Pharmacoinformatics and hypothetical studies on allicin, curcumin, and gingerol as potential candidates against COVID-19-associated proteases.

Medicinal plants have been known to provide the essential raw material for the majority of antiviral drugs. This study demonstrated the putative inhibitory potential of curcumin, allicin, and gingerol towards cathepsin K, COVID-19 main protease, and SARS-CoV 3 C-like protease. The pharmacokinetic properties were predicted through the SwissADME server while the corresponding binding affinity of the selected phytocompounds towards the proteins was computed using PyRx-Python Prescription 0.8 and the binding free energy were computed based on conventional molecular dynamics using LARMD server. The ADMET properties revealed all the drugs possess drug-like properties. Curcumin has the highest binding affinities with all the selected proteases while allicin has the lowest binding affinities towards the proteases. Moreover, it was observed that curcumin exhibited the highest binding free energy of -17.90 ± 0.23,  -18.21 ± 0.25, and -9.67 ± 0.08 kcal/mol for Cathepsin K, COVID-19 main protease, and SARS-CoV 3 C-like protease, respectively. Based on the activities of the phytocompounds against coronavirus target proteases involved in the viral entry as evident from the results, the study, therefore, suggests that these phytocompounds could be valuable for the development of drugs useful for the prevention of coronavirus entry and replication.Communicated by Ramaswamy H. Sarma.

Preclinical evaluation of [11 C]L-235 as a radioligand for Positron Emission Tomography cathepsin K imaging in bone.

The cathepsin K (CatK) enzyme is abundantly expressed in osteoclasts, and CatK inhibitors have been developed for the treatment of osteoporosis. In our effort to support discovery and clinical evaluations of a CatK inhibitor, we sought to discover a radioligand to determine target engagement of the enzyme by therapeutic candidates using positron emission tomography (PET). L-235, a potent and selective CatK inhibitor, was labeled with carbon-11. PET imaging studies recording baseline distribution of [11 C]L-235, and chase and blocking studies using the selective CatK inhibitor MK-0674 were performed in juvenile and adult nonhuman primates (NHP) and ovariectomized rabbits. Retention of the PET tracer in regions expected to be osteoclast-rich compared with osteoclast-poor regions was examined. Increased retention of the radioligand was observed in osteoclast-rich regions of juvenile rabbits and NHP but not in the adult monkey or adult ovariectomized rabbit. Target engagement of CatK was observed in blocking studies with MK-0674, and the radioligand retention was shown to be sensitive to the level of MK-0674 exposure. [11 C]L-235 can assess target engagement of CatK in bone only in juvenile animals. [11 C]L-235 may be a useful tool for guiding the discovery of CatK inhibitors.

Tanshinones that selectively block the collagenase activity of cathepsin K provide a novel class of ectosteric antiresorptive agents for bone.

BACKGROUND AND PURPOSE: Attempts to generate active site-directed cathepsin K (CatK) inhibitors for the treatment of osteoporosis have failed because of side effects. We have previously shown that an ectosteric tanshinone CatK inhibitor isolated from Salvia miltiorrhiza blocked, selectively, the collagenase activity of CatK, without affecting the active site and demonstrated its bone-preserving activity in vivo. Here, we have characterize the antiresorptive potential of other tanshinones, which may provide a scaffold for side effect-free CatK inhibitors. EXPERIMENTAL APPROACH: Thirty-one tanshinones were tested for their activity against CatK in enzymic and cell-based assays. The inhibitory potency against triple helical and fibrillar collagen degradation was determined in enzymic assays, by scanning electron microscopy and mechanical strength measurements. Human osteoclast assays were used to determine the effects of the inhibitors on bone resorption, its reversibility and osteoclastogenesis. Binding sites were characterized by molecular docking. KEY RESULTS: Twelve compounds showed highly effective anti-collagenase activity and protected collagen against destruction and mechanical instability without inhibiting the hydrolysis of non-collagenous substrates. Six compounds were highly effective in osteoclast bone resorption assays with IC50 values of <500 nM. None of these tanshinones had effects on cell viability, reversibility of bone resorption inhibition and osteoclastogenesis. The core pharmacophore of the tanshinones appears to be the three-ring system with either a para- or ortho-quinone entity. CONCLUSIONS AND IMPLICATIONS: Our study identified several potent ectosteric antiresorptive CatK inhibitors from the medicinal plant, S. miltiorrhiza, which may avoid side effects seen with active site-directed inhibitors in clinical trials.

Icariin ameliorates dexamethasone­induced bone deterioration in an experimental mouse model via activation of microRNA­186 inhibition of cathepsin K.

The present study aimed to investigate bone deterioration in glucocorticoid­induced osteoporosis (GIOP) mice, and the anti­osteoporosis effect and underlying molecular mechanism of icariin. Dexamethasone (DSM) treatment was demonstrated to facilitate the induction of hypercalciuria in GIOP mice. Icariin treatment reversed the dexamethasone (DXM)­induced disequilibrium of calcium homeostasis and bone resorption, and increased serum alkaline phosphatase, tartrate resistant acid phosphatase, osteocalcin and deoxypyridinoline. Haematoxylin and eosin staining revealed an increase in disconnections and separation in the trabecular bone network of the tibial proximal metaphysis, in the GIOP group. Icariin treatment reversed the DXM­induced trabecular deleterious effects, and stimulated bone remodeling in GIOP mice. Furthermore, the results demonstrated that the mRNA and protein expression of cathepsin K were significantly increased in GIOP mice, compared with the control group. Icariin treatment may suppress the expression of cathepsin K in the tibia of GIOP mice. The levels of microRNA (miR)­186 were markedly reduced in the tibia of GIOP mice compared with control group; however, this was inhibited by icariin treatment. Bioinformatics analysis demonstrated that miR­186 regulates cathepsin K via binding to the upstream 3'­untranslated region. Furthermore, transfection with miR­186 mimics resulted in inhibition of cathepsin K expression, whereas miR­186 inhibitors facilitated cathepsin K expression in osteoclasts. In conclusion, the present study demonstrated the protective effects of icariin against bone deteriorations in the experimental GIOP mice, and the underlying mechanism was mediated, at least partially, via activation of miR­186­mediated suppression of cathepsin K. These results provide evidence to support the use of icariin as a therapeutic approach in the management of glucocorticoid­induced bone loss, and the disequilibrium of calcium homeostasis.

Inhibition of cathepsin K promotes osseointegration of titanium implants in ovariectomised rats.

The bone mineral deficiency in osteoporosis poses a threat to the long-term outcomes of endosseous implants. The inhibitors of cathepsin K (CatK) significantly affect bone turnover, bone mineral density (BMD) and bone strength in the patients with osteoporosis. Therefore, we hypothesised that the application of a CatK inhibitor (CatKI) could increase the osseointegration of endosseous implants under osteoporotic conditions. Odanacatib (ODN), a highly selective CatKI, was chosen as the experimental drug. Sixteen rats were randomised into 4 groups: sham, ovariectomy (OVX) with vehicle, OVX with low-dose ODN (5 mg/kg) and OVX with high-dose ODN (30 mg/kg). Titanium implants were placed into the distal metaphysis of bilateral femurs of each OVX rat. After 8 weeks of gavaging, CatKI treatment increased the removal torque, BMD and bone-to-implant contact (BIC). Moreover, high-dose CatKI exerted a better influence than low-dose CatKI. Furthermore, CatKI treatment not only robustly suppressed CatK gene (CTSK) expression, but also moderately reduced expression of the osteoblast-related genes Runx2, Collagen-1, BSP, Osterix, OPN, SPP1 and ALP. Thus, CatKI could affect the osteoblast-related genes, although the balance of bone turnover was achieved mainly by CatK inhibition. In conclusion, CatKI prevented bone loss and aided endosseous implantation in osteoporotic conditions.

Proceedings of the 2016 Santa Fe Bone Symposium: New Concepts in the Management of Osteoporosis and Metabolic Bone Diseases.

The Santa Fe Bone Symposium is an annual meeting of healthcare professionals and clinical researchers that details the clinical relevance of advances in knowledge of skeletal diseases. The 17th Santa Fe Bone Symposium was held in Santa Fe, New Mexico, USA, on August 5-6, 2016. The program included plenary lectures, oral presentations by endocrinology fellows, meet-the-professor sessions, and panel discussions, all aimed to provide ample opportunity for interactive discussions among all participants. Symposium topics included recent developments in the translation of basic bone science to patient care, new clinical practice guidelines for postmenopausal osteoporosis, management of patients with disorders of phosphate metabolism, new and emerging treatments for rare bone diseases, strategies to enhance fracture healing, and an update on Bone Health Extension for Community Healthcare Outcomes, using a teleconferencing platform to elevate the level of knowledge of healthcare professionals in underserved communities to deliver best practice care for skeletal diseases. The highlights and important clinical messages of the 2016 Santa Fe Bone Symposium are provided herein by each of the faculty presenters.

Flavonoids from the roots of Artocarpus heterophyllus.

Four new flavonoids, artoheteroids A-D (1-4), together with six known ones (5-10), were isolated from the roots of Artocarpus heterophyllus. Their structures were elucidated by spectroscopic methods, including 1D and 2D NMR, UV, IR, CD, and HR-ESI-MS. All isolated compounds were screened for their inhibitory abilities against cathepsin K (CatK). Among them, compounds 1-2, 4-6, and 10 were found to have suppression capabilities against CatK with IC50 values ranging from 1.4 to 93.9µM.

Discovery of a New Class of Cathepsin K Inhibitors in Rhizoma Drynariae as Potential Candidates for the Treatment of Osteoporosis.

Rhizoma Drynariae (RD), as one of the most common clinically used folk medicines, has been reported to exert potent anti-osteoporotic activity. The bioactive ingredients and mechanisms that account for its bone protective effects are under active investigation. Here we adopt a novel in silico target fishing method to reveal the target profile of RD. Cathepsin K (Ctsk) is one of the cysteine proteases that is over-expressed in osteoclasts and accounts for the increase in bone resorption in metabolic bone disorders such as postmenopausal osteoporosis. It has been the focus of target based drug discovery in recent years. We have identified two components in RD, Kushennol F and Sophoraflavanone G, that can potentially interact with Ctsk. Biological studies were performed to verify the effects of these compounds on Ctsk and its related bone resorption process, which include the use of in vitro fluorescence-based Ctsk enzyme assay, bone resorption pit formation assay, as well as Receptor Activator of Nuclear factor κB (NF-κB) ligand (RANKL)-induced osteoclastogenesis using murine RAW264.7 cells. Finally, the binding mode and stability of these two compounds that interact with Ctsk were determined by molecular docking and dynamics methods. The results showed that the in silico target fishing method could successfully identify two components from RD that show inhibitory effects on the bone resorption process related to protease Ctsk.

Novel advances in the treatment of osteoporosis.

INTRODUCTION: 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. SOURCES OF DATA: 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. AREAS OF AGREEMENT: 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. AREAS OF CONTROVERSY: 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. GROWING POINTS: As with all new treatments, we await results of long-term use and experience in 'real life' patient populations. AREAS TIMELY FOR DEVELOPING RESEARCH: 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.

JiangTang XiaoKe granule attenuates cathepsin K expression and improves IGF-1 expression in the bone of high fat diet induced KK-Ay diabetic mice.

AIM: To assess the beneficial effects of JiangTang XiaoKe (JTXK) granule on the bone metabolism in high fat diet (HFD) fed KK-Ay diabetic mice. MATERIALS AND METHODS: The KK-Ay mice were used as a diabetic model, while C57BL/6 mice were utilized as the non-diabetic control. The left tibia was used for determining bone mineral density (BMD) and bone ash coefficient. The HE and alizarin red S staining of femur were employed to evaluate bone pathology and calcium deposition. The expressions of alkaline phosphatase (ALP), insulin growth factor 1 (IGF-1) and cathepsin K were assessed by western blotting and immunohistochemical staining. KEY FINDINGS: JTXK granule significantly improved the bone ash coefficient, the distribution of trabecular bone and the calcification nodules deposition in KK-Ay mice with diabetes. IGF-1 and ALP expressions were significantly decreased, and cathepsin K expression was dramatically increased in the HFD fed KK-Ay diabetic model mice, which can be reversed by JTXK granule treatment. JTXK granule at medium or high dosage was more efficient in improving diabetic bone quality when compared with that in mice with a low dosage. However, the BMD values in each group of KK-Ay diabetic mice were not significantly different. SIGNIFICANCE: We demonstrate that cathepsin K expression is increased in KK-Ay diabetic mouse model. JTXK granule treatment inhibits osteoclastic bone resorption and promotes the new bone formation by decreasing cathepsin K activity and increasing IGF-1 and ALP levels. These changes may contribute to the increase of bone strength and thus reducing the risk of bone fractures.

Isoprenylated Flavonoids from Roots of Artocarpus styracfolius.

Seven isoprenylated flavonoids were isolated from Artocarpus styracifolius, including one new triisoprenylated flavone, styracifolin D (1,) and six known ones, artocarpone B (2), kuwanon C (3), 6-C-prenyl luteolin (4), albanin A (5), 2,4,2',4'-tetrahydroxy-3'-(3-methyl-2-butenyl)-chalcone (6), and 3'-[γ-hydroxymethyl-(E)- γ-methylallyl]-2,4,2',4'-tetrahydroxychalcone 11'-0-coumarate (7). The structures of these compounds were determined by analysis of their spectroscopic and mass spectrometric data. Of them, 3 and 5 exhibited inhibitory effects on cathepsin K with IC(50) values of 114.6 and 7.4 µM, respectively.

Determination of in Vivo Enzyme Occupancy Utilizing Inhibitor Dissociation Kinetics.

During drug discovery, assessment of in vivo target occupancy by therapeutic candidates is often required for predicting clinical efficacy. Current strategies for determining target occupancy include using radiolabeled or irreversible surrogates, which can be technically challenging, and the results are often not sufficiently quantitative. We developed a straightforward method by applying slow-dissociation kinetics to quantitatively determine enzyme occupancy without using specialized reagents. We applied this method to determine occupancy of Cathepsin K inhibitors in bone tissues harvested from rabbit femurs. Tissues from dosed animals were harvested, flash frozen, lysed, then analyzed by a jump-dilution assay with substrate. The rate of substrate turnover was monitored continuously until reaching steady state and progress curves were fit with the equation [product] = vst + ((vi - vs)/kobs)(1 - exp(-kobst)). The initial rate vi represents the residual activity of the enzyme before inhibitor dissociation; vs is the reaction rate after dissociation of the inhibitor. Occupancy is derived from the ratio of vi/vs. A significant benefit of the method is that data from both the occupied and unoccupied states are obtained in the same assay under identical conditions, which provides greater consistency between studies. The Cat K inhibitor MK-0674 (in vitro IC50 1 nM) was tested in young rabbits (<6 month old) and showed a dose-dependent increase in occupancy, reaching essentially complete occupancy at 1.0 mg/kg. In addition the method enables measurement of the total Cat K in the target tissue. Results confirmed complete occupancy even as the osteoclasts responded to higher doses with increased enzyme production.

Short-term and long-term effects of osteoporosis therapies.

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.

[Cathepsin K antagonists: preclinical and clinical data]. / Cathepsin K-Inhibitoren: präklinische und klinische Daten.

Cathepsin K, a cysteine protease, is an essential enzyme in degradation of collagen type I. Since cathepsin K is relatively specific to osteoclasts, it represents a promising candidate for drug development. In the past decades, efforts have been made in developing highly potent, selective and orally applicable cathepsin K inhibitors. In contrast to balicatib and relacatib, whose drug development programmes were stopped due to cutaneous side-effects related to limited drug specificity, the more specific cathepsin K inhibitors odanacatib (ODN) and ONO-5334 have entered clinical trials. Odanacatib progressively increases bone mineral density (BMD) and decreases bone resorption markers in postmenopausal women with low BMD. Its clinical efficacy and safety was confirmed by several clinical studies but indicates that odanacatib is characterized by a resolution-of-effect with increases in bone resorption and rapid decreases in BMD following treatment discontinuation. A phase III fracture prevention study in postmenopausal women with osteoporosis is currently in the final phase.

Odanacatib for the treatment of postmenopausal osteoporosis: development history and design and participant characteristics of LOFT, the Long-Term Odanacatib Fracture Trial.

SUMMARY: Odanacatib is a cathepsin K inhibitor investigated for the treatment of postmenopausal osteoporosis. Phase 2 data indicate that 50 mg once weekly inhibits bone resorption and increases bone mineral density, with only a transient decrease in bone formation. We describe the background, design and participant characteristics for the phase 3 registration trial. INTRODUCTION: Odanacatib (ODN) is a selective cathepsin K inhibitor being evaluated for the treatment of osteoporosis. In a phase 2 trial, ODN 50 mg once weekly reduced bone resorption while preserving bone formation and progressively increased BMD over 5 years. We describe the phase III Long-Term ODN Fracture Trial (LOFT), an event-driven, randomized, blinded placebo-controlled trial, with preplanned interim analyses to permit early termination if significant fracture risk reduction was demonstrated. An extension was planned, with participants remaining on their randomized treatment for up to 5 years, then transitioning to open-label ODN. METHODS: The three primary outcomes were radiologically determined vertebral, hip, and clinical non-vertebral fractures. Secondary end points included clinical vertebral fractures, BMD, bone turnover markers, and safety and tolerability, including bone histology. Participants were women, 65 years or older, with a BMD T-score≤-2.5 at the total hip (TH) or femoral neck (FN) or with a prior radiographic vertebral fracture and a T-score≤-1.5 at the TH or FN. They were randomized to ODN or placebo tablets. All received weekly vitamin D3 (5600 international units (IU)) and daily calcium supplements as needed to ensure a daily intake of approximately 1200 mg. RESULTS: Altogether, 16,713 participants were randomized at 387 centers. After a planned interim analysis, an independent data monitoring committee recommended that the study be stopped early due to robust efficacy and a favorable benefit/risk profile. Following the base study closeout, 8256 participants entered the study extension. CONCLUSIONS: This report details the background and study design of this fracture end point trial and describes the baseline characteristics of its participants.

Efficacy of a cathepsin K inhibitor in a preclinical model for prevention and treatment of breast cancer bone metastasis.

Cathepsin K (CatK) is essential for osteoclast-mediated bone resorption. CatK expression is also detected in breast cancer cells that metastasize to bone. Here, the CatK inhibitor L-235 dosed in prevention (10, 30, and 100 mg/kg, p.o., b.i.d.) or treatment regimen (30 mg/kg) was compared with the bisphosphonate zoledronic acid (ZOL, 7.5 µg/kg/wk, s.c.) in the intratibial injection model of MDA-MB-231 breast carcinoma in nude rats. Progression of osteolysis, skeletal tumor burden, and local metastasis was evaluated by radiography through 42 days and ex vivo µCT and histology. IHC and RT-PCR confirmed the increases in CatK protein and mRNA levels in human breast cancer primary and metastatic tumors. In the experimental model of breast cancer bone metastasis, L-235 dosed in preventive mode resulted in a dose-related reduction of osteolysis of 72%, 75%, and 87% respectively, compared with ZOL by 86% versus intact. Similarly, L-235 significantly reduced intratibial tumor volume by 29%, 40%, and 63%, respectively, compared with 56% by ZOL versus vehicle. Efficacy of L-235 and ZOL on reduction of osteolytic lesions and tumor burden was comparable in treatment versus preventive regimens. All L-235 doses inhibited cortical disruption and extraskeletal tumor growth to a level comparable with ZOL. Assessment of local metastasis demonstrated that treatment with the CatK inhibitor was more effective than ZOL in reducing breast cancer invasion. These data support the role of CatK in breast cancer skeletal growth and metastasis and CatK inhibitors may represent a novel oral therapy for treatment of metastatic breast cancer.

Salvia miltiorrhiza: an ancient Chinese herbal medicine as a source for anti-osteoporotic drugs.

ETHNOPHARMACOLOGICAL RELEVANCE: Red sage (Salvia miltiorrhiza Bunge), also known as Danshen in Chinese, has been used historically and is currently exploited in combination with other herbs to treat skeletal diseases in traditional Chinese medicine (TCM). With the advance of modern analytical technology, a multitude of bone-targeting, pharmaceutically active, compounds has been isolated and characterized from various sources of TCM including those produced in Salvia miltiorrhiza root. The aim of the review is to provide a comprehensive overview about the historical TCM interpretation of the action of Salvia miltiorrhiza in osteoporosis, its use clinical trials, its main phytochemical constituents, and its action on bone-resorptive and bone formation-stimulating mechanisms in in vitro and in vivo studies. MATERIALS AND METHODS: Literature sources used were Pubmed, CNKI.net, Cqvip.com, PubChem, and the Web of Science. For the inquiry, keywords such as Salvia, danshen, osteoporosis, bone, osteoclast and osteoblast were used in various combinations. About 130 research papers and reviews were consulted. RESULTS: In TCM, the anti-osteopororotic effect of Salvia miltiorrhiza is ascribed to its action on liver and blood stasis as main therapeutic targets defining osteoporosis. 36 clinical trials were identified which used Salvia miltiorrhiza in combination with other herbs and components to treat post-menopausal, senile, and secondary osteoporosis. On average the trials were characterized by high efficacy (>80%) and low toxicity problems. However, various limitations such as small patient samples, short treatment duration, frequent lack of detailed numerical data, and no clear endpoints must be taken into consideration. To date, more than 100 individual compounds have been isolated from this plant and tested in various animal models and biochemical assays. Compounds display anti-resorptive and bone formation-stimulating features targeting different pathways in the bone remodeling cycle. Pathways affected include the activation of osteoblasts, the modulation of osteoclastogenesis, and the inhibition of collagen degradation by cathepsin K. CONCLUSIONS: The inclusion of Salvia miltiorrhiza in more than 30% of all herbal clinical trials successfully targeting osteoporosis has stimulated significant interest in the identification and characterization of individual constituents of this herb. The review highlights the anti-osteoporotic potential of Salvia miltiorrhiza in clinical applications and the potential of the herb to provide potent compounds targeting specific pathways in bone resorption and bone formation.

Status of drug development for the prevention and treatment of osteoporosis.

INTRODUCTION: 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. AREAS COVERED: 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. EXPERT OPINION: 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.

6-Shogaol inhibits chondrocytes' innate immune responses and cathepsin-K activity.

SCOPE: Ginger has long been used in traditional Asian medicine to treat osteoarthritis. Indeed, scientific research has reported that ginger derivatives (GDs) have the potential to control innate immune responses. Given the widespread use and demonstrated properties of GDs, we set out to study their anti-inflammatory and anticatabolic properties in chondrocytes. METHODS AND RESULTS: 6-shogaol (6-S), the most active GD, was obtained from ginger. 6-S was not toxic as measured by MTT assay, and inhibited NO production and IL-6 and MCP-1 induced gene expression in LPSbut not in IL-1ß-stimulated chondrocytes. 6-S also inhibited LPS-mediated ERK1/2 activation as well as NOS2 and MyD88 induced expression as determined by Western blot. Moreover, zymography revealed that 6-S inhibited matrix metalloproteinases (MMP) 2/9 induction in LPS-treated cells. Hydrated 6-S was modified to obtain a compound (SSi6) without 6-S potential anti-inflammatory properties. Both 6-S and SSi6 inhibited cathepsin-K activity. CONCLUSION: 6-S blocked TLR4-mediated innate immune responses and MMP induction in chondrocytes. These results, together with GDs-mediated cathepsin-K inhibition, suggest the potential for GDs use against cartilage and bone degradation. Therefore, considering that clinical trials involving oral administration of ginger achieved relevant nontoxic GDs serum concentrations, we suggest that a ginger-supplemented diet might reduce OA symptoms.

Effects of odanacatib on BMD and safety in the treatment of osteoporosis in postmenopausal women previously treated with alendronate: a randomized placebo-controlled trial.

CONTEXT: Odanacatib (ODN) is a selective cathepsin K inhibitor being developed to treat osteoporosis. OBJECTIVE: The effects of ODN were evaluated on bone mineral density (BMD), biochemical markers of bone turnover, and safety in patients previously treated with alendronate. DESIGN: This was a randomized, double-blind, placebo-controlled, 24-month study. SETTING: The study was conducted at private or institutional practices. PARTICIPANTS: Postmenopausal women (n = 243) ≥ 60 years of age with low BMD at the total hip, femoral neck, or trochanter (T-score ≤-2.5 but >-3.5 without prior fracture or ≤-1.5 but >-3.5 with prior fracture) on alendronate for ≥ 3 years. INTERVENTION: The intervention included ODN 50 mg or placebo weekly. MAIN OUTCOME MEASURES: The primary end point was percentage change from baseline of femoral neck BMD at month 24. BMD was assessed by dual-energy x-ray absorptiometry at baseline and 6, 12, and 24 months. Biochemical markers of bone turnover (serum C-telopeptides of type 1 collagen, urinary N-telopeptides of type 1 collagen, serum bone specific alkaline phosphatase, and serum N-terminal propeptide of type 1 collagen) were measured at baseline and 3, 6, 12, 18, and 24 months. RESULTS: In the ODN group, BMD changes from baseline at the femoral neck, trochanter, total hip, and lumbar spine at 24 months (1.7%, 1.8%, 0.8%, and 2.3%, respectively) were significantly different from the placebo group. ODN significantly decreased urinary N-telopeptides of type 1 collagen to creatinine ratio and significantly increased serum N-terminal propeptide of type 1 collagen compared with placebo. Serum C-telopeptides of type 1 collagen was unexpectedly increased with ODN treatment. The safety profile appeared similar between groups. CONCLUSIONS: ODN provided incremental BMD gains in osteoporotic women after alendronate treatment.