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Effects of Calcium, Vitamin D, and Hormone Therapy on Cardiovascular Disease Risk Factors in the Women's Health Initiative

A Randomized Controlled Trial

Schnatz, Peter F., DO; Jiang, Xuezhi, MD, PhD; Aragaki, Aaron K., MS; Nudy, Matthew, MD; O'Sullivan, David M., PhD; Williams, Mark, MD; LeBlanc, Erin S., MD, MPH; Martin, Lisa W., MD; Manson, JoAnn E., MD, DrPH; Shikany, James M., DrPH; Johnson, Karen C., MD, MPH; Stefanick, Marcia L., PhD; Payne, Martha E., RD, PhD; Cauley, Jane A., DrPH; Howard, Barbara V., PhD; Robbins, John, MD

doi: 10.1097/AOG.0000000000001774
Contents: Original Research
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OBJECTIVE: To analyze the treatment effect of calcium+vitamin D supplementation, hormone therapy, both, and neither on cardiovascular disease risk factors.

METHODS: We conducted a prospective, randomized, double-blind, placebo-controlled trial among Women's Health Initiative (WHI) participants. The predefined primary outcome was low-density lipoprotein cholesterol (LDL-C).

RESULTS: Between September 1993 and October 1998, a total of 68,132 women aged 50–79 years were recruited and randomized to the WHI–Dietary Modification (n=48,835) and WHI–Hormone Therapy trials (n=27,347). Subsequently, 36,282 women from WHI–Hormone Therapy (16,089) and WHI–Dietary Modification (n=25,210) trials were randomized in the WHI–Calcium+Vitamin D trial to 1,000 mg elemental calcium carbonate plus 400 international units vitamin D3 daily or placebo. Our study group included 1,521 women who participated in both the hormone therapy and calcium+vitamin D trials and were in the 6% subsample of trial participants with blood sample collections at baseline and years 1, 3, and 6. The average treatment effect with 95% confidence interval, for LDL-C, compared with placebo, was −1.6, (95% confidence interval [CI] −5.5 to 2.2) mg/dL for calcium+vitamin D alone, −9.0 (95% CI −13.0 to −5.1) mg/dL for hormone therapy alone, and −13.8 (95% CI −17.8 to −9.8) mg/dL for the combination. There was no evidence of a synergistic effect of calcium+vitamin D+hormone therapy on LDL-C (P value for interaction=.26) except in those with low total intakes of vitamin D, for whom there was a significant synergistic effect on LDL (P value for interaction=.03).

CONCLUSION: Reductions in LDL-C were greater among women randomized to both calcium+vitamin D and hormone therapy than for those randomized to either intervention alone or to placebo. The treatment effect observed in the calcium+vitamin D+hormone therapy combination group may be additive rather than synergistic. For clinicians and patients deciding to begin calcium+vitamin D supplementation, current use of hormone therapy should not influence that decision.

CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT00000611.

Additive effects (both positive and some negative) on multiple cardiovascular disease risk factors were observed when menopausal women were randomized to both calcium and vitamin D and hormone therapy.

Departments of Obstetrics and Gynecology and Internal Medicine, Reading Hospital, and the Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pennsylvania; the Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington; Kaiser Permanente, Center for Health Research NW, Portland, Oregon; Department of Internal Medicine, Division of Cardiology, George Washington University School of Medicine and Health Sciences, Washington, DC; the Divisions of Preventive Medicine, Brigham and Women's Hospital/Harvard Medical School, Boston, Massachusetts, University of Alabama at Birmingham, School of Medicine, Birmingham, Alabama, and University of Tennessee Health Science Center, Memphis, Tennessee; the Department of Medicine, Stanford University School of Medicine, Stanford University, Stanford Prevention Research Center, Stanford, California; the Office of Research Development, Duke University School of Medicine, Durham, North Carolina; the University of Pittsburgh, Graduate School of Public Health, Pittsburgh, Pennsylvania; the Department of Epidemiology, MedStar Health Research Institute and Georgetown/Howard Universities Center for Clinical and Translational Science, Washington, DC; and UC Davis Medical Center, Sacramento, California.

Corresponding author: Peter F. Schnatz, DO, Departments of OB/GYN & Internal Medicine, Sidney Kimmel Medical College of Thomas Jefferson University, Associate Chair & Residency Program Director, The Reading Hospital, Department of OB/GYN—R1, PO Box 16052, Reading, PA 19612-6052; email: Peter.Schnatz@readinghealth.org.

The study sponsors had no role in the design of the study; the collection, analysis, and interpretation of the data; the writing of the manuscript; or the decision to submit the manuscript for publication. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute or the National Institutes of Health.

Financial Disclosure Dr. LeBlanc has received grants from Amgen Inc, Bristol Meyers Squibb, Merck, and AstraZeneca (unrelated to the current research). Dr. Payne's effort was supported by a National Institutes of Health Building Interdisciplinary Research Careers in Women's Health (BIRCWH) K12 grant (HD043446). The other authors did not report any potential conflicts of interest.

Presented as a poster at the 26th Annual Scientific Meeting of the North American Menopause Society, September 30–October 3, 2015, Las Vegas, Nevada.

The research reported in this article was supported by the research budget of the Reading Health System. The research on which this publication is based was supported by R01 HL083326 (to Dr Mackey) from the National Heart, Lung, and Blood Institute. The Women's Health Initiative (WHI) program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. Information about the WHI investigators, their academic centers, the program office, and the clinical coordinating center can be found online at: https://www.whi.org/researchers/Documents%20%20Write%20a%20Paper/WHI%20Investigator%20Short%20List.pdf.

For a list of names associated with this study, please see Appendix 1 online at http://links.lww.com/AOG/A892.

Each author has indicated that he or she has met the journal's requirements for authorship.

Whether hormone therapy and vitamin D (or calcium+vitamin D) has a synergistic relationship on the cardiovascular system in women has gained traction in clinical trials and basic science research.1–3 A recent study suggested that menopausal monkeys taking daily oral estrogen and who had greater percent plasma 25-hydroxycholecalciferol increases over the course of the study had the least severe cardiovascular disease and greater coronary artery remodeling compared with those not taking estrogen with lower plasma 25-hydroxycholecalciferol concentrations.3 Daily use of 1.25 mg conjugated equine estrogen has been shown to increase the biologically active form of vitamin D and vitamin D carrier protein in menopausal women.4 In ovariectomized rats, estrogen upregulates the expression of the vitamin D receptors in the small intestine.5 An analysis from the Women's Health Initiative (WHI) reported a statistically significant reduction (a synergistic effect) in the risk of hip fracture attributed to hormone therapy among participants randomized to calcium plus vitamin D compared with WHI–Hormone Therapy trial participants who were randomized to hormone therapy and placebo.1

Because women in the WHI were receiving both vitamin D+calcium, this trial offers an ideal opportunity to study whether there is a synergistic effect on cardiovascular disease risk factors in menopausal women with calcium+vitamin D as well as hormone therapy. The WHI calcium+vitamin D trials were double-blind, randomized, placebo-controlled studies analyzing multiple health outcomes in menopausal women. In the calcium+vitamin D trial, low-density lipoprotein cholesterol (LDL-C) was significantly reduced for women randomized to calcium+vitamin D,6 and for the WHI–Hormone Therapy trials, both estrogen plus progestin and estrogen alone also significantly reduced LDL-C.7,8 Moreover, both hormone therapy preparations had statistically significant favorable effects on high-density lipoprotein cholesterol, glucose, and waist circumference, but significantly unfavorable effects on triglycerides and systolic blood pressure.7,8

We measured changes in our primary outcome (LDL-C) as well as our secondary outcomes (multiple cardiovascular disease risk factors) in four groups of women randomly assigned to different therapeutic combinations: calcium+vitamin D alone, hormone therapy alone, both hormone therapy and calcium+vitamin D, and neither hormone therapy nor calcium+vitamin D. The study hypothesis is that a statistically significant interaction exists between hormone therapy and calcium+vitamin D in terms of the effect on primary study endpoints, LDL-C as well as secondary outcomes including other cardiovascular risk factors. Conceptually, a significant interaction means that we observed a larger benefit among women randomized to both calcium+vitamin D and hormone therapy than the benefit observed among women randomized to only hormone therapy plus the benefit observed among women randomized to only calcium+vitamin D. In other words, a significant interaction corresponds to a synergistic rather than an additive effect relative to the placebo group.

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MATERIALS AND METHODS

The WHI clinical trials were designed to evaluate the risks and benefits of dietary modification, hormone therapy, and supplementation with calcium+vitamin D. The protocol and consent forms were approved by the institutional review boards for all participating institutions (see Acknowledgments in Appendix 1, available online at http://links.lww.com/AOG/A892).

Like previously published secondary analyses,9 the WHI–Hormone Therapy trials data were combined to improve statistical power and further justified because both WHI arms had the same qualitative effects on the measured cardiovascular disease risk factors. These results can apply to a population similar to those enrolled in the WHI–Hormone Therapy trials: 40% without a uterus taking estrogen therapy or placebo and 60% with an intact uterus taking estrogen and progestogen therapy or placebo. The WHI is the largest cohort (n=16,089) randomized to both hormone therapies (active or placebo) and calcium+vitamin D (active or placebo)1 from whom blood data were collected on 1,521 participants. Because we are using pre-existing data, power calculations were not performed.10,11

A total of 68,132 women aged 50–79 years were recruited between September 1993 and October 1998 and were randomly assigned into the WHI–Dietary Modification trial, WHI–Hormone Therapy trials, or both. A total of 27,347 women in the two parallel WHI–Hormone Therapy trials were randomized to 0.625 mg conjugated equine estrogen alone or placebo among women who had a hysterectomy or 0.625 mg conjugated equine estrogen plus 2.5 mg medroxyprogesterone acetate or placebo taken daily among women who had not had a hysterectomy. A total of 48,835 women in the WHI–Dietary Modification trial were randomized to a dietary modification intervention (dietary modification to lower total fat intake; n=19,541) or comparison (usual diet; n=29,294) group. At the first or second annual visit, 36,282 eligible women from WHI–Hormone Therapy (16,089) and WHI–Dietary Modification (n=25,210) trials were randomized further to calcium+vitamin D (1,000 mg elemental calcium [carbonate] plus 400 international units vitamin D3 daily supplementation [n=18,176]) or placebo (n=18,106) with 14% (n=5,017) of participants in both the Dietary Modification and Hormone Therapy trials. The eligibility criteria to be enrolled in the calcium+vitamin D trial included many safety parameters (eg, no previous hypercalcemia or renal calculi) and no competing risk indicators (eg, no medical condition associated with survival of less than 3 years). Eligibility for the WHI–Hormone Therapy trial included postmenopausal (as defined previously12) who were between 50 and 79 years of age at initial screening. Analysis included women who participated in both the calcium+vitamin D trial and the WHI–Hormone Therapy trial (either estrogen and progestogen or estrogen alone) and were also part of the 6% blood subsample (Fig. 1) (n=1,521). Because the calcium+vitamin D trial was initiated after 1 year of the WHI–Hormone Therapy, year 1 of the WHI–Hormone Therapy was considered as baseline for the calcium+vitamin D trial. Lipids along with other cardiovascular risk factors (blood pressure, weight, waist circumference, waist-to-hip ratio, glucose, insulin) were measured at baseline and years 1, 3, and 6 after randomization into the hormone therapy trials. The cardiovascular disease risk factors, which were measured after the estrogen plus progestin trial and the conjugated equine estrogen-alone trial stopped on July 7, 2002, and February 29, 2004, respectively, were censored. Details of biomarker analysis and laboratory methods have been published previously.13

Fig. 1.

Fig. 1.

Repeated-measures models with an unstructured variance–covariance matrix were used to model longitudinal means. Per the randomized partial-factorial design, means were assumed to be equal at baseline for all four hormone therapy+randomization groups and equal at year 1 from hormone therapy randomization for calcium+vitamin D randomization groups; the latter is the calcium+vitamin D “baseline” measure. Constraining the “baseline” means to be equal before randomization is the most efficient use of the data.14,15 To allow for parsimonious 1-degree-of-freedom estimates of treatment effects (treatment group minus placebo) and interactions (calcium+vitamin D+hormone therapy), the postrandomization means at years 3 and 6 are averaged.

For the subgroup analysis, we analyzed whether particular subgroups may modify the calcium+vitamin D+hormone therapy interaction on our main outcome variable, LDL-C (ie, whether a synergistic effect of calcium+vitamin D+hormone therapy might occur for particular subgroups). Statistical significance was based on a test of interaction. We looked at a total of 13 prespecified baseline subgroups (Table 1). No adjustment for multiple testing was made; at most, one interaction was expected to be significant by chance alone. The cutpoints for total vitamin D intake and total calcium were also chosen a priori. The lower cutpoint was suggested previously1 where the effect of hormone therapy appeared to be null for values of total vitamin D below 200 international units and calcium below 800 mg.

Table 1.

Table 1.

To address the skewed distributions of triglycerides, glucose, insulin, and waist-to-hip ratio, log-transformation was used, and geometric means are reported. Statistical significance of a synergistic effect was based on tests of interaction. A significant interaction corresponds to a synergistic rather than an additive effect relative to the placebo group. To graphically show the presence of an additive or synergistic effect between calcium+vitamin D and hormone therapy across all cardiovascular disease biomarkers, Z-scores (treatment effect divided by standard error) are shown. All analyses were done with SAS 9.4 and figures were drawn with R 3.1. All P values are two-sided and P values ≤.05 were regarded as significant.

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RESULTS

Baseline characteristics were similarly distributed by treatment groups (Table 2). The effects of calcium+vitamin D+hormone therapy, on all of the cardiovascular disease risk factors except insulin, were larger in magnitude and in the same direction as the effects of hormone therapy alone, regardless of the size or direction of the calcium+vitamin D effect. In other words, the addition of calcium+vitamin D enhanced the effects of hormone therapy either in a positive or a negative direction. However, none of the hormone therapy+calcium+vitamin D interactions were statistically significant (Fig. 2) and therefore did not provide statistical evidence for the synergistic effects of hormone therapy+calcium+vitamin D. For example, although hormone therapy+calcium+vitamin D had a stronger effect on LDL-C compared with either hormone therapy alone or calcium+vitamin D alone, the observed effects were additive (P value for interaction=.26). Estimates for the primary analysis were precise; the 95% confidence interval (CI) for mean LDL-C in all four treatment groups was ±3 mg/dL. The effects on LDL-C (active minus placebo) were −1.6 (−5.5 to 2.2) mg/dL for calcium+vitamin D alone, −9.0 (−13.0 to −5.1) mg/dL for hormone therapy alone, and −13.8 (−17.8 to −9.8) mg/dL for calcium+vitamin D+hormone therapy (Fig. 3). Appendix 2, available online at http://links.lww.com/AOG/A892, displays the profile means for our primary endpoint, LDL-C, by randomization groups during the study. To investigate the influence of temporal trends, we limited postrandomization follow-up to year 3 and observed a similar pattern (P value for interaction=.44); the treatment effects on LDL-C for this sensitivity analysis were −1.5 (−5.1 to 2.2) mg/dL for calcium+vitamin D alone, −13.9 (−17.8 to −10.1) mg/dL for hormone therapy alone, and −17.4 (−21.2 to −13.6) mg/dL for calcium+vitamin D+hormone therapy. Lastly, a sensitivity analysis was conducted to account for compliance to study pills. Specifically, LDL-C measurements that occurred after a participant became nonadherent (took less than 80% of study pills) were censored. Resulting model estimates produced a similar additive pattern without any evidence for a synergistic effect (P value for interaction=.66).

Table 2.

Table 2.

Fig. 2.

Fig. 2.

Fig. 3.

Fig. 3.

A sensitivity analysis was conducted to determine whether the calcium+vitamin D+hormone therapy interaction depended on hormone therapy preparation by testing the three-way interaction calcium+vitamin D+hormone therapy×cohort (estrogen plus progestogen compared with estrogen therapy alone). As expected, none of the three-way interactions provided statistical evidence against pooling the hormone therapy trials for any of the cardiovascular disease risk factors (all P values >.30). The effect of hormone therapy (active compared with placebo) on LDL-C from baseline to year 1 was −16.8 (−20.4 to −13.2) and −18.4 (−21.5 to −15.3) mg/dL among estrogen therapy and estrogen+progestogen therapy participants, respectively.

Calcium and vitamin D+hormone therapy had a synergistic effect on LDL-C at low total intakes (dietary and supplements) of vitamin D (P value for interaction=.03). In addition, the effect of hormone therapy alone was more attenuated at lower levels of vitamin D intake. Calcium and vitamin D+hormone therapy had an additive (P value for interaction=.06) effect at low intakes of calcium (Fig. 3) and calcium+vitamin D+hormone therapy had a synergistic effect (P value for interaction=.007) among hypertensive women (self-reported of treatment for hypertension or recorded blood pressure 140/90 mm Hg or greater). The effect of calcium+vitamin D+hormone therapy did not vary with age (P=.59). An analysis of the two×two factorial for the main effects of calcium+vitamin D and hormone therapy, without a calcium+vitamin D+hormone therapy interaction term, is presented in Appendix 3 (available online at http://links.lww.com/AOG/A892). As previously shown in the full cohort,6 calcium+vitamin D has a favorable effect on LDL-C with a mean decrease of 3.2 mg/dL (CI −5.9 to −0.5). In addition, we demonstrated a favorable effect on total cholesterol with a mean decrease of 3.2 mg/dL (CI −6.2 to −0.3).

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DISCUSSION

Although there are data to suggest calcium+vitamin D has some beneficial effects on cardiovascular disease risk factors,11,14,15 this has not been well established, and there is a paucity of prospective data regarding the effect of calcium+vitamin D on cardiovascular disease outcomes.16,17 More recent data have suggested that estrogen therapy alone in younger women closer to the time of menopause (the timing hypothesis) could have beneficial cardiovascular disease outcomes, particularly lower rates of myocardial infarction,12,18–21 but no significant reduction was observed with younger women randomized to estrogen plus progestogen therapy.9 Although highly controversial, some observational data have raised questions about the safety of high doses of calcium supplements and potential cardiovascular disease risks,22 although the WHI calcium+vitamin D trial did not.6 Our findings suggest that calcium combined with vitamin D is not detrimental, at least in regard to most cardiovascular disease risk factors.

The well-decomunted7,23 beneficial effect that hormone therapy has on cholesterol parameters aside from triglyceride is felt to be moderate compared with other cholesterol-lowering therapies. Hormone therapy has been shown to have beneficial effects on other cardiovascular disease risks as well, like glucose24 and weight distribution,25 but has increased mean systolic blood pressure in both WHI–Hormone Therapy trials26 and in other randomized clinical trials.27 It would be helpful to know whether the effects of hormone therapy or other interventions with a moderate effect on cardiovascular disease risk would be additive or synergistic with calcium+vitamin D. The data we present suggest an additive relationship with hormone therapy, which is modestly beneficial for some cardiovascular disease risk factors (eg, LDL-C, high-density lipoprotein cholesterol, total cholesterol, glucose, insulin, waist circumference, and the waist-to-hip ratio), but modestly harmful for others (eg, systolic and diastolic blood pressure, triglycerides; Fig. 2).

In a similar study from this population, the effect of calcium+vitamin D and hormone therapy on bone density was also additive.1 A synergistic effect was identified, however, when the effect of hormone therapy and calcium+vitamin D was studied on the primary outcome, fracture.1 Hence, it is possible that calcium+vitamin D and hormone therapy may have a synergistic effect for cardiovascular disease as a primary outcome. Calcium and vitamin D+hormone therapy has a greater effect on cardiovascular disease risk categories when compared with all other combinations. Moreover, for all endpoints except insulin, the effect of calcium+vitamin D+hormone therapy and hormone therapy alone were in the same direction, but the magnitude of calcium+vitamin D+hormone therapy was greater. Therefore, results suggest that the addition of calcium+vitamin D supplementation to a hormone therapy regimen could enhance the effects of hormones. In contrast, for more than half of the endpoints, hormone therapy+calcium+vitamin D and calcium+vitamin D alone went in opposite directions, so the addition of hormone therapy may swamp the effect of calcium and vitamin D supplementation (Fig. 2).

In the subgroup analysis of total vitamin D intake, the effect of hormone therapy alone had an impressive decreasing effect on LDL-C as the intake of total vitamin D increased (CI −3.2 to −7.3, −12.2 to −22.8; P=.03), implying a synergistic relationship (Fig. 3, hormone therapy-alone column for vitamin D effect). Looking at the effect of hormone therapy+calcium+vitamin D on LDL-C, the effect (CI −10.7 to −15.5, −20.1 to −14.9; P=.03) seems to progressively increase until the total vitamin D intake exceeds 600 international units (Fig. 3, hormone therapy+calcium+vitamin D column for vitamin D effect). This implies a threshold phenomenon in which total vitamin D intake is more beneficial to hormone therapy and calcium+vitamin D up to a certain point (or threshold). Based on these findings, for women on estrogen and who have low intake of vitamin D, one should consider supplementation to lower LDL-C that may decrease the risk of heart disease.

A major strength of the study is the double-blind, randomized, placebo-controlled design in a well-characterized population. Given the numbers and demographic diversity of this cohort, the findings should be generalizable to the U.S. population. This is a large study in which women were randomized to calcium+vitamin D, hormone therapy, or both with nearly 400 women in each arm. Several studies have suggested that vitamin D may have a therapeutic window phenomenon with detriment at the extremes and benefit at midlevels.28,29 This may explain why hormone therapy and calcium+vitamin D seemed to be synergistic at lower calcium+vitamin D intakes. Limitations, therefore, include the 400 international units vitamin D, which is typically used to prevent rickets, but may be inadequate to lower LDL-C. Women were allowed to continue their own calcium supplements because it would have been unethical to prohibit concurrent calcium use in a long-term, placebo-controlled trial. Also, the supplement trial used a combination of calcium+vitamin D so that the effects of either nutrient alone cannot be ascertained. We were not able to further explore the observations that calcium+vitamin D+hormone therapy had a synergistic effect on LDL-C at low total intakes (dietary and supplements) of vitamin D and calcium by correlating blood concentration of vitamin D and calcium with total intake, because only a small percentage of women had these serum markers measured.

In summary, with the exception of insulin, the absolute effect of calcium+vitamin D and hormone therapy on cardiovascular disease risk factors was larger compared with hormone therapy alone or calcium+vitamin D alone, including LDL-C, our primary endpoint. For clinicians and most patients deciding to begin calcium+vitamin D supplementation, current use of hormone therapy should not influence that decision. However, based on these findings, for women on estrogen and who have low intake of vitamin D, one should consider calcium+vitamin D supplementation to lower LDL-C that may decrease the risk of heart disease.

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