Protective effects of sodium butyrate on fluorosis in rats by regulating bone homeostasis and serum metabolism.

Fluorosis due to high fluoride levels in drinking water profoundly affects the development of human skeletal and dental structures. Sodium butyrate (NaB) has been found to regulate overall bone mass and prevent pathological bone loss. However, the mechanism of NaB action on fluorosis remains unclear. In this study, a rat model of fluorosis induced by 100 mg/L sodium fluoride was used to investigate the impact of NaB on bone homeostasis and serum metabolomics. It was found that NaB significantly reduced the levels of bone resorption markers CTX-Ⅰ and TRACP-5B in fluorosis rats. Moreover, NaB increased calcium and magnesium levels in bone, while decreasing phosphorus levels. In addition, NaB improved various bone microstructure parameters, including bone mineral density (BMD), trabecular thickness (Tb. Th), trabecular bone separation (Tb. SP), and structural model index (SMI) in the femur. Notably, NaB intervention also enhanced the antioxidant capacity of plasma in fluorosis rats. Furthermore, a comprehensive analysis of serum metabolomics by LC-MS revealed a significant reversal trend of seven biomarkers after the intervention of NaB. Finally, pathway enrichment analysis based on differential metabolites indicated that NaB exerted protective effects on fluorosis by modulating arginine and proline metabolic pathways. These findings suggest that NaB has a beneficial effect on fluorosis and can regulate bone homeostasis by ameliorating metabolic disorders.

Inhibitory effects of norcantharidin on titanium particle-induced osteolysis, osteoclast activation and bone resorption via MAPK pathways.

Wear particles generated from the surface of implanted prostheses can lead to peri-implant osteolysis and subsequent aseptic loosening. In the inflammatory environment, extensive formation and activation of osteoclasts are considered the underlying cause of peri-implant osteolysis. Current medications targeting osteoclasts for the treatment of particle-induced bone resorption are not ideal due to significant side effects. Therefore, there is an urgent need to develop more effective drugs with fewer side effects. Norcantharidin (NCTD), a derivative of cantharidin extracted from blister beetles, is currently primarily used for the treatment of solid tumors in clinical settings. However, the potential role of NCTD in treating aseptic loosening of the prosthesis has not been reported. In this study, the in vitro results demonstrated that NCTD could effectively inhibit the formation of osteoclasts and bone resorption induced by the RANKL. Consistently, NCTD strongly inhibited RANKL-induced mRNA and protein levels of c-Fos and NFATc1, concomitant with reduced expression of osteoclast specific genes including TRAP, CTR and CTSK. The in vivo data showed that NCTD exerted significant protective actions against titanium particle-induced inflammation and subsequent osteolysis. The molecular mechanism investigation revealed that NCTD could suppress the activations of RANKL-induced MAPK (p38, ERK). Overall, these findings support the potential use of NCTD for the treatment of aseptic loosening following total joint arthroplasty.

Would hyaluronic acid-induced mental bone resorption be a concern? A prospective controlled cohort study and an updated retrospective cohort study.

BACKGROUND: Hyaluronic acid (HA) is a widely used filler for face contouring and is generally believed to be safe and effective. However, there have been reports of HA-related bone erosion in the chin area without clear scientific data regarding its existence, incidence, and severity. This exploratory study was to evaluate HA-related mental bone resorption through a prospective, controlled, observer-blind, nonrandomized clinical trial and a retrospective cohort study. METHODS: On the one hand, a prospective, controlled, nonrandomized, single-shot HA-injection clinical trial was conducted. Computed tomographic scans were collected at baseline and at 6-12 months of follow-up for both HA-injection and control groups. On the other hand, an updated retrospective cohort study compared the HA-injection with a blank control group. The primary outcomes composed of three quantitative parameters [bone resorption index (BRI M and BRI N ), bone resorption thickness ratio] and one subjective evaluation index (severity ranking). Information about demographics, complications, and injection volume were also recorded. RESULTS: From June 2021 to March 2023, 78 patients were prospectively recruited for the study. There was a significant association between HA-injection and bone resorption [BRI M : pre (84.24±8.10%) vs post (79.21±8.70%), P <0.001; BRI N : pre 92.50% (73, 144%) vs 87.99% (63, 132%), P <0.001; bone thickness ratio: HA 24.08% (0, 48%) vs control 0 (0, 17%), P <0.001]. However, there was no difference in large-volume (>1 ml) and small-volume (≦1 ml) injection subgroups [bone resorption thickness ratio: (21.50±10.91%) vs (24.51±11.92%), P =0.350]. The imaging manifestation revealed discernible bone resorption in 35.90% of the patients, with an median bone resorption thickness ratio of 24.08%. Between October of 2019 and March 2023, 95 HA-injection patients (190 semimandibular cases), 95 normal controls were enrolled. The BRI M was significantly lower in the HA-injection group compared to the controls ( P <0.001). CONCLUSIONS: HA may induce bone resorption in the mentum. Large-scale randomized controlled clinical trial is warranted for further confirmation. Patients should be informed of this potential complication.

Efficacy of antiresorptive agents in fibrous dysplasia and McCune Albright syndrome, a systematic review and meta-analysis.

Fibrous dysplasia (FD) is a rare skeletal disorder in which normal bone is replaced by a fibro-osseous tissue, resulting in possible deformities and fractures. The aim of this systematic review and meta-analysis was to synthesize the available evidence on the use of antiresorptive drugs in FD in terms of changes in bone turnover markers (BTMs), bone mineral density (BMD), and reducing pain. Three databases were searched in October 2022, with an update in July 2023. Of the 1037 studies identified, 21 were retained after eligibility assessment. A random-effects model was used to calculate global effect size and the corresponding standard error. Pamidronate and Denosumab were the most reported drugs in a total of 374 patients assessed. The initiation of treatments was accompanied by an average reduction of 40.5% [CI95% -51.6, -29.3] in the bone resorption parameters, and 22.0% [CI95% -31.9, -12.1] in the parameters of bone formation after 6-12 months. BMD was increased in both FD lesions and in the unaffected skeleton. Pain was reduced by 32.7% [CI95% -52.7, -12.6] after 6-12 months of treatment, and by 44.5% [CI95% -65.3, -23.6] after a mean 41.2 months of follow-up. The variation in pain was highly correlated to variation in bone resorption (R2 = 0.08, p < 0.0001) and formation parameters (R2 = 0.17, p < 0.0001). This study supports the overall efficacy of antiresorptive therapies in terms of reducing bone remodeling, improving bone density, and pain in FD.

Xl019, a novel JAK inhibitor, suppressed osteoclasts differentiation induced by RANKL through MAPK signaling pathway.

Inbonemetabolism,osteoclastsare the only cellscapableofresorbingbone. Hyperactivity of osteoclasts may lead to osteolytic disease like osteoporosis and arthritis. Although there are several drugs for the treatment of osteolytic diseases, they have limitations and a variety of side effects. An inhibitor of Janus kinase (JAK), XL019, has shown promising results in the treatment of myelofibrosis and other cancers. But whether it can functionally impact osteoclast activity has not been proven. In this study, the effects of XL019 on osteoclastogenesis and the mechanism pathway were investigated in vitro. It was found that XL019 could impair osteoclasts formation, interfere with bone resorption ability and downregulate the osteoclast-specific genes and proteins expression. Furthermore, Western blot and molecular docking studies demonstrated that XL019 inhibited RANKL-induced osteoclastogenesis by suppressing MAPK signaling. A molecular docking analysis explained how XL019 binds to MAPK pathway factors. In addition, titanium particles induced calvarial osteolysis in mice further confirming its beneficial effect on bone homeostasis in vivo. In conclusion, this study demonstrates that Osteoclastactivity canbeeffectivelyinhibitedby XL019viaMAPK signalingpathway,making it a promising alternative pharmacologicaltreatmentfor bone metabolicdisorders.

Sulforaphene suppresses RANKL-induced osteoclastogenesis and LPS-induced bone erosion by activating Nrf2 signaling pathway.

BACKGROUND AND PURPOSE: Inflammatory disorders have been found to induce bone loss through sustained and persistent activation of osteoclast differentiation, leading to heightened bone resorption. The current pharmacological interventions for combating bone loss to harbor adverse effects or contraindications. There is a pressing need to identify drugs with fewer side effects. EXPERIMENTAL APPROACH: The effect and underlying mechanism of sulforaphene (LFS) on osteoclast differentiation were illustrated in vitro and in vivo with RANKL-induced Raw264.7 cell line osteoclastogenesis and lipopolysaccharide (LPS)-induced bone erosion model. KEY RESULTS: In this study, LFS has been shown to effectively impede the formation of mature osteoclasts induced from both Raw264.7 cell line and bone marrow macrophages (BMMs), mainly at the early stage. Further mechanistic investigations uncovered that LFS suppressed AKT phosphorylation. SC-79, a potent AKT activator, was found to reverse the inhibitory impact of LFS on osteoclast differentiation. Moreover, transcriptome sequencing analysis revealed that treatment with LFS led to a significant upregulation in the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and antioxidant-related genes. Then it's validated that LFS could promote NRF2 expression and nuclear translocation, as well as effectively resist oxidative stress. NRF2 knockdown reversed the suppression effect of LFS on osteoclast differentiation. In vivo experiments provide convincing evidence that LFS is protective against LPS-induced inflammatory osteolysis. CONCLUSION AND IMPLICATIONS: These well-grounded and promising findings suggest LFS as a promising agent to addressing oxidative-stress related diseases and bone loss disorders.

Histological Evaluation of the Effect of Alendronate on the Maxillary Bone of Wistar Rats Combined with Orthodontic Movement of Intense Force / Evaluación Histológica del Efecto del Alendronate en el Hueso Maxilar de Ratas Wistar Combinado con Movimiento de Ortodoncia de Fuerzas Intensas

SUMMARY: To evaluate the histological adverse effects of alendronate administered systemically and topically in combination with orthodontic movement by intense force. Thirty-six 24-week-old female Wistar rats, ovariectomized, were used and divided into three groups (n = 12/group): control, locally treated with saline (0.07 ml/kg/week) (group 1) and experimental, treated with alendronic acid systemically (0.07 mg/kg/week) (group 2) and locally (7 mg/kg/week) (group 3). At 14 days, an orthodontic anchor was installed in the right first molar, and a force of 144 cN was applied for 28 days. The samples were processed for histological evaluation. Descriptive statistics, Shapiro-Wilk tests, one-way ANOVA with Bonferroni correction, one-way repeated measures ANOVA and chi-square tests were performed. All tests were statistically significant at p <0.05. The adverse events found in all groups were inflammation and osteoclastic activity. In the bisphosphonate-treated groups, there were statistically significant differences (p = 0.005) in the osteoclastic activity between the two hemiarcates. All rats in group 2 presented paralytic ileus. Compared to local administration, systemic treatment with alendronic acid produces more adverse effects, such as inflammation, fibrinoid necrosis, and osteoclastic activity. During the application of intense forces, it was not possible to show that there is necrosis associated with bisphosphonates.

Evaluar los efectos adversos histológicos del alendronato administrado sistémica y tópicamente en combinación con movimientos ortodóncicos de fuerza intensa. Treinta y seis ratas Wistar hembras de 24 semanas de edad, ovariectomizadas, fueron utilizadas y divididas en tres grupos (n = 12/grupo): control, tratado localmente con solución salina (0,07 ml/kg/semana) (grupo 1) y experimental, tratados con ácido alendrónico por vía sistémica (0,07 mg/kg/semana) (grupo 2) y local (7 mg/kg/semana) (grupo 3). A los 14 días se instaló un anclaje de ortodoncia en el primer molar derecho y se aplicó una fuerza de 144 cN durante 28 días. Las muestras fueron procesadas para evaluación histológica. Se realizó estadística descriptiva, pruebas de Shapiro-Wilk, ANOVA de una vía con corrección de Bonferroni, ANOVA de medidas repetidas de una vía y pruebas de chi-cuadrado. Todas las pruebas fueron estadísticamente significativas con un p <0,05. Los eventos adversos encontrados en todos los grupos fueron inflamación y actividad osteoclástica. En los grupos tratados con bisfosfonatos hubo diferencias estadísticamente significativas (p = 0,005) en la actividad osteoclástica entre los dos hemiarcados. Todas las ratas del grupo 2 presentaron íleo paralítico. En comparación con la administración local, el tratamiento sistémico con ácido alendrónico produce más efectos adversos, como inflamación, necrosis fibrinoide y actividad osteoclástica. Durante la aplicación de fuerzas intensas, no fue posible demostrar que existe necrosis asociada con los bisfosfonatos.

Multiple doses of SHR-1222, a sclerostin monoclonal antibody, in postmenopausal women with osteoporosis: A randomized, double-blind, placebo-controlled, dose-escalation phase 1 trial.

SHR-1222, a novel humanized monoclonal antibody targeting sclerostin, has been shown to induce bone formation and decrease bone resorption at a single dose ranging 50-400 mg in our previous phase 1 trial. This study was a randomized, double-blind, placebo-controlled, dose-escalation phase 1 trial, which further investigated the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of multiple ascending doses of SHR-1222 in women with postmenopausal osteoporosis (POP). A total of 105 women with POP were enrolled and randomly assigned. Twenty-one received placebo and eighty-four received SHR-1222 sequentially (100 mg QM, n=4; 200 or 300 mg QM, n=20; and 400 or 600 mg Q2M, n=20). The most common adverse events included increased blood parathyroid hormone, increased low-density lipoprotein, increased blood alkaline phosphatase, increased blood cholesterol, back pain, and arthralgia, the majority of which were mild in severity without noticeable safety concerns. Serum SHR-1222 exposure (Cmax,ss and AUC0-tau,ss) increased in a greater than dose-proportional manner. Following multiple doses of SHR-1222, the bone formation markers (terminal propeptide of type I procollagen, bone-specific alkaline phosphatase, and osteocalcin) increased in a dose-dependent manner, whereas the bone resorption marker (ß-C-telopeptide) was downregulated. Accordingly, BMD gains in the lumbar spine, total hip, and femoral neck were observed. The maximum BMD increase from baseline at the lumbar spine was detected in the 300 mg QM cohort (14.6% vs. 0.6% in the placebo group on day 169). Six (6/83; 7.2%) subjects developed anti-SHR-1222 antibodies with no discernible effects on PKs, PDs, and safety. Thus, multiple doses of SHR-1222 showed an acceptable safety profile and dose-dependent plasma exposure in women with POP, and could improve their BMD rapidly and prominently by promoting bone formation and inhibiting bone resorption. These findings further support SHR-1222 as a potential alternative agent for the treatment of POP.

Boric Acid Inhibits RANKL-Stimulated Osteoclastogenesis In Vitro and Attenuates LPS-Induced Bone Loss In Vivo.

Boron and boric acid (BA) can promote osteogenic differentiation and reduce bone resorption, which controls bone growth and maintenance of bone tissue. It has been reported that BA activates PERK-eIF2α signaling to induce cytoplasmic stress granules and cell senescence in human prostate DU-145 cells. However, whether BA can affect osteoclasts formation and LPS-induced inflammatory bone loss, and the role of the PERK-eIF2α pathway in the process, remains unknown. In vitro, RAW264.7 cells were pre-treated with boric acid (BA, 1, 10, 100 µmol/L) for 4 h, and then incubated with receptor activator of nuclear factor-kappaB ligand (RANKL, 50 ng/mL) in the presence or absence of BA for 5 days. CCK-8 and tartrate-resistant acid phosphatase (TRAP) were used to examine cell viability, osteoclastogenesis, and bone resorption; quantitative real-time PCR was performed to examine mRNA levels of c-Fos, nuclear factor of activated T cells, cytoplasmic 1 (NFATc1), TRAP, and cathepsin K; western blotting was used to examine protein expressions of glucose-regulated protein 78 (GRP78), protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), phosphorylated PERK (p-PERK), eukaryotic initiation factor 2α (eIF2α), and phosphorylated eIF2α (p-eIF2α). In vivo, lipopolysaccharide (LPS)-induced bone loss model in mice was established, and micro-computed tomography (micro-CT) scanning, bone biochemical analysis, and osteoclastogenic cytokines were detected to evaluate the effect of BA on LPS-induced bone loss. In our vitro results showed that BA treatment for 5 days inhibited osteoclasts formation as well as osteoclastic bone resorption in a dose-dependent manner. The expression of osteoclasts marker genes c-Fos, NFATc1, TRAP, and cathepsin K were attenuated by BA. Immunoblotting analysis demonstrated that BA attenuated RANKL-induced PERK-eIF2α pathway activation. The in vivo data indicated that BA significantly prevented lipopolysaccharide (LPS)-induced bone loss. Our findings strongly suggest that BA may be a promising agent for the treatment of bone destructive diseases caused by excessive osteoclastogenesis.

Changes in bone turnover markers in adolescents with gastroesophageal reflux disease treated with lansoprazole.

Background: Proton pump inhibitors (PPIs) have been suggested to lead to bone resorption, while the effects of PPIs on the bone mineral metabolism in children has received only limited attention in literature to date. The present study investigates whether lansoprazole alters bone turnover markers in adolescents with gastroesophageal reflux disease (GERD). Patients and methods: Included in the study were adolescents aged 16-18 with GERD and a healthy volunteers group. The GERD patient group was treated with lansoprazole 30 mg once daily for eight weeks. The serum calcium, phosphorus, magnesium, alkaline phosphatase (ALP), parathormone (PTH), 25 (OH) vitamin D, osteocalcin and urinary calcium, creatinine, deoxypyridinoline (DPD), collagen type-1 crosslinked C-telopeptide (CTX) and collagen type-1 crosslinked N-telopeptide (NTX) of both groups were studied before and after the end of the treatment. Results: A comparison of the 30 patients with GERD and the 30 volunteers revealed no significant difference in the serum calcium, phosphorus, magnesium, ALP, urinary calcium/creatinine ratio, 25 (OH) vitamin D and PTH levels measured before and after the lansoprazole treatment, while the osteocalcin, DPD, CTX and NTX values were found to be higher after treatment when compared to those at pre- treatment. Conclusions: The results of this study reveal that eight weeks of treatment with 30 mg lansoprazole daily increased the bone turnover markers of CTX, NTX, DPD and osteocalcin in adolescents aged 16-18.

Anabolic therapy for osteoporosis: update on efficacy and safety.

Anabolic agents for the treatment of osteoporosis increase bone density, improve bone strength, and reduce fracture risk. They are distinguished from antiresorptive drugs by their property of increasing osteoblastic bone formation. Teriparatide and abaloparatide are parathyroid hormone receptor agonists that increase bone remodeling with bone formation increasing more than bone resorption. Romosozumab is a humanized monoclonal antibody to sclerostin that has a "dual effect" of increasing bone formation while decreasing bone resorption. The bone forming effects of anabolic therapy appear to be self-limited, making it imperative that it be followed by antiresorptive therapy to enhance or consolidate the beneficial effects achieved. Teriparatide, abaloparatide, and romosozumab each have unique pharmacological properties that must be appreciated when using them to treat patients at high risk for fracture. Clinical trials have shown a favorable balance of expected benefits and possible risks. Anabolic therapy is superior to bisphosphonates for high-risk patients, with greater benefit when initial treatment is with an anabolic agent followed by an antiresorptive drug, rather than the reverse sequence of therapy. Recent clinical practice guidelines have included recommendations with examples of patients who are candidates with anabolic therapy.

Effects of bisphosphonates on appendicular fracture repair in rodents.

The balance between osteoclastic bone resorption and osteoblastic bone formation is ultimately responsible for maintaining a structural and functional skeleton. Despite their strength, bones do break and the main cause of fractures are trauma and decreased bone mineral density as a result of aging and/or pathology that weakens the bone's microarchitecture and subsequently, its material properties. Osteoporosis is a disease marked by increased osteoclast activity and decreased osteoblastic activity tipping the remodeling balance in favor of bone resorption and can be caused by aging, glucocorticoids, disuse and estrogen-deficiency. Ultimately, this leads to brittle and weaker bones which become more prone to trauma or stress-induced fractures. The current treatment for preventing and treating osteoporotic fractures is the use of antiresorptive drugs such as bisphosphonates (BPs) and denosumab, but unfortunately, their long-term use, especially with alendronate and ibandronate, has been associated with increased risk of atypical femoral fractures (AFFs); femoral diaphyseal fractures distal to the lesser trochanter but proximal to the supracondylar flare. The purpose of this review is to examine the information that exists in the literature examining the effects of BPs on fracture repair of long bones in rodent (rat and mouse) models. The focus on rodents stems from the scientific community's unresolved need to develop small animal models to examine the molecular, cellular, tissue and biomechanical mechanisms responsible for the development of AFFs and how best they can be treated.

Stimulation of osteoclast formation and bone resorption by glucocorticoids: Synergistic interactions with the calcium regulating hormones parathyroid hormone and 1,25(OH)2-vitamin D3.

Osteoporosis is a significant health problem, with skeletal fractures increasing morbidity and mortality. Excess glucocorticoids (GC) represents the leading cause of secondary osteoporosis. The first phase of glucocorticoid-induced osteoporosis is increased bone resorption. In this Chapter, in vitro studies of the direct glucocorticoid receptor (GR) mediated cellular effects of GC on osteoclasts to affect bone resorption and indirect effects on osteoblast lineage cells to increase the RANKL/OPG ratio and stimulate osteoclastogenesis and bone resorption are reviewed in detail, together with detailed descriptions of in vivo effects of GC in different portions of the skeleton in research animals and humans. Brief sections are devoted to contrasting functions of GC in osteonecrosis, vitamin D formation, in vitro and in vivo bone resorptive actions dependent on vitamin D receptor and vitamin D toxicity, as well as the molecular basis of GR action. Included are also more detailed assessments of the interactions of GC with the major calcium regulating hormones, 1,25(OH)2-vitamin D3 and parathyroid hormone, describing the in vitro increases in RANKL/OPG ratios, osteoclastogenesis and synergistic bone resorption that occurs when GC is combined with either 1,25(OH)2-vitamin D3 or parathyroid hormone. Additionally, a molecular basic for the synergistic interaction of GC with 1,25(OH)2-vitamin D3 is provided along with a suggested molecular basic for the interaction between GC and parathyroid hormone.

Drug-associated bone resorption with potential dental and implant implications.

Every year more and more innovative pharmacological agents are introduced medicine, to treat systemic diseases. Due to these rapid and recent advancements, many patients are receiving treatment with a high variety of drugs, such as selective serotonin reuptake inhibitors, bisphosphonates, tumor necrosis factor (TNF)-α inhibitors, cyclosporine, and steroids. Since implant and osseous surgery are common treatment modalities used, within dentistry, it is of critical important to acknowledge and discuss the potential effects of selective serotonin reuptake inhibitors, bisphosphonates, TNF-α inhibitors, cyclosporine, and steroids, on bone healing. The present paper discusses the possible detrimental ramifications and risks these drug classes may have on bone healing.

Low levels of cadmium exposure affect bone by inhibiting Lgr4 expression in osteoblasts and osteoclasts.

BACKGROUND: Cadmium exposure is associated with bone loss. However, the mechanisms involved have not yet been fully understood. Leucine-rich repeat containing GPCR-4 (LGR4) can bind with the receptor activator of nuclear factors κB ligand (RANKL) and inhibit osteoclast formation. In addition, Lgr4 plays an important role in maintaining osteoblast activity. In the present study the effect of cadmium exposure on bone was investigated in terms of Lgr4 expression. METHODS: Raw 264.7 cells and primary osteoblasts were exposed to cadmium (0-60 nM/L). The effects of cadmium on osteoclast formation and osteoblast activity were investigated. Osteoclast differentiation-related (Traf6, NFATc1) and osteoblast-related (RANKL; osteoprotegerin, OPG) gene and protein expression were determined. Lgr4 expression in osteoclasts and osteoblasts were also determined. A rat model was established to show the effects of cadmium (50 mg/L) on bone loss and Lgr4 expression in vivo. RESULTS: Cadmium exposure inhibited osteoblast activities and stimulated osteoclast formation. Cadmium exposure also inhibited Lgr4 expression in both osteoclasts and osteoblasts. Low dose of RANKL added to the culture medium could promote osteoclast formation in cadmium-pretreated RAW264.7 cells. Blocking Lgr4 in osteoclasts only slightly inhibited cadmium-induced osteoclast formation in cadmium-pretreated RAW264.7 cells. Cadmium significantly upregulated the AKT/ERK signaling pathway. An in vivo study showed that cadmium exposure promoted osteoclast formation and inhibited Lgr4 expression. CONCLUSIONS: Our data indicates that cadmium may induce bone loss by inhibiting Lgr4-related bone formation and promoting Lgr4-related osteoclast formation.

Effects of odanacatib on bone-turnover markers in osteoporotic postmenopausal women: a post hoc analysis of the LOFT study.

This post hoc analysis and modeling study examined the mechanism of action of odanacatib using a statistical model to explain sCTx response in ODN-treated patients as a function of other bone-turnover biomarkers that, with other observed biomarker changes, showed that odanacatib persistently inhibited osteoclastic bone removal activity without preventing osteoclastogenesis. INTRODUCTION: Odanacatib (ODN) is an oral selective cathepsin K (CatK) inhibitor, previously in development for osteoporosis treatment. A post hoc analysis examined ODN's mechanism of action on bone-turnover biomarkers. METHODS: A subset of patients who completed 60 months' treatment in the Long-Term Odanacatib Fracture Trial (LOFT; NCT00529373) (N = 112 [57 ODN, 55 placebo]) were evaluated. Serum (s) and urine (u) samples were assayed at baseline and months 6-60 for 10 known bone-remodeling biomarkers: sCTx, uαα- and ußßCTx/Cr, uNTx/Cr, sNTx, uDPD/Cr, sICTP, sTRAP5b, sPINP, and sBSAP. Because the CrossLaps® CTx assay identifies the CTx peptide as well as larger molecular weight CTx-containing peptides, including ICTP, a best-fit model was developed to explain the transient sCTx reduction in ODN-treated patients. RESULTS: ODN persistently reduced the bone-resorption markers sNTx, uNTx/Cr, uαα- and ußßCTx/Cr, and uDPD/Cr, and gradually increased the target-engagement marker sICTP and osteoclast number (sTRAP5b), versus placebo from baseline to month 60. sCTx was transiently reduced with ODN within 12 months, returning to baseline by month 48. Modeling suggested that sCTx changes in the ODN group were primarily due to increased accumulation of larger CTx species, including sICTP. The bone-formation markers sPINP and sBSAP showed partial reductions, versus placebo, in the first 6 months but approached baseline by months 48-60. CONCLUSION: Observed changes in bone-turnover biomarkers support the persistent efficacy of ODN in direct inhibition of osteoclastic bone-resorption activity, without inhibition of osteoclastogenesis. Long-term evaluation also underscores the unique mechanism of ODN on osteoclastic collagen processing and subsequently osteoblastic bone formation. TRIAL REGISTRATION: NCT00529373.

Epidural Steroid Injections Acutely Suppress Bone Formation Markers in Postmenopausal Women.

CONTEXT: Over 9 million epidural steroid injections (ESIs) are performed annually in the United States. Although these injections effectively treat lumbar radicular pain, they may have adverse consequences, including bone loss. OBJECTIVE: To investigate acute changes in bone turnover following ESI. We focused on postmenopausal women, who may be at greatest risk for adverse skeletal consequences due to the combined effects of ESIs with aging and estrogen deficiency. METHODS: Single-center prospective observational study. Postmenopausal women undergoing lumbar ESIs and controls with no steroid exposure were included. Outcomes were serum cortisol, markers of bone formation, osteocalcin, and procollagen type-1 N-terminal propeptide (P1NP), and bone resorption by C-telopeptide (CTX) measured at baseline, 1, 4, 12, 26, and 52 weeks after ESIs. RESULTS: Among ESI-treated women, serum cortisol declined by ~50% 1 week after injection. Bone formation markers significantly decreased 1 week following ESIs: osteocalcin by 21% and P1NP by 22%. Both markers remained suppressed at 4 and 12 weeks, but returned to baseline levels by 26 weeks. There was no significant change in bone resorption measured by CTX. Among controls, there were no significant changes in cortisol or bone turnover markers. CONCLUSION: These results provide evidence of an early and substantial reduction in bone formation markers following ESIs. This effect persisted for over 12 weeks, suggesting that ESIs may have lasting skeletal consequences. Given the large population of older adults who receive ESIs, further investigation into the long-term skeletal sequelae of these injections is warranted.

LY450139 Inhibited Ti-Particle-Induced Bone Dissolution via Suppressing Notch and NF-κB Signaling Pathways.

Aseptic loosening of the prosthesis caused by wear-particle-induced osteolysis is a long-term complication and one of the most common reasons for the failure of joint implants. The primary cause of aseptic loosening of the prosthesis is overactive bone resorption caused by wear-particle-activated osteoclasts in both direct and indirect ways. Therefore, drugs that can inhibit differentiation and bone resorption of osteoclasts need investigation as a potential therapeutic strategy to prevent and treat peri-prosthetic osteolysis and thereby prolong the service life of the prosthesis. This study has verified the potential inhibitory effect of LY450139 on inflammatory osteolysis induced by titanium particles in a mice skull model. In addition, we found that LY450139 inhibited receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis, bone resorption, and podosomal actin belt formation in a dose-dependent manner without evidence of cytotoxicity in vitro. In addition, LY450139 significantly decreased the expression of osteoclast-specific markers, including TRAP, CTSK, V-ATPase d2, CTR, DC-STAMP, NFATc1, and the downstream target gene Hes1 in Notch signaling pathway. Further investigation of the molecular mechanism demonstrated that LY450139 inhibited the formation of osteoclasts via inhibition of the NF-κB and Notch signaling pathways. In summary, LY450139 inhibited the formation of RANKL-mediated osteoclasts via NF-κB and Notch signaling and inhibited Ti particle-induced inflammatory osteolysis in vivo. LY450139 is a potential targeted drug for the treatment of peri-prosthetic osteolysis and other osteolytic disease associated with overactive osteoclasts.

Piperlongumine Inhibits Titanium Particles-Induced Osteolysis, Osteoclast Formation, and RANKL-Induced Signaling Pathways.

Wear particle-induced aseptic loosening is the most common complication of total joint arthroplasty (TJA). Excessive osteoclast formation and bone resorptive activation have been considered to be responsible for extensive bone destruction and prosthesis failure. Therefore, identification of anti-osteoclastogenesis agents is a potential therapy strategy for the treatment of aseptic loosening and other osteoclast-related osteolysis diseases. In the present study, we reported, for the first time, that piperlongumine (PL), a key alkaloid compound from Piper longum fruits, could significantly suppress the formation and activation of osteoclasts. Furthermore, PL effectively decreased the mRNA expressions of osteoclastic marker genes such as tartrate-resistant acid phosphatase (TRAP), calcitonin receptor (CTR), and cathepsin K (CTSK). In addition, PL suppressed the receptor activator of nuclear factor-κB ligand (RANKL)-induced activations of MAPKs (ERK, JNK and p38) and NF-κB, which down-regulated the protein expression of nuclear factor of activated T-cells cytoplasmic 1 (NFATc1). Using a titanium (Ti) particle-induced calvarial osteolysis model, we demonstrated that PL could ameliorate Ti particle-induced bone loss in vivo. These data provide strong evidence that PL has the potential to treat osteoclast-related diseases including periprosthetic osteolysis (PPO) and aseptic loosening.

Icariin attenuates thioacetamide­induced bone loss via the RANKL­p38/ERK­NFAT signaling pathway.

There is an increasing incidence of destructive bone disease caused by osteoclast proliferation. This is characterized by reduced bone mass and imbalance of bone homeostasis. Icariin (ICA), a flavonoid compound isolated from Epimedium, has anti­osteoporosis activity and inhibits the formation of osteoclasts and bone resorption. The purpose of the present study was to investigate the protective effect of ICA on osteoclastic differentiation induced by thioacetamide (TAA) and its possible mechanism in Sprague Dawley (SD) rats. In the present study, SD rats were intraperitoneally injected with TAA (300 mg/kg) for the bone loss model, treated with ICA (600 mg/kg, intragastric gavage) in the ICA group and TAA+ICA group for treatment of bone loss for 6 weeks. Indexes associated with bone metabolism, such as alkaline phosphatase, N­terminal telopeptide of type­I collagen (NTX­I), calcium (Ca), phosphorus (P) and magnesium (Mg) in the serum, were detected. Osteoclast differentiation of femoral tissues was detected by hematoxylin and eosin and tartrate­resistant acid phosphatase staining. The femoral bone mass was evaluated using a three­point bending test and micro computed tomography. Western blotting was used to detect the expression levels of osteoclast­related proteins in each group. In the rats treated with TAA, the serum concentrations of Ca, P and Mg were decreased, the serum concentration of NTX­I was increased, osteoclast differentiation of the femur was increased, femur bone stress and bone mass were decreased and the bone loss and osteoclast formation were reduced after ICA treatment. In addition, ICA inhibited the protein expression of receptor activator of nuclear factor κ­Β ligand (RANKL), receptor activator of nuclear factor κ­B (RANK), p38, ERK, c­Fos and nuclear factor of activated T cells 1 (NFATc1) in the femur of rats treated with TAA. The results suggested that ICA may inhibit osteoclast differentiation by downregulating the RANKL­p38/ERK­NFAT signaling pathway and prevent TAA­induced bone loss. The results are helpful to understand the mechanism of osteoclast differentiation induced by TAA, as well as the antiresorptive activity and molecular mechanism of ICA, and to provide new ideas for the treatment of osteolytic diseases.