Archives of Osteoporosis

, 8:124 | Cite as

Vitamin D insufficiency together with high serum levels of vitamin A increases the risk for osteoporosis in postmenopausal women

  • J. M. Mata-Granados
  • J. R. Cuenca-Acevedo
  • M. D. Luque de Castro
  • M. F. HolickEmail author
  • J. M. Quesada-Gómez
Original Article



Postmenopausal women who were vitamin D deficient and had high serum levels of retinol had an eight times higher risk of having osteoporosis. A high retinol level together with vitamin D deficiency/insufficiency is an additional risk factor for osteoporosis.


The aim of this study was to evaluate the association between vitamin D deficiency/insufficiency and excess of vitamin A intake as an osteoporosis risk factor in healthy postmenopausal women


The design is a cross-sectional study of 232 healthy postmenopausal women.


Bone mass was evaluated by dual energy X-ray absorptiometry. Serum calcium, albumin phosphorus, creatinine, total high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol, and triglycerides analyzed by standard methods and retinol and 25-hydroxyvitamin D [25(OH)D] measured by an online solid-phase extraction coupled with high-pressure liquid chromatography–ultraviolet detection.


Prevalence of vitamin D deficiency [25(OH)D < 20 ng/mL] was 70.1 %; 14.3 % had a 25(OH)D < 10 ng/mL, and 23.6 % had insufficiency [25(OH)D 21–29 ng/mL]. Prevalence of high serum levels of retinol (>80 μg/dL) was 36.4 %. Among subjects with 25(OH)D <20 ng/mL (n = 152), 60.4 % (n = 92) had serum levels of retinol > 80 μg/dL. Bone density measurements revealed that the risk of osteoporosis was ~8 times higher in women with the highest retinol levels, as compared with women with the lowest retinol levels. In women with 25(OH)D < 20 ng/mL, the risk for osteoporosis increased substantially in women who had the highest blood levels of retinol compared to the women with lowest retinol levels.


Higher retinol levels together with vitamin D deficiency could be a significant additional risk factor for osteoporosis, underscoring the need for improved physician and public education regarding optimization of vitamin D status in postmenopausal women and developing policies to avoid high serum levels of vitamin A.


Osteoporosis Vitamin D Vitamin A Bone mineral density 25-Hydroxyvitamin D 



This study was supported by grants CS 0200/2008, P06-FQM-01515, and SAF2005-05254 and teams PAI CTS-413 and PAI FQM-227 of Junta de Andalucía and Sanyres 21, Córdoba (Spain).

Conflicts of interest

JMMG, JRCA, MDLC, and JMQG have no conflict of interest. MFH is a consultant for Merck, Sanofi-Aventis, P&G, Quest Diagnostics, and Novartis.


  1. 1.
    Holick MF (2007) Vitamin D deficiency. N Engl J Med 357:266–281PubMedCrossRefGoogle Scholar
  2. 2.
    Lips P (2001) Vitamin D deficiency and secondary hyperparathyroidism in the elderly: consequences for bone loss and fractures and therapeutic implications. Endocr Rev 22:477–501PubMedCrossRefGoogle Scholar
  3. 3.
    Bischoff-Ferrari HA, Giovannucci E, Willett WC, Dietrich T, Dawson-Hughes B (2006) Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes. Am J Clin Nutr 84:18–28PubMedGoogle Scholar
  4. 4.
    IOM (Institute of Medicine) (2011) Dietary reference intakes for calcium and vitamin D. Institute of Medicine Committee to Review Dietary Reference Intakes for Calcium and Vitamin D. The National Academies, Washington, DCGoogle Scholar
  5. 5.
    Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, Murad MH, Weaver CM (2011) Evaluation, treatment & prevention of vitamin d deficiency: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 96(7):1911–1930PubMedCrossRefGoogle Scholar
  6. 6.
    Holick MF, Siris ES, Binkley N, Beard MK, Khan A, Katzer JT et al (2005) Prevalence of vitamin D inadequacy among postmenopausal North American women receiving osteoporosis therapy. J Clin Endocrinol Metab 90:3215–3224PubMedCrossRefGoogle Scholar
  7. 7.
    Lips P, Hosking D, Lippuner K, Norquist JM, Eehreb L, Maalouf G et al (2006) The prevalence of vitamin D inadequacy amongst women with osteoporosis: an international epidemiological investigation. J Intern Med 260:245–254PubMedCrossRefGoogle Scholar
  8. 8.
    Quesada Gómez JM, Mata Granados JM, Delgadillo J, Ramírez R (2007) Low calcium intake and insufficient serum vitamin D status in treated and non-treated postmenopausal osteoporotic women in Spain. J Bone Miner Metab 22:S309Google Scholar
  9. 9.
    Scheven BA, Hamilton NJ (1990) Retinoic acid and 1,25-dihydroxyvitamin D3 stimulate osteoclast formation by different mechanisms. Bone 11:53–59PubMedCrossRefGoogle Scholar
  10. 10.
    Abu-Hijleh G, Padmanabhan R (1997) Retinoic acid-induced abnormal development of hind limb joints in the mouse. Eur J Morphol 35:327–336PubMedGoogle Scholar
  11. 11.
    Hough S, Avioli LV, Muir H, Gelderblom D, Jenkins G, Kurasi H et al (1988) Effects of hypervitaminosis A on the bone and mineral metabolism of the rat. Endocrinology 122:2933–2939PubMedCrossRefGoogle Scholar
  12. 12.
    Moore T, Sharman IM (1979) Hypervitaminosis A combined with calcium deficiency in rats. Int J Vitam Nutr Res 49:14–20PubMedGoogle Scholar
  13. 13.
    Oreffo RO, Teti A, Triffitt JT, Francis MJ, Carano A, Zallone AZ (1988) Effect of vitamin A on bone resorption: evidence for direct stimulation of isolated chicken osteoclasts by retinol and retinoic acid. J Bone Miner Res 3:203–210PubMedCrossRefGoogle Scholar
  14. 14.
    Clark L, Seawright AA, Gartner RJ (1971) Long bone abnormalities in kittens following vitamin A toxicosis in kittens. J Comp Pathol 81:365–371PubMedCrossRefGoogle Scholar
  15. 15.
    Melhus H, Michaelsson K, Kindmark A, Reinhold B, Holmberg L, Hans M et al (1998) Excessive dietary intake of vitamin A is associated with reduced bone mineral density and increased risk for hip fracture. Ann Intern Med 129:770–778PubMedCrossRefGoogle Scholar
  16. 16.
    Feskanich D, Singh V, Willett WC, Colditz GA (2002) Vitamin A intake and hip fractures among postmenopausal women. JAMA 287:47–54PubMedCrossRefGoogle Scholar
  17. 17.
    Michaelsson K, Lithell H, Vessby B, Melhus H (2003) Serum retinol levels and the risk of fracture. N Engl J Med 348:287–294PubMedCrossRefGoogle Scholar
  18. 18.
    Promislow JHE, Goodman-Gruen D, Slymen DJ, Barrett-Connor E (2002) Retinol intake and bone mineral density in the elderly: the Rancho-Bernardo study. J Bone Miner Res 17:1349–1358PubMedCrossRefGoogle Scholar
  19. 19.
    Opotowsky AR, Bilezikian JP (2004) Serum vitamin A concentration and the risk of hip fracture among women 50 to 74 years old in the United States: a prospective analysis of the NHANES I follow-up study. Am J Med 117:169–174PubMedCrossRefGoogle Scholar
  20. 20.
    Mata-Granados JM, Luque de Castro MD, Quesada Gómez JM (2008) Inappropriate serum levels of retinol, alpha-tocopherol, 25 hydroxyvitamin D3 and 24,25 dihydroxyvitamin D3 levels in healthy Spanish adults: simultaneous assessment by HPLC. Clin Biochem 41:676–680PubMedCrossRefGoogle Scholar
  21. 21.
    Rosen CJ, Morrison A, Zhou H, Storm D, Hunter SJ, Musgrave K et al (1994) Elderly women in northern New England exhibit seasonal changes in bone mineral density and calciotropic hormones. Bone Miner 1994(25):83–92CrossRefGoogle Scholar
  22. 22.
    O’Neill TW, Cooper C, Cannata JB, Díaz López JB, Hoszowski K, Johnell O et al (1994) Reproducibility of a questionnaire on risk factors for osteoporosis in a multicentre prevalence survey: the European Vertebral Osteoporosis Study. Int J Epidemiol 23:559–565PubMedCrossRefGoogle Scholar
  23. 23.
    Mata-Granados JM, Quesada Gómez JM, Luque de Castro MD (2009) Fully automatic method for the determination of fat soluble vitamins and vitamin D metabolites in serum. Clin Chim Acta 403:126–130PubMedCrossRefGoogle Scholar
  24. 24.
    Diaz Curiel M, Carrasco de la Peña JL, Honorato Pérez J, Pérez Cano R, Rapado A, Ruiz Martínez I (1997) Study of BMD in lumbar spine and femoral neck in a Spanish population. Multicentre Research Project on Osteoporosis. Osteoporos Int 7:59–64PubMedCrossRefGoogle Scholar
  25. 25.
    Kanis JA, Melton LJ, Christiansen C, Johnston CC, Khaltaev N (1994) The diagnosis of osteoporosis. J Bone Miner Res 9:17–1141Google Scholar
  26. 26.
    Lips P, Duong T, Oleksik AM, Black D, Cummings S, Cox D et al (2001) A global study of vitamin D status and parathyroid function in postmenopausal women with osteoporosis: baseline data from the multiple outcomes of raloxifene evaluation clinical trial. J Clin Endocrinol Metab 86:1212–1221PubMedCrossRefGoogle Scholar
  27. 27.
    Lips P (2007) Vitamin D status and nutrition in Europe and Asia. J Steroid Biochem Mol Biol 103:620–625PubMedCrossRefGoogle Scholar
  28. 28.
    Jacobs ET, Alberts DS, Foote JA, Green SB, Hollis BW, Yu Z, Martínez ME (2008) Vitamin D insufficiency in southern Arizona. Am J Clin Nutr 87:608–613PubMedGoogle Scholar
  29. 29.
    Olmedilla B, Granado F, Southon S, Wright AJ, Blanco I, Gil-Martínez E et al (2001) Serum concentrations of carotenoids and vitamins A, E, and C in control subjects from five European countries. Br J Nutr 85:227–238PubMedCrossRefGoogle Scholar
  30. 30.
    Úbeda N, Basagoiti M, Alonso-Aperte E, Varela-Moreiras G (2007) Hábitos alimentarios, estado nutricional y estilos de vida en una población de mujeres menopáusicas españolas. Nutr Hosp 22:313–321PubMedGoogle Scholar
  31. 31.
    Trumbo P, Yates AA, Schlicker S, Poos M (2001) Dietary reference intakes: vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. J Am Diet Assoc 101:294–301PubMedCrossRefGoogle Scholar
  32. 32.
    Cruz JA, Moreiras-Varela O, van Staveren WA, Trichopoulou A, Roszkowski W (1991) Intakes of vitamins and minerals. Eur J Clin Nutr 45:121–138PubMedGoogle Scholar
  33. 33.
    Granado F, Blázquez S, Olmedilla B (2007) Changes in carotenoid intake from fruit and vegetables in the Spanish population over the period 1964–2004. Public Health Nutr 10:1018–1023PubMedCrossRefGoogle Scholar
  34. 34.
    Harrison EH (2005) Mechanisms of digestion and absorption of dietary vitamin A. Annu Rev Nutr 25:87–103PubMedCrossRefGoogle Scholar
  35. 35.
    Ballew C, Galuska D, Gillespie C (2001) High serum retinyl esters are not associated with reduced bone mineral density in the Third National Health and Nutrition Examination Survey, 1988–1994. J Bone Miner Res 16:2306–2312PubMedCrossRefGoogle Scholar
  36. 36.
    Penniston KL, Weng N, Binkley N, Tanumihardjo SA (2006) Serum retinyl esters are not elevated in postmenopausal women with and without osteoporosis whose preformed vitamin A intakes are high. Am J Clin Nutr 84:1350–1356PubMedGoogle Scholar
  37. 37.
    Krasinski SD, Cohn JS, Russell RM, Schaefer EJ (1990) Postprandial plasma vitamin A metabolism in humans: a reassessment of the use of plasma retinyl esters as markers for intestinally derived chylomicrons and their remnants. Metabolism 39:357–365PubMedCrossRefGoogle Scholar
  38. 38.
    Mezquita-Raya P, Muñoz-Torres M, Luna JD, Luna V, López-Rodríguez F, Torres-Vela E et al (2001) Relation between vitamin D insufficiency, bone density, and bone metabolism in healthy postmenopausal women. Bone Miner Res 16:1408–1415CrossRefGoogle Scholar
  39. 39.
    Quesada-Gómez JM, Alonso J, Bouillon R (1996) Vitamin D insufficiency as a determinant of hip fractures. Osteoporos Int 6:42–47PubMedCrossRefGoogle Scholar
  40. 40.
    Metz AL, Walser MM, Olson WG (1985) The interaction of dietary vitamin A and vitamin D related to skeletal development in the turkey poult. J Nutr 115:929–935PubMedGoogle Scholar
  41. 41.
    Boucher BJ, Chandra RK, Melhus H, Michaelsson K (2003) Serum retinol levels and fracture risk. N Engl J Med 348:1927–1928PubMedCrossRefGoogle Scholar

Copyright information

© International Osteoporosis Foundation and National Osteoporosis Foundation 2013

Authors and Affiliations

  • J. M. Mata-Granados
    • 1
    • 2
  • J. R. Cuenca-Acevedo
    • 3
  • M. D. Luque de Castro
    • 2
  • M. F. Holick
    • 4
    Email author
  • J. M. Quesada-Gómez
    • 1
    • 3
  1. 1.Department of I+D+ISanyres GroupCórdobaSpain
  2. 2.Department of Analytical ChemistryUniversity of CórdobaCórdobaSpain
  3. 3.Mineral Metabolism Unit RETICEF, EndocrinologyReina Sofía HospitalCórdobaSpain
  4. 4.Vitamin D Laboratory, Section of Endocrinology, Diabetes, and Nutrition, Department of MedicineBoston University Medical CenterBostonUSA

Personalised recommendations