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Letter to the Editor |
Department of Medicine (K.S., D.C.B.), Division of Endocrinology and Metabolism (D.S.), and Department of Epidemiology and Biostatistics (D.C.B., S.R.C.), University of California, San Francisco, California 94105; and California Pacific Medical Center Research Institute (S.R.C.), San Francisco, California 94115
Address correspondence to: Katie L. Stone, Ph.D., University of California, San Francisco, 74 New Montgomery Street, Suite 600, San Francisco, California 94105. E-mail: Kstone{at}psg.ucsf.edu.
To the editor:
In our cohort of women aged 65 and older, we found that women with lower serum vitamin B12 levels experience more rapid bone loss from the hip than women with higher levels of vitamin B12 (1). Specifically, participants with baseline serum vitamin B12 levels no greater than 280 pg/ml (207.2 pmol/liter) experienced an average rate of total hip bone loss of 1.6% (0.2 to 2.8%) annually compared with a loss rate of 0.2% (–0.2% to 0.5%) among women with levels above 280 pg/ml.
Drs. Cagnacci et al. (2) make reference to their own recently published cross-sectional study linking serum folate levels, but not vitamin B12 levels, to spine bone mineral density (BMD) in younger postmenopausal women (3) and question whether we may have found folate levels, had we measured them, to be more strongly associated with rates of hip bone loss in our cohort. Unfortunately, this question cannot be answered based on available data. Despite previous studies supporting a direct effect of B12 deficiency (4), we emphasize in our manuscript that other unmeasured dietary correlates of vitamin B12 intake may account for the observed association between serum vitamin B12 levels and rates of bone loss. Only a randomized trial will provide definitive evidence of a causal association of vitamin B12 (or folate) levels with reduction in rates of bone loss or fracture.
In addition, we would like to point out several important differences between our study and the study of Cagnacci et al. (3). Our study is prospective, with rates of change in hip BMD as the primary outcome. In contrast, the Cagnacci study was cross-sectional, with spine BMD as the outcome. Furthermore, our population is considerably older than that of Cagnacci et al. (3). This is an important distinction given that B12 deficiency, although rare in younger healthy people, is considerably more prevalent in the elderly (5, 6). These fundamental differences in both study population and design could easily explain the apparent divergence in results of the two studies.
Cagnacci et al. (3) have also questioned why we did not observe a significant trend in rates of bone loss across quintiles of vitamin B12 levels. We disagree that this would be the expected result. Tissue deficiency of vitamin B12 may only occur when levels fall below a particular threshold. Above that threshold, there may be no benefit of having higher levels of B12. Therefore, we appropriately examined both linear and threshold relationships of vitamin B12 and bone loss. Because there is a lack of consensus as to what level of B12 should be considered as clinically low, we chose to use the lowest quintile (
280 pg/ml in our cohort). We believe that this is reasonable because it has been demonstrated that many individuals with tissue deficiency of B12 have serum B12 levels in what might be considered in the low-normal range (200–300 pg/ml) (5).
Finally, Cagnacci et al. (3) have pointed out that vitamin B12 plays a role in homocysteine metabolism, and given the evidence of association of genetic hyperhomocysteinemia with skeletal abnormalities, this could be a potential mechanism for the relationship of low vitamin B12 and rates of bone loss. We agree that it would have been useful to also have homocysteine measures in our cohort, particularly given recent data on homocysteine levels and fracture (7), and we mentioned this limitation in the discussion. Although we hope that future studies will further the understanding of the mechanism for the relationship between vitamin B12 and bone outcomes, this was beyond the scope of our observational study. Nonetheless, before any formal recommendations can be made concerning supplementation with vitamin B12 or folate for prevention of bone loss, supporting evidence from randomized trials is needed.
Received June 9, 2004.
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