Haakon E. Meyer

A Pooled Analysis of Vitamin D Dose Requirements for Fracture Prevention

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 participants 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.).

Diabetes mellitus and the incidence of hip fracture: results from the Nord-Trøndelag Health Survey.

Aims/hypothesis. To study if people with Type I (insulin-dependent) or Type II (non-insulin-dependent) diabetes mellitus have increased risk of hip fracture. Methods. The study population consisted of 35 444 people 50 years of age and older, attending a health screening in a Norwegian county. They were followed up with respect to hip fracture for 9 years, and 1643 new hip fractures were recorded. Results. The relative risk of hip fracture for women with Type I diabetes compared with women without diabetes was 6.9 (95 % confidence interval 2.2–21.6) adjusted for age, body mass index and daily smoking. The relative risk for men was nearly the same, but not statistically significant. Among women 50–74 years of age with Type II diabetes for more than 5 years, the relative risk was 1.8 (95 % confidence interval 1.1–2.9). This increased risk persisted when insulin-treated women were excluded from the analysis. After additional adjustment for possible medical consequences of diabetes (impaired vision, impaired motor abilities and history of stroke) the relative risk among women 50–75 years of age with Type II diabetes was reduced to 1.5 (95 % confidence interval 0.9–2.5). Conclusion/interpretation. We found an increased risk of hip fracture in women younger than 75 years with Type I diabetes or with Type II diabetes of long duration. In older men, there was an increased risk associated with Type II diabetes of shorter duration. Whether the increased risk is attributed to reduced bone mass or to factors associated with falling has not been determined. [Diabetologia (1999) 42: 920–925]

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.

Survival after Hip Fracture: Short- and Long-Term Excess Mortality According to Age and Gender

Abstract: The purpose of this study was to analyze the excess mortality after hip fracture and to reveal whether, and eventually when, the excess mortality vanished in different groups of age and gender. A population-based, prospective, matched-pair, cohort study among persons 50 years of age and older was conducted involving 1338 female and 487 male hip fracture patients with 11 086 and 8141 controls respectively. Occurrence of hip fracture and mortality were recorded from 1986 until 1995. We studied the excess mortality of the hip fracture patients versus controls by using Kaplan–Meier curves and extended Cox regression with hip fracture (yes/no) as time-dependent covariate. The male hip fracture patients had higher mortality than the women the first year after the injury, irrespective of age, both in absolute terms (31% and 17% respectively) and relative to their age-matched controls. The relative risk (RR) of dying within 1 year for hip fracture patients versus controls was 3.3 (95% confidence interval (CI) 2.1–5.2) for women and 4.2 (95% CI 2.8–6.4) for men below 75 years of age. The corresponding figures for persons 85 years and older were 1.6 (95% CI 1.2–2.0) for women and 3.1 (95% CI 2.2–4.2) for men. All groups of age and gender, except women 85 years and older, had a large and significant excess mortality lasting for many years after the hip fracture – at least 5–6 years for women below 75 years of age (RR = 3.2, 95% CI 1.9–5.6). The excess mortality after hip fracture for women 85 years and older had vanished after 3 months (RR = 1.0, 95% CI 0.8–1.1). When referring to the excess mortality after hip fracture it is therefore necessary to specify sex, age and time since injury.

Epidemiology of hip fractures in Oslo, Norway

The incidence of hip fractures in Oslo has shown a secular increase during the past decades. The main aims of the present study were to report the current incidence of hip fractures in Oslo and to determine whether there is a seasonal variation in the occurrence of fractures. Using the electronic diagnosis registers and the lists of the operating theater for the hospitals in Oslo with somatic care, all patients with ICD-9 code 820.X (hip fracture) from May 1, 1996 to April 30, 1997 were identified. Medical records for all identified patients were obtained and diagnosis was verified. Using the population of Oslo on January 1, 1997 as the population at risk, the age- and gender-specific annual incidence rates were calculated. These rates were compared with those for 1988/89 and 1978/79. Outdoor temperature data for Oslo were obtained to study the relation between temperature and number of hip fractures. A total number of 1316 hip fractures was included, of which 78% occurred in women. An exponential increase in incidence with age was observed in both genders. The age-adjusted fracture rates per 10,000 for the age group > or =50 years were 118.0 and 44.0 in 1996/97, 124.3 and 44.9 in 1988/89, and 104.5 and 35.8 in 1978/79 for women and men, respectively. There was no significant seasonal variation in the incidence of hip fractures and no correlation between mean outdoor temperature and number of fractures for each month in 1996/97. The data show that the incidence of hip fractures in Oslo has not changed significantly during the last decade, and it is still the highest reported. The cold climate of Oslo does not seem to contribute to the high incidence.

Can vitamin D supplementation reduce the risk of fracture in the elderly? A randomized controlled trial.

Randomized controlled trials have shown that a combination of vitamin D and calcium can prevent fragility fractures in the elderly. Whether this effect is attributed to the combination of vitamin D and calcium or to one of these nutrients alone is not known. We studied if an intervention with 10 μg of vitamin D3 per day could prevent hip fracture and other osteoporotic fractures in a double‐blinded randomized controlled trial. Residents from 51 nursing homes were allocated randomly to receive 5 ml of ordinary cod liver oil (n = 569) or 5 ml of cod liver oil where vitamin D was removed (n = 575). During the study period of 2 years, fractures and deaths were registered, and the principal analysis was performed on the intention‐to‐treat basis. Biochemical markers were measured at baseline and after 1 year in a subsample. Forty‐seven persons in the control group and 50 persons in the vitamin D group suffered a hip fracture. The corresponding figures for all nonvertebral fractures were 76 persons (control group) and 69 persons (vitamin D group). There was no difference in the incidence of hip fracture (p = 0.66, log‐rank test), or in the incidence of all nonvertebral fractures (p = 0.60, log‐rank test) in the vitamin D group compared with the control group. Compared with the control group, persons in the vitamin D group increased their serum 25‐hydroxyvitamin D concentration with 22 nmol/liter (p = 0.001). In conclusion, we found that an intervention with 10 μg of vitamin D3 alone produced no fracture‐preventing effect in a nursing home population of frail elderly people.

Factors Associated with Mortality after Hip Fracture

Abstract: There is a well-known excess mortality subsequent to hip fracture, which is probably restricted to subgroups of hip fracture patients with reduced health status. We studied the association between risk factors and death in 248 hip fracture patients and 248 controls originally enrolled in a population-based case–control study. This cohort was followed for 3 1/2 years with respect to total mortality. A markedly increased mortality was found in hip fracture patients passing a mental status test at a low score [relative risk (RR) = 2.3, 95% confidence interval (CI) 1.4-3.7], in hip fracture patients reporting two or more selected chronic diseases (RR = 3.3, 95% CI 1.8–6.1), in hip fracture patients not walking outdoors before the fracture (RR = 3.2, 95% CI 2.0–5.1) and in hip fracture patients in the lower half of handgrip strength distribution (RR = 2.3, 95% CI 1.6–3.4), all compared with the control group. In contrast, hip fracture patients without these risk factors did not have increased mortality compared with the control group. This study suggests that otherwise healthy and fit patients do not have increased mortality subsequent to hip fracture. The excess mortality is restricted to persons with reduced mental status, reduced somatic health and low physical ability. Special attention should be paid to patients with such risk factors in the treatment and rehabilitation period.

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.

Prevalence and predictors of vitamin D deficiency in five immigrant groups living in Oslo, Norway: the Oslo Immigrant Health Study

Objective: To study the prevalence of vitamin D deficiency and to identify possible predictors of vitamin D deficiency in five main immigrant groups in Oslo.Design: Cross-sectional, population-based.Setting: City of Oslo.Subjects: In total, 491 men and 509 women with native countries Turkey, Sri Lanka, Iran, Pakistan and Vietnam living in the county of Oslo.Results: Median serum 25(OH)D level (s-25(OH)D) was 28 nmol/l, ranging from 21 nmol/l in women born in Pakistan to 40 nmol/l in men born in Vietnam. Overall prevalence of vitamin D deficiency defined as s-25(OH)D<25 nmol/l was 37.2%, ranging from 8.5% in men born in Vietnam to 64.9% in women born in Pakistan. s-25(OH)D did not vary significantly with age. s-25(OH)D was higher in blood samples drawn in June compared to samples obtained in April, but not significantly for women. Reported use of fatty fish and cod liver oil supplements showed a strong positive association with s-25(OH)D in all groups. Education length was positively associated with s-25(OH)D in women, whereas body mass index (BMI) was inversely associated with s-25(OH)D in women. These two variables were not related to vitamin D deficiency in men.Conclusions: There is widespread vitamin D deficiency in both men and women born in Turkey, Sri Lanka, Iran, Pakistan and Vietnam residing in Oslo. The prevalence of vitamin D deficiency is higher in women than in men, and it is higher in those born in Pakistan and lower in those born in Vietnam compared to the other ethnic groups. Fatty fish intake and cod liver oil supplements are important determinant factors of vitamin D status in the groups studied. BMI and education length are also important predictors in women.Sponsorship: Supported by the Directorate for Health and Social Affairs, Oslo, and Research Forum, Aker University Hospital, Oslo.

Reduced mortality among whole grain bread eaters in men and women in the Norwegian County Study.

Objective: To study whether mortality is reduced among whole grain eaters in Norway.Design: Non-interventional, prospective, baseline 1977–1983, followed for mortality through to 1994.Setting: Three Norwegian counties.Subjects: A total of 16 933 men and 16 915 women; systematic screening of all residents aged 35–56 y at baseline, not disabled and free of cardiovascular disease (79% response rate).Predictor variable: We combined self-report of type and number of bread slices (white, light whole grain, dense whole grain) to form a whole grain bread score, with range 0.05 (1 slice per day, made with 5% whole grain flour) to 5.4 (9 slices per day, made with 60% whole grain flour).Results: Norwegian whole grain bread eaters were less likely to be smokers, were more physically active, had lower serum cholesterol and systolic blood pressure, and ate less total and saturated fat as a proportion of energy intake than white bread eaters. After adjustment for age, energy intake, sex, serum cholesterol, systolic blood pressure, smoking, body mass index, physical activity at leisure and work, and use of cod liver oil or other vitamin supplements, hazard rate ratios (HRR) for total mortality were inverse and graded across whole grain bread score categories (category 5 vs category 1 HRR: 0.75, 95% confidence interval 0.63–0.89 in men and 0.66, 0.44–0.98 in women).Conclusion: Protection by whole grain intake against chronic disease is suggested in Norway, where four times as much whole grain is consumed as in the United States.Sponsorship: Institute for Nutrition Research, University of Oslo and National Health Screening Service, Oslo, NorwayEuropean Journal of Clinical Nutrition (2001) 55, 137–143