Skip to main content

Advertisement

SpringerLink
Log in

Gender-Dependent Reductions in Vertebrae Length, Bone Mineral Density and Content by Doxorubicin Are Not Reduced by Dexrazoxane in Young Rats: Effect on Growth Plate and Intervertebral Discs

  • Published:
Calcified Tissue International Aims and scope Submit manuscript

Abstract

Doxorubicin (DOX) is widely used in anti-cancer cocktails. Dexrazoxane (DXR) is a cardioprotectant approved for use with DOX. The effect of DOX, with or without DXR, on bone in children is not well understood. The aim of this study was to examine the effect of DOX on vertebrae and femur length and bone density acquisition in young rats, as well as to test the hypothesis that young females are more susceptible to DOX-induced tissue damage than young males. The results of this study suggest that a single injection of DOX in young female and not male rats is associated with low bone turnover resulting in vertebrae and femur bone growth deficits. DOX selectively decreased BMD and BMC accrual in the lumbar verterbrae that was not prevented by DXR. DOX-treated rats also exhibited growth plate and intervertebral disc defects. This information will be useful in the design of interventions to promote bone growth or retard bone loss during DOX treatment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. JM Gertner (1999) Childhood and Adolescence. Primer on the Metabolic Bone Diseases and Disorder of Mineral Metabolism 4th ed Lippincolt Williams and Wilkins New York 45–49

    Google Scholar 

  2. GI Baroncelli G Saggese (2000) ArticleTitleCritical ages and stages of puberty in the accumulation of spinal and femoral bone mass: the validity of bone mass measurements Horm Res 54 2–8 Occurrence Handle1:CAS:528:DC%2BD3MXhs12ku7k%3D Occurrence Handle11146373

    CAS  PubMed  Google Scholar 

  3. AW Root (2002) ArticleTitleBone strength and the adolescent Adolesc Med 13 53–72 Occurrence Handle11841955

    PubMed  Google Scholar 

  4. KK Ong ML Ahmed DB Dunger (1999) ArticleTitleThe role of leptin in human growth and puberty Acta Paediatr 88 IssueIDSuppl 95–98 Occurrence Handle10.1080/080352599750029817 Occurrence Handle1:STN:280:DC%2BD3c%2FovF2rsw%3D%3D

    Article  CAS  Google Scholar 

  5. W Leung MM Hudson DK Strickland et al. (2000) ArticleTitleLate effects of treatment in survivors of childhood acute myeloid leukemia J Clin Oncol 18 3273–3279 Occurrence Handle1:STN:280:DC%2BD3cvotlemsQ%3D%3D Occurrence Handle10986060

    CAS  PubMed  Google Scholar 

  6. V Papadakis C Tan G Heller C Sklar (1996) ArticleTitleGrowth and final height after treatment for childhood Hodgkin disease J Pediatr Hematol Oncol 18 272–276 Occurrence Handle10.1097/00043426-199608000-00007 Occurrence Handle1:STN:280:BymA3c%2FivVA%3D Occurrence Handle8689340

    Article  CAS  PubMed  Google Scholar 

  7. TB Haddy RB Mosher GH Reaman (2001) ArticleTitleOsteoporosis in survivors of acute lymphoblastic leukemia Oncologist 6 278–285 Occurrence Handle10.1634/theoncologist.6-3-278 Occurrence Handle1:STN:280:DC%2BD3Mzmt12gtQ%3D%3D Occurrence Handle11423675

    Article  CAS  PubMed  Google Scholar 

  8. SC Kaste D Jones-Wallace SR Rose et al. (2001) ArticleTitleBone mineral decrements in survivors of childhood acute lymphoblastic leukemia: frequency of occurrence and risk factors for their development Leukemia 15 728–734 Occurrence Handle10.1038/sj.leu.2402078 Occurrence Handle1:STN:280:DC%2BD3M3ntlKmtQ%3D%3D Occurrence Handle11368432

    Article  CAS  PubMed  Google Scholar 

  9. JM Halton SA Atkinson L Fraher et al. (1996) ArticleTitleAltered mineral metabolism and bone mass in children during treatment for acute lymphoblastic leukemia J Bone Miner Res 11 1774–1783 Occurrence Handle1:STN:280:ByiD2szgtlw%3D Occurrence Handle8915786

    CAS  PubMed  Google Scholar 

  10. BL Leeuwen Particlevan WA Kamps RM Hartel et al. (2000) ArticleTitleEffect of single chemotherapeutic agents on the growing skeleton of the rat Ann Oncol 11 1121–1126 Occurrence Handle10.1023/A:1008352620870 Occurrence Handle11061605

    Article  PubMed  Google Scholar 

  11. S Shusterman AT Meadows (2000) ArticleTitleLong-term survivors of childhood leukemia Curr Opin Hematol 7 217–222 Occurrence Handle10.1097/00062752-200007000-00004 Occurrence Handle1:STN:280:DC%2BD3M%2FjtVGmtQ%3D%3D Occurrence Handle10882177

    Article  CAS  PubMed  Google Scholar 

  12. KD Rainsford (1989) ArticleTitleDoxorubicin is a potent inhibitor of interleukin 1-induced cartilage proteoglycan resorption in vitro J Pharm Pharmacol 41 60–63 Occurrence Handle1:CAS:528:DyaL1MXhtVOrsb8%3D Occurrence Handle2565969

    CAS  PubMed  Google Scholar 

  13. GE Friedlaender RB Tross AC Doganis et al. (1984) ArticleTitleEffects of chemotherapeutic agents on bone. I. Short-term methotrexate and doxorubicin (adriamycin) treatment in a rat model J Bone Joint Surg Am 66 602–607 Occurrence Handle1:STN:280:BiuC283itV0%3D Occurrence Handle6707039

    CAS  PubMed  Google Scholar 

  14. DM Young JL Fioravanti HM Olson DJ Prieur (1975) ArticleTitleChemical and morphologic alterations of rabbit bone induced by adriamycin Calcif Tissue Res 18 47–63 Occurrence Handle1:CAS:528:DyaE2MXltVynurY%3D Occurrence Handle1148891

    CAS  PubMed  Google Scholar 

  15. OJ Arola A Saraste K Pulkki et al. (2000) ArticleTitleAcute doxorubicin cardiotoxicity involves cardiomyocyte apoptosis Cancer Res 60 1789–1792 Occurrence Handle1:CAS:528:DC%2BD3cXisVyntb4%3D Occurrence Handle10766158

    CAS  PubMed  Google Scholar 

  16. D Kumar LA Kirshenbaum T Li I Danelisen PK Singal (2001) ArticleTitleApoptosis in adriamycin cardiomyopathy and its modulation by probucol Antioxid Redox Signal 3 135–145 Occurrence Handle10.1089/152308601750100641 Occurrence Handle1:CAS:528:DC%2BD3MXit1Ols7g%3D Occurrence Handle11291592

    Article  CAS  PubMed  Google Scholar 

  17. DM Green YA Grigoriev B Nan et al. (2001) ArticleTitleCongestive heart failure after treatment for Wilms’ tumor: a report from the National Wilms’ Tumor Study group J Clin Oncol 19 1926–1934 Occurrence Handle1:STN:280:DC%2BD3M3js1ylsg%3D%3D Occurrence Handle11283124

    CAS  PubMed  Google Scholar 

  18. MA Grenier SE Lipshultz (1998) ArticleTitleEpidemiology of anthracycline cardiotoxicity in children and adults Semin Oncol 25 72–85 Occurrence Handle1:CAS:528:DyaK1cXmvFWgtLs%3D Occurrence Handle9768828

    CAS  PubMed  Google Scholar 

  19. JP Krischer S Epstein DD Cuthbertson et al. (1997) ArticleTitleClinical cardiotoxicity following anthracycline treatment for childhood cancer: the Pediatric Oncology Group experience J Clin Oncol 15 1544–1552 Occurrence Handle1:CAS:528:DyaK2sXivVehsL4%3D Occurrence Handle9193351

    CAS  PubMed  Google Scholar 

  20. BM Frost S Eksborg O Bjork et al. (2002) ArticleTitlePharmacokinetics of doxorubicin in children with acute lymphoblastic leukemia: multi-institutional collaborative study Med Pediatr Oncol 38 329–337 Occurrence Handle10.1002/mpo.10052 Occurrence Handle11979457

    Article  PubMed  Google Scholar 

  21. LC Kremer EC Dalen Particlevan M Offringa et al. (2001) ArticleTitleAnthracycline-induced clinical heart failure in a cohort of 607 children: long-term follow-up study J Clin Oncol 19 191–196 Occurrence Handle1:CAS:528:DC%2BD3MXot1Wguw%3D%3D Occurrence Handle11134212

    CAS  PubMed  Google Scholar 

  22. JC Kwok DR Richardson (2000) ArticleTitleThe cardioprotective effect of the iron chelator dexrazoxane (ICRF-187) on anthracycline-mediated cardiotoxicity Redox Rep 5 317–324 Occurrence Handle10.1179/135100000101535898 Occurrence Handle1:CAS:528:DC%2BD3MXjvVSrug%3D%3D Occurrence Handle11140743

    Article  CAS  PubMed  Google Scholar 

  23. FA Bu’Lock HM Gabriel A Oakhill et al. (1993) ArticleTitleCardioprotection by ICRF187 against high dose anthracycline toxicity in children with malignant disease Br Heart J 70 185–188 Occurrence Handle1:STN:280:ByuA3M3isVU%3D Occurrence Handle8038032

    CAS  PubMed  Google Scholar 

  24. A Schiavetti MA Castello P Versacci et al. (1997) ArticleTitleUse of ICRF-187 for prevention of anthracycline cardiotoxicity in children: preliminary results Pediatr Hematol Oncol 14 213–222 Occurrence Handle1:CAS:528:DyaK2sXktV2ktbs%3D Occurrence Handle9185206

    CAS  PubMed  Google Scholar 

  25. LH Wexler MP Andrich D Venzon et al. (1996) ArticleTitleRandomized trial of the cardioprotective agent ICRF-187 in pediatric sarcoma patients treated with doxorubicin J Clin Oncol 14 362–372 Occurrence Handle1:CAS:528:DyaK28XhsV2lsLc%3D Occurrence Handle8636745

    CAS  PubMed  Google Scholar 

  26. LM Schuchter ML Hensley NJ Meropol EP Winer InstitutionalAuthorNamefor the Americal Society of Clinical Oncology Chemotherapy and Radiotherapy Expert Panel (2002) ArticleTitle2002 update of recommendations for the use of chemotherapy and radiotherapy protectants: clinical practice guidelines of the American Society of Clinical Oncology J Clin Oncol 20 2895–2903 Occurrence Handle10.1200/JCO.2002.04.178 Occurrence Handle12065567

    Article  PubMed  Google Scholar 

  27. Poole, AR, Laverty, S, Mwale, F (2000) “Endochondral Bone Formation and Development in the Axial and Appendicular Skeleton” In: Henderson, JE, Goltzman, D (editors), The Osteoporosis Primer, Cambridge University Press, United Kingdom, pp 3–17

  28. Y Ueda (1987) ArticleTitleProblems in anti-leukemic drugs chemotherapy of childhood acute leukemia Nippon Ika Daigaku Zasshi 54 573–580 Occurrence Handle1:STN:280:BieC3sbmtlc%3D Occurrence Handle3325522

    CAS  PubMed  Google Scholar 

  29. S Héon M Bernier N Servant et al. (2003) ArticleTitleDexrazoxane does not protect against Doxorubicin-induced damage in the young rat Am J Physiol Heart Circ Physiol 285 499–506

    Google Scholar 

  30. K Jahnukainen T Jahnukainen TT Salmi et al. (2001) ArticleTitleAmifostine protects against early but not late toxic effects of doxorubicin in infant rats Cancer Res 61 6423–6427 Occurrence Handle1:CAS:528:DC%2BD3MXmsF2jsLY%3D Occurrence Handle11522636

    CAS  PubMed  Google Scholar 

  31. C Rivier (1993) ArticleTitleFemale rats release more corticosterone than males in response to alcohol: influence of circulating sex steroids and possible consequences for blood alcohol levels Alcohol Clin Exp Res 17 854–859 Occurrence Handle1:CAS:528:DyaK2cXpvFWqtQ%3D%3D Occurrence Handle8214426

    CAS  PubMed  Google Scholar 

  32. BO Samuelsson I Marky S Rosberg K Albertsson-Wikland (1997) ArticleTitleGrowth and growth hormone secretion after treatment for childhood non-Hodgkin’s lymphoma Med Pediatr Oncol 28 27–34 Occurrence Handle10.1002/(SICI)1096-911X(199701)28:1<27::AID-MPO6>3.0.CO;2-V Occurrence Handle1:STN:280:ByiC3cjlvFc%3D Occurrence Handle8950333

    Article  CAS  PubMed  Google Scholar 

  33. M Bradney MK Karlsson Y Duan et al. (2000) ArticleTitleHeterogeneity in the growth of the axial and appendicular skeleton in boys: implications for the pathogenesis of bone fragility in men J Bone Miner Res 15 1871–1878 Occurrence Handle1:STN:280:DC%2BD3cvnslSlug%3D%3D Occurrence Handle11028438

    CAS  PubMed  Google Scholar 

  34. TE Hefferan GL Evans S Lotinun et al. (2003) ArticleTitleEffect of gender on bone turnover in adult rats during simulated weightlessness J Appl Physiol 95 1775–1780 Occurrence Handle1:STN:280:DC%2BD3svnslGmtg%3D%3D Occurrence Handle12882994

    CAS  PubMed  Google Scholar 

  35. RR Pelker GE Friedlaender MM Panjabi et al. (1985) ArticleTitleChemotherapy-induced alterations in the biomechanics of rat bone J Orthop Res 3 91–95 Occurrence Handle10.1002/jor.1100030111 Occurrence Handle1:CAS:528:DyaL2MXktlajtLs%3D Occurrence Handle3981299

    Article  CAS  PubMed  Google Scholar 

  36. CA Glackin EJ Murray SS Murray (1992) ArticleTitleDoxorubicin inhibits differentiation and enhances expression of the helix-loop-helix genes Id and mTwi in mouse osteoblastic cells Biochem Int 28 67–75 Occurrence Handle1:CAS:528:DyaK3sXhsF2nsQ%3D%3D Occurrence Handle1280141

    CAS  PubMed  Google Scholar 

  37. G Kohler V Shen WA Peck (1984) ArticleTitleAdriamycin inhibits PTH-mediated but not PGE2-mediated stimulation of cyclic AMP formation in isolated bone cells Calcif Tissue Int 36 279–284 Occurrence Handle1:CAS:528:DyaL2cXkvVCmu7o%3D Occurrence Handle6088009

    CAS  PubMed  Google Scholar 

  38. L Ibanez N Potau K Ong DB Dunger F Zegher ParticleDe (2000) ArticleTitleIncreased bone mineral density and serum leptin in non-obese girls with precocious pubarche: relation to low birthweight and hyperinsulinism Horm Res 54 192–197 Occurrence Handle10.1159/000053258 Occurrence Handle1:CAS:528:DC%2BD3MXkvFCgsbw%3D Occurrence Handle11416237

    Article  CAS  PubMed  Google Scholar 

  39. Q Qu M Perala-Heape A Kapanen et al. (1998) ArticleTitleEstrogen enhances differentiation of osteoblasts in mouse bone marrow culture Bone 22 201–209 Occurrence Handle10.1016/S8756-3282(97)00276-7 Occurrence Handle1:CAS:528:DyaK1cXitVGktrs%3D Occurrence Handle9514212

    Article  CAS  PubMed  Google Scholar 

  40. NA Samaan DN deAsis SuffixJr. AU Buzdar GR Blumenschein (1978) ArticleTitlePituitary-ovarian function in breast cancer patients on adjuvant chemoimmunotherapy Cancer 41 2084–2087 Occurrence Handle1:STN:280:CSeC1cfmt1c%3D Occurrence Handle418867

    CAS  PubMed  Google Scholar 

  41. CH Turner RK Roeder A Wieczorek et al. (2001) ArticleTitleVariability in skeletal mass, structure, and biomechanical properties among inbred strains of rats J Bone Miner Res 16 1532–1539 Occurrence Handle1:STN:280:DC%2BD3Mvltlejtg%3D%3D Occurrence Handle11499876

    CAS  PubMed  Google Scholar 

  42. JS Colvin BA Bohne GW Harding (1996) ArticleTitleSkeletal overgrowth and deafness in mice lacking fibroblast growth factor receptor 3 Nat Genet 12 390–397 Occurrence Handle10.1038/ng0496-390 Occurrence Handle1:CAS:528:DyaK28XjtFaju7c%3D Occurrence Handle8630492

    Article  CAS  PubMed  Google Scholar 

  43. LR Wiseman CM Spencer (1998) ArticleTitleDexrazoxane. A review of its use as a cardioprotective agent in patients receiving anthracycline-based chemotherapy Drugs 56 385–403 Occurrence Handle1:CAS:528:DyaK1cXmsVSitb8%3D Occurrence Handle9777314

    CAS  PubMed  Google Scholar 

  44. CF Seifert ME Nesser DF Thompson (1994) ArticleTitleDexrazoxane in the prevention of doxorubicin-induced cardiotoxicity Ann Pharmacother 28 1063–1072 Occurrence Handle1:STN:280:ByqC3c3hvVU%3D Occurrence Handle7803884

    CAS  PubMed  Google Scholar 

  45. PM Mandalunis RL Cabrini AM Ubios (1997) ArticleTitleIron overloading inhibits endochondral ossification Acta Odontol Latinoam 10 55–61 Occurrence Handle1:STN:280:DC%2BD387ltlertg%3D%3D Occurrence Handle11885082

    CAS  PubMed  Google Scholar 

  46. NA Johanson (1990) ArticleTitleMusculoskeletal problems in hemoglobinopathy Orthop Clin North Am 21 191–198 Occurrence Handle1:STN:280:By%2BC3MvpsVI%3D Occurrence Handle2296457

    CAS  PubMed  Google Scholar 

  47. E Tchetina F Mwale AR Poole (2003) ArticleTitleDistinct phases of coordinated early and late gene expression in growth plate chondrocytes in relationship to cell proliferation, matrix assembly, remodeling, and cell differentiation J Bone Miner Res 18 844–851 Occurrence Handle1:CAS:528:DC%2BD3sXjslahsrg%3D Occurrence Handle12733723

    CAS  PubMed  Google Scholar 

  48. I Muller D Niethammer G Bruchelt (1998) ArticleTitleAnthracycline-derived chemotherapeutics in apoptosis and free radical cytotoxicity (Review) Int J Mol Med 1 491–494 Occurrence Handle1:CAS:528:DyaK1cXmvFWhtbY%3D Occurrence Handle9852255

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This research was supported by grants from the Heart and Stroke Foundation of Quebec, the Canadian Institutes of Health Research (to LEC), the Canadian Orthopaedic Foundation and AO Switzerland (to FM) and the Awards Program of the Rx&D Health Research Foundation (to SH). We thank the Department of Pathology, SMBD-Jewish General Hospital and Edouard DePestre for use of the Faxitron. The technical assistance of Miren Graton at McGill University bone center with the PIXImus Bone Densitometer is greatly acknowledged.

Author information

Authors and Affiliations

  1. Lady Davis Institute for Medical Research, Sir Mortimer B. Davis – Jewish General Hospital, 3755 chemin Cote Ste Catherine, Montréal, Quebec, Canada H3T 1E2

    F. Mwale, J. Antoniou, S. Héon, N. Servant, C. Wang, C. N. Demers & L. E. Chalifour

  2. Department of Surgery, McGill University, 3755, Chemin de la Cote St. Catherine, Montréal, Quebec, Canada, H3T 1E2

    F. Mwale & J. Antoniou

  3. Department of Biomedical Sciences, University of Guelph, Guelph, Ontario, Canada, NIG 2W1

    G. M. Kirby

  4. Division of Experimental Medicine, McGill University, Montréal, Quebec, Canada, H3A 1A3

    L. E. Chalifour

  5. Bank of Montréal Research Center for the Study of Heart Disease in Women , Lady Davis Institute for Medical Research, Sir Mortimer B. Davis – Jewish General Hospital, 3755 chemin Cote Ste Catherine, Montréal, Quebec, Canada, H3T 1E2

    L. E. Chalifour

Authors
  1. F. Mwale
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J. Antoniou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S. Héon
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. N. Servant
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. C. Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. G. M. Kirby
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. C. N. Demers
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. L. E. Chalifour
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to F. Mwale.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mwale, F., Antoniou, J., Héon, S. et al. Gender-Dependent Reductions in Vertebrae Length, Bone Mineral Density and Content by Doxorubicin Are Not Reduced by Dexrazoxane in Young Rats: Effect on Growth Plate and Intervertebral Discs. Calcif Tissue Int 76, 214–221 (2005). https://doi.org/10.1007/s00223-004-0304-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00223-004-0304-9

Keywords

Search

Navigation