Effects of Odanacatib on Bone Mineralization Density Distribution in Thoracic Spine and Femora of Ovariectomized Adult Rhesus Monkeys: A Quantitative Backscattered Electron Imaging Study
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Odanacatib (ODN) has been developed as a selective inhibitor of cathepsin K, the major cysteine protease in osteoclasts. In adult rhesus monkeys, treatment with ODN prevents ovariectomy-induced bone loss in lumbar vertebrae and hip. In this study, we evaluate the effects of ODN on bone mineralization density distribution (BMDD) by quantitative backscattered electron imaging in vertebral spongiosa, distal femoral metaphyseal and cortical shaft from monkeys (aged 16–23 years), treated with vehicle (n = 5) or ODN (6 mg/kg, n = 4 or 30 mg/kg, n = 4, PO daily) for 21 months. Dual-energy X-ray absorptiometry was measured in a subset of distal femoral samples. In lumbar vertebrae there was a shift to higher mineralization in samples from ODN-treated groups, compared to vehicle: CaMean (+4 %), CaPeak (+3 %), CaWidth (−9 %), CaLow (−28 %) in the 6 mg/kg group and CaMean (+5.1 %, p < 0.023), CaPeak (+3.4 %, p < 0.046), CaWidth (−15.7 %, p = 0.06) and CaLow (−38.2 %, p < 0.034) in the 30 mg/kg group. In distal femoral metaphyseal cancellous bone, there was a clear tendency toward a dose-dependent increase in matrix mineralization, as in the spine. However, primary and osteonal bone of the distal cortical diaphyses showed no significant change in BMDD, whereas bone mineral density was significantly increased after treatment. In ovariectomized monkeys, this study shows that ODN treatment increased trabecular BMDD, consistent with its previously reported ability to reduce cancellous remodeling. Here, ODN also showed no changes in BMDD in cortical bone sites, consistent with its actions on maintaining endocortical and stimulating periosteal bone formation.
KeywordsBone mineralization density distribution (BMDD) Cathepsin K inhibitor Dual-energy X-ray absorptiometry (DXA) Nonhuman primate Osteopenia Quantitative backscattered electron imaging (qBEI)
We thank Phaedra Messmer, Daniela Gabriel and Sonja Lueger for excellent technical assistance and performing the qBEI measurements. This study was supported by the AUVA (Research funds of the Austrian workers compensation board), the WGKK (Viennese sickness insurance funds), and research funding from Merck Sharp & Dohme.
- 11.Gauthier JY, Chauret N, Cromlish W, Desmarais S, le Duong T, Falgueyret JP, Kimmel DB, Lamontagne S, Leger S, LeRiche T, Li CS, Masse F, McKay DJ, Nicoll-Griffith DA, Oballa RM, Palmer JT, Percival MD, Riendeau D, Robichaud J, Rodan GA, Rodan SB, Seto C, Therien M, Truong VL, Venuti MC, Wesolowski G, Young RN, Zamboni R, Black WC (2008) The discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin K. Bioorg Med Chem Lett 18:923–928PubMedCrossRefGoogle Scholar
- 14.Jensen AB, Wynne C, Ramirez G, He W, Song Y, Berd Y, Wang H, Mehta A, Lombardi A (2010) The cathepsin K inhibitor odanacatib suppresses bone resorption in women with breast cancer and established bone metastases: results of a 4-week, double-blind, randomized, controlled trial. Clin Breast Cancer 10:452–458PubMedCrossRefGoogle Scholar
- 16.Masarachia PJ, Pennypacker BL, Pickarski M, Scott KR, Wesolowski GA, Smith SY, Samadfam R, Goetzmann JE, Scott BB, Kimmel DB, le Duong T (2012) Odanacatib reduces bone turnover and increases bone mass in the lumbar spine of skeletally mature ovariectomized rhesus monkeys. J Bone Miner Res 27:509–523PubMedCrossRefGoogle Scholar
- 17.Cusick T, Chen CM, Pennypacker BL, Pickarski M, Kimmel DB, Scott BB, le Duong T (2012) Odanacatib treatment increases hip bone mass and cortical thickness by preserving endocortical bone formation and stimulating periosteal bone formation in the ovariectomized adult rhesus monkey. J Bone Miner Res 27:524–537PubMedCrossRefGoogle Scholar
- 18.Stoch SA, Zajic S, Stone J, Miller DL, Van Dyck K, Gutierrez MJ, De Decker M, Liu L, Liu Q, Scott BB, Panebianco D, Jin B, Duong LT, Gottesdiener K, Wagner JA (2009) Effect of the cathepsin K inhibitor odanacatib on bone resorption biomarkers in healthy postmenopausal women: two double-blind, randomized, placebo-controlled phase I studies. Clin Pharmacol Ther 86:175–182PubMedCrossRefGoogle Scholar
- 20.Eisman JA, Bone HG, Hosking DJ, McClung MR, Reid IR, Rizzoli R, Resch H, Verbruggen N, Hustad CM, DaSilva C, Petrovic R, Santora AC, Ince BA, Lombardi A (2011) Odanacatib in the treatment of postmenopausal women with low bone mineral density: three-year continued therapy and resolution of effect. J Bone Miner Res 26:242–251PubMedCrossRefGoogle Scholar
- 31.Roschger P, Lombardi A, Misof BM, Maier G, Fratzl-Zelman N, Fratzl P, Klaushofer K (2010) Mineralization density distribution of postmenopausal osteoporotic bone is restored to normal after long-term alendronate treatment: qBEI and sSAXS data from the fracture intervention trial long-term extension (FLEX). J Bone Miner Res 25:48–55PubMedCrossRefGoogle Scholar
- 33.Donnelly E, Meredith DS, Nguyen JT, Gladnick BP, Rebolledo BJ, Shaffer AD, Lorich DG, Lane JM, Boskey AL (2012) Reduced cortical bone compositional heterogeneity with bisphosphonate treatment in postmenopausal women with intertrochanteric and subtrochanteric fractures. J Bone Miner Res 27:672–678PubMedCrossRefGoogle Scholar
- 39.Zoehrer R, Roschger P, Paschalis EP, Hofstaetter JG, Durchschlag E, Fratzl P, Phipps R, Klaushofer K (2006) Effects of 3- and 5-year treatment with risedronate on bone mineralization density distribution in triple biopsies of the iliac crest in postmenopausal women. J Bone Miner Res 21:1106–1112PubMedCrossRefGoogle Scholar