Wintertime Vitamin D Supplementation Inhibits Seasonal Variation of Calcitropic Hormones and Maintains Bone Turnover in Healthy Men

Vitamin D is suggested to have a role in the coupling of bone resorption and formation. Compared with women, men are believed to have more stable bone remodeling, and thus, are considered less susceptible to the seasonal variation of calcitropic hormones. We examined whether seasonal variation exists in calcitropic hormones, bone remodeling markers, and BMD in healthy men. Furthermore, we determined which vitamin D intake is required to prevent this variation. Subjects (N = 48) were healthy white men 21–49 yr of age from the Helsinki area with a mean habitual dietary intake of vitamin D of 6.6 ± 5.1 (SD) μg/d. This was a 6‐mo double‐blinded vitamin D intervention study, in which subjects were allocated to three groups of 20 μg (800 IU), 10 μg (400 IU), or placebo. Fasting blood samplings were collected six times for analyses of serum (S‐)25(OH)D, iPTH, bone‐specific alkaline phosphatase (BALP), and TRACP. Radial volumetric BMD (vBMD) was measured at the beginning and end of the study with pQCT. Wintertime variation was noted in S‐25(OH)D, S‐PTH, and S‐TRACP (p < 0.001, p = 0.012, and p < 0.05, respectively) but not in S‐BALP or vBMD in the placebo group. Supplementation inhibited the winter elevation of PTH (p = 0.035), decreased the S‐BALP concentration (p < 0.05), but benefited cortical BMD (p = 0.09) only slightly. Healthy men are exposed to wintertime decrease in vitamin D status that impacts PTH concentration. Vitamin D supplementation improved vitamin D status and inhibited the winter elevation of PTH and also decreased BALP concentration. The ratio of TRACP to BALP shows the coupling of bone remodeling in a robust way. A stable ratio was observed among those retaining a stable PTH throughout the study. A daily intake of vitamin D in the range of 17.5–20 μg (700–800 IU) seems to be required to prevent winter seasonal increases in PTH and maintain stable bone turnover in young, healthy white men.     

Vitamin D Receptor Genotype is Not Associated with Bone Mineral Density in Three Ethnic/Regional Groups

We report a cross-sectional study of 48 men, 56 premenopausal women, and 80 postmenopausal women who were of three ethnic/regional backgrounds: southern European (Greek, Italian), eastern European (Jewish, Polish, Hungarian), and western European (French, British). We determined bone mineral density (BMD) at four skeletal sites and assessed the vitamin D receptor (VDR) genotype by the Bsml restriction site polymorphism. Age and body mass index had significant effects on BMD by multiple regression analysis. In addition, ethnic/regional group had a significant effect on spinal BMD in premenopausal females (P= 0.014) and in males (P= 0.039). However, VDR genotype had no significant effect on BMD in any of the three study groups. Received: 4 December 1995 / Accepted: 27 March 1996     

Prevalence of Vitamin D Insufficiency and Deficiency in Morbidly Obese Patients: A Comparison with Non-Obese Controls

Background Vitamin D deficiency is common in patients after bariatric surgery. However, obesity itself has also been associated with decreased vitamin D. The prevalence of vitamin D deficiency in obese persons has not previously been compared to non-obese controls when controlling for factors that could affect vitamin D status. Methods We evaluated 25 hydroxy vitamin D, iPTH, calcium, albumin, and creatinine in 41 patients undergoing Roux-en-Y gastric bypass. We then compared them to healthy non-obese controls matched for age, sex, race/ethnicity, and season of vitamin D measurement. Results Ninety percent of the pre-bariatric surgery patients had 25-OH-D levels <75 nmol/l, and 61% had 25-OH-D levels <50 nmol/l versus 32 and 12% in controls, respectively. Additionally, 49% of the pre-bariatric surgery patients had secondary hyperparathyroidism versus 2% of controls. These differences persisted after controlling for sunlight exposure and dietary intake of calcium and vitamin D. Mean calcium, corrected for albumin, and creatinine were not significantly different between the groups, but mean albumin levels were significantly lower among surgery patients. Conclusion Vitamin D deficiency is common in obese patients at the time of bariatric surgery and is also accompanied by secondary hyperparathyroidism approximately half the time. These findings suggest that vitamin D deficiency after bariatric surgery is multifactorial and in part caused by preoperative vitamin D deficiency rather than postoperative malabsorption alone. In this study, increased vitamin D deficiency in obese persons cannot be explained by a difference in calcium/vitamin D intake or sunlight exposure.     

Vitamin D Analogs Versus Native Vitamin D in Preventing Bone Loss and Osteoporosis-Related Fractures: A Comparative Meta-analysis

It has been suggested that early postmenopausal women and patients treated with steroids should receive preventive therapy (calcium, vitamin D, vitamin D analogs, estrogens, or bisphosphonates) to preserve their bone mineral density (BMD) and to avoid fragility fractures. We designed the present study to compare the effects of native vitamin D to its hydroxylated analogs alfacalcidol 1-(OH)D and calcitriol 1,25(OH)₂D. All randomized, controlled, double-blinded trials comparing oral native vitamin D and its analogs, alfacalcidol or calcitriol, to placebo or head-to-head trials in primary or corticosteroids-induced osteoporosis were included in the meta-analysis. Sources included the Cochrane Controlled Trials Register, EMBASE, MEDLINE, and a hand search of abstracts and references lists. The study period January 1985 to January 2003. Data were abstracted by two investigators, and methodological quality was assessed in a similar manner. Heterogeneity was extensively investigated. Results were expressed as effect-size (ES) for bone loss and as rate difference (RD) for fracture while allocated to active treatment or control. Publication bias was investigated. Fourteen studies of native vitamin D, nine of alfacalcidol, and ten of calcitriol fit the inclusion criteria. The two vitamin D analogs appeared to exert a higher preventive effect on bone loss and fracture rates in patients not exposed to glucocorticoids. With respect to BMD, vitamin D analogs versus placebo studies had an ES of 0.36 (P < 0.0001), whereas native vitamin D versus placebo had an ES of 0.17 (P = 0.0005), the interclass difference being highly significant (ANOVA-1, P < 0.05). When restricted to the lumbar spine, this intertreatment difference remained significant: ES = 0.43 (P = 0.0002) for vitamin D analogs and ES = 0.21 (P = 0.001) for native vitamin D (analysis of variance [ANOVA-1], P = 0.047). There were no significant differences regarding their efficacies on other measurement sites (ANOVA-1, P = 0.36). When comparing the adjusted global relative risks for fracture when allocated to vitamin D analogs or native vitamin D, alfacalcidol and calcitriol provided a more marked preventive efficacy against fractures: RD = 10% (95% Confidence interval [CI-2] to 17) compared to RD = 2% (95% CI, 1 to 2), respectively. The analysis of the spinal and nonspinal showed that fracture rates differed between the two classes, thereby confirming the benefits of vitamin D analogs, with significant 13.4% (95% CI 7.7 to 19.8) and. 6% (95% CI 1 to 12) lower fracture rates for vitamin D analogs, respectively. In patients receiving corticosteroid therapy, both treatments provided similar global ESs for BMD: ES = 0.38 for vitamin D analogs and ES = 0.41 for native vitamin D (ANOVA-1, P = 0.88). When restriced to spinal BMD, D analogs provided significant effects, whereas native vitamin D did not: ES = 0.43 (P < 0.0001) and ES = 0.33 (P = 0.21), respectively. The intertreatment difference was nonsignificant (ANOVA-1, P = 0.52). Neither D analogs for native vitamin D significantly prevented fractures in this subcategory of patients: RD = 2.6 (95%CI, –9.5 to 4.3) and RD = 6.4 (95%CI, –2.3 to 10), respectively. In head-to-head studies comparing D analogs and native vitamin D in patients receiving corticosteroids, significant effects favoring D analogs were found for femoral neck BMD: ES = 0.31 at P = 0.02 and spinal fractures: RD = 15% (95%CI, 6.5 to 25). Publication bias was not significant. Our analysis demonstrates a superiority of the D analogs atfacalcidol and calcitriol in preventing bone loss and spinal fractures in primary osteoporosis, including postmenopausal women. In corticosteroid-induced osteoporosis, the efficacy of D analogs differed depending on the comparative approach: indirect comparisons led to nonsignificant differences, whereas direct comparison did provide significant differences. In this setting, D analogs seem to prevent spinal fractures to a greater extent than do native vitamin D, but this assumption should be confirmed on a comprehensive basis in multiarm studies including an inactive comparator.     

Vitamin D insufficiency in adolescent males in Southern Tasmania: prevalence, determinants, and relationship to bone turnover markers

There are limited data on vitamin D insufficiency in healthy children. The aim of this study was to describe the prevalence and determinants of vitamin D insufficiency and its association with bone turnover in adolescent boys (N=136, mean age 16 years). Sun exposure and physical activity were assessed by questionnaire. Vitamin D stores were assessed by serum 25-hydroxyvitamin D₃ (25[OH]D₃). Bone turnover was assessed by bone-specific alkaline phosphatase (BAP) and urinary pyridinoline (PYR) to creatinine (Cr) ratio (mmol PYR/µmol Cr). The mean 25(OH)D₃ level was low (44 nmol/l; 68% <50 nmol/l; range, 16–87) and was associated with self-reported sun exposure on winter weekends (r=0.23, p=0.01), school holidays (r=0.22, p=0.01), and weekdays (r=0.17, p=0.05). It was also associated with number of sports (r=0.34, p<0.001) and vigorous activity (r=0.22, p=0.01) but not television, computer, and video watching (r=-0.04, p=0.68). In multivariate analysis, number of sports but not total sun exposure remained significantly associated with 25(OH)D₃. Furthermore, 25(OH)D₃ was significantly associated with BAP in cutpoint analysis (cutpoint 55 nmol/l, p=0.03) but not continuous analysis (r=–0.12, p=0.16) and PYR in both forms (r=–0.23, p=0.01, cutpoint 43 nmol/l, p=0.01). In conclusion, vitamin D insufficiency is common in healthy adolescent boys in winter in our setting, is primarily derived from sports-related sun exposure, and is associated with bone turnover markers. These data suggest that a 25(OH)D₃ level of at least 43–55 nmol/l is required for optimal bone health in children.     

Longitudinal Evaluation of Vitamin D Status in Healthy Subjects from Southern Italy: Seasonal and Gender Differences

Vitamin D status is currently considered among the relevant determinants of skeletal integrity. Since vitamin D levels present seasonal variations, we longitudinally studied young healthy men and women in order to investigate the related physiologic modifications of both calcium homeostasis and bone remodeling. Thirty-two men (mean age 39.4 ± 7.8 years) and 58 premenopausal women (aged 36.9 ± 6.4 years) from southern Italy were studied. In all subjects the following parameters were measured both in winter and in summer: serum calcium, phosphorus, creatinine, total alkaline phosphatase activity, 25-hydroxyvitamin D (25OHD), parathyroid hormone (PTH), osteocalcin (BGP), together with urinary calcium (Ca/Cr), total pyridinoline (Pyr/Cr) and deoxypyridinoline (d-Pyr/Cr), corrected for creatinine excretion. In both sexes 25OHD levels were significantly higher in summer, while PTH values were lower, than in winter. The prevalence of hypovitaminosis D, defined by concentrations of 25OHD lower than 30 nmol/l, was 17.8% in winter and 2.2% in summer in the whole sample, while it was 27.8% and 3.4%, respectively, among female subjects. Indeed male subjects did not display hypovitaminosis D, having throughout the year significantly higher calcium and 25OHD levels together with lower PTH values, than the women. Moreover, alkaline phosphatase total activity was more elevated in men both in winter and in summer. In women, during winter, bone remodeling markers levels were higher while urinary calcium levels were lower than in summer. In the whole sample serum 25OHD correlated positively with serum calcium and inversely with PTH. The seasonal percentage variations in PTH were inversely correlated with those of Ca/Cr. Our results show a relatively high prevalence of subclinical vitamin D deficiency among young healthy women from southern Italy. Significant gender-specific differences have been demonstrated in both calcium homeostasis and skeletal remodeling indexes; the seasonal fluctuations in the vitamin D–PTH axis are accompanied by cyclical variations of bone turnover rate, which were more pronounced in women. Received: 11 January 2001 / Accepted: 6 July 2001     

Maintenance by cortisone of the calcemic response to parathyroid extract of rats on a diet without vitamin D and low in calcium

Weanling rats raised for 21 days on a vitamin D deprived, low Ca diet (0.02%), and given chronic cortisone administration (5 mg/kg/d), maintain responsiveness to the hypercalcemic effect of endogenous and exogenous parathyroid extract (PTE). The PTE action is a bone effect that does not require the presence of the kidneys, and is not related to a higher concentration of calcium or cortisone. Maintained sensitivity of D− Ca− Cort+ rats to PTE does not appear to be the consequence of a lesser degree of D-deficiency: the whole body vitamin D pool and its chloroform-soluble fraction in these animals are not different from those of their D− Ca− PTE− unresponsive controls. Repeated PTE injections for 4 days exhaust the sensitivity to the hypercalcemic action of PTE of D− Ca− Cort+ rats. The present data seem to indicate that cortisone-treated D− Ca− rats, responsive to the bone action of PTE, are characterized by a near normal bone calcium content and Ca/P ratio, and a significant increase in the number of osteoclasts.     

Different forms of alkaline phosphatase in adult rat femur. Effect of a Vitamin D3-deficient diet and of a sorbitol-enriched diet

Summary In the femoral extremities of the adult rat containing the metaphysis, the epiphyseal cartilage, and the epiphysis, four alkaline phosphatase (AP) forms were distinguished on polyacrylamide gel electrophoresis. Two soluble forms were present in the 160,000 g supernatant: one of Mr 165 kDa and another of Mr 110–115 kDa, which exhibited a strong catalytical activity. Moreover, from the pellet, three membrane-bound forms of Mr 130, 110–115, and 100 kDa could be extacted with sodium deoxycholate. When denaturated AP was visualized by postelectrophoretic autoradiography of the phosphorylated intermediates, subunits always appeared as three monomers of Mr 75–80, 60–70, and 50–60 kDa. As four native forms but only three types of subunits were found to be present in the femur, it seems that, apart from homodimers, some heterodimers could also occur. Three types of diets were administered to three groups of rats for 5 weeks. Two are known to disturb bone mineralization: (1) a vitamin D₃-deficient diet, and (2) the same as (1) but enriched with 12% sorbitol. The third was a normal diet containing vitamin D₃. Concerning the effects on AP of dietary sorbitol and the vitamin D₃-deficient diet, it was found that rats receiving the diet supplemented with sorbitol showed a substantial rise in the activity of the Mr 165 kDa form with the concomitant appearance of a new monomer of Mr 100 kDa. In contrast, rats fed the vitamin D₃-deficient diet always displayed an increase in enzyme activity, principally of the Mr 100 and 110 kDa forms. In conclusion, the femur extracts of normal rats contained different forms of AP: either soluble 110–115 and 165 kDa forms or membrane-bound 130, 110–115, and 100 kDa forms. The administration of sorbitol-enriched diet induced a marked increase of the 165 kDa form whereas the administration of vitamin D₃-deficient diet increased the 100 and 110 kDa forms.     

Positive Correlations Between Free Vitamin D and Bone Variables in a Group of Young Lebanese Women

Optimizing bone mass in adulthood is of great importance to prevent the occurrence of osteoporosis in later age. Vitamin D is an essential component of bone health. Low-serum vitamin D is associated with low bone mineral density (BMD), which is an important predictor of fracture risk. However, most cells, apart from renal tubular cells, are exposed to free rather than to total 25-hydroxyvitamin D. Whether free vitamin D would be a better marker than total vitamin D is still under debate. The aim of the present study was to explore the relationships between serum total vitamin D, vitamin D-binding protein (BP), free vitamin D, and bone parameters in a group of young Lebanese women. This study included 88 young female adults aged between 18 and 35?yr. Body composition and BMD were assessed by dual-energy X-ray absorptiometry, and the lumbar spine trabecular bone score was derived. Bone mineral content (BMC) and BMD were measured at the whole body (WB), the lumbar spine (L1–L4), the total hip (TH), and the femoral neck (FN). To evaluate hip bone geometry, dual-energy X-ray absorptiometry scans were analyzed at the FN, the intertrochanteric region, and the femoral shaft by the Hip Structure Analysis program. The cross-sectional area, the index of axial compression strength, and the section modulus (Z), as well as index of bending strength, were measured from bone mass profiles. Composite indices of FN strength (compressive strength index [CSI], bending strength index, and impact strength index [ISI]) were calculated as previously described. Direct measurement of free 25-hydroxyvitamin D concentrations was performed by immunoassay, which detects free vitamin D by ELISA on a microtiter plate. Serum vitamin D BP was measured using a Quantikine ELISA kit, which employed the quantitative sandwich enzyme immunoassay technique. Serum free vitamin D was positively correlated with WB BMC (r?=?0.26, p?<?0.05), WB BMD (r?=?0.29, p?<?0.05), L1–L4 BMD (r?=?0.28, p?<?0.05), TH BMD (r?=?0.34, p?<?0.01), FN BMD (r?=?0.29, p?<?0.05), CSI (r?=?0.24, p?<?0.05), and ISI (r?=?0.28, p?<?0.05). No positive correlations were detected between the total vitamin D level, the vitamin D BPs, and BMD. The positive associations between free vitamin D and several bone variables (WB BMC, WB BMD, L1–L4 BMD, TH BMD, FN BMD, CSI, bending strength index, and ISI) remained significant after adjustment for weight. In conclusion, the current study suggests that the free vitamin D serum level is a stronger positive determinant of bone parameters and hip bone strength indices in young female adults than total serum vitamin D.     

Vitamin D, parathyroid hormone levels and bone mineral density in community-dwelling older women: The Rancho Bernardo Study

Vitamin D (25(OH)D) increases the efficiency of intestinal calcium absorption. Low levels of serum calcium stimulate the secretion of parathyroid hormone (PTH), which maintains serum calcium levels at the expense of increased bone turnover, bone loss and increased risk of fractures. We studied the association between 25(OH)D and PTH levels, and their associations with bone mineral density (BMD), bone loss, and prevalence of hip fractures in 615 community-dwelling postmenopausal aged 50–97 years. Mean level of 25(OH)D and PTH were 102.0 nmol/l±35.0 nmol/l and 49.4 ng/l±23.2 nmol/l, respectively; 49% of women were current hormone therapy users. The overall prevalence of vitamin D insufficiency (25(OH)D<50 nmol/l) was 2%, and prevalence of high PTH levels (>65 ng/l) was 17.4%. In multiple linear regression analyses hip BMD was negatively and independently associated with PTH levels ( p =0.04), and positively and independently associated with 25(OH)D levels ( p =0.03). There were only 23 women (3.7%) who experienced a hip fracture. In age-adjusted analyses there were no significant differences of 25(OH)D and PTH levels by hip fracture status. Across the entire range of values, the overall correlation between 25(OH)D and PTH was moderate ( r =–0.20). However, after the threshold vitamin D level of 120 nmol/l, all PTH values were below 65 ng/l. Further studies are necessary to identify the optimal vitamin D levels necessary to prevent secondary hyperparathyroidism.     

Association Between Single Gene Polymorphisms and Bone Biomarkers and Response to Calcium and Vitamin D Supplementation in Young Adults Undergoing Military Training

Initial military training (IMT) is associated with increased stress fracture risk. In prior studies, supplemental calcium (Ca) and vitamin D provided daily throughout IMT reduced stress fracture incidence, suppressed parathyroid hormone (PTH), and improved measures of bone health compared with placebo. Data were analyzed from a randomized, double‐blind, placebo‐controlled trial to determine whether single‐nucleotide polymorphisms (SNPs) in Ca and vitamin D–related genes were associated with circulating biomarkers of bone metabolism in young adults entering IMT, and whether responses to Ca and vitamin D supplementation were modulated by genotype. Associations between SNPs, including vitamin D receptor (VDR), vitamin D binding protein (DBP), and 1‐alpha‐hydroxylase (CYP27B1), and circulating biomarkers were measured in fasting blood samples from volunteers (n = 748) starting IMT. Volunteers were block randomized by race and sex to receive Ca (2000 mg) and vitamin D (1000 IU) or placebo daily throughout Army or Air Force IMT (7 to 9 weeks). Total Ca and vitamin D intakes were calculated as the sum of supplemental intake based on intervention compliance and dietary intake. Relationships between SNPs, Ca, and vitamin D intake tertile and change in biomarkers were evaluated in trial completers (n = 391). At baseline, the minor allele of a DBP SNP (rs7041) was positively associated with both 25OHD (B = 4.46, p = 1.97E‐10) and 1,25(OH)₂D₃ (B = 9.63, p < 0.001). Combined genetic risk score (GRS) for this SNP and a second SNP in the VDR gene (rs1544410) was inversely associated with baseline 25OHD (r = –0.28, p < 0.001) and response to Ca and vitamin D intake differed by GRS (p < 0.05). In addition, presence of the minor allele of a second VDR SNP (rs2228570) was associated with lower P1NP (B = –4.83, p = 0.04) and osteocalcin (B = –0.59, p = 0.03). These data suggest that VDR and DBP SNPs are associated with 25OHD status and bone turnover and those with the highest GRS require the greatest vitamin D intake to improve 25OHD during IMT. © 2016 American Society for Bone and Mineral Research.     

Influence of Season,Ethnicity, and Chronicity on Vitamin D Deficiency in Traumatic Spinal Cord Injury

Background:

Inadequate levels of vitamin D increase the risk of osteoporosis, a highly prevalent condition in patients with traumatic spinal cord injury (SCI). Reduced sunlight and dark skin further contribute to low vitamin D levels.

Objectives:

To compare serum 25-hydroxy vitamin D [vitamin D25(OH)] levels in acute and chronic SCI and to explore seasonal and ethnic differences among patients with acute and chronic SCI.

Patients/Methods:

Patients (N  =  96) aged 19 to 55 years with C3-T10 motor complete SCI participated. Acute SCI was 2 to 6 months after injury, whereas chronic SCI was at least 1 year from injury. Serum vitamin D25(OH), calcium, and parathyroid hormone were drawn during summer or winter months. Vitamin D deficiency (<13 ng/mL), insufficiency (<20 ng/mL), and subtherapeutic (<32 ng/mL) levels were compared for all groups. A 3-way analysis of covariance was adopted to determine significant main effects of season, chronicity, and ethnicity. Interactions between season and chronicity, season and ethnicity, and chronicity and ethnicity were evaluated. Evaluation of a 3-way interaction among season, chronicity, and ethnicity was completed.

Results:

In summer, 65% of patients with acute SCI and 81% of patients with chronic SCI had subtherapeutic vitamin D levels, whereas in winter, 84% with acute SCI and 96% with chronic SCI had vitamin D25(OH) (<32ng/mL). Lower vitamin D25(OH) levels were observed in African Americans relative to whites. Significant main effects were noted for season (P  =  0.017), chronicity (P  =  0.003), and ethnicity (P < 0.001). However, interactions between 2 or more factors were not found.

Conclusions:

Vitamin D insufficiency and deficiency are found in the majority of patients with chronic SCI and in many with acute SCI. Initial screening for serum vitamin D25(OH) levels should be performed early in rehabilitation. Periodic monitoring in the chronic setting is highly recommended.     

Vitamin D Supplementation in France in patients with or at risk for osteoporosis: Recent data and new practices

With intermittent vitamin D supplementation, serum 25-hydroxyvitamin D (25OHD) levels may remain stable only if the dosing interval is shorter than 3 months, the ideal perhaps being about 1 month. Recent data support moderate daily vitamin D doses instead of high intermittent doses, notably in elderly patients prone to falls. The level of evidence is low, however, with no head-to-head comparisons of clinical outcomes such as fractures and falls in groups given identical dosages daily versus intermittently. A challenge to daily vitamin D supplementation in France is the absence of a suitable pharmaceutical formulation. In addition, daily dosing carries a high risk of poor adherence. Until suitable vitamin D3 formulations such as tablets or soft capsules each containing 1000 or 1500 IU become available, we suggest intermittent supplementation according to 2011 GRIO guidelines. Among the available dosages, the lowest should be preferred, with the shortest possible interval, e.g., 50,000 IU monthly rather than 100,000 every two months.     

The Effect of Season and Vitamin D Supplementation on Bone Mineral Density in Healthy Women: A Double-Masked Crossover Study

Vitamin D status is known to be an important determinant of bone mineral density (BMD). There is a significant seasonal variation in serum vitamin D, and some studies have reported an associated seasonal variation in BMD. The present study was devised to investigate whether a seasonal variation in BMD could be detected in healthy normal subjects, along with associated variations in serum parathyroid hormone (PTH), intestinal calcium absorption and biochemical markers of bone turnover. A second aim was to investigate whether, if such variations were identified, they could be suppressed by vitamin D supplementation. The subjects were 70 healthy female volunteers (mean age 47.2 years, range 24–70 years) recruited into a double-masked crossover study and followed over 2 years. During the first year 35 subjects received a daily oral supplement containing 800 IU (20 mg) cholecalciferol (group 1) and 35 subjects received a placebo preparation (group 2). During the second year the treatment each group received was reversed. Lumbar spine (L1–L4), left proximal femur and total body BMD were measured by DXA at 3-month intervals. Serum 25-hydroxyvitamin D (25-OHD), serum PTH, bone markers (bone-specific ALP (BSAP) and urinary crosslinks (DYPD/creatinine)) and calcium absorption were also measured at each visit. Cholecalciferol treatment increased serum 25-OHD by 25.4 nmol/l (p <0.001), while a reciprocal decrease in serum PTH of 6.6 ng/l (p = 0.011) was seen in subjects in the lowest quartile of baseline serum 25-OHD. The treatment had no significant effect on spine, femur or total body BMD, calcium absorption or bone markers. When Fourier analysis was used to analyze the data for seasonal effect (defined as twice the amplitude of the 1-year period variation) a highly significant effect for 25-OHD of 18 nmol/l (p <0.001) was found. However, no effect was found for BMD, PTH, calcium absorption or bone markers. The analysis set a 95% confidence limit to the seasonal effect of less than 0.6% for spine, total hip and total body BMD. It was concluded that in the population of healthy women studied there was no evidence of seasonal variation in spine, femur or total body BMD, serum PTH, calcium absorption or bone markers. Vitamin D supplementation was found to have no effect on BMD. Received: 7 July 2000 / Accepted: 14 November 2000     

Correlation Between Vitamin D Receptor Genotypes and Bone Mineral Density in Japanese Patients with Osteoporosis

In order to better understand the pathogenesis of osteoporosis, we investigated the correlation between the vitamin D receptor (VDR) genotypes defined by BsmI restriction enzyme, as well as other related factors, and the bone mineral density (BMD) at the lumbar spine in 90 Japanese patients with osteoporosis. The same study was performed in 36 patients with osteoarthrosis of the hip joint and 92 healthy volunteers. The majority of the VDR genotypes were bb, and a few of the population showed either the BB or Bb genotype in all three groups. There was no statistical difference in the frequencies of these VDR genotypes in the three groups. The mean age-matched value of BMD (Z scores) at the lumbar spine in patients with osteoporosis was significantly lower than that in patients with osteoarthrosis or healthy volunteers. The mean Z scores of the healthy volunteers with bb genotype were significantly higher than those with BB genotype, whereas those of the osteoporosis patients with BB genotype were significantly higher than those with Bb genotype. There was no significant difference in the mean Z scores between bb and Bb genotypes in patients with osteoporosis and healthy volunteers. No significant difference was seen in the mean Z scores in patients with osteoarthrosis regardless of genotype. On the other hand, body weight significantly correlated with BMD in patients with osteoporosis by simple- and multiple-regression analysis. These results indicate that the BMD at the lumbar spine in Japanese patients with osteoporosis is affected by body weight, and might be affected partially by the VDR genotypes defined by BsmI. Received: 22 September 1995 / Accepted: 24 September 1996     

Low Vitamin D Levels in Outpatient Postmenopausal Women from a Rheumatology Clinic in Madrid, Spain: Their Relationship with Bone Mineral Density

To evaluate a possible relationship between vitamin D levels and bone mineral density (BMD) and the prevalence of hypovitaminosis in a population of postmenopausal women from a rheumatologic outpatient clinic in Madrid, Spain, 171 postmenopausal women (aged 47–66 years) divided into two groups (osteoporotic and nonosteoporotic, according to WHO criteria) were studied between November and June. Liver and kidney function were normal in all subjects. Serum parathyroid hormone (PTH) and calcidiol levels were determined and bone densitometry carried out at the lumbar spine and hip level. PTH and calcidiol serum levels did not show any correlation. Serum PTH was inversely related to BMD at both hip and lumbar spine in the total group, and at the hip with calcidiol levels lower than 37 nmol/l. Calcidiol was directly related to hip BMD only when levels were lower than 37 nmol/l. Results of a stepwise multiple regression analysis showed that the single factor which affected BMD at the hip was calcidiol in the subgroup with serum calcidiol levels below 37 nmol/l, while in the subgroup with serum calcidiol levels above 37 nmol/l, the main factor affecting hip BMD was serum PTH. The prevalence of vitamin D deficiency at a cutoff of 37 nmol/l was 64%. In summary, calcidiol serum levels below 37 nmol/l seem to affect bone mass, regardless of the effect of PTH. Vitamin D deficiency is a frequent finding in the postmenopausal women who attend a rheumatology outpatient clinic in Madrid. Vitamin D supplementation should therefore be considered in this population during the winter season. Received: 2 July 1999 / Accepted: 3 March 2000     

Wintertime Vitamin D Deficiency in Male Adolescents: Effect on Parathyroid Function and Response to Vitamin D3 Supplements

The first part of this study consisted of an 18 month follow-up of the vitamin D status and parathyroid function in a group of 54 French male adolescents, aged from 13 to 16 years old and all pupils of a jockey training school. During the 18 month period four samplings were made, one every 6 months. The first was during September of the first year, the second and third during March and October of the second year, and the last in March of the third year. Therefore we had two main periods: summer and winter. The summer 25-hydroxyvitamin D (25(OH)D) concentrations were higher (71.6 ± 19.9 and 52.4 ± 16.5 nmol/l) than the winter ones (20.4 ± 6.9 and 21.4 ± 6.1 nmol/l). Conversely, the winter intact parathyroid hormone (iPTH) serum levels (4.18 ± 1.18 and 4.11 ± 1.35 pmol/l) were higher than the summer ones (2.44 ± 0.82 and 2.71 ± 0.71 pmol/l). At the two winter time points the 25(OH)D concentrations were lower than 25 nmol/l (10 ng/ml) in 72% (2nd year) and 68% (3rd year) of the adolescents. In the second part of the study we tried a vitamin D₃ supplementation procedure designed to maintain the 25(OH)D and iPTH postsummer serum levels throughout the winter. Pairs of male adolescents matched for height, weight and Tanner pubertal stage were randomly assigned to either vitamin D₃ supplementation (2.5 mg, i.e., 100 000 IU) administered orally at three specific periods (end of September, November and January) or no vitamin D₃ treatment (control subjects). Blood was collected just before the first intake of vitamin D₃ and 2 months after the last intake (March). The control subjects had blood drawn at the same time points. In the vitamin D₃-treated subjects, the concentrations of 25 (OH)D (55.3 ± 11.5 nmol/l) and of iPTH (3.09 ± 1.16 pmol/l) in March and September (53.8 ± 12.3 nmol/l and 2.75 ± 1.26 pmol/l) were not significantly different. In the control subjects, March 25(OH)D levels (21.0 ± nmol/l were low, with values below 25 nmol/l in 78% of subjects, and iPTH concentrations (3.97 ± 1.08 pmol/l) were significantly (p<0.001) higher than in September (2.91 ± 0.81 pmol/l). The constant vitamin D wintertime deficiency and wintertime rise in iPTH in adolescent French males throughout puberty has been demonstrated. In adolescents with low dairy calcium intakes, the vitamin D₃ treatment was sufficient to maintain 25(OH)D concentrations at their summer levels throughout winter and to prevent an excessive wintertime rise in iPTH levels. Received: 6 February 2001 / Accepted: 9 May 2001     

Vitamin D Receptor Gene Polymorphisms, Bone Mass, Bone Loss and Prevalence of Vertebral Fracture: Differences in Postmenopausal Women and Men

Bone mineral density (BMD), the major determinant of fracture risk, is under strong genetic control. Although polymorphisms of the vitamin D receptor (VDR) gene have been suggested to account for some of the genetic variation in bone mass, the influence of VDR genotypes on osteoporosis remains controversial. Previous published studies have focused mainly on women, but the pattern of response in men has not been determined. Using the BsmI restriction enzyme, we studied the influence of the different VDR genotypes on bone mass, bone loss and the prevalence of vertebral fractures in a population-based sample of both sexes (n = 326). BMD was measured at the lumbar spine and femoral neck, with a 4-year interval, using dual-energy X-ray absorptiometry. Vertebral fractures were assessed by two lateral radiographs at the beginning and end of the study. The prevalence of the three possible VDR genotypes was similar to those in other Caucasian populations and no differences were found between men and women. Women with the favorable bb genotype showed significantly higher BMD values at the lumbar spine and femoral neck, and a positive rate of BMD change at the femoral neck compared with women with the BB and Bb genotypes. Moreover, women with the bb genotype showed a trend toward a lower prevalence and incidence of vertebral fractures (p= 0.07). We have not found any differences between VDR genotypes in men. In conclusion, VDR gene polymorphisms are related to bone mass and bone loss in women; also a trend in the prevalence of vertebral fractures was observed in postmenopausal women but not in men. Received: 8 June 1998 / Accepted: 7 December 1998