odanacatib and Osteoporosis

Osteoporosis is a metabolic bone disease that commonly results in middle-aged and elderly people following fractures. Odanacatib (ODN), a potential osteoporosis medication, was stopped in the Long-term Odanacatib Fracture Trial (LOFT) phase III study because it increased the risk of stroke. Herein, we conducted a systematic review and meta-analysis to further assess the efficacy and safety of ODN in osteoporosis treatment.. We searched the PubMed, EMBASE, Cochrane Library, and Web of Science, using the core search terms "osteoporosis" and "odanacatib." The primary outcomes were the percentage change in markers of bone turnover and bone formation as well as that in the bone mineral density (BMD) of the lumbar spine, hip, femoral neck, and greater trochanter. The secondary outcome was the risk of adverse events (AEs), used to explore the safety of ODN.. Ten articles-all double-blinded, randomized, placebo-controlled trials-were included. All trials were considered to be of high quality if they met the inclusion and exclusion criteria. We found that ODN increases BMD in the lumbar spine, total hip, and femoral neck, whereas it decreases the concentration of serum C-telopeptides of type I collagen (sCTx) and urinary N-telopeptide/creatinine ratio (uNTx/Cr). We found no significant differences in total, drug-related, serious, or skin AEs between the ODN and control groups. However, significant differences in fracture and stroke AEs were found between the ODN and control groups.. ODN is an appealing long-term osteoporosis treatment method; however, further research should focus on the potential increased risk of fracture and stroke.

Topics: Aged; Bone Density; Bone Density Conservation Agents; Double-Blind Method; Female; Fractures, Bone; Humans; Middle Aged; Osteoporosis; Osteoporosis, Postmenopausal; Stroke

Cathepsin K (CatK) is a cysteine protease abundantly expressed by osteoclasts and localized in the lysosomes and resorption lacunae of these cells. CatK is the principal enzyme responsible for the degradation of bone collagen. Odanacatib is a selective, reversible inhibitor of CatK at subnanomolar potency. The pharmacokinetics of odanacatib have been extensively studied and are similar in young healthy men, postmenopausal women and elderly men, and were qualitatively similar throughout Phase 1 development and in-patient studies. Following 3 weeks of 50 mg once weekly dosing the geometric mean area under the curve from 0 to 168 hours was 41.1 μM h, the concentration at 168 hours was 126 nM and the harmonic mean apparent terminal half-life was 84.8 hr. Odanacatib exposure increased in a less than dose proportional manner due to solubility limited absorption. It is estimated that approximately 70% of the absorbed dose of odanacatib is eliminated via metabolism, 20% is excreted as unchanged drug in the bile or faeces, and 10% is excreted as unchanged drug in the urine. The systemic clearance was low (approximately 13 mL/min). Odanacatib decreases the degradation of bone matrix proteins and reduces the efficiency of bone resorption with target engagement confirmed by a robust decrease in serum C-telopeptides of type 1 collagen (approximately 60%), urinary aminoterminal crosslinked telopeptides of type 1 collagen to creatinine ratio (approximately 50%) and total urine deoxypyridinoline/Cr (approximately 30%), with an increase in serum cross-linked carboxy-terminal telopeptide of type 1 collagen (approximately 55%). The 50-mg weekly dosing regimen evaluated in Phase 3 achieved near maximal reduction in bone resorption throughout the treatment period. The extensive clinical programme for odanacatib, together with more limited clinical experience with other CatK inhibitors (balicatib and ONO-5334), provides important insights into the clinical pharmacology of CatK inhibition and the potential role of CatK in bone turnover and mineral homeostasis. Key findings include the ability of this mechanism to: (i) provide sustained reductions in resorption markers, increases in bone mineral density, and demonstrated fracture risk reduction; (ii) be associated with relative formation-sparing effects such that sustained resorption reduction is achieved without accompanying meaningful reductions in bone formation; and (iii) lead to increases in osteoclast number as well as oth

Topics: Animals; Biphenyl Compounds; Bone and Bones; Bone Density Conservation Agents; Bone Remodeling; Cathepsin K; Cysteine Proteinase Inhibitors; Female; Humans; Male; Osteoporosis; Signal Transduction; Translational Research, Biomedical; Treatment Outcome

There is a need for the development of new drugs to prevent osteoporosis-related fractures. Fractures are projected to increase and the present drugs have modest efficacy, significant side-effects and poor compliance. To illustrate the difficulties in the development of new drugs, the author reviews the fate of several drugs that have failed to gain regulatory approval. These drugs include arzoxifene, lasofoxifene, MK-5442, roncalceret and odanacatib. Romosozumab and abaloparatide are the only new drugs presently in phase-3 development. It is anticipated that ongoing studies of the mechanisms and signaling pathways involved in the regulation of bone remodeling will open up new opportunities for targeted pharmacological interventions to increase bone strength. However, the perfect drug is still a long way off and will face many obstacles before approval.

Topics: Benzoates; Biphenyl Compounds; Bone Density Conservation Agents; Drug Discovery; Humans; Osteoporosis; Osteoporotic Fractures; Piperidines; Propanolamines; Pyrrolidines; Tetrahydronaphthalenes; Thiophenes

Cathepsin K (CatK), a cysteine protease, is highly expressed by osteoclasts and very efficiently degrades type I collagen, the major component of the organic bone matrix. Robust genetic and pharmacological preclinical studies consistently demonstrate that CatK inhibition increases bone mass, improves bone microarchitecture and strength. Recent advances in the understanding of the molecular and cellular mechanisms involved in bone modeling and remodeling suggest that inhibition of CatK decreases bone resorption, but increases the number of cells of osteoclast lineage. This in turn maintains the signals for bone formation, and perhaps may even increase bone formation on some cortical surfaces. Several CatK inhibitors, including relacatib, balicatib, odanacatib and ONO-5334 had entered clinical development for metabolic bone disorders with increased bone resorption, such as postmenopausal osteoporosis. However, odanacatib (ODN) is the only candidate continuing in development. ODN is a highly selective oral CatK inhibitor dosed once-weekly in humans. In a Phase 2 clinical trial, postmenopausal women treated with ODN had sustained reductions of bone resorption markers, while bone formation markers returned to normal after an initial decline within the first 2 years on treatment. In turn areal bone mineral density increased continuously at both spine and hip for up to 5 years. ODN has also been demonstrated to improve bone mass in women with postmenopausal osteoporosis previously treated with alendronate and in men with osteoporosis. ODN is currently in a worldwide Phase 3 fracture outcome trial for the treatment of postmenopausal osteoporosis with interim results supporting its anti-fracture efficacy at the spine, hip and non-vertebral sites.

Topics: Animals; Biphenyl Compounds; Bone Density Conservation Agents; Bone Remodeling; Cathepsin K; Humans; Osteoporosis

Osteoporosis is a significant public health issue affecting over half of women aged over 50. With an aging population, its importance is set to increase further over time. Prevention of fragility fractures avoids significant mortality and morbidity as well as saving significant direct and indirect costs to the economy. In this review, we discuss existing treatments to contextualize the treatment landscape, and demonstrate how our understanding of bone pathophysiology has led to novel therapies-in the form of combinations and altered durations of existing treatments, as well as newer drug therapies.. PubMed and Embase were searched for randomized controlled trials of new therapies for osteoporosis. These searches were supplemented with material presented in abstract form at international meetings.. New drugs that appear promising in the treatment of osteoporosis include the cathepsin K inhibitor, monoclonal antibodies against sclerostin and parathyroid hormone-related protein analog.. Separate to the development of novel drug therapies is the issue of how best to use agents that are currently available to us; specifically which agent to choose, alone or in combination; duration of therapy; how best to identify patients at highest risk of fracture, and to ensure the highest possible adherence to medication. Many of these issues have been addressed in other excellent review papers, and will not be considered in detail here.. As with all new treatments, we await results of long-term use and experience in 'real life' patient populations.. As alluded to above, data are urgently required regarding the optimal duration of therapy; use of combination therapy; ordering of therapies for best therapeutic effect. As stratified medicine becomes more strongly considered in all areas of therapy, its merits in osteoporosis as in other musculoskeletal conditions, is timely and valuable.

Topics: Biphenyl Compounds; Bone Density; Bone Density Conservation Agents; Calcium, Dietary; Cathepsin K; Dietary Supplements; Diphosphonates; Humans; Osteoporosis; Osteoporotic Fractures; Parathyroid Hormone-Related Protein; Randomized Controlled Trials as Topic; Treatment Outcome; Vitamin D

The aim of this study was to evaluate the efficacy and safety of odanacatib (ODN) for the treatment of osteoporosis, using data in studies reported in the literature. We performed a literature search to compare the outcomes of applications of once-weekly ODN 50 mg and control. The outcomes of osteoporosis evaluated include primary outcome as bone mineral density (BMD) at different skeletal sites, and secondary outcomes, including adverse events (AEs), such as incidence of skin AEs, fracture, and serious adverse events (SAEs). Four trials were included. Mean difference (95% CI) of lumbar spine BMD was 3.41 (1.57-5.24) at 12 months and 4.89 (2.72-7.05) at 24 months; mean difference (95% CI) of femoral neck BMD was 1.90 (0.73-3.08) at 12 months and 3.85 (2.55-5.15) at 24 months; mean difference (95% CI) of total hip BMD was 2.65 (1.20-4.09) at 12 months and 3.70 (1.76-5.64) at 24 months; risk ratio (95% CI) of AEs was 0.98 (0.91-1.07); risk ratio (95% CI) of SAEs was 1.11 (0.72-1.72); risk ratio (95% CI) of skin AEs was 0.92 (0.63-1.35); and risk ratio (95% CI) of fracture was 0.34 (0.16-0.70). In this study, application of 50 mg ODN produced significantly greater BMD increases and lower fracture incidence than that of the control. In addition, ODN was generally well tolerated.

Topics: Biphenyl Compounds; Bone Density; Bone Density Conservation Agents; Femur Neck; Humans; Lumbar Vertebrae; Osteoporosis; Pelvic Bones; Risk; Treatment Outcome

Osteoclast research has an exciting history and a challenging future. More than 3 decades ago, it became evident that bone-resorbing osteoclasts are of hematopoietic origin and are ultimately linked to the "basic multicellular unit," where they team up with the other cell types, including bone-forming osteoblasts. Since 2 decades, we have learned about the signaling pathways controlling genes relevant for osteoclastogenesis and bone resorption. It took another decade until the hypothesized "osteoclast differentiation" factor was discovered and was translated into an approved pharmacologic strategy. Here, the focus is on another molecular target, cathepsin K, a cysteine protease being released by the osteoclast into the resorption compartment. Genetic deletion and pharmacological blocking of cathepsin K reduces bone resorption but with ongoing bone formation. This observation not only holds great promise to become a new pharmacologic strategy, but it also provides new insights into the coordinated work of cells in the "basic multicellular unit" and thus, bridges the history and future of osteoclast research. This article is a short primer on osteoclast biology for readers of the special issue on odanacatib, a cathepsin K inhibitor.

Topics: Animals; Biphenyl Compounds; Bone Remodeling; Bone Resorption; Cathepsin K; Humans; Osteoblasts; Osteoclasts; Osteoporosis; RANK Ligand

The skeleton normally responds to mechanical environment to maintain the resulting elastic deformation (strain) of bone, while increased bone strength by an osteoporosis drug results in decreased bone strain. Thus, it can be hypothesized that the effect of osteoporosis therapy is limited by natural homeostatic system in the skeleton. This logic is consistent with the fact that there exists a powerful effect that returns bone mass to its pre-treatment level after the withdrawal of treatment with osteoporosis agents. The present hypothesis provides a new significant insight into the mechanisms by which osteoporosis drugs improve bone fragility. Here we briefly discuss the effects of teriparatide, romosozumab, and odanacatib on bones in animals and humans.

Topics: Animals; Antibodies, Monoclonal; Biphenyl Compounds; Bone Density Conservation Agents; Bone Remodeling; Bone Resorption; Humans; Osteoporosis; Stress, Mechanical; Teriparatide

Progress continues to be made in the development of therapeutics for fracture prevention. Bisphosphonates are now available orally and intravenously, often as inexpensive generics, and remain the most widely used interventions for osteoporosis. The major safety concern associated with the use of bisphosphonates is the development of femoral shaft stress fractures and, although rare, this adverse event affords the principal rationale for restricting bisphosphonate therapy to those individuals with femoral T-scores <-2.5, and for providing drug holidays in those individuals requiring therapy for >5 years. Newer antiresorptive therapies, in the form of denosumab and cathepsin K inhibitors, might increase efficacy and possibly circumvent some of the safety concerns associated with bisphosphonate use (for example, gastrointestinal and renal complications). The combination of teriparatide with antiresorptives markedly increases effects on BMD; new anabolic agents are also very promising in this regard. However, whether or not these changes in BMD translate into improved efficacy of fracture prevention remains to be determined. Vitamin D is important for the prevention of osteomalacia, but does not influence BMD or fracture risk in patients not deficient in vitamin D. The balance of risks and benefits of calcium supplementation is contentious, but patients should be encouraged to adhere to a balanced diet aimed at maintaining a healthy body weight. Consideration of a patient's risk of falling, and its mitigation, are also important. In this Review, I summarize the short-term and long-term effects of osteoporosis therapies.

Topics: Adaptor Proteins, Signal Transducing; Antibodies, Monoclonal; Biphenyl Compounds; Bone Density Conservation Agents; Bone Morphogenetic Proteins; Calcium; Cathepsin K; Denosumab; Diphosphonates; Estrogens; Genetic Markers; Humans; Osteoporosis; Osteoporotic Fractures; Parathyroid Hormone; Strontium; Treatment Outcome; Vitamin D

Osteoporosis and fragility fractures are important public health concerns. Cathepsin K inhibitors, including odanacatib , are a novel class of medications for osteoporosis whose mechanism of action is to directly inhibit bone resorption without killing osteoclasts, thereby permitting the complex coupling between bone resorption and formation to continue.. The physiological basis for the mechanism of action of cathepsin K inhibitors is covered in addition to a review of the preclinical, Phase I, Phase II and preliminary Phase III trial data of odanacatib.. Evidence suggests that odanacatib has similar efficacy to bisphosphonates at increasing bone mineral density and decreasing risk of fragility fractures. Although odanacatib may preferentially inhibit bone resorption more than formation, the clinical significance of this difference in mechanism of action is not yet known. A careful analysis of the Phase III trial data is needed with specific attention to adverse events.

Topics: Animals; Biphenyl Compounds; Bone Density; Bone Density Conservation Agents; Bone Resorption; Cathepsin K; Clinical Trials as Topic; Diphosphonates; Fractures, Bone; Humans; Osteoporosis; Risk

Cathepsin K is a lysosomal cysteine protease, secreted from osteoclasts. It plays a major role in the osteoclastic bone resorption by cleaving type 1 collagen, the major bone matrix protein, under acidic pH. In cathepsin K knockout mice, bone mineral density (BMD) is increased, bone resorption is decreased without reduction in the number of osteoclast whereas bone formation is decreased. Based on these results, cathepsin K inhibitors have been developed for the treatment of osteoporosis. Odanacatib is one of them and is perhaps closest for launching. In phase 1 and 2 trials, it markedly reduced bone resorption with a transient reduction in bone formation, thus resulted in a robust increase in both trabecular and cortical BMD in osteoporotics. Currently, Odanacatib is in phase 3 fracture prevention trial, of which results are anticipated in 2014.

Topics: Animals; Biphenyl Compounds; Bone Density; Bone Remodeling; Bone Resorption; Cathepsin K; Humans; Osteoporosis

Antiresorptive agents, used in the treatment of osteoporosis, inhibit either osteoclast formation or function. However, with these approaches, osteoblast activity is also reduced because of the loss of osteoclast-derived coupling factors that serve to stimulate bone formation. This review discusses how osteoclast inhibition influences osteoblast function, comparing the actions of an inhibitor of osteoclast formation [anti-RANKL/Denosumab (DMAB)] with that of a specific inhibitor of osteoclastic cathepsin K activity [Odanacatib (ODN)]. Denosumab rapidly and profoundly, but reversibly, reduces bone formation. In contrast, preclinical studies and clinical trials of ODN showed that bone formation at some skeletal sites was preserved although resorption was reduced. This preservation of bone formation appears to be due to effects of coupling factors, secreted by osteoclasts and released from demineralized bone matrix. This indicates that bone resorptive activities of osteoclasts are separable from their coupling activities.

Topics: Antibodies, Monoclonal, Humanized; Biphenyl Compounds; Bone Density Conservation Agents; Bone Remodeling; Cathepsin K; Cell Differentiation; Denosumab; Humans; Osteoblasts; Osteoclasts; Osteogenesis; Osteoporosis; RANK Ligand

The metabolic bone disease osteoporosis is a growing health and health-economic problem worldwide. Bisphosphonates are the most widely used antiresorptive medication and the de facto gold standard in fracture prophylaxis all over the world, in conjunction with calcium and vitamin D supplementation. Several new medications for the treatment of postmenopausal osteoporosis are in the pipeline.. The authors present the most recent studies on new and current antiresorptive as well as anabolic drugs. Specifically, the authors present the current knowledge on drugs directed against cathepsin K and sclerostin as well as the new pathways of interest from preclinical studies.. New scientific results have identified novel signaling pathways as potential targets for future development of anti-osteoporotic drugs. The treatments close to marketing at the moment are odanacatib and romosozumab and these are both promising new medications based on bone mineral density results, safety profile and administration. Theoretically, romosozumab may hold the potential to be a drug to 'cure' even advanced stages of osteoporosis with short-term treatment. However, safety, fracture data and cost are key elements that will determine the extent of use.

Topics: Adaptor Proteins, Signal Transducing; Anabolic Agents; Animals; Antibodies, Monoclonal; Biphenyl Compounds; Bone Density Conservation Agents; Bone Morphogenetic Proteins; Cathepsin K; Drug Design; Genetic Markers; Humans; Osteoporosis

Two new approaches for the treatment of osteoporosis are summarized, each having arisen out of important new discoveries in bone biology. Odanacatib (ODN) inhibits the enzyme, cathepsin K, that is essential for the resorbing activity of osteoclasts. It is effective in preventing ovariectomy-induced bone loss in preclinical studies, and a phase II clinical study has shown inhibition of resorption sustained over five years. Outcome of a phase III study is awaited. The finding from mouse and human genetics that Wnt signaling is a powerful inducer of bone formation led to developments aimed at enhancing this pathway. Of the several approaches towards this, the most advanced is with a neutralizing antibody against sclerostin, the osteocyte-derived inhibitor of Wnt signaling. Preclinical studies show a powerful bone anabolic effect, and a clinical phase II study shows dose-dependent increases in bone formation and decreases in bone resorption markers.

Topics: Adaptor Proteins, Signal Transducing; Anabolic Agents; Animals; Biphenyl Compounds; Bone Density Conservation Agents; Bone Morphogenetic Proteins; Cathepsin K; Genetic Markers; Glycogen Synthase Kinase 3; Humans; Intercellular Signaling Peptides and Proteins; Osteoporosis; Parathyroid Hormone; Wnt Proteins

Odanacatib (ODN), a selective cathepsin-K inhibitor, was found to increase bone mineral density (BMD); the effect on fractures is based on adverse event reports.. To estimate current effects and predict future effects of ODN on BMD and fractures.. Electronic databases (Medline, EMBASE, Cochrane Library), conference proceedings, and bibliographies.. Trials that compared ODN 50 mg/wk to placebo for at least 1 year and reported changes in BMD or fractures. Meta-analysis: Two bone outcomes were pooled as independent and as joint outcomes in Bayesian univariate and bivariate random-effects models.. Of 32 potentially eligible articles, six citations describing four trials (993 patients) were included. ODN for 3 years increased mean BMD at the lumbar spine by 5.0% (95% credible interval [CrI], 2.7, 7.5), total hip by 3.6% (95% CrI, 1.6, 5.9), and femoral neck (FN) by 3.6% (95% CrI, 1.6, 5.7). In a future trial of 3-year duration, the predicted mean increase in BMD, adjusted for the effect on fractures, was 4.9% for lumbar spine (95% CrI, 2.5, 7.4), 3.4% for total hip (95% CrI, 1.7, 5.2), and 3.5% for FN (95% CrI, 1.8, 5.3). After accounting for the effect on FN BMD, ODN for 3 years was associated with a population odds ratio of 0.38 (95% CrI, 0.1, 0.8). In a future trial, the odds ratio was 0.41 (95% CrI, 0.1, 1.1). The probability of benefit on fractures was 96-99%. The estimates remained robust in sensitivity analyses.. Our analyses suggest that ODN will increase BMD and decrease all fractures in the fracture outcome trial; however, direct demonstration of this antifracture efficacy is needed.

Topics: Bayes Theorem; Biphenyl Compounds; Bone Density; Cathepsin K; Fractures, Bone; Humans; Osteoporosis; Randomized Controlled Trials as Topic

Odanacatib, a selective cathepsin K inhibitor, decreases bone resorption, whereas osteoclast number increases and bone formation is maintained, perhaps even increased on some cortical surfaces. In a phase 2 clinical trial, post-menopausal women receiving odanacatib presented a sustained reduction of bone resorption markers, whereas procollagen type 1 N-terminal propeptide returned to normal. In turn areal bone mineral density increased continuously at both spine and hip for up to 5 years. Blosozumab and romosozumab are sclerostin neutralizing antibodies that exert potent anabolic effects on both trabecular and cortical compartments. A phase 2 clinical trial has reported areal bone mineral density gains at spine and hip that were greater with romosozumab compared with placebo, but also with teriparatide. It also showed that antagonizing sclerostin results in a transient stimulation of bone formation but progressive inhibition of bone resorption. Other new medical entities that are promising for the treatment of osteoporosis include abaloparatide, a parathyroid hormone-related analogue with improved bone formation-resorption ratio.

Topics: Adaptor Proteins, Signal Transducing; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Biphenyl Compounds; Bone Morphogenetic Proteins; Cathepsin K; Genetic Markers; Humans; Osteoporosis; Parathyroid Hormone-Related Protein

One in three osteoporotic fractures occur in men and the consequences of a fracture in men tend to be more severe than in women. Still, only a small minority of men with high risk of fracture are detected and treated. Although there are gender differences in the pathophysiology of osteoporosis, such as in the pattern of bone loss, similarities predominate, which is also the case for clinical risk factors. It seems appropriate to consider treatment for men and women with a similar 10 year fracture risk. Drugs now approved for treatment of osteoporosis in men include the anti-resorptive bisphosphonates alendronate, residronate and zoledronic acid, the anti-resorptive drug denosumab, the bone-forming agent teriparatide, and (not in the US) strontium ranelate with mild opposite effects on resorption and formation. Although the evidence level for efficacy and safety of these drugs in men is still relatively limited, available data indicate that treatment effects in men are very similar to what has been observed in the treatment of postmenopausal osteoporosis. Denosumab is also approved for treatment in men receiving androgen deprivation therapy for non-metastatic prostate cancer; bisphosphonates and teriparatide are also available to clinicians for treatment of glucocorticoid-induced osteoporosis in men. Testosterone treatment may be indicated in men with documented symptomatic hypogonadism, but osteoporosis is neither a sufficient nor a specific indication for testosterone treatment. New compounds with well advanced clinical development include odanacatib, a selective inhibitor of the cysteine protease cathepsin-K, and romosozumab, a monoclonal antibody against sclerostin.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Biphenyl Compounds; Bone Density Conservation Agents; Denosumab; Humans; Male; Osteoporosis; Teriparatide

Topics: Anabolic Agents; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Benzazepines; Biphenyl Compounds; Bone Density Conservation Agents; Bone Remodeling; Cell Differentiation; Denosumab; Drug Discovery; Drug Evaluation, Preclinical; Harmine; Humans; Indoles; Lithium Compounds; Molecular Targeted Therapy; NFATC Transcription Factors; Osteoblasts; Osteoclasts; Osteogenesis; Osteoporosis; Parathyroid Hormone; Teriparatide; Wnt Signaling Pathway

Cathepsin K is the protease that is primarily responsible for the degradation of bone matrix by osteoclasts. Inhibitors of cathepsin K are in development for treatment of osteoporosis. Currently available antiresorptive drugs interfere with osteoclast function. They inhibit both bone resorption and formation, due to the coupling between these processes. Cathepsin K inhibitors, conversely, target the resorption process itself and may not interfere with osteoclast stimulation of bone formation. In fact, when cathepsin K is absent or inhibited in mice, rabbits, or monkeys, bone formation is maintained or increased. In humans, inhibition of cathepsin K is associated with sustained reductions in bone resorption markers but with smaller and transient reductions in bone formation markers. The usefulness of cathepsin K inhibitors in osteoporosis is now being examined in phase 2 and phase 3 clinical trials of postmenopausal osteoporotic women.

Topics: Alkaline Phosphatase; Animals; Biphenyl Compounds; Bone Density; Bone Remodeling; Bone Resorption; Cathepsin K; Humans; Osteoporosis; Osteoporosis, Postmenopausal; Thiazolidines

Bone homeostasis is maintained by delicate balance between bone resorption by osteoclasts and bone formation by osteoblasts. Bisphosphonates are widely used nowadays by suppressing bone resorption to treat patients with osteoporosis, which results from high bone turnover, causing excessive bone resorption phase. While bisphosphonates increase bone mineral density and improve back pain due to spinal compression fracture, they may have some problems such as osteonecrosis of jaw and excessive suppression of bone turnover. Cathepsin K inhibitor, which has a new mechanism in addition to function of suppressing bone resorption, is recently focused. Cathepsin K is a protease which specifically expresses in osteoclasts and plays an important role in resolution of bone collagen. Cathepsin K inhibitor has a potential of inhibiting bone resorption without suppressing bone formation and could be an attractive therapeutic target of osteoporosis.

Topics: Animals; Biphenyl Compounds; Bone and Bones; Bone Resorption; Cathepsin K; Collagen; Enzyme Inhibitors; Humans; Molecular Targeted Therapy; Osteogenesis; Osteoporosis; Stimulation, Chemical

Osteoporosis is a common disease characterised by a systemic impairment of bone mass and microarchitecture that results in fragility fractures. With an ageing population, the medical and socioeconomic effect of osteoporosis, particularly postmenopausal osteoporosis, will increase further. A detailed knowledge of bone biology with molecular insights into the communication between bone-forming osteoblasts and bone-resorbing osteoclasts and the orchestrating signalling network has led to the identification of novel therapeutic targets. Novel treatment strategies have been developed that aim to inhibit excessive bone resorption and increase bone formation. The most promising novel treatments include: denosumab, a monoclonal antibody for receptor activator of NF-κB ligand, a key osteoclast cytokine; odanacatib, a specific inhibitor of the osteoclast protease cathepsin K; and antibodies against the proteins sclerostin and dickkopf-1, two endogenous inhibitors of bone formation. This overview discusses these novel therapies and explains their underlying physiology.

Topics: Absorptiometry, Photon; Adaptor Proteins, Signal Transducing; Aged; Aged, 80 and over; Anabolic Agents; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Benzodioxoles; Biphenyl Compounds; Bone Density; Bone Density Conservation Agents; Bone Morphogenetic Proteins; Bone Remodeling; Bone Resorption; Calcium; Denosumab; Diphosphonates; Female; Genetic Markers; Humans; Intercellular Signaling Peptides and Proteins; Middle Aged; Osteoblasts; Osteoclasts; Osteoporosis; Osteoporosis, Postmenopausal; Osteoporotic Fractures; Quinazolines; Randomized Controlled Trials as Topic; RANK Ligand; Risk Assessment; Risk Factors; Vitamin D Deficiency; Wnt Proteins

Topics: Animals; Biomarkers; Bone Density; Bone Resorption; Humans; Osteoporosis

High bone remodeling leads to bone loss and microarchitectural deteriorations characteristic of osteoporosis. Bisphosphonates and selective estrogen receptor modulators decrease bone remodeling by preventing osteoclast-mediated bone resorption, whereas parathyroid hormone/teriparatide increase bone remodeling in favor of new bone formation. Better understanding of the molecular processes of bone remodeling has led to the development of agents to inhibit bone resorption, such as the human monoclonal antibody Denosumab targeting osteoclast-activating factor RANK Ligand, and odanacatib targeting the collagen-degrading enzyme cathepsin K. Agents capable to stimulate bone formation independently of bone resorption, such as antagonists of the osteoblast-inhibitory factor sclerostin, may provide new therapeutic approaches to osteoporosis.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Biomarkers; Biphenyl Compounds; Bone Density; Bone Density Conservation Agents; Bone Remodeling; Denosumab; Diphosphonates; Drug Therapy, Combination; Humans; Osteoporosis; Parathyroid Hormone; RANK Ligand; Selective Estrogen Receptor Modulators; Teriparatide; Treatment Outcome

Type 2 diabetes (T2D) is associated with increased risk of fractures. However, it is unclear whether current osteoporosis treatments reduce fractures in individuals with diabetes. The aim of the study was to determine whether presence of T2D influences the efficacy of antiresorptive treatment for osteoporosis using the Foundation for the National Institutes of Health (FNIH)-American Society for Bone and Mineral Research (ASBMR)-Study to Advance Bone Mineral Density (BMD) as a Regulatory Endpoint (SABRE) cohort, which includes individual patient data from randomized trials of osteoporosis therapies. In this study we included 96,385 subjects, 6.8% of whom had T2D, from nine bisphosphonate trials, two selective estrogen receptor modulator (SERM) trials, two trials of menopausal hormone therapy, one denosumab trial, and one odanacatib trial. We used Cox regression to obtain the treatment hazard ratio (HR) for incident nonvertebral, hip, and all fractures and logistic regression to obtain the treatment odds ratio (OR) for incident morphometric vertebral fractures, separately for T2D and non-DM. We used linear regression to estimate the effect of treatment on 2-year change in BMD (n = 49,099) and 3-month to 12-month change in bone turnover markers (n = 12,701) by diabetes status. In all analyses, we assessed the interaction between treatment and diabetes status. In pooled analyses of all 15 trials, we found that diabetes did not impact treatment efficacy, with similar reductions in vertebral, nonvertebral, all, and hip fractures, increases in total hip and femoral neck BMD, and reductions in serum C-terminal cross-linking telopeptide (CTX), urinary N-telopeptide of type I collagen/creatinine (NTX/Cr) and procollagen type 1 N propeptide (P1NP) (all interactions p > 0.05). We found similar results for the pooled analysis of bisphosphonate trials. However, when we considered trials individually, we found a few interactions within individual studies between diabetes status and the effects of denosumab and odanacatib on fracture risk, change in BMD or bone turnover markers (BTMs). In sum, these results provide strong evidence that bisphosphonates and most licensed antiresorptive drugs are effective at reducing fracture risk and increasing BMD irrespective of diabetes status. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Topics: Bone Density; Bone Density Conservation Agents; Denosumab; Diabetes Mellitus, Type 2; Diphosphonates; Hip Fractures; Humans; Osteoporosis

Odanacatib (ODN) was investigated as an osteoporosis treatment in 292 men. Compared with placebo, odanacatib improved bone mineral density and led to sustained bone resorption decreases while producing relatively little bone formation reduction that leveled off with time. However, increased risk of stroke in another study stopped further odanacatib development.. ODN, a selective oral cathepsin K inhibitor, was in development for osteoporosis treatment. This phase 3, double-blind, randomized, placebo-controlled, 24-month study investigated ODN safety and efficacy in men with osteoporosis.. Men with idiopathic osteoporosis or osteoporosis due to hypogonadism and a lumbar spine or hip (total hip [TH], femoral neck [FN], or trochanter) bone mineral density (BMD) T-score of ≤ - 2.5 to ≥ - 4.0 without prior vertebral fracture or ≤ - 1.5 to ≥ - 4.0 with one prior vertebral fracture were randomized (1:1) to once-weekly ODN 50 mg or placebo. All received 5600 IU vitamin D. Overall, 292 men, mean age 68.8 years, were randomly assigned to ODN or placebo. Versus placebo, ODN increased BMD from baseline at the lumbar spine, TH, FN, and trochanter by 5.6%, 2.0%, 1.7%, and 2.1%, respectively (all p < 0.01), and decreased uNTx/Cr (68%, p < 0.001), sCTx (77%, p < 0.001), sP1NP (16%, p = 0.001), and sBSAP (8%, p = 0.019). The between-group bone formation marker decrease peaked at 3 months, then returned toward baseline. The safety profile, including cardiovascular events, was similar between groups.. Though a promising osteoporosis therapy for men, ODN development was discontinued due to increased risk of stroke in the LOFT phase 3 trial.. Clinicaltrials.gov NCT01120600 (registered May 11, 2010).

Topics: Aged; Biphenyl Compounds; Bone Density; Bone Density Conservation Agents; Double-Blind Method; Humans; Male; Osteoporosis

Topics: Aged; Biphenyl Compounds; Bone Density; Bone Density Conservation Agents; Double-Blind Method; Female; Femur Neck; Hip Fractures; Humans; Incidence; Osteoporosis; Osteoporosis, Postmenopausal; Postmenopause

Odanacatib (ODN), a selective oral inhibitor of cathepsin K, was an investigational agent previously in development for the treatment of osteoporosis. In this analysis, the effects of ODN on bone remodeling/modeling and structure were examined in the randomized, double-blind, placebo-controlled, event-driven, Phase 3, Long-term Odanacatib Fracture Trial (LOFT; NCT00529373) and planned double-blind extension in postmenopausal women with osteoporosis. A total of 386 transilial bone biopsies, obtained from consenting patients at baseline (ODN n = 17, placebo n = 23), month 24 (ODN n = 112, placebo n = 104), month 36 (ODN n = 42, placebo n = 41), and month 60 (ODN n = 27, placebo n = 20) were assessed by dynamic and static bone histomorphometry. Patient characteristics at baseline and BMD changes over 5 years for this subset were comparable to the overall LOFT population. Qualitative assessment of biopsies revealed no abnormalities. Consistent with the mechanism of ODN, osteoclast number was higher with ODN versus placebo over time. Regarding bone remodeling, dynamic bone formation indices in trabecular, intracortical, and endocortical surfaces were generally similar in ODN-treated versus placebo-treated patients after 2 years of treatment. Regarding periosteal modeling, the proportion of patients with periosteal double labels and the bone formation indices increased over time in the ODN-treated patients compared with placebo. This finding supported the observed numerical increase in cortical thickness at month 60 versus placebo. In conclusion, ODN treatment for 5 years did not reduce bone remodeling and increased the proportion of patients with periosteal bone formation. These results are consistent with the mechanism of action of ODN, and are associated with continued BMD increases and reduced risk of fractures compared with placebo in the LOFT Phase 3 fracture trial. © 2020 American Society for Bone and Mineral Research.

Topics: Biphenyl Compounds; Bone Density; Bone Density Conservation Agents; Double-Blind Method; Female; Humans; Osteoporosis; Osteoporosis, Postmenopausal; Postmenopause

The efficacy and safety of oral placebo or odanacatib 10, 25, or 50 mg once weekly for 52 weeks were evaluated in a double-blind, randomized, multi-center study in Japanese female and male patients with osteoporosis.. Odanacatib is a selective and reversible cathepsin K inhibitor that decreases bone resorption and increases bone mineral density (BMD).. The primary efficacy endpoint was percent change from baseline to week 52 in lumbar spine BMD. Secondary endpoints included percent change in total hip, femoral neck, and trochanter BMD and in bone biomarkers after treatment for 52 weeks.. In this study, 286 patients [94% female, mean age (SD) 68.2 (7.1) years] were included in the analysis. The least-squares mean percent changes from baseline to week 52 in the groups receiving placebo, 10, 25 and 50 mg of odanacatib for lumbar spine (L1~L4) BMD were 0.5, 4.1, 5.7, and 5.9% and for total hip BMD were -0.4, 1.3, 1.8, and 2.7%, respectively. The changes in femoral neck and trochanter BMD were similar to those at the total hip. Bone turnover markers were reduced in a dose-dependent manner. However, the effects of odanacatib on bone formation markers were less compared with the effects on bone resorption markers. Tolerability and safety profiles were similar among all treatment groups with no dose-related trends in any adverse events.. Weekly odanacatib treatment for 52 weeks increased BMD at the lumbar spine and at all hip sites in a dose-dependent manner and was well tolerated in Japanese patients with osteoporosis.

Topics: Aged; Anthropometry; Biomarkers; Biphenyl Compounds; Bone Density; Bone Density Conservation Agents; Cathepsin K; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Hip Joint; Humans; Lumbar Vertebrae; Male; Middle Aged; Osteoporosis; Osteoporosis, Postmenopausal; Osteoporotic Fractures; Treatment Outcome

To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of odanacatib (ODN), a cathepsin K inhibitor, in humans.. Two double-blind, randomized, placebo-controlled, single oral dose studies were performed with ODN (2-600 mg) in 44 healthy volunteers (36 men and eight postmenopausal women).. Adverse experiences (AEs) with single doses of ODN were transient and mild to moderate, with the exception of one severe AE of gastroenteritis. Headache was the most frequent AE. After absorption of ODN (initial peak concentrations 4-6 h postdose), plasma concentrations exhibited a monophasic decline, with an apparent terminal half-life of ∼40-80 h. The area under the curve0-24 hours (AUC(0-24 h)), concentration at 24 hours (C(24 h)) and maximum concentration (C(max,overal)) increased in a less than dose-proportional manner from 2 to 600 mg. Administration of ODN with a high-fat meal led to ∼100% increases in AUC(0-24 h), C(max,day1), C(max,overall) and C(24 h) relative to the fasted state, while administration with a low-fat meal led to a ∼30% increase in those parameters. Reduction of biomarkers of bone resorption, the C- and N-telopeptides of cross-links of type I collagen, (CTx and NTx, respectively), was noted at 24 h for doses ≥5 mg and at 168 h postdose for ≥10 mg. In postmenopausal women administered 50 mg ODN, reductions in serum CTx of -66% and urine NTx/creatinine (uNTx/Cr) of -51% relative to placebo were observed at 24 h. At 168 h, reductions in serum CTx (-70%) and uNTx/Cr (-78%) were observed relative to baseline. Pharmacokinetic/pharmacodynamic modeling characterized the ODN concentration/uNTx/Cr relation, with a modeled EC50 value of 43.8 nM and ∼80% maximal reduction.. Odanacatib was well tolerated and has a pharmacokinetic and pharmacodynamic profile suitable for once weekly dosing.

Topics: Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Area Under Curve; Biphenyl Compounds; Bone Resorption; Cathepsin K; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Enzyme Inhibitors; Female; Half-Life; Humans; Male; Middle Aged; Osteoporosis; Young Adult

Cathepsin K (CatK) inhibition allows reducing bone resorption with specific advantages compared to the existing anti-osteoporosis drugs. Its clinical use appears even more promising with the recent development of ectosteric inhibitors. A confusing observation, however, is that a low dose of the active site CatK inhibitor odanacatib (ODN) was reported to decrease bone mineral density and increase serum levels of the bone resorption marker carboxy-terminal collagen crosslinks (CTX). The present study provides a possible explanation for this paradox. The resorptive activity of human osteoclasts seeded on bone slices was inhibited when subjected to ODN at doses of 20 nM, but about 100-fold lower doses induced a significant increase in CTX levels and in eroded surface (12 repeats). This low-dose-induced stimulation was prevented by inhibition of non-CatK cysteine proteinases, thereby indicating that the stimulation results from an interplay between CatK and other cysteine proteinases. Effective interplay between these proteinases was also shown in enzymatic assays where the CatK-mediated degradation of collagen was enhanced upon addition of cathepsins B or L. Furthermore, extracts of osteoclasts subjected to a low dose of ODN showed higher levels of cathepsin B compared with extracts of control osteoclasts. In conclusion, the low-dose-induced stimulation of resorption observed in the clinical study can be reproduced in osteoclasts cultured in the absence of any other cell. Our data support an osteoclast-intrinsic mechanism where a mild inhibition of CatK results in increased levels of other proteinases contributing to the collagen degradation process.

Topics: Biphenyl Compounds; Bone and Bones; Bone Density; Bone Resorption; Cathepsin K; Humans; Osteoclasts; Osteoporosis

Cathepsin K (CK), a lysosomal cysteine protease, is highly expressed in mature osteoclasts and degrades type 1 collagen. Odanacatib (ODN) is a selective and reversible CK inhibitor that inhibits bone loss in preclinical and clinical studies. Although an antiresorptive, ODN does not suppress bone formation, which led us to hypothesize that ODN may display restorative effect on the osteopenic bones. In a curative study, skeletally mature New Zealand rabbits were ovarectomized (OVX) and after induction of bone loss were given a steady-state exposure of ODN (9 mM/d) for 14 weeks. Sham-operated and OVX rabbits treated with alendronate (ALD), 17b-estradiol (E2), or parathyroid hormone (PTH) served as various controls. Efficacy was evaluated by assessing bone mineral density (BMD), bone microarchitecture (using micro-computed tomography), fluorescent labeling of bone, and biomechanical strength. Skeletal Ca/P ratio was measured by scanning electron microscopy (SEM) with X-ray microanalysis, crystallinity by X-ray diffraction, and bone mineral density distribution (tissue mineralization) by backscattered SEM. Between the sham and ODN-treated osteopenic groups, lumbar and femur metaphyseal BMD, Ca/P ratio, trabecular microstructure and geometric indices, vertebral compressive strength, trabecular lining cells, cortical parameters (femoral area and thickness and periosteal deposition), and serum P1NP were largely comparable. Skeletal improvements in ALD-treated or E2-treated groups fell significantly short of the sham/ODN/PTH group. However, the ODN group displayed reduced ductility and enhanced brittleness of central femur, which might have been contributed by higher crytallinity and tissue mineralization. Rabbit bone marrow stromal cells expressed CK and when treated with ODN displayed increased formation of mineralized nodules and decreased apoptosis in serum-deficient medium compared with control. In vivo, ODN did not suppress remodeling but inhibited osteoclast activity more than ALD. Taken together, we show that ODN reverses BMD, skeletal architecture, and compressive strength in osteopenic rabbits; however, it increases crystallinity and tissue mineralization, thus leading to increased cortical bone brittleness.

Topics: Alendronate; Animals; Biomechanical Phenomena; Biphenyl Compounds; Bone Density; Bone Diseases, Metabolic; Calcification, Physiologic; Cancellous Bone; Cortical Bone; Crystallization; Diaphyses; Drugs, Investigational; Estrogens; Female; Femur; Lumbar Vertebrae; Osteoblasts; Osteoclasts; Osteoporosis; Parathyroid Hormone; Rabbits

Topics: Adaptor Proteins, Signal Transducing; Animals; Antibodies, Monoclonal; Biphenyl Compounds; Bone Density Conservation Agents; Bone Morphogenetic Proteins; Cathepsin K; Genetic Markers; Humans; Osteoporosis

Topics: Biphenyl Compounds; Bone Density Conservation Agents; Cathepsin K; Clinical Trials as Topic; Drug Industry; Humans; Osteoporosis

Bone events related to bariatric surgery remain controversial. Denosumab, used in osteoporosis treatment, is safe and efficient. Romosozumab, an antibody raised against sclerostin, is a promising bone anabolic agent. Odanacatib, a cathepsin-K inhibitor, decreases bone resorption and reduces osteoporotic fracture risk. Denosumab, as bone resorption inhibitor, and Teriparatide, as anabolic agent, have been tested together in patients with osteoporosis. Calcium supplements and cardiovascular risk are still debated. Drug holiday, after long-term treatment with bisphosphonates, is not associated with an increased fracture rate in patients with moderate risk.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Bariatric Surgery; Biphenyl Compounds; Denosumab; Humans; Osteoporosis

Topics: Adaptor Proteins, Signal Transducing; Biphenyl Compounds; Bone and Bones; Bone Density Conservation Agents; Bone Morphogenetic Proteins; Denosumab; Genetic Markers; Humans; Osteoporosis

Topics: Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Biphenyl Compounds; Bone Density Conservation Agents; Calcium, Dietary; Cause of Death; Combined Modality Therapy; Cross-Sectional Studies; Denosumab; Diphosphonates; Female; Germany; Humans; Life Style; Male; Middle Aged; Osteoporosis; Osteoporotic Fractures; Population Dynamics; Risk Factors; Selective Estrogen Receptor Modulators; Vitamin D

Topics: Biphenyl Compounds; Bone Density Conservation Agents; Humans; Osteoporosis

This study aimed to validate finite element analysis (FEA) estimation of strength, identify high-resolution peripheral quantitative computed tomography (HR-pQCT) measures correlating with strength, and evaluate the precision of HR-pQCT measurements to longitudinally monitor effects of osteoporosis treatment in ovariectomized (OVX) non-human primates (NHPs). HR-pQCT images were acquired in three groups of NHPs: Intact (n=10), OVX-odanacatib treated (OVX-ODN 30 mg/kg, n=10) and OVX-vehicle treated (OVX-Veh, n=10) at the ultradistal (UD) and distal 1/3 radii and tibia at 12, 16 and 20 months. FEA estimates of bone strength using the Pistoia criterion were validated by ex-vivo mechanical compression (r(2)=0.95) of the UD radius. Single linear regressions of FEA-determined ultimate stress showed high correlation with HR-pQCT derived parameters: integral vBMD (r(2)=0.86), bone volume fraction (r(2)=0.84) and cortical thickness (r(2)=0.79). Precision of HR-pQCT measurements, obtained from an excised radius and tibia, showed low variation (CV=0.005%-5.6%) and helped identify possible sources of error. Comparison of OVX-Veh and Intact groups showed decreases in bone parameters demonstrating trends consistent with bone loss. Comparison of OVX-ODN and OVX-Veh groups showed a treatment effect with increases in bone parameters: integral vBMD (477±27 vs. 364±22 mgHA/cm(3)) and cortical thickness (Ct.Th) (0.90±0.07 vs. 0.64±0.04 mm) at the UD radius, Ct.Th (2.15±0.28 vs. 1.56±0.08 mm) at the distal 1/3 radius. Axial compression peak stress calculated and obtained experimentally showed the OVX-ODN group was 33% stronger than the OVX-Veh group. We conclude that HR-pQCT and FEA serve as robust techniques to longitudinally monitor bone parameters and strength in NHP's.

Topics: Animals; Biomechanical Phenomena; Biphenyl Compounds; Bone Density; Cathepsin K; Cysteine Proteinase Inhibitors; Disease Models, Animal; Female; Finite Element Analysis; Humans; Macaca mulatta; Osteoporosis; Ovariectomy; X-Ray Microtomography

Topics: Biphenyl Compounds; Cathepsin K; Clinical Trials as Topic; Drug Approval; Enzyme Inhibitors; Fractures, Bone; Humans; Osteoporosis; United States; United States Food and Drug Administration

Topics: Biphenyl Compounds; Female; Fractures, Bone; Humans; Osteoporosis; Osteoporosis, Postmenopausal; Placebos; Postmenopause; Practice Patterns, Physicians'; Randomized Controlled Trials as Topic; Selective Estrogen Receptor Modulators; Time Factors; Treatment Outcome

Topics: Adaptor Proteins, Signal Transducing; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Biphenyl Compounds; Bone Density Conservation Agents; Bone Morphogenetic Proteins; Cathepsin K; Denosumab; Diphosphonates; Drug Approval; Drugs, Investigational; Genetic Markers; Germany; Humans; Medication Adherence; Osteoporosis; Osteoporosis, Postmenopausal; Osteoporotic Fractures; RANK Ligand

Amino ketone warheads were explored as alternatives to the nitrile group of a potent and selective cathepsin K inhibitor. The resulting compounds were potent and selective inhibitors of cathepsin K and these nitrile replacements had a significant effect on metabolism and pharmacokinetics.

Topics: Animals; Bile; Biphenyl Compounds; Cathepsin K; Chemistry, Pharmaceutical; Drug Design; Humans; Inhibitory Concentration 50; Ketones; Models, Chemical; Nitriles; Osteoporosis; Rats; Structure-Activity Relationship; Time Factors