Abstract
Cathepsin K is a cysteine protease member of the cathepsin lysosomal protease family. Although cathepsin K is highly expressed in osteoclasts, lower levels of cathepsin K are also found in a variety of other tissues. Secretion of cathepsin K from the osteoclast into the sealed osteoclast–bone cell interface results in efficient degradation of type I collagen. The absence of cathepsin K activity in humans results in pycnodysostosis, characterized by increased bone mineral density and fractures. Pharmacologic cathepsin K inhibition leads to continuous increases in bone mineral density for ≤5 years of treatment and improves bone strength at the spine and hip. Compared with other antiresorptive agents, cathepsin K inhibition is nearly equally efficacious for reducing biochemical markers of bone resorption but comparatively less active for reducing bone formation markers. Despite multiple efforts to develop cathepsin K inhibitors, potential concerns related to off-target effects of the inhibitors against other cathepsins and cathepsin K inhibition at nonbone sites, including skin and perhaps cardiovascular and cerebrovascular sites, prolonged the regulatory approval process. A large multinational randomized, double-blind phase III study of odanacatib in postmenopausal women with osteoporosis was recently completed. Although that study demonstrated clinically relevant reductions in fractures at multiple sites, odanacatib was ultimately withdrawn from the regulatory approval process after it was found to be associated with an increased risk of cerebrovascular accidents. Nonetheless, the underlying biology and clinical effects of cathepsin K inhibition remain of considerable interest and could guide future therapeutic approaches for osteoporosis.
There is a clear need for additional therapeutic options for the treatment of osteoporosis. This review summarizes the underlying biology and potential clinical utility of cathepsin K inhibitors.
Essential Points
Cathepsin K inhibitors have been in development as an additional treatment of osteoporosis
In contrast to other drugs that inhibit bone resorption with a coupled reduction in bone formation, cathepsin K inhibitors have been shown to inhibit bone resorption with lessor effects on inhibiting bone formation
Despite extensive preclinical and clinical studies and substantial antifracture efficacy in a large, phase III trial, clinical development of the cathepsin K inhibitor, odanacatib, was terminated owing to an unforeseen increase in cerebrovascular events
Nonetheless, the underlying biology of cathepsin K inhibitors and the lessons learned from the development of odanacatib will help inform future drug development for osteoporosis, in particular, drugs that might dissociate the inhibition of bone resorption from the coupled reduction in bone formation
Brief Overview of Current Osteoporosis Therapies and Gaps
The adult human skeleton undergoes continuous remodeling in which small packets of bone resorbed by osteoclasts are replaced with bone formed through the actions of osteoblasts at specific sites termed “basic multicellular units” (BMUs) (1, 2). Collectively, the processes of bone resorption and formation replace approximately 10% of the skeleton each year; thus, the entire human skeleton is replaced roughly every 10 years (3). Within the cortical BMUs, osteoclasts form a bone resorbing edge. After osteoclasts have cut deeply into bone, osteoblasts are recruited to the resorption site, where they initiate bone formation (4) and gradually become embedded into the bone as osteocytes (5). In contrast to cortical bone turnover, trabecular bone turnover is more rapid, with shorter periods of bone resorption, followed by a reversal phase and subsequent bone and osteocyte formation.
From early to middle adult life, osteoclast-mediated bone resorption is generally well-matched both temporally and spatially by osteoblast-mediated bone formation, such that net bone mass remains approximately stable. This bone remodeling serves to replace damaged bone, maintain calcium homeostasis, and allow for skeletal restructuring if physical stresses on the bone are altered (1, 2, 6, 7). Both local and systemic factors regulate BMU formation and activation rates, which, in turn, regulate whole body bone balance. With progressive aging and across various pathologic conditions, bone remodeling becomes imbalanced, with bone resorption exceeding bone formation, a dynamic that results in the net loss of bone, skeletal microarchitectural deterioration, and an increased fracture risk.
The pharmacologic landscape for the management and treatment of osteoporosis has expanded markedly during the past two decades. At present, most available agents function to limit bone resorption by either directly or indirectly targeting the osteoclast. Agents categorized as antiresorptive agents include members of the bisphosphonate family (alendronate, risedronate, ibandronate, and zoledronate) estrogen, the selective estrogen receptor modulator raloxifene (although estrogen and raloxifene are weaker antiresorptive drugs than bisphosphonates and might also affect bone formation) (8), and most recently denosumab—a fully humanized monoclonal antibody directed against receptor activator of nuclear factor kappa B ligand (RANKL).
In contrast to the antiresorptive agents are pharmacologic agents that can be classified as anabolic for the skeleton. These currently consist of full-length parathyroid hormone (PTH) 1-84 (approved in Europe), its amino-terminal fragment PTH 1-34 (teriparatide), and the PTH-related peptide analog, abaloparatide. Given the current limited options for bone anabolism in the setting of an expanding elderly population likely to benefit clinically from approaches to reduce fracture risk, a clear need exists for additional pharmacologic approaches that can stimulate bone formation or at least inhibit bone resorption without inhibiting bone formation (due to the coupling of bone resorption to bone formation, see the section “Preclinical and Clinical Studies Providing Insights Into the Biology of Osteoclast–Osteoblast Coupling”). It is in this context that the development of cathepsin K inhibitors, which limit osteoclast activity but do not reduce osteoblast function to the same extent as other currently available antiresorptive agents, appears to be best placed.
Biology of Cathepsin K
Role of cathepsin K in osteoclasts
Cathepsin K is a papain-like cysteine protease member of the cathepsin family of lysosomal proteases, a family categorized as consisting of cysteine (cathepsins B, C, F, H, K, L, O, S, V, X, and W), aspartate (cathepsins D and E), and serine (cathepsins A and G) proteases, depending on the active site amino acid, which mediates each member’s catalytic activity (9). An important aspect of cathepsin biology is based on their cellular localization. Although cathepsins have greatest activity in acidic environments such as occurs along the endosomal/lysosomal continuum, cysteine cathepsins secretion into the extracellular space has also been shown to occur under normal physiologic conditions, including skeletal remodeling, wound repair, and prohormone processing (10).
Cathepsin K is the only cathepsin expressed at high levels in osteoclasts. Within osteoclasts, cathepsin K has been shown to reside in lysosomes, cytoplasmic vesicles, and along the osteoclast–bone resorptive interface before release into the resorptive lacunae formed by αvβ3 integrin-mediated osteoclastic sealing to the bone surface (11, 12). Cytochemical assays and immunostaining findings have suggested that cathepsin K processing and activation in vivo occurs intracellularly before secretion into the sealed space underlying the ruffled border (13). In addition to its expression in osteoclasts, considerably lower levels of cathepsin K have been shown to be expressed in other tissues and cells, including adipose (14), skin (15), heart (16), lung (17), smooth muscle cells (18), ovary (19), placenta (16), thyroid (20), liver (16), macrophages (21), cartilage (22), osteoblasts and osteocytes (23), and breast (24) and prostate (25) cancer.
The cathepsin K gene (CTSK), which spans approximately 12 kb, is located on chromosome 1q21 and consists of eight exons with seven intervening introns (26). The codon for the translation initiator methionine is located in exon 2, with the termination codon in exon 8. The cathepsin K protein is synthesized as an inactive precursor of 329 amino acids, including a 15-amino acid preregion, a 99-amino acid proregion, and a mature active enzyme of 215 amino acids. Removal of the N-terminal proregion is required for enzymatic activation and occurs at pH 4.0 or less during a process that can be either autocatalytic or the result of catalysis by other proteases. Cathepsin K expression is mediated by RANKL-induced activation of the transcription factor NFATc1 (nuclear factor of activated T-cells, cytoplasmic 1), which targets the CTSK promoter (27). Cathepsin K expression is also enhanced by p38 pathway activation, and the cathepsin K promoter is a transcriptional target of Mitf (microphthalmia transcription factor) (28, 29). In contrast, factors such as interferon-γ, calcitonin, and estrogen reduce cathepsin K messenger RNA and protein expression (27, 30).
As a protease, cathepsin K is the primary enzyme responsible for degradation of type I collagen, which composes ~90% of the bone organic matrix. In vivo, both type I and type II collagen are composed of two α1 chains and one α2 chain within a triple helix configuration, a structure that is highly resistant to proteolysis. Although both matrix metalloproteases and the serine protease neutrophil elastase can cleave the collagen triple helixes, neither is particularly efficient at doing so nor is either capable of degrading the cross-linked pyridinoline–deoxypyridinoline telopeptides that form the collagen triple helix end region (9). In contrast, cathepsin K efficiently cleaves both the collagen triple helix and the telopeptide to produce collagen monomers (31), such that in vitro, cathepsin K is able to completely dissolve human cortical bone collagen (32).
In addition to the type I and II collagens, cathepsin K efficiently degrades other organic extracellular matrix components. Although type I collagen composes approximately 90% of the organic skeletal matrix, the remaining 10% is composed of an array of noncollagenous proteins, including biglycan, bone sialoprotein, decorin, fibronectin, osteocalcin, osteonectin, and osteopontin (33). Although osteonectin is sensitive to cathepsin K degradation, other components are not as efficiently degraded. However, aggrecan, type II collagen, and elastin, proteins present outside of the organic bone matrix, including within joints and/or vascular walls, are efficiently degraded by cathepsin K, suggesting a potential role for cathepsin K to treat diseases other than osteoporosis such as osteoarthritis, rheumatoid arthritis, and lung and vascular disease (9).
Although cathepsin K is highly conserved across species, it is not identical. Thus, murine cathepsin K shares 88% homology and rabbit cathepsin K 94% homology with human cathepsin K, making mouse and rabbit models useful but not ideal model systems for studies of human cathepsin K biology. In contrast, monkey cathepsin K is identical to human cathepsin K, making the use of nonhuman primates a better model for studies of human cathepsin K inhibitors in vivo (34).
Cathepsin localization (endosomal/lysosomal vs secretion in the extracellular space) dictates many aspects of cathepsin biology, in particular, for the cysteine cathepsins, the group that includes cathepsin K. Accordingly, efforts to develop cathepsin K inhibitors that are not lysosomotropic (i.e. do not accumulate in acidic subcellular organelles such as endosomes and lysosomes, which are enriched for cathepsins other than cathepsin K), was a major focus of pharmacologic efforts to limit off-target (i.e., non–cathepsin K) inhibitory activities of the studied compounds (35, 36).
Data from mouse cathepsin K knockout models
Mice with genetically targeted disruption (“knockout”) of the cathepsin K gene develop skeletal hypermineralization and phenotypically mimic some aspects of the human disease pycnodysostosis, as described in the paragraph after the next. Although mice heterozygous for cathepsin K deletion are phenotypically normal, mice homozygous for cathepsin K deletion have substantial increases in bone mass at both trabecular and cortical sites (37, 38). As originally described, osteoclasts are histologically normal, and demineralization of bone adjacent to the osteoclast–bone interface appears to occur normally. Compared with wild-type osteoclasts, however, cathepsin K-deficient osteoclasts exhibit a poorly defined resorptive surface in which a demineralized bone matrix fringe occurs in the presence of abundant undigested collagen fibrils. In addition, cathepsin K-deficient osteoclasts lack the collagen–fibril-containing vacuoles normally present within the osteoclast cytoplasm during active bone resorption, consistent with their failure to resorb bone organic matrix. However, although bones that undergo endochondral ossification, including both vertebrae and long bones, are hypermineralized in cathepsin K-deficient mice, skeletal sites at which intramembranous ossification occurs, such as the skull and clavicles, are comparatively unaffected (38).
“Cathepsin K is the only cathepsin expressed at high levels in osteoclasts.”
Although the initial studies cited previously documented normal osteoclast numbers in cathepsin K-null mice, other murine models in which cathepsin K deficiency was studied in different mouse strains have suggested that the genetic background might play a modifying role in both the osteoclast and overall skeletal phenotypes (39–41). In these models, the overall osteoclast numbers were significantly increased, with cathepsin K-deficient osteoclasts failing to demonstrate normal apoptosis.
Although pycnodysostosis in humans is associated with an increased fracture risk, a study that evaluated bone strength in 19-week-old homozygous cathepsin K-null mice at both the femur and lumbar vertebrae failed to demonstrate increased bone fragility (42). Thus, cathepsin K-null mice had higher bone mineral content (BMC) at both the femur (a primarily cortical site) and the lumbar vertebrae (a primarily trabecular site), with enhanced ultimate load strength compared with wild-type mice at both sites when assessed biomechanically. This finding strongly suggests that at least in this murine model, targeted disruption of the cathepsin K gene does not affect bone tissue quality. Consistent with this, a study that examined a midshaft femoral fracture healing model in 8- to 10-week-old cathepsin K-null mice found that both fracture callus mineralization and healing were accelerated and callus mechanical strength was increased in cathepsin K-deficient vs wild-type mice (43).
In addition to the effects of cathepsin K deletion on the skeleton, murine cathepsin K knockout models have been used to examine the role of cathepsin K in other tissues. Owing to the presence of cathepsin K within lung bronchial epithelial cells and the importance of the extracellular matrix for maintenance of lung function, Bühling et al. (44) examined chemotherapy-induced pulmonary fibrosis in mice with either normal or absent cathepsin K activity. Compared with wild-type mice, cathepsin K-deficient mice showed significantly more extracellular matrix deposition, although in vitro lung fibroblasts from null mice had decreased collagenolytic activity. In contrast, wild-type mice showed increased cathepsin K activity in regions of pulmonary fibrosis. These findings were also seen in lung specimens from humans with pulmonary fibrosis, suggesting a potential protective role for cathepsin K in modulating excessive collagen matrix deposition in conditions marked by fibrotic lung disease. Consistent with this hypothesis, cathepsin K overexpression was associated with decreased collagen deposition and pulmonary fibrosis in another mouse model of bleomycin-induced pulmonary injury (45). More recently, the effects of cathepsin K deletion in neonatal lung development and response to hyperoxic challenge were examined (46). Although mice with cathepsin K deletion initially showed thinner alveolar walls, these differences did not persist to postnatal day 14. In response to a hyperoxic challenge, wild-type mice rapidly increased cathepsin K expression, which was associated with increased survival compared with their cathepsin K-null littermates. Collectively, these findings suggest that cathepsin K affects neonatal lung development and might also play a role in mediating the response to hyperoxia-induced neonatal lung damage.
Evidence from cathepsin K-null mice suggests that cathepsin K might also play an important role in lipid metabolism and/or atherosclerosis. Compared with wild-type controls, cathepsin K-knockout mice treated with a high-fat diet for 12 weeks demonstrated significantly less weight gain, had a lower liver mass and body fat percentage, had lower circulating triglycerides, cholesterol, and leptin levels, and had increased rates of adipocyte lipolysis (47). Collectively, these data suggest that cathepsin K deficiency might be partially protective against the development of dyslipidemia. Consistent with these findings are data from studies of the effect of cathepsin K gene disruption on atherosclerosis development, in which cathepsin K-null mice were crossed with atherosclerosis-prone apolipoprotein E (apoE)–deficient mice (48). After maintenance with a high-fat atherogenic diet, the plaque area in the cathepsin K/apoE double-null mice was decreased by 42% compared with that in the apoE-null mice alone owing to a decrease in both the number of advanced lesions and the individual advanced plaque area. The advanced plaques of the double-null mice also had an increase in collagen content, consistent with plaque fibrosis, which would be expected increase plaque stability. However, macrophage foam cell formation in the double knockout mice was also increased, which might decrease atheroma stability. Thus, it remains unclear whether deletion of cathepsin K has positive or negative effects on atherosclerosis. Finally, recent work examining cardiac function in cathepsin K-deficient mice has demonstrated that the absence of cathepsin K significantly attenuates cardiac hypertrophy and contractile dysfunction in both pressure overload– and high-fat–induced murine models of cardiac dysfunction (49, 50).
In summary, multiple cathepsins appear to have fundamental roles in skin biology, including cysteine (cathepsins B, H, K, L, S, and V), aspartate (cathepsins D and E), and serine (cathepsins A and G) family members, where they regulate aspects of both normal and pathologic dermal physiology (51–57). As noted in human studies of the cathepsin K inhibitors balicatib and odanacatib (see the section “Clinical Studies”), the development of skin hardening (morphea-like reactions) in a small subset of subjects treated in clinical trial conditions with each compound might reflect either off-target effects of these compounds on other cathepsin family members or, alternatively, direct effects on cathepsin K expressed in dermal fibroblasts (58, 59).
Cathepsin K deficiency in humans: pycnodysostosis
The hypermineralization phenotype found in mice homozygously null for the cathepsin K gene (60) is recapitulated in a very rare human disease. Pycnodysostosis is an autosomal recessive lysosomal storage disorder (Online Mendelian Inheritance in Man no. 265800) which, owing to CTSK gene mutations, causes cathepsin K deficiency and osteosclerosis (61). It is believed that the famed French painter Henri de Toulouse-Lautrec might have been affected by pycnodysostosis (62). Since it was first reported in 1962, <200 patients with pycnodysostosis have been described (63). The incidence of pycnodysostosis has been estimated to be 1.0 to 1.7 per million live births, with an equal sex distribution (64). Although parental consanguinity increases the risk of pycnodysostosis, consanguinity has been reported to occur in <30% of patients. Most reports to date have been from Europe or the United States, although pycnodysostosis has also been described in Japan, China, Thailand, Israel, Indonesia, India, and Africa (65).
Osteoclasts in individuals with pycnodysostosis are unable to degrade type I collagen or other noncollagenous proteins that form the bone matrix. Thus, patients have a bone matrix that is highly mineralized and associated with an increased bone mineral density (BMD). Despite this increased BMD, however, their bone is of poor quality, and affected individuals have an increased risk of fragility fractures, in particular, in the lower extremities, just as occurs in patients with osteopetrosis.
Pathogenesis
Loss of function mutations in the CTSK gene were reported to cause pycnodysostosis by genetic linkage analysis and positional cloning in 1996 (66, 67). At least 44 different mutations have been reported to date (68), with most resulting in total loss or inactivity of the cathepsin K protein owing to a variety of mutations, including missense or nonsense mutations, duplications, deletions, insertions, and splicing mutations (63, 66–86) (Table 1). Of the reported mutations, approximately 70% occur in the mature domain of CTSK, 24% in the proregion, and 6% in the preregion (63). Mutational hot spots have been reported in exons 6 and 7.
Table 1.
Reported CTSK Mutations Causing Pycnodysostosis
| Location in DNA Sequence | Genomic DNA Sequence Variants | Coding DNA Sequence Variants | Effect on Amino Acid | Location in Protein Sequence | Investigator |
|---|---|---|---|---|---|
| Missense | |||||
| Exon 2 | g. | c.3G>A | p.Met1Leu | Preregion | Arman et al. (69) |
| Exon 2 | g.1551T>C | c.20T>C | p.Leu7Pro | Preregion | Donnarumma et al. (70) |
| Exon 2 | g.1557T>C | c.26T>C | p.Leu9Pro | Preregion | Soliman et al. (71) |
| Exon 2 | g. | c.87G>A | p. Trp29X | Proregion | Xue et al. (63) |
| Exon 2 | g. | c.120G>A | p. | Proregion | Utokpat et al. (72) |
| Exon 3 | g.2128C>T | c.136C>T | p.Arg46Trp | Proregion | Schilling et al. (73) |
| Exon 3 | g.2227G>A | c.235G>A | p.Gly79Arg | Proregion | Polymeropoulos et al. (66) |
| Exon 3 | g.2228G>A | c.236G>A | p.Gly79Glu | Proregion | Hou et al. (74) |
| Exon 3 | g. | c.238G>T | p.Asp80Tyr | Proregion | Arman et al. (69) |
| Exon 4 | g. | c.365G>A | p.Arg122Glu | Mature | Zheng et al. (68) |
| Exon 5 | g.4120C>T | c.422C>T | p.Ala141Val | Mature | Chavassieux et al. (75) |
| Exon 5 | g.4134G>C | c.436G>C | p.Gly146Arg | Mature | Gelb et al. (67) |
| Exon 5 | g.4192A>G | c.494A>G | p.Gln165Arg | Mature | Donnarumma et al. (70) |
| Exon 5 | g. | c.505G>A | p.Asp169Asn | Mature | Arman et al. (69) |
| Exon 5 | g.4258A>C | c.560A>C | p.Gln187Pro | Mature | Li et al. (76) |
| Exon 5 | g.4287G>A | c.580G>A | p.Gly194Ser | Mature | Donnarumma et al. (70) |
| Exon 6 | g.8644A>G | c.635A>G | p.Tyr212Cys | Mature | Hou et al. (74) |
| Exon 6 | g.8737G>A | c.728G>A | p.Gly243Glue | Mature | Khan et al. (77) |
| Exon 6 | g.8755T>C | c.746T>C | p.Ile249Thr | Mature | Donnarumma et al. (70) |
| Exon 6 | g.8758A>G | c.749A>G | p.Asp250Gly | Mature | Donnarumma et al. (70) |
| Exon 7 | g.9109C>T | c.830C>T | p.Ala277Val | Mature | Gelb et al. (78) |
| Exon 7 | g.9109C>A | c.830C>A | p.Ala277Val | Mature | Hou et al. (74) |
| Exon 7 | g. | c.848 A>G | p.Tyr283Cys | Mature | Xue et al. (63) |
| Exon 7 | g.9171T>C | c.892T>C | p.Trp298Arg | Mature | Nishi et al. (79) |
| Exon 8 | g.9186G>A | c.908G>A | p.Gly303Glu | Mature | Toral-Lopez et al. (80) |
| Exon 8 | g.11474T>C | c.926T>C | p.Leu309Pro | Mature | Haagerup et al. (81) |
| Exon 8 | g.11479G>C | c.931G>C | p.Ala311 Pro | Mature | Nishi et al. (79) |
| Exon 8 | g.11482C>G | c.934C>G | p.Arg312Gly | Mature | Hou et al. (74) |
| Exon 8 | g.11501G>A | c.953G>A | p.Cys318Tyr | Mature | Bertola et al. (82) |
| Exon 8 | g.11503G>T | c.955G>T | p.Gly319Cys | Mature | Donnarumma et al. (70) |
| Nonsense | |||||
| Exon 3 | g.2146A>T | c.154A>T | p.Lys52X | Proregion | Hou et al. (74) |
| Exon 5 | g.4266C>T | c.568C>T | p.Gln190X | Mature | Hou et al. (74) |
| Exon 6 | g.8730C>T | c.721C>T | p.Arg241X | Mature | Gelb et al. (67) |
| Exon 8 | c.934C>T | p.Arg312X | Mature | Arman et al. (69) | |
| Frameshifts (duplication/deletion/insertion) | |||||
| Exon 2 | g.1591-1592dupGA | c.60_61dupGA | p.Ile21ArgfsX29 | Proregion | Donnarumma et al. (70) |
| Exon 4 | g.2359dupA | c.282dupA | p.Val95SerfsX9 | Proregion | Donnarumma et al. (70) |
| Exon 3 | g.2230delG | c.238delG | p.Asp80ThrfsX2 | Proregion | Fratzl-Zelman et al. (83) |
| Exon 5 | g.4124delT | c.426delT | p.Phe142LeufsX9 | Mature | Fujita et al. (84) |
| Exon 4 | g. | c.354_355insT | p.V119Cfsx25 | Mature | Ozdemir et al. (85) |
| Exon 5 | g. | c.480_481insT | p.Leu160fsX173 | Mature | Singh et al. (86) |
| Intron 7 | g. | c.IVS7-14-15insAlu | p.Asn296fsX54 | Mature | Donnarumma et al. (70) |
| Splicing | |||||
| Intron 2 | g.2112G>A | c.121-1G>A | p.del41Val-81Met | Proregion | Haagerup et al. (81) |
| Exon 7 | g.9169G>A | c.890G>A;785_890del | p.Gly262AlafsX70 | Mature | Donnarumma et al. (70) |
| Stop codon | |||||
| Exon 8 | g.11538A>G | c.990A>G | p.X330TrpextX19 | Mature | Gelb et al. (67) |
Abbreviations: c., coding; g., genomic; p., protein.
Clinical and laboratory manifestations
The diagnosis of pycnodysostosis typically occurs in infancy or young childhood as a result of the characteristic effects on the skeleton during growth and development. Affected persons will have a disproportionately short stature and a comparatively large skull, with fronto-occipital prominence, midfacial hypoplasia, mandibular hypoplasia resulting in a small chin, an obtuse mandibular angle, a high-arched palate, dental malocclusion with retained deciduous teeth, enamel hypoplasia, proptosis, and a beaked and pointed nose (87, 88). The anterior fontanel and other cranial sutures might remain open; however, craniosynostosis of some sutures has been reported to occur in some patients (82). The fingers will be short and clubbed from acro-osteolysis or aplasia of terminal phalanges, and the hands will be small and square. The thorax will be narrow and pectus excavatum, or, rarely, pectus carinatum, could be present. The spine will typically show kyphoscoliosis or increased lumbar lordosis. Low- or minimal-trauma fractures usually affect the lower extremities, including the femoral shafts and patellae and can cause genu valgum. Rickets has also been described. The adult height usually varies from 130 cm (4 ft. 3 in.) to 150 cm (4 ft. 11 in.). Mental retardation affects <10% of cases (87).
Recurrent respiratory infections and right heart failure can result from chronic upper airway obstruction caused by micrognathia, and severe obstructive sleep apnea has been described (89, 90). Craniosynostosis can cause papilledema (91), and hypoacusia has rarely been reported (92). Seizures associated with porencephalic cysts have been reported (93). A single case of chondroblastic osteosarcoma has been reported in a 22- year-old man with pycnodysostosis (94).
Examination of the teeth from a single patient with pycnodysostosis (20) due to unknown compound heterozygous mutations in the CTSK gene showed extensive periradicular high-density clumps, with unclear periodontal space on an orthopantomography examination and microcomputed tomography scanning analysis. Hematoxylin and eosin and toluidine blue staining and atomic force microscopy analysis showed that the cementum was significantly thickened, softened, and full of cementocytes. Disorganized bone structure was the main characteristic of the alveolar bone.
Radiographically, pycnodysostosis is characterized by uniform osteosclerosis throughout the skeleton, which becomes apparent in childhood and increases with age. The condition can be misdiagnosed as intermediate osteopetrosis owing to the similar phenotypes; however, exome sequencing for CTSK mutations will distinguish between these two disorders (95). Fractures tend to occur repeatedly over time. Some femoral fractures might have the radiological appearance and characteristics of atypical femoral fractures (96). The skeletal sclerosis affects the skull (in particular, the base) and orbital ridges; however, the abnormalities in modeling that occur with other forms of osteosclerosis do not develop. Long bone plain films will show narrowing of the medullary canals (73). The cranial sutures and fontanels will typically close late, especially the anterior fontanel. Wormian bones, slender clavicles with hypoplastic lateral ends, partial hyoid bone absence, and hypoplasia of the distal phalanges and ribs are also characteristic findings (97).
In terms of the laboratory findings, the serum calcium, phosphorus, and alkaline phosphatase levels will usually be normal, without anemia. Affected children have been reported to have decreased circulating growth hormone and insulin-like growth factor 1 (IGF-1) levels (71). In a small study in which the biochemical markers of bone metabolism were assayed in serum and urine from seven patients with pycnodysostosis (79), two markers of bone formation, type I collagen carboxy-terminal propeptide and osteocalcin, were normal in all seven patients. Tartrate-resistant acid phosphatase (TRAP), a marker of osteoclast numbers, was also normal in these patients. Two markers that detect type I collagen telopeptide cross-links from the N- and C-termini, NTX and CTX, respectively, were low in these patients. A third marker, which detects a more proximal portion of the C-terminus of type I collagen in serum, ICTP, was increased, a seemingly paradoxical result. The findings of decreased osteoclast-mediated type I collagen degradation, the use of alternative collagen cleavage sites by other proteases, and the accumulation of larger C-terminal fragments containing the ICTP epitope established a unique biochemical phenotype for this disorder.
The findings from only a few transiliac bone biopsy specimens from patients with pycnodysostosis have been reported. An example of bone cell morphology from two patients with pycnodysostosis is shown in Fig. 1. In general, compared with age- and sex-matched control subjects, biopsy specimens from patients with pycnodysostosis have shown increased bone mass, decreased bone remodeling, and severely decreased dynamic parameters of bone formation. The decreased bone turnover with quantitative decreases in static and dynamic parameters of bone formation is thought to explain the increased degree of mineralization and increased risk of fragility fracture (98). Multinucleated osteoclasts adjacent to areas of demineralized matrix and bone-lining cells adjacent to undigested collagen have also been described (83), as has increased inhomogeneity of the mineralized matrix resulting from large inclusions of mineralized cartilage residue. At the nanostructural level, marked increases in the mean thickness of mineral particles, reflecting decreased bone remodeling, have been noted (83). Examination of the trabecular structure revealed that the lamellae were highly disordered, with poor alignment of mineral crystals oriented along the longitudinal axis of collagen fibrils.
Figure 1.
Bone cell morphology by light microscopy on 5-μm-thick undecalcified bone biopsy sections from patients with pycnodysostosis. (a, b, d, e) The top two rows correspond to patient A, and (c, f) the bottom row corresponds to patient B. (Left column) Goldner’s trichrome stain showing osteoclasts. (Right column) Giemsa staining showing lining cells and osteoclasts. (a–c) Defective multinucleated osteoclasts adjacent to demineralized collagen fringes (pink) and mineralized bone matrix (green). Note the comparatively deeper resorption lacunae in (a, b) patient A vs (c) patient B. (d–f) Bone-lining cells (dark blue) in resorption area (light pink, arrows) after osteoclast detachment from (d) bone surface or (e, f) in orphan resorption pits. The mineralized bone surface is dark pink. Reproduced from Fratzl-Zelman et al. (83) with permission.
Taken together, the results from these biopsy specimens in humans with naturally occurring cathepsin K deficiencies strongly suggest that functional cathepsin K is important for balanced bone turnover. The findings also showed that enzyme deficiency results in a profound deterioration of bone quality with respect to trabecular architecture and lamellar arrangement, factors that likely underlie the bone fragility seen in pycnodysostosis.
Treatment
To date, no medical therapy has been shown to improve pycnodysostosis. Because patients with pycnodysostosis can reach near-normal stature and skeletal proportions with personalized growth hormone treatment targeted at appropriate IGF-1 levels, some have proposed that this be offered to affected children (99). Although teriparatide treatment for 6 months was described in one patient, no changes were seen in bone structure, microarchitecture, or turnover, as assessed by high-resolution peripheral quantitative computed tomography (QCT) scanning, bone histologic examination, or measurement of bone turnover marker levels, strongly implying that functional osteoclasts are required for an anabolic effect of teriparatide on bone (75). Although bone marrow transplantation has been evaluated for osteopetrosis, no reports are available of its use in patients with pycnodysostosis.
Long bone fractures are usually transverse and can occur contralaterally, either sequentially or simultaneously, similar to the atypical femoral fractures reported after long-term bisphosphonate therapy. However, in contrast to atypical femoral fractures, long bone fractures appear to heal at a relatively normal rate in patients with pycnodysostosis. In some cases, delayed union can occur, and huge calluses can develop during healing. Internal fixation of long bones with intramedullary nails can be used to repair fractures (100, 101). Plate and screw fixation can also be used, although the hardness of the bone makes this more difficult (102). Tooth extraction can also be difficult owing to the hardness of the bone. Mandibular osteomyelitis can require surgery and antibiotics (103). The treatment of severe obstructive sleep apnea using adenotonsillectomy and palatoplasty has been described (89, 90).
Preclinical Data
Murine cathepsin K is 88% homologous and rabbit cathepsin K 94% is homologous to human cathepsin K. This homology renders both mouse and rabbit models useful but not ideal model systems of study owing to the enzymatic differences between species, limiting the potency of compounds developed as specific inhibitors of human cathepsin K. Monkey cathepsin K, however, is identical to human cathepsin K and, accordingly, makes the use of nonhuman primate models better for pharmacologic studies of cathepsin K inhibitors in vivo (34). Preclinical studies have primarily focused on the effect of cathepsin K inhibition on skeletal outcomes.
Mouse studies
ONO-5334
ONO-5334, an orally active low-molecular-weight synthetic cathepsin K inhibitor, was compared with alendronate for skeletal effects in ovariectomized rats. Compared with untreated mice, daily treatment with ONO-5334 for 8 weeks led to dose-dependent restoration of total body BMC and BMD at the proximal tibia and also decreased markers of bone resorption, urinary deoxypyridinoline, and plasma CTX. Compared with alendronate, ONO-5334 at the highest dose studied of 15 mg/kg was less effective than alendronate at preserving trabecular BMD and BMC but was more potent than alendronate at increasing cortical BMD and BMC. This observed increase in cortical thickness was primarily the result of a decrease in endosteal circumference without an effect on periosteal circumference (104).
Odanacatib
Odanacatib, an oral, nonlysosomotropic, highly selective, reversible cathepsin K inhibitor studied in phase III clinical trials in postmenopausal women (see the section “Phase III clinical trials”) has also been studied in murine models of oral cavity bone loss (105, 106). In these models, administration of odanacatib limited the development of periodontic and endodontic disease, bone erosion, and dampened local periapical inflammation.
Rabbit studies
L-235 and odanacatib
In an ovariectomized rabbit model, the orally available cathepsin K inhibitors L-235 and odanacatib were compared with alendronate (107). Although vehicle-treated rabbits exhibited 9.8% to 12.8% BMD loss at the lumbar spine 13 weeks after ovariectomy, treatment with L-235 at a dose of 10 mg/kg completely prevented this BMD loss, a result comparable to treatment with alendronate. However, although alendronate decreased trabecular mineralizing surface at the spine by 70%, L-235 had no effect, nor was the rate of endocortical bone formation rate or the number of double-labeled Haversian canals in the femoral diaphysis affected by treatment with L-235. Consistent with these findings, treatment of ovariectomized rabbits with the closely related cathepsin K inhibitor odanacatib, at average daily doses of 4 or 9 µM, prevented lumbar spine BMD loss and also increased BMD at the proximal femur and femoral neck. Like L-235, no reduction in bone formation at any site was seen with odanacatib treatment. Furthermore, biomechanical testing of the lumbar vertebrae and central femur demonstrated that the increased BMC found at both sites provided a biomechanical advantage that correlated closely with BMC, consistent with preservation of normal biomechanical properties. Thus, although both cathepsin K inhibitors had efficacy similar to that of alendronate for bone mass preservation, their relative ability to preserve bone formation and inhibit bone resorption was consistent with other studies of cathepsin K inhibitors and, again, suggestive of a different mode of action for agents in this pharmacologic class.
More recently, work from another group, which examined the effects of daily odanacatib treatment at a dose of 9 µM on bone quality using a similar ovariectomy rabbit model, suggested that odanacatib reduced ductility and enhanced brittleness at the femur, perhaps due to greater crystallinity and tissue mineralization (108). The reasons for the discordant results between these two studies were not immediately evident.
The effect of odanacatib has also been assessed in growing rabbits in which it was shown to significantly increase BMD at the distal femur compared with vehicle (109). In addition, in an ulnar osteotomy fracture healing model in skeletally mature rabbits, odanacatib was found to markedly enhance mineralized callus formation during the early phase of fracture repair and also improved biomechanical integrity via increases in callus yield load (by 20%) and stiffness (by 26%) compared with treatment with vehicle alone (110).
Primate studies
Relacatib
Relacatib (SB-462795) is an orally bioavailable small molecule inhibitor with equal potency for cathepsins K, L, and V. In normal and ovariectomized cynomolgus monkeys, relacatib rapidly reduced both serum and urinary markers of bone resorption, an effect maintained for ≤48 hours (111). Treatment of ovariectomized cynomolgus monkeys for 9 months with relacatib reduced bone resorption and formation at sites of cancellous bone when assessed by histomorphometry and simultaneously preserved osteonal bone formation rates in cortical bone and increasing periosteal bone formation (112).
Balicatib
Balicatib (AAE-581) is an orally available reversible cathepsin K inhibitor. In in vitro whole cell assays, it was shown to accumulate in lysosomes (lysosomotropic), where it was found to inhibit cathepsin S, thereby reducing its functional selectivity for cathepsin K (113). When tested in ovariectomized cynomolgus monkeys, balicatib was able to partially prevent ovariectomy-induced bone loss and to prevent increased bone turnover at both the vertebra and femoral neck. However, periosteal bone formation rates and cortical thickness, in particular, at the midfemur, were increased (114). Ultimately, this lysosomotropic effect resulted in the nonselective inhibition of cathepsin S and discontinuation of further clinical development efforts with balicatib.
ONO-5334
A recent study compared the effects of treatment with 8 months of ONO-5334 on bone turnover, BMD, biomechanical strength, and microstructure in ovariectomized cynomolgus monkeys vs alendronate (115). Consistent with human phase II clinical trial data (see the section “Phase II Clinical Studies”), ONO-5334 treatment resulted in dose-dependent decreases in bone resorption markers, prevented the loss of vertebral BMD, improved biomechanical bone strength, and increased total and cortical BMD at the femoral neck. Although alendronate treatment decreased the ovariectomy-induced increase in the femoral midshaft osteonal bone formation rate, ONO-5334 at a dose of 30 mg/kg showed no reduction in periosteal, osteonal, or endocortical rates of bone formation. Collectively, these results are consistent with a substantial effect of ONO-5334 on both cortical BMD and mechanical strength at the femoral neck.
Odanacatib
Odanacatib has also been evaluated in ovariectomized skeletally mature rhesus monkeys in a study in which the monkeys were treated for 21 months with either vehicle or daily oral odanacatib (6 mg/kg or 30 mg/kg). Consistent with previous work in rabbits, odanacatib treatment significantly reduced the biochemical markers of bone resorption (urinary NTX by 75% to 90%; serum CTX by 40% to 55%) compared with vehicle-treated monkeys but did not reduce TRAP 5b (TRAP5b) levels, indicating that odanacatib treatment impaired osteoclast function without a reduction in osteoclast numbers (116). In contrast to its effects on bone resorption markers, odanacatib at both concentrations reduced the bone formation marker P1NP to levels comparable to those seen in intact animals treated only with vehicle. The 6- and 30-mg/kg doses of odanacatib both increased lumbar spine BMD from baseline (by +7% and +15%, respectively), and the biomechanical strength at the lumbar spine showed a trend toward, but did not reach, statistical significance. Histomorphometric analysis showed that the osteoclast numbers were maintained or increased with odanacatib treatment (117). Analyses at the hip found similar dose-dependent results, with increases in femoral neck BMD of 11% to 15% and ultimate load increases of 25% to 30% compared with baseline, with the ultimate load changes correlating closely with the observed increases in femoral neck BMD, BMC, and cortical thickness (118).
As demonstrated by histomorphometry, odanacatib treatment at the 30-mg/kg dose stimulated femoral neck and proximal femur periosteal bone formation rates by 3.5-fold and 6-fold, respectively, compared with vehicle treatment. Additional studies of the effects of odanacatib treatment in ovariectomized adult monkeys using methods to assess bone microstructure, estimates of bone strength from finite element analyses, bone mineralization density distribution, and dynamic histomorphometric changes have reinforced these findings (119–123). In contrast, however, the results at the lumbar spine, a primarily trabecular site, showed that odanacatib treatment led to a reduction in bone formation, a result in contradistinction to earlier findings in trabecular bone with odanacatib treatment in rabbits. The reasons for these noted differences, both between species and the site-specific effects on bone formation at cortical vs trabecular sites, remain uncertain.
Clinical Studies
Phase I clinical trials
Relacatib
Relacatib was studied in a phase I trial of 32 subjects to determine its effects on the metabolism of ibuprofen, acetaminophen, and atorvastatin (124). Despite promising preclinical data, further development was discontinued after this phase I trial owing to concerns raised for potential drug–drug interactions.
Balicatib
In a phase I study of 675 postmenopausal women (mean age, 62 years) with lumbar spine T-scores less than −2 randomized to either placebo or increasing doses of balicatib for 12 months, balicatib treatment resulted in a dose-related increase in BMD at both the lumbar spine (+4.4%) and hip (+2.2%) and a dose-dependent decrease in markers of bone resorption (serum CTX by 61% and urinary NTX by 55%) at the highest two doses studied. At these doses, the differences in the serum markers of bone formation compared with placebo at 12 months were not statistically significant (125). Owing to the development of morphea-like skin hardening in 9 of 709 subjects treated with the higher doses of balicatib, however, the trial was stopped because of safety concerns. Lesions in 8 patients resolved completely with balicatib cessation, with partial resolution occurring in 1 patient (58, 59). The reason for the morphea development is unclear but might be because cathepsin K is normally expressed in dermal fibroblasts, where it mediates extracellular matrix degradation, in particular, in association with scar tissue.
Odanacatib
Odanacatib was studied in three phase I trials designed to examine safety, tolerability, pharmacokinetic, and pharmacodynamic endpoints. In the first study, 49 postmenopausal subjects were randomized in a blinded manner to either once weekly odanacatib at a dose of 5, 25, 50, or 100 mg vs placebo for 21 days (126). The second study included 30 postmenopausal women and randomized subjects to 0.5, 2.5, or 10 mg odanacatib daily for 21 days. The pharmacokinetic analyses demonstrated a half-life of 66 to 93 hours, which would permit once-weekly dosing. After 21 days of treatment, the serum CTX and urinary NTX levels had declined by ~62% from baseline in women treated with once-weekly odanacatib doses of either 50 mg or 100 mg, with even greater reductions in CTX and NTX levels in women treated with the highest daily odanacatib dose of 100 mg. In these short-term studies, no serious adverse events were reported and odanacatib was well tolerated. A more recent study, which examined the safety, tolerability, pharmacokinetics, and pharmacodynamics of odanacatib in 44 healthy volunteers (36 men and 8 postmenopausal women) at doses of ≤600 mg in men and ≤100 mg in women, also reported relatively good tolerability, with the exception of one subject who developed gastroenteritis but who tolerated subsequent higher odanacatib doses without gastroenteritis recurrence (127). That study also demonstrated that odanacatib administration with a high-fat meal increased the plasma odanacatib concentrations by approximately twofold vs the fasted state (127).
Phase II clinical trials
ONO-5334
ONO-5334 was evaluated in 285 postmenopausal women with either osteoporosis (defined as a T-score of −2.5 or less) or osteopenia (defined by a BMD T-score of less than −1 but greater than −2.5) and a history of previous fragility fracture at the lumbar or total hip. All subjects were studied in a 12-month, randomized, blinded, placebo- and active-comparator (alendronate) controlled trial performed in Europe (128). For 12 months, ONO-5334 was effective at increasing lumbar spine BMD (+3.1% to +5.1%), as was alendronate (+5.2%). At the highest dose of 300 mg once daily, ONO-5334 showed a 3.0% increase in total hip BMD and a 2.6% increase in femoral neck BMD, results similar to those seen with alendronate. Just as was seen in the phase I study of balicatib, both ONO-5334 and alendronate decreased biochemical markers of bone resorption by 50% to 70%, with only ONO-5334 at the highest dose of 300 mg daily showing a modest reduction in bone formation markers. These findings again highlight the differences in the mechanism of action between bisphosphonates, which decrease biochemical markers of both bone resorption and formation, and cathepsin K inhibitors, which appear to dissociate these effects.
Extension of the study to 24 months for 197 of the study subjects revealed continued increases in BMD (+6.7% at the lumbar spine; +3.4% at the total hip; and +3.7% at the femoral neck) and a continued reduction in serum CTX and urinary NTX levels but no substantial decreases of bone formation markers with the 300 mg/day ONO-5334 dose (129). As described later (see the section on “Preclinical and Clinical Studies Providing Novel Insights into the Biology of Osteoclast-Osteoblast Coupling”), this apparent cathepsin K inhibition-mediated dissociation of bone resorption and formation in favor of bone formation is likely a critical determinant of the continued increases in BMD that occur with prolonged cathepsin K inhibitor therapy. Treatment discontinuation after 24 months of treatment led to increases in both urinary NTX and serum TRAP5b levels above baseline, demonstrating the rapid reversibility of cathepsin K inhibition. More recently, a small study examining the effects of a sustained release ONO-5334 formulation has been reported (130). A review of the clinical trials registry available at clinicaltrials.gov, however, did not show any ongoing clinical trials involving ONO-5334.
Odanacatib
Odanacatib was evaluated in a double-blind, randomized, placebo-controlled phase II study in which 399 postmenopausal women with low BMD (T-score less than −2 but −3.5 or greater at the lumbar spine, femoral neck, total hip, or trochanter) and no history of fragility fracture were treated with either placebo or 3, 10, 25, or 50 mg of odanacatib once weekly for 12 months, with a planned 12-month extension (131). The endpoints evaluated included the percentage of change from baseline in BMD at all measured sites and the percentage of change from baseline in biochemical indexes of bone resorption and formation. All subjects received vitamin D supplementation, and supplemental calcium was provided to those subjects whose average daily calcium intake from all sources was <1000 mg. At the end of 12 months, 331 of 399 subjects (83%) remained in the study. Of these 399 women, 320 continued in the extension study, with 270 (70%) completing the full preplanned 24 months. Odanacatib treatment at doses of ≥10 mg induced dose-dependent BMD increases at the lumbar spine and all femoral sites at 12 months, which were further increased by 24 months. At the 50-mg once-weekly dose, the BMD increases were 5.7% at the lumbar spine, 4.1% at the total hip, and 4.7% at the femoral neck compared with placebo at 24 months (131) (Fig. 2).
Figure 2.
Changes in BMD. The mean percentage of change from baseline over 24 months in BMD at the (a) lumbar spine (LS), (b) total hip, (c) femoral neck (FN), and (d) distal one-third radius in subjects treated once weekly with either placebo (open circles) or odanacatib (ODN) 50 mg (solid circles). Data from Bone et al. (131) with permission. Weighted LS mean, weighted least squares mean.
At doses of ≥10 mg, odanacatib treatment decreased the markers of bone resorption. The mean urinary NTX values were −60.2% at 12 months and −51.8% at 24 months (132) (Fig. 3). In contrast, the mean serum CTX values in the three highest odanacatib treatment groups decreased rapidly after treatment initiation but then increased progressively during the remaining 24 months of study, eventually approaching the baseline values, but remaining less than the values in the placebo-treated group. Although an initial dose-related decline was seen in TRAP5b levels at week 1, this decrease had diminished by the end of the first month and had resolved by the end of the third month. When assessed at months 18 and 24, the TRAP5b levels were similar across all odanacatib treatment groups and ≤15% greater compared with placebo treatment. In contrast, odanacatib at a weekly dose of ≥10 mg resulted in a decrease in serum markers of bone formation (bone-specific alkaline phosphatase and P1NP) in the first 6 months of treatment, with gradual increases seen thereafter, again approaching baseline for all but the 50-mg dose, which remained reduced to less than baseline, albeit not quite to the level seen in the bone resorption marker level analyses (Fig. 3).
Figure 3.
Changes in biochemical markers of bone resorption and formation. Mean percentage of change from baseline over 24 months for markers of bone resorption [(a) urinary NTX (NTx)/creatinine (Cr) and (b) serum CTX (CTx)] and bone formation [(c) serum bone-specific alkaline phosphatase (BSAP) and (d) serum P1NP] in subjects treated once weekly with either placebo (open circles) or odanacatib (ODN) 50 mg (solid circles). Data from Bone et al. (131) with permission. LS, least squares.
Owing to the potential for skin and pulmonary adverse events based on the previous study of the cathepsin K inhibitor balicatib (58), particular attention was given to these potential side effects. However, the clinical and laboratory adverse events rates (including all reported skin reactions and upper respiratory tract infections) were not different between the treatment groups. Finally, iliac crest bone biopsy specimens obtained for histomorphometric analysis near the end of the second year of treatment in 32 subjects showed no relevant abnormalities in measured indexes, including bone formation rate, activation frequency, or osteoclast surface/bone surface ratio between the placebo- and odanacatib-treated subjects. However, the investigators noted that the small sample sizes limited the power to determine the potential significance of the small differences noted.
In an extension of that clinical trial, the women who had completed 24 months of treatment in the parent phase II dose-ranging study were invited to continue for an additional 12 months. A total of 189 subjects underwent repeat randomization in a 1:1 ratio to continue odanacatib treatment at a fixed dose of 50 mg once weekly or were switched to placebo (132). The women who switched to placebo after 2 years of odanacatib therapy experienced rapid bone loss at the at the lumbar spine, total hip, and femoral neck, with BMD levels returning to near baseline levels within 12 months of odanacatib discontinuation. Furthermore, the biochemical markers of both bone resorption and formation increased markedly within 1 month of placebo initiation before returning to baseline by 36 months (Fig. 4). In contrast, the subjects continuously treated with odanacatib 50 mg for 36 months showed BMD increases from baseline at the lumbar spine of +7.9%, total hip of +5.8%, and femoral neck of +5.0%. Continued treatment with odanacatib at a dose of 50 mg for the full 36-month period resulted in a decrease of urinary NTX levels by approximately 50% from baseline, the P1NP levels had returned to baseline, and the bone-specific alkaline phosphatase levels were 18% greater than baseline (Fig. 4). Consistent with the 24-month data, the TRAP5b levels remained increased to greater than baseline at 36 months in women who had received continuous treatment with odanacatib 50 mg once weekly but had declined to placebo levels in the subjects switched to placebo. Overall, the adverse event rates were again similar between both treatment groups, with the exception that odanacatib-treated subjects had a greater number of uncomplicated urinary tract infections (n = 12) compared with the placebo group (n = 3) in the third year, a finding not seen during the initial 2 years of the study (132). No serious skin disorders were noted, and morphea was not observed in any study subject.
Figure 4.
Changes in biochemical markers of bone resorption and formation. Mean percentage of change from baseline over 36 months for markers of bone resorption [(a) urinary NTX (NTx)/creatinine (Cr) and (b) serum CTX (CTx)] and bone formation [(c) serum bone-specific alkaline phosphatase (BSAP) and (d) serum P1NP] in subjects treated once weekly with placebo/placebo (PBO/PBO; dark squares), odanacatib 50 mg/placebo (ODN/PBO; open circles), or odanacatib 50 mg/odanacatib 50 mg (ODN/ODN; solid circles). Reproduced from Eisman et al. (132) with permission. SE, standard error.
In the prespecified extension, which prolonged this phase II study to 5 years, the women who had received placebo or odanacatib at a weekly dose of 3 mg in the first 2 years and placebo for the third year were treated with odanacatib 50 mg/wk starting at year 4, with the other included subjects continuing with the same treatment as in year 3 (133). The subjects who received odanacatib 50 mg weekly for 5 years demonstrated near linear increases in BMD compared with baseline at the lumbar spine (+11.9%), femoral neck (+9.5%), and total hip (+8.5%; Fig. 5). In the women who had received any dose of odanacatib continuously for 5 years, the urinary NTX and serum CTX levels remained significantly reduced. In contrast, they had returned to near baseline at 5 years in the subjects treated with odanacatib for 2 years followed by placebo for 3 years. In contrast, at 5 years, the bone formation marker serum bone-specific alkaline phosphatase was slightly lower than baseline in the women who had received 5 consecutive years of odanacatib and the women who had been switched to placebo after 2 years. The P1NP levels, however, were not different from baseline for either group at the 5-year endpoint. Consistent with previous results, the levels of TRAP5b, a biochemical surrogate of osteoclast numbers, were greater at 5 years in the women who received odanacatib for the final 2 years than in the subjects who had received placebo for the final 2 years. In the safety endpoints, again, no important differences were seen between subjects treated with placebo vs odanacatib 50 mg in years 4 and 5 of the trial, although the incidence of uncomplicated urinary tract infections was again greater in the subjects who received odanacatib. Finally, an additional extension of this phase II study in which postmenopausal women received continuous treatment with odanacatib for ≤8 years has recently been reported (134). Consistent with the earlier data, continuous odanacatib treatment for 8 years resulted in continued increases in BMD at the lumbar spine of +14.8% vs baseline, with a similar pattern of increases noted at the femoral neck and total hip. Although the bone resorption markers remained decreased relative to baseline, the bone formation markers remained near baseline levels.
Figure 5.
Changes in BMD. Mean percentage of change from baseline over 60 months in BMD at the (a) lumbar spine and (b) total hip in subjects treated once weekly with placebo/placebo (PBO/PBO; dark squares), odanacatib 50 mg/placebo/placebo (50 mg/PBO/PBO; open circles), or odanacatib 50 mg/odanacatib 50 mg/odanacatib 50 mg (50 mg/50 mg/50 mg; solid circles). Reproduced from Langdahl et al. (133) with permission.
A recently reported study of 12 months of odanacatib treatment in Japanese female and male patients with osteoporosis described changes in BMD and bone turnover markers similar to the results previously reported in predominantly white populations (135). In addition, studies that evaluated the effect of odanacatib in older men have confirmed that the pharmacokinetic and pharmacodynamic parameters in older men are comparable to those in older women (136).
The effects of treatment with odanacatib 50 mg once weekly on changes from baseline in BMD and bone turnover markers have also been evaluated in a randomized, double-blind, placebo-controlled study of 24 months in 243 postmenopausal women previously treated with alendronate for ≥3 years (137). Compared with placebo, odanacatib treatment for 24 months led to relevant, but incremental, gains from baseline at the lumbar spine (2.3%), femoral neck (1.7%), and total hip (0.8%).
Odanacatib has also been studied in women with breast cancer and metastatic bone disease. In a small study of 43 women with breast cancer complicated by bone metastases, daily treatment for 4 weeks with odanacatib at a dose of 5 mg reduced urinary NTX levels by 77% from baseline (vs 73% in women treated with a single dose of the potent intravenous bisphosphonate zoledronic acid) (138). In both the odanacatib and the zoledronic acid groups, two subjects experienced disease progression. Rash and pruritus were documented in two patients treated with odanacatib but both resolved after treatment discontinuation.
Phase III clinical trials
Odanacatib
Among the cathepsin K inhibitors, only odanacatib has been studied in the setting of a phase III clinical trial. In a randomized, double-blind study of 214 postmenopausal women with osteoporosis defined by the BMD as determined by dual energy x-ray absorptiometry imaging, treatment with odanacatib 50 mg vs placebo once weekly for 24 months increased the lumbar spine area BMD by 3.5% and induced changes in serum CTX and P1NP levels similar to those previously reported (139). QCT imaging, coupled with finite element analyses, found that odanacatib produced substantial increases in both trabecular volumetric BMD and estimates of compressive strength at both the spine and the hip compared with placebo. In addition, at the cortical envelope of the femoral neck, BMD, thickness, volume, and cross-sectional area were significantly increased with odanacatib treatment compared with baseline. Exploratory analyses using high-resolution peripheral QCT to evaluate cortical geometry and bone strength at the distal radius and tibia demonstrated that odanacatib treatment resulted in significantly greater improvements in total, trabecular, and cortical volumetric BMD, cortical thickness, and estimated strength (failure load) at the distal radius (140). In addition, odanacatib treatment reduced the increase in cortical porosity seen in the placebo-treated women. Similar changes in volumetric BMD and cortical thickness were seen at the distal tibia. The QCT analyses also showed that both trabecular and cortical bone compartments at the proximal femur were affected by similar gains in BMC, with the increases in cortical volume and BMC paralleling the increase in cortical volumetric BMD (141).
The long-term odanacatib fracture trial (LOFT) was a large international, randomized, blinded, placebo-controlled study that included 16,713 postmenopausal women aged ≥65 years with a BMD T-score of −2.5 or less at the total hip or femoral neck or a history of vertebral fracture and a T-score at the total hip or femoral neck of −1.5 or less (142). In this event-driven trial, subjects were randomly assigned in a 1:1 ratio to weekly treatment with either odanacatib 50 mg or placebo. The primary endpoints were radiographically determined vertebral and hip fractures and clinical nonvertebral fractures, with preplanned interim analyses included to permit early study termination if clinically relevant fracture reduction was demonstrated. The secondary endpoints were clinical vertebral fractures, change from baseline in BMD, biochemical markers of bone turnover, and safety and tolerability, including bone histomorphometry analysis. All subjects received 5600 IU supplemental vitamin D once weekly and daily calcium supplementation, as needed, for a total daily calcium intake of approximately 1200 mg. Owing to the robust efficacy for the primary endpoints, an independent data monitoring committee recommended early study termination after a planned interim analysis. After closure of the primary study, 8256 study subjects were enrolled in the study extension. The results of the study extension have not yet been published but have been presented in abstract form at recent annual meetings of the American Society for Bone and Mineral Research.
Consistent with the phase II and smaller phase III studies described, compared with placebo, treatment with odanacatib at 50 mg once weekly for 3 years was associated with relative risk reductions of 54% for new and worsening morphometric vertebral fractures, 47% for clinical hip fractures, 23% for clinical nonvertebral fractures, and 72% for clinical vertebral fractures (143). Subsequent subgroup analyses showed that these relative risk reductions were generally consistent across subgroups as assessed by baseline age, race, bisphosphonate intolerance, history of radiographic vertebral fracture, and baseline BMD (144). A second subgroup analysis of 164 women (78 treated with odanacatib; 84 treated with placebo) demonstrated that odanacatib treatment substantially increased trabecular, cortical, and integral volumetric BMD at the spine and total hip both vs placebo, changes that were associated with increases in whole bone-estimated strength at both sites as assessed using finite element analysis (145). In the preplanned double-blinded LOFT extension study, which included 8257 subjects for a mean follow-up period of 44 months, odanacatib treatment resulted in relative risk reductions of 52% for morphometric vertebral fractures, 48% for hip fractures, 26% for nonvertebral fractures, and 67% for clinical vertebral fractures, with mean increases in BMD at the lumbar spine of 10.9% and 10.3 at the total hip (146).
Because of potential safety concerns raised in the phase II studies, multiple distinct categories of specific adverse events were designated for adjudication by an external independent clinical adjudication committee. The specific categories included dermatologic (morphea-like skin lesions and systemic sclerosis), serious respiratory infections, skeletal (delayed fracture union, osteonecrosis of the jaw, atypical femoral shaft fractures), and major adverse cardiovascular events. Dermatologic and respiratory adverse events were included for adjudication because of the adverse event signals identified in the earlier phase II studies of balicatib. Bone-related adverse events were included because of the adverse events reported in association with other classes of antiresorptive agents. Major adverse cardiovascular events were included owing to earlier reports of an excess incidence of atrial fibrillation in placebo-controlled trials of the antiresorptive zoledronic acid and observations of atheroma stabilization in a murine genetic cathepsin K-null model of dyslipidemia (48).
Although adverse events in LOFT were reported to be generally similar between the odanacatib- and placebo-treated groups (147, 148), the final adjudication of safety endpoints demonstrated that some adverse events were more common in the subjects receiving odanacatib. Both diarrhea and extremity pain were seen more frequently with odanacatib treatment, as was morphea [13 adjudicated cases of morphea-like lesions in subjects treated with odanacatib (0.1% incidence) compared with 3 cases in subjects treated with placebo] (143, 148). Although no cases of osteonecrosis of the jaw were noted in either group, atypical femoral fractures were observed in 10 patients treated with odanacatib (0.1% incidence) vs none in the placebo group (148, 149). No differences were seen in the incidence of serious respiratory infections, systemic sclerosis, or delayed fracture union between the groups.
Ultimately of greater concern were the differences between odanacatib- and placebo-treated patients determined by the independent Thrombosis in Myocardial Infarction adjudication committee, which was tasked specifically with evaluating differences in cardiovascular and cerebrovascular events (150) because of earlier, statistically nonsignificant signals for increases in cerebrovascular accidents and atrial fibrillation and atrial flutter in subjects treated with odanacatib. As reported at the 2016 American Society for Bone and Mineral Research annual meeting, although the adjudicated atrial fibrillation and atrial flutter events were more common in patients treated with odanacatib, the difference did not reach statistical significance (hazard ratio, 1.22; 95% confidence interval, 0.99 to 1.50). Likewise, when considered in aggregate, the incidence of major adverse cardiovascular events was also greater in the odanacatib group vs the placebo group, although the difference also did not reach statistical significance. However, relative to treatment with placebo, odanacatib treatment was associated with a statistically significantly increased risk of cerebrovascular accidents (hazard ratio, 1.37; 95% confidence interval, 1.10 to 1.71; P < 0.01), most of which were ischemic rather than hemorrhagic. Because of the results from this independent analysis, which demonstrated that the earlier trend toward an increased risk of cerebrovascular accidents appeared to be further increased during the extension phase of LOFT, the study sponsor ultimately withdrew odanacatib from regulatory consideration by the U.S. Food and Drug Administration (FDA).
Preclinical and Clinical Studies Providing Insights Into the Biology of Osteoclast–Osteoblast Coupling
Collectively, the preclinical and clinical data presented provide strong evidence for a different mechanism of action for cathepsin K inhibitors compared with other classes of antiresorptive agents such as the bisphosphonates or denosumab. These data have shown that this fundamental difference is the result of comparatively greater decreases in bone resorption compared with bone formation. Although the molecular and cellular bases for how this relative uncoupling of bone resorption from bone formation remain incompletely understood, recent insights into the biology and importance of osteoclast–osteoblast coupling might provide some insight into the skeletal effects seen with cathepsin K inhibition.
As first proposed by Frost (1, 2) and more recently extensively reviewed (151–158), the dynamics of bone remodeling require that bone resorption and subsequent bone formation be coupled. Evidence that coupling of bone formation subsequent to bone resorption occurs has come from rat, mouse, and human studies. In rodents, a “lag phase” between bone resorption and the initiation of new bone formation has been observed, with elevated bone formation measured within 2 to 4 weeks after removal of sex steroids (159, 160). Studies have revealed that this lag phase and coupling also exist in humans. Postmenopausal women treated for 24 weeks with estrogen exhibited an immediate decrease in bone resorption markers; however, the bone formation markers did not decrease until 4 weeks after treatment (161). In addition, suppression of sex steroids in men resulted in immediate increases in serum markers for bone resorption, with a delay (12 weeks) before the bone formation markers increased (159, 162). These data support the concept that changes in bone resorption and, by inference, in the number of osteoclasts, alter bone formation rates and that a lag phase between bone resorption and formation exists in both sexes.
Control of the initiation and progress of this sequence of events is subject to both systemic and local modulators. Osteocyte apoptosis resulting from micro-cracks or damage to bone might serve as a stimulus to initiate remodeling, and immune cells might also promote this process (163–165). Bone remodeling can be initiated by bone damage, a change in the load experienced by bone, or the necessity to remove old bone. An early event in the initiation of bone remodeling is the formation of a bone resorption compartment (BRC) by bone-lining cells, closely associated with capillaries (166–168) (Fig. 6). The signals that initiate the formation of the BRC are not well-understood, although it has been postulated that osteocytes, with their interconnections throughout bone, might somehow recognize the need for bone replacement and convey a stimulus to the bone surface to initiate canopy formation (169). It is also possible that bone-lining cells themselves might sense the need for remodeling and thereby release paracrine factors to drive BRC formation.
Figure 6.
(a–c) Histologic slides (magnification ×40) and (d) composite schematic of the BRC, which comprises the cells constituting the BMU—specifically osteoclasts (OCs), osteoblasts (OBs), and osteocytes—and canopy of bone-lining cells and associated capillary. (a) A BRC in trabecular bone, demonstrating the location of the OBs along the bone-forming surface. The osteocytes are shown embedded in the bone matrix and the canopy of cells consists of bone-lining cells. (b) A BRC in cortical bone (outer demarcation shown by broken line) filled with erythrocyte ghosts (EGs) and OBs; a few OCs can also be seen. (c) A BRC stained with an antibody specific for CD34, demonstrating staining of endothelial cells in the marrow capillary adjacent to the BRC. (d) A composite schematic of the BRC, showing connections between the osteocyte network, surface bone-lining cells, and the BRC. All cells in this network are connected with gap junctions, which might provide a pathway (block arrows) by which signals generated by osteocytes deep within the bone reach the surface and elicit remodeling events by OCs and OBs. Note also the potential direct physical contact between OCs and OBs, which would allow for signaling between these cells. Reproduced, with permission, from Khosla et al. (168). CV, central vessel of the Haversian system, which forms the basic structural unit in cortical bone.
Osteoclasts, which originate from hematopoietic precursors, can be recruited from the local marrow population or arrive at resorption sites through the local capillary blood supply. Osteoblast precursors can likewise arise from the local bone marrow environment (e.g., from perivascular precursor cells) or arrive at the BMUs though the local capillary system (170, 171). Bone-lining cells can become bone forming osteoblasts if stimulated mechanically or by PTH; thus, these cells might also represent an osteoprogenitor pool (172–174). Local endothelial cells and osteoblast lineage cells provide macrophage colony-stimulating factor (M-CSF) and RANKL to drive osteoclast differentiation (175–178). Although it has been recognized that osteoclast precursor differentiation and the initiation of bone resorption require M-CSF and RANKL, how osteoblast progenitors are recruited and induced to differentiate remains an active area of research.
In vitro studies have indicated that osteoprogenitor cells can differentiate into mature osteoblasts within 1 week (179). Expression of osteocyte marker genes follows, with a 2- to 3-week further delay (180, 181). However, the reversal lag phase between bone resorption and bone formation is estimated to be 5 to 8 weeks (154), prompting interest and speculation regarding what is occurring at the bone surface during the reversal phase. Within the BRC, osteoclasts actively resorbing bone are separated from osteoblasts replacing that bone by the recently resorbed surface, ~80% of which is covered with flat cells termed “reversal cells” [reviewed by Delaisse (158)]. Subsequent to resorption, the resorbed surface is further processed by both catabolic and anabolic activities of these flat cells, leaving a smoother bone surface (4).
During bone remodeling, minute areas of bone are resorbed before osteoblast replacement of the resorbed bone, usually with great precision in both location and amount. This requires recruitment of osteoprogenitor cells, stimulation of their differentiation, and control of the amount of new bone formed. Two crucial aspects for coupling bone resorption to formation are correctly targeting the site of bone formation and regulating the amount of new bone formed. Regulation of the site of bone formation could be controlled by highly localized chemokine production, and control of the amount of bone formed might be modulated by regulating the number of osteoblasts that differentiate once recruited to the resorption site, in addition to mechanisms that cause cessation of bone formation once the required amount of bone has been deposited.
A number of candidate factors have been proposed to initiate and drive bone formation, including factors released from the bone matrix itself during the resorption process and factors produced by osteoclast lineage cells themselves. Bone is an important storage compartment for transforming growth factor-β (TGF-β) and IGF-1 (182–184). Osteoclasts release and activate bone-bound TGF-β, which has been documented to participate in the recruitment of osteoblast lineage cells (183, 185, 186). Resorption-released IGF-1 has also been shown to stimulate the differentiation of osteoblasts (187). Thus, TGF-β and IGF-1 released by osteoclast activity have been implicated in osteoclast–osteoblast coupling.
However, evidence has also shown that bone resorption might not be essential for coupling. Both humans and genetically altered mice with reduced osteoclast function or defective osteoclast differentiation have provided important insights into the role of bone resorption in coupling [reviewed by Martin and Sims (152) and Karsdal et al. (188)]. In mice in which osteoclasts are present but unable to degrade bone, such as c-Src or chloride-7 channel-null mice, bone formation appears normal (189–191). Similarly, in humans with an inactivated chloride-7 channel gene, osteoclasts are present but bone resorption is inhibited, with no reduction in bone formation (190, 192, 193). Inhibition of bone resorption achieved via targeting of acid secretion effectively blocked bone degradation and partially blocked anabolic bone formation, further supporting a role for both bone resorption and for osteoclasts, independent of resorption, in coupling (194). In contrast, mice with gene defects that reduce osteoclast differentiation, such as mice lacking c-Fos or M-CSF, also have defects in bone formation (195–197).
Osteopetrosis is a syndrome in which an immense excess of bone is present. Osteopetrosis can be divided into two types: osteoclast-rich and osteoclast-poor (198, 199). In osteoclast-rich osteopetrosis, nonfunctional osteoclasts are present (190, 192, 200–202). In these patients, osteoblast formation appears comparatively normal or elevated despite a lack of ongoing bone resorption (192, 203). A direct correlation exists between osteoclast and osteoblast numbers (192). In contrast, in osteoclast-poor osteopetrosis, a marked reduction in osteoblast numbers is present (204), which likely contributes to the milder phenotype in osteoclast-poor osteopetrosis (198). These observations support the concept that the presence of osteoclasts, whether actively engaged in bone resorption, is needed for normal bone formation. Thus, release of bone-bound factors might not be required to couple bone resorption to bone formation during bone turnover.
A number of groups have examined whether osteoclasts produce coupling factors independently of bone resorption. Recent work from Pederson et al. (205) used an unbiased gene array survey to identify candidate osteoclast coupling factors. Pederson et al. (205) found that osteoclasts express Wnt10b and BMP6 and produce the chemokine sphingosine-1-phosphate (S1P). Wnt10b was primarily involved in promoting differentiation of osteogenic precursors, with little influence on their recruitment (206). In vitro studies of conditioned medium from nonresorbing osteoclasts revealed that although BMP6 and Wnt10b concentrations were individually too low to stimulate osteoblast differentiation, in combination they were capable of promoting differentiation, confirming roles for these candidate coupling factors acting in concert to promote bone formation (194). Additional evidence supports a role for S1P as a candidate coupling factor that recruits osteoblast lineage cells (207, 208). In addition, S1P might be involved in osteoclast recruitment through activation of the S1P receptor S1PR2. In contrast, activation of S1PR1 leads to a chemorepulsion response, reducing bone resorption by maintaining osteoclast precursors in the circulatory system (209). Thus, the roles of S1P in osteoclast–osteoblast coupling appear complex. Cathepsin K-null mouse osteoclasts studies have lent further support for a role for S1P in coupling (210). In these mice, osteoclasts are formed, but bone resorption is compromised. Osteoclasts were generated in vitro from cathepsin K-null mice, and the conditioned medium was examined for effects on osteoblastic cells. The osteoclast-conditioned medium exhibited enhanced promotion of bone formation that was blocked by a S1P receptor antagonist.
In our studies, pharmacologic blockade of BMP6, Wnt10b, and S1P separately reduced the ability of osteoclast-conditioned medium to promote mineralization by mesenchymal cells (205). Inhibition of all three factors combined did not completely block induction, suggesting that other osteoclast–osteoblast coupling factors likely contribute by mechanisms independent of these stimulatory factors. Several other groups have documented that other locally generated factors produced at sites of bone resorption are also likely to function in both recruitment and differentiation of osteoprogenitor cells. For example, platelet-derived growth factor (PDGF)-BB is produced by osteoclasts independently of bone resorbing activity and can induce migration of mesenchymal stem cells and mouse preosteoblasts (211, 212). However, another study reported that PDGF-BB inhibited osteoprogenitor differentiation (213); thus, the potential role of PDGF-BB on coupling requires further clarification.
In global cardiotrophin-1 (CT-1) knockout mice, osteoclasts formed; however, their activity was impaired (214) and bone formation was reduced. Although a reduction in matrix released factors might have contributed to the observed phenotype, further studies documented that CT-1 can directly stimulate bone formation in vivo and osteoblast differentiation in vitro. Thus, the relative contribution of CT-1 to osteoclast–osteoblast coupling remains unresolved. Afamin, a vitamin D/albumin-binding protein family member, is produced by osteoclasts and has been shown to recruit osteoblast progenitors in vitro (215). CTHRC1 (collagen triple helix repeat containing 1) is produced by osteoclasts during the bone resorptive process and can stimulate bone formation in vivo and in vitro (216). Semaphorin 3A is a secreted protein that has been shown to inhibit osteoclast recruitment and promote osteoblast recruitment (217). However, studies by other groups have provided conflicting results, raising questions regarding whether semaphorin 3A has a direct role in osteoclast–osteoblast coupling (218, 219).
Several studies have examined the extent to which coupling factors tethered to membranes might be involved in recruiting osteoprogenitor cells (153–155). The Ephs form a family of tyrosine kinase receptors, and ephrins are ligands for Ephs and are similarly membrane-bound, thus requiring physical contact between cell types for receptor activation. Signaling between ligand and receptor is bidirectional. Ligand binding, not only stimulates receptor signaling, but receptor binding to the ligand also causes rapid phosphorylation of tyrosine residues on the ephrins (220). Osteoclasts express ephrin B2 (221, 222). Also, in vivo and in vitro evidence has indicated that osteoclast lineage ephrinB2 binds to osteoblast lineage EphB4 to promote osteoblast differentiation, and ephrinB2 reverse signaling inhibits osteoclast differentiation. However, targeting ephrinB2 in osteoclast lineage cells did not support that reverse signaling was a major contributor for control of osteoclast differentiation in vivo (221). Semaphorin 4D can exist as either a secreted protein or a membrane-associated regulator of cell differentiation. Semaphorin 4D is an osteoclast-produced inhibitor of bone formation, which suggests a mechanism by which osteoclasts could limit the amount of bone formed after resorption, thereby providing the required fine tuning of bone turnover (223). To fully resolve the effect of each of these candidate coupling factors on the bone remodeling process requires complex in vivo studies.
Currently available antiresorptive therapies target osteoclasts, either by inhibiting their differentiation (estrogen, the selective estrogen receptor modulator raloxifene, and the RANKL inhibitor denosumab) or by disrupting osteoclast viability to the extent that apoptosis is induced (bisphosphonates) (224). However, all currently approved antiresorptive drugs cause a parallel reduction in bone formation (225, 226). In contrast to antiresorptive agents that reduce osteoclast numbers, cathepsin K inhibitors decrease osteoclast function but maintain or even increase osteoclast numbers (131). As shown for odanacatib and other cathepsin K inhibitors in primate studies, cathepsin K inhibition reduces both bone resorption and bone formation in trabecular bone, similar to other antiresorptive therapies. In contrast, in the femur, cathepsin K inhibition treatment reduces bone resorption yet increases histologically measured bone formation rates on periosteal surfaces (117, 118).
These findings suggest that the effects of cathepsin K inhibition on bone are likely complex. Figure 7 provides a conceptual model for how cathepsin K inhibitors might differ from current antiresorptive drugs (226). Figure 7(a) depicts both the direct effects of osteoclasts on bone formation and the indirect effects mediated by release of growth factors from bone. As shown in Fig. 7(b), current antiresorptive drugs, which markedly reduce osteoclast numbers, result in a profound reduction in bone formation on all surfaces. In contrast, the effects of cathepsin K inhibitors are likely both surface and time dependent. As depicted in Fig. 7(c), just as with all antiresorptive agents, the reduction in bone resorption after cathepsin K inhibitor treatment will lead to a reduction in growth factor release from the bone matrix, leading to a reduction in bone formation. However, in contrast to other antiresorptive drugs, cathepsin K inhibition leads to an accumulation of relatively normal (but nonresorbing) osteoclasts (117, 118). As such, the cell–cell and secreted coupling mechanisms described would be expected to remain intact during cathepsin K inhibitor treatment. Deletion of cathepsin K in mice led to increased production of S1P by the mutant osteoclasts, leading to a stimulation of bone formation (210). Thus, the net effect on bone formation would depend on the offsetting effects of the loss of growth factor release from the bone matrix, leading to a reduction in bone formation vs the ongoing, perhaps enhanced, effects of increased numbers of relatively healthy osteoclasts on directly stimulating bone formation. In trabecular bone, with its high remodeling rate (227), the release of growth factors from the bone matrix might be particularly important. In trabecular bone, odanacatib reduces bone formation, as shown in the primate studies (117, 118). In contrast, on periosteal surfaces, where the remodeling rate is much lower (227), the loss of growth factor release from the bone matrix might 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 (228)] on osteoblasts, leading to a net increase in bone formation.
“Cathepsin K inhibitors decrease osteoclast function but maintain or even increase osteoclast numbers.”
Figure 7.
(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) More complex changes in proposed osteoclast–osteoblast coupling after treatment with cathepsin K inhibitors. Reproduced from Khosla (226) with permission.
This model for the cathepsin K inhibitor effects on bone formation might also explain why, in the phase II study of odanacatib, bone formation markers decreased significantly in postmenopausal women during the first 6 months of therapy but had returned to baseline by 24 months, despite a persistent reduction in bone resorption markers (131). As depicted in Fig. 7(c), the initial decrease in bone formation after the initiation of odanacatib 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 direct mechanisms (cell–cell contact and osteoclast secreted factors) this initial inhibitory effect, leading by 24 months to near baseline levels of bone formation.
Potential Clinical Role of Cathepsin K Inhibitors
Given the ongoing concerns regarding the use of pharmacologic agents with potent antiresorptive properties (bisphosphonates and denosumab) and prolonged biologic half-lives (bisphosphonates) and their potential relationship to very rare, but widely reported, complications of prolonged therapy including osteonecrosis of the jaw (229) and subtrochanteric femoral fractures (230), the development of another class of potent antiresorptive agents with a different mechanism of action warrants careful consideration. With the final results of the phase III study of odanacatib now publicly reported, including the independently adjudicated safely endpoints, odanacatib has been withdrawn from the U.S. FDA regulatory approval process. Thus, although odanacatib might not proceed to clinical use, the lessons learned about the underlying biology and clinical efficacy of cathepsin K inhibitors and an understanding of the adverse events that ultimately led to the demise of odanacatib as a therapeutic agent are useful in terms of informing future drug development efforts in osteoporosis, in particular, regarding the development of agents that might inhibit bone resorption without inhibiting bone formation.
Conclusion and Future Directions
Cathepsin K inhibition represents a different approach for the treatment of osteoporosis. Although currently available antiresorptive agents diminish both osteoclast activity and numbers, thereby resulting in both decreased bone resorption and a secondary decrease in bone formation, cathepsin K inhibition results in increased numbers of osteoclasts, which, although impaired in their ability to resorb bone matrix, remain on the bone surface where they appear capable of local signaling to adjacent cells, including osteoblasts and osteoblast-lineage cells, thereby maintaining osteoblast function and activity. Thus, although cathepsin K inhibition effectively limits osteoclast-mediated bone resorption, it also permits a relative preservation of bone formation. Furthermore, these differential effects on osteoclast and osteoblast activity appear to most profoundly affect cortical bone sites such the femur, where increases in both cortical thickness and bone strength have been observed in both preclinical models and clinical studies. Such effects could be anticipated to reduce the nonvertebral fracture risk more than do currently available antiresorptive therapies.
Although it is uncertain whether the relevant suppression of bone remodeling that occurs in patients treated with either bisphosphonates or denosumab leads to impaired skeletal fragility (231), the introduction of cathepsin K inhibitors as a pharmacologic class with a potentially different safety profile and a different mechanism of action was anticipated to have been timely. However, unlike both bisphosphonates and denosumab whose primary biologic target is the osteoclast, cathepsin K inhibitors have the potential to affect other tissues, given that cathepsin K expression is not limited solely to the osteoclast. Such potential concerns limited the development of all cathepsin K inhibitors, except for odanacatib, which, as noted, was recently withdrawn from U.S. FDA consideration because of safety concerns related to an increased risk of cerebrovascular accidents.
However, odanacatib was only tested in phase III trials against a placebo rather than against an active comparator such as alendronate. As such, it might have been challenging for clinicians to know where to place odanacatib within the current range of pharmacologic options. Given the well-documented benefits of other antiresorptive agents for limiting bone loss and fracture risk, it is unclear whether cathepsin K inhibition would have been considered as first-line therapy for all eligible patients. Rather, it is likely that it might have been of particular benefit for those patients for whom other established agents are either contraindicated or deemed unsuitable. Accordingly, the loss of this agent as an anticipated treatment option in our osteoporosis pharmacologic armamentarium was a setback to the bone health community. Nonetheless, the lessons learned about the underlying biology and clinical efficacy, as well as adverse events, of cathepsin K inhibitors should continue to guide future drug development efforts for osteoporosis.
Acknowledgments
Acknowledgments
This study was supported by National Institute of Health Grants AG004875, AG048792, AR027065 (S.K.), and AR067129 (M.J.O. and S.K.).
Disclosure Summary: The authors have nothing to disclose.
Footnotes
- apoE
- apolipoprotein E
- BMC
- bone mineral content
- BMD
- bone mineral density
- BMU
- basic multicellular unit
- BRC
- bone resorption compartment
- CT-1
- cardiotrophin-1
- CTX
- collagen type 1 cross-linked C-telopeptide
- FDA
- Food and Drug Administration
- IGF-1
- insulin-like growth factor 1
- LOFT
- long-term odanacatib fracture trial
- M-CSF
- macrophage colony-stimulating factor
- NTX
- type 1 cross-linked N-telopeptide
- PDGF
- platelet-derived growth factor
- PTH
- parathyroid hormone
- QCT
- quantitative computed tomography
- RANKL
- receptor activator of nuclear factor kappa B ligand
- S1P
- sphingosine-1-phosphate
- TGF-β
- transforming growth factor-β
- TRAP
- tartrate-resistant acid phosphatase
- TRAP5b
- tartrate-resistant acid phosphatase 5b.
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