Changes in bone mineral density related to changes in serum 25-OH vitamin D concentrations over a two-year period in postmenopausal women

Excerpt

In the NHANES III study involving 13,432 women, the serum 25-OH vitamin D was positively correlated with the bone mineral density of the total hip across the 2nd, 3rd, and 4th quintiles of serum 25-OH vitamin D [1]. When the serum 25-OH vitamin D was less than 52 nmol/L there was a significant loss of bone mineral density from the total hip over the subsequent 3–5 years [2]. The idea that a low serum 25-OH vitamin D might be associated with an excess loss of bone mineral density has led to the performance of several trials in which supplemental vitamin D was given and changes in bone mineral density were measured over time. These trials have been subject to meta-analysis [3]. Twenty-six controlled clinical trials were reviewed. Only three showed a positive effect of supplemental vitamin D on the femoral neck bone mineral density [4‐6] and one showed a beneficial effect on total hip bone mineral density with a dose of 1000 IU of vitamin D per day but not with 400 IU per day [7]. A further study in which vitamin D was given in higher doses to postmenopausal women did not show any significant gain in the bone mineral density in the femoral neck or lumbar spine over 12 months [8]. Recently, our group evaluated the effect of the red clover isoflavone, formononetin, on bone mineral density in postmenopausal women over a 24-month interval in a randomized, placebo-controlled, double-blind format [9]. The serum 25-OH vitamin D was also measured sequentially in all participants. Supplemental vitamin D was not given. One-thousand milligram of calcium carbonate per day was given to all participants. The lumbar spine L2-4, femoral neck, and proximal radius bone mineral density fell significantly in the isoflavone treated and placebo groups and there was no significant difference in the magnitude of the fall between the two groups. The serum 25-OH vitamin D also fell significantly over the 24-month interval in both the isoflavone treated and the placebo group and there was no significant difference between the two groups for the magnitude of the change in the serum 25-OH vitamin D or in the mean values of the serum 25-OH vitamin D in the two groups at time 0. The data for the two groups were combined. The serum 25-OH vitamin D was measured in the majority of the participants using the Nichols Advantage assay (San Clemente, CA, USA), interassay variation 10–14%, and in the last 25 participants using the Diasorin Liaison assay (Saluggia, Italy). The assays were cross-correlated. Diasorin Liaison = 1.07 Nichols Advantage + 18 (r = 0.794). The Nichols Advantage values were transformed into Diasorin Liaison equivalents using the correlation equation. The Nichols Advantage assay has been correlated with an high-performance liquid chromatography method and the correlation coefficient was 0.817 [10]. The Diasorin Liaison assay has been correlated with an liquid chromatography–mass spectrometry method and a good correlation was found (r = 0.985) [11]. Bone mineral density measurements were performed for the AP lumbar spine L2-4 and femoral neck using a Norland XR 36 osteodensitometer (Ft Atkinson, WI, USA), and for the proximal radius using a Norland p DEXA scanner (Ft Atkinson, WI, USA). Both scanners were calibrated and an external phantom (Hologic) used to monitor quality control on a daily basis. Participants had to be at least I year postmenopausal, have a serum Follicle Stimulating Hormone (FSH) >30 U/mL, and a bone density t-score of >−2.0 in the lumbar spine L2-4 and femoral neck. Participants were excluded if hormone replacement therapy had been taken within 2 months of screening for entry into the study, if there was a history of clinical vertebral fracture or other symptomatic minimal trauma fracture,(although an X-ray at time 0 identified thoracic wedge fractures in 3 and a lumbar wedge fracture in 1 included in the study) or if they had an intercurrent medical condition such as celiac disease, primary hyperparathyroidism, renal impairment, thyroid overactivity or metabolic bone disease. At 24 months, on X-ray, 5 participants had an asymptomatic thoracic wedge fracture not present at time 0. Participants were also excluded if they had previously taken bisphosphonates, strontium, fluoride or raloxifene. None of the participants took any of these bone preserving medications during the study (Denosumab had not become available for therapeutic use during the time of the study). Also, none were currently taking corticosteroids, anticonvulsants or other medications, which might affect bone or vitamin D metabolism. In this post hoc analysis of the data, the change in the serum 25-OH vitamin D in individual participants was correlated with the change in bone mineral density in the lumbar spine L2-4, femoral neck, and proximal radius in individual participants. The mean age of the participants was 54 ± 4 years. The mean values for the bone mineral density of the lumbar spine L2-4, femoral neck, and proximal radius and for the serum 25-OH vitamin D at time 0 and 24 months are shown in the Table 1. There was a significant fall in the mean values between 0 and 24 months. The correlation coefficients for the change in the bone mineral density of the lumbar spine L2-4, and proximal radius compared to the change in the serum 25-OH vitamin D in individual participants over 24 months was not significant. The change in the serum 25-OH vitamin D over 24 months was inversely correlated with the change in the bone mineral density of the femoral neck over 24 months (r = −0.292, P = 0.005). This was an unexpected finding. The negative correlation coefficient means that a larger fall in the serum 25-OH vitamin D over 24 months was associated with a smaller fall in the femoral neck bone mineral density. The correlation between the change in the serum 25-OH vitamin D and the change in the femoral neck bone mineral density was re-analyzed using only the serum 25-OH vitamin D values obtained with the Nichols Advantage assay (n = 70). The Spearman rank correlation coefficient was −0.364, P = 0.003. The data were re-analyzed separately for those who received formononetin and for those who received placebo. The Spearman rank correlation coefficients comparing the change in the serum 25-OH vitamin D with the change in the femoral neck bone mineral density were −0.275, P = 0.049, n = 52, and −0.229, P = 0.149, n = 41, respectively (not significantly different). The data were further re-analyzed using tertiles of serum 25-OH vitamin D. The Spearman rank correlation coefficients from the lowest to the highest tertile were 0.042,−0.170, and −0.342 (P = 0.060) indicating that the relationship between the change in the serum 25-OH vitamin D and the change in the femoral neck bone mineral density was more marked at higher levels of serum 25-OH vitamin D (third tertile 110.1–177 nmol/L). The baseline serum 25-OH vitamin D at time 0 was significantly positively correlated with the change in the femoral neck bone mineral density over 24 months (r = 0.269, P = 0.009) but not with the change in the bone mineral density of the lumbar spine L2-4, or proximal radius. The higher the baseline serum 25-OH vitamin D at time 0, the smaller the subsequent fall in the femoral neck bone mineral density. In the study of Ooms et al. [4] the baseline serum 25-OH vitamin D was 27 nmol/L, whereas in our study the baseline serum 25-OH vitamin D of those participants who completed 24 months of observation was 99.7 nmol/L, so our data may not be relevant to older women, with low bone mineral density and low levels of serum 25-OH vitamin D. In our study, the larger fall in the femoral neck bone mineral density with lower levels of baseline serum 25-OH vitamin D is consistent with the findings of Stone et al. [2]. In a study by Adams and Lee [12] four persons receiving vitamin D with serum 25-OH vitamin D levels above normal, 132–222 nmol/L showed an increase in the lumbar spine and femoral neck bone mineral density after cessation of vitamin D and a fall in the serum 25-OH vitamin D. In the present study, blood samples were collected at 0 and 24 months from each participant in the same month so that any effect of seasonal variation on the serum 25-OH vitamin D would be eliminated. A limitation of the present study is that it is a post hoc study and that the serum 25-OH vitamin D assay was changed during the study. It is possible that the significant correlations may be due to chance. Also, the exclusion of participants with a clinical or symptomatic minimal trauma fracture regardless of whether they were treated as if osteoporotic or not, may have created a bias in the selection of participants in so far as participants with a fracture may behave differently from those without a fracture in terms of the rate of loss of bone mineral density. In conclusion, in a group of postmenopausal women studied over a 24-month interval and not receiving vitamin D supplements the change in the femoral neck bone mineral density was significantly positively correlated with the baseline serum 25-OH vitamin D but significantly negatively correlated with the change in the serum 25-OH vitamin D so that the magnitude of the change in femoral neck bone mineral density was influenced both by the baseline serum 25-OH vitamin D and by the subsequent change in the serum 25-OH vitamin D. …