Odanacatib: Location and timing are everything - Wiley Online Library

COMMENTARY

JBMR

Odanacatib: Location and Timing Are Everything Sundeep Khosla College of Medicine, Mayo Clinic, Rochester, MN, USA

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ntiresorptive drugs have become the mainstay for the prevention and treatment of osteoporosis. Members of this class include estrogen, the selective estrogen receptor modulator raloxifene, four bisphosphonates (alendronate, risedronate, ibandronate, and zoledronic acid), and the receptor activator of NF-kB ligand (RANKL) inhibitor denosumab.(1) In contrast to this plethora of antiresorptive compounds, the sole formationstimulating agent currently available is teriparatide.(1) Thus, although there is clearly a clinical need for the development of additional formation-stimulating drugs, it remains an open question as to whether the osteoporosis market has room for yet another antiresorptive compound. It is in this context that location and timing become critical for a new antiresorptive drug. In terms of location, does the new drug offer advantages with regards to the compartment-specific (ie, trabecular, endocortical, periosteal) effects of the drug? And in terms of timing, is the new drug coming to market when there are concerns (real or perceived) regarding the efficacy or safety of currently available alternatives? Given the costs of bringing a new drug to market, these are high-stakes questions for another antiresorptive drug for osteoporosis. In the current issue of JBMR, two articles from Merck Research Laboratories(2,3) collectively address the question of location for the antiresorptive compound odanacatib (ODN), which is just entering this high-stakes arena and is currently in phase 3 trials. ODN is a selective and reversible inhibitor of cathepsin K (CatK), which is a lysosomal cysteine proteinase that is highly expressed in osteoclasts and is critical for bone resorption.(4) Both articles are based on analyses of a carefully conducted primate study in which ovariectomized Rhesus monkeys were treated with either vehicle, ODN 6 mg/kg/d, or ODN 30 mg/kg/d for 21 months and compared with intact animals; Masarachia and colleagues(2) report results at the lumbar spine and Cusick and colleagues(3) present the hip data. The spine data are not particularly striking and barely distinguish ODN from other antiresorptive agents.(2) As might be expected with any potent antiresorptive drug, ODN at both doses prevented bone loss at the spine and maintained bone

mass at a level comparable to intact animals. This was accompanied by a suppression of bone resorption markers (urinary N-telopeptide of type I collagen [NTx] by 75% to 90% and serum C-telopeptide of type I collagen [CTx] by 40% to 55%) versus vehicle-treated ovariectomized monkeys. Serum bone formation markers also decreased in the ODN-treated groups compared with vehicle-treated ovariectomized animals (bonespecific alkaline phosphatase [BSAP] by 30% to 35% and aminoterminal propeptide of type I procollagen [P1NP] by 60% to 70%), and consistent with these changes, histologically measured bone formation rates (BFRs) in trabecular bone at the iliac crest and lumbar vertebrae decreased by comparable amounts. It was in the detailed analysis of osteoclast numbers and morphology and the compartment-specific bone formation data at the hip that things got a lot more interesting.(2,3) First, despite the marked reduction in bone resorption, ODN did not reduce but rather tended to increase (by twofold) osteoclast numbers in trabecular bone at both the spine and hip. Moreover, in contrast to previous data with the bisphosphonate alendronate, where there was an increase in apoptotic and giant, hypermultinucleated osteoclasts,(5) the osteoclasts in the ODN-treated animals appeared relatively normal with the exception of an increase in intracellular vesicles that stained darkly with toluidine blue. These findings also contrast sharply with denosumab therapy, which has been shown to lead to a marked reduction in osteoclasts on bone surfaces.(6) The second distinguishing feature of ODN versus other antiresorptive agents came from the analysis of trabecular, intracortical, endocortical, and periosteal BFRs at the hip.(3) Consistent with the findings at the iliac crest and spine, ODN reduced BFR in trabecular bone at the hip. ODN similarly reduced intracortical BFR but interestingly, it had no effect on endocortical BFR. Most surprising, however, were consistent 3.5- and 6-fold increases in periosteal BFRs at the femur neck and proximal femur, respectively. This, in turn, resulted in a 21% ( p ¼ 0.08) and 19% ( p < 0.05) increase in cortical thickness at the femur neck and proximal femur, respectively. Of note, a similar increase in periosteal BFR at the mid-femur has previously

Address correspondence to: Sundeep Khosla, MD, Endocrine Research Unit, Guggenheim 7-11, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. E-mail: [email protected] This is a Commentary on Masarachia et al. (J Bone Mineral Res. 2012;27:509–523. DOI: 10.1002/jbmr.1475) and Cusick et al. (J Bone Mineral Res. 2012;27: 524–537. DOI: 10.1002/jbmr.1477). Journal of Bone and Mineral Research, Vol. 27, No. 3, March 2012, pp 506–508 DOI: 10.1002/jbmr.1541 ß 2012 American Society for Bone and Mineral Research

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been reported in ovariectomized cynomolgus monkeys treated with another CatK inhibitor, balicatib, for 18 months.(7) To summarize, based on the primate data(2,3) and consistent with a previous phase 2 study in postmenopausal women,(8) ODN appears to be a self-respecting antiresorptive agent. But, to break into the saturated antiresorptive market, it needs to be ‘‘more.’’ This more, at least in terms of location, may hinge on its ability to stimulate bone formation on periosteal surfaces while at the same time inhibiting bone resorption on trabecular surfaces. These data also raise the intriguing question of just how ODN (and likely other CatK inhibitors) may have these differential effects on bone formation in trabecular versus perisoteal surfaces. Indeed, this question gets at the very heart of how osteoclasts might regulate osteoblast number, differentiation, activity, and hence, bone formation. Although this is clearly an evolving area, there appear to be two fundamental mechanisms for osteoclastic regulation of osteoblasts (Fig. 1A). First, osteoclastic bone resorption leads to the release of growth factors from the bone matrix, which, in turn, increases osteoblast number, differentiation, and/or activity. To date, TGFb has been identified most convincingly as one such ‘‘coupling’’ growth factor,(9) but other candidates include IGF-1 and -2, as well as BMPs.(10) Second, osteoclasts appear to directly regulate osteoblasts both via cell-cell contact and by secreted factors. To date, ephrinB2 expressed on osteoclasts, and its engagement with EphB4 on osteoblasts, leading to bidirectional signaling between these cells, is the major cell-cell contact mechanism mediating cross-talk between these cells. Binding of ephrinB2 to EphB4 leads to a suppression of osteoclastic activity and enhances osteoblastic differentiation.(11) In addition, however, mature osteoclasts also secrete a number of osteoblast

simulatory factors, including Wnt 10b, BMP-6, and sphingosine-1-phosphate;(12) these factors, along with other, as yet unknown secreted factors, serve to increase osteoblast number and/or activity. Fig. 1B depicts what likely occurs in the setting of treatment with current antiresorptive agents that either markedly reduce (denosumab)(6) or cripple (bisphosphonates)(5) osteoclasts, keeping in mind that this is a working model that requires testing and validation at multiple levels. Because of the marked reduction in bone resorption, there is a concomitant reduction in local growth factor release from the bone matrix. Moreover, because of either the absence (denosumab) or dysfunction (bisphosphonates) of osteoclasts, there is also a marked reduction in stimulatory cell-cell or secreted factors from osteoclasts. The net result is a profound reduction in bone formation on all surfaces—the ‘‘coupled’’ reduction in bone formation reproducibly observed with current antiresorptive agents. Fig. 1C, by contrast, depicts potential changes in osteoclastosteoblast coupling after treatment with ODN (or other CatK inhibitors), demonstrating the possible compartment-specific effects of this class of drugs on bone formation. As with all antiresorptive agents, the reduction in bone resorption will lead to a reduction in growth factor release from the bone matrix; in this regard, ODN is no different from other antiresorptive drugs. The difference comes in the second (direct) pathway of osteoclast-osteoblast coupling. To the extent that, in contrast to bisphosphonates or denosumab, ODN therapy leads to an accumulation of relatively normal (but nonresorbing) osteoclasts,(2,3) the cell-cell and secreted coupling mechanisms would be expected to remain intact in the setting of ODN treatment. Thus, the net effect on bone formation would depend on the offsetting effects of the loss of growth factor release from the

A Proposed mechanisms for osteoclast – osteoblast coupling Net effect on bone formation

Release of growth factors from bone matrix

Direct effects Osteoclast

B Therapy with bisphosphonates, denosumab

Osteoblast

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Therapy with ODN and other CatK inhibitors

Net effect on bone formation



Net effect on bone formation

or no change Direct effects Osteoclast

or

Direct effects Osteoblast

Osteoclast

Osteoblast

Fig. 1. (A) Working model for mechanisms by which osteoclasts regulate osteoblasts and bone formation. (B) Proposed changes in osteoclast-osteoblast coupling after treatment with conventional antiresorptive agents, including bisphosphonates and denosumab. (C) Proposed more complex changes in osteoclast-osteoblast coupling after treatment with ODN and other CatK inhibitors. See text for details.

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bone matrix, leading to a reduction in bone formation, versus the ongoing, perhaps enhanced effects of the increased numbers of relatively healthy osteoclasts on directly stimulating bone formation. In trabecular bone, with its high remodeling rate,(13) the release of growth factors from the bone matrix may be particularly important, and here ODN reduces bone formation, as shown in the current studies.(2,3) By contrast, on periosteal surfaces, where the remodeling rate is much lower,(13) the loss of growth factor release from the bone matrix may have only a minor inhibitory effect on bone formation, with the major effect being the direct stimulatory effects of osteoclasts (which are present on periosteal surfaces(14)) on osteoblasts, leading to a net increase in bone formation, as demonstrated by Cusick and colleagues for ODN(3) and previously by Jerome and colleagues for balicatib.(7) This model for ODN effects on bone formation may also explain why, in the phase 2 study with this drug, bone formation markers decreased significantly in postmenopausal women during the first 6 months of therapy but then returned to baseline by 24 months, despite a persistent reduction in bone resorption markers.(8) As depicted in Fig. 1C, the initial decrease in bone formation after the initiation of ODN therapy likely reflects the dominant effects, in these women with high bone turnover, of reducing bone resorption and coupling factor release from the bone matrix. Over time, however, the accumulation of relatively normal osteoclasts on bone surfaces would be expected to counteract, through the direct mechanisms (cellcell contact and osteoclast-secreted factors), this initial inhibitory effect, leading by 24 months to near baseline levels of bone formation. To the extent, then, that the phase 3 trial with ODN demonstrates preservation of bone mass and structure at trabecular sites and increased cortical bone mass, along with significant vertebral and nonvertebral fracture risk reduction, the ‘‘location’’ question for ODN will be answered with an affirmative. ODN may well offer something more than the other antiresorptive agents currently available. The ‘‘timing’’ question, however, remains unresolved. This will depend on whether some of the well-publicized, but extremely rare, complications of osteonecrosis of the jaw(15) and atypical subtrochanteric fractures(16) associated with bisphosphonates and likely also with denosumab are observed with ODN in the phase 3 trials and beyond. Given the current concerns among some patients and physicians regarding the long-term safety of available antiresorptive drugs, however, the timing may also be just about right for ODN.

Disclosures The author has served or currently serves on scientific advisory boards for Bone Therapeutics, Amgen, and Pfizer.

References 1. Khosla S. Increasing options for the treatment of osteoporosis. N Engl J Med. 2009;361:818–20.

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2. Masarachia PJ, Pennypacker BL, Pickarski M, Scott KR, Wesolowski GA, Smith SY, Samadfam R, Goetzmann JE, Scott BB, Kimmel DB, Duong LT. Odanacatib reduces bone turnover and increases bone mass in the lumbar spine of skeletally mature ovariectomized rhesus monkeys. J Bone Miner Res. 2012;27:509–23. 3. Cusick T, Chen CM, Pennypacker BL, Pickarski M, Kimmel DB, Scott BB, Duong LT. 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. 2012;27:524–37. 4. Costa AG, Cusano NE, Silva BC, Cremers S, Bilezikian JP. Cathepsin K: its skeletal actions and role as a therapeutic target in osteoporosis. Nat Rev Rheumatol. 2011;7:447–56. 5. Weinstein RS, Roberson PK, Manolagas SC. Giant osteoclast formation and long-term oral bisphosphonate therapy. N Engl J Med. 2009; 360:53–62. 6. Reid I, Miller P, Brown J, Kendler D, Fahrleitner-Pammer A, Valter I, Massalu K, Bolognese M, Woodson G, Bone H, Ding B, Wagman R, Martin JS, Ominsky M, Dempster D. Effects of denosumab on bone histomorphometry: the FREEDOM and STAND studies. J Bone Miner Res. 2010;25:2256–65. 7. Jerome C, Missbach M, Gamse R. Balicatib, a cathepsin K inhibitor, stimulates periosteal bone formation in monkeys. Osteoporosis Int. 2011;22:3001–11. 8. Bone HG, McClung MR, Roux C, Recker RR, Eisman JA, Verbruggen N, Hustad CM, DaSilva C, Santora AC, Ince BA. Odanacatib, a cathespin-K inhibitor for osteoporosis: a two-year study in postmenopausal women with low bone density. J Bone Miner Res. 2010;25:937–47. 9. Tang Y, Wu X, Lei W, Pang L, Wan C, Shi Z, Zhao L, Nagy TR, Peng X, Hu J, Feng X, Van Hul W, Cao X. TGF-beta1-induced migration of bone mesenchymal stem cells couples bone resorption with formation. Nat Med. 2009;15:757–65. 10. Baron R, Ferrari S, Russell RG. Denosumab and bisphosphonates: different mechanisms of action and effects. Bone. 2011;48:677– 92. 11. Zhao C, Irie N, Takada Y, Shimoda K, Miyamoto T, Nishiwaki T, Suda T, Matsuo K. Bidirectional ephrinB2-EphB4 signaling controls bone homeostasis. Cell Metab. 2006;4:111–21. 12. Pederson L, Ruan M, Westendorf JJ, Khosla S, Oursler MJ. Regulation of bone formation by osteoclasts involves Wnt/BMP signaling and the chemokine sphingosine-1-phosphate. Proc Natl Acad Sci USA. 2009;105:20764–9. 13. Balena R, Shih MS, Parfitt AM. Bone resorption and formation on the periosteal envelope of the ilium: a histomorphometric study in healthy women. J Bone Miner Res. 1992;7:1475–82. 14. Bliziotes M, Sibonga JD, Turner RT, Orwoll E. Periosteal remodeling at the femoral neck in nonhuman primates. J Bone Miner Res. 2006; 21:1060–7. 15. Khosla S, Burr D, Cauley J, Dempster DW, Ebeling PR, Felsenberg D, Gagel RF, Gilsanz V, Guise T, Koka S, McCauley LK, McGowan J, McKee MD, Mohla S, Pendrys DG, Raisz LG, Ruggiero SL, Shafer DM, Shum L, Silverman SL, Van Poznak CH, Watts N, Woo SB, Shane E. Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2007;22:1479–91. 16. Shane E, Burr D, Ebeling PR, Abrahamsen B, Adler RA, Brown TD, Cheung AM, Cosman F, Curtis JR, Dell R, Dempster D, Einhorn TA, Genant HK, Geusens P, Klaushofer K, Koval K, Lane JM, McKiernan F, McKinney R, Ng A, Nieves J, O’Keefe R, Papapoulos S, Sen HT, van der Meulen MC, Weinstein RS, Whyte M. Atypical subtrochanteric and diaphyseal femoral fractures: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2010; 25:2267–94.

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