Skip to main content
SpringerLink
Log in

Management of Bone Disease in Gaucher Disease Type 1: Clinical Practice

  • Review
  • Published:
Advances in Therapy Aims and scope Submit manuscript

An Erratum to this article was published on 03 April 2015

Abstract

Gaucher disease is a rare autosomal recessive disorder of glycosphingolipid metabolism resulting from deficient activity of the lysosomal enzyme beta-glucocerebrosidase that causes accumulation of glucosylceramide in tissue macrophage with damage to hematological, visceral, and skeletal organ systems. Severity and progression may vary independently among these domains, necessitating individualized therapy. Skeletal involvement is highly prevalent and often associated with intense pain, impaired mobility, and reduced quality of life. Enzyme replacement therapy improves parameters in all affected domains, but skeletal involvement requires longer treatment and higher dosages to obtain significant results. Despite numerous papers on bone complications in patients with Gaucher disease, there are no specific indications on how to assess properly bone involvement in such condition, the frequency of assessment, the use of markers for osteoblast and osteoclast activity, or the administration of bisphosphonates or other symptomatic drugs in adult and pediatric patients. Starting from a re-evaluation of cases with bone involvement, we have identified some common errors in the diagnostic approach and management. The aim of this paper was to propose a methodological and critical approach to the diagnosis, follow-up and treatment of bone disease in patients with Gaucher disease type 1.

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
Fig. 2

Similar content being viewed by others

References

  1. Grabowski GA. Phenotype, diagnosis, and treatment of Gaucher’s disease. Lancet. 2008;372:1263–71.

    Article  CAS  PubMed  Google Scholar 

  2. Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysosomal storage disorders. JAMA. 1999;281:249–54.

    Article  CAS  PubMed  Google Scholar 

  3. Di Rocco M, Giona F, Carubbi F, et al. A new severity score index for phenotypic classification and evaluation of responses to treatment in type I Gaucher disease. Haematologica. 2008;93:1211–8.

    Article  PubMed  Google Scholar 

  4. Zimran A, Gelbart T, Westwood B, Grabowski GA, Beutler E. High frequency of the Gaucher disease mutation at nucleotide 1226 among Ashkenazi Jews. Am J Hum Genet. 1991;49:855–9.

    PubMed Central  CAS  PubMed  Google Scholar 

  5. Wenstrup RJ, Roca-Espiau M, Weinreb NJ, Bembi B. Skeletal aspects of Gaucher disease: a review. Br J Radiol. 2002;75(Suppl 1):A2–12.

    Article  PubMed  Google Scholar 

  6. Kaplan P, Andersson HC, Kacena KA, Yee JD. The clinical and demographic characteristics of non neuronopathic Gaucher disease in 887 children at diagnosis. Arch Pediatr Adolesc Med. 2006;160:603–8.

    Article  PubMed  Google Scholar 

  7. Vom Dahl S, Poll L, Di Rocco M, et al. Evidence-based recommendations for monitoring bone disease and the response to enzyme replacement therapy in Gaucher patients. Curr Med Res Opin. 2006;22:1045–64.

    Article  CAS  PubMed  Google Scholar 

  8. Mistry PK, Weinreb NJ, Kaplan P, Cole JA, Gwosdow AR, Hangartner T. Osteopenia in Gaucher disease develops early in life: response to imiglucerase enzyme therapy in children, adolescents and adults. Blood Cells Mol Dis. 2011;46:66–72.

    Article  PubMed Central  PubMed  Google Scholar 

  9. Pastores GM, Weinreb NJ, Aerts H, et al. Therapeutic goals in the treatment of Gaucher disease. Semin Hematol. 2004;41(Suppl 5):4–14.

    Article  PubMed  Google Scholar 

  10. Weinreb NJ, Charrow J, Andersson HC, et al. Effectiveness of enzyme replacement therapy in 1,028 patients with type 1 Gaucher disease after 2–5 years of treatment: a report from the Gaucher Registry. Am J Med. 2002;113:112–9.

    Article  CAS  PubMed  Google Scholar 

  11. Wenstrup RJ, Kacena KA, Kaplan P, et al. Effect of enzyme replacement therapy with imiglucerase on BMD in type 1 Gaucher disease. J Bone Miner Res. 2007;22:119–26.

    Article  CAS  PubMed  Google Scholar 

  12. Deegan PB, Pavlova E, Tindall J, et al. Osseous manifestations of adult Gaucher disease in the era of enzyme replacement therapy. Medicine (Baltimore). 2011;90:52–60.

    Article  CAS  PubMed  Google Scholar 

  13. Andersson H, Kaplan P, Kacena K, et al. Eight-year clinical outcomes of long-term enzyme replacement therapy for 884 children with Gaucher disease type 1. Pediatrics. 2008;122:1182–90.

    Article  PubMed  Google Scholar 

  14. Mistry PK, Deegan P, Vellodi A, et al. Timing of initiation of enzyme replacement therapy after diagnosis of type 1 Gaucher disease: effect on incidence of avascular necrosis. Br J Haematol. 2009;147:561–70.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Damiano AM, Pastores GM, Ware JE Jr. The health-related quality of life of adults with Gaucher’s disease receiving enzyme replacement therapy: results from a retrospective study. Qual Life Res. 1998;7:373–86.

    Article  CAS  PubMed  Google Scholar 

  16. Giraldo P, Solano V, Pérez-Calvo JI, Giralt M, Rubio-Félix D, Spanish Group on Gaucher disease. Quality of life related to type 1 Gaucher disease: Spanish experience. Qual Life Res. 2005;14:453–62.

    Article  PubMed  Google Scholar 

  17. Weinreb NJ, Aggio MC, Andersson HC, et al. Gaucher disease type 1: revised recommendations on evaluations and monitoring for adult patients. Semin Hematol. 2004;41(Suppl 5):15–22.

    Article  PubMed  Google Scholar 

  18. Maas M, Hangartner T, Mariani G, et al. Recommendations for the assessment and monitoring of skeletal manifestations in children with Gaucher disease. Skeletal Radiol. 2008;37:185–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Bianchi ML, Baim S, Bishop NJ, et al. Official positions of the International Society for Clinical Densitometry (ISCD) on DXA evaluation in children and adolescents. Pediatr Nephrol. 2010;25:37–47.

    Article  PubMed  Google Scholar 

  20. Schousboe JT, Shepherd JA, Bilezikian JP, Baim S. Executive summary of the 2013 International Society for Clinical Densitometry Position Development Conference on bone densitometry. J Clin Densitom. 2013;16:455–66.

    Article  PubMed  Google Scholar 

  21. Gordon CM, Bachrach LK, Carpenter TO, et al. Dual energy X-ray absorptiometry interpretation and reporting in children and adolescents: the 2007 ISCD Pediatric Official Positions. J Clin Densitom. 2008;11:43–58.

    Article  PubMed  Google Scholar 

  22. Johnell O, Kanis JA, Oden A, et al. Predictive value of BMD for hip and other fractures. J Bone Miner Res. 2005;20:1185–94.

    Article  PubMed  Google Scholar 

  23. Kaplan P, Baris H, De Meirleir L, et al. Revised recommendations for the management of Gaucher disease in children. Eur J Pediatr. 2013;172:447–58.

    Article  CAS  PubMed  Google Scholar 

  24. Rosenthal DI, Scott JA, Barranger J, et al. Evaluation of Gaucher disease using magnetic resonance imaging. J Bone Joint Surg Am. 1986;68:802–8.

    CAS  PubMed  Google Scholar 

  25. Poll LW, Koch JA, vom Dahl S. Magnetic resonance imaging of bone marrow changes in Gaucher disease during enzyme replacement therapy: first German long-term results. Skeletal Radiol. 2001;30:496–503.

    Article  CAS  PubMed  Google Scholar 

  26. Terk MR, Dardashti S, Liebman HA. Bone marrow response in treated patients with Gaucher disease: evaluation by T1-weighted magnetic resonance images and correlation with reduction in liver and spleen volume. Skeletal Radiol. 2000;29:563–71.

    Article  CAS  PubMed  Google Scholar 

  27. Vlieger EJ, Maas M, Akkerman EM, Hollak CE, Den Heeten GJ. Vertebra disc ratio as a parameter for bone marrow involvement and its application in Gaucher disease. J Comput Assist Tomogr. 2002;26:843–8.

    Article  PubMed  Google Scholar 

  28. Maas M, van Kuijk C, Stoker J, et al. Quantification of bone involvement in Gaucher disease: MR imaging bone marrow burden score as an alternative to Dixon quantitative chemical shift MR imaging—initial experience. Radiology. 2003;229:554–61.

    Article  PubMed  Google Scholar 

  29. Roca M, Mota J, Alfonso P, Pocoví M, Giraldo P. S-MRI score: a simple method for assessing bone marrow involvement in Gaucher disease. Eur J Radiol. 2007;62:132–7.

    Article  CAS  PubMed  Google Scholar 

  30. Maas M, Hollak CE, Akkerman EM, Aerts JM, Stoker J, Den Heeten GJ. Quantification of skeletal involvement in adults with type I Gaucher’s disease: fat fraction measured by Dixon quantitative chemical shift imaging as a valid parameter. AJR Am J Roentgenol. 2002;179:961–5.

    Article  PubMed  Google Scholar 

  31. Poll LW, Cox ML, Godehardt E, Steinhof V, vom Dahl S. Whole body MRI in type I Gaucher patients: evaluation of skeletal involvement. Blood Cells Mol Dis. 2011;46:53–9.

    Article  PubMed  Google Scholar 

  32. Ficat RP. Idiopathic bone necrosis of the femoral head. Early diagnosis and treatment. J Bone Joint Surg Br. 1985;67:3–9.

    CAS  PubMed  Google Scholar 

  33. Moran MT, Schofield JP, Hayman AR, Shi GP, Young E, Cox TM. Pathologic gene expression in Gaucher disease: up-regulation of cysteine proteinases including osteoclastic cathepsin K. Blood. 2000;96:1969–78.

    CAS  PubMed  Google Scholar 

  34. Drugan C, Jebeleanu G, Grigorescu-Sido P, Caillaud C, Craciun AM. Biochemical markers of bone turnover as tools in the evaluation of skeletal involvement in patients with type 1 Gaucher disease. Blood Cells Mol Dis. 2002;28:13–20.

    Article  CAS  PubMed  Google Scholar 

  35. Ciana G, Addobbati R, Tamaro G, et al. Gaucher disease and bone: laboratory and skeletal mineral density variations during a long period of enzyme replacement therapy. J Inherit Metab Dis. 2005;28:723–32.

    Article  CAS  PubMed  Google Scholar 

  36. Deegan PB, Moran MT, McFarlane I, et al. Clinical evaluation of chemokine and enzymatic biomarkers of Gaucher disease. Blood Cells Mol Dis. 2005;35:259–67.

    Article  CAS  PubMed  Google Scholar 

  37. Vellodi A, Foo Y, Cole TJ. Evaluation of three biochemical markers in the monitoring of Gaucher disease. J Inherit Metab Dis. 2005;28:585–92.

    Article  CAS  PubMed  Google Scholar 

  38. Mikosch P, Reed M, Baker R, et al. Changes of bone metabolism in seven patients with Gaucher disease treated consecutively with imiglucerase and miglustat. Calcif Tissue Int. 2008;83:43–54.

    Article  CAS  PubMed  Google Scholar 

  39. Stirnemann J, Belmatoug N, Vincent C, Fain O, Fantin B, Mentré F. Bone events and evolution of biologic markers in Gaucher disease before and during treatment. Arthritis Res Ther. 2010;12:R156.

    Article  PubMed Central  PubMed  Google Scholar 

  40. van Dussen L, Lips P, Everts VE, et al. Markers of bone turnover in Gaucher disease: modeling the evolution of bone disease. J Clin Endocrinol Metab. 2011;96:2194–205.

    Article  PubMed  Google Scholar 

  41. Stowens DW, Teitelbaum SL, Kahn AJ, Barranger JA. Skeletal complications of Gaucher disease. Medicine (Baltimore). 1985;64:310–22.

    Article  CAS  PubMed  Google Scholar 

  42. Giuffrida G, Cingari MR, Parrinello N, et al. Bone turnover markers in patients with type 1 Gaucher disease. Hematol Rep. 2012;4:e21.

    Article  PubMed Central  PubMed  Google Scholar 

  43. Grabowski GA, Barton NW, Pastores G, et al. Enzyme therapy in type 1 Gaucher disease: comparative efficacy of mannose-terminated glucocerebrosidase from natural and recombinant sources. Ann Intern Med. 1995;122:33–9.

    Article  CAS  PubMed  Google Scholar 

  44. Zimran A, Altarescu G, Philips M, et al. Phase 1/2 and extension study of velaglucerasealfa replacement therapy in adults with type 1 Gaucher disease: 48-month experience. Blood. 2010;115:4651–6.

    Article  CAS  PubMed  Google Scholar 

  45. Aviezer D, Brill-Almon E, Shaaltiel Y, et al. A plant-derived recombinant human glucocerebrosidase enzyme—a preclinical and phase I investigation. PLoS One. 2009;4:e4792.

    Article  PubMed Central  PubMed  Google Scholar 

  46. Starzyk K, Richards S, Yee J, Smith SE, Kingma W. The long-term international safety experience of imiglucerase therapy for Gaucher disease. Mol Genet Metab. 2007;90:157–63.

    Article  CAS  PubMed  Google Scholar 

  47. de Fost M, Hollak CE, Groener JE, et al. Superior effects of high-dose enzyme replacement therapy in type 1 Gaucher disease on bone marrow involvement and chitotriosidase levels: a 2-center retrospective analysis. Blood. 2006;108:830–5.

    Article  PubMed  Google Scholar 

  48. Piran S, Amato D. Gaucher disease: a systematic review and meta-analysis of bone complications and their response to treatment. J Inherit Metab Dis. 2010;33:271–9.

    Article  PubMed  Google Scholar 

  49. Robertson PL, Maas M, Goldblatt J. Semi-quantitative assessment of skeletal response to enzyme replacement therapy for Gaucher’s disease using the bone marrow burden score. AJR Am J Roentgenol. 2007;188:1521–8.

    Article  PubMed  Google Scholar 

  50. Weinreb N, Taylor J, Cox T, Yee J, vom Dahl S. A benchmark analysis of the achievement of therapeutic goals for type 1 Gaucher disease patients treated with imiglucerase. Am J Hematol. 2008;83:890–5.

    Article  CAS  PubMed  Google Scholar 

  51. Andersson HC, Charrow J, Kaplan P, et al. Individualization of long-term enzyme replacement therapy for Gaucher disease. Genet Med. 2005;7:105–10.

    Article  CAS  PubMed  Google Scholar 

  52. Cox TM, Aerts JM, Andria G, et al. The role of the iminosugar N-butyldeoxynojirimycin (miglustat) in the management of type I (non-neuronopathic) Gaucher disease: a position statement. J Inherit Metab Dis. 2003;26:513–26.

    Article  CAS  PubMed  Google Scholar 

  53. Hollak CE, Hughes D, van Schaik IN, Schwierin B, Bembi B. Miglustat (Zavesca) in type 1 Gaucher disease: 5-year results of a post-authorisation safety surveillance programme. Pharmacoepidemiol Drug Saf. 2009;18:770–7.

    Article  CAS  PubMed  Google Scholar 

  54. Lukina E, Watman N, Arreguin EA, et al. Improvement in hematological, visceral, and skeletal manifestations of Gaucher disease type 1 with oral eliglustat tartrate (Genz-112638) treatment: 2-year results of a phase 2 study. Blood. 2010;116:4095–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  55. Lukina E, Watman N, Arreguin EA, et al. A phase 2 study of eliglustat tartrate (Genz-112638), an oral substrate reduction therapy for Gaucher disease type 1. Blood. 2010;116:893–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  56. Wenstrup RJ, Bailey L, Grabowski GA, et al. Gaucher disease: alendronate disodium improves bone mineral density in adults receiving enzyme therapy. Blood. 2004;104:1253–7.

    Article  CAS  PubMed  Google Scholar 

  57. Adami S, Bertoldo F, Brandi ML, et al. Guidelines for the diagnosis, prevention and treatment of osteoporosis. Reumatismo. 2009;61:260–84.

    CAS  PubMed  Google Scholar 

  58. Cox-Brinkman J, van Breemen MJ, van Maldegem BT, et al. Potential efficacy of enzyme replacement and substrate reduction therapy in three siblings with Gaucher disease type III. J Inherit Metab Dis. 2008;31:745–52.

    Article  CAS  PubMed  Google Scholar 

  59. Elstein D, Dweck A, Attias D, et al. Oral maintenance clinical trial with miglustat for type I Gaucher disease: switch from or combination with intravenous enzyme replacement. Blood. 2007;110:2296–301.

    Article  CAS  PubMed  Google Scholar 

  60. Steinberg ME, Brighton CT, Corces A. Osteonecrosis of the femoral head; results of core depression and grafting with electrical stimulation. Clin Orthop. 1989;249:199–208.

    PubMed  Google Scholar 

  61. Weinreb NJ, Goldblatt J, Villalobos J, et al. Long-term clinical outcomes in type 1 Gaucher disease following 10 years of imiglucerase treatment. J Inherit Metab Dis. 2013;36:543–53.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  62. Sims KB, Pastores GM, Weinreb NJ, et al. Improvement of bone disease by imiglucerase (Cerezyme) therapy in patients with skeletal manifestations of type 1 Gaucher disease: results of a 48-month longitudinal cohort study. Clin Genet. 2008;73:430–40.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  63. Charrow J, Dulisse B, Grabowski GA, Weinreb NJ. The effect of enzyme replacement therapy on bone crisis and bone pain in patients with type 1 Gaucher disease. Clin Genet. 2007;71:205–11.

    Article  CAS  PubMed  Google Scholar 

  64. Elstein D, Foldes AJ, Zahrieh D, et al. Significant and continuous improvement in bone mineral density among type 1 Gaucher disease patients treated with velaglucerasealfa: 69-month experience, including dose reduction. Blood Cells Mol Dis. 2011;47:56–61.

    Article  CAS  PubMed  Google Scholar 

  65. Elstein D, Haims AH, Zahrieh D, Cohn GM, Zimran A. Impact of velaglucerasealfa on bone marrow burden score in adult patients with type 1 Gaucher disease: 7-Year follow-up. Blood Cells Mol Dis. 2014;53:56–60.

    Article  CAS  PubMed  Google Scholar 

  66. Weinreb N, Barranger J, Packman S, et al. Imiglucerase (Cerezyme) improves quality of life in patients with skeletal manifestations of Gaucher disease. Clin Genet. 2007;71:576–88.

    Article  CAS  PubMed  Google Scholar 

  67. Ida H, Rennert OM, Kobayashi M, Eto Y. Effects of enzyme replacement therapy in thirteen Japanese paediatric patients with Gaucher disease. Eur J Pediatr. 2001;160:21–5.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

Sponsorship for this study and article processing charges were funded by Genzyme, a Sanofi company, Modena, Italy. Medical writing assistance for this study was provided by Richard Vernell, an independent medical writer on behalf of Springer Healthcare Communications, Milan, Italy, and funded by Genzyme, a Sanofi company, Modena, Italy. All named authors meet the ICMJE criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval for the version to be published.

Author contributions

All authors contributed equally to this work. The authors thank also the collaborators who presented and discussed clinical cases.

Conflict of interest

Gaetano Giuffrida has received honoraria from Genzyme, a Sanofi Company, Modena, Italy; Shire, Florence, Italy; Bayer, Milan, Italy; and Novo Nordisk, Rome, Italy. Maria Domenica Cappellini has received consultancy fees from Novartis, Origgio, Italy; Genzyme, a Sanofi Company, Modena, Italy; and Celgene, Milan, Italy. Francesca Carubbi has received speaker honoraria from Genzyme, a Sanofi Company, Modena, Italy and travel grants from Shire, Florence, Italy and Genzyme, a Sanofi Company, Modena, Italy. Maja Di Rocco has received honoraria from Genzyme, a Sanofi Company, Modena, Italy; Shire, Florence, Italy; Actelion, Imola, Italy; and BioMarin Europe Limited, London, England. Giovanni Iolascon has received honoraria as a speaker from Amgen, Milan, Italy; Grunenthal Italia, Milan, Italy; Eli Lilly Italia, Sesto Fiorentino, Italy; and MSD Italia, Rome, Italy.

Compliance with ethics guidelines

This article does not contain any studies with human or animal subjects performed by any of the authors.

Author information

Authors and Affiliations

  1. Division of Hematology, Department of Clinical and Molecular Biomedicine, University of Catania, Ospedale Ferrarotto, Catania, Italy

    Gaetano Giuffrida

  2. Department of Internal Medicine and Community Health, IRCCS Foundation “Ca’ Granda” Policlinico Hospital, Milan, Italy

    Maria Domenica Cappellini

  3. Department of Medicine, Endocrinology, Metabolism and Geriatrics, University of Modena and Reggio Emilia, AUSL Modena, Modena, Italy

    Francesca Carubbi

  4. Unit of Rare Diseases, Department of Pediatrics, Gaslini Institute, Genoa, Italy

    Maja Di Rocco

  5. Department of Medical and Surgical Specialties and Dentistry, Second University of Naples, Via de Crecchio, 4, 80138, Naples, Italy

    Giovanni Iolascon

Authors
  1. Gaetano Giuffrida
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maria Domenica Cappellini
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Francesca Carubbi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Maja Di Rocco
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Giovanni Iolascon
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Giovanni Iolascon.

Additional information

Collaborators: Elena Cassinerio, Fondazione Ca Granda IRCCS, Policlinico Hospital, Milan, Italy; Rita Lombardo, Ernesto Di Francesco, University of Catania, Ospedale Ferrarotto, Catania, Italy; Annalisa Madeo, Gaslini Institute, Genoa, Italy; Chiara Masetti, University of Modena and Reggio Emilia, AUSL Modena, Italy; Antimo Moretti, Second University of Naples, Italy; Maria Ruberto, Second University of Naples, Italy; Maria Francesca Zenobii, University of Modena and Reggio Emilia, AUSL Modena, Italy.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 188 kb)

Supplementary material 2 (PDF 414 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Giuffrida, G., Cappellini, M.D., Carubbi, F. et al. Management of Bone Disease in Gaucher Disease Type 1: Clinical Practice. Adv Ther 31, 1197–1212 (2014). https://doi.org/10.1007/s12325-014-0174-0

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12325-014-0174-0

Keywords

Search

Navigation