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The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 60:754-759 (2005)
© 2005 The Gerontological Society of America

Vitamin D Supplementation in Older Women

Susan L. Greenspan, Neil M. Resnick and Robert A. Parker

Beth Israel Deaconess Medical Center, Boston, Massachusetts.

Address correspondence to Susan L. Greenspan, MD, Professor of Medicine, University of Pittsburgh, Osteoporosis Prevention and Treatment Center, Kaufmann Medical Building, Suite 1110, 3471 Fifth Avenue, Pittsburgh, PA 15213. E-mail griffithsd{at}msx.dept-med.pitt.edu


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
Background. The purpose of this study was to determine if vitamin D supplementation, 400–800 IU daily, could effectively treat vitamin D deficiency and insufficiency over 3 months.

Methods. To test this hypothesis, we conducted a cross-sectional survey followed by a 3-month, open-label run-in phase prior to a randomized clinical trial. We enrolled 573 community-dwelling women age 65 or older, 373 of whom completed the run-in phase. All women received a daily multivitamin containing 400 IU of vitamin D and one to two calcium supplements containing 200 IU of vitamin D. We assessed bone mineral metabolism (including 25-hydroxyvitamin D and parathyroid hormone), markers of bone turnover, and bone mineral density.

Results. Of the 553 screened participants who had baseline vitamin D levels available, 16% had vitamin D deficiency (serum vitamin D < 10 ng/ml) and 48% had vitamin D insufficiency (serum vitamin D between 10 and 20 ng/ml). Only 36% of participants had normal vitamin D levels (serum vitamin D ≥ 20 ng/ml). Baseline vitamin D intake was negatively associated with serum parathyroid hormone (r = –0.29, p <.0001), and not associated with bone mineral density or bone resorption. Vitamin D deficiency was associated with decreased physical activity and slower gait. Of the 373 women who completed the run-in phase and received treatment with a multivitamin and vitamin D-containing calcium supplement, vitamin D deficiency decreased from 16% at baseline to 0% at 3 months, and vitamin D insufficiency decreased from 48% at baseline to 20% at 3 months (p <.001).

Conclusions. We conclude that vitamin D deficiency and insufficiency, which are common among ambulatory, community-dwelling elderly women, can be normalized in 80% of patients over 3 months with vitamin D supplementation of 400–800 IU/d.

VITAMIN D deficiency is common in older individuals (1–4). It is estimated that 50% of nursing home residents may have vitamin D deficiency (2,3,5), and up to 57% of medical inpatients have hypovitaminosis D (1). Furthermore, the ingestion of a daily multivitamin containing vitamin D may not protect against vitamin D deficiency (1). Previous studies have demonstrated that vitamin D deficiency is associated with low bone mass (6) and osteoporotic fractures (7–10). Moreover, investigators have reported that vitamin D treatment (700–800 IU/d) can reduce hip and nonvertebral fractures in older persons (11,12).

We hypothesized that vitamin D deficiency in healthy, community-dwelling, elderly individuals would be associated with low bone mass, decreased physical performance, and physiologic compensation with increased parathyroid hormone (PTH). We further postulated that the ingestion of a daily multivitamin containing 400 IU of vitamin D, coupled with 200–400 IU of vitamin D from calcium supplements, could resolve vitamin D deficiency in 3 months. To address these issues, we examined the relationship between vitamin D status and bone mass in postmenopausal women screened for an osteoporosis prevention and treatment study. Following a 3-month run-in period with vitamin D therapy (average 600 IU/d), we assessed the efficacy of this treatment and the physiologic response.


   METHODS
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 Abstract
 Methods
Results
 Discussion
 References
 
Participants
We recruited ambulatory, community-dwelling, postmenopausal women aged 65 years or older for an osteoporosis prevention and treatment study (13). Women were ineligible if they had any history of illness or had previously taken any medications known to affect bone mineral metabolism. Other exclusion criteria included a known history of vitamin D deficiency, significant malabsorption, contraindication for hormone replacement therapy or alendronate (the medications used in the trial), and a baseline hip bone mineral density of ≥0.900 g/cm2. The study was approved by the Institutional Review Board at the Beth Israel Deaconess Medical Center in Boston, Massachusetts. All participants were advised of the nature of the study, and written informed consent was obtained prior to enrollment.

Between January 1996 and December 1997, 573 women signed informed consent and were screened for participation. Of these, 485 met the eligibility criteria and were enrolled in a 3-month, open-label run-in phase; 373 of these women successfully completed the run-in phase. Our report focuses on baseline vitamin D levels among all women who were screened and provided a baseline serum sample, and on the results of the intervention during the run-in phase. Reasons for discontinuation during the run-in phase were previously described (14). During the run-in phase, all participants received a daily multivitamin (GeriCare Pharmaceuticals Corp., Brooklyn, NY) containing 400 IU of vitamin D. In addition, if necessary, they received one or two vitamin D-containing calcium supplements (calcium carbonate 600 mg, vitamin D 200 IU; Caltrate Plus D; Wyeth-Ayerst, Philadelphia, PA) so that their total daily calcium intake was >1000 mg and their total daily vitamin D intake was 400–800 IU. If participants were ingesting their own multivitamin, vitamin D supplement, or calcium supplement, they were instructed to discontinue the supplements in favor of those used in the study. Dietary calcium and vitamin D intake were assessed with a validated food frequency questionnaire (15). During the run-in phase, all participants were instructed to take a daily oral alendronate placebo tablet with water 30 minutes prior to breakfast on an empty stomach. In addition, the women received daily oral hormone replacement therapy (conjugated equine estrogen 0.625 mg/d [Premarin; Wyeth-Ayerst) for hysterectomized participants; conjugated equine estrogen 0.625 mg/d with medroxyprogesterone 2.5 mg/d [Prempro; Wyeth-Ayerst] for participants with an intact uterus).

Outcome Variables
Clinical characteristics.-- Weight was measured with an ACME Digital In-Bed Scale (model 0501; ACME Scale Co., San Leandro, CA), and height was measured to the nearest millimeter with a Harpenden stadiometer (Holtain, Ltd., Crymych, Dyfed, U.K.). Body mass index was calculated as kilograms per meter squared.

Indices of bone and mineral metabolism.-- Following an overnight fast, a serum sample was obtained between 6 AM and 8 AM and stored at –80°C. Serum 25-hydroxyvitamin D (ng/ml) was measured by radioimmunoassay (DiaSorin, Stillwater, MN; intra-assay coefficient of variation [CV] 10.8%). We measured intact serum PTH (pg/ml) by Allegro Immunoradiometric Assay (Nichols Allegro, San Juan-Capistrano, CA; intra-assay CV 1.8%–3.4%). Serum tests for bone formation included intact osteocalcin (ng/ml, Novocalcin; Metra Biosystems, Mountainview, CA; intra-assay CV 4.8%–10.0%) and bone-specific alkaline phosphatase (U/L, Alkphase-B; Metra Biosystems; intra-assay CV 3.9%–5.8%). A second-void urine collection, obtained after an overnight fast, was assessed for urinary N-telopeptide cross-linked collagen type 1 (NTx, nmol bone collagen equivalents/mmol creatinine) with an enzyme-linked immunosorbent assay (Osteomark7; Ostex International, Inc., Seattle, WA; interassay CV 5%–19%).

Bone mineral density.-- Bone mineral density of the nondominant hip (total hip, femoral neck), posteroanterior spine (L1-L4), and lateral spine (L2-L4) were measured by dual-energy x-ray absorptiometry (DXA) using a QDR-4500A densitometer (Hologic, Inc., Bedford, MA). The CV at our center was 1.5% at the PA spine, 1.2% at the total hip, and 1.9% at the femoral neck (16,17).

Physical performance and activity scales.-- The Physical Performance Assessment (18–22) consisted of a modified group of previously tested measures of balance and mobility, including the one-legged stand (most difficult), tandem standing (intermediate), side-by-side standing (easiest), timed rise from a chair (three times), and a timed walk measuring 15 feet at both a normal pace and "as fast as felt safe." The Physical Activity Scale of the Elderly (PASE; New England Research Institute, Inc., Watertown, MA) is a brief, reliable, and valid instrument for the assessment of physical activity in older women (23). Scores are calculated from weights and frequency values for each of 12 types of activities, including recreation (light, moderate, strenuous, or sport), muscle strength and endurance exercises, housework (light or heavy), home repairs, lawn work, outdoor gardening, caring for another person, and working as a volunteer. Four hours of light housework each day would give a score of 100. The 27-point Instrumental Activities of Daily Living (IADL) from Lawton and Brody (24) measures a set of behaviors, including using the telephone, shopping, preparing food, housekeeping, laundering, using transportation, using medicines, and handling finances.

Statistics.-- Serum vitamin D status was classified as normal (25-hydroxyvitamin D ≥ 20.0 ng/ml), vitamin D insufficient (10.0 to < 20.0 ng/ml), or vitamin D deficient (< 10.0 ng/ml) as previously described (25,26). Results were presented as mean ± standard deviation. The Wilcoxon signed rank test, a nonparametric version of a paired t test, was used to assess changes from baseline to month 3 for continuous variables. McNemar's test was used to assess the significance of changes in vitamin D status from baseline to month 3, with vitamin D status classified as improvement or no change; no participants' vitamin D status deteriorated between baseline and 3 months. The Kruskal–Wallis test, a nonparametric version of analysis of variance, was used to assess differences at baseline between groups defined by vitamin D deficiency. Spearman's rank correlation was used to assess the relationship between continuous variables.


   RESULTS
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 Results
Discussion
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Clinical Characteristics
Of the 573 participants who were eligible for screening, 553 had baseline serum vitamin D levels available and were included in the analysis. The participants' mean age was 72 ± 6 years, and their mean body mass index was 28 ± 6 kg/m2. The average daily dietary intake of vitamin D and calcium at baseline were 258 ± 220 IU and 889 ± 435 mg, respectively. The mean supplementary intake of calcium was 198 ± 369 mg/d; 7% of participants were taking some form of supplemental vitamin D. As a group, baseline levels of serum calcium and PTH were within the normal range (Table 1). However, 16% of the group had vitamin D deficiency, and 48% had vitamin D insufficiency. At baseline, serum PTH was greatest in the group with vitamin D deficiency (p <.05 between groups).


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  		Table 1. Baseline Variables Grouped by Baseline Vitamin D Status (N = 553).

 
There were no statistically significant differences in baseline bone mineral density of the PA or lateral spine, total hip, or femoral neck, regardless of vitamin D status (Table 1). There were no differences in age or dietary calcium intake among participants grouped by vitamin D status. However, daily dietary intake of vitamin D and supplementary calcium intake were significantly lower in the participants with vitamin D deficiency. Serum osteocalcin was highest in those who were vitamin D deficient, but levels of bone-specific alkaline phosphatase and urinary NTx were not significantly different among the three vitamin D groupings. In patients with vitamin D deficiency, the physical activity score was lowest and the walking time was longest (Table 1).

At baseline, serum vitamin D was negatively correlated with serum PTH (r = –0.29, p <.0001); vitamin D was weakly positively associated with daily vitamin D intake (r = 0.14, p <.001) and supplementary calcium intake (r = 0.13, p <.01). A plot of serum vitamin D versus serum PTH suggested that PTH became elevated as serum vitamin D levels decreased below 28 ng/mL (Figure 1). At baseline, the mean PTH value was 11% higher in participants with vitamin D insufficiency and 36% higher in those with vitamin D deficiency compared to those who had a normal vitamin D level.



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  		Figure 1. Baseline parathyroid hormone (PTH) and 25-hydroxyvitamin D levels in community-dwelling elderly women at baseline. The line shown is a locally smoothed regression line (LOESS) of PTH given 25-hydroxyvitamin D (27). Twenty-six observations with PTH above 80 pg/ml are not shown (mean vitamin D level 13.1 ng/ml) to allow details of the LOESS curve to be visible

 
Vitamin D Status Following 3-Month Run-In Period
During the 3-month run-in phase, 55% (n = 199) of participants received one daily calcium tablet containing 200 IU of vitamin D, and 11% (n = 40) received two daily tablets providing an additional 400 IU of vitamin D. Thirty-four percent (n = 123) did not require a calcium supplement. In the 373 women who completed the 3-month run-in phase, serum 25-hydroxyvitamin D increased by 62% (p <.001, Table 2), serum calcium decreased by 2% (p <.05), and PTH was elevated by 13% (p <.001). At the conclusion of the run-in period, no women had vitamin D deficiency, and vitamin D insufficiency decreased from 48% to 20% (p <.001, Table 2). The vitamin D dose-response was similar in patients receiving 400, 600, or 800 IU of vitamin D per day; i.e., serum vitamin D levels returned to normal in 75%, 81%, and 79% of women, respectively.


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  		Table 2. Vitamin D Status Before and After Run-In (N = 373).

 

   DISCUSSION
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 Abstract
 Methods
 Results
 Discussion
References
 
We found that 16% of women with vitamin D deficiency at baseline were effectively treated with oral vitamin D supplementation of 400–800 IU over 3 months. In addition, the incidence of vitamin D insufficiency in older women decreased from 48% at baseline to 20% after 3 months of therapy with vitamin D supplementation. Furthermore, at baseline, a low level of vitamin D was associated with a higher level of PTH, but was not associated with lower vertebral bone mass or greater bone resorption, as assessed by urinary NTx. Finally, vitamin D deficiency was associated with decreased physical activity and slower gait.

Our findings are concordant with those of several other investigations, which have demonstrated the high prevalence of severe and moderate vitamin D deficiency in older women (1–4). Because our participants were recruited over an 18-month period, their low serum vitamin D levels are unlikely to be due to the seasonal variations found in the New England region (28,29). On average, the vitamin D intake of our cohort was approximately 200–300 IU/d, which is well below the National Academy of Sciences' suggested intake of 400–600 IU/d (30).

We did not find any association between vitamin D status and bone mass, as assessed by DXA of the hip or spine. This is in contrast to Villareal and colleagues (6), who reported that 49 women with low vitamin D levels (<15 ng/mL) had reduced vertebral bone density, as assessed by Quantitative Computed Tomography [QCT]. Ooms and colleagues (31) examined 330 healthy women over the age of 70 years and found that serum 25-hydroxyvitamin D was related to bone mineral density by DXA of the femoral neck, but only in women with levels of approximately 12 ng/mL or less. We analyzed only women with vitamin D deficiency for associations with bone mineral density, and found none. However, we did find an association between vitamin D deficiency, decreased physical activity, and slower gait. Similar findings have been reported in healthy, older men (32).

Following treatment with a daily multivitamin with or without a vitamin D-containing calcium supplement, hormone replacement therapy, and alendronate placebo for 3 months, serum 25-hydroxyvitamin D levels increased 62%. Although 80% of participants were within the normal range, 20% still were vitamin D insufficient. It is unlikely that the elemental calcium or alendronate placebo had an effect on vitamin D status. However, the changes in serum calcium and PTH may be explained by the hormone replacement therapy. Estrogen can antagonize the effect of PTH, which could transiently lower serum calcium. This would stimulate feedback in the form of a slight increase in serum PTH levels. Although estrogen can increase vitamin D binding protein, this does not have an impact on 25-hydroxyvitamin D levels (33,34).

This study has several strengths. All participants were followed at the same facility and were administered the same food frequency questionnaire by the same research team to assess baseline vitamin D intake. Furthermore, bone mass measurements were all performed on the same densitometer by the same technologist. Finally, our cohort included women over the age of 65 years, the population most likely to have osteoporosis, sustain osteoporotic fractures, and be vitamin D deficient.

There are also several weaknesses in this study. To minimize noncompliance and withdrawal following randomization, a 3-month run-in phase was conducted, during which all participants received hormone replacement therapy and alendronate placebo in addition to calcium and vitamin D supplementation. As anticipated, approximately 25% withdrew during the run-in period (14). Therefore, we could not determine if any women discontinued due to side effects or inconvenience caused by the calcium or vitamin D supplement. Second, we elected not to examine changes in bone mass, biochemical markers of bone turnover, or physical activity, as these outcomes may be substantially influenced by hormone replacement therapy. Thus, we could not assess whether there were changes in bone markers specifically related to calcium and vitamin D supplementation alone. Finally, we performed pill counts for hormone replacement therapy and alendronate placebo to determine eligibility for randomization, but we did not verify adherence with the calcium and vitamin D supplements. However, women who were randomized into the clinical trial were ≥80% adherent with hormone replacement therapy and alendronate (13). It is probable that the adherence rate was similar for calcium and vitamin D supplementation, because the women had no knowledge of what would be involved in determining adherence.

Vitamin D sufficiency has been shown to be important in several clinical trials (11,12,35), but not all investigators agree on the degree of importance (36–38). Chapuy and colleagues (11) administered calcium and 800 IU of vitamin D to nursing home residents, and demonstrated a 43% reduction in hip fractures over 1.5 years. Baseline levels of 25-hydroxyvitamin D were in the moderately low range and increased with treatment, suggesting that the treatment of hypovitaminosis D played a significant role in hip fracture reduction. Lips and colleagues (39) have previously shown that 400 IU of vitamin D normalized vitamin D status in approximately 12 weeks in an elderly, nursing home-based female population. Our study is in agreement with the above findings and suggests that an inexpensive multivitamin containing 400 IU of vitamin D plus one to two calcium supplements containing 200 IU of vitamin D per tablet, for a total vitamin D intake ranging from 400–800 IU/d, can return the majority of healthy, community-dwelling women to what may be considered "normal" in 3 months. However, whereas some investigators have considered that serum vitamin D levels of 20 ng/mL are a reasonable cut-off for normal (1,40), others feel that vitamin D levels should be greater than 30 ng/mL for maintenance of skeletal integrity (41). In the present study, with vitamin D levels at 28 ng/ml and above, serum PTH levels had reached a plateau.

Conclusion
We found that mild vitamin D deficiency was common in healthy, community-dwelling elderly women. In addition, we found that daily ingestion of a multivitamin, containing 400 IU of vitamin D, and a calcium supplement containing 200–400 IU of vitamin D allowed serum vitamin D levels to normalize in 80% of women within 3 months. In these healthy participants, baseline vitamin D levels were not associated with bone mass, but were associated with decreased physical activity. Physicians should consider adding vitamin D assessments to their list of preventive health evaluations in older patients. Further studies are needed to examine the impact of vitamin D supplementation on biochemical markers of bone turnover and to determine if treatment efficacy is dependent on duration of vitamin D supplementation.


   Acknowledgments
 
Financial support was provided to Dr. Susan Greenspan from the National Institutes of Health/National Institute on Aging (grant R01 AG13069) and to the Harvard-Thorndike General Clinical Research Center, Beth Israel Deaconess Medical Center, from the National Institutes of Health/National Center for Research Resources (grant M01 RR013032). Merck Research Laboratories provided the alendronate and alendronate placebo, and Wyeth-Ayerst Laboratories provided the hormone replacement therapy and supplements for this study.

We gratefully acknowledge the assistance of the nursing, nutrition, study, and administrative staff of the Harvard-Thorndike General Clinical Research Center and the Osteoporosis Prevention and Treatment Center at the Beth Israel Deaconess Medical Center where the study was conducted. We also thank Wyeth-Ayerst Laboratories (Philadelphia, PA) for providing the vitamin D and calcium for this study.

Neil M. Resnick is now with the University of Pittsburgh, Pittsburgh, Pennsylvania.

Robert A. Parker is now with the Harvard School of Public Health, Boston, Massachusetts.


   Footnotes
 
Decision Editor: John E. Morley, MB, BCh

Received February 19, 2004

Accepted March 22, 2004


   References
Top
 Abstract
 Methods
 Results
 Discussion
 References
 

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