Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Future Med Chem. Author manuscript; available in PMC 2010 Feb 1.
Published in final edited form as:
Future Med Chem. 2009 Apr 1; 1(1): 21.
PMCID: PMC2780340

Future of anticathepsin K drugs: dual therapy for skeletal disease and atherosclerosis?



Until fairly recently, cathepsin K was recognized solely as a bone-resorbing enzyme expressed selectively in the osteoclast. Evidence of its requirement for normal bone remodeling has resulted in this protease receiving considerable attention from the pharmaceutical industry. In the last decade, intense research efforts were aimed at development of cathepsin K inhibitors for treatment of osteoporosis and other skeletal disorders associated with pathological bone loss. Emerging new evidence suggests that in addition to bone resorption, cathepsin K is involved in the turnover of extracellular matrix proteins in organs, such as the lung, thyroid and skin, and plays important roles in cardiovascular disease, inflammation and obesity.


This review highlights the physiological and pathophysiological implications of this potent protease, with a focus on recent developments in the design and use of cathepsin K inhibitors to target skeletal pathologies. Therapeutic implications of anticathepsin K drugs in the context of common links between bone disease and atherosclerosis are also discussed.


The association of cathepsin K with skeletal and cardiovascular disorders offers intriguing future applications for inhibitors of this potent protease.

Skeletal pathologies and cardiovascular disease are both widely prevalent in aging populations, and together account for significant morbidity and mortality [1-3]. There is growing evidence that a biological association exists between bone density and cardiovascular health. Skeletal disorders, such as osteoporosis and tumor-induced bone resorption, are caused by increased activity of bone resorbing osteoclasts [4,5]. The processes of bone resorption and bone formation are tightly coupled and treatments that primarily target the osteoclasts generally exert secondary inhibitory effects on bone formation. This is true for currently available antiresorptive treatments such as bisphosphonates and hormone-replacement therapy, which target osteoclastogenesis and, thus, affect osteoclast numbers [4,6]. Therefore, considerable efforts are being made by the pharma ceutical industry to develop new, more selective agents capable of effectively restoring the balance between osteoclast and osteoblast activity in favor of bone formation. Cathepsin K is a potent collagenase expressed highly in the osteoclast, which makes it a natural target for inhibition of osteoclastic-bone resorption [7-9]. More recently, its roles in obesity, inflammation and atherosclerosis have been revealed, suggesting that this protease might be one of the common biological links connecting low bone density to cardiovascular disease [10-12].

Recently, the osteoprotegerin/receptor activator of NF-κB/receptor activator of NF-κB ligand axis, a key regulatory system in bone homeostasis and a regulator of cathepsin K gene expression, has also been implicated in cardiovascular disease and immunity [13-15]. Given the growing experimental and epidemiological evidence supporting the concept of coincidence of osteoporosis and vascular disease, dual therapies that target both pathologies may become viable strategies in the future.


Disease of the bone manifested by reduced bone mineral density (BMD) and increased risk of fracture


Class of drugs that inhibits activity of the osteoclast and, ultimately bone resorption. Currently used for the treatment of osteoporosis and osteoarthritis

Cathepsin K: a protease with unique physiological functions

Cathepsin K is the only known mammalian protease capable of degrading both the helical and non-helical regions of collagen I [9]. In fact, this protease can completely digest the insoluble collagen of adult cortical bone in the absence of other proteolytic enzymes. This process occurs extracellularly in acidic resorptive pits between the bone surface and the osteoclast, and intracellularly in lysosomes of the osteoclast [9,16]. It has been estimated that approximately 4% of the cDNA from an osteoclast-derived library encodes cathepsin K, and this protease accounts for 98% of all cysteine protease-expressed sequence tags in the osteoclast [17]. The importance of cathepsin K in normal bone remodeling is demonstrated by the fact that a mutation in the cathepsin K gene in humans results in a bone-sclerosing disorder called pycnodysostosis and a cathepsin K deficiency in mice leads to severe osteopetrosis [9,18,19]. Accordingly, accelerated bone turnover indicative of osteoporosis occurs in transgenic mice overexpressing this potent collagenase [12,19]. In osteoporosis patients, N-telopeptide collagen fragments, typical products of cathepsin K cleavage, have been detected in urine and serum. Evidence of over 60% reduction in N-telopeptide upon treatment with a selective cathepsin K inhibitor further highlights the essential role of this protease in osteoclast-mediated collagen degradation [201].

Cathepsin K

Lysosomal cysteine cathepsin predominantly expressed in osteoclasts and the major enzyme involved in bone resorption


An inflammatory disease associated with extensive remodeling of arterial wall and formation of plaque


Complex biological reaction to infection, irritation or other injury; an important risk factor in tumor development and progression


Type of bone cell that degrades bone tissue and is responsible for bone resorption and fracture risk


Type of arthritis that is caused by the breakdown and eventual loss of cartilage in joints

■ Synovial cathepsin K expression, & implications for pathogenesis of rheumatoid arthritis & osteoarthritis

Although characteristic of osteoclasts in the bone, expression of cathepsin K has also been reported in other parts of the skeleton, specifically in osteoarthritic cartilage and inflamed synovial tissue associated with rheumatoid arthritis [9,17,20]. Within the inflamed joints, cathepsin K appears to localize to synovial fibroblasts, macrophages and giant cells, where it degrades collagen II and aggrecans, a process leading to joint destruction [9]. In order to digest aggrecan, cathepsin K must form specific complexes with bone- or cartilage-derived glycosaminoglycans such as chondroitin and keratan sulfates [21,22]. Interestingly, both of the glycosaminoglycans are tethered in abundance to the aggrecan core protein. Following enzymatic processing, products of aggrecan potentiate the collagenolytic activity of cathepsin K against type I and II collagens [9,17,22]. Expression of cathepsin K in osteoarthritic cartilage correlates with the severity of osteoarthritis [23]. Similarly, patients with rheumatoid arthritis exhibit elevated serum levels of cathepsin K, which correlate with the Larsen score reflecting the degree of joint destruction [9,24]. This suggests that cathepsin K might be a good biomarker for the assessment of the severity of the disease and a potential therapeutic target for inhibition of progressive erosion of the cartilage.

■ Cathepsin K & inflammation

Cysteine proteases have long been known to be involved in adaptive immunity, particularly antigen processing and presentation, but have not been linked to innate immune response [25,26]. A recent report by Asagiri et al. reveals that cathepsin K might affect the innate immune response to pathogen DNA by compromising the signaling of Toll-like receptor 9 [27]. The authors demonstrated anti-inflammatory effects of cathepsin K inhibition in a rat model of autoimmune arthritis, and further highlighted the therapeutic effect of cathepsin K deficiency in a mouse model of autoimmune encephalomyelitis. Cathepsin K did not appear to share antigen-processing capabilities with cathepsin S and L, proteases normally involved in this process. Regulatory activity of cathepsin K was specific to Toll-like receptor 9 and did not affect immune responses of other Toll-like receptors to natural or synthetic ligands.

■ Well-established role of cathepsin K in inflammation

Cathepsin K has been found in serum of Gaucher patients and its transcripts are expressed at high levels in inflamed gastric mucosa [9]. In inflamed lung tissues, where the extracellular matrix is destroyed by an imbalance in levels of proteases and their inhibitors, macrophage-derived cathepsin K exhibits characteristics of a kininase and is suggested to regulate bradykinin receptors, a process involved in broncho constriction during airway obstructive diseases [28]. In a mouse model of emphysema, levels of cathepsin K and other cysteine proteases are increased and correlate with the extent of tissue damage. Furthermore, conditions like pulmonary fibrosis, where increased matrix deposition by activated fibroblasts occurs, demonstrate a pivotal role for cathepsin K in lung matrix homeostasis [9].

■ Cathepsin K in cancer

The first evidence for cathepsin K involvement in tumor progression came from studies of breast and prostate cancer, both of which have a propensity to metastasize to skeleton [29-31]. In both cancers, levels of cathepsin K have been shown to be significantly increased in bone tumors, as compared with primary tumors and soft tissue metastases from the same patient [29,30]. In addition to osteoclasts, cathepsin K was shown to localize to bone tumor cells, which is in agreement with the hypothesis of osteomimicry suggesting that tumor cells need to acquire characteristics of bone cells to grow within the bone microenvironment (e.g., express and secrete cathepsin K) [32,33]. Emerging literature evidence also points to the importance of stromaderived cathepsin K in malignant progression. An association of this potent collagenase with the host stroma in lung cancer xenografts, and a specific localization to macrophages and fibroblasts in the stroma of invasive adenocarcinomas have recently been demonstrated [34,35]. The importance of cathepsin K-expressing peritumoral fibroblasts has been established in melanoma invasion and breast cancer progression [36,37]. It has been suggested that increased expression of cathepsin K in tumors and tumor-associated cells might be a direct result of transcriptional regulation by ets family members [38]. Specifically, ETS-1 transcription factor has been shown to bind to 5′ region of cathepsin K promoter and thus potentially influence synthesis of this protease [9]. Given the evidence of aberrant expression of ets factors in various tumors and their association with tumor development and progression [39,40], their involvement in transactivation of the cathepsin K gene calls for further investigation.

Strategies to target cathepsin K activity: therapeutic implications

■ Evolution of cathepsin K inhibitors

Despite substantial interest in cathepsin K as a therapeutic target during the last decade, development of cathepsin K inhibitors has proven to be somewhat challenging. Complications came from the fact that there are significant species-specific differences in key amino acid residues involved in substrate–inhibitor recognition between humans and rodents [41]. Since cathepsin K inhibitors were generally designed against the human enzyme, they tended to be an order or two of magnitude less potent against mouse or rat cathepsin K [42]. This led to discrepancies in the inhibitory potential of analyzed compounds and inability to utilize rodent models for drug evaluation. Nevertheless, antiresorptive properties of cathepsin K inhibitors were demonstrated in acute models of in vivo bone resorption, including the thyroparathyroidectomized and ovarectomized rat and mouse models [7]. Subsequently, knowledge of the sequence and kinetics identity between human and monkey cathepsin K and the fact that ovarectomized monkey is an excellent model for human osteoporosis, have led to the use of nonhuman primate models for the evaluation of cathepsin K inhibitors [43-45]. In vitro preclinical models have also been successfully used to assess antiresorptive properties of anticathepsin K drugs. These include the well-established osteoclast bone resorption assays and more recently, activity-based probe (ABP) assays [46-48]. ABPs are electrophile-containing inhibitors that irreversibly react with an active site residue critical for enzyme activity. ABP enzyme occupancy assays have been utilized to define cellular selectivity of cathepsin K inhibitors against other cysteine cathepsins [48].

The challenge in designing selective anticathepsin K drugs came from the common proteolytic mechanisms and the similarity of substrate recognition among members of the cysteine cathepsin family [49]. The design of an inhibitor of a cysteine protease, such as cathepsin K, depends on the presence of an electrophilic center capable of forming a covalent bond with a thiol group of the active site cysteine [50]. The initial anticathepsin K drugs utilized electrophiles like epoxides or fluoromethyl ketones, which bound irreversibly to the active site of the enzyme [50]. Although such compounds are excellent tools for elucidating the mechanisms of action of proteases, they pose serious safety concerns if used as actual drugs. Specifically, since they are intended to be used chronically to treat the disease, irreversible inhibitors present selectivity problems and the possibility of antigenic and immunological complications [7]. Therefore, subsequent generations of inhibitors that have emerged in recent years were designed to minimize unfavorable side effects, and utilized other classes of electrophiles like ketones and nitriles, capable of trapping the nucleophilic cysteine in a covalent yet reversible fashion [41,50]. There has been a considerable amount of work published in recent years by researchers at GlaxoSmithKline and Merck that documents development of anticathepsin K drugs, with respect to various warheads and substrate-binding sites. Results of in vivo animal studies and clinical developments all point to nitrile-based compounds as the most promising class of inhibitors [7,8,16,19,51].

■ Lysosomotropism: off-target effects & effects on inhibitor selectivity

Although there are currently no cathepsin K inhibitors approved for clinical use, two nitrile-based compounds, Merck’s odabnacatib (MK-0822) and Novartis’s balicatib (AAE581), have demonstrated excellent potency against human cathepsin K (Table 1). Both of these inhibitors have been shown to successfully reduce markers of bone resorption and increase bone mass density (BMD) in postmenopausal women [7,8]. The drawback of balicatib is that it contains a basic functional group that results in accumulation of the drug in acidic lysosomes of cells, a phenomenon also known as lysosomotropism [16,50]. Lysosomotropism is a feature of many drugs and it may actually improve pharmacokinetic properties of the inhibitor by allowing the lysosome to store and release it slowly over extended periods of time [50]. However, for drugs that target lysosomal enzymes, this is an undesirable property leading to an increase in inhibitor potency against other related cathepsins present in these compartments. Therefore, despite more than a 1000-fold selectivity for cathepsin K over other cysteine cathepsins in vitro, and excellent antiresorptive properties in the clinic, balicatib, which is a basic peptidic nitrile, was withdrawn after completion of a Phase II trial (Table 1). Adverse skin effects, including rash, scleroderma and morphea-like changes were suggested as the key reason for discontinued use of this inhibitor [7,52]. Whether skin effects of balicatib are the main complication from its lysosomal entrapment remains to be proven. Another lysosomotropic compound that reached clinical trials was peptide nitrile AFG-495 developed by Novartis (Table 1). This compound proved to be far more potent against other cysteine cathepsins in cellular assays, and was shown to increase off-target antigen presentation mediated by cathepsin S [53].

Table 1
Clinical development of anticathepsin K drugs.

Odanacatib (MK-0822)

Inhibitor of cathepsin K and investigational treatment for osteoporosis, developed by Merck. Currently in Phase III clinical trials for treatment of osteoporosis in postmenopausal women

L-873724, Merck’s first nonbasic, non-lysosomotropic inhibitor, was developed to address the selectivity issues with cathepsin K inhibitors described above, and was demonstrated to have a greater than 800-fold selectivity over other cysteine cathepsins [54]. L-873724 exhibited an excellent ability to suppress markers of bone resorption in a nonhuman primate model; however, metabolic liabilities prevented its further development. Its successor, odanacatib (MK-0822), designed by blocking the metabolic sites on L-873724, exhibited greater selectivity against off-target cysteine cathepsins and increased antiresorptive activity than balicatib and relacatib [51]. To date, odanacatib is the most advanced and promising anticathepsin K drug in clinical development. Results from the 12-month Phase IIB osteoporosis study demonstrated dose-dependent increases in BMD at key fracture sites (i.e., hip, spine and wrist) and reduced bone turnover compared with placebo in postmenopausal women with low BMD [7]. Furthermore, a recent report at the American Society of Clinical Oncology 2008 Breast Cancer Symposium indicated that in breast cancer patients with metastatic bone disease, 4 weeks of treatment with odanacatib suppressed markers of bone resorption and led to an increase in serum crosslinked C-terminal peptide of type I collagen (s1CTP), suggesting a specific inhibition of cathepsin K [55].

Four Phase III clinical trials were designed to evaluate the efficacy of odanacatib in various aspects of bone disease (Table 1). Specifically, two osteoporosis trials are currently ongoing to determine the safety and tolerability of odanacatib and its effect on BMD and the effects on fractures in postmenopausal women with osteoporosis. Two trials to assess effectiveness of odanacatib in reducing the risk of bone metastasis in women with breast cancer and prolonging time to first bone metastasis in men with castration-resistant prostate cancer were announced but withdrawn prior to recruitment for undisclosed reasons.

In addition to odanacatib there are two other cathepsin K inhibitors currently in clinical trials. MIV-701 developed by Medivir, reached Phase I trials for osteoporosis, osteoarthritis and bone metastasis (Table 1), but according to the latest interim report from Medivir, MIV-701 has not moved beyond the Phase I at this point [207]. ONO-5334, made by Ono Pharma is under going Phase II assessment for its efficacy against osteoporosis and osteopenia, but is not recruiting new participants (Table 1). The chemical nature of MIV-701 or ONO-5334 has not been disclosed by the companies.

■ Cathepsin K inhibitors versus existing treatment regimens for skeletal diseases: how to restore normal bone remodeling?

Metabolic changes associated with aging and obesity lead to significant increases in the incidence of osteoporosis and associated vertebral fractures in women and men [56,57]. There is also a high prevalence of metastatic bone disease from cancers of the breast, prostate, lung, thyroid and kidney, processes where osteoclast-mediated bone loss leads to severe morbidity and mortality [58]. There is no doubt that the prevention and treatment of the abovementioned skeletal disorders is a major public health and socioeconomic issue in aging global populations.

Because pathological activation of osteoclasts appears to play a central role in most disease-related skeletal complications, the rational treatment approach is the primary inhibition of bone resorption. The most commonly prescribed antiresorptive pharmacological agents today, by virtue of their efficacy and long-term safety, are bisphosphonates, administered until recently as weekly or monthly oral therapies [4,5,58]. A recent advancement in bisphosphonate treatment is a once-yearly intravenous injection of zoledronic acid approved by the US FDA for treatment of osteoporosis in postmenopausal women [211]. Bisphosphonates bind avidly to the bone matrix and achieve therapeutic concentrations at the sites of active bone remodeling [59,60]. They exert their effect on osteoclasts via disruption of the mevalonic acid pathway or generation of cytotoxic ATP analogues [4,59,60]. Their clinical efficacy, however, appears to be limited to reduction of resorbed space in the bone and osteoblast-mediated refilling of spaces remodeled by osteoclast [6,61]. As bone resorption is physiologically coupled to bone formation, both processes decline with bisphosphonate treatment, leading to slower overall bone turnover. Accordingly, fracture reduction in postmenopausal women treated with bisphosphonates reaches an efficiency of only 40–50% [6,61].

Bone metastasis

Secondary growth site of growth for aggressive cancers (e.g., prostate and breast) leading to significant morbidity and mortality

In contrast to bisphosphonates, cathepsin K inhibitors do not interfere with osteoclast survival or function, but inhibit proteolysis of the organic component of the bone matrix [45,61,62]. Specifically, cathepsin K-deficient osteoclasts are capable of removing bone mineral without digesting collagenolytic matrix [45,61,62]. Results of several long-term studies with cathepsin K inhibitors in nonhuman primates and clinical evidence of increases in BMD in odanacatib-treated patients suggest a possible uncoupling of osteoclast and osteoblast activity that favors bone formation [7,45,55]. In attempting to design inhibitors that help to rebuild lost bone while restoring normal bone remodeling, researchers at Merck have recently identified MK-1256, a new nonbasic nitrile-based inhibitor built on a cyclohexanecarboxamide scaffold [61]. This is a reversible and potent compound with more than 1100-fold selectivity for cathepsin K over other cysteine cathepsins and excellent efficacy in the ovarectomized rhesus model of osteo porosis. Whether this inhibitor will achieve greater fraction reduction efficacy in the clinical setting remains to be seen. One characteristic of bisphosphonates that one may consider advantageous over cathepsin K inhibitors is their high affinity for bone. Although cathepsin K inhibitors are being developed to target cathepsin K in the bone, where levels of this protease are much higher than in other tissues [9,63], it is not known how these compounds will affect cathepsin K in other tissues. Attempts to potentially increase the tissue selectivity of anticathepsin K drugs have not been reported.

Other antiresorptive agents under consideration for treatment of skeletal disorders include hormone-replacement therapy, selective estrogen receptor modulators (SERMs), calcitonin, monoclonal antibodies to receptor activator of NF-κB ligand (RANKL), c-src kinase inhibitors and αvβ3 inhibitors [4,6]. All of these compounds modulate bone resorption via alteration of osteoclast numbers and/or osteoclast function; thus exerting secondary inhibitory effects on bone formation. RANKL antagonists like AMG162 (denosumab) offer some promise, as they appear to have better antifracture efficacy than bisphosphonates [4,6,64]. Multiple clinical trials are currently ongoing to evaluate these agents for treatment of osteoporosis, chemotherapy-induced bone loss and skeletal metastasis [212].

Less advanced in their development are emerging anabolic therapies targeted at bone-forming osteoblast. Nevertheless, some impressive results are available from parathyroid hormone/parathyroid hormone-related peptide (PTH/PTHrP) therapies, and emerging evidence points to strontium or wnt/β-catenin signaling as promising treatment options [4,6]. Based on the differences in modes of action of antiresorptive agents such as cathepsin K and anabolic compounds like PTH/PTHrP, it is only natural to suspect that combination therapies might very well represent a future approach to restoring normal bone remodeling. This has not been confirmed in clinical studies performed so far, but several trials are ongoing to assess the efficacy of such combination therapies.

■ Targeting tumor cells in the bone: dual benefit of cathepsin K inhibitors

The unique feature of cathepsin K inhibitors that sets them apart from other antiresorptive agents is the fact that their target (i.e., cathepsin K) is not only expressed in osteoclasts, but also in bone-residing tumor cells [29-31,65], stromal cells like fibroblasts and macrophages [34,35]. A recent study by Le Gall et al. demonstrated that the nitrile-based inhibitor AFG-495 substantially reduced formation and progression of breast tumors in the bones of mice, yet had no effect on the growth of subcutaneous tumor xenografts [30]. The authors therefore suggested that the main reason for the lower skeletal tumor burden was decreased availability due to reduced bone resorption of bone-derived growth factors required for tumor growth. One has to remember, however, that the bone microenvironment is known to modulate the expression of several cysteine proteases, including cathepsins B and K, in tumor cells [65,66]. Tumor cells might not require cathepsin K to grow subcutaneously, but do express high levels of this potent collagenase when growing in the bone, both in animal models and human samples [29,31,65]. In fact, in order to grow in the skeleton, tumor cells have been proposed to acquire characteristics of bone cells [32,33]. Thus, expression of cathepsin K, a protease normally found in bone-resorbing osteoclasts, may provide the means for tumor cells to thrive in the bone. This concept is further supported by the ability of prostate tumor cells to directly degrade collagen I, the organic matrix of the bone [66]. Tumor-associated macrophages and fibroblasts represent other contributing factors to tumor progression [36,37,67,68]. Whether expression and secretion of cathepsin K by these cells plays functional significance in colonization and progression of tumors in the bone remains to be determined. However, it is plausible to hypothesize that by targeting multiple cell types (i.e., osteoclasts, tumor cells, macrophages) that are known to interact with each other in the vicious cycle of bone metastasis, cathepsin K inhibitors may offer an unique advantage in the treatment of patients with skeletal diseases.

Biological link between osteoporosis & atherosclerosis: cathepsin K inhibitors as a combined therapy for both?

■ Osteoporosis & vascular calcification

Vascular calcification, a key manifestation of atherosclerosis, is a tightly regulated process with similarities to bone remodeling [1,2,69]. Several proteins implicated in normal bone metabolism (e.g., osteocalcin, osteonectin, osteoprotegrin, bone morphogenic protein and collagen I) have also been shown to localize to the arterial wall and the artherosclerotic plaque [70,71]. Mice deficient in osteoprotegrin, an indirect inhibitor of osteoclastogenesis, have both severe osteoporosis and extensive arterial calcification [72]. Interestingly, calcification of the aorta has been shown to correlate with incidence of vertebral fractures and low BMD in human subjects, and is considered to be an independent predictor of cardiovascular mortality [1,2]. In addition, lipid derangements like high plasma levels of low-density lipoprotein (LDL) and low levels of high-density lipoprotein, risk factors for atherosclerosis, have now been linked to low BMD in postmenopausal women [73]. One example of the potential association between osteoporosis and atherosclerosis are antiresorptive treatments like estrogen replacement therapies and bisphosphonates, which appear to have cardio-protective effects as exhibited by a positive impact on lipid metabolism and reduced atherosclerotic plaque formation [1,2]. Furthermore, recent studies with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have reported beneficial effects of these antilipidemic and cholesterol-lowering drugs on BMD and the healing of fractures [1,2,74,75]. Results of human trials assessing anabolic effects of statins are at this point controversial [76,77]. However, two comprehensive analyses of clinical studies on statins and BMD suggested that low systemic bioavailability of statins, their diversity (i.e., lipophilic vs hydrophilic compounds) and the administered dose may be reasons for reported discrepancies [75,78]. Statins are safe, readily available and inexpensive drugs that have already been well-characterized for their cardio-protective effects. Since several studies point to their beneficial fracture-healing effects, both by anabolic and bone-resorptive mechanisms [75,78], statins deserve further investigation in the context of association between osteoporosis and atherosclerosis.

■ Atherosclerotic plaque formation & stability: a role of cathepsin K

Extracellular matrix remodeling plays a central role in the development and progression of cardiovascular disease. Extensive destruction of elastin and collagen due to overexpression of cathepsins K and S has been linked to damage and inflammation of the arterial wall, resulting in plaque formation [9,11,79]. Based on the findings that human atheromas, but not healthy blood vessels, contain cathepsin K-positive macrophages, smooth muscle cells and endothelial cells, the role of this collagenase in atherosclerosis has been further explored [80]. A functional involvement of cathepsin K in atherogenesis was revealed using apolipoprotein (ApoE)/cathepsin K-null mice [81,82]. Initial reports demonstrated that cathepsin K deficiency reduces progression of atherosclerotic plaques and induces plaque fibrosis, but aggravates formation of macrophage foam cells. A subsequent study from Samokhin et al. utilized a more aggressive pro-inflammatory atherosclerosis apoE-deficiency model, in which a high fat diet was supplemented with cholate to increase proteolytic destruction of the elastic tunica media [83]. In this model, cathepsin K deficiency resulted in reduced collagen degradation in the plaque and higher stability to rupture, indicating a significant role of this protease in remodeling of the brachiocephalic artery. The thickness of the fibrous cap and the numbers of buried caps, the major determinants of plaque stability, clearly correlated with expression of cathepsin K. Elevated levels of apoptosis in vascular smooth muscle cells and macrophages were found in cathepsin K-expressing mice. Since vascular smooth muscle cells apoptosis was recently shown to be mediated by collagen degradation products, it is likely that one positive effect of cathepsin K deficiency on plaque stability is due to inhibition of collagen degradation [84,85].

More evidence for the pro-atherogenic properties of cathepsin K came from studies demonstrating that macrophage- and smooth muscle-derived cysteine cathepsins, including cathepsin K, act on LDL particles to form potentially cytotoxic lipid deposits [11,86,87]. Sites in Apo B-100 cleaved by cysteine cathepsins have been identified and associated with changes in the structure of LDL particles [87]. In addition, cathepsin K deficiency has been shown to lead to increases in modified LDL uptake and storage whereas extracellular activity of this protease has been linked to reduced cholesterol efflux, findings further substantiating its proatherosclerotic role [11].

Although increased levels of cathepsin K have been observed during formation of neointima in patients with severe vascular disease, levels of cystatin C, a natural inhibitor of cathepsin K are also significantly decreased [88]. Similarly, a lack of cystatin C in ApoE-deficient mice showed a promoting effect on plaque formation [89]. Although the mechanisms by which cystatin C deficiency affects progression of atherosclerosis are not well understood, it appears that increases in plaque size or increases in elastinolytic activity are major contributing factors [11].


Cholesterol and lipid-lowering drugs that are currently being used for the treatment of osteoporosis

Despite the abovementioned indications that inhibition of cathepsin K may have beneficial effects on cardiovascular health, experimental proof is still limited and reports in the literature are controversial. Recently Guo et al. reported on the effects of cell-specific cathepsin K inhibition on atherosclerotic plaque formation and stability [90]. The authors used an atherosclerotic mouse model, in which bone marrow from cathepsin K-deficient mice was transplanted into x-ray irradiated LDL receptor-deficient mice. By targeting cathepsin K in leukocytes, the authors demonstrated an increased number of macrophages in the plaques and enhanced uptake of lipoproteins via caveolin-1-dependent mechanisms. In addition, cathepsin K deficiency in bone marrow-derived macrophages inhibited their elastinolytic activity, affected smooth muscle cell (SMC) migration and subsequent collagen deposition. This suggested a negative rather than positive effect for cathepsin K inhibition on plaque stability, a result, which was contradictory to the previous report by Samokhin et al. [83], but in agreement with the study by Lutgens et al. [81].

Given the above discrepancies, will cathepsin K inhibition have a protective or promoting effect on atherogenesis? In a recent editorial, Hofnagel et al. points out that despite the negative effect on plaque stability, cathepsin K deficiency in the Lutgens et al. study resulted in almost 50% reduction of the total plaque area [91]. This suggests possible therapeutic implications for anticathepsin K drugs in atherosclerosis treatment. The authors suggest that combining anticathepsin K therapies with lipid-lowering agents might counteract the adverse plaque-destabilizing effects. Clearly, more studies are needed to determine the effects of cathepsin K on plaque formation and stability. There are currently no human studies investigating the effects of cathepsin K inhibitors on cardio vascular health. Assessment of human patients that have been treated with cathepsin K inhibitors for osteoporosis would be invaluable to our under-standing of cathepsin K-dependent association between osteoporosis and atherosclerosis.

■ Atherosclerosis & osteoporosis: the inflammatory link

Inflammation plays a key role in all stages of atherosclerosis and has certainly been implicated in accelerated bone resorption [2,92]. Activation of nuclear factor κB (NF-κB) in osteoclasts in bone and macrophages within arterial walls has been proposed as one of the most crucial events linking osteoporosis and atherosclerosis [2,13,14]. The RANKL is a key stimulator of cathepsin K expression [15,93]. The imbalance in serum levels of cathepsin K and osteoprotegrin, a decoy receptor for RANKL, has been correlated with progression of autoimmune rheumatoid arthritis [94]. Since cathepsin K may have pro-atherogenic properties and osteoprotegrin may play a protective role in pathological calcification [3,95], it would be interesting to assess whether the balance between these two proteins impacts the correlation between osteoporosis and atherosclerosis.

Clinical evidence supports the involvement of proinflammatory cytokines in the development and progression of atherosclerosis, processes that overlap with inflammatory/immunologic responses observed in conditions like rheumatoid arthritis [96]. Destructive proinflammatory cascades involving cytokines, such as IL-1, IL-6, IL-8 and TNF-α, produced locally in inflamed joints or at the systemic level, are known to amplify atherosclerosis on multiple levels. Protease–chemokine interactions, complex events affected by the microenvironment, are also bound to influence the progression of cardiovascular disease [97]. Our recent data suggest that cathepsin K might interact with several proinflammatory factors, including IL-6 and IL-8 [Podgorski I et al., Manuscript Submitted]. Interestingly, the 5′-untranslated region of cathepsin K contains a response element for IL-6 consistent with a regulatory role for this protease in IL-6 production [98]. How inhibition of cathepsin K would affect the function of pro-inflammatory cytokines in atherosclerotic plaque formation is currently unknown.

This intricate association between inflammation, bone density and atherosclerosis is further complicated by metabolic factors like adiposity. Associated with adiposity are levels of adipo nectin, a fat hormone, which plays a role in regulation of bone formation through interaction with its receptors on osteoblasts and osteoclasts [99,100]. Levels of adiponectin inversely correlate with obesity, which has important implications for both atherosclerosis and BMD [2]. Adiponectin has a protective function in cardiovascular disease, as highlighted by the evidence of increased atherosclerotic plaque formation in adiponectin-null mice following vascular injury [101,102]. Adiponectin increases insulin sensitivity and decreases hepatic glucogenesis and muscle triglycerides [2]. The biological activity of adiponectin is modulated by its cleavage; it is the full-length protein that has anti-inflammatory, antitumorigenic and anti-angiogenic properties [12]. We have previously reported that adiponectin is a cathepsin K substrate [12]. Given the fact that cathepsin K-null animals appear to be resistant to diet-induced obesity, it is plausible to speculate that proteolytic processing of adiponectin might have a negative effect on its bioactivity [10].

Above are just a few examples of potential interactions that might represent common biological links between osteoporosis and athero-sclerosis. Cathepsin K appears to play a role in many aspects of this complex network of factors and pathways that negatively affect bone metabolism and vasculature (Figure 1). Certainly further studies are needed to validate a cathepsin K-dependent association between skeletal and cardiovascular pathologies, and implications of this association for therapies.

Figure 1
Common themes in osteoporosis and atherosclerosis: involvement of cathepsin K

Anticathepsin K drugs: future perspective

There is no doubt that cathepsin K is a valid and attractive target for therapies against osteoporosis and other skeletal pathologies. Since its discovery over a decade ago, this protease has proven to be a major player in bone remodeling. Although there are currently no approved anticathepsin K drugs, promising clinical results with odanacatib, and vigorous pharmaceutical industry efforts to develop new and more selective agents that are effective inhibitors of osteoclastic bone resorption, offer much hope. Clinical data demonstrating that cathepsin K inhibitors not only inhibit bone resorption, but also allow bone formation to continue, further underscore their viability for future therapies. At least in the case of antiosteoporosis treatments, there is likely to be an approved anticathepsin K compound in the clinic in the foreseeable future. Furthermore, based on experimental data that demonstrates the efficacy of cathepsin K inhibitors in reducing skeletal tumor burden, applications of these agents in the treatment of patients with bone metastasis are likely to follow.

The future of therapeutics for skeletal pathologies likely lies in combination treatments that will reduce fracture incidence and shift the balance toward bone formation, which is not possible with current single drug-based therapies. One option might be combining two or more antiresorptive therapies that differentially affect osteoclast-mediated bone remodeling. For example, use of paclitaxel (anti-cell-cycle drug), and imatinib (a tyrosine kinase inhibitor that targets macrophage colony stimulating factor [M-CSF]receptor in osteoclasts) was recently shown to increase the inhibitory effect of the bisphosphonate zoledronic acid on growth of bone tumors in animals [8]. A combination of antiresorptive agents with anabolic compounds that produce substantial reversal of bone mass might offer an even better potential to revolutionize the treatment of osteoporosis and other skeletal disorders. Impressive results have already emerged from sequential therapies combining parathyroid hormone and bisphosphonates [103,104]. The use of parathyroid hormone as a treatment for osteoporosis is limited to 2 years or less, and its effects on bone density appear to be lost after discontinuation of therapy [104]. Sequential use of antiresorptive therapy is needed to consolidate the gains made in trabecular and cortical bone density during PTH treatment. Given the effectiveness and antiresorptive properties of cathepsin K inhibitors, they are likely candidates for future combination therapies targeting p athologies associated with increased bone resorption.

Finally, as anticathepsin K drugs are closer to the clinic than they have ever been before, studies will begin to emerge that assess their effects on physiological and pathophysio logical processes other than bone resorption. Given the association cathepsin K has with inflammation, cardiovascular disease and metabolic disorders, anticathepsin K drugs are likely to be investigated in the context of these pathologies. In particular, evidence of correlations between low bone density and athero sclerosis suggests intriguing future applications for inhibitors of this potent protease. Owing to its position within a network of inflammatory and metabolic factors, cathepsin K might be a better target for inhibition than more general molecules with systemic implications, like proinflammatory cytokines. It is certain that in the short term, numerous anticathepsin K agents will be used as mechanism-based drugs to validate existing hypotheses and identify novel functions/pathways for cathepsin K in various pathologies. Vigorous research and time will determine whether some of these agents will become future disease-modifying therapeutics.

Executive summary

  • There is a biological association between low bone density and cardiovascular health.
  • Cathepsin K is a key protease responsible for osteoclastic bone resorption.
  • Conditions associated with pathological bone loss (e.g., osteoporosis, osteoarthritis, rheumatoid arthritis, bone metastasis) have been linked to increased cathepsin K expression and activity.
  • Cathepsin K is a pharmaceutical industry target for treatment of osteoporosis.
  • Challenges in designing selective cathepsin K inhibitors derive from their lysosomotropic nature.
  • Most promising anticathepsin K agents today are nitrile-based, non-basic compounds like odanacatib, currently in Phase III clinical trials,
  • Cathepsin K inhibitors offer an advantage over other antiresorptive drugs by reducing bone resorption, but inhibiting bone formation to a lesser extent.
  • Cathepsin K plays a functional role in atherogenesis, and its deficiency reduces plaque formation and plaque rupture.
  • Cathepsin K is associated with obesity and inflammation, major contributors to skeletal and vascular health.
  • Cathepsin K may be a common link between skeletal disorders and atherosclerosis.


I would like to thank Drs Bonnie F, Sloane and Karin List for critically reviewing this manuscript.


Financial & competing interests disclosure Dr Podgorski’s research is supported by the Department of Defense DOD PC074031 (I Podgorski) and National Institutes of Health R01 CA 56586 (BF Sloane). The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.


Papers of special note have been highlighted as:

of interest

■■ of considerable interest

1. Burnett JR, Vasikaran SD. Cardiovascular disease and osteoporosis: is there a link between lipids and bone? Ann. Clin. Biochem. 2002;39:203–210. [PubMed]
2. Hamerman D. Osteoporosis and atherosclerosis: biological linkages and the emergence of dual-purpose therapies. Q. J. Med. 2005;98:467–484. [PubMed]Comprehensive review on clinical inter-relations between osteoporosis and atherosclerosis.
3. Van Campenhout A, Golledge J. Osteoprotegerin, vascular calcification and atherosclerosis. Atherosclerosis. 2008 DOI: 10.1016/j.atherosclerosis.2008.09.033. (Epub ahead of print)
4. Grey A. Emerging pharmacologic therapies for osteoporosis. Expert Opin. Emerg. Drugs. 2007;12:493–508. [PubMed]Review on current antiresorptive and anabolic treatments for osteoporosis.
5. Suzuki A, Sekiguchi S, Asano S, Itoh M. Pharmacological topics of bone metabolism: recent advances in pharmacological management of osteoporosis. J. Pharmacol. Sci. 2008;106:530–535. [PubMed]
6. Gasser JA. The relative merits of anabolics versus antiresorptive compounds: where our targets should be, and whether we are addressing them. Curr. Opin Pharmacol. 2006;6:313–318. [PubMed]
7. Stoch SA, Wagner JA. Cathepsin K inhibitors: a novel target for osteoporosis therapy. Clin. Pharmacol. Ther. 2008;83:172–176. [PubMed]Analysis of human anti-osteoporosis studies with balicatib and odanacatib.
8. Le Gall C, Bonnelye E, Clezardin P. Cathepsin K inhibitors as treatment of bone metastasis. Curr. Opin. Support Palliat. Care. 2008;2:218–222. [PubMed]
9. Lecaille F, Bromme D, Lalmanach G. Biochemical properties and regulation of cathepsin K activity. Biochimie. 2008;90:208–226. [PubMed]Comprehensive review of current knowledge on the regulation, properties and physiological and pathophysiological implications of cathepsin K.
10. Funicello M, Novelli M, Ragni M, et al. Cathepsin K null mice show reduced adiposity during the rapid accumulation of fat stores. PLoS ONE. 2007;2(1):E683. [PubMed]First paper to report that cathepsin K-deficient mice are resistant to diet-induced obesity.
11. Lutgens SP, Cleutjens KB, Daemen MJ, Heeneman S. Cathepsin cysteine proteases in cardiovascular disease. FASEB J. 2007;21:3029–3041. [PubMed]Review on the roles of cysteine cathepsins, including cathepsin K, in cardiovascular disease.
12. Podgorski I, Linebaugh BE, Sloane BF. Cathepsin K in the bone microenvironment: link between obesity and prostate cancer? Biochem. Soc. Trans. 2007;35:701–703. [PubMed]
13. Kiechl S, Werner P, Knoflach M, Furtner M, Willeit J, Schett G. The osteoprotegerin/RANK/RANKL system: a bone key to vascular disease. Expert. Rev. Cardiovasc. Ther. 2006;4:801–811. [PubMed]
14. Montecucco F, Steffens S, Mach F. The immune response is involved in atherosclerotic plaque calcification: could the RANKL/RANK/OPG system be a marker of plaque instability? Clin. Dev. Immunol. 2007;2007:75805. [PMC free article] [PubMed]
15. Troen BR. The regulation of cathepsin K gene expression. Ann. N. Y. Acad. Sci. 2006;1068:165–172. [PubMed]
16. Desmarais S, Black WC, Oballa R, et al. Effect of cathepsin K inhibitor basicity on in vivo off-target activities. Mol. Pharmacol. 2008;73:147–156. [PubMed]
17. Yasuda Y, Kaleta J, Brömme D. The role of cathepsins in osteoporosis and arthritis: rationale for the design of new therapeutics. Adv. Drug. Deliv. Rev. 2005;57:973–993. [PubMed]
18. Saftig P, Hunziker E, Everts V, et al. Functions of cathepsin K in bone resorption. Lessons from cathepsin K deficient mice. Adv. Exp. Med. Biol. 2000;477:293–303. [PubMed]
19. Turk B. Targeting proteases: successes, failures and future prospects. Nat. Rev. Drug Discov. 2006;5:785–799. [PubMed]Comprehensive review on the status of protease research and prospects of protease-targeted drugs.
20. Salminen-Mankonen HJ, Morko J, Vuorio E. Role of cathepsin K in normal joints and in the development of arthritis. Curr. Drug. Targets. 2007;8:315–323. [PubMed]
21. Li Z, Yasuda Y, Li W, et al. Regulation of collagenase activities of human cathepsins by glycosaminoglycans. J. Biol. Chem. 2004;279:5470–5479. [PubMed]
22. Li Z, Kienetz M, Cherney MM, James MN, Brömme D. The crystal and molecular structures of a cathepsin K:chondroitin sulfate complex. J. Mol. Biol. 2008;383:78–91. [PubMed]
23. Konttinen YT, Takagi M, Mandelin J, et al. Acid attack and cathepsin K in bone resorption around total hip replacement prosthesis. J. Bone Miner. Res. 2001;16:1780–1786. [PubMed]
24. Skoumal M, Haberhauer G, Kolarz G, Hawa G, Woloszczuk W, Klingler A. Serum cathepsin K levels of patients with longstanding rheumatoid arthritis: correlation with radiological destruction. Arthritis Res. Ther. 2005;7:R65–R70. [PMC free article] [PubMed]
25. Hsieh CS, deRoos P, Honey K, Beers C, Rudensky AY. A role for cathepsin L and cathepsin S in peptide generation for MHC class II presentation. J. Immunol. 2002;168:2618–2625. [PubMed]
26. Shi GP, Bryant RA, Riese R, et al. Role for cathepsin F in invariant chain processing and major histocompatibility complex class II peptide loading by macrophages. J. Exp. Med. 2000;191:1177–1186. [PMC free article] [PubMed]
27. Asagiri M, Hirai T, Kunigami T, et al. Cathepsin K-dependent Toll-like receptor 9 signaling revealed in experimental arthritis. Science. 2008;319:624–627. [PubMed]First paper to report involvement of cathepsin K in the regulation of Toll-like receptors.
28. Godat E, Lecaille F, Desmazes C, et al. Cathepsin K: a cysteine protease with unique kinin-degrading properties. Biochem. J. 2004;383:501–506. [PMC free article] [PubMed]
29. Brubaker KD, Vessella RL, True LD, Thomas R, Corey E. Cathepsin K mRNA and protein expression in prostate cancer progression. J. Bone Miner. Res. 2003;18:222–230. [PubMed]Demonstrates the expression of cathepsin K in human samples from bone metastasis patients.
30. Le Gall C, Bellahcène A, Bonnelye E, et al. A cathepsin K inhibitor reduces breast cancer induced osteolysis and skeletal tumor burden. Cancer Res. 2007;67:9894–9902. [PubMed]
31. Littlewood-Evans AJ, Bilbe G, Bowler WB, et al. The osteoclast-associated protease cathepsin K is expressed in human breast carcinoma. Cancer Res. 1997;57:5386–5390. [PubMed]First paper to report cathepsin K expression in human breast cancer cells.
32. Chung LW, Huang WC, Sung SY, et al. Stromal-epithelial interaction in prostate cancer progression. Clin. Genitourin. Cancer. 2006;5:162–170. [PubMed]
33. Huang WC, Xie Z, Konaka H, Sodek J, Zhau HE, Chung LW. Human osteocalcin and bone sialoprotein mediating osteomimicry of prostate cancer cells: role of cAMP-dependent protein kinase A signaling pathway. Cancer Res. 2005;65:2303–2313. [PubMed]
34. Acuff HB, Sinnamon M, Fingleton B, et al. Analysis of host- and tumor-derived proteinases using a custom dual species microarray reveals a protective role for stromal matrix metalloproteinase-12 in non-small cell lung cancer. Cancer Res. 2006;66:7968–7975. [PubMed]
35. Rapa I, Volante M, Cappia S, Rosas R, Scagliotti GV, Papotti M. Cathepsin K is selectively expressed in the stroma of lung adenocarcinoma but not in bronchioloalveolar carcinoma. A useful marker of invasive growth. Am. J. Clin. Pathol. 2006;125:847–854. [PubMed]
36. Kleer CG, Bloushtain-Qimron N, Chen YH, et al. Epithelial and stromal cathepsin K and CXCL14 expression in breast tumor progression. Clin. Cancer Res. 2008;14:5357–5367. [PMC free article] [PubMed]
37. Quintanilla-Dieck MJ, Codriansky K, Keady M, Bhawan J, Rünger TM. Cathepsin K in melanoma invasion. J. Invest. Dermatol. 2008;128:2281–2288. [PubMed]
38. Mohamed MM, Sloane BF. Cysteine cathepsins: multifunctional enzymes in cancer. Nat. Rev. Cancer. 2006;6:764–775. [PubMed]
39. Hahne JC, Okuducu AF, Sahin A, Fafeur V, Kiriakidis S, Wernert N. The transcription factorets-1: its role in tumour development and strategies for its inhibition. Mini. Rev. Med. Chem. 2008;8:1095–1105. [PubMed]
40. Seth A, Watson DK. ETS transcription factors and their emerging roles in human cancer. Eur. J. Cancer. 2005;41:2462–2478. [PubMed]
41. Grabowskal U, Chambers TJ, Shiroo M. Recent developments in cathepsin K inhibitor design. Curr. Opin. Drug Discov. Devel. 2005;8:619–630. [PubMed]Review on design of cathepsin K inhibitors.
42. Marquis RW, Ru Y, LoCastro SM, et al. Azepanone-based inhibitors of human and rat cathepsin K. J. Med. Chem. 2001;44:1380–1395. [PubMed]
43. McQueney MS, Feild J, Hanning CR, et al. Cynomolgus monkey (Macaca fascicularis) cathepsin K: cloning, expression, purification, and activation. Protein Expr. Purif . 1998;14:387–394. [PubMed]
44. Stroup GB, Lark MW, Veber DF, et al. Potent and selective inhibition of human cathepsin K leads to inhibition of bone resorption in vivo in a nonhuman primate. J. Bone Miner. Res. 2001;16:1739–1746. [PubMed]
45. Kumar S, Dare L, Vasko-Moser JA, et al. A highly potent inhibitor of cathepsin K (relacatib) reduces biomarkers of bone resorption both in vitro and in an acute model of elevated bone turnover in vivo in monkeys. Bone. 2007;40:122–131. [PubMed]
46. James IE, Lark MW, Zembryki D, et al. Development and characterization of a human in vitro resorption assay: demonstration of utility using novel antiresorptive agents. J. Bone Miner. Res. 1999;14:1562–1569. [PubMed]
47. Votta BJ, Levy MA, Badger A, et al. Peptide aldehyde inhibitors of cathepsin K inhibit bone resorption both in vitro and in vivo. J. Bone Miner. Res. 1997;12:1396–1406. [PubMed]
48. Falgueyret JP, Black WC, Cromlish W, et al. An activity-based probe for the determination of cysteine cathepsin protease activities in whole cells. Anal. Biochem. 2004;335:218–227. [PubMed]
49. Otto HH, Schirmeister T. Cysteine proteases and their inhibitors. Chem. Rev. 1997;97:133–172. [PubMed]
50. Black WC, Percival MD. The consequences of lysosomotropism on the design of selective cathepsin K inhibitors. Chembiochem. 2006;7:1525–1535. [PubMed]Paper on lysosomotropism, an important issue in the design of cathepsin K inhibitors.
51. Gauthier JY, Chauret N, Cromlish W, et al. The discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin K. Bioorg. Med. Chem. Lett. 2008;18:923–928. [PubMed]Covers the discovery and properties of the most successful cathepsin K inhibitor to date.
52. Adami S, Supronik J, Hala T, et al. Effect of one year treatment with the cathepsin K inhibitor, balicatib, on bone mineral density (BMD) in postmenopausal women with osteopenia/osteoporosis. J. Bone Miner. Res. 2006;21:S24.
53. Falgueyret JP, Desmarais S, Oballa R, et al. Lysosomotropism of basic cathepsin K inhibitors contributes to increased cellular potencies against off-target cathepsins and reduced functional selectivity. J. Med. Chem. 2005;48:7535–7543. [PubMed]
54. Li CS, Deschenes D, Desmarais S, et al. Identification of a potent and selective non-basic cathepsin K inhibitor. Bioorg. Med. Chem. Lett. 2006;16:1985–1989. [PubMed]
55. Ramirez G, Jensen AB, Olmeo N, et al. Effect of cathepsin K inhibition on supression of bone resorption in women with breast cancer and established bone metastases in a 4-week, double-blind, randomized controlled trial. Presented at: 2008 Breast Cancer Symposium; Washington, DC, USA. 5–7 September 2008.
56. Bonnick SL. Osteoporosis in men and women. Clin. Cornerstone. 2006;8:28–39. [PubMed]
57. Rosen CJ, Bouxsein ML. Mechanisms of disease: is osteoporosis the obesity of bone? Nat. Clin. Pract. Rheumatol. 2006;2:35–43. [PubMed]
58. Coleman RE. Risks and benefits of bisphosphonates. Br. J. Cancer. 2008;98:1736–1740. [PMC free article] [PubMed]
59. Kavanagh KL, Guo K, Dunford JE, et al. The molecular mechanism of nitrogen-containing bisphosphonates as antiosteoporosis drugs. Proc. Natl Acad. Sci. USA. 2006;103:7829–7834. [PMC free article] [PubMed]
60. Rondeau JM, Bitsch F, Bourgier E, et al. Structural basis for the exceptional in vivo efficacy of bisphosphonate drugs. ChemMedChem. 2006;1:267–273. [PubMed]
61. Robichaud J, Black WC, Therien M, et al. Identification of a nonbasic, nitrile-containing cathepsin K inhibitor (MK-1256) that is efficacious in a monkey model of osteoporosis. J. Med. Chem. 2008;51:6410–6420. [PubMed]First report on the newest cathepsin K inhibitor, MK-1256.
62. Palermo C, Joyce JA. Cysteine cathepsin proteases as pharmacological targets in cancer. Trends Pharmacol. Sci. 2008;29:22–28. [PubMed]Perspective on cysteine proteases, including cathepsin K, as therapeutic targets in cancer.
63. Brömme D, Okamoto K. Human cathepsin O2, a novel cysteine protease highly expressed in osteoclastomas and ovary molecular cloning, sequencing and tissue distribution. Biol. Chem. Hoppe-Seyler. 1995;376:379–384. [PubMed]
64. Smith MR. Osteoclast targeted therapy for prostate cancer: bisphosphonates and beyond. Urol. Oncol. 2008;26:420–425. [PMC free article] [PubMed]
65. Podgorski I, Linebaugh B, Cher M, Bromme D, Sloane B. Cathepsin K in osteoclasts and prostate tumor cells. J. Bone Miner. Res. 2005;20:47.
66. Podgorski I, Linebaugh BE, Sameni M, et al. Bone microenvironment modulates expression and activity of cathepsin B in prostate cancer. Neoplasia. 2005;7:207–223. [PMC free article] [PubMed]
67. Condeelis J, Pollard JW. Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell. 2006;124:263–266. [PubMed]
68. Pollard JW. Tumour-educated macrophages promote tumour progression and metastasis. Nat. Rev. Cancer. 2004;4:71–78. [PubMed]
69. Varma R, Aronow WS, Basis Y, et al. Relation of bone mineral density to frequency of coronary heart disease. Am. J. Cardiol. 2008;101:1103–1104. [PubMed]
70. Dhore CR, Cleutjens JP, Lutgens E, et al. Differential expression of bone matrix regulatory proteins in human atherosclerotic plaques. Arterioscler. Thromb. Vasc. Biol. 2001;21:1998–2003. [PubMed]
71. Parhami F, Morrow AD, Balucan J, et al. Lipid oxidation products have opposite effects on calcifying vascular cell and bone cell differentiation. A possible explanation for the paradox of arterial calcification in osteoporotic patients. Arterioscler Thromb Vasc Biol. 1997;17:680–687. [PubMed]
72. Bucay N, Sarosi I, Dunstan CR, et al. Osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev. 1998;12:1260–1268. [PMC free article] [PubMed]
73. Yamaguchi T, Sugimoto T, Yano S, et al. Plasma lipids and osteoporosis in postmenopausal women. Endocr. J. 2002;49:211–217. [PubMed]
74. Mundy G, Garrett R, Harris S, et al. Stimulation of bone formation in vitro and in rodents by statins. Science. 1999;286:1946–1949. [PubMed]
75. Tang QO, Tran GT, Gamie Z, et al. Statins: under investigation for increasing bone mineral density and augmenting fracture healing. Expert Opin. Investig. Drugs. 2008;17:1435–1463. [PubMed]Comprehensive ana lysis of clinical trials assessing effects of statins on bone mineral density (BMD).
76. Bone HG, Kiel DP, Lindsay RS, et al. Effects of atorvastatin on bone in postmenopausal women with dyslipidemia: a double-blind, placebo-controlled, dose-ranging trial. J. Clin. Endocrinol. Metab. 2007;92:4671–4677. [PubMed]
77. Rejnmark L, Buus NH, Vestergaard P, et al. Effects of simvastatin on bone turnover and BMD: a 1-year randomized controlled trial in postmenopausal osteopenic women. J. Bone Miner. Res. 2004;19:737–744. [PubMed]
78. Uzzan B, Cohen R, Nicolas P, Cucherat M, Perret GY. Effects of statins on bone mineral density: a meta-analysis of clinical studies. Bone. 2007;40:1581–1587. [PubMed]Meta-ana lysis of clinical trials assessing effects of statins on BMD.
79. Liu J, Sukhova GK, Sun JS, Xu WH, Libby P, Shi GP. Lysosomal cysteine proteases in atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 2004;24:1359–1366. [PubMed]
80. Platt MO, Ankeny RF, Shi GP, et al. Expression of cathepsin K is regulated by shear stress in cultured endothelial cells and is increased in endothelium in human atherosclerosis. Am. J. Physiol. Heart Circ. Physiol. 2007;292:H1479–H1486. [PubMed]
81. Lutgens E, Lutgens SP, Faber BC, et al. Disruption of the cathepsin K gene reduces atherosclerosis progression and induces plaque fibrosis but accelerates macrophage foam cell formation. Circulation. 2006;113:98–107. [PubMed]Study suggesting cathepsin K deficiency compromises plaque stability.
82. Lutgens SP, Kisters N, Lutgens E, et al. Gene profiling of cathepsin K deficiency in atherogenesis: profibrotic but lipogenic. J. Pathol. 2006;210:334–343. [PubMed]
83. Samokhin AO, Wong A, Saftig P, Bromme D. Role of cathepsin K in structural changes in brachiocephalic artery during progression of atherosclerosis in apoE-deficient mice. Atherosclerosis. 2008;200:58–68. [PubMed]Demonstrates the beneficial effects of cathepsin K deficiency on cardiovascular health.
84. Clarke MC, Figg N, Maguire JJ, et al. Apoptosis of vascular smooth muscle cells induces features of plaque vulnerability in atherosclerosis. Nat. Med. 2006;12:1075–1080. [PubMed]
85. von Wnuck Lipinski K, Keul P, Lucke S, et al. Degraded collagen induces calpain-mediated apoptosis and destruction of the X-chromosome-linked inhibitor of apoptosis (xIAP) in human vascular smooth muscle cells. Cardiovasc. Res. 2006;69:697–705. [PubMed]
86. Pentikainen MO, Oorni K, Ala-Korpela M, Kovanen PT. Modified LDL – trigger of atherosclerosis and inflammation in the arterial intima. J. Intern. Med. 2000;247:359–370. [PubMed]
87. Linke M, Gordon RE, Brillard M, Lecaille F, Lalmanach G, Bromme D. Degradation of apolipoprotein B-100 by lysosomal cysteine cathepsins. Biol. Chem. 2006;387:1295–1303. [PubMed]
88. Shi GP, Sukhova GK, Grubb A, et al. Cystatin C deficiency in human atherosclerosis and aortic aneurysms. J. Clin. Invest. 1999;104:1191–1197. [PMC free article] [PubMed]
89. Bengtsson E, To F, Grubb A, et al. Absence of the protease inhibitor cystatin C in inflammatory cells results in larger plaque area in plaque regression of apoE-deficient mice. Atherosclerosis. 2005;180:45–53. [PubMed]
90. Guo J, Bot I, de Nooijer R, et al. Leucocyte cathepsin K affects atherosclerotic lesion composition and bone mineral density in low-density lipoprotein receptor deficient mice. Cardiovasc. Res. 2009;81:278–285. [PubMed]
91. Hofnagel O, Robenek H. Cathepsin K: boon or bale for atherosclerotic plaque stability? Cardiovasc. Res. 2009;81:242–243. [PubMed]Editorial on the potential effects of anticathepsin K therapies on plaque stability and atherogenesis.
92. Silva TA, Garlet GP, Fukada SY, Silva JS, Cunha FQ. Chemokines in oral inflammatory diseases: apical periodontitis and periodontal disease. J. Dent. Res. 2007;86:306–319. [PubMed]
93. Kollet O, Dar A, Shivtiel S, et al. Osteoclasts degrade endosteal components and promote mobilization of hematopoietic progenitor cells. Nat. Med. 2006;12:657–664. [PubMed]
94. Skoumal M, Haberhauer G, Kolarz G, et al. The imbalance between osteoprotegerin and cathepsin K in the serum of patients with longstanding rheumatoid arthritis. Rheumatol. Int. 2008;28:637–641. [PubMed]
95. Schoppet M, Preissner KT, Hofbauer LC. RANK ligand and osteoprotegerin: paracrine regulators of bone metabolism and vascular function. Arterioscler. Thromb. Vasc. Biol. 2002;22:549–553. [PubMed]
96. Libby P. Role of inflammation in atherosclerosis associated with rheumatoid arthritis. Am. J. Med. 2008;121:S21–S31. [PubMed]
97. Wolf M, Albrecht S, Marki C. Proteolytic processing of chemokines: implications in physiological and pathological conditions. Int. J. Biochem. Cell Biol. 2008;40:1185–1198. [PubMed]
98. Rood JA, Van Horn S, Drake FH, Gowen M, Debouck C. Genomic organization and chromosome localization of the human cathepsin K gene (CTSK) Genomics. 1997;41:169–176. [PubMed]
99. Barb D, Pazaitou-Panayiotou K, Mantzoros CS. Adiponectin: a link between obesity and cancer. Expert Opin. Investig. Drugs. 2006;15:917–931. [PubMed]Review implicating adiponectin in inflammation, obesity and cancer progression.
100. Shinoda Y, Yamaguchi M, Ogata N, et al. Regulation of bone formation by adiponectin through autocrine/paracrine and endocrine pathways. J. Cell. Biochem. 2006;99:196–208. [PubMed]
101. Kubota N, Terauchi Y, Yamauchi T, et al. Disruption of adiponectin causes insulin resistance and neointimal formation. J. Biol. Chem. 2002;277:25863–25866. [PubMed]
102. Beltowski J, Jamroz-Wisniewska A, Widomska S. Adiponectin and its role in cardiovascular diseases. Cardiovasc. Hematol. Disord. Drug Targets. 2008;8:7–46. [PubMed]
103. Bilezikian JP. Combination anabolic and antiresorptive therapy for osteoporosis: opening the anabolic window. Curr. Osteoporos. Rep. 2008;6:24–30. [PubMed]
104. Black DM, Bilezikian JP, Ensrud KE, et al. One year of alendronate after one year of parathyroid hormone (1–84) for osteoporosis. N. Engl. J. Med. 2005;353:555–565. [PubMed]Paper reporting on the effectiveness of sequential antiresorptive therapies following parathyroid hormone treatment.
201. Odanacatib, Merck’s investigational cathepsin K inhibitor, increased bone mineral density (BMD) over two years at key fracture sites in Phase IIB study. www.merck.com/newsroom/press_releases/research_and_development/2008_0916.html.
202. BMD efficacy and safety of odanacatib in postmenopausal women. www.clinicaltrials.gov/ct2/show/NCT00729183?term=odanacatib&rank=2.
203. A Study of MK0822 in postmenopausal women with osteoporosis to assess fracture risk reduction. www.clinicaltrials.gov/ct2/show/NCT00529373?term=odanacatib&rank=4.
204. A study to assess the effects of MK0822 in reducing the risk of bone metastasis in women with breast cancer. www.clinicaltrials.gov/ct2/show/NCT00692458?term=odanacatib&rank=5.
205. A study to assess the effects of MK0822 in prolonging time to first bone metastasis in men with castration-resistant prostate cancer. www.clinicaltrials.gov/ct2/show/NCT00691899?term=odanacatib&rank=6.
206. Medivir begins initial clinical trial of osteoporosis drug cathepsin K inhibitor. www.mskreport.com/print.cfm?articleID=1219.
207. Press Release, 23 April 2008 MEDIVIR, INTERIM REPORT. www.medivir.com/v3/images/ir_media/Q1_2008_ENG.pdf.
208. Controlled study of ONO-5334 in postmenopausal women with osteopenia or osteoporosis. www.clinicaltrials.gov/ct2/show/NCT00532337?spons=%22Ono+Pharma%22&spons_ex=Y&rank=13.
209. Safety/efficacy of balicatib (AAE581) in adults with osteoarthritis of the knee. www.clinicaltrials.gov/ct2/show/NCT00371670.Study to determine the effects of doses of relacatib on the metabolism of acetaminophen, ibuprofen and atorvastatin.
211. Reclast®. www.reclast.com
PubReader format: click here to try


Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


  • MedGen
    Related information in MedGen
  • PubMed
    PubMed citations for these articles
  • Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...