Bone Protective Agents Research Articles

Current and Developing Pharmacologic Agents for Improving Skeletal Health in Adults with Osteogenesis Imperfecta.

Osteogenesis imperfecta (OI) is a genetic disorder characterized by increased bone fragility largely caused by defects in structure, synthesis, or post-translational processing of type I collagen. Drugs currently used to improve skeletal health in OI were initially developed to treat osteoporosis and clinical trials are ongoing to study their effectiveness in OI adults. Additionally, novel bone-protective agents are in preclinical studies and various phases of OI clinical trials. This review summarizes current knowledge on available pharmacologic agents and current drug trials involving OI participants. A PubMed online database search of all study types published in the English language using the terms "osteogenesis imperfecta," "OI," and "brittle bone disease" was performed in August 2022. Articles screened were restricted to adults. A ClinicalTrials.gov database search of all studies involving "osteogenesis imperfecta" was performed in August 2023. Although clinical trial data are limited, bisphosphonates and teriparatide may be useful in improving bone mineral density. As of yet, no clinical trials are available that adequately evaluate the usefulness of current therapies in reducing fracture risk. Several therapeutics, including teriparatide, setrusumab, anti-TGF-β antibodies, and allogeneic stem cells, are being studied in clinical trials. Preclinical studies involving Dickkopf-1 antagonists present promising data in non-OI bone disease, and could be useful in OI. Research is ongoing to improve therapeutic options for adults with OI and clinical trials involving gene-editing may be possible in the coming decade.

Survival and fracture risk with radium-223 therapy in metastatic castrate-resistant prostate cancer (mCRPC): A real-world analysis.

50 Background: Radium-223 is a life-prolonging radionuclide therapy for men with bone-predominant metastatic castrate-resistant prostate cancer (mCRPC). It accumulates at sites of high bone turnover with emerging evidence suggesting use of radium-223 increases risk of pathologic fractures. Bone-protective agents (BPAs) reduce skeletal-related events including pathologic fractures in men with mCRPC. We evaluated real-world outcomes of patients treated with radium-223, including the effect of BPA use on pathologic fracture risk. Methods: This was a single institution retrospective cohort study that included patients with mCRPC treated with radium-223 in Manitoba, Canada from 2014 to 2021. Outcomes of interest included incidence of pathologic fracture, pain response, alkaline phosphatase (ALP) response, and overall survival. Kaplan-Meier method was used for time to event outcomes and multivariable Cox regression models were used to adjust for covariates. Results: We identified 92 patients who received radium-223 for mCRPC (Table). Thirty patients (33%) completed 6 cycles of radium-223. Documented pain relief occurred in 39% of patients. For those with elevated ALP at baseline (n = 46), 57% had at least 30% reduction in total ALP. PSA reduction occurred in 29% with 11% having at least 30% reduction in PSA. Median overall survival (OS) was 9.4 months (95% CI 5.8 to 15.9). Of those who did not receive concurrent BPA, 26% developed a pathologic fracture, compared to 3% who received concurrent BPA during a median follow up of 8.1 months. BPA use was associated with significant delay in time to pathologic fracture (median not reached vs. 15.9 months; HR = 0.20, 95% CI: 0.05 – 0.76, p < 0.05) after adjusting for number of bone metastases and corticosteroid use. Conclusions: In this real-world study, concurrent BPA use was associated with significant reduction in risk of pathologic fractures in mCRPC patients receiving radium-223. BPA administration should be considered for patients receiving radium-223. [Table: see text]

Research progress on the clinical application and mechanism of iguratimod in the treatment of autoimmune diseases and rheumatic diseases.

Autoimmune diseases are affected by complex pathophysiology involving multiple cell types, cytokines, antibodies and mimicking factors. Different drugs are used to improve these autoimmune responses, including nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, antibodies, and small molecule drugs (DMARDs), which are prevalent clinically in the treatment of rheumatoid arthritis (RA), etc. However, low cost-effectiveness, reduced efficacy, adverse effects, and patient non-response are unattractive factors driving the development of new drugs such as iguratimod. As a new disease-modifying antirheumatic drug, iguratimod has pharmacological activities such as regulating autoimmune disorders, inflammatory cytokines, regulating immune cell activation, differentiation and proliferation, improving bone metabolism, and inhibiting fibrosis. In recent years, clinical studies have found that iguratimod is effective in the treatment of RA, SLE, IGG4-RD, Sjogren 's syndrome, ankylosing spondylitis, interstitial lung disease, and other autoimmune diseases and rheumatic diseases. The amount of basic and clinical research on other autoimmune diseases is also increasing. Therefore, this review systematically reviews the latest relevant literature in recent years, reviews the research results in recent years, and summarizes the research progress of iguratimod in the treatment of related diseases. This review highlights the role of iguratimod in the protection of autoimmune and rheumatic bone and related immune diseases. It is believed that iguratimod's unique mode of action and its favorable patient response compared to other DMARDs make it a suitable antirheumatic and bone protective agent in the future.

A Five-Year Retrospective Audit on Bone Protection Prescribing in Patients With Fragility Fractures in Primary Care.

Background Fragility fractures typically occur in the elderly population due to low-energy trauma in the context of underlying osteoporotic bone disease. These fractures are becoming increasingly more common as the population of the United Kingdom ages, representing a significant public health issue. In the community, a joint care approach is adopted between general practitioners and fracture liaison services for the management of patients with fragility fractures. Despite this, preventive care for these patients remains substandard. This project aimed to conduct an audit of patients with a coded diagnosis of a fragility fracture in our primary care practice to ascertain fracture type and the prescription of bone protective agents. When necessary, the appropriate therapy was commenced per best practice guidelines. Methodology A search of patients with the diagnosis of Fragility fracture on our electronic patient database, SystmOne, was conducted for the period of April 2019 to April 2023 inclusive. A retrospective audit of electronic patient records was done to identify patient demographic data, fracture types and dates, osteoporosis prescriptions, vitamin D/calcium supplementation, and bone densitometry scan results (dual-energy X-ray absorptiometry). Results A total of 47 patients were identified with a coded diagnosis of a Fragility fracture, of whom 36 were females and 11 were males. The average age of the patients was 76.89 years with a range of 50 to 97. In total, 49 fractures were identified. More than two-thirds of the fractures identified were either distal forearm or neck of femur fractures (18 and 15, respectively). Of the 47 patients identified, 33 were on bone protection agents. Further, 26 received both bisphosphonates and calcium/vitamin D supplementation. Seven patients were on bisphosphonate monotherapy, and the remaining two patients were on vitamin D/calcium supplementation alone. Of the 47 patients, 12 had neither form of therapy prescribed. Conclusions Despite the joint effort between fracture liaison services and general practitioners, the secondary prevention of fragility fractures within the community remains inadequate. Fragility fractures are associated with significant morbidity, mortality, and re-fracture rates and incur significant costs to the National Health Service. Local practitioners must routinely evaluate their data to identify opportunities to improve patient care. Effective and timely treatment could be key to the prevention of new or second fractures.

Ginsenoside compound K alleviates osteoarthritis by inhibiting NLRP3‑mediated pyroptosis.

Ginsenoside compound K (GCK) has been previously reported to be a potent antiarthritic and bone-protective agent. Therefore, the present study aimed to explore the potential effects of GCK on osteoarthritis and its regulatory effects on the pyroptosis of chondrocytes. Primary mouse chondrocytes (PMCs) were used for in vitro analysis. ELISA assays revealed that compared with the untreated cells, TNF-α induced a significant increase in IL-6, MMP13, A disintegrin and metalloproteinase with thrombospondin motifs 5 and MMP3 expression but induced a significant decrease in aggrecan and collagen II expression. By contrast, GCK reversed the aforementioned alterations in a dose-dependent manner. Experimental osteoarthritis was subsequently induced in mice through transection of the medial meniscotibial ligament and medial collateral ligament in the right knee [destabilization of the medial meniscus (DMM) mice]. GCK was found to reduce cartilage degradation in vivo in DMM mice, which was assessed using the Osteoarthritis Research Society International (OARSI) score, collagen II and MMP13 expression. Cartilage degradation is associated with higher OARSI score, decreased collagen II and increased MMP13 expression. In PMCs, TNF-α treatment stimulated an increase in the expression of NLR family pyrin domain containing 3 (NLRP3), Gasdermin D-N terminal (GSDMD-NT), cleaved caspase-1 and mature IL-1β, markers that indicate the occurrence of pyroptosis. However, GCK treatment suppressed the increase of the aforementioned proteins in a dose-dependent manner. Immunohistochemistry staining of the knee joint tissue sections from the DMM mice confirmed that GCK attenuated the NLRP3 and GSDMD-NT expression that was induced by DMM surgery. In conclusion, the present study revealed that GCK can reduce cartilage degradation in an osteoarthritis model by inhibiting the NLRP3-inflammasome activation and subsequent pyroptosis.

MP11-13 CLINICAL FRACTURE INCIDENCE IN METASTATIC HORMONE-SENSITIVE PROSTATE CANCER (mHSPC) AND RISK-REDUCTION FOLLOWING ADDITION OF ZOLEDRONIC ACID TO ANDROGEN DEPRIVATION THERAPY (ADT) WITH OR WITHOUT DOCETAXEL (DOC): LONG-TERM RESULTS FROM 2 PHASE 3 TRIALS FROM THE STAMPEDE PLATFORM PROTOCOL

You have accessJournal of UrologyCME1 Apr 2023MP11-13 CLINICAL FRACTURE INCIDENCE IN METASTATIC HORMONE-SENSITIVE PROSTATE CANCER (mHSPC) AND RISK-REDUCTION FOLLOWING ADDITION OF ZOLEDRONIC ACID TO ANDROGEN DEPRIVATION THERAPY (ADT) WITH OR WITHOUT DOCETAXEL (DOC): LONG-TERM RESULTS FROM 2 PHASE 3 TRIALS FROM THE STAMPEDE PLATFORM PROTOCOL Craig Jones, Ashwin Sachdeva, Laura Murphy, Macey Murray, Louise Brown, Eugene McCloskey, Janet Brown, Gerhardt Attard, Mahesh Parmar, Nicholas James, Matthew Sydes, and Noel Clarke Craig JonesCraig Jones More articles by this author , Ashwin SachdevaAshwin Sachdeva More articles by this author , Laura MurphyLaura Murphy More articles by this author , Macey MurrayMacey Murray More articles by this author , Louise BrownLouise Brown More articles by this author , Eugene McCloskeyEugene McCloskey More articles by this author , Janet BrownJanet Brown More articles by this author , Gerhardt AttardGerhardt Attard More articles by this author , Mahesh ParmarMahesh Parmar More articles by this author , Nicholas JamesNicholas James More articles by this author , Matthew SydesMatthew Sydes More articles by this author , and Noel ClarkeNoel Clarke More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003226.13AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Long-term ADT is recommended for men with mHSPC: bone loss and increased fracture risk are known complications. The STAMPEDE trial compared ADT±docetaxel (Doc)±zoledronic acid (ZA): adding ZA did not improve overall survival (OS) but long-term effects of bisphosphonate treatment on skeletal health was not formally collected as part of the trial. Accessible, high quality, routinely-collected healthcare data (RCHD) enables analysis of outcome data beyond standard trial follow-up to evaluate long-term treatment toxicity and clinical efficacy of ZA as a bone protective agent in mHSPC. The Hospital Episode Statistics (HES) database provides RCHD for patients in England and Wales. METHODS: HES data up to 2018 were obtained for patients (pts) randomised 2:1 between ADT (Arm A) and ADT+ZA (Arm B), or ADT+Doc (Arm C) or ADT+Doc+ZA (Arm E). ZA (4 mg) was six 3-weekly cycles, then 4-weekly for 2 years. Clinical fracture events were identified using a bespoke pre-specified coding framework of International Classification of Diseases (ICD 10) diagnosis and Classification of Interventions and Procedures (OPCS 4) procedure codes. Multivariate Cox regression models were developed to adjust for age, N stage, WHO performance status, Gleason score and NSAID use to determine impact of ZA on fracture risk. RESULTS: Connected datasets were available for 2,145 eligible pts (796 M0, 1,349 M1) of 2,962 (72%). Overall, 5-year fracture incidence was 6.4%; higher in M1 pts (9.6% in M1 vs 2.1% in M0, p<0.0001), and lower amongst M1 pts allocated ZA (4.55% with ZA vs 12.9% without ZA, p<0.0001) (Figure 1). ZA significantly reduced fracture risk in M1 pts (HR 0.36, 95% CI 0.22-0.57, p<0.0005) but not in M0 pts (HR 0.67, 95% CI 0.32-1.39, p=0.28). CONCLUSIONS: By accessing RCHD, we evaluated long-term fracture events amongst patients in STAMPEDE. Fracture rates were clinically notable in M1 and reduced significantly in pts allocated ZA with ADT±Doc. These data support using bone protective agents to reduce clinically significant fractures in mHSPC. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e129 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Craig Jones More articles by this author Ashwin Sachdeva More articles by this author Laura Murphy More articles by this author Macey Murray More articles by this author Louise Brown More articles by this author Eugene McCloskey More articles by this author Janet Brown More articles by this author Gerhardt Attard More articles by this author Mahesh Parmar More articles by this author Nicholas James More articles by this author Matthew Sydes More articles by this author Noel Clarke More articles by this author Expand All Advertisement PDF downloadLoading ...

Rate of skeletal-related events (SREs) for abiraterone acetate (AA) versus enzalutamide (ENZ) in prostate cancer: A population-based study using the SEER-Medicare database.

e17038 Background: Skeletal-related events are common in men with prostate cancer, and are associated with significant morbidity and mortality. AA and ENZ are novel androgen signaling inhibitors used in the treatment of metastatic prostate castration-resistant prostate cancer (mCRPC). As directly comparative efficacy data do not exist between AA and ENZ, the differing toxicity profiles inform treatment selection. It is unknown whether SRE rates differ in a real-world population between AA, which is given with corticosteroids, and ENZ, which is associated with imbalance and falls. Methods: The national SEER-Medicare linked database was used to identify men with prostate cancer who received AA or ENZ between 2011-2015; approval during this period was solely for mCRPC. Inclusion criteria included Medicare Part A+B coverage 1 year before and after first receipt of AA/ENZ, without any HMO enrollment. Baseline demographic and comorbidity data were gathered. Diagnosis and procedure claims codes were used to identify SREs, defined as pathologic fracture, surgery to bone, radiation to bone, or spinal cord compression. The time to SRE was defined as time from first receipt of AA/ENZ to the first SRE of any type. A multivariable competing risk regression analysis including death as a competing risk was performed. Results: 5,856 men with prostate cancer who first received AA (N = 4,207) or ENZ (N = 1,649) were identified. The median age at initiation of AA/ENZ was 70 years (range 65-101); 78% were White, 12% Black, 4% Hispanic, 3% Asian, and 4% Other. The median follow-up was 14 months. The overall SRE rate was 13.1% after AA/ENZ start: 574 (13.6%) AA and 194 (11.8%) ENZ, with a cumulative incidence of 11.9% at 2 years. Median overall survival was 16 months (14.4 months for AA and 18.3 months for ENZ). Age, stage at diagnosis, race/ethnicity, baseline comorbidities, and prior history of SRE were balanced between AA vs ENZ, aside from baseline osteoarthritis or rheumatoid arthritis (48.0% AA vs 53.2% ENZ, P &lt; 0.001) and baseline Alzheimer’s dementia (9.2% AA vs 11.1% ENZ, P = 0.03). After controlling for these potential risk factors, receipt of AA versus ENZ was not associated with time to SRE (relative risk ratio [RR] = 0.90, 95% CI 0.77-1.06, P = 0.22). Osteoporosis (RR 1.22, 95% CI 1.01-1.49, P = 0.04), osteoarthritis or rheumatoid arthritis (RR 1.23, 95% CI 1.06-1.43, P &lt; 0.01), and prior history of SRE (RR 1.31, 95% CI 1.07-1.59, P &lt; 0.01) were statistically significant risk factors for SRE. Conclusions: In this real-world population of men with prostate cancer, there was no difference in time to SRE between AA and ENZ. Clinical decision-making on whether to prescribe AA or ENZ should be informed by other potential toxicities as well as cross-resistance with sequencing of these therapies. Analysis of impact of bone protective agent use is underway.

The Role of Piper sarmentosum Aqueous Extract as a Bone Protective Agent, a Histomorphometric Study.

Glucocorticoids are one of the causes of secondary osteoporosis. The aqueous extract of Piper sarmentosum contains flavonoids that possess antioxidant effects. In this study, we determined the effects of aqueous Piper sarmentosum leaf extract on structural, dynamic and static histomorphometric changes from osteoporotic bones of rats induced with glucocorticoids. Thirty-two Sprague-Dawley rats were divided equally into four groups—Sham control group given vehicles (intramuscular (IM) olive oil and oral normal saline); AC: Adrenalectomised (Adrx) control group given IM dexamethasone (DEX) (120 μg/kg/day) and vehicle (oral normal saline); AP: Adrx group administered IM DEX (120 μg/kg/day) and aqueous Piper sarmentosum leaf extract (125 mg/kg/day) orally; and AG: Adrx group administered IM DEX (120 μg/kg/day) and oral glycyrrhizic acid (GCA) (120 mg/kg/day). Histomorphometric measurements showed that the bone volume, trabecular thickness, trabecular number, osteoid and osteoblast surfaces, double-labelled trabecular surface, mineralizing surface and bone formation rate of rats given aqueous Piper sarmentosum leaf extract were significantly increased (p < 0.05), whereas the trabecular separation and osteoclast surface were significantly reduced (p < 0.05). This study suggests that aqueous Piper sarmentosum leaf extract was able to prevent bone loss in prolonged glucocorticoid therapy. Thus, Piper sarmentosum has the potential to be used as an alternative medicine against osteoporosis and osteoporotic fractures in patients undergoing long-term glucocorticoid therapy.

Treatment with Cinacalcet in Hemodialysis Patients with Severe Secondary Hyperparathyroidism, Influences Bone Mineral Metabolism and Anemia Parameters

Background: Due to the premium rate of Chronic Kidney Disease, we have increased our knowledge with respect to diagnosis and treatment of Bone Mineral Disease (BMD) in End- Stage Renal Disease (ESRD). Currently, various treatment options are available. The medication used for Secondary Hyper-Parathyroidism gives promising results in the regulation of Ca, P and Parathormone levels, improving the quality of life. The aim of the present study was to investigate the relation of cinacalcet administration to not only parathormone, Ca and P but also to anemia parameters such as hematocrit and hemoglobin. Materials and Methods: retrospective observational study was conducted in a Chronic Hemodialysis Unit. One-hundred ESRD patients were recruited for twenty-four months and were evaluated on a monthly rate. Biochemical parameters were related to medication prescribed and the prognostic value was estimated. Cinacalcet was administered to 43 out of 100 patients in a dose of 30-120 mg. Results: Significant differences were observed in PTH, Ca and P levels with respect to Cinacalcet administration. Ca levels appeared to be higher at 30mg as compared to 60mg cinacalcet. Furthermore, a decreasing age-dependent pattern was observed with respect to cinacalcet dosage. A positive correlation was observed between Dry Weight (DW) and cinacalcet dose. Finally, a positive correlation between Hematocrit and Hemoglobin and cinacalcet was manifested. Conclusions: Cinacalcet, is a potential cardiovascular and bone protective agent, which is approved for use in ESRD patients to assist SHPT. A novel information was obtained from this study, regarding the improvement of the control of anemia.

Advanced Prostate Cancer: AUA/ASTRO/SUO Guideline PART II.

The summary presented herein represents Part II of the two-part series dedicated to Advanced Prostate Cancer: AUA/ASTRO/SUO Guideline discussing prognostic and treatment recommendations for patients with castration-resistant disease. Please refer to Part I for discussion of the management of patients with biochemical recurrence without metastatic disease after exhaustion of local treatment options as well as those with metastatic hormone-sensitive prostate cancer. The Advanced Prostate Cancer Panel created evidence- and consensus-based guideline statements to aid clinicians in the management of patients with advanced prostate cancer. Such statements are summarized in figure 1[Figure: see text] and detailed herein. The systematic review utilized to inform this guideline was conducted by an independent methodological consultant. A research librarian conducted searches in Ovid MEDLINE (1998 to January Week 5 2019), Cochrane Central Register of Controlled Trials (through December 2018), and Cochrane Database of Systematic Reviews (2005 through February 6, 2019). An updated search was conducted prior to publication through January 20, 2020. The methodology team supplemented searches of electronic databases with the studies included in the prior AUA review and by reviewing reference lists of relevant articles. This guideline attempts to improve a clinician's ability to treat patients diagnosed with advanced prostate cancer. Continued research and publication of high-quality evidence from future trials will be essential to improve the level of care for these patients.

Efficacy of tasquinimod in men with metastatic castration-resistant prostate cancer: A meta-analysis of randomized controlled trials.

Tasquinimod is an oral quinoline-3-carboxamide derivative for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Tasquinimod has antiangiogenic, immunomodulatory, and antimetastatic properties, but it is also associated with toxicities, including skeletal pain, digestive disorders, fatigue, insomnia, and mental disorders. We aimed to perform a meta-analysis to evaluate the efficacy, safety, and long-term survival for tasquinimod in patients with mCRPC. Searches were carried out in PubMed, Embase, and the Cochrane Library. Eligible articles included randomized clinical trials (RCTs) comparing systemic or combination therapy (excluding primary or secondary androgen deprivation therapy, bone protective agents, or radionuclides) with placebo in men with mCRPC. Three RCTs were selected for final evaluation. The pooled results from the 3 studies indicated that tasquinimod was associated with good radiologic progression-free survival (rPFS) in mCRPC. For adverse effects (AEs), the results of meta-analysis indicated that patients with mCRPC who received tasquinimod had obvious anemia (risk ratio (RR) 1.35, 95% confidence interval (CI) 1.06-1.73, P = .02), back pain (RR: 1.57, 95% CI: 1.01-2.47, P = .05), pain in the extremities (RR: 1.90, 95% CI: 1.14-3.17, P = .01), insomnia (RR: 1.50, 95% CI: 1.03-2.17, P = .03), vomiting (RR: 1.52, 95% CI: 1.04-2.21, P = .03), and peripheral edema (RR: 1.52, 95% CI: 1.03-2.23, P = .03). Tasquinimod is associated with better rPFS in mCRPC. The toxicity of tasquinimod requires further investigation, it is not recommended for routine clinical use.

Bone loss from Wnt inhibition mitigated by concurrent alendronate therapy

Dysregulated Wnt signaling is associated with the pathogenesis of cancers, fibrosis, and vascular diseases. Inhibition of Wnt signaling has shown efficacy in various pre-clinical models of these disorders. One of the key challenges in developing targeted anti-cancer drugs is to balance efficacy with on-target toxicity. Given the crucial role Wnts play in the differentiation of osteoblasts and osteoclasts, acute inhibition of Wnt signaling is likely to affect bone homeostasis. In this study, we evaluated the skeletal effect of small molecule inhibitor of an o-acyl transferase porcupine (PORCN) that prevents Wnt signaling by blocking the secretion of all Wnts. Micro-computed tomography and histomorphometric evaluation revealed that the bones of mice treated with two structurally distinct PORCN inhibitors LGK974 and ETC-1922159 (ETC-159) had loss-of-bone volume and density within 4 weeks of exposure. This decreased bone mass was associated with a significant increase in adipocytes within the bone marrow. Notably, simultaneous administration of a clinically approved anti-resorptive, alendronate, a member of the bisphosphonate family, mitigated loss-of-bone mass seen upon ETC-159 treatment by regulating activity of osteoclasts and blocking accumulation of bone marrow adipocytes. Our results support the addition of bone protective agents when treating patients with PORCN inhibitors. Mitigation of bone toxicity can extend the therapeutic utility of Wnt pathway inhibitors.

Suppressor of cytokine signaling 2 (Socs2) deletion protects bone health of mice with DSS-induced inflammatory bowel disease.

ABSTRACTIndividuals with inflammatory bowel disease (IBD) often present with poor bone health. The development of targeted therapies for this bone loss requires a fuller understanding of the underlying cellular mechanisms. Although bone loss in IBD is multifactorial, the altered sensitivity and secretion of growth hormone (GH) and insulin-like growth factor-1 (IGF-1) in IBD is understood to be a critical contributing mechanism. The expression of suppressor of cytokine signaling 2 (SOCS2), a well-established negative regulator of GH signaling, is stimulated by proinflammatory cytokines. Therefore, it is likely that SOCS2 expression represents a critical mediator through which proinflammatory cytokines inhibit GH/IGF-1 signaling and decrease bone quality in IBD. Using the dextran sodium sulfate (DSS) model of colitis, we reveal that endogenously elevated GH function in the Socs2−/− mouse protects the skeleton from osteopenia. Micro-computed tomography assessment of DSS-treated wild-type (WT) mice revealed a worsened trabecular architecture compared to control mice. Specifically, DSS-treated WT mice had significantly decreased bone volume, trabecular thickness and trabecular number, and a resulting increase in trabecular separation. In comparison, the trabecular bone of Socs2-deficient mice was partially protected from the adverse effects of DSS. The reduction in a number of parameters, including bone volume, was less, and no changes were observed in trabecular thickness or separation. This protected phenotype was unlikely to be a consequence of improved mucosal health in the DSS-treated Socs2−/− mice but rather a result of unregulated GH signaling directly on bone. These studies indicate that the absence of SOCS2 is protective against bone loss typical of IBD. This study also provides an improved understanding of the relative effects of GH/IGF-1 signaling on bone health in experimental colitis, information that is essential before these drugs are explored as bone protective agents in children and adults with IBD.

Predisposing factors associated with atypical femur fracture among postmenopausal Korean women receiving bisphosphonate therapy: 8years' experience in a single center.

The purpose of the present study is to determine whether rheumatoid arthritis (RA) and other clinical factors are associated with an increased risk of bisphosphonate (BP)-related atypical femur fracture (AFF). A retrospective nested case-control study of patients who had taken BPs for at least 1year was conducted. Patients with AFF were identified by reviewing surgical and radiographic records. Three controls with no history of AFFs were randomly selected and age- and sex-matched to each patient with AFFs. Cox proportional hazard models were used to analyze the independent contribution of risk factors to BP-related AFF. Among the 35,104 patients prescribed BPs for at least 1year, 43 females (mean age, 68years) suffered AFFs (0.12%). Patients with AFFs were exposed to BPs for a mean of 7.3years. Patients with AFFs were exposed to BPs for longer than those without AFFs and continued treatment without a drug holiday. More patients with AFF than controls had taken glucocorticoids and disease-modifying anti-rheumatic drugs. Multivariate Cox regression analyses estimated that long-term use of glucocorticoids, prolonged exposure to BP without cessation, and every 1kg/m2 increase in the body mass index (BMI) increased the hazard ratio for AFFs by 3.0, 5.2, and 1.2, respectively. Prolonged and continuous use of BPs, long-term use of glucocorticoids, and a higher BMI increase the risk of AFFs. Switching long-term BP and glucocorticoid users to other bone-protective agents should be considered.

Long-Term Effects of Severe Burn Injury on Bone Turnover and Microarchitecture.

Severe burn injury triggers massive alterations in stress hormone levels with a dose-dependent hypermetabolic status including increased bone resorption. This study evaluated bone microarchitecture measured by noninvasive high-resolution peripheral quantitative computed tomography (HR-pQCT). Changes of serum bone turnover markers (BTM) as well as regulators of bone signaling pathways involved in skeletal health were assessed. Standardized effect sizes as a quantitative measure regarding the impact of serum changes and the prediction of these changes on bone microarchitecture were investigated. In total, 32 male patients with a severe burn injury (median total body surface area [TBSA], 40.5%; median age 40.5 years) and 28 matched male controls (median age 38.3 years) over a period of 24 months were included. In patients who had sustained a thermal injury, trabecular and cortical bone microstructure showed a continuous decline, whereas cortical porosity (Ct.Po) and pore volume increased. Initially, elevated levels of BTM and C-reactive protein (CRP) continuously decreased over time but remained elevated. In contrast, levels of soluble receptor activator of NF-κB ligand (sRANKL) increased over time. Osteocalcin, bone-specific alkaline phosphatase (BALP), intact N-terminal type 1 procollagen propeptide (P1NP), and cross-linked C-telopeptide (CTX) acutely reflected the increase of Ct.Po at the radius (R2 = 0.41), followed by the reduction of trabecular thickness at the tibia (R2 = 0.28). In adult male patients, early and sustained changes of markers of bone resorption, formation and regulators of bone signaling pathways, prolonged inflammatory cytokine activities in conjunction with muscle catabolism, and vitamin D insufficiency were observed. These alterations are directly linked to a prolonged deterioration of bone microstructure. The probably increased risk of fragility fractures should be of clinical concern and subject to future interventional studies with bone-protective agents. © 2017 American Society for Bone and Mineral Research.

Novel bone protective agents in patients with prostate cancer

Prostate cancer is the most commonly diagnosed non-cutaneous cancer and the second leading cause of cancer death in men. The tissue tropism of prostate cancer for bone coupled with the skeletal- related adverse effects of Androgen Deprivation Therapy has led to heightened awareness of SREs in castration resistant prostate cancer. In the European Association of Urology updated 2015 guidelines on the management of castration resistant prostate cancer the grade of recommendation is ‘A’ for offering bone protective agents to patients with bone metastases (denosumab being superior to zoledronic acid). The results of larger ongoing studies that assess the efficacy, safety and cost-effectiveness of denosumab are warranted. O καρκίνος του προστάτη αποτeλeί τον πιο συχνά διαγνωζόμeνο μη δeρματικό καρκίνο και τη δeύτeρη πιο συχνή αιτία θανάτου από καρκίνο στους άνδρeς. Ο ιστικός τροπισμός του προστατικού καρκίνου για τα οστά σe συνδυασμό μe τις σχeτιζόμeνeς μe τα οστά ανeπιθύμητeς eνέργeιeς (SREs) της αντιανδρογονικής αγωγής, έχουν οδηγήσeι σe αυξημένη προσοχή στα SREs στον eυνουχοάντοχο καρκίνο του προστάτη (CRPC). Σύμφωνα μe τις πιο πρόσφατeς οδηγίeς της Eυρωπαικής Ουρολογικής Eταιρίας το 2015 για τη διαχeίριση ασθeνών μe CRPC, προτeίνeται μe βαθμό σύστασης ¨Α¨, η προσφορά οστeοπροστατeυτικών παραγόντων σe ασθeνeίς μe οστικές μeταστάσeις (μe το denosumab να υπeρτeρeί έναντι του ζολeδρονικού οξέος). Τα αποτeλέσματα των σe eξέλιξη μeλeτών που eπeξeργάζονται την αποτeλeσματικότητα, ασφάλeια και κόστος του denosumab eίναι eγγυήμeνα.

Advantages and Disadvantages of Bone Protective Agents in Metastatic Prostate Cancer: Lessons Learned.

Nine out of ten metastatic prostate cancer (PCa) patients will develop osseous metastases. Of these, every second will suffer from skeletal-related events (SRE). SRE are associated with an increased risk for death, which is markedly increased in the presence of pathological fracture. Moreover, health insurance costs nearly double in the presence of SRE. Zoledronic acid and denosumab are both approved drugs for the prevention or delay of SRE in castration-resistant prostate cancer (CRPC) patients with osseous metastases. However, long-term treatment with one of these two drugs is associated with the development of medication-related osteonecrosis of the jaw (MRONJ). Routine inspections of the oral cavity before and during treatment are mandatory in these patients. Regarding imaging techniques, bone scintigraphy seems to be a promising tool to detect early stage MRONJ. Zoledronic acid does not reduce the incidence of SRE in hormone-sensitive PCa. First data shows 3-monthly application of zoledronic acid to be equi-effective to monthly application.

Cost–effectiveness of denosumab as a bone protective agent for patients with castration resistant prostate cancer

Fortunately, novel agents are nowadays available for the management of patients with castration-resistant prostate cancer (CRPC). Denosumab is a new bone-protective agent, approved for the prevention and management of skeletal-related events. Studies have demonstrated that denosumab has better efficacy and similar rate of adverse effects in comparison with zoledronic acid, which was the standard bone-protective agent. In the present review we study the cost–effectiveness of denosumab in patients with CRPC.

Anti-inflammatory activity of sappanchalcone isolated from Caesalpinia sappan L. in a collagen-induced arthritis mouse model.

Sappanchalcone, a bioactive flavonoid isolated from the heartwood of Caesalpinia sappan L. possesses anti-inflammatory effects. We studied the efficacy of sappanchalcone in attenuating collagen-induced arthritis (CIA) in a mouse model of rheumatoid arthritis. Sappanchalcone was purified to homogeneity from the chloroform fraction of the methanolic extract of C. sappan, and identified using mass spectrometry and (1)H-nuclear magnetic resonance spectroscopy. CIA-induced male DBA/1J mice were divided into control, sappanchalcone-treated, and methotrexate-treated groups (n = 10 per group). Paw swelling, arthritis severity, radiographic and histomorphometric changes were assessed to measure the protective role of sappanchalcone against chronic disease progression. Sappanchalcone administration significantly reduced clinical arthritis and inflammatory edema in paws. Bone mineral density and trabecular structure were maintained in CIA mice administered sappanchalcone. The levels of pro-inflammatory cytokines (TNF-α, IL-6, and 1L-1β) were significantly lower in the serum of sappanchalcone-treated mice as compared with the control group. Our results suggest that sappanchalcone could be used as an anti-inflammatory and bone-protective agent during the treatment of rheumatoid arthritis.

The Polyphenol Fisetin Protects Bone by Repressing NF-κB and MKP-1-Dependent Signaling Pathways in Osteoclasts

Osteoporosis is a bone pathology leading to increase fractures risk and challenging quality of life. Since current treatments could exhibit deleterious side effects, the use of food compounds derived from plants represents a promising innovative alternative due to their potential therapeutic and preventive activities against human diseases. In this study, we investigated the ability of the polyphenol fisetin to counter osteoporosis and analyzed the cellular and molecular mechanisms involved. In vivo, fisetin consumption significantly prevented bone loss in estrogen deficiency and inflammation mice osteoporosis models. Indeed, bone mineral density, micro-architecture parameters and bone markers were positively modulated by fisetin. Consistent with in vivo results, we showed that fisetin represses RANKL-induced osteoclast differentiation and activity as demonstrated by an inhibition of multinucleated cells formation, TRAP activity and differentiation genes expression. The signaling pathways NF-κB, p38 MAPK, JNK and the key transcription factors c-Fos and NFATc1 expressions induced by RANKL, were negatively regulated by fisetin. We further showed that fisetin inhibits the constitutive proteasomal degradation of MKP-1, the phosphatase that deactivates p38 and JNK. Consistently, using shRNA stable cell lines, we demonstrated that impairment of MKP-1 decreases fisetin potency. Taken together, these results strongly support that fisetin should be further considered as a bone protective agent.