Inhibition Of Resorption Research Articles

Prescribing of low- versus high-cost Part B drugs in Medicare Advantage and traditional Medicare.

Examine whether Medicare Advantage (MA) coverage is associated with more efficient prescribing of Part B drugs than traditional Medicare (TM) coverage. Twenty percent sample of 2016 outpatient and carrier TM claims and MA encounter records and Master Beneficiary Summary File data. We analyzed whether MA enrollees compared to TM enrollees more often received the low-cost Part B drug in four clinical scenarios where multiple similarly effective drugs exist: (1) anti-VEGF agents to treat macular degeneration, (2) bone resorption inhibitors for osteoporosis, (3) bone resorption inhibitors for malignant neoplasms, and (4) intravenous iron for iron deficiency anemia. We then estimated differences in spending if TM prescribing aligned with MA prescribing. Finally, using linear probability models, we examined whether differences in MA and TM prescribing patterns were attributable to differences in the hospitals and clinician practices who treat MA and TM enrollees or differences in how these hospitals and clinician practices treat their MA versus TM patients. Not applicable. In all cases, a larger share of MA enrollees received the low-cost drug compared to TM enrollees, ranging from 8 percentage points higher for anemia to 16 percentage points higher for macular degeneration in the unadjusted analysis. Results were similar in regression analyses controlling for enrollee characteristics and market factors (5-13 percentage points). If TM prescribing matched MA prescribing, we estimated savings ranging from 6% to 20% of TM spending for each scenario. Differences in prescribing patterns were driven both by MA enrollees receiving treatment at more efficient hospitals and clinician practices and hospitals and clinician practices more often prescribing low-cost drugs to their MA patients. Our findings show MA enrollees were more likely than TM enrollees to receive low-cost Part B drugs in four clinical scenarios where multiple similarly or equally effective treatment options exist.

Exploring the Mechanisms Underlying Drug-Induced Fractures Using the Japanese Adverse Drug Event Reporting Database.

Fractures occur when bones become fragile and are subjected to external forces as occurring during falls. The use of drugs that increase bone fragility or fall risk increases the risk of fracture. This study investigates drug-induced fractures reported in the Japanese Adverse Drug Event Report (JADER) database in patients using 4892 drugs. Atypical femur fracture was the most frequently reported fracture, and 58 other fractures were also reported. Using Volcano plots and multiple logistic regression analysis, we identified the risk factors for drug-induced fractures as being female, of older age, higher body mass index, and using one of 90 drugs. The drug groups significantly associated with drug-induced fractures included bone resorption inhibitors, antiviral drugs, dopaminergic drugs, corticosteroids, and sleep sedatives. Principal component analysis was used to examine the relationship between the use of specific drugs and the site of drug-induced fracture. Bone resorption inhibitors and corticosteroids were associated with atypical femur fractures, jaw fractures, and ulna fractures through an osteoclast-mediated process. Other drugs were found to increase fracture risk via non-osteoclast-mediated mechanisms. These findings suggest that many drugs can result in drug-induced fractures through a variety of mechanisms.

Aspects of intercellular communication in bone and implications in therapy.

Communication processes among the cells of bone are essential for the structure and function of the organ. After it was proposed that communication from the osteoblast lineage to hemopoietic cells initiated osteoclastogenesis, the molecular controls were identified to be the tumour necrosis factor ligand and receptor families. This was followed by revelation of very many signalling processes among the cells of bone that regulate the three phases of bone remodelling, the resorption, reversal and formation phases. In many instances the ways in which these mechanisms operate can determine how drugs act on bone, whether they be inhibitors of resorption or promoters of formation.

Medication Related Osteonecrosis of the Jaw: 2021 Position Statement of the Korean Society for Bone and Mineral Research and the Korean Association of Oral and Maxillofacial Surgeons.

Antiresorptives are the most widely prescribed drugs for the treatment of osteoporosis. They are also used in malignant bone metastases, multiple myeloma, and Paget’s disease, and provide therapeutic efficacy on those diseases. However, it was reported that the occurrence of osteonecrosis of the jaw (ONJ) could be related to antiresorptive exposures, and there have been many cases regarding this issue. Therefore, a clearer definition and treatment guidelines were needed for this disease. The American Society for Bone and Mineral Research and the Amnerican Association of Oral and Maxillofacial Surgeons reported statements on bisphosphonate-related ONJ (BRONJ), and a revised version was recently presented. In the revised edition, the diagnosis BRONJ was changed to medication-related ONJ (MRONJ), which reflects consideration of the fact that ONJ also occurs for denosumab, a bone resorption inhibitor of the receptor activator of the nuclear factor-κB ligand antibody family, and bevacizumab, an anti-angiogenesis inhibitor. The Korean Society for Bone and Mineral Research and the Korean Association of Oral and Maxillofacial Surgeons had collectively formed a task force for the preparation of an official statement on MRONJ based on a previous position paper in 2015. The task force reviewed current knowledge and coordinated dental and medical opinions to propose the guideline customized for the local Korean situation.

Osteoporosis: From Molecular Mechanisms to Therapies 3.0

Osteoporosis is a common skeletal disorder that occurs as a result of an imbalance between bone resorption and bone formation, with bone breakdown exceeding bone building. Bone resorption inhibitors, e.g., bisphosphonates, have been designed to treat osteoporosis. Teriparatide, an anabolic agent, stimulates bone formation and corrects the characteristic changes in the trabecular microarchitecture. However, these drugs are associated with significant side effects. It is therefore crucial that we continue to research the pathogenesis of osteoporosis and seek novel modes of therapy. This editorial summarizes and discusses the themes of the six articles published in our Special Issue “Osteoporosis: From Molecular Mechanisms to Therapies 3.0”, a continuation of our 2020 Special Issue "Osteoporosis: From Molecular Mechanisms to Therapies". These Special Issues detail important global scientific findings that contribute to our current understanding of osteoporosis.

Cross-linked hyaluronic acid slows down collagen membrane resorption in diabetic rats through reducing the number of macrophages.

We previously showed that accelerated degradation of collagen membranes (CMs) in diabetic rats is associated with increased infiltration of macrophages and blood vessels. Since pre-implantation immersion of CMs in cross-linked high molecular weight hyaluronic acid (CLHA) delays membrane degradation, we evaluated here its effect on the number of macrophages and endothelial cells (ECs) within the CM as a possible mechanism for inhibition of CM resorption. Diabetes was induced with streptozotocin in 16 rats, while 16 healthy rats served as control. CM discs were labeled with biotin, soaked in CLHA or PBS, and implanted under the scalp. Fourteen days later, CMs were embedded in paraffin and the number of macrophages and ECs within the CMs was determined using antibodies against CD68 and transglutaminase II, respectively. Diabetes increased the number of macrophages and ECs within the CMs (∼2.5-fold and fourfold, respectively). Immersion of CMs in CLHA statistically significantly reduced the number of macrophages (p < 0.0001) in diabetic rats, but not that of ECs. In the healthy group, CLHA had no significant effect on the number of either cells. Higher residual collagen area and membrane thickness in CLHA-treated CMs in diabetic animals were significantly correlated with reduced number of macrophages but not ECs. Immersion of CM in CLHA inhibits macrophage infiltration and reduces CM degradation in diabetic animals. The combination of CLHA and CM may represent a valuable approach when guided tissue regeneration or guided bone regeneration procedures are performed in diabetic patients.

Effect of fasting hyperglycemia and insulin resistance on bone turnover markers in children aged 9-11years.

Impaired regulation of glucose metabolism in childhood adversely affects bone health. We assessed the effect of fasting hyperglycemia and insulin resistance on bone turnover markers in prepubertal children with normal glycemia (<100mg/dL) and fasting hyperglycemia (100-125mg/dL). Glucose, hemoglobin A1c, IGF-I (insulin-like growth factor I), iP1NP (N-terminal propeptide of type I procollagen), CTX-1 (C-terminal telopeptide of type I collagen) and insulin were measured. Bone turnover index (BTI) and HOMA-IR (homeostasis model assessment) were calculated. Bone resorption marker (CTX) levels were decreased by 26.5% in boys with hyperglycemia, though only 7% in girls. Hyperglycemia had no effect on the bone formation marker iP1NP. IGF-1, the best predictor of bone marker variance accounted for 25% of iP1NP and 5% of CTX variance. Girls presented significantly higher BTI indicating the predominance of bone formation over resorption. Insulin resistance significantly decreased CTX. In girls, HOMA-IR and IGF-1 predicted 15% of CTX variance. Fasting hyperglycemia and insulin resistance in children impact bone turnover suppressing bone resorption. Hyperglycemia decreased resorption, particularly in boys, while suppression of resorption by insulin resistance was more pronounced in girls. We suggest that the progression of disturbances accompanying prediabetes, may interfere with bone modelling and be deleterious to bone quality in later life.

Bisphosphonate Use May Reduce the Risk of Urolithiasis in Astronauts on Long-Term Spaceflights.

ABSTRACTLong‐duration spaceflight is associated with an increased risk of urolithiasis, and the pain caused by urinary calculi could result in loss of human performance and mission objectives. The present study investigated the risk of urolithiasis in astronauts during 6 months on the International Space Station, and evaluated whether the suppression of bone resorption by the bisphosphonate, alendronate (ALN), can reduce the risk. A total of 17 astronauts were included into the analysis: exercise using the advanced resistive exercise device (ARED) plus weekly oral 70 mg alendronate (ARED+ALN group, n = 7) was compared to resistive exercise alone (ARED group, n = 10). Urine volume decreased in both groups during spaceflight but recovered after return. The ARED group showed increased urinary calcium excretion from the 15th to 30th day of spaceflight, whereas urinary calcium was slightly decreased in the ARED+ALN group. Urinary N‐terminal telopeptide (NTX) and helical peptide (HP) of type I collagen, as bone resorption markers, were elevated in the ARED group during and until 0 days after spaceflight, while there was no elevation in these parameters in the ARED+ALN group. Urinary oxalate and uric acid excretion tended to be higher in the ARED group than in the ARED+ALN group during spaceflight. These results demonstrate that astronauts on long‐duration spaceflights may be at high risk for the formation of urinary calcium oxalate and calcium phosphate stones through increased urinary excretion of oxalate and uric acid, from degraded type I collagen, as well as of calcium from enhanced bone resorption. Our findings suggest that increased bone resorption during spaceflight, as a risk factor for urinary calculus formation, could be effectively prevented by an inhibitor of bone resorption. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Risk factors of medication‐related osteonecrosis of the jaw in preventive tooth extraction before bone resorption inhibitor administration: A multicenter nested case–control study

AbstractIntroductionMedication‐related osteonecrosis of the jaw (MRONJ) occurs even after teeth with poor prognosis had been preventively extracted and medication had been initiated. In this nested case–control study, we focused on tooth extraction before bone resorption inhibitor administration for the treatment of malignant tumors.Materials and MethodsA total of 180 teeth of 58 patients who were treated with zoledronic acid and/or denosumab from April 2012 to December 2016 at our hospital or partner institutions were included in this multicenter study. All participants underwent tooth extraction within 1 year before initiating therapy and were followed up for at least 1 year or at most 3 years after initiating bone resorption inhibitor administration. We evaluated the systemic and local risk factors: sex, age, cancer type, overweightness/obesity, anemia, undernutrition, diabetes, smoking, concomitant drugs, tooth extraction site, use of antibacterial drugs, wound closure, and waiting period between tooth extraction and medication.ResultsMRONJ occurred in 18 teeth of 10 patients and not in 162 teeth of 48 patients. Based on the Cox proportional hazards model, concomitant administration of angiogenesis inhibitors, mandibular molar, periapical radiolucency, and osteosclerosis of the surrounding areas were considered essential risk factors for MRONJ.ConclusionsChronic inflammation of the bone surrounding extracted teeth may be an essential risk factor for MRONJ when preventive tooth extraction is performed before the administration of bone resorption inhibitors for patients with malignant tumors.

Use of Bone Resorption Inhibitors in Metastatic Castration-Resistant Prostate Cancer—20 Years Later, and the Answer Is Still Yes

Use of Bone Resorption Inhibitors in Metastatic Castration-Resistant Prostate Cancer—20 Years Later, and the Answer Is Still Yes

Association of Concomitant Bone Resorption Inhibitors With Overall Survival Among Patients With Metastatic Castration-Resistant Prostate Cancer and Bone Metastases Receiving Abiraterone Acetate With Prednisone as First-Line Therapy

Bone resorption inhibitors (BRIs) are recommended by international guidelines to prevent skeletal-related events (SREs) among patients with metastatic castration-resistant prostate cancer (mCRPC) and bone metastases. Abiraterone acetate with prednisone is currently the most common first-line therapy for the treatment of patients with mCRPC; however, the clinical impact of the addition of BRIs to abiraterone acetate with prednisone in this disease setting is unknown. To evaluate the association of the use of concomitant BRIs with overall survival (OS) and time to first SRE among patients with mCRPC and bone metastases receiving abiraterone acetate with prednisone as first-line therapy. This retrospective cohort study collected data from 745 consecutive patients who began receiving abiraterone acetate with prednisone as first-line therapy for mCRPC with bone metastases between January 1, 2013, and December 31, 2016. Data were collected from 8 hospitals in Canada, Europe, and the US from June 15 to September 15, 2019. Patients were classified by receipt vs nonreceipt of concomitant BRIs and subclassified by volume of disease (high volume or low volume, using definitions from the Chemohormonal Therapy Vs Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer [CHAARTED] E3805 study) at the initiation of abiraterone acetate with prednisone therapy. The primary end point was OS. The secondary end point was time to first SRE. The Kaplan-Meier method and Cox proportional hazards models were used. Of the 745 men (median age, 77.6 years [interquartile range, 68.1-83.6 years]; 699 White individuals [93.8%]) included in the analysis, 529 men (71.0%) received abiraterone acetate with prednisone alone (abiraterone acetate cohort), and 216 men (29.0%) received abiraterone acetate with prednisone plus BRIs (BRI cohort). A total of 420 men (56.4%) had high-volume disease, and 276 men (37.0%) had low-volume disease. The median follow-up was 23.5 months (95% CI, 19.8-24.9 months). Patients in the BRI cohort experienced significantly longer OS compared with those in the abiraterone acetate cohort (31.8 vs 23.0 months; hazard ratio [HR], 0.65; 95% CI, 0.54-0.79; P < .001). The OS benefit in the BRI cohort was greater for patients with high-volume vs low-volume disease (33.6 vs 19.7 months; HR, 0.51; 95% CI, 0.38-0.68; P < .001). The BRI cohort also had a significantly shorter time to first SRE compared with the abiraterone acetate cohort (32.4 vs 42.7 months; HR, 1.27; 95% CI, 1.00-1.60; P = .04), and the risk of a first SRE was more than double in the subgroup with low-volume disease (HR, 2.29; 95% CI, 1.57-3.35; P < .001). In the multivariable analysis, concomitant BRIs use was independently associated with longer OS (HR, 0.64; 95% CI, 0.52-0.79; P < .001). In this study, the addition of BRIs to abiraterone acetate with prednisone as first-line therapy for the treatment of patients with mCRPC and bone metastases was associated with longer OS, particularly in patients with high-volume disease. These results suggest that the use of BRIs in combination with abiraterone acetate with prednisone as first-line therapy for the treatment of mCRPC with bone metastases could be beneficial.

Inhibiteurs de la résorption osseuse et risque d’ostéonécrose des mâchoires (ONM)

Prescription of bone resorption inhibitors implies a thorough evaluation of associated risks weighed against expected benefits. Although quite infrequent but highly debilitating, medication-related osteonecrosis of the jaw (MRONJ) is the most highly feared complication of such treatments, both by patients and some healthcare professionals. A concerted multiprofessional approach, primary prevention via systematic oral health examination as whenever possible, but also regular follow-up with an oral health professional, could all help limit the risk of MRONJ, increase patient adherence to treatment and improve the overall quality of care.

Anti-osteoclastogenesis potential agents from plants naturalized in Vietnam

Background: The balance between bone formation and bone resorption which is attributed to osteoblast and osteoclast is required to maintain skeleton homeostasis. Osteoclast differentiation is regulated by a tumor necrosis factor–receptor activator of nuclear factor NF-kB ligand (RANKL). The dysregulation of bone-resorbing osteoclast differentiation can lead to osteoporosis. The adverse effects of the long-term use of bone resorption inhibitors are of concern and so the development of new osteoporosis therapy treatment is desirable. Objective: In this study, 67 plants (70 samples) were screened for osteoclastogenesis inhibitory activities on RAW264.7 mouse macrophages and bone marrow-derived macrophages (BMMs). Materials and Methods: The RAW264.7 cells and the BMMs isolated from male ICR mice were treated with various doses of plant extracts and TRAP histochemical staining of the cells was performed. TRAP-positive multinucleated cells were photographed under microscopy to observe the effects of the extracts on osteoclast differentiation. Results: Among 70 methanol extracts, we found that nine samples exhibited significant inhibitory effects in RANKL-induced osteoclast differentiation. They included Aleurites moluccana (S16 and S17), Aporosa dioca (S19), Antidesma bunius (S21), Cinnamomum balansae (S32), Macrosolen cochinchinensis (S41), Pinus kesiya (S52), Photinia benthamiana (S54), and Mischocarpus pentapetalus (S59). Conclusion: In the present study, 70 plant extracts were screened for the osteoclastogenesis inhibitory effects in RAW264.7 murine macrophages and BMMs. Nine extracts have the potential as effective agents against osteoclastogenesis. This is the first report on the anti-osteoclastogenetic activity of these plants.

Comprehensive in vitro comparison of cellular and osteogenic response to alternative biomaterials for spinal implants

A variety of novel biomaterials are emerging as alternatives to conventional metals and alloys, for use in spinal implants. These promise potential advantages with respect to e.g. elastic modulus compatibility with the host bone, improved radiological imaging or enhanced cellular response to facilitate osseointegration. However, to date there is scarce comparative data on the biological response to many of these biomaterials that would give insights into the relative level of bone formation, resorption inhibition and inflammation. Thus, in this study, we aimed to evaluate and compare the in vitro biological response to standard discs of four alternative biomaterials: polyether ether ketone (PEEK), zirconia toughened alumina (ZTA), silicon nitride (SN) and surface-textured silicon nitride (ST-SN), and the reference titanium alloy Ti6Al4V (TI). Material-specific characteristics of these biomaterials were evaluated, such as surface roughness, wettability, protein adsorption (BSA) and apatite forming capacity in simulated body fluid. The activity of pre-osteoblasts seeded on the discs was characterized, by measuring viability, proliferation, attachment and morphology. Then, the osteogenic differentiation of pre-osteoblasts was compared in vitro from early to late stage by Alizarin Red S staining and real-time PCR analysis. Finally, osteoclast activity and inflammatory response were assessed by real-time PCR analysis. Compared to TI, all other materials generally demonstrated a lower osteoclastic activity and inflammatory response. ZTA and SN showed generally an enhanced osteogenic differentiation and actin length. Overall, we could show that SN and ST-SN showed a higher osteogenic effect than the other reference groups, an inhibitive effect against bone resorption and low inflammation, and the results indicate that silicon nitride has a promising potential to be developed further for spinal implants that require enhanced osseointegration.

Knowledge and attitudes of French dentists on bone resorption inhibitors (bisphosphonates and denosumab): A cross-sectional study

IntroductionA cross-sectional study by questionnaire was performed to evaluate the knowledge of French dentists about bone resorption inhibitors (BRIs) and medication-related osteonecrosis of the jaw (MRONJ). Materials and Methods498 digital questionnaires were collected and 358 complete responses of French dental practionners in active practice except for orthodontists were analyzed. Descriptive analysis was computed and categorical variables were compared by Z test. The independence of the compared variables was tested by χ2 test. The scores obtained to the knowledge questions were compared by Mann-Whitney's tests depending on age, gender and year of graduation. Results84% of the respondents routinely record antiresorptive medication history in the medical chart. Therefore, almost all the practitioners know the importance to report in anamnesis the use of BRIs, but we noticed some contradictions: Less than half of the respondents recognized the brand names of BRIs and their indications. The combination of BRIs with other drugs like antiangiogenic or corticosteroid therapies is identified as a MRONJ systemic risk factor by respectively 46,3% and 29,7% of the respondents. Likewise, only 43,2% of the practitioners identified removable dentures as a local risk factor. We showed that practitioners under 30 years old and/or who graduated for less than 10 years reached a significantly higher score putting university as the main source of information on that subject. ConclusionAccording to our results, it is evident that there is a lack of knowledge about BRI, the risk of MRONJ, and the methods and means of preventing this complication.

Mn-containing bioceramics inhibit osteoclastogenesis and promote osteoporotic bone regeneration via scavenging ROS

Osteoporosis is caused by an osteoclast activation mechanism. People suffering from osteoporosis are prone to bone defects. Increasing evidence indicates that scavenging reactive oxygen species (ROS) can inhibit receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclastogenesis and suppress ovariectomy-induced osteoporosis. It is critical to develop biomaterials with antioxidant properties to modulate osteoclast activity for treating osteoporotic bone defects. Previous studies have shown that manganese (Mn) can improve bone regeneration, and Mn supplementation may treat osteoporosis. However, the effect of Mn on osteoclasts and the role of Mn in osteoporotic bone defects remain unclear. In present research, a model bioceramic, Mn-contained β-tricalcium phosphate (Mn-TCP) was prepared by introducing Mn into β-TCP. The introduction of Mn into β-TCP significantly improved the scavenging of oxygen radicals and nitrogen radicals, demonstrating that Mn-TCP bioceramics might have antioxidant properties. The in vitro and in vivo findings revealed that Mn2+ ions released from Mn-TCP bioceramics could distinctly inhibit the formation and function of osteoclasts, promote the differentiation of osteoblasts, and accelerate bone regeneration under osteoporotic conditions in vivo. Mechanistically, Mn-TCP bioceramics inhibited osteoclastogenesis and promoted the regeneration of osteoporotic bone defects by scavenging ROS via Nrf2 activation. These results suggest that Mn-containing bioceramics with osteoconductivity, ROS scavenging and bone resorption inhibition abilities may be an ideal biomaterial for the treatment of osteoporotic bone defect.

Novel mutation in the ALPL gene with a dominant negative effect in a Japanese family.

Hypophosphatasia (HPP) is caused by mutations in the ALPL gene encoding tissue nonspecific alkaline phosphatase (TNSALP) and inherited in either an autosomal recessive or autosomal dominant manner. It is characterized clinically by defective mineralization of bone, dental problems, and low serum ALP levels. In the current report, we demonstrate a novel mutation in the ALPL gene (c.244G > A p.Gly82Arg) in a Japanese family with low serum ALP levels. The ALPL gene analysis using hybridization capture-based next-generation sequencing was performed. The expression plasmids of the wild type and mutated TNSALP were introduced into COS-7 cells. The enzymatic activity of ALP in the cell lysates was measured using p-nitrophenylphosphate as a substrate. TNSALP with the novel ALPL mutation (c.244G > A p.Gly82Arg) completely lost its enzymatic activity and suppressed that of wild-type TNSALP, corroborating its dominant negative effect. The diagnosis of autosomal dominant HPP was confirmed in three members of the family. Our approach would help to avoid the inappropriate use of bone resorption inhibitors for currently mis- or under-diagnosed HPP, given that the presence of further, yet undetected mutations of the ALPL gene are plausible.

Osseointegrated Implants in the Scenario of Osteonecrosis Occurrence with the use of Bisphosphonates: A Descriptive Review of Clinical Studies

&#x0D; &#x0D; &#x0D; &#x0D; The most common bone disorder found by implant dentists is osteoporosis, which is a systemic skeletal disorder associated with aging, which is characterized by loss of bone mass, making bones fragile and more susceptible to fractures. The World Health Organization has defined osteoporosis as a bone mineral density level greater than 2.5 standard deviations below the mean of young normal women. After 60 years of age, a third of the population have this disorder, it occurs twice as often in women than in men. It is estimated that 1.3 million fractures and 133,000 all hip fractures occur every year as a result of osteoporosis. The aim of this study was to discuss aspects of the pharmacological action of Bisphosphonates (BP) and their influence on the bone tissue when associated with treatment with dental implants. There are several types of treatments which prevent or prevent the progression of osteoporosis. So, BP, such as alendronate, are inhibitors of bone resorption. Act as controlling the development of osteoporosis by increasing the process of bone density and decrease its reabsorption, often acting as supporting the process of osseointegration of dental implants.&#x0D; &#x0D; &#x0D; &#x0D;

Cardiovascular Safety and Sclerostin Inhibition.

Sclerostin, which is primarily produced by the osteocytes, inhibits the canonical Wnt pathway and thereby the osteoblasts and stimulates RANKL release by the osteocytes and thereby osteoclast recruitment. Inhibition of sclerostin therefore causes stimulation of bone formation and inhibition of resorption. In clinical trials, romosozumab, an antibody against sclerostin, increases bone mineral density and reduces the risk of fractures compared with placebo and alendronate. The cardiovascular safety of romosozumab was adjudicated in 2 large clinical osteoporosis trials in postmenopausal women. Compared with placebo, the incidence of cardiovascular events was similar in the 2 treatment groups. Compared with alendronate, the incidence of serious cardiovascular events was higher in women treated with romosozumab. The incidence of serious cardiovascular adverse events was low and post hoc analyses should therefore be interpreted with caution; however, the relative risk seemed unaffected by preexisting cardiovascular disease or risk factors. Sclerostin is expressed in the vasculature, predominantly in vascular smooth muscle cells in the media. However, preclinical and genetic studies have not demonstrated any increased cardiovascular risk with continuously low sclerostin levels or inhibition of sclerostin. Furthermore, no potential mechanisms for such an effect have been identified. In conclusion, while there is no preclinical or genetic evidence of a harmful effect of sclerostin inhibition on cardiovascular safety, the evidence from the large clinical trials in postmenopausal women is conflicting. Romosozumab should therefore be used for the treatment of postmenopausal women with osteoporosis at high risk of fracture after careful consideration of the cardiovascular risk and the balance between benefits and risks.

Febuxostat Attenuates the Progression of Periodontitis in Rats

Introduction: Periodontitis is a lifestyle-related disease that is characterized by chronic inflammation in gingival tissue. Febuxostat, a xanthine oxidase inhibitor, exerts anti-inflammatory and antioxidant effects. Objective: The present study investigated the effects of febuxostat on periodontitis in a rat model. Methods: Male Wistar rats were divided into 3 groups: control, periodontitis, and febuxostat-treated periodontitis groups. Periodontitis was induced by placing a ligature wire around the 2nd maxillary molar and the administration of febuxostat (5 mg/kg/day) was then initiated. After 4 weeks, alveolar bone loss was assessed by micro-computed tomography and methylene blue staining. The expression of osteoprotegerin (OPG), a bone resorption inhibitor, was detected by quantitative RT-PCR and immunological staining, and the number of osteoclasts in gingival tissue was assessed by tartrate-resistant acid phosphatase staining. The mRNA and protein expression levels of the proinflammatory cytokines, tumor necrosis factor-alpha (TNF-α), and interleukin-1 beta (IL-1β), in gingival tissue were measured using quantitative RT-PCR and immunological staining. Oxidative stress in gingival tissue was evaluated by the expression of 4-hydroxy-2-nonenal (4-HNE), and 8-hydroxy-2-deoxyguanosine (8-OHdG). To clarify the systemic effects of periodontitis, blood pressure and glucose tolerance were examined. Results: In rats with periodontitis, alveolar bone resorption was associated with reductions in OPG and increases in osteoclast numbers. The gingival expression of TNF-α, IL-1β, 4-HNE, and 8-OHdG was up-regulated in rats with periodontitis. Febuxostat significantly reduced alveolar bone loss, proinflammatory cytokine levels, and oxidative stress. It also attenuated periodontitis-induced glucose intolerance and blood pressure elevations. Conclusion: Febuxostat prevented the progression of periodontitis and associated systemic effects by inhibiting proinflammatory mediators and oxidative stress.