Skip to main content

Advertisement

SpringerLink
Log in

Effects of doxorubicin administration on bone strength and quality in sedentary and physically active Wistar rats

  • Original Article
  • Published:
Osteoporosis International Aims and scope Submit manuscript

Abstract

Summary

Doxorubicin (DOX) is used in pediatric cancer treatment. This study assessed the effects of 7 weeks of DOX and 10-week recovery on bone quality and biomechanical properties in sedentary and exercised Wistar rats. DOX decreases femur diaphysis radial growth and biomechanical properties. Some of these DOX effects were aggravated by exercise.

Introduction

Bone growth in pre-pubertal years critically influences adult fracture risk. DOX is widely used in the treatment of pediatric cancers, but there is limited evidence on its potential negative effects on bone growth. Exercise improves bone growth in children, but there is no evidence if it protects against DOX-induced bone toxicity. This study investigates the early and intermediate effects of a 7-week course of DOX on bone histomorphometry and strength in sedentary and exercised growing animal models.

Methods

Sixty-eight male Wistar rats (8 weeks) were treated with DOX (2 mg kg−1) or vehicle for 7 weeks and afterward housed in standard cages or in cages with a running wheel and killed 2 or 10 weeks after last DOX administration. Femurs and blood were collected for assaying geometry, trabecular microarchitecture (histology), biomechanical properties (three-point bending and shearing of the femoral neck), bone calcium content and density (atomic absorption spectroscopy), and bone turnover markers (ELISA).

Results

DOX treatment reduced the femur diaphysis radial growth, with DOX-treated animals having a lower tissue area, cortical area, cortical thickness, and moment of inertia. DOX also decreased distal femur trabecular bone volume and trabecular number and increased trabecular separation. Femur diaphysis stiffness and maximum load were also reduced in past DOX-treated animals. Exercise was shown to worsen the effects of past DOX treatment on the femur diaphysis mechanical properties.

Conclusion

DOX negatively affects bone geometry, trabecular microarchitecture, and femur mechanical properties in growing Wistar rats. Exercise further aggravates the detrimental effects of past DOX treatment on bone mechanical properties.

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.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Shusterman S, Meadows AT (2000) Long term survivors of childhood leukemia. Curr Opin Hematol 7:217–222

    Article  CAS  PubMed  Google Scholar 

  2. Noguchi C, Miyata H, Sato Y, Iwaki Y, Okuyama S (2011) Evaluation of bone toxicity in various bones of aged rats. J Toxicol Pathol 24:41–48

    Article  PubMed  PubMed Central  Google Scholar 

  3. van Leeuwen BL, Hartel RM, Jansen HW, Kamps WA, Hoekstra HJ (2003) The effect of chemotherapy on the morphology of the growth plate and metaphysis of the growing skeleton. Eur J Surg Oncol J Eur Soc Surg Oncol Br Assoc Surg Oncol 29:49–58

    Google Scholar 

  4. Mwale F, Antoniou J, Heon S, Servant N, Wang C, Kirby GM, Demers CN, Chalifour LE (2005) 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

    Article  CAS  PubMed  Google Scholar 

  5. Rana T, Chakrabarti A, Freeman M, Biswas S (2013) Doxorubicin-mediated bone loss in breast cancer bone metastases is driven by an interplay between oxidative stress and induction of TGFbeta. PLoS One 8:e78043

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Buttiglieri S, Ruella M, Risso A, Spatola T, Silengo L, Avvedimento EV, Tarella C (2011) The aging effect of chemotherapy on cultured human mesenchymal stem cells. Exp Hematol 39:1171–1181

    Article  CAS  PubMed  Google Scholar 

  7. Friedlaender GE, Tross RB, Doganis AC, Kirkwood JM, Baron R (1984) Effects of chemotherapeutic agents on bone. I. Short-term methotrexate and doxorubicin (adriamycin) treatment in a rat model. J Bone Joint Surg 66:602–607

    Article  CAS  PubMed  Google Scholar 

  8. Young DM, Fioravanti JL, Olson HM, Prieur DJ (1975) Chemical and morphologic alterations of rabbit bone induced by adriamycin. Calcif Tissue Res 18:47–63

    Article  CAS  PubMed  Google Scholar 

  9. Glackin CA, Murray EJ, Murray SS (1992) Doxorubicin inhibits differentiation and enhances expression of the helix-loop-helix genes Id and mTwi in mouse osteoblastic cells. Biochem Int 28:67–75

    CAS  PubMed  Google Scholar 

  10. Gewirtz DA (1999) A critical evaluation of the mechanisms of action proposed for the antitumor effects of the anthracycline antibiotics adriamycin and daunorubicin. Biochem Pharmacol 57:727–741

    Article  CAS  PubMed  Google Scholar 

  11. Chicco AJ, Hydock DS, Schneider CM, Hayward R (2006) Low-intensity exercise training during doxorubicin treatment protects against cardiotoxicity. J Appl Physiol 100:519–527

    Article  CAS  PubMed  Google Scholar 

  12. Behringer M, Gruetzner S, McCourt M, Mester J (2014) Effects of weight-bearing activities on bone mineral content and density in children and adolescents: a meta-analysis. J Bone Miner Res 29:467–478

    Article  PubMed  Google Scholar 

  13. Saarto T, Sievanen H, Kellokumpu-Lehtinen P et al (2012) Effect of supervised and home exercise training on bone mineral density among breast cancer patients. A 12-month randomised controlled trial. Osteoporos Int 23:1601–1612

    Article  CAS  PubMed  Google Scholar 

  14. Schwartz AL, Winters-Stone K, Gallucci B (2007) Exercise effects on bone mineral density in women with breast cancer receiving adjuvant chemotherapy. Oncol Nurs Forum 34:627–633

    Article  PubMed  Google Scholar 

  15. Hydock DS, Parry TL, Wymore JD, Iwaniec UT, Turner RT, Schneider CM, Hayward R (2014) Effects of treadmill training on combined goserelin acetate and doxorubicin-induced osteopenia in female rats. J Musculoskelet Neuronal Interact 14:10–18

    CAS  PubMed  Google Scholar 

  16. Hayward R, Iwaniec UT, Turner RT, Lien CY, Jensen BT, Hydock DS, Schneider CM (2013) Voluntary wheel running in growing rats does not protect against doxorubicin-induced osteopenia. J Pediatr Hematol Oncol 35:e144–148

    Article  CAS  PubMed  Google Scholar 

  17. National Research Council (U.S.). Committee for the Update of the Guide for the Care and Use of Laboratory Animals., Institute for Laboratory Animal Research (U.S.), National Academies Press (U.S.) (2011) Guide for the care and use of laboratory animals. National Academies Press, Washington, DC

    Google Scholar 

  18. Jepsen KJ, Silva MJ, Vashishth D, Guo XE, van der Meulen MC (2015) Establishing biomechanical mechanisms in mouse models: practical guidelines for systematically evaluating phenotypic changes in the diaphyses of long bones. J Bone Miner Res 30:951–966

    Article  PubMed  PubMed Central  Google Scholar 

  19. Turner CH, Burr DB (1993) Basic biomechanical measurements of bone: a tutorial. Bone 14:595–608

    Article  CAS  PubMed  Google Scholar 

  20. Fonseca H, Moreira-Goncalves D, Esteves JL, Viriato N, Vaz M, Mota MP, Duarte JA (2011) Voluntary exercise has long-term in vivo protective effects on osteocyte viability and bone strength following ovariectomy. Calcif Tissue Int 88:443–454

    Article  CAS  PubMed  Google Scholar 

  21. Erben RG, Glosmann M (2012) Histomorphometry in rodents. Methods Mol Biol 816:279–303

    Article  CAS  PubMed  Google Scholar 

  22. D’Haese PC, Van Landeghem GF, Lamberts LV, Bekaert VA, Schrooten I, De Broe ME (1997) Measurement of strontium in serum, urine, bone, and soft tissues by Zeeman atomic absorption spectrometry. Clin Chem 43:121–128

    PubMed  Google Scholar 

  23. Fonseca H, Moreira-Goncalves D, Vaz M, Fernandes MH, Ferreira R, Amado F, Mota MP, Duarte JA (2012) Changes in proximal femur bone properties following ovariectomy and their association with resistance to fracture. J Bone Miner Metab 30:281–292

    Article  PubMed  Google Scholar 

  24. Lebrecht D, Setzer B, Ketelsen UP, Haberstroh J, Walker UA (2003) Time-dependent and tissue-specific accumulation of mtDNA and respiratory chain defects in chronic doxorubicin cardiomyopathy. Circulation 108:2423–2429

    Article  CAS  PubMed  Google Scholar 

  25. Momparler RL, Karon M, Siegel SE, Avila F (1976) Effect of adriamycin on DNA, RNA, and protein synthesis in cell-free systems and intact cells. Cancer Res 36:2891–2895

    CAS  PubMed  Google Scholar 

  26. Eliot H, Gianni L, Myers C (1984) Oxidative destruction of DNA by the adriamycin-iron complex. Biochemistry 23:928–936

    Article  CAS  PubMed  Google Scholar 

  27. Ichikawa Y, Ghanefar M, Bayeva M, Wu R, Khechaduri A, Naga Prasad SV, Mutharasan RK, Naik TJ, Ardehali H (2014) Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation. J Clin Invest 124:617–630

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Eom YW, Kim MA, Park SS, Goo MJ, Kwon HJ, Sohn S, Kim WH, Yoon G, Choi KS (2005) Two distinct modes of cell death induced by doxorubicin: apoptosis and cell death through mitotic catastrophe accompanied by senescence-like phenotype. Oncogene 24:4765–4777

    Article  CAS  PubMed  Google Scholar 

  29. Berthiaume JM, Wallace KB (2007) Adriamycin-induced oxidative mitochondrial cardiotoxicity. Cell Biol Toxicol 23:15–25

    Article  CAS  PubMed  Google Scholar 

  30. Bouxsein ML, Karasik D (2006) Bone geometry and skeletal fragility. Curr Osteoporos Rep 4:49–56

    Article  PubMed  Google Scholar 

  31. Seeman E (2003) Periosteal bone formation—a neglected determinant of bone strength. N Engl J Med 349:320–323

    Article  PubMed  Google Scholar 

  32. Baxter-Jones AD, Faulkner RA, Forwood MR, Mirwald RL, Bailey DA (2011) Bone mineral accrual from 8 to 30 years of age: an estimation of peak bone mass. J Bone Miner Res 26:1729–1739

    Article  PubMed  Google Scholar 

  33. Tandon N, Fall CH, Osmond C et al (2012) Growth from birth to adulthood and peak bone mass and density data from the New Delhi Birth Cohort. Osteoporos Int 23:2447–2459

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Zebaze RM, Jones A, Knackstedt M, Maalouf G, Seeman E (2007) Construction of the femoral neck during growth determines its strength in old age. J Bone Miner Res 22:1055–1061

    Article  PubMed  Google Scholar 

  35. Busse B, Djonic D, Milovanovic P, Hahn M, Puschel K, Ritchie RO, Djuric M, Amling M (2010) Decrease in the osteocyte lacunar density accompanied by hypermineralized lacunar occlusion reveals failure and delay of remodeling in aged human bone. Aging Cell 9:1065–1075

    Article  CAS  PubMed  Google Scholar 

  36. Delgado-Calle J, Arozamena J, Garcia-Renedo R, Garcia-Ibarbia C, Pascual-Carra MA, Gonzalez-Macias J, Riancho JA (2011) Osteocyte deficiency in hip fractures. Calcif Tissue Int 89:327–334

    Article  CAS  PubMed  Google Scholar 

  37. Noble BS (2008) The osteocyte lineage. Arch Biochem Biophys 473:106–111

    Article  CAS  PubMed  Google Scholar 

  38. Nilsson M, Ohlsson C, Oden A, Mellstrom D, Lorentzon M (2012) Increased physical activity is associated with enhanced development of peak bone mass in men: a five-year longitudinal study. J Bone Miner Res 27:1206–1214

    Article  PubMed  PubMed Central  Google Scholar 

  39. Burr DB, Martin RB, Schaffler MB, Radin EL (1985) Bone remodeling in response to in vivo fatigue microdamage. J Biomech 18:189–200

    Article  CAS  PubMed  Google Scholar 

  40. Schaffler MB, Radin EL, Burr DB (1989) Mechanical and morphological effects of strain rate on fatigue of compact bone. Bone 10:207–214

    Article  CAS  PubMed  Google Scholar 

  41. Mori S, Burr DB (1993) Increased intracortical remodeling following fatigue damage. Bone 14:103–109

    Article  CAS  PubMed  Google Scholar 

  42. Yadav VK, Oury F, Suda N et al (2009) A serotonin-dependent mechanism explains the leptin regulation of bone mass, appetite, and energy expenditure. Cell 138:976–989

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Soyka LA, Grinspoon S, Levitsky LL, Herzog DB, Klibanski A (1999) The effects of anorexia nervosa on bone metabolism in female adolescents. J Clin Endocrinol Metab 84:4489–4496

    CAS  PubMed  Google Scholar 

  44. Zanker CL, Swaine IL (2000) Responses of bone turnover markers to repeated endurance running in humans under conditions of energy balance or energy restriction. Eur J Appl Physiol 83:434–440

    Article  CAS  PubMed  Google Scholar 

  45. Morelli D, Menard S, Colnaghi MI, Balsari A (1996) Oral administration of anti-doxorubicin monoclonal antibody prevents chemotherapy-induced gastrointestinal toxicity in mice. Cancer Res 56:2082–2085

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors are thankful to Celeste Resende for her technical support regarding animal care and to Teresa Caldeira for her technical support with the atomic absorption spectroscopy. The Research Centre on Physical Activity Health and Leisure (CIAFEL) is supported by UID/DTP/00617/2013. HF and DMG were supported by individual grants from the Portuguese Foundation for Science and Technology (FCT) SFRH/BPD/78259/2011 and SFRH/BPD/90010/2012, respectively.

Author information

Authors and Affiliations

  1. Research Centre of Physical Activity, Health and Leisure (CIAFEL), Faculty of Sport, University of Porto, Rua Dr. Plácido Costa 91, 4200-450, Porto, Portugal

    H. Fonseca, A. Carvalho, D. Moreira-Gonçalves & J. A. Duarte

  2. Institute of Science and Innovation in Mechanical and Industrial Engineering (INEGI), Faculty of Engineering, University of Porto, Rua Dr. Roberto Frias 400, 4200-465, Porto, Portugal

    J. Esteves

  3. Centre for Environmental and Marine Studies (CESAM), Department of Chemistry, University of Aveiro, Campus Universitário de Santiago, 3810-193, Aveiro, Portugal

    V. I. Esteves

  4. Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine, University of Porto, Al. Prof. Hernâni Monteiro, 4200-319, Porto, Portugal

    D. Moreira-Gonçalves

Authors
  1. H. Fonseca
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A. Carvalho
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J. Esteves
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. V. I. Esteves
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. D. Moreira-Gonçalves
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J. A. Duarte
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to H. Fonseca.

Ethics declarations

Conflicts of interest

None.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fonseca, H., Carvalho, A., Esteves, J. et al. Effects of doxorubicin administration on bone strength and quality in sedentary and physically active Wistar rats. Osteoporos Int 27, 3465–3475 (2016). https://doi.org/10.1007/s00198-016-3672-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00198-016-3672-x

Keywords

Search

Navigation