Effect of vitamin D supplementation on serum 25-hydroxy vitamin D levels, joint pain, and fatigue in women starting adjuvant letrozole treatment for breast cancer

  • Qamar J. KhanEmail author
  • Pavan S. Reddy
  • Bruce F. Kimler
  • Priyanka Sharma
  • Susan E. Baxa
  • Anne P. O’Dea
  • Jennifer R. Klemp
  • Carol J. Fabian
Clinical trial


Vitamin D deficiency and insufficiency may contribute to musculoskeletal symptoms and bone loss observed in women taking aromatase inhibitors (AIs). This study was conducted to determine the prevalence of suboptimal vitamin D levels in women initiating adjuvant letrozole for breast cancer and to determine whether supplementation with 50,000 IU of vitamin D3 weekly could reduce musculoskeletal symptoms and fatigue in women who have suboptimal vitamin D levels. Sixty women about to begin an adjuvant AI were enrolled. Baseline 25OHD levels were obtained, and women completed symptom questionnaires. They were then started on letrozole, along with standard dose calcium and vitamin D. Four weeks later, women with baseline 25OHD levels ≤40 ng/ml started additional vitamin D3 supplementation at 50,000 IU per week for 12 weeks. 25OHD levels were re-assessed at 4, 10, and 16 weeks; the questionnaires were repeated at weeks 4 and 16. At baseline, 63% of women exhibited vitamin D deficiency (<20 ng/ml) or insufficiency (20–31 ng/ml). 25OHD levels >40 ng/ml were achieved in all 42 subjects who received 12 weeks of supplementation with 50,000 IU vitamin D3 weekly, with no adverse effects. After 16 weeks of letrozole, more women with 25OHD levels >66 ng/ml (median level) reported no disability from joint pain than did women with levels <66 ng/ml (52 vs. 19%; P = 0.026). Vitamin D deficiency and insufficiency are prevalent in post-menopausal women initiating adjuvant AI. Vitamin D3 supplementation with 50,000 IU per week is safe, significantly increases 25OHD levels, and may reduce disability from AI-induced arthralgias.


Breast cancer Vitamin D Letrozole Vitamin D deficiency Aromatase inhibitors Endocrine therapy Joint pain Arthralgias 



Letrozole and funding for this study were provided by Novartis Pharmaceutical Corporation (East Hanover, NJ). 50,000 IU vitamin D3 weekly supplementation was provided as Maximum D3 by BTR Group, Inc. (Pittsfield, IL). However, the design, conduct, and analysis of the study were the sole responsibility of the authors.


  1. 1.
    Baum M, Budzar AU, Cuzick J et al (2002) Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet 359:2131–2139CrossRefPubMedGoogle Scholar
  2. 2.
    Howell A, Cuzick J, Baum M et al (2005) Results of the ATAC (arimidex, tamoxifen, alone or in combination) trial after completion of 5 years’ adjuvant treatment for breast cancer. Lancet 365:60–62CrossRefPubMedGoogle Scholar
  3. 3.
    Coates AS, Keshaviah A, Thürlimann B et al (2007) Five years of letrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer: update of study BIG 1–98. J Clin Oncol 25:486–492CrossRefPubMedGoogle Scholar
  4. 4.
    Coombes RC, Hall E, Gibson LJ et al (2004) A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. New Engl J Med 350:1081–1092CrossRefPubMedGoogle Scholar
  5. 5.
    Coombes RC, Kilburn LS, Snowdon CF et al (2007) Survival and safety of exemestane versus tamoxifen after 2–3 years’ tamoxifen treatment (intergroup exemestane study): a randomized controlled trial. Lancet 369:559–570CrossRefPubMedGoogle Scholar
  6. 6.
    Crew KD, Greenlee H, Capodice J et al (2007) Prevalence of joint symptoms in postmenopausal women taking aromatase inhibitors for early-stage breast cancer. J Clin Oncol 25:3877–3883CrossRefPubMedGoogle Scholar
  7. 7.
    Partridge AH, LaFountain A, Mayer E et al (2008) Adherence to initial adjuvant anastrozole therapy among women with early-stage breast cancer. J Clin Oncol 26:556–562CrossRefPubMedGoogle Scholar
  8. 8.
    Dent S, DeValentin T, Vandermeer L et al (2006) Long-term toxicities in women with early stage breast cancer treated with aromatase inhibitors: data from a tertiary care center. Breast Cancer Res Treat 100(suppl 1):S190 (abstr 4057)Google Scholar
  9. 9.
    Morales L, Neven P, Timmerman D et al (2004) Acute effects of tamoxifen and third-generation aromatase inhibitors on menopausal symptoms of breast cancer. Anti-Cancer Drugs 15:753–760CrossRefPubMedGoogle Scholar
  10. 10.
    Holick MF (2006) High prevalence of vitamin D inadequacy and implications for health. Mayo Clin Proc 1:353–373CrossRefGoogle Scholar
  11. 11.
    Holick MF (2007) Vitamin D deficiency. N Engl J Med 357:266–281CrossRefPubMedGoogle Scholar
  12. 12.
    Bischoff-Ferrari HA, Dietrich T, Orav EJ et al (2004) Higher 25-hydroxyvitamin D concentrations are associated with better lower-extremity function in both active and inactive persons aged ≥60 y. Am J Clin Nutr 80:752–758PubMedGoogle Scholar
  13. 13.
    Taylor M, Rastelli A, Civitelli R et al. (2004) Incidence of 25-OH vitamin D deficiency in patients with a history of breast cancer who have musculoskeletal symptomatology. 27th Annual San Antonio Breast Cancer Symposium; December 8–11, 2004; San Antonio, TX (abstract 3072)Google Scholar
  14. 14.
    Plotnikoff GA, Quigley JM (2003) Prevalence of severe hypovitaminosis D in patients with persistent nonspecific musculoskeletal pain. Mayo Clin Proc 78:1463–1470CrossRefPubMedGoogle Scholar
  15. 15.
    Thomas MK, Lloyd-Jones DM, Thadhani RI et al (1998) Hypovitaminosis D in medical inpatients. N Engl J Med 338:777–783CrossRefPubMedGoogle Scholar
  16. 16.
    Malabanan A, Veronikis IE, Holick MF (1998) Redefining vitamin D insufficiency [letter]. Lancet 351:805–806CrossRefPubMedGoogle Scholar
  17. 17.
    Hanley DA, Davison KS (2005) Vitamin D insufficiency in North America. J Nutr 135:332–337PubMedGoogle Scholar
  18. 18.
    Buchanan JR, Santen R, Cauffman S, Cavaliere A, Greer RB, Demers LM (1986) The effect of endogenous estrogen fluctuation on metabolism of 25-hydroxyvitamin D. Calcif Tissue Int 39:139–144CrossRefPubMedGoogle Scholar
  19. 19.
    Wolfe F, Michaud K, Pincus T (2004) Development and validation of health assessment questionnaire II: a revised version of health assessment questionnaire. Arthritis Rheum 50:3296–3305CrossRefPubMedGoogle Scholar
  20. 20.
    Mendoza TR, Wang XS, Cleeland CS, Morrissey M, Johnson BA, Wendt JK, Huber SL (1999) The rapid assessment of fatigue severity in cancer patients: use of the brief fatigue inventory. Cancer 85:1186–1196CrossRefPubMedGoogle Scholar
  21. 21.
    Hilditch JR, Lewis J, Peter A, van Maris B (1996) A menopause-specific quality of life questionnaire: development and psychometric properties. Maturitas 6:161–175Google Scholar
  22. 22.
    Brodie AM, Njar VC (1996) Aromatase inhibitors and breast cancer. Semin Oncol 23(4 Suppl 9):10–20PubMedGoogle Scholar
  23. 23.
    Lønning PE, Geisler J, Krag LE et al (2005) Effects of exemestane administered for 2 years versus placebo on bone mineral density, bone biomarkers, and plasmalipids in patients with surgically resected early breast cancer. J Clin Oncol 23:4847–4849CrossRefGoogle Scholar
  24. 24.
    Chapuy MC, Arlot ME, Duboeuf F et al (1992) Vitamin D3 and calcium to prevent hip fractures in elderly women. N Engl J Med 327:1637–1642PubMedGoogle Scholar
  25. 25.
    Holick MF, Siris ES, Binkley N et al (2005) Prevalence of vitamin D inadequacy among postmenopausal North American women receiving osteoporosis therapy. J Clin Endocrinol Metab 90:3215–3224CrossRefPubMedGoogle Scholar
  26. 26.
    Lester J, Coleman R (2005) Bone loss and the aromatase inhibitors. Br J Cancer 93:S16–S22CrossRefPubMedGoogle Scholar
  27. 27.
    Lønning P, Geisler J, Krag LE et al (2006) Vitamin D deficiency: a threat to bone health in breast cancer patients during adjuvant treatment with aromatase inhibitors. J Clin Oncol 24:18s (abstr 554)CrossRefGoogle Scholar
  28. 28.
    Crew KD, Shane E, Cremers S, McMahon DJ, Irani D, Hershman DL (2009) High prevalence of vitamin D deficiency despite supplementation in premenopausal women with breast cancer undergoing adjuvant chemotherapy. J Clin Oncol 27:2151–2156CrossRefPubMedGoogle Scholar
  29. 29.
    Heaney RP (2003) Long-latency deficiency disease: insights from calcium and vitamin D. Am J Clin Nutr 78:912–919PubMedGoogle Scholar
  30. 30.
    Wells GA, Tugwell P, Kraag GR, Baker PR, Groh J, Redelmeier DA (1993) Minimum important difference between patients with rheumatoid arthritis: the patient’s perspective. J Rheumatol 20:557–560PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2009

Authors and Affiliations

  • Qamar J. Khan
    • 1
    Email author
  • Pavan S. Reddy
    • 2
  • Bruce F. Kimler
    • 3
  • Priyanka Sharma
    • 1
  • Susan E. Baxa
    • 1
  • Anne P. O’Dea
    • 1
  • Jennifer R. Klemp
    • 1
  • Carol J. Fabian
    • 1
  1. 1.Department of Internal MedicineUniversity of Kansas Medical CenterKansas CityUSA
  2. 2.Cancer Centers of KansasWichitaUSA
  3. 3.Department of Radiation OncologyUniversity of Kansas Medical CenterKansas CityUSA

Personalised recommendations