Response to Letters by Lee and Greenfield, and Tsuda
In response to the valuable comment of Drs Lee and Greenfield, we analyzed statin use in the LUdwigshafen RIsk and Cardiovascular Health (LURIC) study1 and found significantly reduced statin use in patients who developed fatal stroke (31.0%) when compared to survivors (47.7%; P=0.037 for χ2 test). 25(OH)D levels were, however, not significantly different in persons using (median [with interquartile range]: 39.7 [25.9 to 57.4] in nmol/L) and not using statins (39.7 [24.7 to 57.2]; P=0.957 for ANOVA). This does not support the hypothesis that beneficial effects of statins are mediated by an increase in 25(OH)D levels.2 Furthermore, low z values of 25(OH)D and 1,25-dihydroxyvitamin D [1,25(OH)2D]1 remained significantly associated with fatal stroke after adjustment for statin use, age, sex, high-density and low-density lipoprotein cholesterol, smoking status, body mass index, C-reactive protein, glomerular filtration rate, arterial hypertension, diabetes mellitus and N-terminal pro–B-type natriuretic peptide: odds ratio per z value (with 95% CI) was 0.67 (0.48 to 0.94) for 25(OH)D (P=0.021) and 0.71 (0.52 to 0.97) for 1,25(OH)2D (P=0.031). In conclusion, we did not observe a confounding effect of statin use for the association between vitamin D deficiency and risk of fatal stroke.
Referring to the interesting comment of Dr Tsuda we evaluated the association between serum vitamin D levels and hypertension in the LURIC study.1 25(OH)D levels were significantly reduced in patients with arterial hypertension (n=2397) when compared to normotensive study participants (n=902; 38.2 [24.7 to 56.7] versus 42.1 [26.4 to 59.2] in nmol/L; P=0.002 for ANOVA) but significance was lost after adjustment for age (P=0.326). 1,25(OH)2D levels were not significantly different in patients with and without arterial hypertension (86.3 [65.5 to 111.2] versus 85.8 [66.3 to 113.1] in pmol/L; P=0.344 for ANOVA). Thus, our findings are not in line with previous longitudinal studies showing that vitamin D deficiency is independently associated with incident hypertension.3 Our observations, however, are only cross-sectional and may be limited and/or biased by the high prevalence of advanced vascular and myocardial morbidity in our study participants.1,4 Dr Tsuda also outlined the association between low bone mineral density and increased risk of stroke in previous studies.5,6 We did not measure bone mineral density in our study but determined serum β crosslaps, a routine clinical biomarker indicating bone resorption activity, in 3244 (98%) of our study participants. Age- and sex-adjusted correlation analyses showed that 25(OH)D and 1,25(OH)2D levels were significantly and inversely correlated with serum β crosslaps with a partial Pearson correlation coefficient of −0.085 (P<0.001) and −0.051 (P=0.003), respectively. Serum β crosslaps were not significantly different in patients with (n=267) and without a history of previous cerebrovascular events (n=2977; 0.30 [0.20 to 0.47] versus 0.31 [0.21 to 0.45] in ng/mL; P=0.963 for logistic regression analysis). However, patients who died from stroke during follow-up (n=40) had significantly elevated β crosslaps compared to the remaining study cohort (n=3180; 24 patients lost during follow-up; 0.38 [0.24 to 0.60] versus 0.31 [0.21 to 0.45] in ng/mL; P=0.027 for logistic regression analysis). This association remained significant after adjustment for age and sex (P=0.039) and after additional adjustments for high-density and low-density lipoprotein cholesterol, smoking status, body mass index, C-reactive protein, glomerular filtration rate, arterial hypertension, diabetes mellitus and N-terminal pro–B-type natriuretic peptide (P=0.041). Thus, our results show a significant association between bone resorption activity and the risk of fatal stroke, warranting confirmation and more in-depth investigation in future studies. We are of course aware that the causality of the relationship between vitamin D status, bone resorption activity and stroke risk still remains to be further analyzed in randomized controlled trials, but our results as well as the fact that a sufficient vitamin D status is also important for optimal bone cell function and matrix mineralization supports the notion that vitamin D supplementation should be included in a multifactorial approach aiming at the prevention of cerebrovascular disease.
Pilz S, Dobnig H, Fischer JE, Wellnitz B, Seelhorst U, Boehm BO, März W. Low vitamin D levels predict stroke in patients referred to coronary angiography. Stroke. 2008; 39: 2611–2613.
Forman JP, Giovannucci E, Holmes MD, Bischoff-Ferrari HA, Tworoger SS, Willett WC, Curhan GC. Plasma 25-hydroxyvitamin D levels and risk of incident hypertension. Hypertension. 2007; 49: 1063–1069.
Pilz S, März W, Wellnitz B, Seelhorst U, Fahrleitner-Pammer A, Dimai HP, Boehm BO, Dobnig H. Association of vitamin D deficiency with heart failure and sudden cardiac death in a large cross-sectional study of patients referred for coronary angiography. J Clin Endocrinol Metab. 2008; 93: 3927–3935.
Browner WS, Pressman AR, Nevitt MC, Cauley JA, Cummings SR, for the Study of Osteoporotic Fractures Research Group. Association between low bone density and stroke in elderly women: the study of Osteoporotic Fractures. Stroke. 1993; 24: 940–946.
Jorgensen L, Engstad T, Jacobsen BK. Bone mineral density in acute stroke patients: low bone mineral density may predict first stroke in women. Stroke. 2001; 32: 47–51.