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Osteopetrosis

Pathogenesis and Rationale for the Use of Interferon-γ-1b

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Summary

Congenital osteopetrosis is a group of disorders resulting in decreased osteoclastic function and hence decreased bone resorption. Various medical treatments have been attempted to ameliorate the osteopetrotic condition. A calcium-deficient diet has limited further sclerosis in some patients. Prednisone therapy has improved haematological function in some patients, but has not resulted in a reduction in bone mass. Calcitrophic hormones, such as parathyroid hormone (PTH) infusions and oral calcitriol, stimulate osteoclastic activity, and calcitriol in particular has stimulated osteoclastic bone resorption in some patients with osteopetrosis. Bone marrow transplantation, although curative, is limited by paucity of donors, risk of graft-versus-host disease and relapse of the disease.

The demonstration of defective leucocyte superoxide production in osteopetrotic patients and the premise that osteoclasts appear to arise from the granulocyte macrophage lineage have led to attempts at treating osteopetrosis with immunomodulators. Since treatment with recombinant interferon-γ-1b (interferon gamma-1b, IFNγ-1b) has resulted in increased level of superoxide generation and clinical improvement in chronic granulomatous disease, a similar strategy has been employed using IFNγ-1b to treat patients with osteopetrosis.

IFNγ-1b has been demonstrated to increase osteoclastic bone resorption and leucocytic function. Long term therapy with IFNγ-1b by subcutaneous injection 3 times weekly resulted in marked clinical improvement, a decreased incidence of infections, a decreased trabecular bone mass, and an increased marrow space resulting in improved haemopoiesis. The therapy has been associated with few adverse effects, mainly fever and diarrhoea which have been managed with a reduction in IFNγ-1b dosage. The low-calcium diet occasionally results in hypocalcaemic tetany, which may be corrected by increased dietary calcium intake.

Thus, IFNγ-1b has a distinct place in the therapeutic armamentarium for patients with osteopetrosis and is a feasible treatment option in such patients.

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References

  1. Dent CE, Smellie JM, Watson L. Studies in osteopetrosis. Arch Dis Child 1965; 40: 7–15

    Article  PubMed  CAS  Google Scholar 

  2. Shapiro F, Glimcher MJ, Holtrop ME, et al. Human osteopetrosis: a histological, ultrastructural, and biochemical study. J Bone Joint Surg 1980; 62: 384–99

    PubMed  CAS  Google Scholar 

  3. Brown DM, Dent PB. Pathogenesis of osteopetrosis. A comparison of human and animal spectra. Pediatr Res 1971; 5: 181–91

    Article  CAS  Google Scholar 

  4. Key Jr LL, Carnes D, Cole S, et al. Treatment of congenital osteopetrosis with high-dose calcitriol. N Engl J Med 1984; 310: 409–15

    Article  PubMed  CAS  Google Scholar 

  5. Gerritsen EJA, Vossen JM, G. van Loo IH. Autosomal recessive osteopetrosis: variability of findings at diagnosis and during the natural course. Pediatrics 1994; 93: 247–53

    PubMed  CAS  Google Scholar 

  6. Reeves JD, August CS, Humbert JR, et al. Host defense in infantile osteopetrosis. Pediatrics 1979; 64: 202–6

    PubMed  CAS  Google Scholar 

  7. Beard CJ, Key LL, Newburger PE, et al. Neutrophil defect associated with malignant infantile osteopetrosis. J Lab Clin Med 1986; 108: 498–505

    PubMed  CAS  Google Scholar 

  8. Helfrich MH, Thensingh SW, Nimret RHP, et al. Osteoclast generation from fetal bone marrow cultures in co-culture with murine fetal long bones [abstract]. Cell Tissue Res 1987; 249: 159

    Article  Google Scholar 

  9. Garrett IR, Boyce BF, Oreffo ROC, et al. Oxygen-derived free radicals stimulate osteoclastic bone resorption in rodent bone in vitro and in vivo. J Clin Invest 1990; 85: 632–9

    Article  PubMed  CAS  Google Scholar 

  10. Key LL, Ries WL, Taylor RG, et al. Oxygen-derived free radicals in osteoclasts: the specificity and location of the nitroblue tetrazolium reaction. Bone 1990; 11: 115–9

    Article  PubMed  CAS  Google Scholar 

  11. Key LL. Osteopetrosis: a genetic window into osteoclast function. A CPC series. Cases Metab Bone Dis 1987; 2: 1–7

    Google Scholar 

  12. Reeves JD, Huffer WE, August CS, et al. The hematopoietic effects of prednisone therapy in four infants with osteopetrosis. J Pediatr 1979; 94: 210–4

    Article  PubMed  CAS  Google Scholar 

  13. Dorantes LM, Mejia AM, Dorantes S. Juvenile osteopetrosis: effects on blood and bone of prednisone and a low calcium, high phosphate diet. Arch Dis Child 1986; 61: 666–70

    Article  PubMed  CAS  Google Scholar 

  14. Silberman M, Moar G. Mechanisms of glucocorticoid-induced growth retardation: impairment of cartilage mineralization [abstract]. Acta Anat 1978; 101: 140

    Article  Google Scholar 

  15. Hahn TJ, Halstead LR, Baran DT. Effects of short term glucocorticoid administration and intentional calcium absorption and circulating vitamin D metabolic concentration in man [abstract]. J Clin Endocrinol Metab 1981; 52: 11

    Article  Google Scholar 

  16. Aarskog D, Asknes L, Haneberg B, et al. Acute response of parathyroid hormone in congenital osteopetrosis. Acta Paediatr Scand 1979; 277Suppl.: 75–80

    Article  CAS  Google Scholar 

  17. Glorieux FH, Pettifor JM, Marie PJ, et al. Induction of bone resorption by parathyroid hormone in congenital malignant osteopetrosis. Metab Bone Dis Relat Res 1981; 3: 143–50

    Article  PubMed  CAS  Google Scholar 

  18. Van Lie Peters EM, Aronson DC, Everts V, et al. Failure of calcitriol treatment in a patient with malignant osteopetrosis. Eur J Pediatr 1993; 152: 818–21

    Article  PubMed  Google Scholar 

  19. Kubo T, Tanaka H, Ono H, et al. Malignant osteopetrosis treated with high doses of 1α-hydroxyvitamin D3 and interferon gamma. J Pediatr 1993; 123: 264–8

    Article  PubMed  CAS  Google Scholar 

  20. Holtrop ME, Raisz LG. Comparison of the effects of 1,25 dihydroxycholecalciferol, prostaglandin E2, and osteoclast activating factor with parathyroid hormone on the ultrastructure of osteoclasts in cultured long bones of fetal rats. Calcif Tissue Int 1979; 29: 201–5

    Article  PubMed  CAS  Google Scholar 

  21. Key LL, Carnes DL, Weichselbaum R, et al. Calcitriol stimulates osteosarcoma cells to produce a factor which increases monocyte-dependent bone resorption [abstract]. Calcif Tissue Int 1983; 35: 696

    Google Scholar 

  22. Ballet JJ, Griscelli C, Contris C, et al. Bone-marrow transplantation in osteopetrosis. Lancet 1977; 11: 1137

    Article  Google Scholar 

  23. Sorrell M, Kapoor N, Kirkpatrick D. Marrow transplantation for juvenile osteopetrosis. Am J Med 1981; 70: 1280–7

    Article  Google Scholar 

  24. Coccia PF, Krivit W, Cervenka J, et al. Successful bone-marrow transplantation for infantile malignant osteopetrosis. N Engl J Med 1980; 302: 701–8

    Article  PubMed  CAS  Google Scholar 

  25. Walker DG. Bone resorption restored in osteopetrotic mice by transplants of normal bone marrow and spleen cells. Science 1975; 190: 784

    Article  PubMed  CAS  Google Scholar 

  26. Gerritsen EJA, Vossen JM, Fasth A, et al. Bone marrow transplantation for autosomal recessive osteopetrosis. J Pediatr 1994; 125: 896–902

    Article  PubMed  CAS  Google Scholar 

  27. Wagner JE, Kernan NA, Steinbuch M, et al. Allogenic sibling umbilical-cord-blood transplantation in children with malignant and nonmalignant disease. Lancet 1995; 346: 214–19

    Article  PubMed  CAS  Google Scholar 

  28. Ezekowitz RAB. Orkin S, Newberger PN. Recombinant interferon gamma augments phagocyte superoxide production and gene expression in x-linked chronic granulomatous disease by subcutaneous interferon gamma. N Engl J Med 1988; 319: 146–51

    Article  PubMed  CAS  Google Scholar 

  29. Key LL, Ries WL, Rodriguiz R, et al. Interferon gamma stimulates bone resorption in the microphthalmic mouse via production of superoxide by NADPH oxidase [abstract]. J Bone Miner Res 1994; 9Suppl. 1: A108

    Google Scholar 

  30. Key LL, Rodriguiz RM, Willi SM, et al. Long-term treatment of osteopetrosis with interferon gamma. N Engl J Med 1995; 332: 1594–9

    Article  PubMed  Google Scholar 

  31. Key Jr LL, Ries WL, Rodriguiz RM, et al. Recombinant human interferon gamma therapy for osteopetrosis. J Pediatr 1992; 121: 119–24

    Article  PubMed  Google Scholar 

  32. Felix R, Cecchini MG, Hofstetter W, et al. Impairment of macrophage colony-stimulating factor production and lack of resident bone marrow macrophages in the osteopetrotic op/op mouse. J Bone Miner Res 1990; 5: 781–9

    Article  PubMed  CAS  Google Scholar 

  33. Chong KT, Langlois L, Doyle L. Recombinant human macrophage colony-stimulating factor (M-CSF) enhanced murine splenic natural-killer (NK) cell activity [abstract]. FASEB J 1989; 3: A816

    Google Scholar 

  34. M-CSF treatment protocol. New York: Memorial Sloan Kettering Hospital, 1992

  35. Shapiro F, Key LL, Anast CS. Variable osteoclast appearance in human infantile osteopetrosis. Calcif Tissue Int 1988; 43: 67–76

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

This work has been supported in part by the FDA Orphan Drug Grant Program FDR-00768 and the NIH funded General Clinical Research Center, M01-RR-01070.

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Authors and Affiliations

  1. Department of Pediatrics and General Clinical Research Center, Medical University of South Carolina, CSB316E, 96 Jonathan Lucas Avenue, Charleston, South Carolina, 29425-2248, USA

    Lakshmi Shankar &  L. Lyndon Key Jr

  2. Department of Immunology, Hospital for Sick Children NHS Trust and Institute of Child Health, London, England

    Egbert J. A. Gerritsen

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  1. Lakshmi Shankar
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  2. Egbert J. A. Gerritsen
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  3. L. Lyndon Key Jr
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Correspondence to L. Lyndon Key Jr.

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Shankar, L., Gerritsen, E.J.A. & Key, L.L. Osteopetrosis. BioDrugs 7, 23–29 (1997). https://doi.org/10.2165/00063030-199707010-00004

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