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Vitamin D Status as a Determinant of Peak Bone Mass in Young Finnish Men

Division of Endocrinology, Department of Medicine (V.-V.V., M.J.V.), and Department of Clinical Chemistry (H.A., U.-H.S.), Helsinki University Central Hospital, FIN-00290 Helsinki, Finland; Finnish Defense Forces (E.Le., T.S.), FIN-00131 Helsinki, Finland; Department of Statistics, University of Turku (E.Lö.), FIN-20014 Turku, Finland; and Department of Health Sciences, University of Jyväskylä (H.S.), FIN-40014 Jyväskylä, Finland

Address all correspondence and requests for reprints to: Dr. Matti Välimäki, Division of Endocrinology, Department of Medicine, Helsinki University Central Hospital, FIN-00290 Helsinki, Finland. E-mail: matti.valimaki{at}hus.fi.

	Abstract

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Severe vitamin D deficiency causes rickets, but scarce data are available about the extent to which vitamin D status determines the development of the peak bone mass in young adults. Our aim was to evaluate the prevalence of vitamin D deficiency [serum 25-hydroxyvitamin D (25-OHD) less than the lower limit of the reference range of 20–105 nmol/liter] and the relationship between vitamin D status and peak bone mass among young Finnish men. A cross-sectional study of determinants of peak bone mass with data on lifestyle factors collected retrospectively was performed in 220 young men, aged 18.3–20.6 yr. One hundred and seventy men were recruits of the Finnish Army, and 50 were men of similar age who had postponed their military service for reasons not related to health. Bone mineral content, bone mineral density, and scan area were measured in lumbar spine and upper femur by dual energy x-ray absorptiometry. Serum 25-OHD concentrations were followed prospectively for 1 yr. In July 2000, only 0.9% of the men had vitamin D deficiency, but 6 months later, in the winter, the respective percentage was 38.9%. After adjusting for age, height, weight, exercise, smoking, calcium, and alcohol intake, there existed a positive correlation between serum 25-OHD and bone mineral content at lumbar spine (P = 0.057), femoral neck (P = 0.041), trochanter (P = 0.010), and total hip (P = 0.025). The correlation coefficients for the bone mineral densities at the four measurement sites were 0.035, 0.061, 0.056, and 0.068, respectively. No correlation was found to scan area. We conclude that vitamin D deficiency is very common in Finnish young men in the winter, and it may have detrimental effects on the acquisition of maximal peak bone mass. As in Finland vitamin D supplementation to infants is now stopped at the age of 3 yr, it can be asked whether at our latitude it should be continued from that age onward, not for the prevention of rickets, but as prophylaxis for osteoporosis.

	Introduction

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SEVERE VITAMIN D deficiency causes rickets and osteomalacia, whereas milder hypovitaminosis contributes to the development of osteoporosis. In Finland, vitamin D supplementation is recommended to infants from the age of 2 wk to 3 yr (previously 2 yr) to prevent rickets and to elderly people for prophylaxis of osteoporosis. After the prevention of rickets in infancy, less attention has been paid to the role of vitamin D in the building-up of peak bone mass in growing children and young adults. This has been the case despite alarming findings of the poor vitamin D state of young people in Finland and other countries. Three of four Finnish girls, aged 9–15 yr, had moderate hypovitaminosis D [serum 25-hydroxyvitamin D (25-OHD), 37.5 nmol/liter] in the winter of 1997 (1). In the winter, 70% of French boys, aged 13–16 yr, had serum 25-OHD concentrations less than 25 nmol/liter (2). In a Finnish study, stopping vitamin D supplementation after infancy clearly resulted in an increase in the prevalence of severe hypovitaminosis D (serum 25-OHD, 12.5 nmol/liter), from 7.5% in children 2–5 yr of age to 23.5% in the 11–17 yr age group (3).

Although adolescence is a crucial time for bone health, the relationship in young people between vitamin D status, defined by serum 25-OHD measurements, and bone mass has been addressed in only two studies (4, 5). A weak association between forearm bone mineral density (BMD) and serum 25-OHD concentrations was found in Finnish female adolescents, aged 14–16 yr; spine or hip measurements were not performed (4). In a very recent follow-up study of 171 Finnish girls, aged 9–15 yr, the adjusted 3-yr increase in lumbar spine BMD was greater, the higher the serum 25-OHD level at baseline (5).

The present study was undertaken to examine vitamin D status of young Finnish men and its impact on peak bone mass measured in the lumbar spine and the upper femur by dual energy x-ray absorptiometry. The seasonal variation in serum 25-OHD concentrations was also followed, and it was related to changes in serum intact PTH (iPTH) concentrations and bone turnover markers.

	Subjects and Methods

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Subjects

The study population comprised 220 young men, aged 18.3–20.6 yr. They were participants in a study aimed at elucidating the roles of genes, hormones, and lifestyle factors as determinants of peak bone mass and studying exercise-induced changes in bone mass during military service. One hundred and seventy men were recruits of the Finnish Army, and 50 subjects, men of similar age who had postponed their military service for reasons unrelated to health, formed a control group for the exercise part of the study. For the purpose of the present study, the 2 groups were combined. The study was approved by the ethical committee of Department of Medicine, Helsinki University Central Hospital, and a written consent was obtained from the participants.

Study design

Both groups were always examined at the same time. They were first studied during early July 2000 at the beginning of the military service of the recruits. BMD was measured, and blood was sampled in the morning before 1000 h for determination of serum 25-OHD, iPTH, type I procollagen amino-terminal propeptide (PINP), and tartrate-resistant acid phosphatase 5b (TRAP5b). Second-void urine samples were collected for the determination of type I collagen amino-terminal telopeptide (NTX). The samples were stored at -70C until assayed.

Current exercise, smoking, calcium intake, and alcohol consumption were recorded using a questionnaire. To study the seasonal variation in serum 25-OHD concentrations and other biochemical parameters, blood and urine sampling was repeated after 6 and 12 months. Altogether 167 men were studied at 6 months, and 94 men were studied at 12 months. The main reason for the decrease in the number of men studied was the duration of the military service, which in Finland varies from 6–12 months.

Exercise

The participation in various physical activities over the last year was recorded at baseline using a questionnaire. The questions used for the purpose of this report included 30 different types of physical activity and training, which were weighted according to their bone loading effect. Light or nonweight-bearing activities, such as walking, cycling, and swimming, scored 1; activities producing repetitive weight-bearing impact (e.g. endurance running and skiing) scored 1.5; and high impact or high magnitude loading (e.g. jumping, sprint running, and weight-lifting) scored 2. For each type of exercise practiced, the subjects were asked to indicate the average number of occasions per month and the duration (minutes) and intensity (1 = light, 2 = moderate, 3 = heavy) of each occasion. An exercise index was then calculated by summing up the products of frequency, duration, intensity, and bone loading effect of different activities in summer and wintertime.

Calcium intake

Calcium intake was calculated on the basis of the supply from dairy products only by using the following estimations: 1 dl milk, sour milk, and yogurt contains 120 mg calcium, and one slice of cheese contains 100 mg. In the calculations 1.8 dl was used as the volume of one glass.

Biochemical measurements

Serum 25-OHD was measured by RIA kits from Diasorin (Stillwater, MN). At vitamin D levels of 30 and 100 nmol/liter, the intraassay coefficients of variation (CVs) were 8.9% and 5.9%, and the interassay CVs were 12.8% and 8.8%, respectively. Serum iPTH was assayed using intact PTH kits from Diagnostics Products Corp. (Los Angeles, CA) and the IMMULITE 2000 immunoassay analyzer. At levels of 22 and 38 ng/liter, the intraassay CVs were 4.3% and 4.2%, and the interassay CVs were 5.3% at the level of 68 ng/liter and 3.4% at the level of 366 ng/liter. Urinary NTX was measured with NTX reagent kits (Amersham Pharmacia Biotech, Little Chalfont, UK) on the Vitros Eci Immunodiagnostics Systems analyzer (Ortho-Clinical Diagnostics, Inc., Rochester, NY). The intraassay CV was 8.0% at the level of 55 nM bone collagen equivalents (BCE)/liter and 3.0% at the level of 187 nM BCE/liter. The interassay CV was 9.8% at the level of 60 nM BCE/liter and 5.3% at the level of 403 nM BCE/liter. The values were corrected for creatinine excretion measured by a standard laboratory method. Serum intact PINP was determined by a competitive RIA with a commercial kit (Intact PINP RIA) from Orion Diagnostica (Oulunsalo, Finland). The analytical sensitivity of this assay was 2 µg/liter, and the intra- and interassay CVs ranged from 2–6%. Serum TRAP5b activity was measured by an immunoextraction method with BoneTRAP reagents from Suomen Bioanalytiikka Oy (Turku, Finland) (6). The analytical sensitivity of this assay was 0.1 U/liter, and the intra- and interassay CVs were 6% or less at relevant concentrations.

Vitamin D deficiency

Vitamin D deficiency was defined as a value lower than the lower limit of the Finnish reference range (20–105 nmol/liter) of serum 25-OHD concentration.

Bone mass measurements

Bone mineral content (BMC) and BMD of the lumbar spine and three femoral sites (femoral neck, trochanter, and total hip) was measured by dual energy x-ray absorptiometry using a Prodigy densitometer (Lunar Corp., Madison, WI). The scan areas of the lumbar spine and the femoral neck were also taken into account in the calculations.

Statistics

Baseline BMC, BMD, and scan area values were analyzed using a multiple regression model by adjusting for age, height, weight, calcium intake, smoking, alcohol consumption, exercise, and biochemical marker (separate model for each marker). In addition, Pearson correlation was calculated between BMC and biochemical markers. The study population was divided into two categories based on the median value of serum 25-OHD at baseline (=44 nmol/liter), and then those above and below the median were compared with respect to bone mass variables and biochemical markers using one-way ANOVA. The changes over time in biochemical markers were analyzed using repeated measures ANOVA. For all biochemical markers, natural logarithm transformation was used to achieve normality assumption in the models. All tests were performed as two-sided, with a 0.05 significance level. All analyses were performed with the SAS system (version 8.02 for Windows, SAS Institute, Inc., Cary, NC).

	Results

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The baseline characteristics of the study population are given in Table 1.

In the beginning of the study in July 2000, 2 of 220 men (0.9%) had serum 25-OHD less than 20 nmol/liter. Six months later in the winter, the corresponding proportion was 38.9% (65 of 167 men), and during the next summer it was 2.1% (2 of 94 men). The median levels of serum 25-OHD were 44, 24, and 41 nmol/liter, respectively.

Determinants of bone mass

In Table 2 lumbar spine and femoral neck BMC, BMD, and the respective scan areas as well as trochanteric and total hip BMC and BMD are related to anthropometric and lifestyle factors and vitamin D status in a multiple regression model. Current exercise (P < 0.0001) and weight (P < 0.0001–0.13) correlated most consistently with the BMCs studied. Due to its very narrow range, age was a determinant only for lumbar spine BMC. Calcium intake was not a determinant of BMC, but was of borderline significance for BMD in the femoral neck, trochanter, and total hip. Smoking history and alcohol intake did not have any relationship to bone mass. Interestingly, the serum 25-OHD concentration was a determinant of BMC at all four measurement sites, the P values being 0.057 for lumbar spine, 0.041 for femoral neck, 0.010 for trochanter, and 0.025 for total hip BMC. The correlation coefficients to the BMDs were 0.035, 0.061, 0.056, and 0.068, respectively. No correlation was found between serum 25-OHD and scan area. Unadjusted Pearson correlation coefficients (r values) between 25-OHD and BMCs were between 0.17 and 0.24, with the respective P values ranging from 0.0005–0.013 (Table 3).

At baseline the median level for serum 25(OH)D was 44 nmol/liter. Those above this level had a higher BMC in the trochanter (P = 0.015) and total hip (P = 0.037) than those below the median (Table 4). Serum iPTH was higher (P = 0.058) in those below than above the median serum 25-OHD.

Serum 25-OHD correlated negatively with serum iPTH (r = -0.24; P = 0.0007), but we could not find any threshold level for serum 25-OHD at which serum iPTH would have started to rise. Serum 25-OHD correlated positively with serum TRAP5b (r = 0.17; P = 0.012). Urinary NTX, serum TRAP5b, and PINP correlated with each other (r = 0.45–0.52; P < 0.0001). Serum 25-OHD was not dependent on smoking history (r = -0.11; P = 0.11), and serum iPTH was not associated with calcium intake (r = -0.08; P = 0.26).

Seasonal variation in biochemical markers

As presented above, serum 25-OHD exhibited an expected seasonal variation, with a nadir in the winter (P < 0.0001; Table 5). Serum iPTH showed inverse changes over time (P = 0.0001), with a maximum in the winter, but the magnitude of this variation was smaller than that of vitamin D (Table 5). Urinary excretion of NTX (P < 0.0001) and serum TRAP5b (P < 0.0001) and PINP (P = 0.0002) concentrations declined over time, with a nadir at the end of the study (Table 5).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

We defined vitamin D deficiency as values lower than the lower limit of the Finnish reference range, but several different definitions can be found for vitamin D deficiency and hypovitaminosis D in the literature. Thomas et al. (7) defined hypovitaminosis D as the level of serum 25-OHD at which serum iPTH concentrations started to increase. In their study the level was 37.5 nmol/liter, but this threshold varies with different studies. In our earlier study of middle-aged and elderly Finnish people, a dramatic rise in serum iPTH occurred when serum 25-OHD concentrations fell below 12.5 nmol/liter, although a significant rise was observed below a level of 50 nmol/liter (8). In a French adult population, serum iPTH levels began to increase already when serum 25-OHD fell below 78 nmol/liter (9). Although serum 25-OHD and iPTH concentrations correlated negatively in the present study population, we were not able to determine a distinct threshold for the PTH rise. This is compatible with a recent finding showing that for similar 25-OHD concentrations, PTH concentrations are consistently higher in the elderly than in younger adults (10). Hypovitaminosis D has also been defined as the threshold above which there was no increase in serum iPTH values during the winter; in one study the rise disappeared at the level of 95 nmol/liter (11). Furthermore, calcium absorptive performance at 50 nmol/liter was significantly reduced relative to that at a mean 25-OHD level of 86 nmol/liter, meaning that individuals with serum 25-OHD levels at the low end of the current reference range may not be getting the full benefit from their calcium intake (12). Finally, among people aged 65 yr or more, increasing a mean 25-OHD level from 53 to 74 nmol/liter by supplementation reduced fracture risk at hip, forearm, and spine by 33% in 5 yr (13). Independently of the definition used for sufficient vitamin D state, the median levels of 24 nmol/liter in the winter and 41–44 nmol/liter during the summer were low in our study population. However, when defining hypovitaminosis D in absolute terms of serum concentrations of 25-OHD, it has to be taken into account that the values from different laboratories cannot be assumed to be comparable unless a careful cross-calibration has been performed (14).

To our knowledge this is the first report to show that vitamin D status contributes to peak bone mass in male adolescents. Our study population consisted of men aged 18.3–20.6 yr, by which age peak bone mass has been achieved; in a study by Bonjour et al. (15), bone accretion in the lumbar spine and femoral neck was completed in men at 17–18 yr of age. Serum 25-OHD concentrations correlated positively with BMC in the lumbar spine and the three measurement sites of the upper femur also after adjusting for anthropometric and lifestyle factors in a multiple regression model. For two femoral sites, the BMC was higher for those with a serum 25-OHD concentration above its median of 44 nmol/liter than for those with levels below this cut-off value. The fact that BMC, but not scan area (and, accordingly, bone size), correlated with serum 25-OHD favors the idea that in growing children and adolescents vitamin D increases mineral accretion rather than bone size, and consequently, true density also increases.

Serum 25-OHD concentrations as a determinant of peak bone mass has not been studied in young men, but the relationship has been addressed in female adolescents in two studies. Among 178 Finnish girls, aged 14–16 yr, ulnar and radial BMDs adjusted for exercise were slightly lower in those with serum 25-OHD of 40 nmol/liter or less than in those above this cut-off level (4). In another study, among 171 Finnish girls, aged 9–15 yr, the adjusted 3-yr accumulation from baseline in lumbar spine BMD was 4% smaller in those with serum 25-OHD levels below 20 nmol/liter than in those with serum 25-OHD exceeding 37.5 nmol/liter (5). Two previous studies provide indirect evidence for a relationship between vitamin D status and peak bone mass. Insufficient vitamin D intake was considered as one explanation for reduced bone mass in Dutch adolescents, aged 9–15 yr, who were fed a macrobiotic diet in early life; the reduction in comparison with controls could not be attributed to group differences in calcium intake or physical activity (16). In 371 subjects, aged 20–23 yr, among other factors, forearm BMD was positively associated with vitamin D intake during adolescence (17).

Our study confirmed the role of exercise as the most important lifestyle factor in achieving a high peak bone mass (18, 19, 20). Calcium intake had a borderline positive effect on BMD of the upper femur, which is in accordance with earlier findings (21). We were not able to confirm our earlier findings of a negative effect of smoking on bone mass in men aged 20–29 yr (20). The differences in age and consequently in the length of smoking history most obviously explained the discrepancy between the 2 studies. Smoking was also not negatively associated with serum 25-OHD concentration, which was the case in a study of 328 Finnish adults, aged 31–43 yr (22).

Serum iPTH correlated negatively with 25-OHD at baseline, and it also showed a seasonal variation that was inverse to but in magnitude smaller than that in vitamin D. Serum calcium and phosphate concentrations are the main determinants of serum iPTH, but its regulation is multifactorial (22). We tested the dependency of serum iPTH on calcium intake, but no association was found in this study population. At baseline, serum iPTH did not correlate with markers of bone resorption, urinary NTX and serum TRAP5b, or a marker of bone formation, serum PINP. The increase in iPTH concentration during the winter was also not reflected in an increase in bone markers. Instead, all of the markers showed a declining trend over the whole study period, which is explained by the completion of growth in our subjects. In boys, bone markers are at their maximum in pubertal stage G4, decline thereafter, relate directly to height velocity, and are positive predictors of gain in bone mass (23). All of these biochemical findings favor the idea that in this age group vitamin D increases bone accretion rather directly than by suppressing bone resorption through lowered iPTH levels.

In conclusion, vitamin D deficiency is very common in Finnish young men during the winter, and it may have detrimental effects on the acquisition of maximal peak bone mass. The results strongly favor intervention studies on the effects of vitamin D supplementation on the growing skeleton. Our results also raises the question of whether at Finland’s latitude vitamin D supplementation should be continued beyond 3 yr of age, not for the prevention of rickets but as a prophylaxis for osteoporosis. This suggestion is further supported by a recent finding of an association between poor vitamin D intake and high incidence of type I diabetes in Finland (24).

	Footnotes

 
This work was supported by a grant from the Ministry of Education (Helsinki, Finland) and research funding from Helsinki University Central Hospital (Erityisvaltionosuus).

Abbreviations: BCE, Bone collagen equivalent; BMC, bone mineral content; BMD, bone mineral density; CV, coefficient of variation; iPTH, intact PTH; NTX, type I collagen amino-terminal telopeptide; 25-OHD, 25-hydroxyvitamin D; PINP, type I procollagen amino-terminal propeptide; TRAP5b, tartrate-resistant acid phosphatase 5b.

Received May 23, 2003.

Accepted September 29, 2003.

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