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bone resorption inhibitors [keywords]
- Exemestane with ovarian suppression in premenopausal breast cancer. [Comment, Letter]
- N Engl J Med 2014 Oct 2; 371(14):1358-9.
- The relevance of leukotrienes for bone resorption induced by mechanical loading. [JOURNAL ARTICLE]
- Bone 2014 Sep 27.
5-lipoxygenase (5-LO) metabolites are important pro inflammatory lipid mediators. However, much still remains to be understood about the role of such mediators in bone remodeling. This study aimed to investigate the effect of 5-LO metabolites, LTB4 and CysLTs, in a model of mechanical loading-induced bone remodeling. Strain-induced tooth movement and consequently alveolar bone resorption/apposition was achieved by using a coil spring placed on molar and attached to incisors of C57BL6 (wild-type-WT), 5-LO deficient mice (5-LO(-/-)) and mice treated with 5-LO inhibitor (zileuton-ZN) or with antagonist of CysLTs receptor (montelukast-MT). The amount of bone resorption and the number of osteoclasts were determined morphometrically. The expression of inflammatory and bone remodeling markers in periodontium were analyzed by qPCR. Osteoclast differentiation and TNF-α production were evaluated in vitro using RAW 264.7 cells treated with LTB4 or LTD4. Bone resorption, TRAP(+) cells and expression of Tnfa, Il10 and Runx2 were significantly diminished in 5-LO(-/-), ZN- and MT-treated mice. The expression of Rank was also reduced in 5-LO(-/-) and MT-treated mice. Accordingly, LTB4 and LTD4 in association with RANKL promoted osteoclast differentiation and increased TNF-α release in vitro. These data demonstrate that the absence of 5-LO metabolites, LTB4 and CysLTs, reduce osteoclast recruitment and differentiation, consequently diminishing bone resorption induced by mechanical loading. Thus, 5-LO might be a potential target for controlling bone resorption in physiological and pathological conditions.
- Bisphosphonate-related osteonecrosis of the jaw: what we have learned. [Journal Article, Review]
- Alpha Omegan 2014; 107(2):8-15.
Bisphosphonate related osteonecrosis of the jaws (BRONJ) is an entity that has become prevalent upon the dental and medical community for more than 10 years. This entity is unfortunate because both oral and intravenous nitrogen containing bisphosphonates have beneficial effects for patients for certain conditions. The exact pathology of BRONJ has yet to be determined, although many hypotheses have been put forth. Since its prevalence, a clinical staging system has been developed and radiological findings have been described. BRONJ can be prevented if oral healthcare is undertaken before the start of bisphosphonate therapy or after a short time from the start of their use. However, after BRONJ has developed in patients, a myriad of treatments have been proposed that may help these patients.
- Exercise prevented the lansoprazole-induced reduction of anti-osteoporotic efficacy of alendronate in androgen deficiency rats. [Journal Article, Research Support, Non-U.S. Gov't]
- Acta Pol Pharm 2014 May-Jun; 71(3):485-95.
Clinical studies indicate that proton pump inhibitors (PPIs), used long-term in elderly patients, increase the risk of osteoporotic fractures, and decrease the anti-fracture efficacy of alendronate. The aim of the present study was to examine the effect of physical exercise on the anti-osteoporotic efficacy of alendronate administered concurrently with lansoprazole, a PPI, in male rats with androgen deficiency induced by orchidectomy. Male Wistar rats at 3 months of age were divided into: sham-operated control rats, orchidectomized (ORX) control rats, ORX rats receiving alendronate, ORX rats receiving alendronate and lansoprazole, ORX rats receiving alendronate and subjected to exercise, and ORX rats receiving alendronate and lansoprazole and subjected to exercise. The orchidectomy or sham-operation was performed 7-8 days before the start of drug administration. The rats were subjected to the exercise on the treadmill 1 hour/day for 7 weeks (6 days a week). Alendronate sodium (3 mg/kg p.o.) and lansoprazole (4 mg/kg p.o.) were administered once daily for 7 weeks (6 days a week). Mechanical properties of the tibial metaphysis and femoral neck were assessed. Bone turnover markers, histomorphometric parameters, bone mass and mass of bone mineral were also studied. Lansoprazole weakened the anti-osteoporotic efficacy of alendronate. The exercise increased the alendronate effect. Similar changes were observed in the rats treated with lansoprazole and alendronate, subjected to exercise; no deleterious effects of lansoprazole were observed. In conclusion, the exercise prevented the lansoprazole-induced reduction the anti-osteoporotic efficacy of alendronate in orchidectomized rats.
- Vitamin D immunoassay systems: a comparison. [Comparative Study, Journal Article]
- Br J Biomed Sci 2014; 71(3):127-30.
- [Assessment of anthropometric parameters and serum leptin and fetuin-A levels in children and adolescents with osteosarcoma after anticancer treatment]. [Controlled Clinical Trial, English Abstract, Journal Article]
- Pol Merkur Lekarski 2014 Aug; 37(218):86-90.
Cancer and the use of a comprehensive anti-cancer treatment are unfavorable factors, which have a significant impact on bone mass accumulation, bone mineralization and consequently the occurrence of osteoporosis. Bone turnover is regulated by complex mechanisms, among which an important role play OPG/RANK/RANKL signaling pathway, adipokines, and fetuin-A. The aim of the study was to evaluate bone mineral density and concentrations of leptin and fetuin-A in patients with osteosarcoma after anti-cancer treatment.The study included 50 children and adolescents aged 10-21 years. The study group consisted of 25 patients with osteosarcoma and 25 healthy counterparts as a control group. The examination was conducted 2 months after the last course of postoperative chemotherapy and included densitometric measurements: bone mineral content (BMC), bone mineral density (BMD), fat mass, lean mass and biochemical measurements: serum concentrations of calcium, magnesium, phosphate, 25-hydroksyvitamin D, alkaline phosphatase, leptin and fetuin-A. Concentrations of leptin and fetuin-A were determined by immunoenzymatic methods.In patients with osteosarcoma after anti-cancer treatment, we observed significantly reduced bone mineral content, bone mineral density and lean body mass compared with the healthy children (p < 0.05, p < 0.01, p < 0.05, respectively). Mean values of z-score of the whole body BMD and z-score of the lumbar BMD L1-L4 were significantly lower in patients than in the controls (p < 0.001). The serum concentrations of phosphate, magnesium, and alkaline phosphatase in both studied groups were similar, while calcium was significantly lower (p < 0.05) in patients than in the healthy children. The concentration of 25-hydroxyvitamin D was about two-fold lower, while leptin approximately 2.5-fold higher in patients than in the controls. The mean value of fetuin-A was similar in both studied groups. Statistically significant positive correlations between body composition parameters and the values of BMD, as well as between anthropometric parameters and leptin and fetuin-A were observed.The deficit in bone mass observed in patients with malignant bone tumors after anti-cancer treatment might be the result of decreased serum calcium and vitamin D concentrations. The observed correlation between anthropometric and biochemical parameters may indicate the link between bone and adipose tissue metabolism.
- Efficacy of a Cathepsin K Inhibitor in a Preclinical Model for Prevention and Treatment of Breast Cancer Bone Metastasis. [JOURNAL ARTICLE]
- Mol Cancer Ther 2014 Sep 23.
Cathepsin K (CatK) is essential for osteoclast mediated bone resorption. CatK expression is also detected in breast cancer (BrCa) cells that metastasize to bone. Here, the CatK inhibitor L-235 dosed in prevention (10, 30 and 100mg/kg, p.o., b.i.d.) or treatment regimen (30mg/kg) was compared to the bisphosphonate zoledronic acid (ZOL, 7.5microg/kg/wk, s.c.) in the intratibial injection model of MDA-MB-231 breast carcinoma in nude rats. Progression of osteolysis, skeletal tumor burden and local metastasis were evaluated by radiography through 42 days and ex vivo microCT and histology. Immunohistochemistry and RT-PCR confirmed the increases in CatK protein and mRNA levels in human BrCa primary and metastatic tumors. In the experimental model of BrCa bone metastasis, L-235 dosed in preventive mode resulted in a dose-related reduction of osteolysis of 72, 75, and 87% respectively, compared to ZOL by 86% vs. intact. Similarly, L-235 significantly reduced intratibial tumor volume by 29, 40 and 63% respectively, compared to 56% by ZOL vs. vehicle. Efficacy of L-235 and ZOL on reduction of osteolytic lesions and tumor burden were comparable in treatment vs. preventive regimens. All L-235 doses inhibited cortical disruption and extraskeletal tumor growth to a level comparable with ZOL. Assessment of local metastasis demonstrated that treatment with the CatKi was more effective than ZOL in reducing BrCa invasion. These data support the role of CatK in BrCa skeletal growth and metastasis and CatK inhibitors may represent a novel oral therapy for treatment of metastatic breast cancer.
- Intravenous Zoledronate for a Patient with Paget's Disease. [Journal Article]
- J Bone Metab 2014 Aug; 21(3):223-6.
Paget's disease (PD) of bone is characterized by increase of bone resorption by atypical osteoclasts, followed by rapid new bone formation resulting in a disorganized mosaic bone. Although the pathophysiology is not fully understood, bisphosphonate, which is a potent anti-resorptive agent for treatment of osteoporosis, have been the most effective agents available for the treatment of PD. We report a case of PD of bone in a 49-year-old woman patient, who was treated with intravenous zoledronate.
- A novel therapeutic approach with Caviunin-based isoflavonoid that en routes bone marrow cells to bone formation via BMP2/Wnt-β-catenin signaling. [Journal Article]
- Cell Death Differ 2014.:e1422.
Recently, we reported that extract of Dalbergia sissoo made from leaves and pods have antiresorptive and bone-forming effects. The positive skeletal effect attributed because of active molecules present in the extract of Dalbergia sissoo. Caviunin 7-O-[β-D-apiofuranosyl-(1-6)-β-D-glucopyranoside] (CAFG), a novel isoflavonoid show higher percentage present in the extract. Here, we show the osteogenic potential of CAFG as an alternative for anabolic therapy for the treatment of osteoporosis by stimulating bone morphogenetic protein 2 (BMP2) and Wnt/β-catenin mechanism. CAFG supplementation improved trabecular micro-architecture of the long bones, increased biomechanical strength parameters of the vertebra and femur and decreased bone turnover markers better than genistein. Oral administration of CAFG to osteopenic ovariectomized mice increased osteoprogenitor cells in the bone marrow and increased the expression of osteogenic genes in femur and show new bone formation without uterine hyperplasia. CAFG increased mRNA expression of osteoprotegerin in bone and inhibited osteoclast activation by inhibiting the expression of skeletal osteoclastogenic genes. CAFG is also an effective accelerant for chondrogenesis and has stimulatory effect on the repair of cortical bone after drill-hole injury at the tissue, cell and gene level in mouse femur. At cellular levels, CAFG stimulated osteoblast proliferation, survival and differentiation. Signal transduction inhibitors in osteoblast demonstrated involvement of p-38 mitogen-activated protein kinase pathway stimulated by BMP2 to initiate Wnt/β-catenin signaling to reduce phosphorylation of GSK3-β and subsequent nuclear accumulation of β-catenin. Osteogenic effects were abrogated by Dkk1, Wnt-receptor blocker and FH535, inhibitor of TCF-complex by reduction in β-catenin levels. CAFG modulated MSC responsiveness to BMP2, which promoted osteoblast differentiation via Wnt/β-catenin mechanism. CAFG at 1 mg/kg(/)day dose in ovariectomy mice (human dose ∼0.081 mg/kg) led to enhanced bone formation, reduced bone resorption and bone turnover better than well-known phytoestrogen genistein. Owing to CAFG's inherent properties for bone, it could be positioned as a potential drug, food supplement, for postmenopausal osteoporosis and fracture repair.
- Osteoporosis drugs: which one is right for you? There's no one-size-fits-all answer. Understanding your options begins with knowing what's available. [Journal Article]
- Harv Womens Health Watch 2014 Jul; 21(11):4-5.