Supportive Care in Cancer

, Volume 21, Issue 4, pp 1077–1087 | Cite as

Phase II study of glucosamine with chondroitin on aromatase inhibitor-associated joint symptoms in women with breast cancer

  • Heather Greenlee
  • Katherine D. Crew
  • Theresa Shao
  • Grace Kranwinkel
  • Kevin Kalinsky
  • Matthew Maurer
  • Lois Brafman
  • Beverly Insel
  • Wei Yann Tsai
  • Dawn L Hershman
Original Article



Many women with hormone receptor-positive breast cancer discontinue effective aromatase inhibitor (AI) treatment due to joint symptoms.


We conducted a single-arm, open-label, phase II study evaluating glucosamine-sulfate (1,500 mg/day) + chondroitin-sulfate (1,200 mg/day) for 24 weeks to treat joint pain/stiffness in postmenopausal women with early stage breast cancer who developed moderate-to-severe joint pain after initiating AIs. The primary endpoint was improvement in pain/stiffness at week 24 assessed by the Outcome Measure in Rheumatology Clinical Trials and Osteoarthritis Research Society International (OMERACT-OARSI) criteria. Secondary endpoints assessed changes in pain, stiffness, and function using the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) Index for hips/knees and the Modified Score for the Assessment and Quantification of Chronic Rheumatoid Affections of the Hands (M-SACRAH) for hands/wrists. The Brief Pain Inventory (BPI) assessed pain interference, severity, and worst pain.


Of 53 patients enrolled, 39 were evaluable at week 24. From baseline to week 24, 46 % of patients improved according to OMERACT-OARSI criteria. At week 24, there were improvements (all P < 0.05) in pain and function as assessed by WOMAC and M-SACRAH, and in pain interference, severity, and worst pain as assessed by BPI. Estradiol levels did not change from baseline. The most commonly reported side effects were headache (28 %), dyspepsia (15 %), and nausea (17 %).


In this single-arm study, 24 weeks of glucosamine/chondroitin resulted in moderate improvements in AI-induced arthralgias, with minimal side effects, and no changes in estradiol levels. These results suggest a need to evaluate efficacy in a placebo-controlled trial.


Breast cancer Aromatase inhibitors Arthralgias Dietary supplement Glucosamine Chondroitin 



We thank the women who participated in the study. This research was supported by AstraZeneca (D.L.H.), the Breast Cancer Research Foundation (D.L.H.), the National Cancer Institute (K23CA141052 to H.G.), and Grant Number UL1 RR024156 from the National Center for Research Resources, a component of the National Institutes of Health and National Institutes of Health Roadmap for Medical Research. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the funding agencies.

Ethical standards

The CUMC institutional review board approved the study, and all participants provided written informed consent in English or Spanish.

Conflict of interest

The authors declare that they have no conflict of interest. We have full control of all primary data, and we agree to allow the journal to review the data if requested.


  1. 1.
    Baum M, Budzar AU, Cuzick J, Forbes J, Houghton JH, Klijn JG, Sahmoud T, Group AT (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(9324):2131–2139PubMedCrossRefGoogle Scholar
  2. 2.
    Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ, Castiglione M, Tu D, Shepherd LE, Pritchard KI, Livingston RB, Davidson NE, Norton L, Perez EA, Abrams JS, Therasse P, Palmer MJ, Pater JL (2003) A randomized trial of letrozole in postmenopausal women after 5 years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 349(19):1793–1802PubMedCrossRefGoogle Scholar
  3. 3.
    Howell A, Cuzick J, Baum M, Buzdar A, Dowsett M, Forbes JF, Hoctin-Boes G, Houghton J, Locker GY, Tobias JS (2005) Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years’ adjuvant treatment for breast cancer. Lancet 365(9453):60–62PubMedCrossRefGoogle Scholar
  4. 4.
    Thurlimann B, Keshaviah A, Coates AS, Mouridsen H, Mauriac L, Forbes JF, Paridaens R, Castiglione-Gertsch M, Gelber RD, Rabaglio M, Smith I, Wardly A, Price KN, Goldhirsch A (2005) A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 353(26):2747–2757PubMedCrossRefGoogle Scholar
  5. 5.
    Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ, Castiglione M, Tu D, Shepherd LE, Pritchard KI, Livingston RB, Davidson NE, Norton L, Perez EA, Abrams JS, Cameron DA, Palmer MJ, Pater JL (2005) Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: updated findings from NCIC CTG MA.17. J Natl Cancer Inst 97(17):1262–1271PubMedCrossRefGoogle Scholar
  6. 6.
    Coombes RC, Hall E, Gibson LJ, Paridaens R, Jassem J, Delozier T, Jones SE, Alvarez I, Bertelli G, Ortmann O, Coates AS, Bajetta E, Dodwell D, Coleman RE, Fallowfield LJ, Mickiewicz E, Andersen J, Lonning PE, Cocconi G, Stewart A, Stuart N, Snowdon CF, Carpentieri M, Massimini G, Bliss JM (2004) A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 350(11):1081–1092PubMedCrossRefGoogle Scholar
  7. 7.
    Crew KD, Greenlee H, Capodice J, Raptis G, Brafman L, Fuentes D, Sierra A, Hershman DL (2007) Prevalence of joint symptoms in postmenopausal women taking aromatase inhibitors for early-stage breast cancer. J Clin Oncol 25(25):3877–3883. doi:10.1200/JCO.2007.10.7573 PubMedCrossRefGoogle Scholar
  8. 8.
    Sestak I, Cuzick J, Sapunar F, Eastell R, Forbes JF, Bianco AR, Buzdar AU (2008) Risk factors for joint symptoms in patients enrolled in the ATAC trial: a retrospective, exploratory analysis. Lancet Oncol 9(9):866–872. doi:10.1016/S1470-2045(08)70182-7 PubMedCrossRefGoogle Scholar
  9. 9.
    Henry NL, Giles JT, Ang D, Mohan M, Dadabhoy D, Robarge J, Hayden J, Lemler S, Shahverdi K, Powers P, Li L, Flockhart D, Stearns V, Hayes DF, Storniolo AM, Clauw DJ (2008) Prospective characterization of musculoskeletal symptoms in early stage breast cancer patients treated with aromatase inhibitors. Breast Cancer Res Treat 111(2):365–372. doi:10.1007/s10549-007-9774-6 PubMedCrossRefGoogle Scholar
  10. 10.
    Mao JJ, Stricker C, Bruner D, Xie S, Bowman MA, Farrar JT, Greene BT, DeMichele A (2009) Patterns and risk factors associated with aromatase inhibitor-related arthralgia among breast cancer survivors. Cancer 115(16):3631–3639. doi:10.1002/cncr.24419 PubMedCrossRefGoogle Scholar
  11. 11.
    Mortimer JE (2010) Managing the toxicities of the aromatase inhibitors. Curr Opin Obstet Gynecol 22(1):56–60. doi:10.1097/GCO.0b013e328334e44e PubMedCrossRefGoogle Scholar
  12. 12.
    Hershman DL, Kushi LH, Shao T, Buono D, Kershenbaum A, Tsai WY, Fehrenbacher L, Lin Gomez S, Miles S, Neugut AI (2010) Early discontinuation and nonadherence to adjuvant hormonal therapy in a cohort of 8,769 early-stage breast cancer patients. J Clin Oncol 28(27):4120–4128. doi:10.1200/JCO.2009.25.9655 PubMedCrossRefGoogle Scholar
  13. 13.
    Hershman DL, Shao T, Kushi LH, Buono D, Tsai WY, Fehrenbacher L, Kwan M, Gomez SL, Neugut AI (2011) Early discontinuation and non-adherence to adjuvant hormonal therapy are associated with increased mortality in women with breast cancer. Breast Cancer Res Treat 126(2):529–537. doi:10.1007/s10549-010-1132-4 PubMedCrossRefGoogle Scholar
  14. 14.
    Rao JK, Mihaliak K, Kroenke K, Bradley J, Tierney WM, Weinberger M (1999) Use of complementary therapies for arthritis among patients of rheumatologists. Ann Intern Med 131(6):409–416PubMedGoogle Scholar
  15. 15.
    Barnes PM, Bloom B, Nahin RL (2008) Complementary and alternative medicine use among adults and children: United States, 2007. Natl Health Stat Report 12:1–23PubMedGoogle Scholar
  16. 16.
    Chou R, McDonagh MS, Nakamoto E, Griffin J (2011) Analgesics for osteoarthritis: an update of the 2006 comparative effectiveness review [Internet]. AHRQ comparative effectiveness reviews, vol 38. Agency for Healthcare Research and Quality (US), Rockville (MD)Google Scholar
  17. 17.
    Kapoor M, Mineau F, Fahmi H, Pelletier JP, Martel-Pelletier J (2011) Glucosamine sulfate reduces prostaglandin E2 production in osteoarthritic chondrocytes through inhibition of microsomal PGE synthase-1. J Rheumatol. doi:10.3899/jrheum.110621
  18. 18.
    Petersen SG, Beyer N, Hansen M, Holm L, Aagaard P, Mackey AL, Kjaer M (2011) Nonsteroidal anti-inflammatory drug or glucosamine reduced pain and improved muscle strength with resistance training in a randomized controlled trial of knee osteoarthritis patients. Arch Phys Med Rehabil 92(8):1185–1193. doi:10.1016/j.apmr.2011.03.009 PubMedCrossRefGoogle Scholar
  19. 19.
    Wildi LM, Raynauld JP, Martel-Pelletier J, Beaulieu A, Bessette L, Morin F, Abram F, Dorais M, Pelletier JP (2011) Chondroitin sulphate reduces both cartilage volume loss and bone marrow lesions in knee osteoarthritis patients starting as early as 6 months after initiation of therapy: a randomised, double-blind, placebo-controlled pilot study using MRI. Ann Rheum Dis 70(6):982–989. doi:10.1136/ard.2010.140848 PubMedCrossRefGoogle Scholar
  20. 20.
    Setnikar I, Cereda R, Pacini MA, Revel L (1991) Antireactive properties of glucosamine sulfate. Arzneimittelforschung 41(2):157–161PubMedGoogle Scholar
  21. 21.
    Shikhman AR, Kuhn K, Alaaeddine N, Lotz M (2001) N-acetylglucosamine prevents IL-1 beta-mediated activation of human chondrocytes. J Immunol 166(8):5155–5160PubMedGoogle Scholar
  22. 22.
    Bassleer C, Rovati L, Franchimont P (1998) Stimulation of proteoglycan production by glucosamine sulfate in chondrocytes isolated from human osteoarthritic articular cartilage in vitro. Osteoarthritis Cartilage 6(6):427–434. doi:10.1053/joca.1998.0146 PubMedCrossRefGoogle Scholar
  23. 23.
    Pavelka K, Gatterova J, Olejarova M, Machacek S, Giacovelli G, Rovati LC (2002) Glucosamine sulfate use and delay of progression of knee osteoarthritis: a 3-year, randomized, placebo-controlled, double-blind study. Arch Intern Med 162(18):2113–2123PubMedCrossRefGoogle Scholar
  24. 24.
    Lippiello L, Woodward J, Karpman R, Hammad TA (2000) In vivo chondroprotection and metabolic synergy of glucosamine and chondroitin sulfate. Clin Orthop Relat Res 381:229–240PubMedCrossRefGoogle Scholar
  25. 25.
    Clegg DO, Reda DJ, Harris CL, Klein MA, O’Dell JR, Hooper MM, Bradley JD, Bingham CO 3rd, Weisman MH, Jackson CG, Lane NE, Cush JJ, Moreland LW, Schumacher HR Jr, Oddis CV, Wolfe F, Molitor JA, Yocum DE, Schnitzer TJ, Furst DE, Sawitzke AD, Shi H, Brandt KD, Moskowitz RW, Williams HJ (2006) Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. N Engl J Med 354(8):795–808PubMedCrossRefGoogle Scholar
  26. 26.
    Bellamy N, Buchanan WW, Goldsmith CH, Campbell J, Stitt LW (1988) Validation study of WOMAC: a health status instrument for measuring clinically important patient relevant outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee. J Rheumatol 15(12):1833–1840PubMedGoogle Scholar
  27. 27.
    Sautner J, Andel I, Rintelen B, Leeb BF (2004) Development of the M-SACRAH, a modified, shortened version of SACRAH (Score for the Assessment and Quantification of Chronic Rheumatoid Affections of the Hands). Rheumatology (Oxford) 43(11):1409–1413CrossRefGoogle Scholar
  28. 28.
    Cleeland CS, Ryan KM (1994) Pain assessment: global use of the Brief Pain Inventory. Ann Acad Med Singapore 23(2):129–138PubMedGoogle Scholar
  29. 29.
    Brady MJ, Cella DF, Mo F, Bonomi AE, Tulsky DS, Lloyd SR, Deasy S, Cobleigh M, Shiomoto G (1997) Reliability and validity of the functional assessment of cancer therapy-breast quality-of-life instrument. J Clin Oncol 15(3):974–986PubMedGoogle Scholar
  30. 30.
    Fallowfield LJ, Leaity SK, Howell A, Benson S, Cella D (1999) Assessment of quality of life in women undergoing hormonal therapy for breast cancer: validation of an endocrine symptom subscale for the FACT-B. Breast Cancer Res Treat 55(2):189–199PubMedCrossRefGoogle Scholar
  31. 31.
    Anderson JW, Nicolosi RJ, Borzelleca JF (2005) Glucosamine effects in humans: a review of effects on glucose metabolism, side effects, safety considerations and efficacy. Food Chem Toxicol 43(2):187–201PubMedCrossRefGoogle Scholar
  32. 32.
    Pham T, van der Heijde D, Altman RD, Anderson JJ, Bellamy N, Hochberg M, Simon L, Strand V, Woodworth T, Dougados M (2004) OMERACT-OARSI initiative: Osteoarthritis Research Society International set of responder criteria for osteoarthritis clinical trials revisited. Osteoarthritis Cartilage 12(5):389–399. doi:10.1016/j.joca.2004.02.001 PubMedCrossRefGoogle Scholar
  33. 33.
    Rastelli AL, Taylor ME, Gao F, Armamento-Villareal R, Jamalabadi-Majidi S, Napoli N, Ellis MJ (2011) Vitamin D and aromatase inhibitor-induced musculoskeletal symptoms (AIMSS): a phase II, double-blind, placebo-controlled, randomized trial. Breast Cancer Res Treat 129(1):107–116. doi:10.1007/s10549-011-1644-6 PubMedCrossRefGoogle Scholar
  34. 34.
    Khan QJ, Reddy PS, Kimler BF, Sharma P, Baxa SE, O’Dea AP, Klemp JR, Fabian CJ (2010) 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. Breast Cancer Res Treat 119(1):111–118. doi:10.1007/s10549-009-0495-x PubMedCrossRefGoogle Scholar
  35. 35.
    Prieto-Alhambra D, Javaid MK, Servitja S, Arden NK, Martinez-Garcia M, Diez-Perez A, Albanell J, Tusquets I, Nogues X (2011) Vitamin D threshold to prevent aromatase inhibitor-induced arthralgia: a prospective cohort study. Breast Cancer Res Treat 125(3):869–878. doi:10.1007/s10549-010-1075-9 PubMedCrossRefGoogle Scholar
  36. 36.
    Henry NL, Banerjee M, Wicha M, Van Poznak C, Smerage JB, Schott AF, Griggs JJ, Hayes DF (2011) Pilot study of duloxetine for treatment of aromatase inhibitor-associated musculoskeletal symptoms. Cancer 117(24):5469–5475. doi:10.1002/cncr.26230 PubMedCrossRefGoogle Scholar
  37. 37.
    Crew KD, Capodice JL, Greenlee H, Brafman L, Fuentes D, Awad D, Yann Tsai W, Hershman DL (2010) Randomized, blinded, sham-controlled trial of acupuncture for the management of aromatase inhibitor-associated joint symptoms in women with early-stage breast cancer. J Clin Oncol 28(7):1154–1160. doi:10.1200/JCO.2009.23.4708 PubMedCrossRefGoogle Scholar
  38. 38.
    Crew KD, Capodice JL, Greenlee H, Apollo A, Jacobson JS, Raptis G, Blozie K, Sierra A, Hershman DL (2007) Pilot study of acupuncture for the treatment of joint symptoms related to adjuvant aromatase inhibitor therapy in postmenopausal breast cancer patients. J Cancer Surviv 1(4):283–291. doi:10.1007/s11764-007-0034-x PubMedCrossRefGoogle Scholar
  39. 39.
    Mao JJ, Bruner DW, Stricker C, Farrar JT, Xie SX, Bowman MA, Pucci D, Han X, DeMichele A (2009) Feasibility trial of electroacupuncture for aromatase inhibitor-related arthralgia in breast cancer survivors. Integr Cancer Ther 8(2):123–129. doi:10.1177/1534735409332903 PubMedCrossRefGoogle Scholar
  40. 40.
    Galantino ML, Desai K, Greene L, Demichele A, Stricker CT, Mao JJ (2011) Impact of yoga on functional outcomes in breast cancer survivors with aromatase inhibitor-associated arthralgias. Integr Cancer Ther. doi:10.1177/1534735411413270
  41. 41.
    Briot K, Tubiana-Hulin M, Bastit L, Kloos I, Roux C (2010) Effect of a switch of aromatase inhibitors on musculoskeletal symptoms in postmenopausal women with hormone-receptor-positive breast cancer: the ATOLL (Articular Tolerance of Letrozole) study. Breast Cancer Res Treat 120(1):127–134. doi:10.1007/s10549-009-0692-7 PubMedCrossRefGoogle Scholar
  42. 42.
    Gabay C, Medinger-Sadowski C, Gascon D, Kolo F, Finckh A (2011) Symptomatic effects of chondroitin 4 and chondroitin 6 sulfate on hand osteoarthritis: a randomized, double-blind, placebo-controlled clinical trial at a single center. Arthritis Rheum 63(11):3383–3391. doi:10.1002/art.30574 PubMedCrossRefGoogle Scholar
  43. 43.
    Wilkens P, Scheel IB, Grundnes O, Hellum C, Storheim K (2010) Effect of glucosamine on pain-related disability in patients with chronic low back pain and degenerative lumbar osteoarthritis: a randomized controlled trial. JAMA 304(1):45–52. doi:10.1001/jama.2010.893 PubMedCrossRefGoogle Scholar
  44. 44.
    Dworkin RH, Turk DC, Wyrwich KW, Beaton D, Cleeland CS, Farrar JT, Haythornthwaite JA, Jensen MP, Kerns RD, Ader DN, Brandenburg N, Burke LB, Cella D, Chandler J, Cowan P, Dimitrova R, Dionne R, Hertz S, Jadad AR, Katz NP, Kehlet H, Kramer LD, Manning DC, McCormick C, McDermott MP, McQuay HJ, Patel S, Porter L, Quessy S, Rappaport BA, Rauschkolb C, Revicki DA, Rothman M, Schmader KE, Stacey BR, Stauffer JW, von Stein T, White RE, Witter J, Zavisic S (2008) Interpreting the clinical importance of treatment outcomes in chronic pain clinical trials: IMMPACT recommendations. J Pain 9(2):105–121. doi:10.1016/j.jpain.2007.09.005 PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • Heather Greenlee
    • 1
    • 2
    • 3
  • Katherine D. Crew
    • 1
    • 2
    • 3
  • Theresa Shao
    • 2
    • 3
  • Grace Kranwinkel
    • 3
  • Kevin Kalinsky
    • 2
    • 3
  • Matthew Maurer
    • 2
    • 3
  • Lois Brafman
    • 3
  • Beverly Insel
    • 1
  • Wei Yann Tsai
    • 3
    • 4
  • Dawn L Hershman
    • 1
    • 2
    • 3
    • 5
  1. 1.Department of Epidemiology, Mailman School of Public HealthColumbia UniversityNew YorkUSA
  2. 2.Department of Medicine, College of Physicians and SurgeonsColumbia UniversityNew YorkUSA
  3. 3.Herbert Irving Comprehensive Cancer CenterColumbia UniversityNew YorkUSA
  4. 4.Department of Biostatistics, Mailman School of Public HealthColumbia UniversityNew YorkUSA
  5. 5.Columbia UniversityNew YorkUSA

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