odanacatib (MK-0822) / Merck (MSD) - LARVOL DELTA

Pyrrolopyrimidines: A promising scaffold for the development of novel cathepsin K inhibitors. (PubMed, Eur J Med Chem) - "Incorporating a basic residue capable of forming ionic interactions within the side chain of the core pyrrolopyrimidine structure enhanced selectivity for cathepsin K. In particular, analog 9d exhibited a superior selectivity compared to odanacatib. Furthermore, the preclinical compound 9d exhibited promising oral bioavailability of 28.3 %, which, along with a significant reduction in systemic toxicity, further supports the development this compound as an oral therapeutic agent. The promising pharmacokinetic properties and low toxicity of 9d make it an ideal candidate for osteoporosis treatment."

Journal • Osteoporosis • Rheumatology • CTSK

Trans-endothelial Trafficking of Fibroblast-like Synoviocytes Amplifies Synovial Inflammation in Rheumatoid Arthritis (ACR Convergence 2025) - "Our findings demonstrate that FLS undergo trans-endothelial migration in RA synovium and identify a mechanism driven by such migration and involving PKD1 and CTSK, which amplifies EC-driven inflammation and RA severity. These results might also provide mechanistic insight into the generation of PRIME cells and highlight FLS–EC spatial interactions as a potential therapeutic target in RA."

Immunology • Inflammation • Inflammatory Arthritis • Osteoarthritis • Rheumatoid Arthritis • Rheumatology • CTSK • PKD1 • PRKD1

Cathepsin K (CTSK) in Inflammatory and Immune-Mediated Diseases. (PubMed, Immunol Invest) - "Small-molecule inhibitors (odanacatib, MIV-711, ONO-5334) and biologics attenuate pathology in arthritis, periodontitis, and atherosclerosis. CTSK is a promising diagnostic biomarker and therapeutic target, yet its promise hinges on inhibitors that act only where needed, sparing other tissues. Next steps must therefore craft more selective allosteric compounds and test ways to confine them to diseased sites."

Journal • Review • Atherosclerosis • Cardiovascular • Dental Disorders • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammatory Arthritis • Inflammatory Bowel Disease • Oncology • Periodontitis • Rheumatoid Arthritis • Rheumatology • CTSK

Cathepsin K and glycosaminoglycans differentially regulate matrix metalloproteinase activity in dentin under various pH conditions. (PubMed, Int J Biol Macromol) - "The direct effects of catK were evaluated in the catK-active, catK-deficient, and odanacatib (ODN)-inhibited groups, whereas indirect GAG/ tissue inhibitor of metalloproteinase (TIMP)-mediated regulation was assessed in the catK-active, ODN-inhibited, and chondroitin sulfate (CS)-treated groups through dimethylmethylene blue (DMMB) assays, in situ zymography, and immunofluorescence staining...These results demonstrate the dual regulatory mechanism of catK involving direct MMP activation and GAG-mediated TIMP modulation, which is strongly pH dependent. The increased efficacy of ODN under acidic conditions suggests its therapeutic potential for preventing dentin erosion when it is applied following acidic challenges."

Journal • CTSK • MMP2 • MMP9 • TIMP1 • TIMP2

Odanacatib Coating Supports Osseointegration of Implants: A Preclinical Study. (PubMed, Clin Oral Implants Res) - "These findings suggest that topical delivery of a cathepsin K inhibitor can support the early osseointegration phase in an ectopic rodent implantation model."

Journal • Preclinical • Osteoporosis • Rheumatology • CTSK

Targeting Cathepsin K to Accelerate Diabetic Wound Healing. (PubMed, ACS Pharmacol Transl Sci) - "This study examined the effects of odanacatib, a cathepsin K inhibitor, on wound healing in a diabetic porcine model...Innovation and This study is the first to demonstrate that inhibiting cathepsin K, either genetically or pharmacologically, improves diabetic wound healing. These findings position cathepsin K as a promising therapeutic target for the treatment of chronic wounds."

Journal • Diabetes • Metabolic Disorders • CD31 • CTSK • PECAM1

Treatment-related changes in total hip bone mineral density are applicable to trials of varied study designs and to drugs with differing mechanisms of action: meta-regression results from the FNIH-ASBMR SABER study. (PubMed, J Bone Miner Res) - "We analyzed individual patient data from 22 randomized, placebo-controlled trials (17 anti-resorptive, 3 PTH analogues, 1 odanacatib, and 1 romosozumab placebo-controlled phase), and three trials of an anabolic followed by an anti-resorptive(1 PTH analogue and 2 romosozumab). For trials of an anabolic followed by an anti-resorptive, the association between THBMD change and fracture risk reduction was similar to that for the placebo-controlled monotherapy trials. Our analyses indicate robust associations between treatment-induced THBMD changes and fracture risk reduction across various anti-osteoporosis therapies and trial designs, suggesting that treatment-induced changes in THBMD predict anti-fracture efficacy regardless of drug mechanism or trial design."

Journal • Musculoskeletal Diseases • Orthopedics • Osteoporosis • Rheumatology

Calcium-dependent pathway as a primary cause of hypoxic RGC damage in monkey retinal explants. (PubMed, PLoS One) - "Calcium-independent cathepsins do not contribute to RGC damage in monkey retinal explants cultured under hypoxia/reperfusion. In contrast, calcium influx from extracellular sources plays a critical role in inducing RGC damage. Elevated intracellular calcium levels could activate calpains, leading to RGC damage; however, other calcium-dependent pathways might also be involved in this process."

Journal • Preclinical • Glaucoma • Ophthalmology • Retinal Disorders • CAPN1 • CTSS

Cathepsin K inhibitors promote osteoclast-osteoblast communication and engagement of osteogenesis. (PubMed, JBMR Plus) - "Therefore, we used a novel approach, co-culturing human osteoclasts and osteoblast lineage cells on bone slices and monitoring through time-lapse their response to an active site (odanacatib) or an ectosteric (T06) cathepsin K inhibitor...The combined effects of cathepsin K on resorption and formation render cathepsin K inhibitors unique tools to prevent bone loss. They stress the clinical interest of developing ectosteric inhibitors that may not have the side effects of active site inhibitors."

Journal • Osteoporosis • CTSK

Treatment-Related Changes In Total Hip Bone Mineral Density And Fracture Risk Reduction For Trials With Active Control And Sequential Therapy: The Fnih-Asbmr-Sabre Project (ENDO 2025) - "This analysis aimed to determine if these associations and STEs apply to trials using active control or sequential therapies.Material and methods We used individual patient data from 19 trials: 16 randomized, placebo-controlled trials (14 anti-resorptive, 1 teriparatide, 1 odanacatib), and 3 trials with active control or sequential therapy (1 abaloparatide/alendronate and 2 romosozumab/alendronate or denosumab).For each trial, we calculated the treatment-related difference in mean percentage change in THBMD at 24 months and the risk reductions for the entire follow-up period. In trials with active control or sequential therapy, the increase in THBMD was greater than STE and associated with a significant decrease in fracture risk: the increase in THBMD was 4.57%; 3.69% and 3.12%respectively for romosozumab/denosumab, romosozumab/alendronate and abaloparatide/alendronate trials, and the STE was 1.43% for vertebral and 2.04% for all clinical fractures. Conclusion Our..."

Late-breaking abstract • Musculoskeletal Diseases • Orthopedics • Osteoporosis • Rheumatology

Enantioconvergent Synthesis of α-Fluoroalkyl Alcohols Enabled by Photocatalytic Radical Brook Rearrangement. (PubMed, Angew Chem Int Ed Engl) - "The reaction exhibits exceptional scope (>40 examples), outstanding enantiocontrol (up to 99% ee), and broad functional group tolerance. The synthetic utility is demonstrated through formal syntheses of bioactive Odanacatib and LX-1031, along with diverse downstream derivatizations."

Journal

Sophoraflavanone G as an ectosteric inhibitor of cathepsin K attenuates ovariectomy-induced bone loss by suppressing bone resorption. (PubMed, Phytomedicine) - "SG acts as an ectosteric CTSK inhibitor, offering a safer alternative for postmenopausal osteoporosis treatment by selectively inhibiting bone resorption without the side effects associated with active-site inhibitors."

Journal • Osteoporosis • Rheumatology • CTSK • TGFB1

Cathepsin K cleavage of Angiopoietin-2 creates detrimental Tie2 antagonist fragments in sepsis. (PubMed, J Clin Invest) - "Cathepsin K inhibition with the Phase-3 small molecule inhibitor odanacatib improved survival in distinct murine sepsis models...Septic humans accumulated circulating Angiopoietin-2 fragments, which were associated with adverse outcomes. These results identify cathepsin K as a candidate marker of sepsis and a proteolytic mechanism for the conversion of Angiopoietin-2 from Tie2 agonist to antagonist with therapeutic implications for inflammatory conditions associated with Angiopoietin-2 induction."

Journal • Infectious Disease • Inflammation • Septic Shock • CTSK

CLEAVAGE BY CATHEPSIN K OF ANGIOPOIETIN-2 CREATES TIE2 ANTAGONIST FRAGMENTS IN SEPSIS (SCCM 2025) - "Cathepsin K inhibition with the Phase-3 small molecule inhibitor odanacatib improved survival in distinct murine sepsis models... These results identify a novel proteolytic mechanism for the conversion of ANGPT2 from Tie2 agonist to antagonist with therapeutic implications for inflammatory conditions associated with ANGPT2 induction."

Acute Respiratory Distress Syndrome • Gene Therapies • Infectious Disease • Inflammation • Respiratory Diseases • Septic Shock • CTSK

Cytokine expression of soft tissue cells cultured with titanium discs and their respective supernatants in vitro. (PubMed, Clin Oral Investig) - "The soft tissue surrounding a dental implant can impact rehabilitation success. Understanding how soft tissue cells respond to titanium surface is potentially relevant to understand clinical outcomes."

Journal • Preclinical • Inflammation • Oncology • Oral Cancer • Squamous Cell Carcinoma • CTSK • CXCL8 • IL6

The Management of Osteoporosis in Chronic Kidney Disease: A Review of Diagnostic and Therapeutic Approaches. (PubMed, Cureus) - "While traditional osteoporosis treatments such as bisphosphonates, denosumab, and teriparatide have been adapted for CKD patients, recent innovations have introduced agents aimed at enhancing bone mass and reducing fracture incidence...Osteoporosis management in CKD patients necessitates a personalized approach guided by the disease's stage and individual profile. This review underscores the potential of emerging therapies and emphasizes the need for further research to refine treatment protocols, aiming to enhance patient outcomes in this complex population."

Journal • Review • Chronic Kidney Disease • Musculoskeletal Diseases • Nephrology • Orthopedics • Osteoporosis • Renal Disease • Rheumatology

WILMS TUMOR 1 AND HIF-1Α INDUCE HEPATIC STELLATE CELL INVASION THAT DEVELOPS BRIDGING FIBROSIS IN CHRONIC LIVER INJURY (AASLD 2024) - "Ctsk inhibitor Odanacatib prevented BF formation after the BDL... Spatio-temporal single cell analysis of BF liver and functional assay of HSC defined unique invasive phenotype of HSCs that is distinguished from ECM-producing fully activated HSC. The invasive HSCs and BF formation are regulated by TF WT1 and HIF-1α. We also found that Ctsk is a downstream effector of WT1, which can be a promising therapeutic target for liver fibrosis."

Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Liver Failure • Nephrology • Oncology • Solid Tumor • Wilms Tumor • CTSK • HIF1A • WT1

Immune regulatory and anti-resorptive activities of tanshinone IIA sulfonate attenuates rheumatoid arthritis in mice. (PubMed, Br J Pharmacol) - "The combined anti-resorptive and anti-inflammatory activities characterize T06 as a novel therapeutic agent for RA."

Journal • Preclinical • Immunology • Inflammation • Inflammatory Arthritis • Musculoskeletal Pain • Pain • Rheumatoid Arthritis • Rheumatology • CTSK • IL17A • NFKBIA

Impact of cathepsin K-induced proteoglycans degradation on dentin collagen. (PubMed, Arch Oral Biol) - "CatK-mediated degradation of PGs negatively impacted the stability of collagen fibers, promoted gaps, led to a less organized arrangement of dentin collagen fibers, ultimately increasing collagen degradation."

Journal • CTSK

Efficacy and safety of odanacatib in the treatment of postmenopausal women with osteoporosis: a meta-analysis. (PubMed, J Orthop Surg Res) - "ODN is a promising alternative for the treatment of PMOP on account of its excellent efficacy and credible safety. Unclear links between ODN and cardiovascular AEs require further research to clarify."

Biomarker • Clinical • Journal • Retrospective data • Review • Cardiovascular • Osteoporosis • Rheumatology • CTSK

Enhanced anticancer efficacy of TRAIL-conjugated and odanacatib-loaded PLGA nanoparticles in TRAIL resistant cancer. (PubMed, Biomaterials) - "In conclusion, we evealed that our formulation demonstrated synergistic effects against TRAIL compared with the combination of free drug in vitro and in vivo models. Therefore, TRAIL-ODN-PLGA-NPs may be a novel candidate for TRAIL-induced apoptosis in cancer treatment."

Journal • Oncology • CTSK • IL6

Process-Induced Crystal Surface Anisotropy and the Impact on the Powder Properties of Odanacatib. (PubMed, Pharmaceutics) - "Here, we investigate the surface properties of different batches of Odanacatib prepared through either jet milling or fast precipitation from various solvent systems, all of which meet the particle size specification established to ensure equivalent biopharmaceutical performance. This work highlights the use of orthogonal surface techniques such as Inverse Gas Chromatography (IGC), Brunauer-Emmett-Teller (BET) surface area, contact angle, and X-ray Photoelectron Spectroscopy (XPS) to demonstrate the effect of processing history on particle surface properties to explain differences in bulk powder properties."

Journal

Treatment-Related Changes in Total Hip Bone Mineral Density and Fracture Risk Reduction for Drugs With Different Mechanisms of Action: The FNIH-ASBMR-SABRE Project (ENDO 2024) - "To further explore the use of THBMD as a surrogate endpoint, here we examine whether the association is robust across drugs with different mechanisms of action. We used IDP (n>120,000 participants) from 22 randomized, placebo-controlled, double-blind trials of osteoporosis medications (17 anti-resorptive, 3 PTH analogs, 1 odanacatib, and 1 romosozumab). These results demonstrate that the associations between treatment-related changes in THBMD and fracture risk reductions are robust across anti-osteoporosis therapies with varying mechanisms of action. We conclude that the treatment-related difference in THBMD change would predict fracture reduction equally well for drugs with different mechanisms of action.Unless otherwise noted, all abstracts presented at ENDO must not be released to the press or the public until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins."

Musculoskeletal Diseases • Orthopedics • Osteoporosis • Rheumatology

Real-time analysis of osteoclast resorption and fusion dynamics in response to bone resorption inhibitors. (PubMed, Sci Rep) - "Using live-cell imaging, we monitored the bone resorptive behaviour of OCs during dose-dependent inhibition of CatK by an ectosteric (Tanshinone IIA sulfonate) and an active site inhibitor (odanacatib)...Using an activity-based probe, we demonstrated the presence of active CatK at the resorbing front in pits and trenches. In conclusion, our data document how OCs respond to CatK-inhibition with respect to movement, bone resorption activity, and their attempt to compensate for inhibition by activating fusion."

Journal • Osteoporosis • Rheumatology • CTSK

Cathepsin K inhibition alleviates periodontal bone resorption by promoting type H vessel formation through PDGF-BB/PDGFR-β axis. (PubMed, Oral Dis) - "CTSK inhibition promotes type H vessel formation and attenuates alveolar bone resorption within periodontitis via PDGF-BB/PDGFR-β axis."

Journal • Dental Disorders • Osteoporosis • Periodontitis • CTSK • PDGFRB