help button home button Endocrine Society JCEM JCEM Call for Nominations for EIC
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Rapuri, P. B.
Right arrow Articles by Haynatzka, V.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Rapuri, P. B.
Right arrow Articles by Haynatzka, V.
The Journal of Clinical Endocrinology & Metabolism Vol. 87, No. 5 2024-2032
Copyright © 2002 by The Endocrine Society

Endocrine Care

Seasonal Changes in Calciotropic Hormones, Bone Markers, and Bone Mineral Density in Elderly Women

Prema B. Rapuri, H. Karimi Kinyamu, J. Christopher Gallagher and Vera Haynatzka

Bone Metabolism Unit (P.B.R., J.C.G.), Creighton University School of Medicine, Omaha, Nebraska 68131; Laboratory of Reproductive and Developmental Toxicology (H.K.K.), National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709; and Department of Preventive Medicine, Creighton University School of Medicine (V.H.), Omaha, Nebraska 68131

Address all correspondence and requests for reprints to: Prema B. Rapuri, Bone Metabolism Unit, Creighton University, School of Medicine, 601 North 30th Street, Room 6718, Omaha, Nebraska 68131. E-mail: . thiyyari{at}creighton.edu

Abstract

Seasonal variation of serum vitamin D metabolites, PTH, bone turnover markers, and bone mineral density (BMD), adjusted for confounding variables, was studied in a cross-sectional population of 251 ambulatory elderly women aged 65–77 yr. A significant (P < 0.05) seasonal change was observed in serum 25 hydroxyvitamin D (25OHD), bone resorption marker (urine N-telopeptide), and BMD of the spine, total body, and mid-radius. Serum 25OHD was significantly lower (P < 0.05) in winter (December, January, February, March) compared with summer (June, July, August, September), with the nadir in February (68.4 ± 6.74 nmol/liter) and the zenith in August (85.6 ± 5.12 nmol/liter). Mean serum PTH levels were higher in winter when serum 25OHD was low, and mean serum PTH was lower in summer when serum 25OHD was high, although the seasonal change in serum PTH was not significant. The change in serum 1,25-dihydroxy vitamin D3 paralleled that of serum 25OHD levels, but the seasonal effect was not significant. Mean 24-h urine N-telopeptide showed a significant seasonal change (P < 0.05); it was about 24% higher in February (zenith) compared with that in August (nadir). The zenith month of urine N-telopeptide levels corresponded to the nadir month of serum 25OHD levels and vice versa. A significant (P < 0.05) inverse correlation was observed between 24-h urine N-telopeptides and serum 25OHD levels. There was a significant (P < 0.05) seasonal change in mean BMD of spine, total body, and mid-radius. These changes paralleled those in serum 25OHD levels. Spine BMD was 8.4% higher in August (zenith) compared with that in February (nadir), whereas total body BMD and mid-radius BMD were 6.1 and 7.6% higher, respectively, in July (zenith) compared with that in January (nadir). There was a nonsignificant increase of 3.6% in total hip BMD. In summary (see Fig. 5Go), the seasonal changes in vitamin D metabolism in elderly women are closely associated with small changes in serum PTH, changes in bone resorption, and BMD.



View larger version (10K):
[in this window]
[in a new window]
  		Figure 5. Overview of changes in calcitropic hormones, calcium absorption, serum calcium, bone markers, and BMD during the summer and winter. The curves were fitted using the periodic function of the form, F(m) = A*sin(B + m*{pi}/6) + C, where m designates the month variable while A, B, and C are parameters to be estimated. The effect of the covariates, age, height, weight, BMI, calorie intake, fiber intake, dietary calcium intake, dietary caffeine intake, alcohol status, smoking status, and age at menopause were adjusted for in these analyses. A significant (P < 0.05) seasonal effect was noted for serum 25OHD, serum calcium, urine N-telopeptide/Cr, spine BMD, and total body BMD.

 
THERE ARE TWO major sources of vitamin D: sunlight exposure and dietary vitamin D intake. Vitamin D is synthesized by the action of UV B radiation on 7-dehydrocholesterol on the skin and is subsequently hydroxylated in the liver and kidney to form 25 hydroxyvitamin D (25OHD) and 1,25 dihydroxyvitamin D [1,25(OH)2 D], respectively. The quantity and quality of solar radiation and the duration of exposure to the UV B radiation determines the endogenous synthesis of vitamin D in the skin.

Seasonal variation in serum 25 hydroxy metabolite of vitamin D has been well established in both the young and the elderly (1, 2, 3, 4, 5, 6, 7, 8, 9 10, 11, 12, 13, 14, 15, 16, 17, 18, 19). The seasonal changes in serum 25OHD concentration are associated with an increase and a decrease in sunlight exposure in the summer and winter months (20, 21, 22), respectively. Conversely, seasonal changes in serum 1,25(OH)2 D, the active metabolite of vitamin D, are less clearly defined (11, 12, 13, 23, 25, 26, 27). Furthermore, it is not clear whether the seasonal changes in serum 25OHD influence the circulating levels of 1,25(OH)2 D. Bouillon et al. (11) observed constant levels of serum 1,25(OH)2 D in young normal subjects, but in the same study serum 1,25(OH)2 D in elderly subjects increased significantly in the summer months compared with winter months. Serum calcium and serum phosphorus levels were also suggested to be affected by season by some, but not others (1, 2, 28, 29).

Seasonal changes in serum PTH have been closely associated with seasonal changes in serum 25OHD (12, 19, 22, 26, 30). In the winter, serum PTH is high when serum 25OHD is low, and in the summer serum PTH is low when serum 25OHD is high. Seasonal changes in serum PTH are implicated in the pathogenesis of bone loss in the elderly (12, 26, 31). Most studies have examined seasonal changes in serum 25OHD and serum PTH, but there are very few studies that examined corresponding changes in biochemical markers of bone turnover and made contrasting observations (15, 32, 33, 34, 35, 36, 37, 38). Recently, Woitge et al. (32, 33) demonstrated in healthy subjects that specific markers of bone turnover show significant seasonal changes that are directly related to variations in the hormonal regulation of skeletal homeostasis. Seasonal variation in bone mass has also been reported by some investigators, with bone mass decreasing in winter and increasing in summer periods (15, 22, 39, 40, 41, 42). However, this observation has not been replicated by others (34, 35, 43). We hypothesized that in elderly women seasonal changes in serum 25OHD are associated with seasonal changes in serum PTH. The change in serum PTH contributes to bone resorption, which is indicated by changes in biochemical markers of bone turnover, which further leads to decreased bone mineral density (BMD). The objective of this cross-sectional study was to examine comprehensively the seasonal changes in vitamin D metabolites, PTH, biochemical markers of bone turnover, and BMD in normal elderly women living in Omaha, Nebraska (latitude, 41° N).

Subjects and Methods

Subjects

The results presented in this paper are derived from baseline measurements collected from 489 women (age range, 65–77 yr) who were enrolled in one of the three centers evaluating osteoporosis prevention [Sites Testing Osteoporosis Prevention/Intervention Treatment (STOP IT)]. The STOP IT study population is fully described elsewhere (44). Subjects in the Omaha site were healthy volunteers who responded to advertisements in local newspapers inviting them to participate in a 3-yr study. These included 472 Caucasian, 11 black, and 4 Hispanic women, 1 Asian woman, and 1 woman of mixed race. The results are presented on only 251 women of the total 489 enrolled into the study. Two hundred thirty-eight subjects were excluded from this analysis because 135 were taking vitamin D supplements and 102 were taking diuretic medication at the time of the baseline measurements; one more subject with Paget’s disease was excluded. The protocol was approved by the Creighton University Institutional Review Board.

Dietary intake

Dietary intake data were collected using 7-d food diaries. Participants were carefully instructed by a dietitian to complete a 7-d food record and a nutrient supplement record. Plastic food models (NASCO, Fort Artinson, WI) were used to help participants better estimate the quantities consumed. Average daily calcium and vitamin D intake was calculated using the Food Processor II Plus Nutrition and diet analysis system (version 5.1, Esha Research, Salem, OR).

Calcium absorption test

Calcium absorption was measured in a fasting state by oral administration of 5 µCi (18.5 x 104 Bq) of 45Ca (Amersham Pharmacia Biotech, Arlington Heights, IL) in 100 mg calcium chloride (CaCl2) carrier given in a total of 250 ml distilled water (45). A blood sample was collected at 2 and 3 h after the oral dose. 45Ca activity was counted in 2 ml of serum using the 1900 CA Tricarb Liquid Scintillation Analyzer (Packard Instrument, Meriden, CT). A parallel standard taken from the patient’s dose before ingestion was counted at the same time. Calcium absorption was expressed as a percentage of actual dose per liter of blood and corrected for body mass index (BMI).

Biochemical analysis

Fasting blood and spot urine samples were collected before the calcium absorption test. Blood specimens were allowed to clot and were centrifuged at 4 C for 15 min at 2056 x g and serum separated. All samples were aliquoted and stored frozen at -70 C until analyzed.

Serum and urine chemistries

All serum and urine chemistries were measured using fresh samples. Serum and urine creatinine (Cr) were measured by automated procedures (Nova Nucleus Chemistry Analyzer, Waltham, MA).

Serum calciotropic hormones

Serum 25OHD was measured by a competitive binding assay (46) after extraction and purification of serum on Sep-Pak cartridges (Waters Associates, Milford, MA) (47). The limit for detection for the assay is 12.5 nmol/liter, and our interassay variation was 5%. The assay was cross-calibrated against direct HPLC measurements (Shimadzu) (48). Serum 1,25(OH)2 D was measured by a nonequilibrium RRA (INCSTAR Corp., Stillwater, MN) using the calf thymus receptor, after extraction and purification of the serum on nonpolar C18OH octadecysilanol silica cartridge (49, 50). The limit of detection for the assay is 12 pmol/liter, and our interassay variation was 10%. Serum intact PTH was measured with the Allegro immunoradiometric assay (Nichols Institute Diagnostics, San Juan Capistrano, CA) (51). The limit of detection for the assay is 1 ng/liter, and our interassay variation was 3.5%.

Bone markers

Serum osteocalcin was measured by RIA (INCSTAR Corp.). The limit for detection for the assay is 0.78 µg/liter, and the interassay variation is 5%. Urine cross-links of collagen were measured by ELISA (Osteomark International, Seattle, WA) as N-telopeptide, which is a specific marker for bone type 1 collagen. The lower limit of detection is 20 nmol bone collagen equivalents (BCEs), and the interassay variation was 6%.

Bone density measurements

BMD (grams per square centimeter) was determined using dual-energy x-ray absorptiometry (Model DPX-L, Lunar Corp., Madison, WI). The lumbar spine (L1-L4), total femur, three sites in proximal femur (femoral neck, trochanter, and Ward’s triangle), whole body, and mid-radius BMD were measured using standardized protocols for uniform subject positioning, scan mode, and scan analysis. The hip and spine scans were performed in duplicate, and the average value calculated was used for analysis.

Data analysis

Data from this cross-sectional study were analyzed using SAS package 8.0. Seasonal changes in vitamin D metabolites, serum chemistry measurements, PTH, bone markers, and bone density measurements were examined. The effects of the covariates, age, weight, height, BMI, calorie intake, fiber intake, dietary calcium intake, dietary caffeine intake, alcohol status, smoking status, and age at menopause were adjusted for in these analyses. Periodic functions of the form f(m) = A*sin(B + m*{pi}/6) + C were fitted to the adjusted values, where m designates the month variable while A, B, and C are parameters to be estimated. It should be noted that the fitted curve will not always go through the adjusted means of the month because the curve is fitted to the entire data set but not to the individual months. When adjusting, in most cases BMI was used unless weight and/or height proved to be more significant, in which case they were used. Also, when the data were skewed, the data were transformed before fitting the periodic functions. A P value less than 0.05 was considered significant. The associations between variables of interest in the study population were examined by Pearson correlation coefficients. The data of the variables for the zenith and the nadir months are presented as mean ± SEM and are adjusted for the covariates. Similarly, the data for the summer (June, July, August, and September) and winter (December, January, February, and March) months are given as adjusted means ± SEM.

Results

Table 1Go shows the biochemical characteristics of the study population.


View this table:
[in this window]
[in a new window]
  		Table 1. Descriptive and biochemical characteristics of the study population

 
Calcitropic hormones and calcium absorption

A significant (P < 0.05) seasonal variation was found in the serum 25OHD concentrations, adjusted for confounding variables. The overall mean of the study population for serum 25OHD was 73.6 nmol/liter (Table 1Go). Serum 25OHD concentration increased 17.3 nmol/liter from a nadir of 68.4 ± 6.74 nmol/liter in February to the zenith of 85.6 ± 5.12 nmol/liter observed in August. Serum 25OHD was significantly lower (P < 0.05) in the winter months (December, January, February, March) compared with summer months (June, July, August, September) (Fig. 1Go). In the winter months between December and March, 6% of the subjects had serum 25OHD levels below 30 nmol/liter. In the summer months between June and September, no subjects had serum 25OHD levels below 30 nmol/liter. There were no significant seasonal changes in serum 1,25(OH)2 D, serum PTH, and calcium absorption (Fig. 1Go). There was a 6.3 pmol/liter difference in serum 1,25 (OH)2 D concentration between the lowest level in the month of April and the highest level in the month of October. There is a lag of 2 months in zenith periods of serum 25OHD and 1,25 (OH)2 D. Serum PTH was 4 ng/liter higher in the month of March compared with that in September. The month with the highest value of serum PTH was 1 month later compared with the lowest level of serum 25OHD (Fig. 1Go). Calcium absorption was lower in March, April, and May and increased in the months of August, September, October, and November.



View larger version (31K):
[in this window]
[in a new window]
  		Figure 1. Seasonal changes in serum 25OHD, 1,25(OH)2 D, PTH, and intestinal calcium absorption in elderly women. The individual data points represent the adjusted observed values for the respective variable. The curve was fitted using the periodic function of the form, F(m) = A*sin(B + m*{pi}/6) + C, where m designates the month variable, while A, B, and C are parameters to be estimated. The effect of the covariates, age, height, weight, BMI, calorie intake, fiber intake, dietary calcium intake, dietary caffeine intake, alcohol status, smoking status, and age at menopause were adjusted for in these analyses. {blacktriangleup}, Observed; {diamondsuit}, fitted. Numbers in the x-axis represent months (1 = January, 2 = February, etc.).

 
Serum chemistry measurements

The data on serum chemistry measurements are given in Fig. 2Go. A significant (P < 0.05) seasonal effect was noted in the serum calcium levels. The serum calcium levels were higher in the months of December, January, February, and March and lower in the months of June, July, August, and September, with the lowest levels being seen in the month of July (2.29 ± 0.018 mmol/liter) and the highest in the month of January (2.33 ± 0.009 mmol/liter). Similar nonsignificant seasonal change was observed in serum ionized calcium concentrations. The serum phosphorus levels did not demonstrate any significant seasonal changes (data not given). Serum albumin levels showed a significant (P < 0.05) seasonal change, with higher levels in the winter months and lower levels in the summer months. The nadir of serum albumin levels was found in the month of June (38.9 ± 0.88 g/liter) and the zenith was in the month of December (41.1 ± 0.41 g/liter), 1 month preceding the nadir and zenith months of serum calcium levels.



View larger version (14K):
[in this window]
[in a new window]
  		Figure 2. Seasonal changes in serum ionized calcium, total calcium, and albumin levels in elderly women. The individual data points represent the adjusted observed values for the respective variable. The curve was fitted using the periodic function of the form, F(m) = A*sin(B + m*{pi}/6) + C, where m designates the month variable while A, B, and C are parameters to be estimated. The effect of the covariates, age, height, weight, BMI, calorie intake, fiber intake, dietary calcium intake, dietary caffeine intake, alcohol status, smoking status, and age at menopause were adjusted for in these analyses. {blacktriangleup}, Observed; {diamondsuit}, fitted.

 
Bone markers

There was no seasonal trend for serum osteocalcin, but mean 24-h urine N-telopeptide/Cr concentrations changed significantly (P < 0.05) by season, with higher values in the months of December, January, February, and March (56.6 ± 2.84 nmol BCE/mmol Cr) compared with the months of June, July, August, and September (46.5 ± 3.08 nmol BCE/mmol Cr) (Fig. 3Go). A difference of 9.9 nmol BCE/mmol Cr was observed between the nadir month of August and the zenith month of February. The urinary calcium/Cr ratio did not vary significantly with season (Fig. 3Go). The serum alkaline phosphatase showed a significant (P < 0.05) variation with season. Higher values of serum alkaline phosphatase were found in the months of December, January, and February, and lower values were noted in the months of April, May, and June (Fig. 3Go).



View larger version (15K):
[in this window]
[in a new window]
  		Figure 3. Seasonal changes in bone turnover markers in elderly women. The individual data points represent the adjusted observed values for the respective variable. The curve was fitted using the periodic function of the form, F(m) = A*sin(B + m*{pi}/6) + C, where m designates the month variable while A, B, and C are parameters to be estimated. The effect of the covariates, age, height, weight, BMI, calorie intake, fiber intake, dietary calcium intake, dietary caffeine intake, alcohol status, smoking status, and age at menopause were adjusted for in these analyses. {blacktriangleup}, Observed; {diamondsuit}, fitted.

 
BMD

There were significant (P < 0.05) seasonal changes in BMD measurements at spine, total body, and mid-radius. The BMD of the spine (4.2%), total body (5%), and mid-radius (4.5%) was significantly higher in summer (June, July, August, and September) compared with that in winter (December, January, February, and March). Spine (L1-L4) BMD was 8.4% higher in the zenith month of August (1.03 ± 0.03 g/cm2) compared with the nadir month of February (0.95 ± 0.05 g/cm2) (Fig. 4Go). Total body BMD was 6.1% higher in the zenith month, July (1.04 ± 0.02 g/cm2), compared with the nadir month, January (0.99 ± 0.01 g/cm2) (Fig. 4Go). Mid-radius BMD was 7.6% higher in the zenith month, July (0.71 ± 0.02 g/cm2), compared with the nadir month, January (0.66 ± 0.01 g/cm2) (Fig. 4Go). There were small nonsignificant seasonal changes in femoral neck BMD (zenith in July, 0.78 ± 0.02 g/cm2; nadir in January, 0.76 ± 0.01 g/cm2), total femur BMD (zenith in July, 0.85 ± 0.03 g/cm2; nadir in January, 0.82 ± 0.01 g/cm2), and trochanter BMD (zenith in June, 0.71 ± 0.02 g/cm2; nadir in December, 0.69 ± 0.03 g/cm2).



View larger version (31K):
[in this window]
[in a new window]
  		Figure 4. Seasonal changes in BMD (spine, total body, mid-radius, and total femur) in elderly women. The individual data points represent the adjusted observed values for the respective variable. The curve was fitted using the periodic function of the form, F(m) = A*sin(B + m*{pi}/6) + C, where m designates the month variable while A, B, and C are parameters to be estimated. The effect of the covariates, age, height, weight, BMI, calorie intake, fiber intake, dietary calcium intake, dietary caffeine intake, alcohol status, smoking status, and age at menopause were adjusted for in these analyses. {blacktriangleup}, Observed; {diamondsuit}, fitted.

 
Correlation among variables in the study population

In all 251 subjects, serum PTH was inversely correlated with serum 25OHD (r = -0.32; P < 0.001). Serum PTH was inversely correlated with serum 25OHD in winter (r = -0.29; P = 0.002) and in summer (r = -0.39; P = 0.003), respectively. Serum 1,25(OH)2 D was significantly correlated with serum PTH (r = 0.18; P = 0.005) and serum 25OHD (r = 0.13; P < 0.05). Serum 25OHD was significantly correlated (inverse) with 24-h urine N-telopeptides (r = -0.14; P = 0.02), but not with serum osteocalcin (r = -0.027). Serum 25OHD was significantly correlated (inverse) with BMD at spine, (r = -0.127; P = 0.045), but not with BMD at the other skeletal sites. Serum PTH was not significantly correlated with 24-h urine N-telopeptides (r = 0.11), but was significantly correlated with serum osteocalcin (r = 0.13; P = 0.03). Serum 1,25(OH)2 D was significantly correlated with 24-h urine N-telopeptides (r = 0.12; P = 0.05) and with serum osteocalcin (r = 0.22; P < 0.001).

Figure 5Go gives an overview of the composite changes in the calcitropic hormones, calcium absorption, bone markers, and BMD during the summer and winter.

Discussion

Vitamin D and its major circulating metabolite 25OHD are determined predominantly by UV radiation from the sun. In countries located in the northern latitudes, the capacity of sun irradiation to synthesize previtamin D3 is restricted to late spring and summer months (21, 22). Omaha, Nebraska, where this study was conducted, is located 41° Northern latitude, and there are extreme changes in temperature and sunlight hours between winter and summer.

The seasonality of serum 25OHD concentration has been extensively studied in both young and elderly subjects (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19). Most of these studies have observed a nadir level for serum 25OHD during the months of January and February and a zenith value during the months of July to September similar to our study, the summer to winter differences ranging from 15–30 nmol/liter. In this cross-sectional study, the seasonal change of 17.3 nmol/liter in serum 25OHD is comparable with that reported for a normal population in the Baltimore Longitudinal Study of Aging (13) and that of the STOP-IT population at the Boston site (31). Seasonal changes in serum 25OHD may be influenced by vitamin D intake (31, 52). In the study by Salamone et al. (52), the increase in serum 25OHD during high sunlight exposure was lower in elderly subjects with high vitamin D intake (>400 IU/d) compared with those with low intake (<320 IU/d). However, in the present study, vitamin D intake was below 200 IU/d in 80% of the subjects and was similar between the winter and summer months. Thus, sunlight exposure during the summer months is the more likely explanation for the seasonal change in serum 25OHD.

Seasonal variation in serum 1,25(OH)2 D levels has rarely been reported in normal subjects (13, 24, 34), probably because the serum level of 1,25(OH)2 D is tightly regulated. In this study population, the seasonal change in serum 1,25(OH)2 D of about 6.3 pmol/liter was not statistically significant, however, the lowest level was observed during the month of April and the highest in the month of October, 2 months later than that seen with serum 25OHD levels. This suggests that there is some substrate dependency of 1,25(OH)2 D production, a fact supported by a significant correlation between serum 1,25(OH)2 D and serum 25OHD concentration in these subjects. Further support for the substrate importance is the fact that during the months when serum 25OHD is low, serum PTH, which is the main physiological stimulus of 1,25(OH)2 D production, is increased, suggesting that the limiting factor in 1,25(OH)2 D production during these months is the availability of the substrate. Bouillon et al. (11) have shown previously that in an elderly population with much lower levels of serum 25OHD, seasonal changes in serum 1,25(OH)2 D are influenced by the level of serum 25OHD.

Although there appeared to be seasonal changes in serum PTH in this elderly population, the change was not significant. Seasonal changes in serum PTH were first reported by Lips et al. (26) in a group of elderly in The Netherlands. Krall et al. (12) reported that serum PTH levels were lowest between August and October and highest between March and May in postmenopausal women consuming less than 220 IU/d of vitamin D as seen in this study. Krall et al. (12) also reported an inverse correlation between serum PTH and serum 25OHD in women consuming less than 220 IU/d vitamin D. These observations are confirmed in the present study, because serum PTH was high in those months when serum 25OHD was low. Other factors related to parathyroid function in the elderly may influence the seasonal changes in serum PTH. Calcium malabsorption in this age group is normally associated with secondary hyperparathyroidism.

Seasonal changes in calcium absorption and urine calcium excretion were not statistically significant, although both were lower in spring and winter compared with summer months. There is little information on seasonal changes in calcium absorption in the elderly. Krall et al. (53) have shown that fractional whole body calcium retention was higher in summer to fall months (August–October) compared with late winter to spring months (March–May). The lower urine calcium excretion in the spring and winter months may be explained either by lower calcium absorption or higher serum PTH concentration during these months.

In the present study, the serum calcium levels showed a significant seasonal variation, with lower values in summer and higher values in winter. The serum-ionized calcium and serum phosphorus levels did not show any significant seasonal effect, however, changes over the year in serum ionized calcium levels followed the same pattern as that of serum calcium levels. Because about 50% of the calcium is protein bound, it is of interest that the seasonal change in albumin is similar to that of serum calcium. Vanderschueren et al. (34) also found a similar decrease in total serum calcium levels in summer months. But the majority of the studies that reported the serum calcium, ionized calcium, and phosphorus levels did not find a seasonal effect (1, 2, 25, 27, 54).

Seasonal variation in biochemical markers of bone turnover shows conflicting results (15, 22, 32, 33, 34, 35, 36, 37, 38). Woitge et al. (32) recently reported that the biochemical markers of bone turnover are increased during winter, especially in women, and coincided with a reduction in serum 25OHD levels. They reported an increase of 37% in urine pyridinoline and deoxypyridinoline levels and 16% in serum osteocalcin levels in winter compared with that of summer, with zenith in February and nadir in July. These results were further confirmed in a longitudinal study (33). In addition, Storm et al. (15) reported an increase in urine N-telopeptide (45%) and serum osteocalcin levels (70%) during winter months. A significant seasonal variation in serum osteocalcin levels was also reported by Douglas et al. (36) and Thomsen et al. (37). In contrast, Rosen et al. (22) and Overgaard et al. (35) reported a lack of seasonal variation of bone turnover markers. In this study, we found a significant seasonal effect on 24-h urine N-telopeptide levels, with the increase being approximately 24% between February and August. Another interesting finding in this study is that, the urine N-telopeptide excretion was inversely correlated with serum 25OHD. Thus, as noted by Woitge et al. (32), the low 25OHD levels in winter months coincided with the high urine N-telopeptide excretion. However, we did not find any significant seasonal effect on serum osteocalcin levels. Another less specific index of bone turnover, the alkaline phosphatase showed a significant seasonal effect in the present study in contrast to that reported by Overgaard et al. (35). Vitamin D insufficiency is implicated in bone loss, the effect probably mediated by PTH, which weakly correlated with 24-h urine N-telopeptide excretion (55). Twenty-four-hour urine N-telopeptide excretion in turn has been shown to be inversely correlated with bone density in the STOP-IT population (44). A number of studies have suggested that the increased levels of bone turnover markers are associated with accelerated bone loss (56, 57, 58).

There are several reports that examined the seasonal changes in bone mass (34, 35, 39, 40, 41, 42, 59). Most of these studies have examined the changes in lumbar spine and reported a seasonal pattern in BMD with increase in summer and decrease in winter. However, Overgaard et al. (35) did not find any seasonal effect on BMD. In line with the positive studies, in the present study we found a significant seasonal effect on BMD at spine, total body, and mid-radius with the respective BMD values in summer (June, July, August, September) being 4.2, 5, and 4.5% higher, respectively, than in winter (December, January, March, February). Krolner et al. (42) reported a 1.7% increase in lumbar BMD in summer (July to September) whereas Aitken et al. (41) observed a 4.8% higher metacarpal BMD in summer than in winter. Rosen et al. (22) also provided evidence for a seasonal effect on BMD of the spine and hip. In healthy postmenopausal women, Dawson-Hughes and colleagues (39, 60) found a significant winter decline in spine (-1.02%) and total body (-0.67%) BMD. Storm et al. (15) recently reported a 3.2% loss at femoral neck and greater trochanter during winter in elderly women. The large seasonal changes in BMD show the importance of repeating BMD measurements in the same month during the follow-up.

In summary, seasonal changes in serum vitamin D metabolites, serum PTH, bone turnover markers, and BMD follow an orderly sequence throughout the year (Fig. 5Go). Vitamin D stored during the summer months lasts approximately 10–12 weeks. As shown in this study, serum 25OHD levels show a noticeable decline from the month of December, and at the same time serum PTH starts to rise. The rise in PTH follows (peaks in March) the decline in serum 25OHD (lowest in February) with a lag of 1 month. This is accompanied by increase in bone resorption, shown by the peak in the level of N-telopeptide during February. The increased bone resorption leads to accelerated bone loss and decreased BMD as seen by lowest BMD values for spine, total body, and mid-radius in the months of January and February. In addition, in the winter months a decline in serum 25OHD may decrease the substrate available for the production of 1,25(OH)2 D, which results in a decline in calcium absorption, which further increases serum PTH in this elderly population. In contrast, in the summer months, the increase in sunlight hours reverses the above events. Serum 25OHD increases (peaks in August), accompanied by a decrease in serum PTH (lowest in September). The increase in serum 25OHD provides substrate for production of 1,25(OH)2 D, which leads to an increase in serum 1,25(OH)2D and calcium absorption. Vitamin D sufficiency in summer reduces the circulating levels of PTH; consequently, bone resorption is reduced (lowest in the month of August), and high BMD values are noticed (peaks in July or August).

Acknowledgments

We thank Research Coordinators Kimberly Petranick, Michelle Wilson, and Patty Fannon for their efforts in this study. We thank Karen A. Rafferty for her help in food diary data collection and analysis. We also thank Kurt E. Balhorn for the laboratory analysis.

Footnotes

This study was presented in part at the 18th Annual Meeting of the American Society for Bone and Mineral Research, 1996, Seattle, Washington (Kinyamu et al. 1996 J Bone Miner Res 11:S434).

This work was supported by National Institute of Health Research Grants UO1-AG10373 and RO1-AG10358.

Abbreviations: 1,25(OH)2 D, 1,25 Dihydroxyvitamin D; 25OHD, 25 hydroxy vitamin D; BCE, bone collagen equivalent; BMD, bone mineral density; BMI, body mass index; Cr, creatinine; STOP IT, Sites Testing Osteoporosis Prevention/Intervention Treatment.

Received August 29, 2001.

Accepted January 22, 2002.

References

  1. Stamp TC, Round JM 1974 Seasonal changes in human plasma levels of 25 hydroxyvitamin D. Nature 247:563–565[CrossRef][Medline]
  2. Lester E, Skinner RK, Wills MR 1977 Seasonal variation in serum 25 hydroxyvitamin D in the elderly in Britain. Lancet I:979–980
  3. Lawson DEM, Paul AA, Black AE, Cole TJ, Mandal AR, Davie M 1979 Relative contributions of diet and sunlight to vitamin D state in the elderly. Br Med J 2:303–305
  4. Poskitt EME, Cole TJ, Lawson DEM 1979 Diet, sunlight and 25 hydroxyvitamin D in healthy children and adults. Br Med J 1:221–223
  5. Stryd P, Gilbertson J, Brunden MN 1979 A seasonal variation study of 25-hydroxyvitamin D3 serum levels in normal humans. J Clin Endocrinol Metab 48:771–775[Abstract]
  6. Devgun MS, Paterson CR, Johnson BE, Cohen C 1981 Vitamin D nutrition in relation to season and occupation. Am J Clin Nutr 34:1501–1504[Abstract/Free Full Text]
  7. Omdahl JL, Garry PJ, Hunsaker LA, Hunt WC, Goodwin JS 1982 Nutritional status in a healthy elderly population: vitamin D. Am J Clin Nutr 36:1225–1233[Abstract/Free Full Text]
  8. Dattani JT, Exton-Smith AN, Stephen JM 1984 Vitamin D status of the elderly in relation to age and exposure to sunlight. Hum Nutr Clin Nutr 38:131–137[Medline]
  9. Davies M, Mawer EB, Hann JT, Taylor JL 1986 Seasonal changes in the biochemical indices of vitamin D deficiency in the elderly: a comparison of people in residential homes, long-stay wards and attending a day hospital. Age Ageing 15:77–83[Abstract/Free Full Text]
  10. Lamberg-Allardt C 1984 Vitamin D intake, sunlight exposure and 25-hydroxyvitamin D levels in the elderly during one year. Ann Nutr Metab 28:144–150[CrossRef][Medline]
  11. Bouillon RA, Auwerx JH, Lissens WD, Pelemans WK 1987 Vitamin D status in the elderly: seasonal substrate deficiency causes 1,25 dihydroxycholecalciferol deficiency. Am J Clin Nutr 45:755–763[Abstract/Free Full Text]
  12. Krall EA, Sahyoun N, Tannenbaum S, Dallal GE, Dawson-Hughes B 1989 Effect of vitamin D intake on seasonal variations in parathyroid hormone secretion in postmenopausal women. N Engl J Med 321:1777–1783[Abstract]
  13. Sherman SS, Hollis BW, Tobin JD 1990 Vitamin D status and related parameters in a healthy population: the effects of age, sex and season. J Clin Endocrinol Metab 71:405–413[Abstract]
  14. Harris SS, Dawson-Hughes B 1998 Seasonal changes in plasma 25-hydroxyvitamin D concentrations of young American black and white women. Am J Clin Nutr 67:1232–1236[Abstract]
  15. Storm D, Eslin R, Porter ES, Musgrave K, Musgrave K, Vereault D, Patton C, Kessenich C, Mohan S, Chen T, Holick MF, Rosen CJ 1998 Calcium supplementation prevents seasonal bone loss and changes in biochemical markers of bone turnover in elderly New England women: a randomized placebo-controlled trial. J Clin Endocrinol Metab 83:3817–3825[Abstract/Free Full Text]
  16. Perry III HM, Horowitz M, Morley JE, Patrick P, Vellas B, Baumgartner R, Garry PJ 1999 Longitudinal changes in serum 25-hydroxy vitamin D in older people. Metabolism 48:1028–1032[CrossRef][Medline]
  17. Lips P, Duong T, Oleksik A, Black D, Cummings S, Cox D, Nickelsen T 2001 A global study of vitamin D status and parathyroid function in postmenopausal women with osteoporosis: baseline data from the multiple outcomes of raloxifene evaluation clinical trial. J Clin Endocrinol Metab 86:1212–1221[Abstract/Free Full Text]
  18. Nakamura K, Nashimoto M, Yamamoto M 2000 Summer/winter differences in the serum 25-hydroxyvitamin D3 and parathyroid hormone levels of Japanese women. Int J Biometeorol 44:186–189[CrossRef][Medline]
  19. Webb AR, Pilbeam C, Hanafin N, Holick MF 1990 An evaluation of the relative contributions of exposure to sunlight and of diet to the circulating concentrations of 25-hydroxyvitamin D in an elderly nursing home population in Boston. Am J Clin Nutr 51:1075–1081[Abstract/Free Full Text]
  20. Lips P, van Ginkel FC, Jongen MJM, Rubertus F, van der Vijgh WJF, Netelenbos JC 1987 Determinants of vitamin D status in patients with hip fracture and in elderly control subjects. Am J Clin Nutr 46:1005–1010[Abstract/Free Full Text]
  21. Webb AR, Kline L, Holick MF 1988 Influence of season and latitude on the cutaneous synthesis of vitamin D3: exposure to winter sunlight in Boston and Edmonton will not promote vitamin D3 synthesis in human skin. J Clin Endocrinol Metab 67:373–378[Abstract]
  22. Rosen CJ, Morrison A, Zhou H, Storm D, Hunter SJ, Musgrave K, Chen T, Wei W, Holick MF 1994 Elderly women in northern New England exhibit seasonal changes in bone mineral density and calciotropic hormones. Bone Miner 25:83–92[Medline]
  23. Chesney RW, Rosen JF, Hamstra AJ, Smith C, Mahaffey K, DeLuca HF 1981 Absence of seasonal variation in serum concentrations of 1,25 dihydroxyvitamin D despite a rise in 25 hydroxyvitamin D in summer. J Clin Endocrinol Metab 53:139–142[Abstract]
  24. Juttman JR, Visser TJ, Buurman C, de Kam E, Birkkenhager JC 1981 Seasonal fluctuations in serum concentrations of vitamin D metabolites in normal subjects. Br Med J 282:1349–1352
  25. Tjellesen L, Christiansen C 1983 Vitamin D metabolites in normal subjects during one year. A longitudinal study. Scand J Clin Lab Invest 43:85–89[Medline]
  26. Lips P, Hackeng WHL, Jongen MJM, van Ginkel FC, Netelenbos JC 1983 Seasonal variation in serum concentrations of parathyroid hormone in elderly people. J Clin Endocrinol Metab 57:204–206[Abstract]
  27. Hine TJ, Roberts NB 1994 Seasonal variation in serum 25-hydroxy vitamin D3 does not affect 1,25-dihydroxy vitamin D. Ann Clin Biochem 31:31–34
  28. Iwanami M, Osiba S, Yamada T, Yoshimura H 1959 Seasonal variations in serum inorganic phosphate and calcium with special reference to parathyroid activity. J Physiol 149:23–33
  29. McLaughlin M, Raggatt PR, Fairney A, Brown DJ, Lester E, Wills MR 1974 Seasonal variations in serum 25-hydroxy cholecalciferol in healthy people. Lancet 1:536–538[CrossRef][Medline]
  30. Malabanan A, Veronikis IE, Holick MF 1998 Redefining vitamin D insufficiency. Lancet 351:805–806.[Medline]
  31. Dawson-Hughes B, Harris SS, Dallal GE 1997 Plasma calcidiol, season, and serum parathyroid hormone concentrations in healthy elderly men and women. Am J Clin Nutr 65:67–71[Abstract/Free Full Text]
  32. Woitge HW, Scheidt-Nave C, Kissling C, Leidig-Bruckner G, Meyer K, Grauer A, Scharla SH, Ziegler R, Seibel MJ 1998 Seasonal variation of biochemical indexes of bone turnover: results of a population-based study. J Clin Endocrinol Metab 83:68–75[Abstract/Free Full Text]
  33. Woitge HW, Knothe A, Witte K, Schmidt-Gayk H, Ziegler R, Lemmer B, Seibel MJ 2000 Circannual rhythms and interactions of vitamin D metabolites, parathyroid hormone, and biochemical markers of skeletal homeostasis: a prospective study. J Bone Miner Res 15:2443–2450[CrossRef][Medline]
  34. Vanderschueren D, Gevers G, Dequeker J, Geusens P, Nijs J, Devos P, De Roo M, Bouillon R 1991 Seasonal variation in bone metabolism in young healthy subjects. Calcif Tissue Int 49:84–89[Medline]
  35. Overgaard K, Nilas L, Johansen JS, Christiansen C 1988 Lack of seasonal variation in bone mass and biochemical estimates of bone turnover. Bone 9:285–288[Medline]
  36. Douglas AS, Miller MH, Reid DM, Hutchison JD, Porter RW, Robins SP 1996 Seasonal differences in biochemical parameters of bone remodelling. J Clin Pathol 49:284–289[Abstract/Free Full Text]
  37. Thomsen K, Eriksen EF, Jorgensen JC, Charles P, Mosekilde L 1989 Seasonal variation of serum bone GLA protein. Scand J Clin Lab Invest 49:605–611[Medline]
  38. Hyldstrup L, McNair P, Jensen GF, Transbol I 1986 Seasonal variations in indices of bone formation precede appropriate bone mineral changes in normal men. Bone 7:167–170[Medline]
  39. Dawson-Hughes B, Dallal GE, Krall EA, Harris S, Sokoll LJ, Falconer G 1991 Effect of vitamin D supplementation on wintertime and overall bone loss in healthy postmenopausal women. Ann Intern Med 115:505–512
  40. Rico H, Revilla M, Cardenas JL, Villa LF, Fraile E, Martin FJ, Arribas I 1994 Influence of weight and seasonal changes on radiogrammetry and bone densitometry. Calcif Tissue Int 54:385–388[CrossRef][Medline]
  41. Aitken JM, Anderson JB, Horton PW 1973 Seasonal variations in bone mineral content after the menopause. Nature 241:59–60[CrossRef][Medline]
  42. Krolner B 1983 Seasonal variation of lumbar spine bone mineral content in normal women. Calcif Tissue Int 35:145–147[CrossRef][Medline]
  43. Tsai KS, Hsu SHJ, Cheng JP, Yang RS 1997 Vitamin D stores of urban women in Taipei: effect on bone density and bone turnover, and seasonal variation. Bone 20:371–374[Medline]
  44. Krall EA, Dawson-Hughes B, Hirst K, Gallagher JC, Sherman SS, Dalsky G 1997 Bone mineral density and biochemical markers of bone turnover in healthy elderly men and women. J Gerontol A Biol Sci Med Sci 52:M61–M67
  45. Gallagher JC, Riggs BL, Eisman J, Hamstra A, Arnaud SB, DeLuca HF 1979 Intestinal calcium absorption and serum vitamin D metabolites in normal subjects and osteoporotic patients: effect of age and dietary calcium. J Clin Invest 64:729–736
  46. Haddad JG, Chyu KJ 1971 Competitive protein-binding radioassay for 25-hydroxycholecalciferol. J Clin Endocrinol Metab 33:992–993[Medline]
  47. Reinhardt TA, Horst RL 1988 Simplified assays for the determination of 25-OHD, 24, 25-(OH)2D and 1,25-(OH)2D. In: Norman AW, Schaefer K, Grigoleit H-G, Herrath DV, eds. Vitamin D, molecular, cellular and clinical endocrinology. Berlin and New York: Walter de Gruyter & Co; 720–726
  48. Thiyyari PP, Gallagher JC, Balhorn KE 1998 Serum 25-hydroxy vitamin D2 and D3 in elderly subjects. Bone S450:F163
  49. Reinhardt TA, Horst RL, Orf JW, Hollis BW 1984 A microassay for 1,25-dihydroxyvitamin D not requiring high performance liquid chromatography: application to clinical studies. J Clin Endocrinol Metab 58:91–98[Abstract]
  50. Hollis BW 1986 Assay of circulating 1,25-dihydroxyvitamin D involving a novel single-cartridge extraction and purification procedure. Clin Chem 32:2060–2063[Abstract/Free Full Text]
  51. Nussbaum SR, Zahradnik RJ, Lavigne JR, Brennan GL, Nozawa-Ung K, Kim LY, Keutmann HT, Wang CA, Potts Jr JT, Segre GV 1987 Highly sensitive two-site immunoradiometric assay of parathyrin, and its clinical utility in evaluating patients with hypercalcemia. Clin Chem 33:1364–1367[Abstract/Free Full Text]
  52. Salamone LM, Dallal GE, Zantos D, Makrauer F, Dawson-Hughes B 1994 Contributions of vitamin D intake and seasonal sunlight exposure to plasma 25 hydroxyvitamin D concentration in elderly women. Am J Clin Nutr 59:80–86[Abstract/Free Full Text]
  53. Krall EA, Dawson-Hughes B 1991 Relation of fractional 47Ca retention to season and rates of bone loss in healthy postmenopausal women. J Bone Miner Res 6:1323–1329[Medline]
  54. Rudnicki M, Thode RJ, Jorgensen T, Heitmann BL, Sorensen OH 1993 Effects of age, sex, season and diet on serum ionized calcium, parathyroid hormone and vitamin D in a random population. J Intern Med 234:195–200[Medline]
  55. Lips P, Netelenbos JC, Jongen MJM, van Ginkel FC, Althuis AL, van Schaik CL, van der Vijgh WJ, Vermeiden JP, van der Meer C 1982 Histomorphometric profile and vitamin D status in patients with femoral neck fracture. Metab Bone Dis Relat Res 4:85–93[CrossRef][Medline]
  56. Ross PD, Knowlton W 1998 Rapid bone loss is associated with increased levels of biochemical markers. J Bone Miner Res 13:297–302[CrossRef][Medline]
  57. Christiansen C, Riis BJ, Rodbro P 1987 Prediction of rapid bone loss in postmenopausal women. Lancet 1:1105–1108[Medline]
  58. Dresner-Pollak R, Parker RA, Poku M, Thompson J, Seibel MJ, Greenspan SL 1996 Biochemical markers of bone turnover reflect femoral bone loss in elderly women. Calcif Tissue Int 59:328–333[CrossRef][Medline]
  59. Bergstralh EJ, Sinaki M, Offord KP, Wahner HW, Melton III LJ 1990 Effect of season on physical activity score, back extensor muscle strength, and lumbar bone mineral density. J Bone Miner Res 5:371–377[Medline]
  60. Dawson-Hughes B, Harris S 1993 Thiazides and seasonal bone change in healthy postmenopausal women. Bone Miner 21:41–51[Medline]



This article has been cited by other articles:


Home page
 Nephrol Dial TransplantHome page
S.-Y. Li, J.-Y. Chen, C.-L. Chuang, and T.-W. Chen
Seasonal variations in serum sodium levels and other biochemical parameters among peritoneal dialysis patients
Nephrol. Dial. Transplant., February 1, 2008; 23(2): 687 - 692.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Clin. Nutr.Home page
Y. Manios, G. Moschonis, G. Trovas, and G. P Lyritis
Changes in biochemical indexes of bone metabolism and bone mineral density after a 12-mo dietary intervention program: the Postmenopausal Health Study
Am. J. Clinical Nutrition, September 1, 2007; 86(3): 781 - 789.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
J. C. Gallagher, P. B. Rapuri, and L. M. Smith
An Age-Related Decrease in Creatinine Clearance Is Associated with an Increase in Number of Falls in Untreated Women But Not in Women Receiving Calcitriol Treatment
J. Clin. Endocrinol. Metab., January 1, 2007; 92(1): 51 - 58.
[Abstract] [Full Text] [PDF]

Home page
 J. Am. Coll. Nutr.Home page
J. M. Lappe, K. M. Davies, D. Travers-Gustafson, and R. P. Heaney
Vitamin d status in a rural postmenopausal female population.
J. Am. Coll. Nutr., October 1, 2006; 25(5): 395 - 402.
[Abstract] [Full Text] [PDF]

Home page
 J. Nutr.Home page
M. S. Calvo, S. J. Whiting, and C. N. Barton
Vitamin D Intake: A Global Perspective of Current Status
J. Nutr., February 1, 2005; 135(2): 310 - 316.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Rapuri, P. B.
Right arrow Articles by Haynatzka, V.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Rapuri, P. B.
Right arrow Articles by Haynatzka, V.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals