebo ( P ≤ 0.0006). As a result of the study not being designed and powered to show an effect on non-vertebral fractures and the overall population being at low risk for osteoporotic fractures, differences in the incidence of non-vertebral fractures were similar between groups (8.2-9.1%) However, a post hoc analysis in a subgroup of patients with a femoral neck BMD T-score < −3.0 showed that daily ibandronate significantly reduced the risk of non-vertebral fractures ( P = 0.012). Both regimens were associated with significant increases in lumbar spine and proximal femur BMD and normalization of bone turnover. As determined by adverse event incidence and laboratory evaluation, the safety profile for both ibandronate regimens was similar to that observed for placebo. The BONE study therefore confirmed that daily or intermittent ibandronate is an effective and well-tolerated treatment for postmenopausal women. Being the first study to demonstrate antifracture efficacy with an intermittent regimen, it provided ‘proof of concept’ for beyond weekly dosing with ibandronate and prompted further development of a more convenient once-monthly regimen.

WITHDRAWN: Calcium supplementation on bone loss in postmenopausal women.

Although calcium is one the simplest and least expensive strategies for preventing osteoporotic fractures calcium supplementation is nevertheless not without controversy (Kanis 1989; Nordin 1990). The Food and Drug Administration in the US has permitted a bone health claim for calcium-rich foods, and the NIH in its Consensus Development Process approved a statement that high calcium intake reduces the risk of osteoporosis. To assess the effects of calcium on bone density and fractures in postmenopausal women. We searched Cochrane Controlled Register, MEDLINE and EMBASE up to 2001, and examined citations of relevant articles and proceedings of international meetings. Trials that randomized postmenopausal women to calcium supplementation or usual calcium intake in the diet and reported bone mineral density of the total body, vertebral spine, hip, or forearm or recorded the number of fractures, and followed patients for at least one year were considered for inclusion. Three independent reviewers assessed the methodologic quality and extracted data for each trial. For each bone density site (lumbar spine, total body, combined hip and combined forearm), we calculated the weighted mean difference in bone density between treatment and control groups using the percentage change from baseline. We constructed regression models in which the independent variables were year and dose, and the dependent variable was the effect size. This regression was used to determine the years across which pooling was appropriate. Heterogeneity was assessed. For each fracture analysis we calculated a risk ratio. Fifteen trials, representing 1806 participants, were included. Calcium was more effective than placebo in reducing rates of bone loss after two or more years of treatment. The pooled difference in percentage change from baseline was 2.05% (95% CI 0.24 to 3.86) for total body bone density, 1.66% (95% CI 0.92 to 2.39) for the lumbar spine at 2 years, 1.60% (95% CI 0.78 to 2.41) for the hip, and 1.91% (95% CI 0.33 to 3.50) for the distal radius. The relative risk of fractures of the vertebrae was 0.79 (95% CI 0.54 to 1.09); the relative risk for non-vertebral fractures was 0.86 (95% CI 0.43 to 1.72). Calcium supplementation alone has a small positive effect on bone density. The data show a trend toward reduction in vertebral fractures, but it is unclear if calcium reduces the incidence of non vertebral fractures.

Protelos: Nonvertebral and hip antifracture efficacy in postmenopausal osteoporosis

Strontium ranelate is a new treatment for postmenopausal osteoporosis, simultaneously increasing bone formation and decreasing bone resorption, thus rebalancing bone turnover in favor of bone formation. Strontium ranelate was demonstrated to significantly reduce the relative risk of vertebral fracture whatever the severity of the disease. In the TReatment Of Peripheral OSteoporosis (TROPOS) study, the incidence of nonvertebral and hip fractures, following treatment with strontium ranelate (Protelos®, Servier) at a dosage of 2 g/day orally, was assessed over a 3-year period. In this double-blind, placebo-controlled trial, 5091 women with postmenopausal osteoporosis were assigned to either strontium ranelate ( n = 2479) or placebo ( n = 2453) treatment. Overall, the reduction in risk for nonvertebral fractures in patients treated with strontium ranelate was 16% ( P = 0.04) and for major fractures (hip, wrist, pelvis and sacrum, ribs and sternum, clavicle and humerus), it was 19% ( P = 0.031), compared with those treated with placebo. Women with osteoporosis and aged 74 years or more who were treated with strontium ranelate ( n = 982) had a 36% reduction in risk of hip fracture ( P = 0.046) over 3 years compared with those treated with placebo ( n = 995). The difference in bone mineral density between groups was 8.2% for femoral neck and 9.8% for total hip at 3 years. The incidence of adverse events was comparable between groups. The study demonstrates that strontium ranelate treatment offers a safe and effective means of reducing the risk of nonvertebral and hip fractures in postmenopausal women with osteoporosis.

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.

Osteoporosis diagnosis and screening

Osteoporosis and osteoporotic fracture are major causes of morbidity and mortality in the United States and worldwide. Nearly half of all women and one quarter of men >50 years of age will experience an osteoporosis-related fracture during their lifetime. The diagnosis of osteoporosis in postmenopausal women and older men can be made definitively by comparing bone mineral density (BMD) measurements from dual-energy x-ray absorptiometry (DXA) to mean peak bone mass in young adults. Efforts to increase access to DXA and improve the sensitivity and specificity of osteoporosis risk assessment instruments may help ensure that individuals with osteoporosis are diagnosed early. The early identification of individuals with low BMD and/or clinical risk factors, accurate diagnosis of osteoporosis and osteopenia, and initiation of appropriate treatment are crucial to reducing the incidence of vertebral and nonvertebral fractures. The World Health Organization is moving toward absolute risk assessment and this may help to better identify patients for screening and treatment in the future.

Relationship Between Changes in BMD and Nonvertebral Fracture Incidence Associated With Risedronate: Reduction in Risk of Nonvertebral Fracture Is Not Related to Change in BMD

Whether greater treatment-related changes in BMD result in greater decreases in fracture risk is controversial. We analyzed the relationship between BMD change and nonvertebral fracture risk in postmenopausal osteoporotic women from the risedronate fracture program. Change in BMD did not influence the magnitude of risedronate's effect on nonvertebral fractures; the incidence of nonvertebral fractures was equally low in treated patients whose BMD increased or decreased. In untreated patients, low BMD correlates with increased fracture risk. Whether greater increases in BMD induced by anti-osteoporosis drugs are related to greater decreases in vertebral fracture risk is controversial, and little has been written about the relationship between change in BMD and nonvertebral fracture risk. We analyzed the relationship between BMD change and nonvertebral fracture incidence using individual patient data from postmenopausal osteoporotic women receiving antiresorptive treatment with risedronate. This posthoc analysis combined data from three pivotal risedronate fracture endpoint trials. Women received risedronate 2.5 or 5 mg (n = 2,561) or placebo (n = 1,418) daily for up to 3 years. BMD and nonvertebral fractures confirmed by radiograph (hip, wrist, pelvis, humerus, clavicle, and leg) were assessed periodically over 3 years. The incidence of nonvertebral fractures in risedronate-treated patients was not different between patients whose spine BMD decreased (7.8%) and those whose spine BMD increased (6.4%; hazard ratio to subgroup of patients who lost BMD [HR], 0.79; 95% CI, 0.50, 1.25) or between those whose femoral neck BMD decreased (7.6%) and those whose femoral neck BMD increased (7.5%; HR, 0.93; 95% CI, 0.68, 1.28). The changes in lumbar spine and femoral neck BMD explained only 12% (95% CI, 2%, 21%; p = 0.014) and 7% (95% CI, 2%, 13%; p = 0.005), respectively, of risedronate's nonvertebral fracture efficacy. For patients treated with risedronate, changes in BMD as measured by DXA do not predict the degree of reduction in nonvertebral fractures.