Women’s health initiative clinical trials: interaction of calcium and vitamin D with hormone therapy

John A. Robbins, Aaron Aragaki, Carolyn J. Crandall

Abstract


This study aims to test the added value of calcium and vitamin D (CaD) in fracture prevention among women taking postmenopausal hormone therapy (HT).

This is a prospective, partial-factorial, randomized, controlled, double-blind trial among Women’s Health Initiative postmenopausal participants aged 50 to 79 years at 40 centers in the United States with a mean follow-up of 7.2 years. A total of 27,347 women were randomized to HT (0.625 mg of conjugated estrogens alone, or 0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate daily), and 36,282 women were randomized to 1,000 mg of elemental calcium (carbonate) plus 400 IU of vitamin D3 daily, each compared with placebo. A total of 16,089 women participated in both arms. The predefined outcomes were adjudicated hip fractures and measured bone mineral density.

Interaction between HT and CaD on hip fracture (р interaction = 0.01) was shown. The effect of CaD was stronger among women assigned to HT (hazard ratio [HR], 0.59; 95% CI, 0.38–0.93) than among women assigned to placebo (HR, 1.20; 95% CI, 0.85–1.69). The effect of HT on hip fracture was stronger among women assigned to active CaD (HR, 0.43; 95% CI, 0.28–0.66) than among women assigned to placebo (HR, 0.87; 95% CI, 0.60–1.26). CaD supplementation enhanced the antifracture effect of HT at all levels of personal calcium intake.

There was no interaction between HT and CaD on change in hip or spine bone mineral density.

Conclusions: Postmenopausal women at normal risk for hip fracture who are on CaD supplementation experience significantly reduced incident hip fractures beyond HT alone at all levels of personal baseline total calcium intake.


Keywords


calcium; vitamin D; hormone therapy; estrogens

References


Ross, A.C., Manson, J.E., Abrams, S.A., et al. “The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know.” J Clin Endocrinol Metab, 97 (2010): 1146–1152.

Moyer, V.A.; on behalf of the US Preventive Services Task Force. “Vitamin D and calcium supplementation to prevent fractures in adults: US Preventive Services Task Force recommendation statement.” Ann Intern Med, pub. online Feb 26, 2013. DOI: 10.7326/0003-4819-158-9-201305070-00603

Black, D.M., Cummings, S.R., Karpf, D.B., et al. “Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group.” Lancet, 348(1996):1535–1541.

Peris, P., Martinez-Ferrer, A., Monegal, A., Martinez de Osaba, M.J., Muxi, A., Guanabens, N. “25 Hydroxyvitamin D serum levels influence adequate response to bisphosphonate treatment in postmenopausal osteoporosis.” Bone, 51(2012):54–56.

Antoniucci, D.M., Vittinghoff, E., Palermo, L., Black, D.M., Sellmeyer, D.E. “Vitamin D insufficiency does not affect response of bone mineral density to alendronate.” Osteoporos Int, 20(2009):1259–1266.

Bourke, S., Bolland, M.J., Grey, A., et al. “The impact of dietary calcium intake and vitamin D status on the effects of zoledronate.” Osteoporos Int, 24(2013): 349–354.

Olmos, J.M., Hernandez, J.L., Llorca, J., Nan, D., Valero, C., Gonzalez-Macıas, J. “Effects of 25-hydroxyvitamin D3 therapy on bone turnover markers and PTH levels in postmenopausal osteoporotic women treated with alendronate.” Clin Endocrinol Metab, 97(2012): 4491–4497.

The North American Menopause Society. “The hormone therapy position statement of The North American Menopause Society.” Menopause, 19(2012): 257–271.

Jackson, R.D., Wactawski-Wende, J., LaCroix, A.Z., et al. Women’s Health Initiative Investigators. “Effects of conjugated equine estrogen on risk of fractures and BMD in postmenopausal women with hysterectomy: Results from the Women’s Health Initiative randomized trial.” J Bone Miner Res, 21(2006): 817–828.

Cauley, J.A., Robbins, J., Chen, Z., et al. Women’s Health Initiative Investigators. “Effects of estrogen plus progestin on risk of fracture and bone mineral density: the Women’s Health Initiative randomized trial.” JAMA, 290(2003): 1729–1738.

The Women’s Health Initiative Study Group. “Design of the Women’s Health Initiative clinical trial and observational study.” Control Clin Trials, 19(1998): 61–109.

Heiss, G., Wallace, R., Anderson, G.L., et al. WHI Investigators. “Health risks and benefits 3 years after stopping randomized treatment with estrogen and progestin.” JAMA, 299(2008): 1036–1045.

Chen, Z., Kooperberg, C., Pettinger, M.B., et al. “Validity of self-report for fractures among a multiethnic cohort of postmenopausal women: results from the Women’s Health Initiative observational study and clinical trials.” Menopause, 11(2004): 264–274.

Anderson, G.L., Limacher, M., Assaf, A.R., et al. Women’s Health Initiative Steering Committee. “Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial.” JAMA, 291(2004): 1701–1712.

Rossouw, J.E., Anderson, G.L., Prentice, R.L., et al. Writing Group for the Women’s Health Initiative Investigators. “Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial.” JAMA, 288(2002): 321–333.

The Writing Group for the PEPI. “Effects of hormone therapy on bone mineral density: results from the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial.” JAMA, 276(1996): 1389–1396.

Lindsay, R., Gallagher, J.C., Kleerekoper, M., Pickar, J.H. “Effect of lower doses of conjugated equine estrogens with and without medroxyprogesterone acetate on bone in early post menopausal women.” JAMA, 287(2009): 2668–2676.

Cauley, J.A., Lui, L.Y., Stone, K.L., et al. “Longitudinal study of changes in hip bone mineral density in Caucasian and African-American women.” J Am Geriatr Soc, 53(2005): 183–189.

Fink, H.A., Milavetz, D.L., Palermo, L., et al. “Fracture Intervention Trial Research Group. What proportion of incident radiographic vertebral deformities is clinically diagnosed and vice versa?” J Bone Miner Res, 20(2005): 1216–1222.


GOST Style Citations


1. Ross, A.C., Manson, J.E., Abrams, S.A., et al. “The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know.” J Clin Endocrinol Metab, 97 (2010): 1146–1152.

2. Moyer, V.A.; on behalf of the US Preventive Services Task Force. “Vitamin D and calcium supplementation to prevent fractures in adults: US Preventive Services Task Force recommendation statement.” Ann Intern Med, pub. online Feb 26, 2013. DOI: 10.7326/0003-4819-158-9-201305070-00603

3. Black, D.M., Cummings, S.R., Karpf, D.B., et al. “Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group.” Lancet, 348(1996):1535–1541.

4. Peris, P., Martinez-Ferrer, A., Monegal, A., Martinez de Osaba, M.J., Muxi, A., Guanabens, N. “25 Hydroxyvitamin D serum levels influence adequate response to bisphosphonate treatment in postmenopausal osteoporosis.” Bone, 51(2012):54–56.

5. Antoniucci, D.M., Vittinghoff, E., Palermo, L., Black, D.M., Sellmeyer, D.E. “Vitamin D insufficiency does not affect response of bone mineral density to alendronate.” Osteoporos Int, 20(2009):1259–1266.

6. Bourke, S., Bolland, M.J., Grey, A., et al. “The impact of dietary calcium intake and vitamin D status on the effects of zoledronate.” Osteoporos Int, 24(2013): 349–354.

7. Olmos, J.M., Hernandez, J.L., Llorca, J., Nan, D., Valero, C., Gonzalez-Macıas, J. “Effects of 25-hydroxyvitamin D3 therapy on bone turnover markers and PTH levels in postmenopausal osteoporotic women treated with alendronate.” Clin Endocrinol Metab, 97(2012): 4491–4497.

8. The North American Menopause Society. “The hormone therapy position statement of The North American Menopause Society.” Menopause, 19(2012): 257–271.

9. Jackson, R.D., Wactawski-Wende, J., LaCroix, A.Z., et al. Women’s Health Initiative Investigators. “Effects of conjugated equine estrogen on risk of fractures and BMD in postmenopausal women with hysterectomy: Results from the Women’s Health Initiative randomized trial.” J Bone Miner Res, 21(2006): 817–828.

10. Cauley, J.A., Robbins, J., Chen, Z., et al. Women’s Health Initiative Investigators. “Effects of estrogen plus progestin on risk of fracture and bone mineral density: the Women’s Health Initiative randomized trial.” JAMA, 290(2003): 1729–1738.

11. The Women’s Health Initiative Study Group. “Design of the Women’s Health Initiative clinical trial and observational study.” Control Clin Trials, 19(1998): 61–109.

12. Heiss, G., Wallace, R., Anderson, G.L., et al. WHI Investigators. “Health risks and benefits 3 years after stopping randomized treatment with estrogen and progestin.” JAMA, 299(2008): 1036–1045.

13. Chen, Z., Kooperberg, C., Pettinger, M.B., et al. “Validity of self-report for fractures among a multiethnic cohort of postmenopausal women: results from the Women’s Health Initiative observational study and clinical trials.” Menopause, 11(2004): 264–274.

14. Anderson, G.L., Limacher, M., Assaf, A.R., et al. Women’s Health Initiative Steering Committee. “Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial.” JAMA, 291(2004): 1701–1712.

15. Rossouw, J.E., Anderson, G.L., Prentice, R.L., et al. Writing Group for the Women’s Health Initiative Investigators. “Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial.” JAMA, 288(2002): 321–333.

16. The Writing Group for the PEPI. “Effects of hormone therapy on bone mineral density: results from the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial.” JAMA, 276(1996): 1389–1396.

17. Lindsay, R., Gallagher, J.C., Kleerekoper, M., Pickar, J.H. “Effect of lower doses of conjugated equine estrogens with and without medroxyprogesterone acetate on bone in early post menopausal women.” JAMA, 287(2009): 2668–2676.

18. Cauley, J.A., Lui, L.Y., Stone, K.L., et al. “Longitudinal study of changes in hip bone mineral density in Caucasian and African-American women.” J Am Geriatr Soc, 53(2005): 183–189.

19. Fink, H.A., Milavetz, D.L., Palermo, L., et al. “Fracture Intervention Trial Research Group. What proportion of incident radiographic vertebral deformities is clinically diagnosed and vice versa?” J Bone Miner Res, 20(2005): 1216–1222.





DOI: http://dx.doi.org/10.18370/2309-4117.2015.26.94-101

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