Abstract
Background:
Receptor activator of nuclear factor-κB ligand (RANKL) inhibitors are being considered for use in children with osteogenesis imperfecta (OI). We sought to assess efficacy of two doses of a RANKL inhibitor, osteoprotegerin–immunoglobulin Fc segment complex (OPG–Fc), in a growing animal model of OI, the col1α2-deficient mouse (oim/oim) and its wild-type controls (+/+).
Methods:
Treated mice showed runting and radiographic evidence of osteopetrosis with either high- (20 mg/kg twice weekly) or low-dose (1 mg/kg/week) OPG–Fc. Because of this adverse event, OPG–Fc treatment was halted, and the mice were killed or monitored for recovery with monthly radiographs and assessment of serum osteoclast activity (tartrate-resistant acid phosphatase 5b, TRACP-5b) until 25 wk of age.
Results:
Twelve weeks of OPG–Fc treatment resulted in radiographic and histologic osteopetrosis with no evidence of bone modeling and negative tartrate-resistant acid phosphatase staining, root dentin abnormalities, and TRACP-5b activity suppression. Signs of recovery appeared 4–8 wk post-treatment.
Conclusion:
Both high- and low-dose OPG–Fc treatment resulted in osteopetrotic changes in infant mice, an outcome that was not seen in studies with the RANKL inhibitor RANK–immunoglobulin Fc segment complex (RANK–Fc) or in studies with older animals. Further investigations of RANKL inhibitors are necessary before their consideration for use in children.
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References
Cheung MS, Glorieux FH Osteogenesis Imperfecta: update on presentation and management. Rev Endocr Metab Dis 2008; 9:153–60.
Rauch F, Munns C, Land C, Glorieux FH . Pamidronate in children and adolescents with osteogenesis imperfecta: effect of treatment discontinuation. J Clin Endocrinol Metab 2006;91:1268–74.
Munns CF, Rauch F, Zeitlin L, Fassier F, Glorieux FH . Delayed osteotomy but not fracture healing in pediatric osteogenesis imperfecta patients receiving pamidronate. J Bone Miner Res 2004;19:1779–86.
Land C, Rauch F, Travers R, Glorieux FH . Osteogenesis imperfecta type VI in childhood and adolescence: effects of cyclical intravenous pamidronate treatment. Bone 2007;40:638–44.
Whyte MP, Wenkert D, Clements KL, McAlister WH, Mumm S . Bisphosphonate-induced osteopetrosis. N Engl J Med 2003;349:457–63.
Kearns AE, Khosla S, Kostenuik PJ . Receptor activator of nuclear factor kappaB ligand and osteoprotegerin regulation of bone remodeling in health and disease. Endocr Rev 2008;29:155–92.
Brown JP, Prince RL, Deal C, et al. Comparison of the effect of denosumab and alendronate on BMD and biochemical markers of bone turnover in postmenopausal women with low bone mass: a randomized, blinded, phase 3 trial. J Bone Miner Res 2009;24:153–61.
Ellis GK, Bone HG, Chlebowski R, et al. Randomized trial of denosumab in patients receiving adjuvant aromatase inhibitors for nonmetastatic breast cancer. J Clin Oncol 2008;26:4875–82.
Dougall WC, Glaccum M, Charrier K, et al. RANK is essential for osteoclast and lymph node development. Genes Dev 1999;13:2412–24.
Kostenuik PJ, Nguyen HQ, McCabe J, et al. Denosumab, a fully human monoclonal antibody to RANKL, inhibits bone resorption and increases BMD in knock-in mice that express chimeric (murine/human) RANKL. J Bone Miner Res 2009;24:182–95.
Canon JR, Roudier M, Bryant R, et al. Inhibition of RANKL blocks skeletal tumor progression and improves survival in a mouse model of breast cancer bone metastasis. Clin Exp Metastasis 2008;25:119–29.
Delos D, Yang X, Ricciardi BF, Myers ER, Bostrom MP, Camacho NP . The effects of RANKL inhibition on fracture healing and bone strength in a mouse model of osteogenesis imperfecta. J Orthop Res 2008;26:153–64.
Kim HK, Morgan-Bagley S, Kostenuik P . RANKL inhibition: a novel strategy to decrease femoral head deformity after ischemic osteonecrosis. J Bone Miner Res 2006;21:1946–54.
Miller RE, Branstetter D, Armstrong A, et al. Receptor activator of NF-kappa B ligand inhibition suppresses bone resorption and hypercalcemia but does not affect host immune responses to influenza infection. J Immunol 2007;179:266–74.
Ominsky MS, Kostenuik PJ, Cranmer P, Smith SY, Atkinson JE . The RANKL inhibitor OPG-Fc increases cortical and trabecular bone mass in young gonad-intact cynomolgus monkeys. Osteoporos Int 2007;18:1073–82.
Ominsky MS, Li X, Asuncion FJ, et al. RANKL inhibition with osteoprotegerin increases bone strength by improving cortical and trabecular bone architecture in ovariectomized rats. J Bone Miner Res 2008;23:672–82.
Padagas J, Colloton M, Shalhoub V, et al. The receptor activator of nuclear factor-kappaB ligand inhibitor osteoprotegerin is a bone-protective agent in a rat model of chronic renal insufficiency and hyperparathyroidism. Calcif Tissue Int 2006;78:35–44.
Stolina M, Adamu S, Ominsky M, et al. RANKL is a marker and mediator of local and systemic bone loss in two rat models of inflammatory arthritis. J Bone Miner Res 2005;20:1756–65.
Zwerina J, Hayer S, Tohidast-Akrad M, et al. Single and combined inhibition of tumor necrosis factor, interleukin-1, and RANKL pathways in tumor necrosis factor-induced arthritis: effects on synovial inflammation, bone erosion, and cartilage destruction. Arthritis Rheum 2004;50:277–90.
Hsu H, Lacey DL, Dunstan CR, et al. Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation induced by osteoprotegerin ligand. Proc Natl Acad Sci USA 1999; 96:3540–5.
Askmyr MK, Fasth A, Richter J . Towards a better understanding and new therapeutics of osteopetrosis. Br J Haematol 2008;140:597–609.
Marks SC Jr, Lane PW . Osteopetrosis, a new recessive skeletal mutation on chromosome 12 of the mouse. J Hered 1976;67:11–8.
Yoshino M, Yamazaki H, Yoshida H, et al. Reduction of osteoclasts in a critical embryonic period is essential for inhibition of mouse tooth eruption. J Bone Miner Res 2003;18:108–16.
Bargman R, Posham R, Boskey AL, DiCarlo E, Raggio C, Pleshko N . Comparable outcomes in fracture reduction and bone properties with RANKL inhibition and alendronate treatment in a mouse model of osteogenesis imperfecta. Osteoporos Int 2012;23:1141–50.
Chipman SD, Sweet HO, McBride DJ Jr, et al. Defective pro alpha 2(I) collagen synthesis in a recessive mutation in mice: a model of human osteogenesis imperfecta. Proc Natl Acad Sci USA 1993;90:1701–5.
Camacho NP, Raggio CL, Doty SB, et al. A controlled study of the effects of alendronate in a growing mouse model of osteogenesis imperfecta. Calcif Tissue Int 2001;69:94–101.
Min H, Morony S, Sarosi I, et al. Osteoprotegerin reverses osteoporosis by inhibiting endosteal osteoclasts and prevents vascular calcification by blocking a process resembling osteoclastogenesis. J Exp Med 2000; 192:463–74.
Kaczmarczyk-Sedlak I, Janiec W . Effects of catecholamines on blood pressure in the long bone marrow cavity in rats with bisphosphonate-induced osteopetrosis. Pharmacol Rep 2005;57:623–34.
Reynolds JJ, Murphy H, Mühlbauer RC, Morgan DB, Fleisch H . Inhibition by diphosphonates of bone resorption in mice and comparison with grey-lethal osteopetrosis. Calcif Tissue Res 1973;12:59–71.
Jin Q, Cirelli JA, Park CH, et al. RANKL inhibition through osteoprotegerin blocks bone loss in experimental periodontitis. J Periodontol 2007;78:1300–8.
Iotsova V, Caamaño J, Loy J, Yang Y, Lewin A, Bravo R . Osteopetrosis in mice lacking NF-kappaB1 and NF-kappaB2. Nat Med 1997;3:1285–9.
Kaczmarczyk-Sedlak I . The effects of pamidronate on mechanical properties, growth and structural changes in rat bones. Acta Pol Pharm 1995; 52:509–13.
Whyte MP, McAlister WH, Novack DV, Clements KL, Schoenecker PL, Wenkert D . Bisphosphonate-induced osteopetrosis: novel bone modeling defects, metaphyseal osteopenia, and osteosclerosis fractures after drug exposure ceases. J Bone Miner Res 2008;23:1698–707.
Lekic P, Rubbino I, Krasnoshtein F, Cheifetz S, McCulloch CA, Tenenbaum H . Bisphosphonate modulates proliferation and differentiation of rat periodontal ligament cells during wound healing. Anat Rec 1997;247:329–40.
Kawata T, Tokimasa C, Nowroozi N, et al. Lack of the bone remodeling in osteopetrotic (op/op) mice associated with microdontia. J Craniofac Genet Dev Biol 1999;19:113–7.
Niida S, Abe M, Suemune S, Yoshiko Y, Maeda N, Yamasaki A . Restoration of disturbed tooth eruption in osteopetrotic (op/op) mice by injection of macrophage colony-stimulating factor. Exp Anim 1997;46:95–101.
Heinrich J, Bsoul S, Barnes J, Woodruff K, Abboud S . CSF-1, RANKL and OPG regulate osteoclastogenesis during murine tooth eruption. Arch Oral Biol 2005;50:897–908.
Kamoun-Goldrat A, Ginisty D, Le Merrer M . Effects of bisphosphonates on tooth eruption in children with osteogenesis imperfecta. Eur J Oral Sci 2008;116:195–8.
Raghunath M, Bruckner P, Steinmann B . Delayed triple helix formation of mutant collagen from patients with osteogenesis imperfecta. J Mol Biol 1994;236:940–9.
Akatsu T, Murakami T, Ono K, et al. Osteoclastogenesis inhibitory factor exhibits hypocalcemic effects in normal mice and in hypercalcemic nude mice carrying tumors associated with humoral hypercalcemia of malignancy. Bone 1998;23:495–8.
Filgueira L . Fluorescence-based staining for tartrate-resistant acidic phosphatase (TRAP) in osteoclasts combined with other fluorescent dyes and protocols. J Histochem Cytochem 2004;52:411–4.
Acknowledgements
We thank Lyudmila Lukashova for assistance with micro-CT and Stephen Doty and the Analytical Microscopy Core for assistance with histology.
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Bargman, R., Posham, R., Boskey, A. et al. High- and low-dose OPG–Fc cause osteopetrosis-like changes in infant mice. Pediatr Res 72, 495–501 (2012). https://doi.org/10.1038/pr.2012.118
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DOI: https://doi.org/10.1038/pr.2012.118
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