We read with interest the article by Lu et al. (1), which concluded that a low 25-hydroxyvitamin D [25(OH)D] level was associated with an increased risk of prevalent metabolic syndrome among middle-aged and elderly Chinese men and women. However, as the investigators acknowledge, vitamin D may exert its effects through the regulation of extra- and intracellular calcium. The calcium homeostasis, on the other hand, is tightly regulated by parathyroid hormone (PTH). There is therefore a close relationship between 25(OH)D, calcium, and PTH (2) to the extent that changes in the levels of any one of these biomarkers affect the levels of the others. Unfortunately, PTH and serum calcium were neither measured nor adjusted for in the Chinese study.
Lu et al. partly acknowledge this limitation, arguing that “data from NHANES [National Health and Nutrition Examination Survey] 2003–2004 and the Medical Research Council Ely Prospective Study suggested that the associations between 25(OH)D and insulin resistance and metabolic syndrome were independent of calcium and parathyroid hormone” (1). We argue that this interpretation is partly incorrect. Firstly, Reis et al. (3) confirmed the results from their previous Rancho Bernardo Study by showing in older men a statistically significant increased risk of metabolic syndrome with elevated PTH levels independent of vitamin D levels. Secondly, the Medical Research Council Ely Prospective Study (4) showed that the inverse association between baseline 25(OH)D levels and the metabolic syndrome risk z score was no longer significant after adjustments for PTH, calcium, and IGF-1.
Data from our own cross-sectional study of 1,017 consecutive Caucasian morbidly obese men and women (2) add further support to the hypothesis that PTH is associated with metabolic syndrome. After adjustment for 25(OH)D, magnesium, calcium, phosphate, creatinine, age, sex, season of serum sampling, BMI, current smoking, albuminuria, C-reactive protein, insulin resistance, and type 2 diabetes, patients with PTH levels in the second to fourth quartiles (≥4.4 pmol/l) had higher odds of prevalent metabolic syndrome (odds ratio 1.47 [95% CI 0.92–2.35], 2.33 [1.40–3.87], and 2.09 [1.23–3.56], respectively) than those in the first quartile (<4.4 pmol/l).
A recent Swedish 10-year follow-up study of elderly men (mean age 71 years) (5) showed that plasma PTH level, even in the normal range, was associated with a higher risk of cardiovascular mortality, even after adjustments for established cardiovascular risk factors and vitamin D deficiency.
Future observational studies addressing the association between vitamin D and cardiovascular risk should therefore include PTH and calcium in their analyses. Although a recently published randomized controlled trial (6) could not demonstrate that vitamin D supplementation has a significant effect on the glucose metabolism of subjects with type 2 diabetes, sufficiently powered and well-designed randomized controlled clinical trials (including therapeutic strategies to increase 25[OH]D levels and lower PTH levels, e.g., calcium/vitamin D supplementation or calcimimetics, the therapeutic drugs demonstrated to lower PTH levels through an increase in the intracellular calcium of parathyroid cells) are needed to explore any cause-and-effect relationships.
Acknowledgments
No potential conflicts of interest relevant to this article were reported.
