In our prospective case-cohort study, we found that men with the lowest total 25(OH)D concentration (<19.9 ng/mL) at study entry had a significantly increased risk for subsequent hip fractures during the next 5 years over men with the highest concentrations (≥27.9 ng/mL). A similar association was observed between vitamin D3 and hip fracture, but vitamin D2 was unrelated to hip fractures. Vitamin D concentrations were not related to risk of any nonspine fractures, suggesting an association with more frailty-related fractures.
To our knowledge, few studies have examined the relationship between total 25(OH)D and fractures in older men. Five of 12 case-control studies included men, and all reported lower 25(OH)D levels in men with acute hip fracture compared with controls.(5
) Only three prospective studies included men. Woo (21
) studied 427 patients, including 171 men. Subjects who experienced an incident fracture had lower total 25(OH)D levels, but the relationship was not significant. The association between total 25(OH)D and fracture was studied in 730 incident fracture patients (155 men) and 1445 matched controls (309 men).(6
) There was no evidence of an association between 25(OH)D and fracture in men or women. These results are consistent with our findings that 25(OH)D concentrations were unrelated to all nonspine fractures. There were too few hip fractures (n
= 5) to examine hip fractures separately.
Our hip fracture results are consistent with a report from the Third National Health and Nutrition Examination Survey (NHANES III), in which the relative risk for hip fracture was significantly reduced in subjects with 25(OH)D concentrations greater than 25 ng/mL.(7
) This study included 62 men with hip fractures and 869 control men, but results were not stratified by gender. Our results also are consistent with a recent report in women that low total serum 25(OH)D levels are associated with an increased risk of hip fracture.(22
We studied several possible mechanisms whereby 25(OH)D concentrations may influence hip fracture risk. The increased fracture risk could be related to impaired muscle strength and balance and poor health status, all of which could increase the risk of falls and subsequently fracture.(8
) Inclusion of health status or neuromuscular function reduced the HR by 10% and 18%, respectively, meeting our criteria for mediation. Lower bioavailability of vitamin D in obese patients and inverse associations between 25(OH)D and adiposity have been reported.(23
) Low fat mass and body weight have been linked to an increased risk of hip fracture.(26
) Hence the higher degree of adiposity in men with the lowest 25(OH)D levels could confound our results. Adjusting for percent body fat in our analyses resulted in a 22% attenuation in the HR association. Surprisingly, addition of falls had little effect on the relationship between 25(OH)D and hip fracture, perhaps because we assessed falls at baseline and did not adjust for falls over the follow-up period.
Low circulating vitamin D has been shown to affect bone strength.(1
) Vitamin D deficiency in milder forms can lead to secondary hyperparathyroidism and subsequently faster rates of bone turnover and bone loss. Positive relationships have been observed between serum 25(OH)D and BMD.(27
) Adjustment for BMD attenuated the association between total 25(OH)D and hip fracture such that the overall trend was borderline significant. Adjustment for BMD completely attenuated the relationship bewteen vitamin D3
level and hip fracture. This suggests that the association between low vitamin D level and increased hip fracture risk is at least in part due to lower hip BMD among the men with low vitamin D levels. This result differs from the NHANES III study, where the relationship between 25(OH)D and hip fracture was independent of BMD.(7
) Low BMD is associated with an increased risk of all nonspine fractures,(29
) and if BMD is the mediator, it is somewhat surprising that there was no relationship between 25(OH)D and nonspine fracture. The relationship between BMD and nonspine fracture is, however, weaker than for hip fracture. Further studies are needed to confirm the mechanism underlying the association of 25(OH)D and hip fracture. In particular, future studies should include markers of bone turnover. In women, we observed that high bone resorption may be an important mechanism for the association between low 25(OH)D and hip fracture.(22
The optimal serum 25(OH)D concentration needed to maintain bone health has not been established. Optimal concentrations have been defined as those at which serum parathyroid hormone levels plateau in the normal range;(30
) however, this definition has led to a wide range of optimal 25(OH)D concentration thresholds (8–46 ng/mL). More recently, the optimal threshold concentration of 25(OH)D, based on BMD levels, was found to be at least 31 ng/mL, with a target of 37–42 ng/mL.(28
) Randomized trials of vitamin D supplementation that brought mean serum 25(OH)D concentrations up to 30–41 ng/mL found significantly lower fracture rates.(31
) Trials in which the mean serum 25(OH)D concentration did not reach this threshold showed no effect on fractures.(32
) Our results showed the greatest risk of hip fracture among men with a 25(OH)D level of less than 19.9 ng/mL, consistent with our recent findings among older women.(22
) This suggests a somewhat lower threshold for defining “optimal” levels by hip fracture risk, although the threshold model was not significant, and we had limited power to detect a threshold.
Our study is unique in the measurement of total 25(OH)D, vitamin D2
, and vitamin D3
. Results generally were similar between total 25(OH)D and vitamin D3
, albeit a bit weaker for vitamin D3
. We found no relationship with vitamin D2
, but the majority of men did not have measurable vitamin D2
. The major determinant of having measurable vitamin D2
was self-report of vitamin D supplements.(19
) At the time that the serum was collected, vitamin D supplementation was limited primarily to vitamin D2
. This implies that the level of supplement used by these men was ineffective in preventing hip fractures. Nevertheless, the clinical advantage of measuring both vitamin D2
and vitamin D3
separately is uncertain and has been shown to cause some clinical confusion.(34
) Results were strongest for total 25(OH)D, and it is currently recommended that separate reporting should not be carried out until the clinical utility has been demonstrated.
Our study has several limitations. Nonwhite men are more likely to be vitamin D deficient;(17
) however, most of the fractures occurred in white men. We do not have measures of parathyroid hormone, which could contribute to the relationship between 25(OH)D and hip fracture.(1
) Finally, few men had 25(OH)D concentrations greater than 30 ng/mL, so we could not test whether even higher concentrations offer greater protection against hip fracture.
Despite these limitations, we conclude that low serum 25(OH)D concentrations are associated with an increased risk of hip fracture in community-dwelling men. Low BMD may contribute to this association. Similar to our results in older women,(22
) our findings suggest that low serum 25(OH)D concentrations may help to identify men at high risk of hip fracture.