Kari Salovaara

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.

Effect of vitamin D3 and calcium on fracture risk in 65‐ to 71‐year‐old women: A population‐based 3‐year randomized, controlled trial—the OSTPRE‐FPS

Antifracture efficacy of high‐dose vitamin D (800 IU) and calcium (1000 mg) remains controversial. To determine whether daily 800 IU of vitamin D and 1000 mg of calcium supplementation prevents fractures, we randomized 3432 women of the population‐based Osteoporosis Risk Factor and Prevention (OSTPRE) Study cohort (ages 65 to 71 years) living in the region of northern Savonia, Finland (latitude 62° to 64°N) for 3 years to receive 800 IU of cholecalciferol and 1000 mg of calcium as calcium carbonate or to a control group that did not receive placebo. The main outcome measure was incident fractures. Fracture data were collected in telephone interviews and validated. Data on 3195 women, 1586 in the intervention group and 1609 in the control group, were available for analysis. In adjusted Cox proportional hazards models, the risk of any fracture decreased in the vitamin D and calcium group by 17% [adjusted hazard ratio (aHR) = 0.83; 95% confidence interval (CI) 0.61–1.12], and the risk of any nonvertebral fracture decreased by 13% (aHR = 0.87; 95% CI 0.63–1.19). The risk of distal forearm fractures decreased by 30% (aHR = 0.70; 95% CI 0.41–1.20), and the risk of any upper extremity fractures decreased by 25% (aHR = 0.75; 95% CI 0.49–1.16), whereas the risk of lower extremity fractures remained essentially equal (aHR = 1.02; 95% CI 0.58–1.80). None of these effects reached statistical significance. In conclusion, this study did not produce statistically significant evidence that vitamin D and calcium supplementation prevents fractures in a 65‐ to 71‐year‐old general population of postmenopausal women.

Physical activity slows femoral bone loss but promotes wrist fractures in postmenopausal women: A 15-year follow-up of the OSTPRE study

Results on fracture risk among physically active persons are contradictory. The aim of this study was to investigate the long‐term association between the self‐reported physical activity (PA), the risk of fractures, and bone loss among peri‐ and postmenopausal women. The association between PA and fracture risk was examined during 15 years of follow‐up in the population‐based Osteoporosis Risk Factor and Prevention (OSTPRE) Study among 8560 women with a mean age of 52.2 years (range 47 to 56 years) at baseline. The amount and type of PA, as well as the types and mechanisms of fractures, were registered with self‐administered questionnaires at 5‐year intervals (ie, 1989, 1994, 1999, and 2004). A total of 2641 follow‐up fractures were verified in 2073 women (24.2%). The study cohort was divided into quartiles by average hours of reported PA during the whole follow‐up. Areal bone mineral density (aBMD) at the proximal femur (n = 2050) and lumbar spine (L2–L4; n = 1417) was followed at 5‐year intervals from a random stratified subsample with dual X‐ray absorptiometry (DXA). Risk of fracture was estimated by using the Cox proportional hazards model with a mean follow‐up time of 15.2 years. Weekly average time spent on leisure‐time PA was 0.4, 1.7, 3.3, and 7.0 hours from the least to the most active quartiles, respectively. The risk of wrist fracture was higher in the active quartiles (II to IV) than in the most inactive quartile (I), with hazard ratios (HRs) of 1.3 [95% confidence interval (CI) 1.05–1.57, p = .014] for the second (II), 1.2 (95% CI 1.01–1.51, p = .045) for the third (III), and 1.4 (95% CI 1.14–1.69, p = .001) for the fourth (IV) quartile, respectively. Overall, most of the fractures were reported as a result of a fall (69.0%), with a 2.1 times higher rate of wrist fractures during the winter (November to April) than during summer season. There were no significant associations of PA with any other fracture types. Bone loss at the femoral neck, trochanter, and Wards triangle was significantly associated with long‐term PA (ANCOVA p < .05), whereas no associations of bone loss and PA in lumbar spine were seen. PA is associated with a moderate rise in wrist fracture risk, which might be explained in part by a higher number of outdoor activities. Regular PA of at least 1½ hours per week does not seem to increase the risk of other fractures and might significantly decrease proximal femur bone loss among peri‐ and postmenopausal women.

Physical tests for patient selection for bone mineral density measurements in postmenopausal women

INTRODUCTION There is a need for cost-effective clinical methods to select women for bone densitometry. The aim of the present study was to determine whether relatively simple and clinically applicable physical tests could be useful in prediction of bone density in postmenopausal women. METHODS A total of 606 women (age range 66-71 years) taking part in the population based OSTPRE Fracture Prevention Study were investigated. Spinal and femoral bone mineral density (BMD) was measured by Dual X-ray Absorptiometry (DXA). Physical tests included the standing-on-one-foot (SOOF), grip strength (GS), leg extension strength, ability to squat down, standing 10 s eyes closed, chair rising, regular walk for 10 m and tandem walk for 6 m. All linear regression models were adjusted for age, body mass index, years on hormone therapy, years since menopause, current smoking and use of oral glucocorticoids. RESULTS The SOOF was associated with lumbar spine BMD (r2=0.16, p=0.004) and the femoral regions (r2 values from 0.17 to 0.23 and p-values all<0.001). The GS was associated with lumbar spine BMD (r2=0.16, p=0.011) and the femoral regions (r2 values from 0.16 to 0.21 and p-values from <0.001 to 0.004). The ability to squat down on the floor was associated with the femoral regions (r2 values from 0.15 to 0.21 and p-values from 0.028 to 0.040). In addition, functional capacity was decreased in women with femoral neck osteoporosis (WHO classification) compared to women with normal or osteopenic BMD: SOOF -39% (p=0.001), GS -18% (p<0.001), leg extension strength -19% (p=0.007) and ability to squat down on the floor -40% (p=0.004). For osteoporosis prediction (ROC analysis) a threshold of a 22 kg in GS would yield a true-positive rate (sensitivity) of about 58% and a true-negative rate (specificity) of 86% (AUC 0.76). CONCLUSIONS We suggest that grip strength could be used in medical decision making to identify those women who would benefit from BMD measurements albeit alone it may not provide accurate enough tool for osteoporosis screening.

Bone Loss Rate May Interact with Other Risk Factors for Fractures among Elderly Women: A 15-Year Population-Based Study

Aim was to investigate fracture risk (FR) according to bone loss (BL) rate. A random sample of 1652 women aged 53.5 years was measured with dual X-ray absorptiometry in femoral neck in 1989 and 1994 and divided into tertiles of annual BL rate: high >0.84%, moderate 0.13%–0.84%, and low <0.13%. Low trauma energy fractures during following 10 years were recorded. There were no differences in FR between BL tertiles in Cox regression model. Factors predicting lower FR in Cox model were in high tertile: high T-score (HR 0.71; 95% CI 0.54–0.93, P = .012), no sisters fracture (HR 0.35; 0.19–0.64, P = .001), no mothers fracture (HR 0.52; 0.31–0.88, P = .015), in moderate tertile: high T-score (HR 0.69;0.53–0.91, P = .008) and good grip strength (HR 0.98; 0.97–0.99, P = .022). In low tertile there were no predictors for FR. BL predicted FR in women with mothers fracture in univariate and multivariate model (OR 2.6; 1.15–5.7, P = .021) but with sisters fracture this was observed only in multivariate model (OR 2.66; 1.09–6.7, P = .039). Accordingly, the risk factors for postmenopausal fractures, especially mothers fracture, may interact with BL.

Bone health-related factors and the use of bisphosphonates in community setting—15-year follow-up study

SummaryThe present study investigated the bone health related factors that were associated with the use of bisphosphonates (BP) among 2,050 postmenopausal Finnish women. Low BMD + low trauma energy fracture was the strongest determinant of BP use, while other secondary causes of osteoporosis were less strongly related with BP use. BP use was associated with reduced femoral neck (FN) and lumbar spine (LS) bone loss rate.IntroductionThe aim was to identify bone health related factors associated with the use of BP in a community setting.MethodsA population-based sample of 2,050 Finnish postmenopausal women was measured with dual X-ray absorptiometry at the FN and LS in 1989, 1994, 1999 and 2004, and information on osteoporosis risk factors, including low-trauma energy fractures, were collected with postal inquiries. Self-reported use of BP in 2004 was considered as the end point variable.ResultsAmong BP users, 12% had T-score > −2.0 SD and no fracture during follow-up (FU). In women without any bone medication, 26% had T-score < −2.0 SD or low-trauma energy fracture or both during the FU. In BP users, a significant reduction in FN and LS bone loss rate, cumulative with duration of use, was observed in ANCOVA (p < 0.001). Among BP users, there was a significantly higher proportion of women with several independent risk factors for osteoporosis and more spine and humerus fractures but less ankle fractures. T-score < −2 SD combined with low-trauma energy fracture was significantly related to the use of BPs (p < 0.001, OR = 15.96) and T-score < −2 SD was a stronger predictor of BP use (p < 0.001, OR = 13.29) than fracture (p > 0.05, OR = 1.35) in multivariate logistic regression. Other factors related with BP use were vitamin D use (p = 0.001, OR = 2.27), high number of medications (p < 0.001, OR = 1.26) and rheumatoid arthritis (p < 0.05, OR 2.55).ConclusionsThese findings reveal the recent bone health-related indications for BP prescription.

Response to understanding power calculations in clinical trials

We would like to thank Professor Prince and colleagues for their interest and their comments on our recently published article on calcium and vitamin D. Quite justified, they bring forward some problems of our trial that are also often present in investigator-initiated trials. For the most part, we agree. In fact, what they conclude of the results of the trial is correct and brought to more understandable form for possible users of the intervention. The result is still negative. But whenever relative risk is estimated, even a negative result can be interpreted in terms of confidence intervals. In our article, this interpretation was left to the reader. The number of subjects filling our inclusion criteria (including age 65 years) was larger than our power analysis would require. However, we wanted to maintain the population-based approach of the previously existing OSTPRE cohort and decided not to further restrict the population. Therefore, the number of subjects enrolled was larger than preplanned. Unfortunately, the