OBJECTIVETo evaluate the influence and safety of denosumab on bone mineral density (BMD) of lumbar spine in women with low bone mass.

METHODSThe clinical literatures concerning denosumab for the treatment of osteopenia or osteoporosis in women were searched from Medline, Embase, Cochrane Central Register of Controlled Trials, Wanfang database, China National Knowledge Infrastructure database, Chinese Biomedical Database. Randomized controlled trials (RCT) were selected by the inclusive and exclusive criteria. The jadad scale was used in the quality assessment of included studies. Meta-analysis of valid data picked from included studies was performed by RevMan 5.0.24 software.

RESULTS5 RCT were included in this meta-analysis. The results of meta-analysis using the fixed effects model showed that, the increase level of lumbar BMD after 12 month was 5.45% (95% CI, 5.05%~5.84%) higher in denosumab group than in placebo control group (P<0.00001). The serious adverse event, serious infection event and pack pain occurred during the followed-up were analysed using fixed effects model. The results showed no significant difference between two groups.

CONCLUSIONCompared with placebo control group, denosumab can significant increase the BMD of lumbar spine, and the safety of two groups is similar.

Antibodies, Monoclonal, Humanized ; adverse effects ; pharmacology ; Bone Density ; drug effects ; Bone Density Conservation Agents ; adverse effects ; pharmacology ; Denosumab ; Female ; Humans ; Lumbar Vertebrae ; Randomized Controlled Trials as Topic

Animals ; Bone Density Conservation Agents ; pharmacology ; Calcitriol ; pharmacology ; Calcium Channel Agonists ; pharmacology ; Humans ; Pulmonary Fibrosis ; metabolism ; Signal Transduction ; drug effects ; Transforming Growth Factor beta ; metabolism ; Wnt Proteins ; metabolism

PURPOSE: Bisphosphonates have been used to treat osteoporosis for more than ten years. However, complications associated with long-term administration of bisphosphonates, such as nonunion after pelvic insufficiency fracture or osteonecrosis of the jaw, have been recently reported in the literature. We investigated the relationships among the mechanical properties of the intact rat femur as well as healing fracture calluses and the intraosseous concentration of pamidronate (ICP), after long-term administration of pamidronate in a rat osteoporosis model. MATERIALS AND METHODS: We performed bilateral ovariectomy in 25 3-month-old female Sprague-Dawley rats. Beginning three months after ovariectomy, disodium pamidronate (0.5mg/kg) was injected every month. After the six-month administration period, the left femoral shaft was fractured using the closed fracture technique. Five weeks after fracture, 23 rats were euthanized and both femora were removed. We checked the mechanical properties of the intact (right) and fractured (left) femora using a three-point bending technique. Intraosseous concentration of pamidronate was checked by high-performance liquid chromatography. RESULTS: The mean ICP was 61.8+/-15.7ng/mg of bone. High ICP decreased the ultimate load to failure, stiffness, and ultimate stress of the intact femora (p=0.015, 0.027, 0.039, respectively). There was a tendency to decrease the ultimate load to failure in the healing callus when the ICP increased (p= 0.183). High ICP decreased the bone mineral density of the femoral head (p=0.005). CONCLUSION: High concentrations of pamidronate in intact bone decreased the bone mineral density and weakened the mechanical strength of the rat femora. The mechanical strength of the early healing callus was not correlated with concentration of pamidronate in the bone.
Animals ; Bone Density Conservation Agents/*pharmacology ; Diphosphonates/*pharmacology ; Disease Models, Animal ; Female ; Femur/*drug effects/physiology ; Fracture Healing/physiology ; Osteoporosis/*metabolism ; Rats ; Rats, Sprague-Dawley ; Stress, Mechanical

To provide a support to the clinical application of alendronate (Alen) on cytology, we studied the effects of Alen on the function of osteoblasts. In this experiment, we observed the influence of MG63 cell line co-incubation with Alen at concentrations of 1 x 10(-9) mol/L, 1 x 10(-7) mol/L or 1 x 10(-5) mol/L on the osteoblastic function (proliferation, cell morphology, alkali phosphatase (ALP) activity, expression of type I collagen and effect of calcium deposition). The proliferation, cell morphology, ALP activity and type I collagen synthesis of MG63 were not affected by Alen at concentration of 1 x 10(-9) mol/L and 1 x 10(-7) mol/L, but the ALP activity as well as type I collagen production were promoted at higher concentration (1 x 10(-5) mol/L). The calcium deposition of MG63 could be increased at the lower concentration (1 x 10(-9) mol/L), while it was inhibited at the higher concentration. In conclusion, Alen at low concentration can promote the mineralization ability of osteoblasts to a certain extent, and this benefits the bone formation.
Alendronate ; pharmacology ; Alkaline Phosphatase ; metabolism ; Bone Density Conservation Agents ; pharmacology ; Cell Line ; Cell Proliferation ; drug effects ; Collagen Type I ; metabolism ; Humans ; Osteoblasts ; cytology ; Osteogenesis ; drug effects

Zebrafish was selected as model animal, and glucocorticoid dexamethasone was used as a model compound to establish a rapid and high efficient osteopenia model. Zebrafish larvae at 4 days post fertilization (dpf) were exposed to a serial concentrations of dexamethasone solutions, and 0.5% DMSO was selected as the vehicle control group. All groups were incubated in 24-well plates (28.5 degrees C) until 9 dpf. In addition, effects of 10 micromol x L(-1) dexamethasone on preventing against osteopenia induced by etidronate disodium were also investigated. Zebrafish bones at 9 dpf were stained with alizarin red. Quantitative analysis of the stained area was performed by microscopic inspection and digital imaging methods to reflect the amount of bone mineralization. Results showed that dexamethasone group at 2.5, 10 and 25 micromol x L(-1) can decrease the staining area and the staining optical density values of zebrafish head bones when compared with the vehicle control group (0.5% DMSO), which suggested that dexamethasone can significantly reduce the zebrafish mineralized bone and the bone mineral density. Results also showed that 15 and 30 microg x mL(-1) etidronate disodium can increase the mineralized matrix of zebrafish head bone and prevent against osteopenia induced by dexamethasone. In conclusion, the study indicated that zebrafish can be an idea osteopenia model induced by dexamethasone.
Animals ; Bone Density ; drug effects ; Bone Density Conservation Agents ; pharmacology ; therapeutic use ; Bone Diseases, Metabolic ; chemically induced ; prevention & control ; Calcification, Physiologic ; drug effects ; Dexamethasone ; toxicity ; Disease Models, Animal ; Etidronic Acid ; pharmacology ; therapeutic use ; Larva ; drug effects ; growth & development ; Zebrafish

PURPOSE: Genetic factor is an important predisposing element influencing the susceptibility to osteoporosis and related complications. The purpose of the present study is to investigate whether genetic polymorphisms of farnesyl diphosphate synthase (FDPS) or geranylgeranyl diphosphate synthase (GGPS) genes were associated with the response to bisphosphonate therapy. MATERIALS AND METHODS: In the present study, 144 Korean women with osteoporosis were included. Among 13 genetic polymorphisms found within the FDPS and GGPS1 gene, 4 genetic polymorphisms with frequencies > 5% were selected for further study. Bone mineral density (BMD) response after 1 year treatment of bisphosphonate therapy was analyzed according to the genotypes. RESULTS: Women with 2 deletion allele of GGPS1 -8188A ins/del (rs3840452) had significantly higher femoral neck BMD at baseline compared with those with one or no deletion allele (0.768 +/- 0.127 vs. 0.695 +/- 0.090 respectively; p = 0.041). The response rate of women with 2 deletion allele of GGPS1 -8188A ins/del (28.6%) was significantly lower than the rate of women with one (81.4%) or no deletion allele (75.0%) (p = 0.011). Women with 2 deletion allele of GGPS1 -8188A ins/del had 7-fold higher risk of non-response to bisphosphonate therapy compared with women with other genotypes in GGPS1 -8188 after adjusting for baseline BMD (OR = 7.48; 95% CI = 1.32-42.30; p = 0.023). Other polymorphisms in FDPS or GGPS1 were not associated with lumbar spine BMD or femoral neck BMD. CONCLUSION: Our study suggested that GGPS1 - 8188A ins/del polymorphism may confer susceptibility to femoral neck BMD response to bisphosphonate therapy in Korean women. However, further study should be done to confirm the results in a larger population.
Aged ; Asian Continental Ancestry Group ; Bone Density/*drug effects/*genetics ; Bone Density Conservation Agents/*pharmacology ; Dimethylallyltranstransferase/*genetics ; Diphosphonates/*pharmacology ; Farnesyltranstransferase/*genetics ; Female ; Geranyltranstransferase/*genetics ; Humans ; Middle Aged ; Polymorphism, Genetic/*genetics

OBJECTIVETo explore the role of bone morphogenetic protein-7 (BMP-7) in strontium ranelate (Sr)-induced osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs).

METHODSBMSCs were isolated from 4-week-old rats and cultured in vitro. The third or fourth passages of BMSCs were examined using alkaline phosphatase kit for changes in ALP activity in response to treatment with different concentrations of Sr. Calcium nodules in the induced cells were detected using alizarin red staining, and the cellular BMP-7 expression was detected by Western blotting.

RESULTSWithin the concentration range of 0.1-3.0 mmol/L, Sr dose-dependently increased ALP activity in rat BMSCs. ALP activity reached the highest level after treatment with 3 mmol/L Sr, which also significantly promoted the formation of calcium nodules. Within the range of 0.1-3.0 mmol/L, Sr dose-dependently enhanced the expression of BMP-7, and its peak expression occurred following 3 mmol/L Sr treatment. Noggin (100 ng/ml), an inhibitor of BMP-7, obviously suppressed Sr-induced over-expression of BMP-7 and reduced ALP activity and calcium nodule formation in the BMSCs.

CONCLUSIONSr promotes osteogenic differentiation of rat BMSCs by increasing the expression of BMP-7.

Animals ; Bone Density Conservation Agents ; pharmacology ; Bone Marrow Cells ; cytology ; Bone Morphogenetic Protein 7 ; genetics ; metabolism ; Cell Differentiation ; drug effects ; Cells, Cultured ; Female ; Male ; Mesenchymal Stromal Cells ; cytology ; metabolism ; Organometallic Compounds ; pharmacology ; Osteoblasts ; cytology ; Osteogenesis ; drug effects ; Rats ; Thiophenes ; pharmacology

Bisphosphonates are used routinely to reduce bone-related events in breast cancer patients with bone metastasis. We evaluated the effects of zoledronic acid, a third generation, nitrogen-containing bisphosphonate, to prevent bone metastasis in breast cancer. Zoledronic acid or vehicle alone was administered to nude mice either simultaneously or after intracardiac injection of human breast cancer MDA-MB-231 cells. Nude mice treated with zoledronic acid at early time points showed a lower incidence of bone metastases than did vehicle-treated nude mice, but these differences were not statistically significant. Only 37.5% of mice treated with zoledronic acid at the time of tumor cell inoculation developed bone metastases compared to over 51.8% of mice receiving vehicle alone (P = 0.304). Cell count of apoptosis confirmed by immunohistochemical staining in metastatic bone tissue significantly increased in the zoledronic acid-treated groups compared to non-treated group (1,018.3 vs 282.0; P = 0.046). However, metastatic tumor cells, which invade soft tissue around the bone, did not show extensive apoptosis; there were no differences between the zoledronic acid-treated and control groups. These results suggest that zoledronic acid increases apoptosis of metastatic breast tumor cells in the bone and could therefore reduce metastatic tumor burden. These results support the use of zoledronic acid to reduce the incidence of bone metastasis in breast cancer.
Animals ; Apoptosis/drug effects ; Bone Density Conservation Agents/pharmacology ; Bone Neoplasms/prevention & control/*secondary ; Bone and Bones/drug effects/pathology ; Breast Neoplasms/*drug therapy/*pathology ; Diphosphonates/*pharmacology ; Female ; Humans ; Imidazoles/*pharmacology ; Mice ; Mice, Nude ; Xenograft Model Antitumor Assays

OBJECTIVETo investigate the effect of local application of zoledronic acid (ZA) on the expression of type I collagen and vascular endothelial growth factor (VEGF).

METHODSFifty-four male Wistar rats were divided into ZA group, gelatin sponge group, and blank control group after one-side tooth extraction. The expression of type I collagen and VEGF were detected with SP immunohistochemistry method 1, 2 and 4 weeks after operation.

RESULTSThe gray value of type I collagen in ZA group (60.00 ± 1.81, 63.47 ± 3.02) was lower than those in gelatin sponge group (68.58 ± 2.90, 71.15 ± 5.57) and blank control group (69.16 ± 9.63, 72.50 ± 4.10, P < 0.05) in the 1 and 2 week. In the ZA and gelatin sponge groups, the gray values of type I collagen were higher in the 4th week than in the 1st and 2nd week (P < 0.05). The expression of VEGF was higher in ZA group (69.93 ± 2.74) than in gelatin sponge group (60.86 ± 4.79) and blank control group (61.52 ± 2.28) in the 1st week (P < 0.05). There was significant difference in VEGF expression between the 2nd week and 1st and 4th week (P < 0.05).

CONCLUSIONSLocal application of ZA could enhance the expression of type I collagen but inhibit the expression of VEGF in the early stage.

Administration, Topical ; Animals ; Bone Density Conservation Agents ; administration & dosage ; pharmacology ; Bone Regeneration ; drug effects ; Diphosphonates ; administration & dosage ; pharmacology ; Imidazoles ; administration & dosage ; pharmacology ; Male ; Rats ; Rats, Wistar ; Tooth Extraction ; Vascular Endothelial Growth Factor A ; metabolism

PURPOSE: The comparative effects of alendronate and alfacalcidol on bone mineral density (BMD) and bone turnover have already been established in postmenopausal women with osteoporosis. An open-labeled prospective study was conducted to compare the treatment effects of alendronate and alfacalcidol on hip BMD and bone turnover in Japanese men with osteoporosis or osteopenia with clinical risk factors for fractures. MATERIALS AND METHODS: One hundred twelve men with osteoporosis or osteopenia with clinical risk factors for fractures (mean age: 71.4 years) were randomly divided into two groups of 56 patients each: the alendronate (5 mg daily) and alfacalcidol (1 microgram daily) groups. The BMD of the total hip, urinary level of cross-linked N-terminal telopeptides of type I collagen (NTX), and serum levels of bone-specific alkaline phosphatase (BSAP) were measured during the 12-month-treatment period. RESULTS: Forty-five patients in the alendronate group and 42 patients in the alfacalcidol group completed the trial. Alendronate increased BMD (+2.3% at 12 months) following reductions in the urinary level of NTX (-46.4% at 3 months) and serum level of BSAP (-34.1% at 12 months), while alfacalcidol sustained BMD (-1.9% at 12 months) as well as the urinary level of NTX (+13.2% at 3 months) and serum level of BSAP (+1.8% at 12 months). CONCLUSION: The present study confirmed that alendronate has better efficacy than alfacalcidol (active control) in increasing hip BMD and reducing bone turnover in Japanese men with osteoporosis or osteopenia with clinical risk factors for fractures.
Aged ; Aged, 80 and over ; Alendronate/pharmacology/therapeutic use ; Asian Continental Ancestry Group ; Bone Density/*drug effects ; *Bone Density Conservation Agents/pharmacology/therapeutic use ; Bone Diseases, Metabolic/*drug therapy ; Fractures, Bone/*prevention & control ; Hip Joint/*drug effects/pathology ; Humans ; *Hydroxycholecalciferols/pharmacology/therapeutic use ; Male ; Middle Aged ; Osteoporosis/*drug therapy ; Treatment Outcome