Kim Brixen

Patient level pooled analysis of 68,500 patients from seven major vitamin D fracture trials in US and Europe

Objectives To identify participants’ characteristics that influence the anti-fracture efficacy of vitamin D or vitamin D plus calcium with respect to any fracture, hip fracture, and clinical vertebral fracture and to assess the influence of dosing regimens and co-administration of calcium. Design Individual patient data analysis using pooled data from randomised trials. Data sources Seven major randomised trials of vitamin D with calcium or vitamin D alone, yielding a total of 68 517 participants (mean age 69.9 years, range 47-107 years, 14.7% men). Study selection Studies included were randomised studies with at least one intervention arm in which vitamin D was given, fracture as an outcome, and at least 1000 participants. Data synthesis Logistic regression analysis was used to identify significant interaction terms, followed by Cox’s proportional hazards models incorporating age, sex, fracture history, and hormone therapy and bisphosphonate use. Results Trials using vitamin D with calcium showed a reduced overall risk of fracture (hazard ratio 0.92, 95% confidence interval 0.86 to 0.99, P=0.025) and hip fracture (all studies: 0.84, 0.70 to 1.01, P=0.07; studies using 10 μg of vitamin D given with calcium: 0.74, 0.60 to 0.91, P=0.005). For vitamin D alone in daily doses of 10 μg or 20 μg, no significant effects were found. No interaction was found between fracture history and treatment response, nor any interaction with age, sex, or hormone replacement therapy. Conclusion This individual patient data analysis indicates that vitamin D given alone in doses of 10-20 μg is not effective in preventing fractures. By contrast, calcium and vitamin D given together reduce hip fractures and total fractures, and probably vertebral fractures, irrespective of age, sex, or previous fractures.

Effects of long-term strontium ranelate treatment on the risk of nonvertebral and vertebral fractures in postmenopausal osteoporosis: Results of a five-year, randomized, placebo-controlled trial.

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.

Large-Scale Analysis of Association Between LRP5 and LRP6 Variants and Osteoporosis

CONTEXT Mutations in the low-density lipoprotein receptor-related protein 5 (LRP5) gene cause rare syndromes characterized by altered bone mineral density (BMD). More common LRP5 variants may affect osteoporosis risk in the general population. OBJECTIVE To generate large-scale evidence on whether 2 common variants of LRP5 (Val667Met, Ala1330Val) and 1 variant of LRP6 (Ile1062Val) are associated with BMD and fracture risk. DESIGN AND SETTING Prospective, multicenter, collaborative study of individual-level data on 37,534 individuals from 18 participating teams in Europe and North America. Data were collected between September 2004 and January 2007; analysis of the collected data was performed between February and May 2007. Bone mineral density was assessed by dual-energy x-ray absorptiometry. Fractures were identified via questionnaire, medical records, or radiographic documentation; incident fracture data were available for some cohorts, ascertained via routine surveillance methods, including radiographic examination for vertebral fractures. MAIN OUTCOME MEASURES Bone mineral density of the lumbar spine and femoral neck; prevalence of all fractures and vertebral fractures. RESULTS The Met667 allele of LRP5 was associated with reduced lumbar spine BMD (n = 25,052 [number of participants with available data]; 20-mg/cm2 lower BMD per Met667 allele copy; P = 3.3 x 10(-8)), as was the Val1330 allele (n = 24,812; 14-mg/cm2 lower BMD per Val1330 copy; P = 2.6 x 10(-9)). Similar effects were observed for femoral neck BMD, with a decrease of 11 mg/cm2 (P = 3.8 x 10(-5)) and 8 mg/cm2 (P = 5.0 x 10(-6)) for the Met667 and Val1330 alleles, respectively (n = 25 193). Findings were consistent across studies for both LRP5 alleles. Both alleles were associated with vertebral fractures (odds ratio [OR], 1.26; 95% confidence interval [CI], 1.08-1.47 for Met667 [2001 fractures among 20 488 individuals] and OR, 1.12; 95% CI, 1.01-1.24 for Val1330 [1988 fractures among 20,096 individuals]). Risk of all fractures was also increased with Met667 (OR, 1.14; 95% CI, 1.05-1.24 per allele [7876 fractures among 31,435 individuals)]) and Val1330 (OR, 1.06; 95% CI, 1.01-1.12 per allele [7802 fractures among 31 199 individuals]). Effects were similar when adjustments were made for age, weight, height, menopausal status, and use of hormone therapy. Fracture risks were partly attenuated by adjustment for BMD. Haplotype analysis indicated that Met667 and Val1330 variants both independently affected BMD. The LRP6 Ile1062Val polymorphism was not associated with any osteoporosis phenotype. All aforementioned associations except that between Val1330 and all fractures and vertebral fractures remained significant after multiple-comparison adjustments. CONCLUSIONS Common LRP5 variants are consistently associated with BMD and fracture risk across different white populations. The magnitude of the effect is modest. LRP5 may be the first gene to reach a genome-wide significance level (a conservative level of significance [herein, unadjusted P < 10(-7)] that accounts for the many possible comparisons in the human genome) for a phenotype related to osteoporosis.

Strontium ranelate reduces the risk of vertebral and nonvertebral fractures in women eighty years of age and older

Strontium ranelate produces an early and sustained reduction of both vertebral and nonvertebral fractures in patients ≥80 years of age.

Fracture risk and zoledronic acid therapy in men with osteoporosis

BACKGROUND Fractures in men are a major health issue, and data on the antifracture efficacy of therapies for osteoporosis in men are limited. We studied the effect of zoledronic acid on fracture risk among men with osteoporosis. METHODS In this multicenter, double-blind, placebo-controlled trial, we randomly assigned 1199 men with primary or hypogonadism-associated osteoporosis who were 50 to 85 years of age to receive an intravenous infusion of zoledronic acid (5 mg) or placebo at baseline and at 12 months. Participants received daily calcium and vitamin D supplementation. The primary end point was the proportion of participants with one or more new morphometric vertebral fractures over a period of 24 months. RESULTS The rate of any new morphometric vertebral fracture was 1.6% in the zoledronic acid group and 4.9% in the placebo group over the 24-month period, representing a 67% risk reduction with zoledronic acid (relative risk, 0.33; 95% confidence interval, 0.16 to 0.70; P=0.002). As compared with men who received placebo, men who received zoledronic acid had fewer moderate-to-severe vertebral fractures (P=0.03) and less height loss (P=0.002). Fewer participants who received zoledronic acid had clinical vertebral or nonvertebral fractures, although this difference did not reach significance because of the small number of fractures. Bone mineral density was higher and bone-turnover markers were lower in the men who received zoledronic acid (P<0.05 for both comparisons). Results were similar in men with low serum levels of total testosterone. The zoledronic acid and placebo groups did not differ significantly with respect to the incidence of death (2.6% and 2.9%, respectively) or serious adverse events (25.3% and 25.2%). CONCLUSIONS Zoledronic acid treatment was associated with a significantly reduced risk of vertebral fracture among men with osteoporosis. (Funded by Novartis Pharma; ClinicalTrials.gov number, NCT00439647.).

Hip Fracture Patients at Risk of Second Hip Fracture: A Nationwide Population-Based Cohort Study of 169,145 Cases During 1977–2001†‡

In patients with prior hip fracture (HFx), little is known about time frame and risk factors of second HFx, as well as the ensuing mortality. The aim of the study was to elucidate the incidence of second HFx and subsequent mortality. All 169,145 patients with a first HFx in Denmark during 1977–2001 were followed for up to 25 yr and compared with the background population. Data on fractures, vital status, comorbidity, redeemed prescriptions, and socio‐demographic variables were retrieved from national registers. Median follow‐up was 3.8 yr, corresponding to 1,041,177 patient‐years. A total of 27,834 patients had a second HFx. The cumulative incidence was 9% after 1 yr and 20% after 5 yr, being significantly higher than expected (2% and 12%, respectively; p < 0.05). The RR of second HFx was 2.2 (95% CI: 2.0–2.5) at 1 yr and did not normalize until 15 yr (RR = 1.01, 95% CI: 1.0–1.02). Risk factors for a second HFx were female sex (HR = 1.36, 95% CI: 1.32–1.40), age (HR = 1.68, 95% CI: 1.60–1.76 in patients >85 yr), alcoholism (HR = 1.61, 95% CI: 1.51–1.72), any prior fracture (HR = 1.08, 95%CI :1.04–1.11), and living alone (HR = 1.06, 95% CI: 1.04–1.09). Both sexes had higher mortality at 1 and 5 yr after a second HFx compared with the background population (men—1 yr: 27% versus 9%, p < 0.05; 5 yr: 64% versus 40%, p < 0.05; women—1 yr: 21% versus 10%, p < 0.05; 5 yr: 58% versus 41%, p < 0.05). Patients with HFx are at 2‐fold risk of further HFx and the subsequent mortality is highly increased. We propose that programs for secondary prevention should be developed and tested.

Vitamin D with Calcium Reduces Mortality: Patient Level Pooled Analysis of 70,528 Patients from Eight Major Vitamin D Trials

INTRODUCTION Vitamin D may affect multiple health outcomes. If so, an effect on mortality is to be expected. Using pooled data from randomized controlled trials, we performed individual patient data (IPD) and trial level meta-analyses to assess mortality among participants randomized to either vitamin D alone or vitamin D with calcium. SUBJECTS AND METHODS Through a systematic literature search, we identified 24 randomized controlled trials reporting data on mortality in which vitamin D was given either alone or with calcium. From a total of 13 trials with more than 1000 participants each, eight trials were included in our IPD analysis. Using a stratified Cox regression model, we calculated risk of death during 3 yr of treatment in an intention-to-treat analysis. Also, we performed a trial level meta-analysis including data from all studies. RESULTS The IPD analysis yielded data on 70,528 randomized participants (86.8% females) with a median age of 70 (interquartile range, 62-77) yr. Vitamin D with or without calcium reduced mortality by 7% [hazard ratio, 0.93; 95% confidence interval (CI), 0.88-0.99]. However, vitamin D alone did not affect mortality, but risk of death was reduced if vitamin D was given with calcium (hazard ratio, 0.91; 95% CI, 0.84-0.98). The number needed to treat with vitamin D plus calcium for 3 yr to prevent one death was 151. Trial level meta-analysis (24 trials with 88,097 participants) showed similar results, i.e. mortality was reduced with vitamin D plus calcium (odds ratio, 0.94; 95% CI, 0.88-0.99), but not with vitamin D alone (odds ratio, 0.98; 95% CI, 0.91-1.06). CONCLUSION Vitamin D with calcium reduces mortality in the elderly, whereas available data do not support an effect of vitamin D alone.

Efficacy of wheat germ lectin-precipitated alkaline phosphatase in serum as an estimator of bone mineralization rate: Comparison to serum total alkaline phosphatase and serum bone Gla-protein

SummarySerum levels of total alkaline phosphatase activity (S-T-AP), wheat germ lectin-precipitated alkaline phosphatase activity (S-L-AP), and bone Gla-protein immunoreactivity (S-BGP) were measured in 26 patients (23 females and 3 males) aged 35–73 years (mean 59 years) with primary hyperparathyroidism (n=7), hyperthyroidism (n=9), and hypothyroidism (n=10) in whom the bone mineralization rate (m) was determined by47Ca-kinetics (continuously expanding calcium pool model). A weak positive correlation (r=0.42,P<0.05) was found between S-T-AP and m, which in the range from 0–18 mmol Ca/day could be estimated with a standard error of 4.6 mmol/day. A closer correlation (r=0.65,P<0.001) was found between S-L-AP and m which was estimated with an error of 3.9 mmol Ca/day. The AP activity in the supernatant showed no significant correlation to m (r=0.11,P>0.50). The highest correlation coefficient (r=0.81,P<0.001) was found between S-BGP and m which could be predicted with an error of 3.4 mmol Ca/day. S-BGP showed a closer correlation to S-L-AP (r=0.71,P<0.001) than to S-T-AP (r=0.58,P<0.01). We concluded that S-L-AP predicts bone mineralization at organ level better than S-T-AP in selected metabolic bone disorders and that the supernatant activity shows no relation to bone turnover. We find the assay easy to handle and suitable for large-scale use in the diagnosis and monitoring of metabolic bone disease.

Sequential Treatment of Severe Postmenopausal Osteoporosis After Teriparatide: Final Results of the Randomized, Controlled European Study of Forsteo (EUROFORS)

It is unclear which treatment should be given after stopping teriparatide therapy for severe osteoporosis. In a prospective, randomized, controlled, 2‐yr study, we compared BMD effects and clinical safety of three follow‐up treatments (anabolic with teriparatide, antiresorptive with raloxifene, or no active treatment) after 1 yr of teriparatide. Postmenopausal women with osteoporosis and a recent fragility fracture received open‐label teriparatide (20 μg/d) for 12 mo before they were randomized (3:1:1) to continue teriparatide (n = 305), switch to raloxifene 60 mg/d (n = 100), or receive no active treatment for the second year (n = 102). All patients received calcium and vitamin D supplementation. Changes in areal BMD from baseline to 24 mo were analyzed using mixed‐model repeated measures. Daily teriparatide treatment for 2 yr significantly increased spine BMD by 10.7%. Patients receiving raloxifene in year 2 had no further change in spine BMD from year 1 (change from baseline, 7.9%), whereas patients receiving no active treatment had a BMD decrease of 2.5% in year 2 (change from baseline, +3.8%). At the total hip, BMD increases from baseline at 2 yr were 2.5% with teriparatide, 2.3% with raloxifene, and 0.5% with no active treatment; the respective changes at the femoral neck were 3.5%, 3.1%, and 1.3%. The study had insufficient power to assess antifracture efficacy. In conclusion, BMD increases progressively over 2 yr of teriparatide therapy in women with severe osteoporosis. After discontinuation of teriparatide, raloxifene maintains spine BMD and increases hip BMD.

Effects of strontium ranelate on spinal osteoarthritis progression

Objective: The aim of this study was to determine whether a 3-year treatment with strontium ranelate could delay the progression of spinal osteoarthritis (OA). Methods: This study was a post-hoc analysis of pooled data from the Spinal Osteoporosis Therapeutic Intervention (SOTI) and TReatment Of Peripheral OSteoporosis (TROPOS) trials performed on 1105 women with osteoporosis and concomitant radiological spinal OA at baseline, and for whom lumbar x-rays were available at baseline and over the 3-year treatment period. The presence and severity of osteophytes, disc space narrowing and sclerosis in the lumbar intervertebral spaces was graded according to a validated method, and an overall OA score was calculated for each intervertebral space. Back pain (measured on a five-point Likert scale only in SOTI) and health-related quality of life (SF-36 questionnaire) were assessed at baseline and after 3 years. Patients who suffered an incident or progressive vertebral fracture during the study were excluded from the analysis. Results: The proportion of patients with worsening overall spinal OA score was reduced by 42% in the strontium ranelate group, compared with placebo (RR, 0.58; 95% CI, 0.42 to 0.79; p = 0.0005). Significantly more patients in the strontium ranelate group experienced an improvement in back pain after 3 years, compared with placebo (p = 0.03), while no significant difference was observed in terms of health-related quality of life between these patient groups. Conclusions: The results of this post-hoc analysis suggest that strontium ranelate could reduce the progression of the radiographic features of spinal OA and back pain in women with osteoporosis and prevalent spinal OA.