Bone Breakdown Research Articles

Bone-targeted agents in the treatment of lung cancer.

Over a third of patients with lung cancer will develop bone metastases during the course of their disease, resulting in symptoms of pain and immobility, and skeletal-related events (SREs) such as fracture, hypercalcaemia, surgery or radiotherapy to bones, and malignant spinal cord compression. These reduce quality of life and increase mortality. Preclinical research has identified the interactions between tumour cells and bone that are key to tumour cell survival and associated osteolysis. These data have led to the development of drugs to prevent osteoclast-mediated bone breakdown, such as zoledronic acid and denosumab, which are now licensed for use in patients with bone metastases from solid tumours. Both zoledronic acid and denosumab reduce the risk of SREs and increase time to first SRE, with minimal side effects. In addition, denosumab improved survival in patients with lung cancer compared with zoledronic acid. Ongoing trials are testing whether these drugs can prevent the development of bone metastases from lung cancer. New bone-targeted agents showing promise in breast and prostate cancer include radium-223, cabozantinib and Src inhibitors. These agents require further evaluation in patients with lung cancer.

Treating Bone Quality in Chronic Kidney Disease

While patients with chronic kidney disease (CKD) experience significant bone loss, little is known about the role of bone quality (properties independent of size and shape). Calcitriol is used to prevent bone loss by inhibiting parathyroid hormone (the main cause of bone breakdown in CKD), yet its impact on bone quality is unknown. Raloxifene improves bone quality, but its effects in CKD are unknown. This study examined the hypothesis that bone quality is deteriorated in CKD and that raloxifene but not calcitriol would improve bone quality. Using a rat model of CKD, mechanical properties of the tibia were assessed by nanoindentation, and composition was assessed by Raman spectroscopy. Animals with CKD were not different from normal controls with regard to elastic modulus, hardness, mineral‐to‐matrix ratio, or mineral crystallinity. Calcitriol treatment resulted in a higher mineral‐to‐matrix ratio (+20%), but it did not improve mechanics. Raloxifene, on the other hand, did not impact bone composition but led to substantially higher tissue hardness (+82%), consistent with previous data showing a mechanical effect independent of changes in tissue composition or bone mass. While animals with CKD may not have significant defects in bone quality at this stage of disease, these results indicate that improving the quality of the remaining tissue may be an effective means to compensate for bone loss in CKD. Nanoindentation Raman Spectroscopy Hardness (MPa) Elastic Modulus (GPa) Mineral‐to‐Matrix Ratio Mineral Crystallinity Normal (n=8) 196.97 +/‐ 23.53 11.13 +/‐ 2.57 2.69 +/‐ 0.44 0.053 +/‐ 0.0009 Chronic Kidney Disease ‐ No Treatment (n=9) 212.15 +/‐ 52.79 10.63 +/‐ 1.66 2.30 +/‐ 0.48 0.054 +/‐ 0.0008 Chronic Kidney Disease ‐ Calcitriol (n=11) 209.43 +/‐ 47.29 9.99 +/‐ 2.51 2.76 +/‐ 0.36 (*) 0.053 +/‐ 0.0004 Chronic Kidney Disease ‐ Raloxifene (n=10) 386.84 +/‐ 282.29 (*) 12.64 +/‐ 3.31 2.29 +/‐ 0.45 0.053 +/‐ 0.0005

Bone changes in alcoholic liver disease.

Alcoholism has been associated with growth impairment, osteomalacia, delayed fracture healing, and aseptic necrosis (primarily necrosis of the femoral head), but the main alterations observed in the bones of alcoholic patients are osteoporosis and an increased risk of fractures. Decreased bone mass is a hallmark of osteoporosis, and it may be due either to decreased bone synthesis and/or to increased bone breakdown. Ethanol may affect both mechanisms. It is generally accepted that ethanol decreases bone synthesis, and most authors have reported decreased osteocalcin levels (a "marker" of bone synthesis), but some controversy exists regarding the effect of alcohol on bone breakdown, and, indeed, disparate results have been reported for telopeptide and other biochemical markers of bone resorption. In addition to the direct effect of ethanol, systemic alterations such as malnutrition, malabsorption, liver disease, increased levels of proinflammatory cytokines, alcoholic myopathy and neuropathy, low testosterone levels, and an increased risk of trauma, play contributory roles. The treatment of alcoholic bone disease should be aimed towards increasing bone formation and decreasing bone degradation. In this sense, vitamin D and calcium supplementation, together with biphosphonates are essential, but alcohol abstinence and nutritional improvement are equally important. In this review we study the pathogenesis of bone changes in alcoholic liver disease and discuss potential therapies.

Association of Simvastatin and Hyperlipidemia With Periodontal Status and Bone Metabolism Markers

The objective of this study is to determine whether simvastatin consumption and hyperlipidemia are associated with a worse periodontal condition and specific bone activity biomarkers. This cross-sectional and analytic study includes 73 patients divided into three groups: 1) simvastatin-treated patients with hyperlipidemia (n = 29); 2) patients with hyperlipidemia treated by diet alone (n = 28); and 3) normolipidemic patients (controls, n = 16). The periodontal clinical variables of all participants were gathered, a blood sample was drawn from each to determine the lipid profile (total cholesterol, triglycerides, low-density lipoprotein, and high-density lipoprotein), serum levels of acute-phase reactants (C-reactive protein), erythrocyte sedimentation rate, and bone metabolism markers (osteoprotegerin [OPG], osteocalcin, procollagen type I N-terminal propeptide, and C-terminal telopeptide of type I collagen). The mean ESR was higher in the diet-treated patients with hyperlipidemia than in the normolipidemic controls (P = 0.04). Serum OPG concentrations were significantly higher in the simvastatin-treated patients with hyperlipidemia than in the diet-treated patients with hyperlipidemia (P = 0.05). Multivariable linear regression analysis adjusted for age, sex, tobacco, and alcohol revealed that, compared with the normolipidemic patients, the simvastatin-treated patients with hyperlipidemia showed a mean reduction of 0.8 mm (95% confidence interval = -1.5 to 0.0, P = 0.05) in clinical attachment loss. Within the limits of this study, the findings suggest that the intake of simvastatin is associated with increasing serum OPG concentrations, and this could have a protective effect against bone breakdown and periodontal attachment loss. The baseline systemic inflammatory state of patients with hyperlipidemia is indicated by their increased erythrocyte sedimentation rate.

Comparison of Denosumab Vs Zoledronic Acid for Treatment of Bone Disease in Adults with Newly Diagnosed Multiple Myeloma: a Randomized, Double-Blind, Multinational Phase 3 Trial

ABSTRACT Background: A characteristic feature of multiple myeloma (MM) is bone destruction mediated by osteoclasts. This breakdown of bone releases factors that mediate myeloma cell growth, creating a cycle of skeletal damage and tumor cell growth. Patients with MM and bone lesions can experience debilitating pain and skeletal complications including pathologic fractures, need for radiotherapy or surgery to bone, and spinal cord compression, collectively termed skeletal-related events (SREs). RANKL is the key mediator of osteoclast activity. Denosumab, a fully human monoclonal antibody specific to RANKL, inhibits the formation, function, and survival of osteoclasts, thus decreasing cancer-mediated bone destruction. The primary endpoint of this trial is to determine whether denosumab is noninferior to zoledronic acid (ZA) in delaying the time to 1st on-study SRE in patients with MM. Secondary endpoints include superiority of denosumab vs ZA in delaying the time to 1st on-study SRE and time to 1st-and-subsequent SRE and overall survival. Safety endpoints will be assessed. This trial is registered (ClinicalTrials.gov NCT01345019) and sponsored by Amgen Inc. Trial design: We are targeting enrollment of ∼1520 adults with newly diagnosed MM and ≥1 bone lesion. Patients with ≤30 days of anti-myeloma therapy, ≤1 prior dose of IV bisphosphonate, an ECOG status ≤2, and adequate organ function are eligible. Use of any approved treatment regimen is permitted as anti-myeloma treatment in this trial. Enrolled patients are stratified by whether they intend to undergo autologous stem cell transplant; use of novel vs non-novel anti-myeloma agents as 1st-line therapy; stage at diagnosis per the International Staging System; SRE at time of presentation; and geographic region. Randomized (1:1) patients receive either SC denosumab 120 mg+IV placebo or IV ZA 4 mg (adjusted for CrCl)+SC placebo once every 4 weeks. Daily calcium (≥500 mg) and vitamin D (≥400 IU) supplements are strongly recommended. The primary analysis is planned when ∼800 patients experience an on-study SRE. Enrollment is currently ongoing and enrollment rates are as planned. Reused with permission from the American Society of Clinical Oncology (ASCO). This abstract was accepted and previously presented at the 2014 ASCO Annual Meeting (TPS8628). All rights reserved. Disclosure: E. Terpos: Consultant for Amgen, Janssen-Cilag, and Morphosys; Honoraria from Celgene and Novartis; N. Raje: Consultant for Amgen; R. Garcia-Sanz: Honoraria from Amgen; Research funding from Novartis; K. Shimizu: Consultant for and honoraria and research funding from Daiichi Sankyo; Expert testimony on behalf of Amgen; W. Willenbacher: Consultant for and honoraria and research funding from Amgen; L. Zhu: Employee of Amgen; Own stock or stock options in Amgen; A. Braun: Previous employee of Amgen; Own stock or stock options in Amgen; R. Jain: Employee of Amgen; Own stock or stock options in Amgen; A. Palumbo: Consultant for and honoraria from Amgen, Bristol-Myers Squibb, Celgene, Janssen, Millenium, and Onyx. All other authors have declared no conflicts of interest.

Management strategies for osteochondritis dissecans of the knee in the skeletally immature athlete.

Osteochondritis dissecans (OCD) is a disorder resulting in focal breakdown of the subchondral bone, with potential disruption of the overlying articular cartilage. The femoral condyles of the knee are the most common locations for OCD, and the incidence of OCD appears to be increasing among active children. Juvenile OCD (JOCD) can be distinguished from adult OCD by the presence of open growth plates. Due to a lack of evidence on its early diagnosis, optimal treatment, and long-term course of healing, JOCD presents a unique challenge for the health care team. Approximately 50% to 67% of stable JOCD lesions heal successfully with nonoperative treatment. For unstable lesions and stable lesions that fail nonoperative treatment, a variety of surgical interventions can be utilized to stimulate bony healing and address articular cartilage lesions. It is recommended that rehabilitation of JOCD be tailored to the individual patient, based on the stage and radiographic status of the lesion and the mode of surgery employed when surgically addressed. Although there is a growing body of literature on this condition, the etiology and optimal methods for treatment, rehabilitation, and evaluating outcomes remain inconclusive due to a lack of quality evidence. Therapy, level 5.

Impact of Dietary Aromatic Amino Acids on Osteoclastic Activity

We had shown that aromatic amino acid (phenylalanine, tyrosine, and tryptophan) supplementation prevented bone loss in an aging C57BL/6 mice model. In vivo results from the markers of bone breakdown suggested an inhibition of osteoclastic activity or differentiation. To assess osteoclastic differentiation, we examined the effects of aromatic amino acids on early /structural markers as vitronectin receptor, calcitonin receptor, and carbonic anhydrase II as well as, late/functional differentiation markers; cathepsin K and matrix metalloproteinase 9 (MMP-9). Our data demonstrate that the aromatic amino acids down-regulated early and late osteoclastic differentiation markers as measured by real time PCR. Our data also suggest a link between the vitronectin receptor and the secreted cathepsin K that both showed consistent effects to the aromatic amino acid treatment. However, the non-attachment related proteins, calcitonin receptor, and carbonic anhydrase II, demonstrated less consistent effects in response to treatment. Our data are consistent with aromatic amino acids down-regulating osteoclastic differentiation by suppressing remodeling gene expression thus contributing initially to the net increase in bone mass seen in vivo.

A randomized, double-blind, multinational trial comparing denosumab with zoledronic acid for treatment of bone disease in adults with newly diagnosed multiple myeloma.

TPS8628 Background: A characteristic feature of multiple myeloma (MM) is bone destruction mediated by osteoclasts. This breakdown of bone releases factors that mediate myeloma cell growth, creating...

Altered Gene Expression in Gingival Tissues and Enhanced Bone Loss in Rats With Diabetes With Experimental Periodontitis

Systemic hyperglycemia is clearly related to severity of periodontitis, meaning that periodontitis can be exacerbated by diabetes mellitus (DM). However, the biologic mechanisms responsible for this relationship remain unclear. Thus, in this study, the global gene expression in gingival tissue with periodontitis is profiled in Zucker diabetic fatty (ZDF) rats compared with Zucker normoglycemic littermates (Lean). At age 8 weeks, ZDF and Lean rats received ligature placement around the maxillary right second molar. At 0, 14, 28, 42, and 56 days after ligature placement, the maxilla around the molar was analyzed using microcomputed tomography. Two and 7 days after ligature placement, total RNA in the gingival tissue was isolated, and gene expression analysis was conducted using a rat oligo array. To validate the microarray findings, the selected genes were analyzed using real-time quantitative polymerase chain reaction assays. There was a significant difference regarding the average amount of bone resorption between ZDF and Lean rats from days 14 to 56. On day 2, it was found that 113 genes were regulated (20 upregulated, 93 downregulated) in the presence of DM. Lipopolysaccharide binding protein (LBP) messenger RNA (mRNA) expression was significantly higher in gingival tissue with periodontitis from ZDF rats compared with that from Lean rats. On day 7, interleukin (IL)-10 and IL-24 mRNA levels were significantly lower, whereas IL-2 level was significantly elevated. The results of this study indicate that the role of DM in modulating bone breakdown related to periodontitis may involve an increased level of LBP and reduced levels of T-helper 2 cytokines.

Orally Administered Liposomal Lactoferrin Inhibits Inflammation‐Related Bone Breakdown Without Interrupting Orthodontic Tooth Movement

Bovine lactoferrin (bLF) modulates the production of tumor necrosis factor-alpha (TNF-α) and inhibits alveolar bone breakdown associated with periodontitis. This study is designed to examine the effects of orally administered liposomal bLF (LbLF) on orthodontic force (OF)-induced alveolar bone remodeling during experimental tooth movement. Two groups of male Wistar rats were treated with either LbLF or control solution in drinking water 7 days before OF application. Lipopolysaccharide (LPS) was injected into the gingival sulcus in half the rats in each group. Thus, four groups: OF, OF+LbLF, OF+LPS, and OF+LPS+LbLF were established. Orally administered LbLF significantly reduced apical migration of junctional epithelium in the OF and OF+LPS groups. In OF+LPS, osteoclast number in the alveolar crestal area was increased by LPS treatment, whereas osteoclast number was significantly reduced in OF+LPS+LbLF through suppression of TNF-α production. Osteoclastic induction in the middle part, mainly from OF application, was not affected by LbLF administration. Inhibition of tooth movement was not induced by LbLF. Orally administered LbLF significantly inhibits LPS-induced alveolar bone resorption but not OF-induced bone remodeling. LbLF could be a potent therapeutic and preventive agent to control periodontal inflammation in patients undergoing orthodontic treatment.

Randomized phase II placebo-controlled trial of fulvestrant plus vandetanib in postmenopausal women with bone only or bone predominant, hormone receptor-positive metastatic breast cancer (MBC): OCOG Zamboney study—NCT00811369.

574 Background: Biomarkers of bone turnover, including urine N-telopeptide (uNTx) and serum C-telopeptide (sCTx) reflect tumor-related bone breakdown and have been used as surrogate measures of response to therapy in trials. Vascular endothelial growth factor (VEGF) levels correlate with extent of bone metastases (BM). We assessed whether vandetanib, an inhibitor of VEGF, epidermal growth factor receptor and RET signalling, improved uNTx response when added to fulvestrant (F) in patients with BM. Methods: Postmenopausal patients with bone only, or bone predominant, hormone receptor positive MBC were randomised to F (500mg IM day 1, 14, 28, then monthly) with either vandetanib (100mg PO OD) (FV) or placebo (FP) until progression. The primary objective was uNTx response (>30% reduction from baseline). uNTx was collected at baseline, weekly to wk 4, at wk 12 and then every 12 wks. Secondary objectives included PFS, OS, RECIST response, pain and toxicity. Results: 61 patients were allocated to FV and 68 to FP. Median age was 59. 18% had received 1 prior chemotherapy regime and 73% prior endocrine therapy for MBC. uNTx response (n=124 pts) was 64% for FV vs. 52% for FP (p=0.20). No difference was detected between groups for median PFS; 6 months for FV vs. 4.8 months for FP, HR=0.93 (95% CI: 0.64 to 1.36). 16 patients died in FV arm vs. 21 in the FP arm, HR=0.71 (95% CI: 0.37 to 1.36). For those patients with measurable disease, clinical benefit rates were 41% and 43%, respectively, p=1.00. Serious adverse events were similar, 3.3% for FV vs. 5.9% for FP. Elevated baseline uNTx (>65 nM BCE/mmol Cr) was prognostic for PFS, HR=1.62 (95% CI: 1.08 to 2.43 and for mortality, HR= 2.4 (95% CI: 1.2 to 4.6). In an exploratory analysis uNTx was predictive of responsiveness to FV for PFS, HR=0.60 when uNTx >65 vs. HR=1.37 when uNTx <65, P = 0.025 for interaction. Conclusions: The addition of vandetanib to F did not improve biomarker response, PFS or OS compared to F alone in patients with bone predominant disease. Exploratory analyses confirmed that baseline bone turnover markers are prognostic for PFS and OS. Clinical trial information: NCT00811369.

The effect of victim age on burnt bone fragmentation: Implications for remains recovery

This research investigates how victim bone age affects the fragmentation and subsequent recovery of burnt bone. It could be inferred that the lower density and higher organic content of bone from younger individuals results in more significant bone breakdown compared to bone from older individuals. Previous research has suggested that while neonate bone can be difficult to destroy in a burn environment it is more fragile post-burning. Results comparing fragmentation of calcined piglet and fattening-pig remains reveal that, while consisting of smaller fragments, the younger material is less fragmented with more complete or almost complete bone elements. These observations have significant implications for remains recovery, especially of younger remains, as it highlights the value of this material as well as the importance of utilising search and recovery strategies that minimise post-burning disturbance. Younger bone responds differently to the burn environment and, therefore; it needs to be taken into consideration when planning remains discovery and retrieval to ensure maximum benefit to the investigation and individuals involved.

Collinin Reduces Porphyromonas gingivalis Growth and Collagenase Activity and Inhibits the Lipopolysaccharide‐Induced Macrophage Inflammatory Response and Osteoclast Differentiation and Function

Collinin is a secondary plant metabolite belonging to the class of geranyloxycoumarins. We explored the potential beneficial impact of collinin on periodontal health by investigating its effect on Porphyromonas gingivalis (P. gingivalis), lipopolysaccharide (LPS)-induced inflammatory response of macrophages, and osteoclastogenesis. Collinin was synthesized from pyrogallol and propiolic acid. A microdilution assay was used to determine antibacterial activity of collinin. The effect of collinin on collagenase activity of P. gingivalis was determined using fluorescent collagen. Macrophages were treated with collinin before being stimulated with LPS. The secretion of interleukin-6, chemokine (C-C motif) ligand 5, and prostaglandin E2 was assessed by enzyme-linked immunosorbent assays (ELISA). The inhibitory effect of collinin on differentiation of human preosteoclastic cells was assessed by tartrate-resistant acid phosphatase staining, whereas the secretion of matrix metalloproteinase-9 (MMP-9) was measured by ELISA. Bone resorption activity was investigated by using a human bone plate coupled with an immunoassay that detected the release of collagen fragments. Collinin inhibited the growth of P. gingivalis. The effect was more pronounced under iron-restricted conditions. Collinin dose dependently inhibited the degradation of type I collagen by P. gingivalis. It was also a potent inhibitor of the LPS-induced inflammatory response in macrophages and completely inhibited receptor activator of nuclear factor κB ligand-dependent osteoclast differentiation and MMP-9 secretion. Last, collinin affected bone degradation mediated by mature osteoclasts by significantly decreasing the release of collagen helical peptides. Although clinical trials are required, data from these in vitro analyses support the potential of collinin as a therapeutic agent for treating inflammatory periodontitis associated with bone breakdown.

Abstract 3947: AMG 161, a fully human monoclonal antibody to human RANKL, inhibits tumor-induced osteoclastogenesis and reduces skeletal tumor burden in mice that express chimeric (murine / human) RANKL.

Abstract Tumor cells can induce RANKL expression in the bone stroma, causing activation of osteoclasts which consequently mediate bone breakdown and subsequent tumor proliferation. RANKL is an essential mediator of osteoclast function and survival. RANKL inhibition by OPG-Fc can prevent tumor-induced osteolysis, decrease skeletal tumor burden, and increase survival in preclinical models. Denosumab is an anti-huRANKL antibody approved for the prevention of skeletal-related events due to bone metastases from solid tumors. Selective anti-huRANKL antibodies do not bind murine RANKL, therefore efficacy cannot be tested in typical mouse models. We developed a breast cancer bone metastasis model in mice in which exon 5 from murine RANKL was replaced with its human ortholog (“mu/huRANKL”). We tested the effect of AMG 161, an antibody which binds huRANKL and chimeric mu/huRANKL, on tumor burden and associated osteoclasts. After intra-cardiac injection of MCF-7Luc breast carcinoma cells, hind limb metastases formed and tumor burden was tracked by bioluminescence imaging (BLI). AMG 161 (0.3 or 3.0 mg/kg, 2x/week), OPG-Fc (3.0 mg/kg, 2x/week) or vehicle were administered beginning 10 days post tumor injection to treat established bone metastases until study termination at day 31. AMG 161 resulted in a dose-dependent decrease in skeletal tumor burden (3.0 mg/kg: 84% decrease vs. control p=0.0052) similar to that observed with OPG-Fc (85% decrease vs. control, p=0.0038). Histological analysis at the end of the study showed reductions in skeletal tumor burden consistent with the BLI. AMG 161 treatment resulted in a significant decrease in tumor-associated osteoclasts (TRAP staining) and inhibition of osteolytic lesions (X-ray). The inhibition of tumor burden by the anti-RANKL antibody was indirect via osteoclast inhibition since MCF-7Luc cells do not express RANK, and RANKL inhibition does not affect subcutaneous growth of MCF-7Luc cells. These data support the efficacy of anti-RANKL antibody treatment to inhibit tumor-induced osteoclastogenesis and to block the growth of bone metastases. Citation Format: Jude R. Canon, Rebecca Bryant, Martine Roudier, William C. Dougall. AMG 161, a fully human monoclonal antibody to human RANKL, inhibits tumor-induced osteoclastogenesis and reduces skeletal tumor burden in mice that express chimeric (murine / human) RANKL. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3947. doi:10.1158/1538-7445.AM2013-3947

Effect Immune‐modulator Metallo‐peptide (IMMP) on inflammation and joint damage in a model of arthritis induced by collagen type II

Rheumatoid arthritis is an inflammatory disease, chronic and degenerative pathology which is involved the immune system. New treatments seek to modify the immune response. The IMMP due to its immunomodulatory properties is a candidate to be evaluated as a treatment for arthritis.Our aim is to evaluate IMMF effect on inflammation and joint damage in a model RA. RA in Wistar rats was induced by administration of bovine collagen II. IMMP (25, 50, 100 y 200 ng/Kg), i.p., three times a week for 3 weeks was administrated. Rats treated with the 50, 100 and 200 ng/kg of IMMP showed a decrease of inflamation and in the breakdown of bone and cartilage, as well. In addition, rats treated with IMMP had no alterations in the liver, kidneys, thymus, spleen and weight.

Estrogens in the time of blood-thinners.

Estrogens in the time of blood-thinners.

Preclinical evaluation of zoledronate using an in vitro mimetic cellular model for breast cancer metastatic bone disease

BackgroundThe interactions between metastatic breast cancer cells and host cells of osteoclastic lineage in bone microenvironment are essential for osteolysis. In vitro studies to evaluate pharmacological agents are mainly limited to their direct effects on cell lines. To mimic the communication between breast cancer cells and human osteoclasts, a simple and reproducible cellular model was established to evaluate the effects of zoledronate (zoledronic acid, ZOL), a bisphosphonate which exerts antiresorptive properties. MethodsHuman precursor osteoclasts were cultured on bone-like surfaces in the presence of stimuli (sRANKL, M-CSF) to ensure their activation. Furthermore, immature as well as activated osteoclasts were co-cultured with MDA-MB-231 breast cancer cells. TRAP5b and type I collagen N-terminal telopeptide (NTx) were used as markers. Osteoclasts’ adhesion to bone surface and subsequent bone breakdown were evaluated by studying the expression of cell surface receptors and certain functional matrix macromolecules in the presence of ZOL. ResultsZOL significantly suppresses the precursor osteoclast maturation, even when the activation stimuli (sRANKL and M-SCF) are present. Moreover, it significantly decreases bone osteolysis and activity of MMPs as well as precursor osteoclast maturation by breast cancer cells. Additionally, ZOL inhibits the osteolytic activity of mature osteoclasts and the expression of integrin β3, matrix metalloproteinases and cathepsin K, all implicated in adhesion and bone resorption. ConclusionsZOL exhibits a beneficial inhibitory effect by restricting activation of osteoclasts, bone particle decomposition and the MMP-related breast cancer osteolysis. General significanceThe proposed cellular model can be reliably used for enhancing preclinical evaluation of pharmacological agents in metastatic bone disease.

Serum Sclerostin in Alcoholics: A Pilot Study

Sclerostin is an endogenous inhibitor of the Wnt/β-catenin pathway secreted by osteocytes, which inhibits osteoblast function, differentiation and survival. As a consequence, sclerostin tends to decrease bone mass. Alcoholics frequently present osteoporosis, mainly due to decreased bone synthesis. The behaviour of sclerostin in these patients is unknown. The aim of this work was to analyse the relationship between serum sclerostin levels and bone mineral density (BMD), ethanol consumption, nutritional status, liver function derangement and biomarkers of bone homeostasis in alcoholic patients. We included 31 alcoholic patients, of whom 11 were infected with Hepatitis C virus (HCV) and 7 age and sex-matched controls. All underwent densitometry, and serum sclerostin, osteocalcin, collagen telopeptide, parathyroid hormone (PTH), vitamin D, cortisol and testosterone were determined. Sclerostin levels were significantly higher in patients (30.95 ± 18.91 pmol/l) than controls (t = 4.4; P < 0.001), especially in non-HCV patients; they showed an inverse correlation with osteocalcin, prothrombin activity and serum albumin, and a direct correlation with bilirubin and telopeptide, but not with BMD, nutritional status or ethanol intake. Serum sclerostin was raised in alcoholic patients, and it correlated with decreased markers of bone synthesis and increased markers of bone breakdown. The elevation in sclerostin levels was clearly related with liver function, but not with ethanol intake, nutritional status or concomitant HCV infection.

Osteogenic potential of cissus qudrangularis assessed with osteopontin expression

Purpose:Fracture healing involves complex processes of cell and tissue proliferation and differentiation. Many factors are involved, including growth factors, inflammatory cytokines, antioxidants, bone breakdown (osteoclast) and bone building (osteoblast) cells, hormones, amino acids, and uncounted nutrients. We studied the osteogenic potential of Cissus quadrangularis (CQ), a plant that has been customarily used in the Indian subcontinent to hasten the process of healing in bone fractures.Materials and Methods:Total of 60 patients (age, 20-35 years) of mandible fracture was divided in two groups. Patients of group 1 were given capsules of CQ and fracture healing was assessed with osteopontin expression during treatment. Group 2 was control group.Results:Clinical and radiological analysis in our study was suggestive of better healing of fractures in group 1. All the samples of group 1 examined for osteopontin expression using western blot analysis and flow cytometry showed significant levels of expression of osteopontin protein and CD4+ T cells expressing osteopontin, respectively.Conclusion:We conclude that CQ accelerates fracture healing and also causes early remodeling of fracture callus.

Antimicrobial effect of &amp;lt;i&amp;gt;Anacardium occidentale&amp;lt;/i&amp;gt; leaf extract against pathogens causing periodontal disease

The oral cavity is perpetually colonized by different species of microorganisms and at times it is difficult to characterize the periodontal pathogen causing breakdown of tissue and bone. But over the years, based on scientific knowledge, it has been observed that various gram negative anaerobic bacteria have been involved with the initiation of periodontal disease. Based on literature reviews, a study was undertaken to investigate the antimicrobial effect of Anacardium occidentale (cashew) leaf extract on Porphyromonas gingivalis and Prevotella intermedia. Methanol and aqueous extracts of cashew leaves were prepared. Its antimicrobial activity against P. gingivalis and P. intermedia was tested using the agar diffusion method at various dilutions of 75 μ, 50 μl, 25 μl, 10 μl and 5 μl respectively. 0.2% Clorhexidine gluconate (CHX) was used as control. Cultures of P. gingivalis and P. intermedia strains were maintained on Kanamycin blood agar. The agar plates were then incubated at 37?C for 72 hours after which the zone of inhibition was measured and the mean was recorded for each test solution. The results of this study demonstrated that, for both P. gingivalis and P. intermedia, the highest concentration (75 μl) of both the extracts showed maximum antimicrobial action. For P. ginigvalis, the aqueous extract demonstrated significant inhibitory activity compared to the methanolic extract (p = 0.005), which was comparable to that of CHX. For P. intermedia, similar results were observed with aqueous extract being more effective compared to methanolic (p = 0.007), however, CHX was most effective compared to both the extracts (p = 0.007). This study revealed that Anacardium occidentale leaf extracts have efficient antimicrobial activity against P. gingivalis & P. intermedia. Hence, this preliminary study suggests that the antimicrobial action of A. occidentale leaf could be utilized for the preparation of chemical plaque control formulations.