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Bisphosphonates
Kinds of Bisphosphonates Terms modified by Bisphosphonates Selected AbstractsBisphosphonate determination using 1H-NMR spectroscopy for biomedical applicationsJOURNAL OF TISSUE ENGINEERING AND REGENERATIVE MEDICINE, Issue 2 2009J. Chou Abstract Bisphosphonate is known to be a very active drug in the treatment of osteoporosis and bone regeneration. A new method has been developed, utilizing nuclear magnetic resonance spectroscopy to identify and measure the amount of bisphosphonate in solution. A standard reference with similar functional group to that of the bisphosphonate was chosen and applied in the experimentation. The results showed that the use of nuclear magnetic resonance spectroscopy (1H-NMR) in determining the solvent residues of various pharmaceutical drugs has proved to be effective. Unlike chromatography, it is possible to use a universal reference standard as an internal standard assayed by quantitative NMR. Using the same theory, this method is capable of both identifying and quantifying the bisphosphonate in various solutions. This paper is the first publication showing this unique measurement method, which can be used in a range of pharmaceutical and biomedical applications. Copyright © 2008 John Wiley & Sons, Ltd. [source] Effects of Bisphosphonate on the Endochondral Bone Formation of the Mandibular CondyleANATOMIA, HISTOLOGIA, EMBRYOLOGIA, Issue 5 2009M. S. Kim Summary The development of the mandibular condylar cartilage is important for the overall growth of the mandible. However, there have been a few researches into medical approaches aimed at controlling condylar growth. This study examined the effects of bisphosphonate on the growth of the condylar cartilage. Alendronate (3.5 mg/kg/week) was administered to postnatal day 1 SD rats for 7 and 10 days. The thickness of each chondrocyte layer and the level of MMP-9 expression were measured. The anteroposterior diameter of the developing condyle was unaffected by the alendronate treatment for 7 days (P > 0.05). The total thickness of the cartilage layers was also unaffected by the treatment for 7 days (P > 0.05). In particular, there was no change in the thickness of the perichondrium and reserve cell layer at the measured condylar regions (P > 0.05). However, the thickness of the proliferating cell layer was reduced significantly, whereas the thickness of hypertrophied cartilage layer was increased (P < 0.05). The number of chondroclasts engaged in hypertrophied cartilage resorption was reduced significantly by the alendronate treatment (P < 0.05). The level of MMP-9 expression was reduced at both the transcription and translation levels by the alendronate treatment for 7 and 10 days. These results indicate that alendronate (>3.5 mg/kg/week) inhibits the longitudinal growth of the mandibular condyle by inhibiting chondrocyte proliferation and the resorption of hypertrophied cartilage for ossification. [source] Potente und selektive Inhibition der sauren Sphingomyelinase durch Bisphosphonate,ANGEWANDTE CHEMIE, Issue 41 2009Nicht nur gegen Osteoporose? Ein einfaches geminales Aminobisphosphonat (siehe Bild) ist der bisher potenteste und selektivste Inhibitor der sauren Sphingomyelinase. Die Verbindung kann in einer Stufe synthetisiert werden und inhibiert den Zelltod in vitro. Weil die saure Sphingomyelinase ein potenzieller Angriffspunkt für Wirkstoffe bei der Behandlung entzündlicher Lungenerkrankungen ist, könnten die Bisphosphonate neue Therapiemöglichkeiten eröffnen. [source] In vivo microfocal computed tomography and micro,magnetic resonance imaging evaluation of antiresorptive and antiinflammatory drugs as preventive treatments of osteoarthritis in the ratARTHRITIS & RHEUMATISM, Issue 9 2010Michael D. Jones Objective To determine whether treatment with an antiresorptive drug in combination with an antiinflammatory drug reduces periarticular bone and soft tissue adaptations associated with the progression of posttraumatic secondary osteoarthritis (OA). Methods We used in vivo microfocal computed tomography (micro-CT) to map bony adaptations and in vivo micro,magnetic resonance imaging (micro-MRI) to examine joint inflammation in a rat model of surgically induced OA secondary to knee triad injury. We examined the arthroprotective effects of the bisphosphonates alendronate and risedronate and the nonsteroidal antiinflammatory drug (NSAID) meloxicam. Results Micro-CT revealed reduced levels of periarticular trabecular bone loss in animals with knee triad injury treated with the bisphosphonate drugs alendronate or risedronate, or the NSAID meloxicam, compared with untreated animals. Alendronate treatment reduced bony osteophyte development. While risedronate as a monotherapy did not positively impact osteophytogenesis, combination therapy with risedronate and meloxicam reduced osteophyte severity somewhat. Micro-MRI revealed an increased, diffuse water signal in the epiphyses of untreated rats with knee triad injury 8 weeks after surgery, suggestive of a bone marrow lesion,like stimulus. In contrast, meloxicam-treated rats showed a significant reduction in fluid signal compared with both bisphosphonate-treated groups 8 weeks after surgery. Histologic analysis qualitatively confirmed the chondroprotective effect of both bisphosphonate treatments, showing fewer degradative changes compared with untreated rats with knee triad injury. Conclusion Our findings indicate that select combinations of bisphosphonate and NSAID drug therapy in the early stages of secondary OA preserve trabecular bone mass and reduce the impact of osteophytic bony adaptations and bone marrow lesion,like stimulus. Bisphosphonate and NSAID therapy may be an effective disease-modifying drug regimen if administered early after the initial injury. [source] Bisphosphonate associated osteonecrosis: an unusual caseAUSTRALIAN DENTAL JOURNAL, Issue 3 2010P Mehanna Abstract The management of bisphosphonate associated osteonecrosis of the jaws (bisphosphonate associated ONJ) is emerging as a significant problem in the field of dentistry and oral and maxillofacial surgery. We present a case of a 55-year-old female taking oral bisphosphonates, steroids and immunosuppressant agents presenting with a life-threatening neck swelling. We discuss management options, as well as recent guidelines for treatment. [source] Alveolar bone and the bisphosphonatesAUSTRALIAN DENTAL JOURNAL, Issue 2009A Cheng Abstract Bisphosphonate associated osteonecrosis of the jaws (ONJ) usually commences at the alveolus. Comparison is made between the structure and function of long bones and alveolar bone and the differing susceptibilities of the bisphosphonates at these different sites are explored. Current concepts of the causation of ONJ are discussed. The clinical implications of these findings to dentists managing periodontal conditions are presented. [source] Stereoselective Synthesis of Substituted Trifluoromethylated Ethenylphosphonates via Sequential Transformations of Bisphosphonate.CHEMINFORM, Issue 36 2003Yanchang Shen Abstract For Abstract see ChemInform Abstract in Full Text. [source] Pharmacologic profile of zoledronic acid: A highly potent inhibitor of bone resorptionDRUG DEVELOPMENT RESEARCH, Issue 4 2002Jonathan R. Green Abstract Bisphosphonates are effective in treating benign and malignant skeletal diseases characterized by enhanced osteoclastic bone resorption (i.e., osteoporosis, Paget's disease, tumor-induced osteolysis). The nitrogen-containing bisphosphonate pamidronate is currently the standard treatment for hypercalcemia of malignancy (HCM) and skeletal complications of bone metastases. Zoledronic acid, a novel nitrogen-containing bisphosphonate with an imidazole substituent, has demonstrated more potent inhibition of osteoclast-mediated bone resorption than all other bisphosphonates, including pamidronate, in both in vitro and in vivo preclinical models. Zoledronic acid inhibited ovariectomy-induced bone loss in adult monkeys and rats, and long-term treatment prevented skeletal turnover and subsequent bone loss, reduced cortical porosity, and increased mechanical strength. Zoledronic acid also significantly inhibited bone loss associated with arthritis, bone metastases, and prosthesis loosening. The increased potency of zoledronic acid vs. pamidronate has been demonstrated clinically: zoledronic acid (4 or 8 mg iv) was superior to pamidronate (90 mg iv) in normalizing corrected serum calcium in patients with HCM. In patients with bone metastases, low doses of zoledronic acid (, 2 mg) suppressed bone resorption markers , 50% below baseline, whereas pamidronate 90 mg yielded only 20 to 30% suppression. Importantly, the increased potency of zoledronic acid is not associated with an increased incidence of local (bone) or systemic adverse events. Zoledronic acid does not impair bone mineralization and, compared with pamidronate, has a greater renal and intestinal tolerability therapeutic index. Thus, based on preclinical assays and clinical data, zoledronic acid is the most potent bisphosphonate tested to date. Given its potency and excellent safety profile, zoledronic acid is now poised to become the new standard of treatment for HCM and metastatic bone disease. Drug Dev. Res. 55:210,224, 2002. © 2002 Wiley-Liss, Inc. [source] Over-expression of CCL3,,MIP-1, in a blastoid mantle cell lymphoma with hypercalcemiaEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 5 2010Norimichi Hattori Abstract We analyzed a case with the blastoid variant of mantle cell lymphoma (MCL-BV), a rare subtype of B-cell lymphoma, presenting with marked hypercalcemia at diagnosis. Enzyme-linked immunosorbent assay (ELISA) showed elevated serum levels of interleukin-6 (IL-6), tumor necrosis factor-, (TNF-,), macrophage inflammatory protein-1, (MIP-1,), and type I collagen telopeptide, but not parathyroid hormone, calcitriol or parathyroid hormone-related peptide at diagnosis, suggesting local osteoclastic hypercalcemia in this case. By reverse transcription polymerase chain reaction (RT-PCR) analysis, we found predominant expression of mRNA for MIP-1, in addition to those for receptor-activator of nuclear-factor kappa B ligand (RANKL), TNF-,, and IL-6 in lymphoma cells obtained from the patient. Furthermore, recombinant MIP-1, significantly stimulated 3H-thymidine uptake by isolated MCL cells in vitro. Treatment with intravenous fluids, bisphosphonate, and methylprednisolone followed by combination chemotherapy promptly corrects the hypercalcemia and successfully induced complete remission, which was accompanied by a decrease of these cytokines in the serum, including MIP-1,. In the present case, MIP-1,, an osteoclast-activating factor produced by mantle lymphoma cells, may contribute to the development of hypercalcemia. It likely acts through RANKL expression in tumor cells and/or stroma cells, as indicated in multiple myeloma (MM) and adult T-cell leukemia/lymphoma (ATLL). Furthermore, MIP-1, is also involved in the development of an aggressive phenotype on MCL by stimulating proliferation of these lymphoma cells. In summary, the present study demonstrated that MIP-1, is an important factor in the development of both hypercalcemia and an aggressive phenotype in some types of B-cell lymphoma. [source] Zoledronate-induced remission of acute panmyelosis with myelofibrosisEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 3 2004I. Español Abstract:, Acute panmyelosis with myelofibrosis is a rare and aggressive form of acute myeloid leukemia. We describe a new case with a huge proliferation of megakaryocytes, blast cells and reticulin fibers. The patient was treated with zoledronate, a third-generation bisphosphonate, and a gradual recovery from pancytopenia was observed. A new bone marrow biopsy performed 4 months later showed a surprising disappearance of the leukemic infiltration. Ten months after the diagnosis, the patient is still in healthy condition. This may support the recently described anti-tumor activity of zoledronate. [source] Medical Potentialities of Biomimetic Apatites through Adsorption, Ionic Substitution, and Mineral/Organic Associations: Three Illustrative Examples,ADVANCED ENGINEERING MATERIALS, Issue 7 2010Ahmed Al-Kattan Biomimetic calcium phosphate apatites are particularly adapted to bio-medical applications due to their biocompatibility and high surface reactivity. In this contribution we report three selected examples dealing with mineral/organic interactions devoted to convey new functionalities to apatite materials, either in the form of dry bioceramics or of aqueous colloids. We first studied the adsorption of risedronate (bisphosphonate) molecules, which present potential therapeutic properties for the treatment of osteoporosis. We then addressed the preparation of luminescent Eu-doped apatites for exploring apatite/collagen interfaces through the FRET technique, in view of preparing "advanced" biocomposites exhibiting close spatial interaction between apatite crystals and collagen fibers. Finally, we showed the possibility to obtain nanometer-scaled apatite-based colloids, with particle size tailorable in the range 30,100,nm by controlling the agglomeration state of apatite nanocrystals by way of surface functionalization with a phospholipid moiety. This paper is aimed at illustrating some of the numerous potentialities of calcium phosphate apatites in the bio-medical field, allowing one to foresee perspectives lying well beyond bone-related applications. [source] In vivo Performance of Osteoactivated Cellulose-Based Scaffolds in Bony Critical-Size Defects,ADVANCED ENGINEERING MATERIALS, Issue 8 2009Sabine Ponader Cellulose-based scaffolds osteoactivated with different sodium silicate coatings (pure and bisphosphonate or strontium enriched respectively) can serve as long-term depots for a slow drug-release. Thus they are a promising and cost-saving alternative to the short-lived drug delivery systems of recombinant bone promoting proteins. [source] Zoledronic acid prevents bone loss after allogeneic haemopoietic stem cell transplantationINTERNAL MEDICINE JOURNAL, Issue 9 2006A. B. D'Souza Abstract Allogeneic haemopoietic stem cell transplant (alloHSCT) patients are at increased risk of osteoporosis. Zoledronic acid (ZA) is a potent i.v. bisphosphonate; however, there are few data on ZA use after alloHSCT. The aim of this study is to examine the effect of a single 4 mg ZA infusion in alloHSCT patients with either osteoporosis (T -score < ,2.5) or rapid bone loss post-alloHSCT. An uncontrolled, prospective study of 12 consecutive patients receiving ZA, predominantly within the first year post-HSCT. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry at the spine and proximal femur pretransplant, pre-ZA and post-ZA. The median annualized percentage change in total hip BMD between the pretransplant scan and the scan immediately before ZA was ,13% (range, ,51 to +3.6%). After ZA treatment, the total hip BMD increased by a median of +3.3% (range, ,20.4 to +14.8%) in 75% of patients. The median annualized percentage change in femoral neck BMD between the pretransplant scan and the scan immediately before ZA was ,13.2% (range, ,40 to +1.0%). Post-ZA, femoral neck BMD increased by a median of +1.4% (range, ,22.2 to +33.6%). Only one patient continued to lose bone from the femoral neck post-ZA infusion. The median annualized percentage change in spinal BMD pretransplant was ,12.5% (range, ,38 to +6.9%). Post-ZA, spinal BMD decreased by a median of ,2.8% (range, ,27.6 to +24.4%). Four patients continued to lose bone from the spine post-ZA. ZA reduces bone loss in most patients after alloHSCT. Our data require confirmation in a larger prospective, randomized study. [source] Cytotoxic effects of ,, T cells expanded ex vivo by a third generation bisphosphonate for cancer immunotherapyINTERNATIONAL JOURNAL OF CANCER, Issue 1 2005Kiyoshi Sato Abstract Nitrogen containing-bisphosphonates (N-BPs), widely used to treat bone diseases, have direct antitumor effects via the inactivation of Ras proteins. In addition to the direct antitumor activities, N-BPs expand gd,,T cells, which exhibit major histocompatibility complex-unrestricted lytic activity. BPs accumulate intermediate metabolites which may be tumor antigens in target cells. The purpose of our study was to clarify the cytotoxicity of gd,, T cells expanded ex vivo by the most potent N-BP, zoledronate (ZOL). Especially, we focused on the importance of pretreatment against target cells also with ZOL; 1 m,M ZOL plus IL-2 increased the absolute number of gd,,T cells 298,768 fold for 14 days incubation. The small cell lung cancer and fibrosarcoma cell lines pretreated with 5 m,M ZOL showed a marked increase in sensitivity to lysis by gd,,T cells. While, untreated cell lines were much less sensitive to lysis by gdT cells. Video microscopy clearly demonstrated that gd,,T cells killed target cells pre-treated with ZOL within 3 hr. Pretreatment with 80 m,g/kg ZOL also significantly enhanced the antitumor activity of gd,,T cells in mice xenografted with SBC-5 cells. These findings show that ZOL significantly stimulated the proliferation of gd,,T cells and that gd,,T cells required pre-treatment with ZOL for cytotoxic activity against target cells. © 2005 Wiley-Liss, Inc. [source] Differing Patterns of Antiresorptive Pharmacotherapy in Nursing Facility Residents and Community DwellersJOURNAL OF AMERICAN GERIATRICS SOCIETY, Issue 8 2005Carolyn M. Jachna MD Objectives: Little is known about differences between current patterns of antiresorptive therapy (ART) use in nursing facility (NF) residents and by community-dwelling older adults (CDs). ART use was compared in older NF residents and CDs. Design: Cross-sectional analysis. Setting: Kansas Medicaid files from May 2000 through April 2001. Participants: Women aged 65 and older having at least 9 months of data as a CD or NF resident. Measurements: Pharmacy claims were used to identify any ART prescription, including hormone replacement therapy (HRT), a bisphosphonate, raloxifene, or calcitonin. Demographic and clinical variables were identified from the claims files. Factors associated with ART use in bivariate analyses were entered into logistic regression models. Similar analyses were performed for bisphosphonate use among non-estrogen replacement therapy (non-ERT) ARTs (excluding HRT). Results: The final study sample (N=2,289) included 898 NF (mean age 85.2) residents and 1,391 CDs (mean age 76.6). CDs were more likely to receive any ART (24.5%) than NF residents (19.6%). After adjustment for potential confounders, NF residents aged 65 to 84 were less likely (odds ratio (OR)=0.61, 95% confidence interval (CI)=0.44,0.85) to receive ART than CDs of the same age. Conversely, of those aged 85 and older, NF residents were more likely than CDs to receive ART (OR=1.96, 95% CI=1.18,3.25). Calcitonin was the most common non-ERT ART prescribed for NF residents, whereas bisphosphonates were more often prescribed for CDs. Conclusion: Underusage of ART is common in NF and CD cohorts. NF residents are less likely to receive bisphosphonates and more likely to receive calcitonin, for which efficacy is less clear. Further research is needed to identify factors influencing ART prescribing and selection of specific ARTs in different settings. [source] Cell-based immunotherapy with mesenchymal stem cells cures bisphosphonate-related osteonecrosis of the jaw,like disease in miceJOURNAL OF BONE AND MINERAL RESEARCH, Issue 7 2010Takashi Kikuiri Abstract Patients on high-dose bisphosphonate and immunosuppressive therapy have an increased risk of bisphosphonate-related osteonecrosis of the jaw (BRONJ); despite the disease severity, its pathophysiology remains unknown, and appropriate therapy is not established. Here we have developed a mouse model of BRONJ-like disease that recapitulates major clinical and radiographic manifestations of the human disease, including characteristic features of an open alveolar socket, exposed necrotic bone or sequestra, increased inflammatory infiltrates, osseous sclerosis, and radiopaque alveolar bone. We show that administration of zoledronate, a potent aminobisphosphonate, and dexamethasone, an immunosuppressant drug, causes BRONJ-like disease in mice in part by suppressing the adaptive regulatory T cells, Tregs, and activating the inflammatory T-helper-producing interleukin 17 cells, Th17. Most interestingly, we demonstrate that systemic infusion with mesenchymal stem cells (MSCs) prevents and cures BRONJ-like disease possibly via induction of peripheral tolerance, shown as an inhibition of Th17 and increase in Treg cells. The suppressed Tregs/Th17 ratio in zoledronate- and dexamethasone-treated mice is restored in mice undergoing salvage therapy with Tregs. These findings provide evidence of an immunity-based mechanism of BRONJ-like disease and support the rationale for in vivo immunomodulatory therapy using Tregs or MSCs to treat BRONJ. © 2010 American Society for Bone and Mineral Research [source] Fluorescent risedronate analogues reveal bisphosphonate uptake by bone marrow monocytes and localization around osteocytes in vivoJOURNAL OF BONE AND MINERAL RESEARCH, Issue 3 2010Anke J Roelofs Abstract Bisphosphonates are effective antiresorptive agents owing to their bone-targeting property and ability to inhibit osteoclasts. It remains unclear, however, whether any non-osteoclast cells are directly affected by these drugs in vivo. Two fluorescent risedronate analogues, carboxyfluorescein-labeled risedronate (FAM-RIS) and Alexa Fluor 647,labeled risedronate (AF647-RIS), were used to address this question. Twenty-four hours after injection into 3-month-old mice, fluorescent risedronate analogues were bound to bone surfaces. More detailed analysis revealed labeling of vascular channel walls within cortical bone. Furthermore, fluorescent risedronate analogues were present in osteocytic lacunae in close proximity to vascular channels and localized to the lacunae of newly embedded osteocytes close to the bone surface. Following injection into newborn rabbits, intracellular uptake of fluorescently labeled risedronate was detected in osteoclasts, and the active analogue FAM-RIS caused accumulation of unprenylated Rap1A in these cells. In addition, CD14high bone marrow monocytes showed relatively high levels of uptake of fluorescently labeled risedronate, which correlated with selective accumulation of unprenylated Rap1A in CD14+ cells, as well as osteoclasts, following treatment with risedronate in vivo. Similar results were obtained when either rabbit or human bone marrow cells were treated with fluorescent risedronate analogues in vitro. These findings suggest that the capacity of different cell types to endocytose bisphosphonate is a major determinant for the degree of cellular drug uptake in vitro as well as in vivo. In conclusion, this study shows that in addition to bone-resorbing osteoclasts, bisphosphonates may exert direct effects on bone marrow monocytes in vivo. © 2010 American Society for Bone and Mineral Research [source] Retention, Distribution, and Effects of Intraosseously Administered Ibandronate in the Infarcted Femoral Head,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 1 2007James Aya-ay Abstract The local distribution, retention, and effects of intraosseous administration of ibandronate in the infarcted femoral heads were studied. Intraosseous administration effectively delivered and distributed ibandronate in the infarcted femoral heads and decreased the femoral head deformity in a large animal model of Legg-Calve-Perthes disease. Introduction: Bisphosphonate therapy has gained significant attention for the treatment of ischemic osteonecrosis of the femoral head (IOFH) because of its ability to inhibit osteoclastic bone resorption, which has been shown to contribute to the pathogenesis of femoral head deformity. Because IOFH is a localized condition, there is a need to explore the therapeutic potential of local, intraosseous administration of bisphosphonate to prevent the femoral head deformity. The purpose of this study was to investigate the distribution, retention, and effects of intraosseous administration of ibandronate in the infarcted head. Materials and Methods: IOFH was surgically induced in the right femoral head of 27 piglets. One week later, a second operation was performed to inject 14C-labeled or unlabeled ibandronate directly into the infarcted head. 14C-ibandronate injected heads were assessed after 48 h, 3 weeks, or 7 weeks later to determine the distribution and retention of the drug using autoradiography and liquid scintillation analysis. Femoral heads injected with unlabeled ibandronate were assessed at 7 weeks to determine the degree of deformity using radiography and histomorphometry. Results: Autoradiography showed that 14C-Ibandronate was widely distributed in three of the four heads examined at 48 h after the injection. Liquid scintillation analysis showed that most of the drug was retained in the injected head, and almost negligible amount of radioactivity was present in the bone and organs elsewhere at 48 h. At 3 and 7 weeks, 50% and 30% of the 14C-drug were found to be retained in the infarcted heads, respectively. Radiographic and histomorphometric assessments showed significantly better preservation of the infarcted heads treated with intraosseous administration of ibandronate compared with saline (p < 0.001). Conclusions: This study provides for the first time the evidence that local intraosseous administration is an effective route to deliver and distribute ibandronate in the infarcted femoral head to preserve the femoral head structure after ischemic osteonecrosis. In a localized ischemic condition such as IOFH, local administration of bisphosphonate may be preferable to oral or systemic administration because it minimizes the distribution of the drug to the rest of the skeleton and bypasses the need for having a restored blood flow to the infarcted head for the delivery of the drug. [source] Sustained Nonvertebral Fragility Fracture Risk Reduction After Discontinuation of Teriparatide TreatmentJOURNAL OF BONE AND MINERAL RESEARCH, Issue 9 2005Richard Prince Abstract A follow-up in 1262 women was conducted after the discontinuation of teriparatide. The hazard ratio for combined teriparatide group (20 and 40 ,g) for the 50-month period after baseline was 0.57 (p = 0.002), suggesting a sustained effect in reducing the risk of nonvertebral fragility fracture. Introduction: Treatment with teriparatide {rhPTH(1-34)} 20 and 40 ,g once-daily subcutaneous dosing significantly reduced the risk of nonvertebral fragility fractures over a median exposure of 19 months. Materials and Methods: All participants in the Fracture Prevention Trial were invited to participate in a follow-up study. Prior treatment assignments were revealed, and patients were able to receive osteoporosis treatments without restriction. Results: Approximately 60% of the 1262 patients received an osteoporosis treatment at some time during follow-up, with greater use in the former placebo group than in the combined former teriparatide group (p < 0.05). The hazard ratios for nonvertebral fragility fractures in each teriparatide group relative to placebo were statistically significant for the 50-month period including treatment and follow-up (p < 0.03). In the follow-up period, the hazard ratio was significantly different between the 40 ,g and combined groups versus placebo but not for the 20 ,g group versus placebo. However, the 20 and 40 ,g groups were not different from each other. Kaplan-Meier analysis of time to fracture showed that the fracture incidence in the former placebo and teriparatide groups diverged during the 50-month period including teriparatide treatment and follow-up (p = 0.009). Total hip and femoral neck BMD decreased in teriparatide-treated patients who had no follow-up treatment; BMD remained stable or further increased in patients who received a bisphosphonate after teriparatide treatment. Conclusions: While the study design is observational, the results support a sustained effect of teriparatide in reducing the risk of nonvertebral fragility fractures up to 30 months after discontinuation of treatment. [source] Monthly Oral Ibandronate Therapy in Postmenopausal Osteoporosis: 1-Year Results From the MOBILE StudyJOURNAL OF BONE AND MINERAL RESEARCH, Issue 8 2005Paul D Miller MD Abstract Once-monthly (50/50, 100, and 150 mg) and daily (2.5 mg; 3-year vertebral fracture risk reduction: 52%) oral ibandronate regimens were compared in 1609 women with postmenopausal osteoporosis. At least equivalent efficacy and similar safety and tolerability were shown after 1 year. Introduction: Suboptimal adherence to daily and weekly oral bisphosphonates can potentially compromise therapeutic outcomes in postmenopausal osteoporosis. Although yet to be prospectively shown in osteoporosis, evidence from randomized clinical trials in several other chronic conditions shows that reducing dosing frequency enhances therapeutic adherence. Ibandronate is a new and potent bisphosphonate with antifracture efficacy proven for daily administration and also intermittent administration with a dose-free interval of >2 months. This report presents comparative data on the efficacy and safety of monthly and daily oral ibandronate regimens. Materials and Methods: MOBILE is a 2-year, randomized, double-blind, phase III, noninferiority trial. A total of 1609 women with postmenopausal osteoporosis were assigned to one of four oral ibandronate regimens: 2.5 mg daily, 50 mg/50 mg monthly (single doses, consecutive days), 100 mg monthly, or 150 mg monthly. Results: After 1 year, lumbar spine BMD increased by 3.9%, 4.3%, 4.1%, and 4.9% in the 2.5, 50 /50, 100, and 150 mg arms, respectively. All monthly regimens were proven noninferior, and the 150 mg regimen superior, to the daily regimen. All monthly regimens produced similar hip BMD gains, which were larger than those with the daily regimen. All regimens similarly decreased serum levels of C-telopeptide, a biochemical marker of bone resorption. Compared with the daily regimen, a significantly larger proportion of women receiving the 100 and 150 mg monthly regimens achieved predefined threshold levels for percent change from baseline in lumbar spine (6%) or total hip BMD (3%). All regimens were similarly well tolerated. Conclusions: Monthly ibandronate is at least as effective and well tolerated as the currently approved daily ibandronate regimen in postmenopausal osteoporosis. [source] Treatment of Idiopathic Hyperphosphatasia With Intensive Bisphosphonate TherapyJOURNAL OF BONE AND MINERAL RESEARCH, Issue 5 2004Tim Cundy MD Abstract In a family with IH, a rare high turnover bone disease, two older siblings were wheelchair-bound with severe skeletal deformity by age 15. Their youngest affected sibling was treated intensively with intravenous bisphosphonates for 3 years. The treatment was well tolerated and prevented the development of deformity and disability. Introduction: Idiopathic hyperphosphatasia (IH, also known as juvenile Paget's disease) is a rare genetic bone disease characterized by very high bone turnover and progressive bony deformity. Inhibitors of bone resorption have been used to suppress bone turnover in the short term, but there is no published data on long-term efficacy. Materials and Methods: An 11-year-old girl with IH, who had two severely affected older siblings, presented with progressive deformity and deafness and long bone fractures. Conventional pediatric doses of pamidronate had failed to prevent clinical deterioration or suppress bone turnover completely. Intensive bisphosphonate therapy (frequent 5-mg ibandronate infusions) was given to try and arrest progression of the skeletal disease. Growth and development, pure tone audiometry, biochemistry, radiology, densitometry (DXA), and bone histology were monitored. Results: A total of 45 mg ibandronate was given over 3 years until skeletal maturity was reached (20, 15, and 10 mg for years 1,3, respectively). Ibandronate treatment was well tolerated, and biochemical markers of bone turnover suppressed to within the age-appropriate normal range There was some progression of her thoracic kyphosis, but she had no further fractures and remained mobile and active at an age when her siblings had become wheelchair-bound. A significant recovery of hearing (p < 0.01) was documented, particularly at low frequencies. Radiographs showed improvement in spinal osteoporosis and cortical bone dimensions and arrest of progressive acetabular protrusion. Areal bone density increased substantially (lumbar spine z-score from ,2.2 to + 1.8). Tetracycline-labeled bone biopsy specimens were taken before and after 18 months of intensive treatment. The second biopsy showed suppression of bone turnover and a doubling of trabecular thickness, with no mineralization defect, and no osteopetrosis. Conclusions: Intensive bisphosphonate treatment prevented the development of deformity and disability and improved hearing in this child with IH. The dose of bisphosphonate, which is substantially greater than is usually used in pediatric bone disease, had no adverse effects, in particular on bone mineralization. [source] Inhibition of osteoblast function in vitro by aminobisphosphonatesJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 1 2009Isabel R. Orriss Abstract Bisphosphonates are analogues of pyrophosphate, a key physicochemical inhibitor of mineralisation. We examined the direct actions of bisphosphonates on the function of cultured osteoblasts derived from rat calvariae. Treatment with zoledronate, the most potent bisphosphonate studied, reduced osteoblast number at concentrations ,100 nM and was strongly toxic at 10 µM, causing a threefold decrease in osteoblast viability after 2 days and a 90% decrease in cell numbers after 14 days. In control osteoblast cultures on plastic, abundant formation of ,trabecular' mineralised bone matrix nodules began after 10 days. Continuous exposure to zoledronate inhibited bone mineralisation at concentrations as low as 10 nM. Pamidronate and clodronate exerted similar effects but at higher doses (,1 and ,10 µM, respectively). Short-term or intermittent exposure of osteoblasts to zoledronate and pamidronate (1,10 µM) was sufficient to inhibit bone mineralisation by ,85%. Zoledronate but not pamidronate or clodronate also strongly inhibited osteoblast alkaline phosphatase activity at concentrations ,100 nM and soluble collagen production at concentrations ,1 µM. We additionally studied the effects of zoledronate on osteoblasts cultured on dentine, a bone-like mineralised substrate, observing similar inhibitory effects, although at concentrations 10,100-fold higher; this shift presumably reflected adsorption of zoledronate to dentine mineral. Thus, zoledronate blocked bone formation in two ways: first, a relatively non-toxic, selective inhibition of mineralisation at concentrations in the low nanomolar range and second, a cytotoxic inhibition of osteoblast growth and function at concentrations ,1 µM. Although no data are available on the bisphosphonate concentrations that osteoblasts could be exposed to in vivo, our results are consistent with earlier observations that bisphosphonates may inhibit bone formation. J. Cell. Biochem. 106: 109,118, 2009. © 2008 Wiley-Liss, Inc. [source] Local alendronate increases fixation of implants inserted with bone compaction: 12-week canine studyJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 4 2007Thomas Jakobsen Abstract Bone compaction has been shown to increase initial implant fixation. Furthermore, bone compaction creates a peri-implant zone of autograft that exerts osteoconductive properties. We have previously shown that locally applied bisphosphonate (alendronate) at 4-week observation can preserve the autograft generated by bone compaction. We now investigate whether the increased amount of autograft, seen at 4 weeks, can increase implant osseointegration and biomechanical fixation. Porous-coated titanium implants were bilaterally inserted with bone compaction into the proximal part of tibia of 10 dogs. On the right side, local bisphosphonate was injected into the bone cavity prior to bone compaction immediately prior to implant insertion. On the left side, saline was used as control. Observation period was 12 weeks. Locally applied bisphosphonate significantly increased biomechanical implant fixation (approximately twofold), bone-to-implant contact (1.2-fold), and peri-implant bone volume fraction (2.3-fold). This study indicates that local alendronate treatment can increase early implant osseointegration and biomechanical fixation of implants inserted by use of bone compaction. Long term effects remain unknown. © 2006 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 25:432,441, 2007 [source] Addition of bisphosphonate to antibiotic and anti-inflammatory treatment reduces bone resorption in experimental Staphylococcus aureus -induced arthritisJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 3 2007Margareta Verdrengh Abstract Bacterial arthritis is a disease with high morbidity leading to rapidly progressive bone resorption. We have shown earlier that treatment with antibiotics in combination with corticosteroids decreases joint inflammation and mortality but does not significantly affect bone/cartilage destruction of the joints. This study was performed to assess the effect of treatment with bisphosphonate [zoledronic acid (ZA)] in combination with antibiotics and corticosteroids, on the course and outcome of Staphlococcus aureus -induced arthritis. Three days after intravenous inoculation with S. aureus, mice were treated with antibiotics alone, ZA alone, ZA and antibiotics, or ZA combined with antibiotics and corticosteroids, respectively. One group served as controls and received PBS. Clinical assessment of arthritis was performed as well as histological analysis of bone and cartilage destruction in the joints. One femur from each mouse was collected for bone mineral density (BMD) analysis. In addition, serum levels of type I collagen fragments (RatLaps), and osteocalcin, markers for osteoclastic and osteoblastic activity, respectively, were analyzed. Mice treated with ZA and antibiotics or with ZA in combination with antibiotics and corticosteroids lost significantly less in trabecular bone density compared to infected control mice. Furthermore, the addition of corticosteroids to animals treated with ZA and antibiotics, significantly decreased serum levels of RatLaps and osteocalcin, compared to animals treated with ZA and antibiotics or ZA alone. Treatment with bisphosphonates in combination with antimicrobial agents and corticosteroids significantly decreases the activity of osteoclasts in septic arthritis, thereby reducing the risk of skeletal destruction. © 2006 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res [source] Inhibitory effects of a new bisphosphonate, minodronate, on proliferation and invasion of a variety of malignant bone tumor cellsJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 6 2006Tadahiko Kubo Abstract Little is known about the biological effects of bisphosphonates on primary malignant bone tumors. The purpose of this study was to investigate the antitumor effects of newly developed minodronate (MIN) on a variety of human malignant bone tumors. We examined the effects of MIN and clinically relevant incadronate (INC) on the proliferation, apoptosis, and cell cycle of two osteosarcoma (Saos-2, MG-63), two chondrosarcoma (SW1353, OUMS27), and two Ewing's sarcoma (RD-ES, SK-ES-1) cell lines. Furthermore, we investigated the anti-invasion effects of MIN on sarcoma cells and the effects of MIN on tumor growth in nude mice. MIN inhibited the viability of all six cell lines in a dose-dependent manner with IC50 values of 2.7 to 5.0 µM, which were significantly lower than those of INC. Importantly, both bisphosphonates affected the viability of normal bone marrow stromal cells much less than sarcoma cells. Both bisphosphonates induced cell cycle perturbation in all sarcoma cells tested and apoptosis in Saos-2 and SW1353 cells, although they failed to induce apoptosis in RD-ES and SK-ES-1 cells. MIN significantly suppressed invasion, even at a low concentration of 1 µM (p,<,0.01). Daily injection of 5 µg of MIN inhibited the growth of SK-ES-1 xenograft sarcoma in nude mice without loss of body weight. These findings suggest that MIN may have a beneficial adjuvant role in the treatment of patients with malignant bone tumors. © 2006 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 24:1138,1144, 2006 [source] A novel bisphosphonate inhibits inflammatory bone resorption in a rat osteolysis model with continuous infusion of polyethylene particlesJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 3 2002Miho Iwase Abstract This study examined the inhibitory effect of a new bisphosphonate (TRK-530) on wear debris-mediated bone resorption in a rat osteolysis model involving continuous infusion of high density polyethylene (HDPE) particles. TRK-530 (TRK) is a novel synthetic bisphosphonate that has been shown to decrease the level of tumor necrosis factor alpha (TNF-,) in the bone marrow of rats with adjuvant arthritis. Forty Wistar rats were randomized to two groups (n = 20 each). In each rat, a Kirshner (K) wire was inserted into the femur and HDPE particles were continuously infused into the knee joint. Thereafter, the animals were subcutaneously injected with saline (control group) or 1 mg/kg of TRK (TRK group) every second day, and were sacrificed at 4 or 8 weeks after surgery. Radiographs obtained at the time of sacrifice were evaluated for periprosthetic osteolysis. We also examined the thickness of the reactive membrane as well as the number of osteoclast-like cells around the K-wire. In addition, we examined the expression of genes for bone-resorbing cytokines in the reactive membrane. Radiographic peri-implant osteolysis was more frequent in the control group compared with the TRK group at each time of assessment (p < 0.01). The interfacial membrane was significantly thinner in the TRK group compared with the control group (p < 0.01) and the average number of osteoclast-like cells around the K-wire was significantly fewer in the TRK group (p < 0.01). In addition, the expression of interleukin 1-alpha messenger ribonucleic acid (IL-1, mRNA) and TNF-, mRNA was suppressed in the TRK group at each time of assessment. We conclude that the TRK can inhibit the formation of inflammatory peri-implant osteolysis induced by HDPE particles. © 2002 Orthopaedic Research Society. Published by Elsevier Science Ltd. All rights reserved. [source] Bisphosphonate determination using 1H-NMR spectroscopy for biomedical applicationsJOURNAL OF TISSUE ENGINEERING AND REGENERATIVE MEDICINE, Issue 2 2009J. Chou Abstract Bisphosphonate is known to be a very active drug in the treatment of osteoporosis and bone regeneration. A new method has been developed, utilizing nuclear magnetic resonance spectroscopy to identify and measure the amount of bisphosphonate in solution. A standard reference with similar functional group to that of the bisphosphonate was chosen and applied in the experimentation. The results showed that the use of nuclear magnetic resonance spectroscopy (1H-NMR) in determining the solvent residues of various pharmaceutical drugs has proved to be effective. Unlike chromatography, it is possible to use a universal reference standard as an internal standard assayed by quantitative NMR. Using the same theory, this method is capable of both identifying and quantifying the bisphosphonate in various solutions. This paper is the first publication showing this unique measurement method, which can be used in a range of pharmaceutical and biomedical applications. Copyright © 2008 John Wiley & Sons, Ltd. [source] Clinical trial: comparison of alendronate and alfacalcidol in glucocorticoid-associated osteoporosis in patients with ulcerative colitisALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 4 2009S. KITAZAKI Summary Background, Bone loss is often observed in patients with ulcerative colitis, particularly if they require glucocorticoids. Aim, To determine whether the bisphosphonate, alendronate, is safe and effective in preserving bone mass compared to the active vitamin D3, alfacalcidol, in ulcerative colitis patients receiving glucocorticoids. Methods, Thirty-nine patients with ulcerative colitis and treated with glucocorticoids were randomized to receive alendronate (5 mg/day) or alfacalcidol (1 ,g/day) daily for 12 months. Loss of bone mass was evaluated by bone mineral density, bone resorption by urinary N -telopeptide for type I collagen, and bone formation by serum bone alkaline phosphatase. Results, Alendronate, but not alfacalcidol, significantly increased bone mineral density in the lumbar spine. Alendronate decreased serum bone alkaline phosphatase levels, but alfacalcidol did not. Urinary N -telopeptide for type I collagen levels decreased in both groups, but were significantly lower in the alendronate group. There were no significant differences in the adverse events in the two groups. Conclusion, Our study indicates that alendronate is a safe, well-tolerated and more effective therapy than alfacalcidol for preventing glucocorticoid-associated bone loss in patients with ulcerative colitis. [source] Dental management of patients at risk of osteochemonecrosis of the jaws: a critical reviewORAL DISEASES, Issue 8 2009S Fedele Osteonecrosis of the jaw bones is a complication of bisphosphonate (BP) drug usage characterised by trans-mucosal exposure of necrotic bone, often followed by infection and pain. Osteonecrosis is observed in cancer patients on high-potency intravenous BP more frequently than in osteoporotic individuals using low-potency oral BP. The management of osteonecrosis caused by BP is often unsatisfactory and control of risk factors is considered the most effective means of prevention. Surgical manipulation and dental infection of the jawbone are the major risk factors, hence it is suggested that careful management of oral health and relevant dental procedures may decrease the risk of osteonecrosis in individuals on BP. Recommendations for dentists and oral surgeons have been suggested by different groups of clinicians but they are often controversial and there is no clear evidence for their efficacy in reducing the likelihood of osteonecrosis development. This report critically reviews current dental recommendations for individuals using BP with the aim of helping the reader to transfer them into practice as part of pragmatic and non-detrimental clinical decisions making. [source] PTHrP-independent hypercalcemia with increased proinflammatory cytokines and bone resorption in two children with CD19-negative precursor B acute lymphoblastic leukemiaPEDIATRIC BLOOD & CANCER, Issue 7 2007Hidetaka Niizuma MD Abstract Hypercalcemia in childhood acute lymphoblastic leukemia (ALL) is rare and occasionally associated with parathyroid hormone-related protein (PTHrP). However, the pathogenesis of PTHrP-independent hypercalcemia remains unclear. We report two children with precursor B ALL who had marked hypercalcemia (15.8 and 16.6 mg/dl, respectively) and disseminated osteolysis. Serum tumor necrosis factor-, (TNF-,) and IL-6 were markedly elevated, whereas 1,25(OH)2 vitamin D3, intact PTH and PTHrP were decreased or undetected. Analysis of urinary deoxypyridinoline (DPY) or bone biopsy of the osteolytic lesion showed an increased bone resorption, and administration of bisphosphonate improved the hypercalcemia. Patients had ALL with immunophenotype positive for CD10, CD34, and HLA-DR but negative for CD19 and obtained remission with chemotherapy. These findings suggest that increased osteoclastic bone resorption via stimulation with TNF-, and IL-6 may be mechanism causing PTHrP-independent hypercalcemia in some patients with precursor B ALL lacking CD19 expression. Pediatr Blood Cancer 2007;49:990,993. © 2006 Wiley-Liss, Inc. [source] | |||||||||||||||||||