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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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Abstract

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.

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References

  1. Kafienah W, Bromme D, Buttle DJ, Croucher LJ, Hollander AP (1998) Human cathepsin K cleaves native type I and II collagens at the N-terminal end of the triple helix. Biochem J 331(pt 3):727–732

    PubMed  CAS  Google Scholar 

  2. Garnero P, Borel O, Byrjalsen I, Ferreras M, Drake FH, McQueney MS, Foged NT, Delmas PD, Delaisse JM (1998) The collagenolytic activity of cathepsin K is unique among mammalian proteinases. J Biol Chem 273:32347–32352

    Article  PubMed  CAS  Google Scholar 

  3. Salminen-Mankonen HJ, Morko J, Vuorio E (2007) Role of cathepsin K in normal joints and in the development of arthritis. Curr Drug Targets 8:315–323

    Article  PubMed  CAS  Google Scholar 

  4. Henriksen K, Bollerslev J, Everts V, Karsdal MA (2011) Osteoclast activity and subtypes as a function of physiology and pathology—implications for future treatments of osteoporosis. Endocr Rev 32:31–63

    Article  PubMed  CAS  Google Scholar 

  5. Gelb BD, Shi GP, Chapman HA, Desnick RJ (1996) Pycnodysostosis, a lysosomal disease caused by cathepsin K deficiency. Science 273:1236–1238

    Article  PubMed  CAS  Google Scholar 

  6. Fratzl-Zelman N, Valenta A, Roschger P, Nader A, Gelb BD, Fratzl P, Klaushofer K (2004) Decreased bone turnover and deterioration of bone structure in two cases of pycnodysostosis. J Clin Endocrinol Metab 89:1538–1547

    Article  PubMed  CAS  Google Scholar 

  7. Schilling AF, Mulhausen C, Lehmann W, Santer R, Schinke T, Rueger JM, Amling M (2007) High bone mineral density in pycnodysostotic patients with a novel mutation in the propeptide of cathepsin K. Osteoporos Int 18:659–669

    Article  PubMed  CAS  Google Scholar 

  8. Saftig P, Hunziker E, Everts V, Jones S, Boyde A, Wehmeyer O, Suter A, von Figura K (2000) Functions of cathepsin K in bone resorption. Lessons from cathepsin K deficient mice. Adv Exp Med Biol 477:293–303

    Article  PubMed  CAS  Google Scholar 

  9. Li CY, Jepsen KJ, Majeska RJ, Zhang J, Ni R, Gelb BD, Schaffler MB (2006) Mice lacking cathepsin K maintain bone remodeling but develop bone fragility despite high bone mass. J Bone Miner Res 21:865–875

    Article  PubMed  CAS  Google Scholar 

  10. Pennypacker B, Shea M, Liu Q, Masarachia P, Saftig P, Rodan S, Rodan G, Kimmel D (2009) Bone density, strength, and formation in adult cathepsin K(−/−) mice. Bone 44:199–207

    Article  PubMed  CAS  Google Scholar 

  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 18:923–928

    Article  PubMed  CAS  Google Scholar 

  12. Podgorski I (2009) Future of anticathepsin K drugs: dual therapy for skeletal disease and atherosclerosis? Future Med Chem 1:21–34

    Article  PubMed  CAS  Google Scholar 

  13. McDougall JJ, Schuelert N, Bowyer J (2010) Cathepsin K inhibition reduces CTXII levels and joint pain in the guinea pig model of spontaneous osteoarthritis. Osteoarthr Cartil 18:1355–1357

    Article  PubMed  CAS  Google 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 10:452–458

    Article  PubMed  CAS  Google Scholar 

  15. Pennypacker BL, le Duong T, Cusick TE, Masarachia PJ, Gentile MA, Gauthier JY, Black WC, Scott BB, Samadfam R, Smith SY, Kimmel DB (2011) Cathepsin K inhibitors prevent bone loss in estrogen-deficient rabbits. J Bone Miner Res 26:252–262

    Article  PubMed  CAS  Google 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 27:509–523

    Article  PubMed  CAS  Google 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 27:524–537

    Article  PubMed  CAS  Google 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 86:175–182

    Article  PubMed  CAS  Google Scholar 

  19. Perez-Castrillon JL, Pinacho F, De Luis D, Lopez-Menendez M, Duenas Laita A (2010) Odanacatib, a new drug for the treatment of osteoporosis: review of the results in postmenopausal women. J Osteoporos 2010:401581

    PubMed  Google 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 26:242–251

    Article  PubMed  CAS  Google Scholar 

  21. Stoch SA, Wagner JA (2008) Cathepsin K inhibitors: a novel target for osteoporosis therapy. Clin Pharmacol Ther 83:172–176

    Article  PubMed  CAS  Google Scholar 

  22. Karsdal MA, Martin TJ, Bollerslev J, Christiansen C, Henriksen K (2007) Are nonresorbing osteoclasts sources of bone anabolic activity? J Bone Miner Res 22:487–494

    Article  PubMed  CAS  Google Scholar 

  23. Karsdal MA, Neutzsky-Wulff AV, Dziegiel MH, Christiansen C, Henriksen K (2008) Osteoclasts secrete non-bone derived signals that induce bone formation. Biochem Biophys Res Commun 366:483–488

    Article  PubMed  CAS  Google Scholar 

  24. Fuller K, Lawrence KM, Ross JL, Grabowska UB, Shiroo M, Samuelsson B, Chambers TJ (2008) Cathepsin K inhibitors prevent matrix-derived growth factor degradation by human osteoclasts. Bone 42:200–211

    Article  PubMed  CAS  Google Scholar 

  25. Bone HG, McClung MR, Roux C, Recker RR, Eisman JA, Verbruggen N, Hustad CM, DaSilva C, Santora AC, Ince BA (2010) Odanacatib, a cathepsin-K inhibitor for osteoporosis: a two-year study in postmenopausal women with low bone density. J Bone Miner Res 25:937–947

    PubMed  Google Scholar 

  26. Eastell R, Nagase S, Ohyama M, Small M, Sawyer J, Boonen S, Spector T, Kuwayama T, Deacon S (2011) Safety and efficacy of the cathepsin K inhibitor, ONO-5334, in postmenopausal osteoporosis—the OCEAN study. J Bone Miner Res 26:1303–1312

    Article  PubMed  CAS  Google Scholar 

  27. Jerome C, Missbach M, Gamse R (2012) Balicatib, a cathepsin K inhibitor, stimulates periosteal bone formation in monkeys. Osteoporos Int 23:339–349

    Article  PubMed  CAS  Google Scholar 

  28. Neutzsky-Wulff AV, Sorensen MG, Kocijancic D, Leeming DJ, Dziegiel MH, Karsdal MA, Henriksen K (2010) Alterations in osteoclast function and phenotype induced by different inhibitors of bone resorption—implications for osteoclast quality. BMC Musculoskelet Disord 11:109

    Article  PubMed  Google Scholar 

  29. Ruffoni D, Fratzl P, Roschger P, Phipps R, Klaushofer K, Weinkamer R (2008) Effect of temporal changes in bone turnover on the bone mineralization density distribution: a computer simulation study. J Bone Miner Res 23:1905–1914

    Article  PubMed  CAS  Google Scholar 

  30. Roschger P, Paschalis EP, Fratzl P, Klaushofer K (2008) Bone mineralization density distribution in health and disease. Bone 42:456–466

    Article  PubMed  CAS  Google 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 25:48–55

    Article  PubMed  CAS  Google Scholar 

  32. Gourion-Arsiquaud S, Allen MR, Burr DB, Vashishth D, Tang SY, Boskey AL (2010) Bisphosphonate treatment modifies canine bone mineral and matrix properties and their heterogeneity. Bone 46:666–672

    Article  PubMed  CAS  Google 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 27:672–678

    Article  PubMed  CAS  Google Scholar 

  34. Roschger P, Fratzl P, Eschberger J, Klaushofer K (1998) Validation of quantitative backscattered electron imaging for the measurement of mineral density distribution in human bone biopsies. Bone 23:319–326

    Article  PubMed  CAS  Google Scholar 

  35. Roschger P, Fratzl P, Klaushofer K, Rodan G (1997) Mineralization of cancellous bone after alendronate and sodium fluoride treatment: a quantitative backscattered electron imaging study on minipig ribs. Bone 20:393–397

    Article  PubMed  CAS  Google Scholar 

  36. Roschger P, Rinnerthaler S, Yates J, Rodan GA, Fratzl P, Klaushofer K (2001) Alendronate increases degree and uniformity of mineralization in cancellous bone and decreases the porosity in cortical bone of osteoporotic women. Bone 29:185–191

    Article  PubMed  CAS  Google Scholar 

  37. Boivin G, Meunier PJ (2002) Changes in bone remodeling rate influence the degree of mineralization of bone. Connect Tissue Res 43:535–537

    PubMed  CAS  Google Scholar 

  38. Boivin G, Meunier PJ (2002) Effects of bisphosphonates on matrix mineralization. J Musculoskelet Neuronal Interact 2:538–543

    PubMed  CAS  Google 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 21:1106–1112

    Article  PubMed  CAS  Google Scholar 

  40. Fratzl P, Roschger P, Fratzl-Zelman N, Paschalis EP, Phipps R, Klaushofer K (2007) Evidence that treatment with risedronate in women with postmenopausal osteoporosis affects bone mineralization and bone volume. Calcif Tissue Int 81:73–80

    Article  PubMed  CAS  Google Scholar 

  41. Leung P, Pickarski M, Zhuo Y, Masarachia PJ, Duong LT (2011) The effects of the cathepsin K inhibitor odanacatib on osteoclastic bone resorption and vesicular trafficking. Bone 49:623–635

    Article  PubMed  CAS  Google Scholar 

  42. Goldman HM, Bromage TG, Boyde A, Thomas CD, Clement JG (2003) Intrapopulation variability in mineralization density at the human femoral mid-shaft. J Anat 203:243–255

    Article  PubMed  CAS  Google Scholar 

  43. Wergedal JE, Baylink DJ (1974) Electron microprobe measurements of bone mineralization rate in vivo. Am J Physiol 226:345–352

    PubMed  CAS  Google Scholar 

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Acknowledgments

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.

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Authors and Affiliations

  1. Ludwig Boltzmann Institute of Osteology of WGKK and AUVA Trauma Centre Meidling, 1st Medical Department, Hanusch Hospital, 1140, Vienna, Austria

    Nadja Fratzl-Zelman, Paul Roschger & Klaus Klaushofer

  2. Bone Biology Group, Merck Research Laboratory, West Point, PA, USA

    John E. Fisher & Le T. Duong

  3. Ludwig Boltzmann Institute of Osteology, UKH Meidling, Kundratstrasse 37, 1120, Vienna, Austria

    Nadja Fratzl-Zelman

Authors
  1. Nadja Fratzl-Zelman
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  2. Paul Roschger
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  3. John E. Fisher
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  4. Le T. Duong
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  5. Klaus Klaushofer
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Corresponding author

Correspondence to Nadja Fratzl-Zelman.

Additional information

L. Duong and J. Fisher are employees of Merck. All other authors have stated that they have no conflict of interest.

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Fratzl-Zelman, N., Roschger, P., Fisher, J.E. et al. Effects of Odanacatib on Bone Mineralization Density Distribution in Thoracic Spine and Femora of Ovariectomized Adult Rhesus Monkeys: A Quantitative Backscattered Electron Imaging Study. Calcif Tissue Int 92, 261–269 (2013). https://doi.org/10.1007/s00223-012-9673-7

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  • DOI: https://doi.org/10.1007/s00223-012-9673-7

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