Relation of Ascorbic Acid to Bone Mineral Density and Self-reported Fractures among US Adults
Joel A. Simon1,2 and
Esther S. Hudes2
1 General Internal Medicine Section, Medical Service, Veterans Affairs Medical Center, San Francisco, and University of California, San Francisco, CA.
2 Department of Epidemiology and Biostatistics, University of California, San Francisco, CA.
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ABSTRACT
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Ascorbic acid is an essential nutrient involved in collagen formation, and its deficiency is associated with abnormal bone development. To examine the relation of ascorbic acid to bone mineral density and the prevalence of self-reported fractures, the authors analyzed data collected from 13,080 adults enrolled in the Third National Health and Nutrition Examination Survey (NHANES III) during 19881994. Because they identified three-way interactions among smoking, history of estrogen use, and dietary and serum ascorbic acid in postmenopausal women, they analyzed these relations stratified by smoking and estrogen use. Dietary ascorbic acid intake was independently associated with bone mineral density among premenopausal women (p = 0.002). Among men, serum ascorbic acid was associated in a nonlinear fashion with bone mineral density (p < 0.05), and dietary ascorbic acid intake was associated in a nonlinear fashion with self-reported fracture (p = 0.05). Among postmenopausal women without a history of smoking or estrogen use, serum ascorbic acid was unexpectedly associated with lower bone mineral density (p = 0.01). However, among postmenopausal women with a history of smoking and estrogen use, a standard deviation increase in serum ascorbic acid was associated with a 49% decrease in fracture prevalence (p = 0.001). Dietary and serum ascorbic acid measures were associated inconsistently with bone mineral density and self-reported fracture among adult participants in NHANES III.
ascorbic acid; bone density; fractures; osteoporosis
Abbreviations:
NHANES III, Third National Health and Nutrition Examination Survey
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INTRODUCTION
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Osteoporosis, affecting both women and men, is highly prevalent among older Americans and is an important risk factor for clinical fractures (1
). A number of dietary factors have been identified as associated with bone mineral density including calcium, vitamin D, caffeine, and alcohol. Ascorbic acid deficiency has been associated with decreased bone density in a few experimental animal studies (2
, 3
). In animals, such deficiency affects vitamin D metabolism and, in turn, the risk of osteoporosis (4
). In humans, some observational studies (5





12
), but not all (13
), have reported an association between ascorbic acid intake or blood levels and bone mineral density. Although marked abnormalities in bone metabolism and growth have been described among children with scurvy (14
), the relation of ascorbic acid to bone density over a wide range of intakes and blood levels has not been examined among a representative sample of the US population.
We undertook this study to examine whether dietary ascorbic acid intake and serum ascorbic acid levels were associated with bone mineral density and the prevalence of self-reported fractures among participants in the Third National Health and Nutrition Examination Survey (NHANES III). We were specifically interested in whether low serum ascorbic acid levels (<0.2 mg/dl) (15
) were a risk factor for low bone mineral density. Because other investigators have described possible interactions between ascorbic acid and calcium intake (11
), smoking (12
), and postmenopausal estrogen therapy (10
) on bone mineral density or fracture, we also were interested in exploring whether these factors modified the association between ascorbic acid, bone mineral density, and self-reported fractures.
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MATERIALS AND METHODS
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Subjects
NHANES III was a national probability survey of approximately 40,000 Americans conducted between 1988 and 1994 that used a stratified, cluster sampling design to oversample populations of special interest (16
). Participants aged from 2 months to > 90 years were enrolled, interviewed, and examined by study personnel (16
). Our analysis used data from the examination, laboratory, and adult participant files. A total of 17,705 participants had at least some information in all three files. Complete data from 6,943 women and 6,137 men between the ages of 20 and 90 years were available for analyses examining the relation of ascorbic acid to self-reported fracture, representing approximately 86 percent of the total number of adult participants with valid serum ascorbic acid values. Because not all these adult participants obtained bone mineral density measurements, analyses examining the relation of ascorbic acid to bone mineral density were possible for 3,204 premenopausal women, 2,906 postmenopausal women, and 5,739 men representing 78 percent of the total number of adult participants with valid serum ascorbic acid values. NHANES III recorded subjects >90 years as being aged 90. A total of 25 participants with extremely high serum ascorbic acid levels (>170 µmol/liter (3.0 mg/dl)) were excluded because such values were deemed of questionable validity (15
). Participants were excluded if there were missing data on variables judged to be potential predictors of bone mineral density or if outcome data on bone mineral density were unavailable. Comparison of participants included in analyses examining history of fracture with participants excluded for missing data revealed that both groups were similar demographically, but excluded participants were, on average, 3 years older, more likely women (55 percent vs. 52 percent), to have attained a lower level of education (11.6 years vs. 12.4 years), and more likely non-White (86 percent vs. 81 percent).
Measurements
NHANES III questionnaire data included self-reported age; race (categorized as White, Black, other); sex; years of education completed; level of leisure time physical activity; history of smoking; diabetes mellitus; level of alcohol intake; menopausal status; use of diuretic, cholesterol-lowering, and estrogen-containing medications; and dietary intake (16
). We considered women to be postmenopausal if 1) they were aged
55 years or if 2) they were younger than 55 years, had a uterus and at least one ovary, were not pregnant or breastfeeding, and reported no menstrual period during the prior 12 months. Quantitative nutrition data were collected using a 24-hour dietary recall. Because quantitative data on vitamin supplement use were not available, intake estimates were based solely on the 24-hour diet recall. Body mass index (weight (kg)/height (m)2) was provided in the data set to the nearest tenth and was entered into all models in that fashion. The questionnaires, dietary methods, and examination procedures used in NHANES III have been described in detail (16
).
Serum ascorbic acid and serum vitamin E (
-tocopherol) levels were measured at the Centers for Disease Control and Prevention by isocratic high performance liquid chromatography (17
). Serum ascorbic acid levels ranged from 0.0 to the upper cutpoint of 170 µmol/liter (3.0 mg/dl). Bone mineral density measurements of the proximal femur were made using dual-energy x-ray absorptiometry. We used the bone mineral density estimates from the total proximal femoral region for these analyses. Dual-energy x-ray absorptiometry scans were reviewed at the Mayo Clinic for quality control (16
). We ascertained whether participants had a history of clinical fracture by a positive response to the following questions: "Has a doctor ever told you that you had broken or fractured your hip, wrist, or spine?" (16
). Radiographs of the vertebral spine were not obtained.
Statistical methods
To account for all exclusions in a consistent fashion, we used unweighted numbers when reporting the starting sample sizes, exclusions, and final sample sizes in each of the three sex-stratified groups (premenopausal women, postmenopausal women, and men) and for the number of fracture events. All prevalence rates, means, and standard deviations are reported using sample weights. We used age- and multivariable-adjusted linear and logistic regression to examine the associations of dietary and serum ascorbic acid level with bone mineral density and with prevalence of self-reported fracture among the three sex-stratified groups. All the analyses take into account the complex survey design of NHANES III. The level of physical activity was analyzed as an ordinal variable. The multivariate models included age; race; level of education; physical activity; body mass index; cigarette smoking; alcohol consumption; thiazide diuretic use; diabetes mellitus; serum levels of vitamin D, vitamin E, and thyroid-stimulating hormone; and dietary intake of calories, fat, protein, calcium, and caffeine. For premenopausal women, oral contraceptive use, history of pregnancy, and number of livebirths were also entered into the models. Among postmenopausal women, we identified interactions among smoking, estrogen use, and bone mineral density/fracture by including cross-product terms in linear and logistic regression models. We tested for but did not find an interaction among dietary calcium intake, ascorbic acid, and bone mineral density/fractures. All the variables included in the models have been reported, in at least some studies, to be associated with bone mineral density. Serum vitamin E was included in the multivariate models because it an important antioxidant nutrient often correlated with ascorbic acid intake and may be itself a predictor of bone mineral density. We tested for nonlinear relations by including linear and quadratic terms for dietary and serum ascorbic acid. For men, the figures examining the relation of serum ascorbic acid to bone mineral density and the relation of dietary ascorbic acid to self-reported fractures are based on multivariate linear and logistic regression models, respectively. We plotted predicted bone mineral density as a function of serum ascorbic acid level (within each 0.1-mg/dl increment of serum ascorbic acid) and predicted prevalence of self-reported fracture as a function of dietary ascorbic acid intake (in 1-mg/day increments). These predicted values were then smoothed using a locally weighted symmetric nearest neighbor linear smoother (18
, 19
) that allows for the use of sample weights (20
, 21
).
Analyses were performed using Stata Corporation software that included commands for the analysis of complex survey data (22
). For each predictor variable, we calculated slopes (for bone mineral density) and odds ratios (for self-reported fractures) with corresponding 95 percent confidence intervals. We considered two-tailed p values of <0.05 to be statistically significant.
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RESULTS
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The baseline characteristics of 6,943 women and 6,137 men, aged 2090 years and enrolled in NHANES III with complete data available for these analyses, are presented in table 1. A total of 186 premenopausal women (7 percent), 392 postmenopausal women (13 percent), and 649 men (12 percent) reported a history of one or more fractures. Of these participants, 6 percent of premenopausal women, 18 percent of postmenopausal women, and 7 percent of men reported a hip fracture; 84 percent of premenopausal women, 74 percent of postmenopausal women, and 81 percent of men reported a wrist fracture; and 12 percent of premenopausal women, 18 percent of postmenopausal women, and 16 percent of men reported a vertebral fracture. On average, men had higher caloric intakes; greater dietary consumption of fat, protein, alcohol, and caffeine; and greater bone mineral density measurements. We also examined whether the percentage of calories from fat and protein differed among the three groups. There was no significant difference between premenopausal women and men in the percentage of calories consumed from fat or protein (both p > 0.05), but postmenopausal women consumed a slightly smaller percentage of calories from fat (p < 0.01) and a slightly larger percentage of calories from protein compared with men (p < 0.001). Standard deviations for serum ascorbic acid level were approximately 0.40.5 mg/dl for the three groups. The correlation coefficients between serum ascorbic acid and dietary ascorbic acid ranged from 0.26 to 0.29 among the three groups (all p < 0.001). The correlations between bone mineral density and self-reported fracture (analyzed as a dichotomous variable) were -0.02 among premenopausal women (p = 0.46), -0.14 among postmenopausal women (p < 0.001), and -0.05 among men (p = 0.07).
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TABLE 1. Characteristics of 13,080 participants aged 2090 years enrolled in the Third National Health and Nutrition Examination Survey, 19881994*
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Premenopausal women
Among premenopausal women, increasing levels of dietary ascorbic acid were independently associated with bone mineral density; each 100-mg/day increase in dietary ascorbic acid was independently associated with an increase of 0.01 g/cm2 in total hip bone mineral density (p = 0.002) (table 2). Serum ascorbic acid, however, was not associated with bone mineral density and neither dietary ascorbic acid nor serum ascorbic acid was associated with self-reported fracture (all p > 0.55).
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TABLE 2. Relation of ascorbic acid level to hip bone mineral density (g/cm2) among 11,849 participants aged 2090 years enrolled in the Third National Health and Nutrition Examination Survey, 19881994
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FIGURE 1. Serum ascorbic acid and hip bone mineral density among men, Third National Health and Nutrition Examination Survey (NHANES III), 19881994. The relation of predicted hip bone mineral density (BMD) (g/cm2) among men enrolled in the NHANES III as a function of serum ascorbic acid (mg/dl). The figure is based on a multivariate model that adjusted for age; race; level of education; physical activity; body mass index; use of thiazide diuretics; dietary intake of calories, fat, protein, calcium, caffeine, and alcohol; history of smoking (never/past/current); history of diabetes; and serum levels of thyroid-stimulating hormone, vitamin D, and vitamin E. Multivariate analyses revealed significant linear and quadratic terms for serum ascorbic acid (p < 0.05).
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TABLE 3. Relation of ascorbic acid level to self-reported fractures among 13,080 participants aged 2090 years enrolled in the Third National Health and Nutrition Examination Survey, 19881994
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FIGURE 2. Dietary ascorbic acid and self-reported fracture among men, Third National Health and Nutrition Examination Survey (NHANES III), 19881994. The relation of predicted probability of self-reported fracture among men enrolled in NHANES III as a function of dietary ascorbic acid intake (mg/day). The figure is based on a multivariate model that adjusted for age; race; level of education; physical activity; body mass index; use of thiazide diuretics; dietary intake of calories, fat, protein, calcium, caffeine, and alcohol; history of smoking (never/past/current); history of diabetes; and serum levels of thyroid-stimulating hormone, vitamin D, and vitamin E. Multivariate analyses revealed significant linear and quadratic terms for dietary ascorbic acid intake (p < 0.05).
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Postmenopausal women
In analyses unstratified by smoking status and use of estrogen-containing medication, neither dietary ascorbic acid intake nor serum ascorbic acid was associated with bone mineral density or self-reported fracture (all p
0.35) (tables 2 and 3). Because we detected significant three-way interactions with smoking and use of estrogen-containing medication, additional analyses examining the relation of ascorbic acid to bone mineral density and self-reported fractures were conducted stratified by smoking history (ever vs. never) and history of postmenopausal estrogen use (ever vs. never). Among postmenopausal women who had no history of smoking or estrogen use, serum ascorbic acid levels were inversely associated with bone mineral density; each standard deviation (0.49 mg/dl) increase was associated with a 0.01-g/cm2 decrease in total hip bone mineral density (p < 0.05) (table 4). Neither dietary ascorbic acid intake nor serum ascorbic acid levels among the other subgroups of postmenopausal women were associated with bone mineral density, although dietary ascorbic acid intake was marginally associated with increased bone mineral density among smokers without a history of postmenopausal estrogen use (p = 0.05). In analyses examining the relation of ascorbic acid to prevalence of self-reported fractures, each standard deviation increase in serum ascorbic acid levels in postmenopausal women with a history of both smoking and estrogen use was independently associated with a 49 percent lower prevalence of fractures (p = 0.001) (table 5). Otherwise, dietary ascorbic acid intake and serum ascorbic acid levels were not significantly associated with prevalence of self-reported fracture.
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TABLE 4. Relation of ascorbic acid level to hip bone mineral density (g/cm2) among 2,906 postmenopausal women participants enrolled in the Third National Health and Nutrition Examination Survey, 19881994, stratified by smoking status and history of estrogen replacement therapy use
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TABLE 5. Relation of ascorbic acid level to self-reported fracture among 3,165 postmenopausal women participants enrolled in the Third National Health and Nutrition Examination Survey, 19881994, stratified by smoking status and history of estrogen replacement therapy use
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Men
Among men, serum ascorbic acid levels were associated in a nonlinear fashion with bone mineral density (p < 0.05); predicted bone mineral density peaked at serum ascorbic acid levels between 0.5 mg/dl and 1 mg/dl and declined gradually at higher serum ascorbic acid levels (figure 1). Dietary ascorbic acid intake was associated in a nonlinear fashion with self-reported fracture (p = 0.01) (figure 2). A dietary ascorbic acid intake of approximately 200 mg/day was associated with the lowest prevalence of self-reported fractures. At ascorbic acid intakes less than approximately 100 mg/day and greater than 250 mg/day, the prevalence of self-reported fractures among men rose. We specifically found that low serum ascorbic acid levels (<0.2 mg/dl) were associated with lower bone mineral density levels (p < 0.01) and with a nonsignificant 24 percent increased prevalence of self-reported fractures (p = 0.22).
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DISCUSSION
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Our principal findings were 1) among premenopausal women, dietary ascorbic acid was associated with greater bone mineral density in a linear fashion; 2) among postmenopausal women with a history of smoking and estrogen use, serum ascorbic acid was associated with a marked decreased prevalence of self-reported fractures but, unexpectedly, was also associated with lower bone mineral density among postmenopausal women without a history of either smoking or estrogen use; and 3) among men, serum ascorbic acid and dietary ascorbic acid were associated in a nonlinear fashion with bone mineral density and self-reported fracture, respectively.
On the basis of the observation that ascorbic acid is a nutrient essential for collagen formation and normal bone development (14
), we hypothesized that ascorbic acid status would be associated with bone mineral density. In the guinea pig, ascorbic acid deficiency results in decreased collagen synthesis and bone density (2
, 3
), in part by affecting vitamin D metabolism and binding (4
). Ascorbic acid has also been reported to affect markers of osteoblast activity (23
). Ascorbic acid deficiency has also been associated with osteoporosis in Black South African men in several older studies (5
7
). More recent studies have examined dietary and supplement intake of ascorbic acid as a correlate of bone mineral density (9
11
, 24

27
) or hip fracture (12
). With the exception of the Honolulu Heart Study that included 1,208 men of Japanese ancestry (24
), these studies have included only women (9

12
, 25
27
) and none have examined the relation of blood ascorbic acid levels to bone mineral density or fracture. The prior studies have measured bone mineral density at different sites and reported, albeit inconsistently, a positive association between dietary ascorbic acid consumption or supplement use and bone mineral density. We tested for nonlinear associations and found several significant or marginally significant curvilinear associations, particularly among men. Although osteoporosis affects approximately one of eight men (28
), most of the studies examining the relation of ascorbic acid to bone mineral density have focused on women and, hence, we are unable to compare our findings among men with those of other published studies.
Some investigators found ascorbic acid associated with bone mineral density or hip fracture only among subgroups of women (10
12
). Although we were unable to detect an interaction between ascorbic acid and calcium intake, we did find that smoking and use of postmenopausal estrogens modified the association of ascorbic acid with bone mineral density or self-reported fracture. We found that increasing serum ascorbic acid levels were associated with a decreased prevalence of self-reported fractures among postmenopausal women with a history of estrogen use (and smoking), whereas the Fracture Intervention Trial reported an association between ascorbic acid supplement use and bone mineral density, but only among postmenopausal women without a history of estrogen use (10
). Although the explanation for the differences between studies is unclear and may be the result of chance, the interactions themselves were not entirely unexpected. Estrogen-containing medication increases the turnover of ascorbic acid (29
) and is associated with lowered ascorbic acid levels in the leukocytes, platelets, and plasma of guinea pigs, primates, and humans (30


34
). Many studies have also demonstrated that smoking decreases the absorption and increases the turnover of ascorbic acid, thereby lowering blood ascorbic acid levels (15
).
Our study has several strengths and limitations worthy of mention. Because NHANES III surveyed a large probability sample of Americans, our findings should be generalizable to the US population. We believe the slight demographic differences between the 86 percent of adult participants included and the 14 percent of participants excluded are unlikely to substantially affect the generalizability of our findings. Further, the measurement of serum ascorbic acid levels on a large sample of the population allows a more reliable assessment of ascorbic acid status as a correlate of bone mineral density compared with studies using dietary intake estimations only. We found a three-way interaction among ascorbic acid, smoking, and postmenopausal estrogen use. Because three-way interactions are often difficult to replicate and may be the result of chance, these results should be interpreted cautiously. We detected several nonlinear associations and one inverse association between serum ascorbic acid and bone mineral density among postmenopausal women without a history of smoking or estrogen use that were unexpected, and it is possible that some of these associations may also be chance findings. Measurement error as reflected in the relatively low correlations between dietary ascorbic acid intake and serum ascorbic acid level and between bone mineral density and fracture prevalence may also be a factor in the inconsistency of our findings. Most importantly, because of the cross-sectional nature of the study, inferences regarding causality should be made cautiously.
Among a probability sample of the US population, dietary ascorbic acid intake and serum ascorbic acid levels were associated, at least in some subgroups, with bone mineral density and self-reported fracture. These associations were inconsistent and similar to prior reports, and some were nonlinear. Ongoing clinical trials of antioxidants for the prevention of cardiovascular and eye disease provide other potential venues for examining these relations, unbiased by differential recall or unknown confounding.
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ACKNOWLEDGMENTS
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This study was supported by Roche Vitamins, Inc., and US Public Health Service grant HL53479.
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NOTES
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Reprint requests to Dr. Joel A. Simon, General Internal Medicine (111A1), San Francisco VA Medical Center, 4150 Clement Street, San Francisco, CA 94121 (e-mail: jasimon{at}itsa.ucsf.edu).
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Received for publication August 1, 2000.
Accepted for publication February 15, 2001.