Bone Resorption ; China ; Cytokines ; physiology ; Diphosphonates ; pharmacology ; Estrogens ; pharmacology ; Humans ; Jaw ; drug effects ; metabolism

Bisphosphonate-Associated Osteonecrosis of the Jaw ; diagnosis ; etiology ; prevention & control ; therapy ; Diphosphonates ; chemistry ; pharmacokinetics ; pharmacology ; Humans ; Risk Factors

BACKGROUNDBisphosphonates (BPs) have been reported to reduce local recurrence in giant cell tumor (GCT) of bone because of their osteoclast-suppressing effect; however, the optimal mode of delivery and the dose and duration of treatment of BPs remain to be established. To address these issues, it is first necessary to clarify the manner of action of BPs on osteoclasts. We herein evaluated the osteoclast-suppressing effect of sodium ibandronate in vitro.

METHODSMouse osteoclasts (OCLs) were generated in vitro using mouse bone marrow mononuclear cells. First, various concentrations of sodium ibandronate and equal amounts of phosphate-buffered saline were added to cell culture media. The number of multinucleated cells (over three nuclei) was recorded in each group, OCL formation was compared, and the most effective concentration of sodium ibandronate was determined. Then, high concentrations of sodium ibandronate were added to the experimental cell culture media; no ibandronate was given in the control group. Comparisons were made between the two groups in terms of OCL adhesion, migration, and bone resorption.

RESULTSOCL formation was suppressed by sodium ibandronate in vitro; the most pronounced effect was observed at the concentration of 10(-5) mol/L. OCL migration and bone resorption were significantly suppressed at this concentration, though there was no effect on OCL adhesion.

CONCLUSIONSSodium ibandronate was effective in suppressing OCLs and decreasing resorption in GCT. The strong anti-OCL effectiveness at a high concentration in vitro indicates a topical mode of application.

Animals ; Bone Resorption ; Cell Movement ; drug effects ; Cells, Cultured ; Diphosphonates ; pharmacology ; Mice ; Osteoclasts ; cytology ; drug effects

OBJECTIVETo study the inhibitory effect of zoledronic acid (ZA) on the growth and CD138 expression of myeloma cell line KM3.

METHODSKM3 cells were treated with different concentrations of ZA The growth of KM3 cells was measured by trypan blue dye exclusion, and the changes of apoptosis rate, cell cycle and expression of CD138 induced by ZA by flow cytometry.

RESULTSWithin the concentration of 10(-5)-10(-3) mol/L, ZA obviously inhibited the growth of KM3 cells in a dose dependent manner. IBN at 10(-5)-10(-4) moL/L increased Annexin V positive rate, blocked cells at the S/G2 boundary, reduced the expression of CD138 and its fluorescence intensity.

CONCLUSIONZA can inhibit the growth of KM3 cells in a dose-dependent manner and inhibited CD138 expression. The mechanism is probably related to induction cell cycle accumulation in S phase and apoptosis.

Apoptosis ; drug effects ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Diphosphonates ; pharmacology ; Humans ; Imidazoles ; pharmacology ; Syndecan-1 ; metabolism

Bone metastases is a serious complication of patients with tumor. It is associated with substantial morbidity, including bone pain, pathological fracture,neurological deficit and (or) hypercalcemia. Thus, the management of bone metastasis is a clinically significant issue. Bisphosphonates have now become a part of standard therapy to treat and prevent skeletal-related events (SRE), it could inhibit osteoclast-mediated bone resorption and demonstrate antitumor activity in preclinical models. Bisphosphonates are the most effective agent for treating and (or) preventing complications of bone metastasis, reducing the incidence of skeletal-related events, and improving quality of life in patients with bone metastasis.
Apoptosis ; drug effects ; Bone Neoplasms ; drug therapy ; pathology ; secondary ; Diphosphonates ; adverse effects ; pharmacology ; therapeutic use ; Humans ; Neoplasm Invasiveness

The purpose of the present study was to discuss the effects of risedronate on osteoarthritis (OA) of the knee by reviewing the existing literature. The literature was searched with PubMed, with respect to prospective, double-blind, randomized placebo-controlled trials (RCTs), using the following search terms: risedronate, knee, and osteoarthritis. Two RCTs met the criteria. A RCT (n = 231) showed that risedronate treatment (15 mg/day) for 1 year improved symptoms. A larger RCT (n = 1,896) showed that risedronate treatment (5 mg/day, 15 mg/day, 35 mg/week, and 50 mg/week) for 2 years did not improve signs or symptoms, nor did it alter radiological progression. However, a subanalysis study (n = 477) revealed that patients with marked cartilage loss preserved the structural integrity of subchondral bone by risedronate treatment (15 mg/day and 50 mg/week). Another subanalysis study (n = 1,885) revealed that C-terminal crosslinking telopeptide of type II collagen (CTX-II) decreased with risedronate treatment in a dose-dependent manner, and levels reached after 6 months were associated with radiological progression at 2 years. The results of these RCTs show that risedronate reduces the marker of cartilage degradation (CTX-II), which could contribute to attenuation of radiological progression of OA by preserving the structural integrity of subchondral bone. The review of the literature suggests that higher doses of risedronate (15 mg/day) strongly reduces the marker of cartilage degradation (CTX-II), which could contribute to attenuation of radiological progression of OA by preserving the structural integrity of subchondral bone.
Animals ; Calcium Channel Blockers/pharmacology/*therapeutic use ; Cartilage/drug effects ; Diphosphonates/therapeutic use ; Etidronic Acid/*analogs & derivatives/pharmacology/therapeutic use ; Humans ; Osteoarthritis, Knee/*drug therapy

OBJECTIVETo investigate the effect of zoledronic acid on proliferation and osteogenic differentiation of osteoblasts.

METHODSOsteoblasts were obtained from newly born rabbit jaw bones and cultured by the method of bone-tissue cultivation. Primary cultivated osteoblast was identified by alkaline phosphatase (ALP) and the mineralization nodes. Zoledronic acid at various concentrations was added to six groups of media with serial subcultivated cells (the final concentration: 0, 10(-5), 10(-6), 10(-7), 10(-8) and 10(-9) mol/L). At different time, ALP, osteoprotegerin and osteocalcin were observed and calculated.

RESULTSThe concentration of 10(-6), 10(-7), 10(-8) and 10(-9) mol/L zoledronic acid significantly increased ALP activity [(5.91 ± 0.35), (7.62 ± 0.33), (10.00 ± 0.38), (8.91 ± 0.29) U/L]. Protein expression of osteoprotegerin and osteocalcin was enhanced. The differences among the groups were significant (P < 0.01). Peak level was attained at a concentration of 10(-8) mol/L.

CONCLUSIONSZoledronic acid promotes osteoblast proliferation and maturation and modulates osteoprotegerin production.

Alkaline Phosphatase ; Animals ; Bone and Bones ; Cell Differentiation ; Cell Proliferation ; Cells, Cultured ; Diphosphonates ; pharmacology ; Imidazoles ; pharmacology ; Osteoblasts ; drug effects ; Osteocalcin ; drug effects ; metabolism ; Osteogenesis ; Osteoprotegerin ; drug effects ; metabolism ; Rabbits

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

OBJECTIVETo investigate the influence of zoledronic acid on vascular endothelial cells.

METHODSThe influence of zoledronic acid on proliferation, migration and adhesion of vascular endothelial cells were tested with 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), cell migration assay and cell adhesion assay. The results of each experimental group were compared with the control group and the data statistically analyzed.

RESULTSIn a concentration of 0-0.5 mmol/L, the absorbance value decreased from 0.09 to 0.34 as the drug concentration increased. Scratch test showed that the change of width of scratch before and after 24 hours in control, low, medium and high concentration groups were (38.7 ± 0.42), (35.8 ± 4.17), (19.9 ± 0.57) mm (P < 0.001), (12.5 ± 3.89) mm (P < 0.05). Adhesion test showed that the absorbance value in control, low, medium and high concentration groups were 1.14 ± 0.18, 0.95 ± 0.13, 0.81 ± 0.11 (P < 0.01), 0.67 ± 0.19 (P < 0.001). Comparisons between control and experimental groups were analyzed by t-test and P values < 0.05 were considered statistically significant.

CONCLUSIONSZoledronic acid inhibits the proliferation, migration and adhesion of vascular endothelial cells.

Cell Adhesion ; drug effects ; physiology ; Cell Movement ; drug effects ; physiology ; Cell Proliferation ; drug effects ; Diphosphonates ; pharmacokinetics ; pharmacology ; Endothelial Cells ; cytology ; drug effects ; Imidazoles ; pharmacokinetics ; pharmacology

OBJECTIVETo explore the effect of zoledronate (ZOL) on osteoclast differentiation and expressions of transient receptor potential vanilloid 5 channel (TRPV5) and nuclear factor of activated T-cells cytoplasmic 1 (NFATc1).

METHODSRAW264.7 cells were divided into two groups for treatment with RANKL for 5 days (group A) or with additional ZOL treatment in the last 2 days of RANKL treatment (group B). Osteoclastogenesis of the cells and the mRNA and protein expressions of TRPV5 and NFATc1 after the treatments were examined.

RESULTSIn group B, the number of newly generated osteoclasts (≥ 3 nuclei), number and size of dentin resorption lacunaes were 29.0 ± 2.4, 24.8 ± 1.1, and 2 030.0 ± 165.7 µm², respectively, which were significantly lower than those in group A (56.5 ± 4.5, 49.3 ± 0.9, and 3 946.7 ± 367.5 µm², respectively, P<0.01). Fluorescent intensity of TRPV5 and NFATc1 were also significantly decreased in group B (P<0.01). Compared with those in group A, TRPV5 mRNA and protein expressions in group B were down-regulated by 50.4% and 37.8%, and those of NFATc1 by 68.0% and 48.4%, respectively (P<0.01).

CONCLUSIONZOL can significantly inhibit osteoclastogenesis and bone resorption, which may be attributed, at least partly, to ZOL-induced inhibition of TRPV5 and NFATc1 expressions.

Animals ; Bone Resorption ; Calcium Channels ; metabolism ; Cell Differentiation ; drug effects ; Cell Line ; Diphosphonates ; pharmacology ; Down-Regulation ; Imidazoles ; pharmacology ; Mice ; NFATC Transcription Factors ; metabolism ; Osteoclasts ; drug effects ; RANK Ligand ; pharmacology ; RNA, Messenger ; TRPV Cation Channels ; metabolism