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bone resorption inhibitors [keywords]
- [Osteoporosis: treatment and pharmaceutical care]. [English Abstract, Journal Article, Review]
- J Pharm Belg 2014 Jun; (2):14-24.
Osteoporosis is a chronic disease with an increasing prevalence due to the ageing of the population. The consequences of this disease are not negligible because of the morbidity and mortality associated with it. Osteoporotic fractures are often the cause of loss of independence in the elderly, requiring considerable resources in terms of health services. Osteoporosis can be prevented and treated. However, it remains underestimated, underdiagnosed and undertreated. Thanks to his frequent contact with the public, the pharmacist can play an important role at multiple levels: supporting patients in treatment, by providing information on the disease, its treatment, proper use of medication, adherence and persistence, as well as raising awareness for the prevention of osteoporosis and identifying patients at risk.
- [Osteoporosis: risk factors and prevention]. [English Abstract, Journal Article, Review]
- J Pharm Belg 2014 Jun; (2):4-12.
Osteoporosis is a chronic disease with an increasing prevalence due to the ageing of the population. The consequences of this disease are not negligible because of the morbidity and mortality associated with it. Osteoporotic fractures are often the cause of loss of independence in the elderly, requiring considerable resources in terms of health services. Osteoporosis can be prevented effectively, but remains underestimated. Thanks to his frequent contacts with the public, the pharmacist can play an important role by informing about the disease and raising awareness for the prevention of it.
- DPP4 inhibitor treatment attenuates bone loss and improves mechanical bone strength in male diabetic rats. [JOURNAL ARTICLE]
- Am J Physiol Endocrinol Metab 2014 Jul 22.
Dipeptidyl peptidase 4 (DPP4) modulates protein activity by removing dipeptides. DPP4 inhibitors are currently used to improve glucose tolerance in type 2 diabetes patients. DPP4 substrates do not only increase insulin secretion, but also affect bone metabolism. In this study, the effect of DPP4 inhibitor sitagliptin on bone was evaluated in normal and streptozotocin-induced diabetic rats. This study included 64 male Wistar rats, divided into 4 groups (n=16): 2 diabetic and 2 control groups. One diabetic and one control group received sitagliptin through drinking water. Tibiae were scanned every 3 weeks using an in vivo micro-CT scanner. After 6 and 12 weeks, rats were sacrificed for histomorphometric analysis of bone parameters. The mechanical resistance of femora to fracture was assessed using a three-point bending test and serum levels of bone metabolic markers were measured. Efficient DPP4 inhibition was achieved in sitagliptin-treated groups. Trabecular bone loss, the decrease in trabecular number and the increase of trabecular spacing was attenuated through sitagliptin treatment in diabetic rats as shown by in vivo micro-CT. Bone histomorphometry was in line with these results. Micro-CT analysis furthermore showed that sitagliptin prevented cortical bone growth stagnation in diabetic rats, resulting in stronger femora during three-point bending. Finally, the serum levels of the resorption marker CTX-I were significantly lower in sitagliptin treated diabetic animals compared to untreated diabetic animals. In conclusion, sitagliptin treatment attenuates bone loss and increases bone strength in diabetic rats, probably through reduction of bone resorption and independent of glycemic management.
- Triptolide, a diterpene, inhibits osteoclastogenesis, induced by RANKL signaling and human cancer cells. [JOURNAL ARTICLE]
- Biochimie 2014 Jul 15.
Most bone-related diseases are characterized by excessive bone resorption by osteoclasts. Receptor activator of nuclear factor-kappa B (NF-κB) ligand (RANKL) has emerged as a major mediator of bone resorption, commonly associated with cancer and chronic inflammatory diseases. Thus inhibitors of RANKL signaling have a potential in preventing bone loss. In the present study, we investigated the ability of triptolide, a diterpenoid isolated from Thunder of God Vine, to inhibit signaling by receptor activator of NF-κB (RANK) and its ligand (RANKL) and to modulate osteoclastogenesis induced by RANKL and human cancer cells. We found that triptolide suppressed RANKL-induced differentiation of precursor cells to osteoclasts, and also inhibited osteoclast formation induced by human breast tumor cells (MDA-MB-231), multiple myeloma cells (U266) and prostate tumor cells (PC-3). Triptolide inhibited RANKL-induced NF-κB activation in osteoclast precursor cells by inhibiting IκBα kinase activation, IκBα phosphorylation, and IκBα degradation. Our results suggest that triptolide effectively inhibits RANKL-induced NF-κB activation and RANKL- and tumor cell-induced osteoclastogenesis. This warrants further study of triptolide as a potential therapy for osteoporosis and cancer-associated bone loss.
- Inhibition of Bone Resorption by the Cathepsin K Inhibitor Odanacatib is Fully Reversible. [JOURNAL ARTICLE]
- Bone 2014 Jul 16.
The cathepsin K (CatK) inhibitor odanacatib (ODN) is currently being developed for the treatment of osteoporosis. In clinical trials, efficacy and resolution of effect of ODN treatment on bone turnover biomarkers and accrued bone mass have been demonstrated. Here, we examine the effects of continuing treatment and discontinuation of ODN versus alendronate (ALN) on osteoclast (OC) function. First, accessibility and reversible engagement of active CatK in intracellular vesicles and resorption lacunae of actively resorbing OCs were demonstrated by the selective and reversible CatK inhibitors, BODIPY-L-226 (IC50=39nM) and L-873,724 (IC50=0.5nM). Next, mature human OCs on bone slices were treated with vehicle, ODN, or ALN for 2days, followed by either continuing with the same treatment, or replacement of the inhibitors by vehicle for additional times as specified per experimental conditions. Maintaining OCs on ODN or ALN significantly reduced CTx-I release compared to vehicle controls. However, only the treatment of OCs with ODN resulted in the formation of small shallow discrete resorption pits, retention of intracellular vesicles enriched with CatK and other lysosomal enzymes, increase in 1-CTP release and number of TRAP(+) OCs. Upon discontinuation of ODN treatment, OCs rapidly resumed bone resorption activity, as demonstrated by a return of OC functional markers (CTx-I, 1-CTP), cell number and size, morphology and number of resorption pits, and vesicular secretion of CatK towards the respective vehicle levels. As expected, discontinuation of ALN did not reverse the treatment-related inhibition of OC activity in the time frame of the experiment. In summary, this study demonstrated rapid kinetics of inhibition and reversibility of the effects of ODN on OC bone resorption, that differentiated the cellular mechanism of CatK inhibition from that of the bisphosphate antiresorptive ALN.
- Bone anabolics in osteoporosis: Actuality and perspectives. [Journal Article, Review]
- World J Orthop 2014 Jul 18; 5(3):247-54.
Vertebral and nonvertebral fractures prevention is the main goal for osteoporosis therapy by inhibiting bone resorption and/or stimulating bone formation. Antiresorptive drugs decrease the activation frequency, thereby determining a secondary decrease in bone formation rate and a low bone turnover. Bisphosphonates are today's mainstay among antiresorptive treatment of osteoporosis. Also, oral selective estrogen receptor modulators and recently denosumab have a negative effect on bone turnover. Agents active on bone formation are considered a better perspective in the treatment of severe osteoporosis. Recombinant-human parathyroid hormone (PTH) has showed to increase bone formation and significantly decrease vertebral fractures in severe patients, but with a modest effect on nonvertebral fractures. The study of Wnt signaling pathway, that induces prevalently an osteoblastic activity, opens large possibilities to antagonists of Wnt-inhibitors, such as sclerostin antibodies and dickkopf-1 antagonists, with potential effects not only on trabecular bone but also on cortical bone.
- [Endometrial cancer, estrogens and metabolic syndrome: scenario becomes more complicated]. [English Abstract, Journal Article]
- Vopr Onkol 2014; 60(3):254-62.
Simultaneously with keeping one of the leading positions in the structure of oncogynecological morbidity, endometrial cancer (EC) presents for many decades 'the food for brains' of cancer endocrinologists. Step by step development of contemporary ideas and collecting the data on mechanisms of hormonal carcinogenesis, the role of excessive estrogenic stimulation and metabolic syndrome/insulin resistance as risk factors for EC, very probable gradual changing of the disease phenotype and significance of genetic damages (with PTEN-mutations as one of the examples), as a consequence point at potential perspectives in the usage of preventive and therapeutic approaches in this important area.
- The role of hormones and aromatase inhibitors on breast tumor growth and general health in a postmenopausal mouse model. [JOURNAL ARTICLE]
- Reprod Biol Endocrinol 2014 Jul 15; 12(1):66.
Breast cancer is the most frequently diagnosed cancer in women in the United States. Approximately 70% of breast cancers are diagnosed in postmenopausal women. Major clinical trials and experimental studies showed that aromatase inhibitors are effective against postmenopausal breast cancer. Despite their effectiveness in reducing tumor recurrence, aromatase inhibitors have adverse effects on the cardiovascular system and increase osteoporosis and bone fractures. Our study is aimed at investigating the role of natural steroid hormones on serum cardiovascular and bone resorption markers in an established mouse model mimicking postmenopausal breast cancer.Ovariectomized nude mice were transplanted with MCF-7 breast cancer cells constitutively expressing aromatase. The mice were treated with different combinations and doses of steroids, [estrogen (25 pg, 40 pg, 100 pg), progesterone (6 ng) and testosterone (50 ng)] along with dehydroepiandrostenedione (100ug). Serum levels of HDL, LDL/VLDL, free and total cholesterol, total and bone specific alkaline phosphatase and triglycerides were analyzed after 5, 10 and 15 months.Free cholesterol and LDL/VLDL levels in serum were reduced in groups mimicking estrous cycle and menstrual cycle hormones treatment. HDL cholesterol was increased in all the hormone treated groups except the estrous cycle-mimicking group. Bone specific alkaline phosphatase was decreased in menstrual cycle levels of estrogen and progesterone treatment.All together our results show that use of natural hormones in appropriate combinations have beneficial effects on cardiac and bone toxicity, along with better tumor reduction than current treatments.
- γ-tocotrienol protects against ovariectomy-induced bone loss via mevalonate pathway as HMG-CoA reductase inhibitor. [JOURNAL ARTICLE]
- Bone 2014 Jul 11.
γ-tocotrienol (GT3), an analogue of vitamin E, has gained increasing scientific interest recently as it provides significant health benefits. GT3 exerts its biological effects not only by virtue of antioxidant properties but also by inhibiting hydroxy-methyl-glutaryl-coenzyme A (HMG-CoA) reductase. Studies have reported that the mevalonate pathway is relevant for bone metabolism and HMG-CoA reductase inhibitors can increase bone mass and are useful in osteoporosis therapy. However, whether it is involved in the bone anabolic activity of GT3 is not clear. This study was conducted to investigate the ability of GT3 to protect against ovariectomy-induced bone loss, as well as the correlation between the protections and mevalonate pathway. Results showed that mice supplemented with 100mg/kg emulsified GT3 via subcutaneous injection once per month for three months were significantly protected from ovariectomy-induced bone loss as evaluated by various bone structural parameters, bone metabolic gene expression levels and serum levels of biochemical markers for bone resorption and bone formation. Importantly, the effect of GT3 on preventing against ovariectomy-induced bone loss could be reversed by daily supplementation with mevalonate, indicating that GT3 may via an HMG-CoA reductase-dependent mechanism to protect against ovariectomy-induced bone loss. Our results suggest that GT3 is suitable as dietary supplement and has potential as an alternative drug to treat or prevent osteoporosis.