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* Department of Nutritional Sciences and
Department of Physiology, University of Arizona, Tucson, AZ 85721;
** Department of Pediatrics, Center for Applied Research and Evaluation, University of Arkansas for Medical Sciences, Little Rock, AR 72202
2To whom correspondence should be addressed. E-mail: maurerj{at}email.arizona.edu.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONLITERATURE CITED |
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0.05) with greater positive BMD change at the trochanter and Ward’s triangle in women using HRT. Calcium was associated (P 0.05) with BMD change at the trochanter and femur neck for women not using HRT. In women using HRT in the lowest tertile of calcium intake, change in femur neck BMD increased linearly as iron intake increased. In women not using HRT, BMD increased in the women in the highest tertile of calcium intake. We conclude that HRT use appears to influence the associations of iron and calcium on change in BMD.
KEY WORDS: • bone mineral density • hormone replacement therapy • iron • postmenopausal
Osteoporosis is a debilitating disease that is characterized by substantial loss of bone mass and structure, which leads to increased risk of fracture. It is estimated that 10 million Americans are currently diagnosed with the disease, whereas an additional 34 million have decreased bone mass that increases their risk for osteoporosis-related fractures in their lifetime (1). There will be a larger increase in the incidence of osteoporosis unless effective preventative strategies are developed. Numerous studies have explored the relations among nutrients and bone health (2–6), mainly calcium and vitamin D; however, little research has been done examining the relation of bone with other nutrients, such as iron, that have a more minor but still biologically important role in bone health (7–11). Animal studies have found a relation between iron deficiency and bone strength (9–11) that may be associated with iron’s role in collagen maturation and osteoblast function (10,12). In light of this research, there is a need to explore the role of dietary iron in osteoporosis prevention in humans.
Research published to date exploring how nutrient-bone mineral density (BMD)3 relations in postmenopausal women are affected by the use of hormone replacement therapy (HRT) has been limited mainly to calcium. This research indicates that higher calcium intake (closer to dietary recommended intake levels) may augment the beneficial effects of HRT on bone (13–16). The recent controversy over the safety and efficacy of the use of HRT in the treatment of postmenopausal osteoporosis (17) has decreased the number of women using HRT to around 28% of females 50–74 y old compared with 42% just 2 y earlier (18). Given that over one-quarter of women in this age range still use HRT, continued research into the effects of HRT on nutrient-BMD relations, outside of calcium in particular, is important.
This study was conducted as an extension of our unique findings from our cross-sectional analysis, which indicated that dietary iron was associated with baseline BMD in 242 healthy, nonsmoking postmenopausal women (19). Further cross-sectional analysis revealed a complex relation between iron and calcium with BMD. Based on these findings, our longitudinal analysis sought to determine whether cross-sectional nutrient-BMD relations persisted after 1 y and whether HRT use influenced these relations in 228 postmenopausal women who completed the first year of intervention in the Bone, Estrogen and Strength Training (B.E.S.T.) Study.
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METHODS |
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Subject recruitment and entry criteria. Inclusion criteria were as follows: 40–65 y old; surgical or natural menopause (3.0–10.9 y); BMI > 19.0 kg/m2 and <32.9 kg/m2; nonsmoking; no history of osteoporotic fracture and an initial BMD greater than Z-score of –3.0; undergoing HRT (1.0–5.9 y) or not undergoing HRT (>1 y); no weight gain or loss > 13.6 kg (30 lb) in the previous year; cancer and cancer treatment free for the past 5 years (excluding skin cancer); not using BMD-altering medications (examined on a case-by-case basis), ß-blockers or steroids; dietary calcium intake > 300 mg/d; performing <120 min of low-intensity, low-impact exercise per week and no weightlifting or similar physical activity. Subjects included in the study agreed to accept randomization to exercise or no-exercise groups, to continue their baseline level of physical activity (if not randomized to exercise) and dietary practices for the duration of the study, and to consume calcium supplements provided by the study.
Three hundred twenty-one women were enrolled into the study. Subjects were randomly assigned to either exercise or no-exercise conditions. Of the sample used in this analysis, 120 women were assigned to the exercise and 108 to the no-exercise conditions. The intervention for subjects randomized to exercise was described previously (21). Women who did not have a dual-energy X-ray absorptiometry (DXA) bone scan at baseline (n = 1) or 1 y (n = 50) or had implausible reported energy intake (n = 42) as described previously (19) were excluded from the analyses. After the exclusion criteria were applied, 228 women were included in the analysis; yielding 4 groups: HRT, exercise (n = 62); HRT, no exercise (n = 54); no HRT, exercise (n = 58); no HRT, no exercise (n = 54).
HRT. Women who used HRT followed regimens prescribed by their primary care providers. Consequently, a variety of regimens were used, although most women took oral estrogen (30%) or oral estrogen and progesterone (48%). Another 17% used transdermal (patch) estrogen and progesterone or estrogen alone, whereas the remaining 5% used estrogen and testosterone, progesterone alone, or other. Participants were encouraged to maintain the same regimen throughout the study and to report changes if they occurred. HRT use (type and regimen) was assessed at 6-mo intervals to monitor potential changes.
Calcium supplements. All participants received 800 mg/d of elemental calcium in the form of calcium citrate (Citracal, Mission Pharmacal) supplied by the study in blister packs in 2-mo allotments. The subjects were instructed to take 2 tablets (200 mg elemental calcium/tablet), twice a day, without food, with a minimum of 4 h between doses. The unused tablets were returned at the end of each 2-mo period and percentage compliance with calcium supplements was monitored at these time periods. Participants were considered compliant if they consumed at least 80% of the allotted pills during each period. The mean daily total calcium intake was calculated as the sum of reported mean daily calcium intake obtained from the diet records and mean intake from the calcium supplements.
DXA and anthropometry and body composition. The methodology for measurement of BMD of the 5 sites of interest, lumbar spine L2–L4, femur trochanter, femur neck, Ward’s triangle, and total body, along with anthropometric and body composition measurements, was described previously (20).
Diet assessment. Dietary intake was assessed from 8 randomly assigned days of diet records collected at baseline (3 d), 6 mo (2 d), and 12 mo (3 d). Each 2- to 3-wk recording period included 1 weekend day and 1–2 nonconsecutive weekdays. Subjects completed 11/2 h of diet record training prior to each recording period. Training consisted of participatory portion size and dimension estimation, directions on recording food descriptions, evaluation of portion size estimation accuracy, and calcium supplement intake directions. Participants did not receive dietary advice and were instructed not to change their diets during the study. Diet records were reviewed with the participants for completeness and accuracy by trained technicians. The diet records were analyzed for nutrient intake by trained technicians using the Minnesota Nutrient Data System versions 2.8–2.92.
Dietary analysis: nutrient inclusion criteria. The associations for mean dietary nutrient intake for iron (iron) and mean dietary plus supplemental nutrient intake for calcium (calcium) with 1-y changes in regional and total body BMD were the focus of this study. Iron supplementation was recorded on dietary records; however, use was subject-selected (of the 57% of women reporting supplement use <1% reported iron-alone supplements, <5% reported multivitamin with minerals) and compliance was not controlled nor was it measured; only a mean for dietary iron was used in analyses. Women were encouraged to report any supplements consumed as part of their dietary recall; however, they were advised not to take supplements with additional minerals to help prevent calcium supplementation above that provided by the study. The low percentage of women (<5%) who consumed supplements with minerals shows that adherence to this recommendation was high.
Statistical analysis. Statistical analyses were completed using the Statistical Package for the Social Sciences (Version 11.5). Distributions of all variables were examined and nutrient variables were log-transformed to meet the assumptions of statistical tests. All analyses were run including and excluding outliers for calcium and iron intake. Results did not differ, so outliers were included in final analyses. Subject characteristics at baseline and 1 y change were computed for all women and stratified by HRT use. Average nutrient intakes at each collection period (baseline, 6 mo, 12 mo) did not differ from one another; therefore, 8-d means of energy, dietary iron, and dietary plus supplemental calcium were calculated and used in analysis. Differences between nutrient data collection periods and HRT use groups were tested using the independent samples t test.
Multiple linear regression analysis was used to examine associations between iron and calcium as continuous variables (individually and combined) on the 1-y BMD change on each of the 5 bone sites adjusting for the effects of years past menopause (YPM), HRT use (HRT), 8-d mean energy intake (energy), change in body weight from baseline to 1 y (
wt), and baseline BMD (BBMD) of the bone site of interest. In addition, exercise (yes/no) was included as a covariate because it was shown to be predictive of BMD at the trochanter in previous analysis (20); however, because approximately equal numbers of exercisers and nonexercisers were in each tertile of calcium or iron intake, analyses were not stratified by exercise group for this paper. All of the listed potentially confounding variables have been shown to provide the best prediction model from our preliminary analyses, and previous research demonstrated that they can influence BMD (2,19). As a result of our previous findings that showed a complex relation between iron and calcium intake on cross-sectional BMD associations (19), nutrient interactions between dietary iron and calcium intake on BMD change were also examined. Due to our design (prospective, intervention), we were able to examine associations of dietary and supplemental calcium intake on BMD change, which could not be done in our previous cross-sectional analyses (19).
We used 3 models to test our hypotheses. Model 1 examined the association of iron on change in BMD, adjusting for YPM, HRT, exercise status, energy, wt, and BBMD. Model 2 examined the association of calcium on change in BMD, adjusting for the effects of the above-mentioned variables. Model 3, also called the "FullModel," included iron and calcium as independent variables, in addition to the covariates identified above, and the change in BMD as the dependent variable.
In order to depict the associations of iron and calcium on change in BMD, we created separate tertiles of iron and calcium and graphed the adjusted means (including all confounding variables from regression analyses) against the 1-y change in BMD using the general linear model procedure. These analyses are reported stratified by HRT status.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONLITERATURE CITED |
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Multiple regression with individual nutrients regressed on BMD.
The relations of iron and calcium were tested individually and together with 1-y change in BMD at all 5 bone sites using linear regression analysis while adjusting for the effects of YPM, HRT, exercise, energy, wt, and BBMD (Table 2). Only the results for the 3 bone sites (Ward’s triangle, femur neck, and trochanter) that demonstrated associations (P < 0.05) with iron and/or calcium from regression analysis are presented. To evaluate whether hormonal status affected nutrient-BMD relations, the same analysis was conducted with the sample stratified by HRT status (Table 2). In the total sample, using Model 1, iron was positively associated with change in femur trochanter and Ward’s triangle BMD (ß = 0.035, P < 0.05, and ß = 0.051, P < 0.05), but not with femur neck. After calcium was added to the model (Model 3), iron remained positively associated with change in BMD at the femur trochanter and Ward’s triangle (ß = 0.041, P < 0.05, and ß = 0.055, P < 0.05), indicating that iron is independently associated with change in BMD at these bone sites.
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When examining the association of calcium on BMD change in all women, we found that calcium was only associated with femur neck (ß = 0.062, P < 0.001). After adding iron to the model (Model 3), associations of calcium and BMD change remained significant, indicating that calcium has an independent effect on femur neck. However, after adding iron to the model, there was a negative effect on femur trochanter (ß = –0.04, P < 0.03). This led to the conclusion that iron may modify the relation between calcium and BMD.
Results from examining the calcium relations stratified by HRT supported the hypothesis that HRT use influences the relations of nutrients on BMD change. Interestingly, in women not using HRT, calcium (Model 2) was positively (ß = 0.07, P < 0.05) associated with change in femur neck BMD, but negatively (ß = –0.053, P < 0.05) associated with change in femur trochanter BMD. Similar associations were found when iron was added to the model (Model 3). No significant relationships were found between calcium and women using HRT, suggesting perhaps that HRT may override any effect of calcium on BMD. Overall, in regression models, calcium, alone or in combination with iron, accounted for between 6 and 10% of variance in BMD regardless of HRT use status.
Nutrient associations with BMD using tertiles of nutrient intake. Based on significant associations that were determined from regression Models 1 and 3 (Table 2), we further examined the nutrient-BMD relations using tertiles of iron intake with 1-y adjusted mean change in BMD stratified by HRT status (Fig. 1). A positive, linear relation occurred in change in femur trochanter and Ward’s triangle BMD as mean iron intake increased in women using HRT. In women not using HRT, there was the same positive linear relation between the first and second tertiles at the femur trochanter, but then a threshold effect of iron on change in BMD appeared. The positive linear relation found in women using HRT (Fig. 1) mirrored the relation shown when tertile of iron intake was graphed against adjusted mean change in femur trochanter and Ward’s triangle BMD for the full sample (data not shown).
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DISCUSSION |
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The mechanism for calcium’s beneficial effect on BMD has been described previously (4,24,25). Further, a recent meta-analysis based on 15 randomized controlled trials of 1806 patients concluded that calcium supplementation has a small but significant positive effect on bone density (26). The research to date exploring how calcium in combination with HRT affects BMD has reported synergistic effects; however, in our analyses calcium was significantly associated with BMD change only in women not using HRT. This discrepancy among studies could have resulted from our sample having overall higher mean calcium intakes (
1500 mg/d) compared to other studies (mean intakes 350 to 1100 mg/d) (13–15) and this higher calcium intake may have exceeded the threshold for which calcium would potentiate the beneficial effects of HRT on BMD.
Interpreting the unique finding of a positive association of iron with change in BMD in relation to HRT use is complicated. Two human studies previously reported a beneficial effect of iron on adult BMD, although both were cross-sectional (7,8). Angus et al. (7) also showed a positive association of iron on femur neck BMD (and forearm bone mineral content, which was not measured in our study) in premenopausal but not postmenopausal women. These researchers (7) did not report whether the postmenopausal women they assessed were on HRT and they used a less precise method for measuring BMD (dual photon absorptiometry) than that used in this study. Michaelsson et al. (8) demonstrated a positive association of iron from weighed dietary records with femur neck and also with lumbar spine and total body (not found in our analysis) using linear regression models. Michaelsson et al. (8) did include HRT in the regression model but did not stratify analysis by users and nonusers. Neither study discussed the biological significance or the potential mechanism(s) behind these associations of iron with BMD.
Three animal studies have found a relation between iron deficiency and bone (9–11). Most recently, Medeiros et al. (11) demonstrated significant morphological deterioration in trabecular bone in the spine of rats fed iron or calcium-restricted diets, concluding that iron contributes significantly to bone strength and integrity. Iron’s biological importance to bone is related to its role as a cofactor for hydroxylases in collagen synthesis (27), but it also has other implications in bone health and prevention of osteoporosis. It has been postulated that iron deficiency could decrease hydroxylation of 1,25-dihydroxycholecalciferol and lead to a decline in calcium absorption from the gut (10) and research has shown an association between iron overload and low bone mass (12). Unfortunately, no research exists that evaluates the optimal level of iron intake for bone health, making interpretation of our results complicated (in an overall iron replete population: 4 women had iron intakes of 7.3–7.8 mg/d and 1 woman had iron intake of 46 mg/d). Because the overall mean iron intake did not differ throughout 1 y or by HRT status in our population, the possibility arises that the individual variation in amount of iron consumed may be the factor related to change in BMD.
An additional unique finding was a direct relation of iron on positive change in BMD in relation to HRT use. The associations at the femur trochanter and Ward’s triangle bone sites illustrate an additive effect of higher iron with HRT use on change in BMD. Because the nutrient to BMD change relation varies with bone site, these findings lend support for more than one mechanism being involved in the demonstrated relation. There appears to be a synergistic effect on change in BMD at a particular level of iron intake, indicated by the steep slope of the lines between tertiles 2 and 3 for tertile of iron intake and 1-y change in BMD, both in femur trochanter and in Ward’s triangle for HRT users. For non-HRT users, this was also evident for Ward’s triangle, but there was a threshold effect for femur trochanter. These findings can support the potential for 2 mechanisms concerning different bone sites, but also a possible synergistic effect of the nutrient iron combined with hormone levels.
The results from the analysis of iron’s effect on change in BMD in relation to tertile of calcium intake further illustrate the complexity of the HRT and nutrient-BMD relation. Figures 3 and 4 illustrate these relations compared by HRT status and clearly show that HRT influences the relation between iron and calcium on change in BMD. The influence of HRT on nutrient relations with change in BMD is not consistent across bone sites. These inconsistencies among HRT status group and bone sites further support the theory that the relation of HRT and iron on change in BMD may differ by bone site and may be influenced in part by calcium intake, particularly at the femur neck in women not using HRT. The results from a recent meta-analysis of the efficacy of HRT in treating and preventing osteoporosis in postmenopausal women demonstrated a strong effect of HRT on BMD at both cortical and trabecular sites (28), suggesting that the differences in BMD change by bone site seen in this study in the women on HRT are likely mainly due to differences in calcium and/or iron. These results are limited by the small number of subjects in each category of calcium and iron intake. The relations found must be verified using a randomized clinical trial.
The complex relation between iron and calcium observed in our cross-sectional study (19) was not as clear in this longitudinal analysis, likely due to 4 main differences in this current analysis: 1) stratification by HRT status, 2) longitudinal design, 3) wider range of calcium intake due to inclusion of calcium supplementation, and 4) stratification of subjects into tertiles instead of grouping subjects by ranges of nutrient intake that reflected level of adequacy of intake in relation to the recommended daily allowances.
Understanding our finding that HRT status influences nutrient interactions with BMD change, particularly iron, in healthy postmenopausal women is difficult. Limited research has been reported on the effects of HRT on mineral status, not including iron (29–31), showing that women taking HRT have reduced excretion of zinc, calcium, and magnesium (29–31); improved serum levels of calcium, magnesium, copper, and zinc (29,30); and higher serum chromium levels (29), but clear mechanistic reasons for these influences on mineral status have not yet been identified.
Given that the B.E.S.T. study was not designed to evaluate the mechanism underlying the observed nutrient-BMD relations, we can only speculate from our longitudinal results that HRT, most likely estrogen, has some direct relation with bone metabolism in relation to iron level in postmenopausal women. This direct association of iron with change in BMD in women using HRT may be controversial because reported nutrient intake during 1 menopausal year may not be representative of nutrient intake during the years of peak bone mass accrual. Additionally, the accuracy of self-reported dietary intake is limited. However, the fact that bone is continually being remodeled lends credence to our findings because this would indicate that current nutrient intake plays an essential role in preservation of bone mass and mineral content (4). Last, 8 d of diet records provide more than a sufficient number of days to accurately estimate iron and calcium nutrient intake in postmenopausal women (32).
In conclusion, the results of this longitudinal analysis extend the unique findings of a positive association of iron with BMD in our cross-sectional study and demonstrate an influence of HRT on nutrient (iron and calcium)-BMD relations. These current results not only further support our original finding of an iron-BMD relation that may be influenced by calcium, but also extend it to change in BMD and suggest that the relation may be dependent upon HRT use. To our knowledge, this is the first study to report on the complex relation between iron and calcium on change in BMD in postmenopausal women using or not using HRT. Without biochemical assessments or molecular analysis, we are unable to propose a biological mechanism(s) for this relation; however, these results provide the basis for additional research into such a mechanism(s) underlying nutrient-BMD relations. Because HRT continues to be used by many women for the treatment of postmenopausal symptoms as well as defense against bone loss, more research must be done to explore the mechanisms behind the unique findings of this study.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations used: BBMD, baseline bone mineral density; B.E.S.T, Bone, Estrogen, Strength Training; BMD, bone mineral density; calcium, dietary plus supplemental calcium; DRI, dietary reference intake; DXA, dual-energy X-ray absorptiometry; HRT, hormone replacement therapy; iron, dietary iron; YPM, years past menopause.
Manuscript received 13 July 2004. Initial review completed 9 August 2004. Revision accepted 5 January 2005.
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LITERATURE CITED |
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