In our prospective nested case-control study, we found that women with low vitamin D levels, 25(OH) vitamin D<47.6 nM (<19ng/ml), at entry to the study had a significantly greater increased risk of subsequent hip fracture over the next seven years compared to women with levels >70.7 nM (≥23ng/ml) . Testing specific thresholds of < 50 nM (20ng/ml) did not differ significantly from the linear model suggesting a continuous linear relationship between serum 25(OH) vitamin D and hip fracture, at least within the ranges of 25(OH) vitamin D found in this study. The association between 25(OH) vitamin D and hip fracture was observed in both younger (<70) and older (age≥70) women. This observation is clinically important because hip fractures are the most serious consequence of osteoporosis, resulting in substantial morbidity, loss of independence, institutionalism and mortality(32
). Our results suggest that measurement of 25(OH) vitamin D may be useful for identifying women at high risk of hip fracture.
Using an English language Medline search until January 2008, we identified five prospective studies of vitamin D and fracture. Our results are consistent with a recent report from the Third National Health and Nutrition Examination Survey (NHANES III), where the relative risk of hip fracture was 0.64 (0.46−0.89) among subjects with 25(OH) vitamin D levels >60 nM (24 ng/ml) compared to those with lower levels. Similarly, Swedish women with 25(OH) vitamin D <52.5 nM had a two-fold increased risk of fracture(33
). Previous cohort studies which failed to find a significant association between 25(OH) vitamin D and fracture were limited by small sample size and high lost to follow rate(34
) or use of an older assay(35
). A nested case-control study of 730 incident fracture cases and 1,445 controls found no evidence of an association between 25(OH) vitamin D and fracture(6
). However, they studied a heterogeneous group of fractures, including only 22 hip fractures and studied a younger population (mean age ≈ 50). Vitamin D may be more strongly linked to frailty related fractures like hip fractures which tend to occur in much older women.
Vitamin D deficiency can cause secondary hyperparathyroidism, high bone turnover, low bone mineral density and mineralization defects(1
), all of which could contribute to an increased fracture risk. In our study, C-terminal telopeptide of Type I, a marker of bone resorption, tended to be higher among hip fracture cases with the lowest 25(OH) vitamin D , an association that may be driven by higher parathyroid hormone levels in this group(1
). Adjustment for bone resorption resulted in a 18% relative reduction in the odds ratio, suggesting that high bone resorption may in part mediate this association.
The increased fracture risk could also be related to impaired muscle strength and balance, poor physical function, all of which could lead to an increased risk of falls(8
). Hip fracture cases had lower physical function scores and were more likely to be frail. Higher 25(OH) vitamin D was association with a lower likelihood of being frail and higher physical function, but the association between vitamin D and hip fracture was independent of these factors.
In vitro and in vivo studies have also shown that vitamin D may modulate the activity of estrogen compounds in bone cells(36
). Thus, we hypothesized that sex steroid hormones could influence the relationship between 25(OH) vitamin D and hip fracture. Bioavailable estradiol decreased across quartiles of 25(OH) vitamin D in the controls, but this was largely explained by obesity. There was no relationship with testosterone and 25(OH) vitamin D. However, addition of either sex hormone to our models had no effect on our results.
Renal function could affect bone metabolism directly through its effects on vitamin D and parathyroid hormone metabolism(12
). Cystatin C levels were significantly higher in hip fracture cases compared to controls and decreased with increasing 25(OH) vitamin D. Nevertheless, Inclusion of cystatin C in our models did not attenuate the association between 25(OH) vitamin D and hip fracture.
We matched cases and controls on blood draw data, +/−120 days and thus, seasonal variability in 25(OH) vitamin D could have confounded our results. However, the mean difference in blood draw date between cases and controls was 0.27 ± 6.12 days; 99% of cases and controls were matched within one month. Geographic variation in 25(OH) vitamin D has been reported with greater vitamin D deficiency observed in northern latitudes(37
). Women from the northern region (>40 degrees N), had lower 25(OH) vitamin D levels but the relationship between 25(OH) vitamin D and hip fracture was independent of geographic location.
The prevalence of obesity was significantly lower in subjects with the highest 25(OH) vitamin D, consistent with the lower bioavailability of vitamin D reported in obese subjects(38
) and with reports of an inverse association between 25(OH)D and adiposity (39
). Lower 25(OH) vitamin D in obese subjects may reflect lower physical activity (less sunlight exposure) and deposition in body fat compartments(38
). Nevertheless, the association between 25(OH) vitamin D and hip fracture was independent of obesity.
The optimal serum 25(OH) vitamin D needed to maintain bone health is not established. Optimal 25(OH) vitamin D levels have been defined as the level in which serum parathyroid hormone levels plateau in the normal range but this approach has led to a wide range of optimal thresholds (20−115 nM) (41
). More recently, the optimal threshold of 25(OH) vitamin D based on bone mineral density levels was found to be at least 78 nM with a target of 92−105 nM(42
). Randomized trials of vitamin D supplementation (with or without calcium) that brought mean serum 25(OH) vitamin D levels up to 75 nM −102.5 nM found significantly lower fracture rates(43
). Trials in which the mean serum 25(OH) vitamin D did not reach this threshold showed no overall effect on fractures (44
). However, in the largest study to date, a 29% reduction in hip fractures was observed among adherent women, despite not achieving this 25(OH) vitamin D threshold(45
In the WHI Calcium-Vitamin D Trial, no relationship was found between 25(OH) vitamin D and fracture. The characteristics of women in the Calcium-Vitamin D Trial differed from the women in our study. Of importance, over 50% of the women in the Calcium-Vitamin D Trial were on hormone therapy while we excluded women on any bone active agents from this analysis. In addition, different cut points were used and their results were unadjusted.
Strengths of our study include the control for numerous confounders, elimination of hormone use as a confounder, and the ability to explore several mechanisms underlying this association. We used the currently recommended 25(OH) vitamin D assay in a research endocrine laboratory. There are however, several limitations. Minority women are more likely to be vitamin D deficient(46
), but only 20 hip fractures occurred in minority women. Bone mineral density was measured in only three WHI clinics and thus we were unable to test whether the association between low 25(OH) vitamin D and hip fracture is mediated by bone mineral density. In the NHANES III study, the association between 25(OH) vitamin D and hip fracture was independent of bone density(7
). We measured total 25(OH) vitamin D and were unable to distinguish 25(OH) vitamin D2
from 25(OH) vitamin D3.
However, reporting D2
separately has been shown to cause some clinical confusion(47
). We did not measure parathyroid hormone, which could contribute to the relationship between 25(OH) vitamin D and hip fracture. We have few women with 25(OH) vitamin D levels >75 nM so we could not test whether even higher levels offer greater protection against hip fracture risk. We estimated dietary intake of vitamin D using a food frequency questionnaire but few foods contain or are fortified with vitamin D. Circulating 25(OH) vitamin D is standardly used to determine an individual's vitamin D nutritional stores(46
). Finally, we used an observational study design and adjusted for many factors that could confound the association. However, there may be residual confounding by unmeasured factors.
We conclude that low serum 25(OH) vitamin D concentrations are associated with an increased risk of hip fracture in community dwelling women. Measurement of 25(OH) vitamin D may be useful in identifying women at high risk of hip fracture.