Ibandronate-Loaded Carbon Nanohorns Fabricated Using Calcium Phosphates as Mediators and Their Effects on Macrophages and Osteoclasts.

Carbon nanohorns (CNHs), a type of nanocarbon, have been studied for the application of drug delivery systems (DDSs) because they are easily functionalized, support bone regeneration, can be used to perform photohyperthermia, have low toxicity, and are easily phagocytosed by macrophages. To take advantage of these features of CNHs, we developed a DDS for the local treatment of bone metastasis by loading the antibone resorption drug ibandronate (IBN) onto CNHs. The poor adsorption of IBN onto CNHs due to the weak hydrophilic-hydrophobic interaction was overcome by using calcium phosphates (CaPs) as mediators. In the fabrication process, we used oxidized CNH (OxCNH), which is less hydrophobic, onto which IBN was coprecipitated with CaP from a labile supersaturated CaP solution. OxCNH-CaP-IBN composite nanoparticles exerted stronger cell-suppressive effects than OxCNH and IBN in both murine macrophages (RAW264.7 cells) and osteoclasts (differentiated from RAW264.7 cells). OxCNH-CaP-IBN composite nanoparticles were efficiently phagocytosed by macrophage cells, where they specifically accumulated in lysosomes. The stronger cell-suppressive effects were likely due to intracellular delivery of IBN, i.e., the release of IBN from OxCNH-CaP-IBN composite nanoparticles via dissociation of CaP in the acidic environment of lysosomes. Our findings suggest that OxCNH-CaP-IBN composite nanoparticles are potentially useful for the local treatment of metastatic bone destruction.

Enhancement of Oral Bioavailability of Ibandronate Through Gastroretentive Raft Forming Drug Delivery System: In Vitro and In Vivo Evaluation.

BACKGROUND: Bisphosphonates have very low bioavailability and cause irritation of the esophagus and stomach. This study was planned to improve the oral bioavailability of ibandronate through the formation of a raft in the stomach. Bisphosphonate-induced irritation of the esophagus and stomach is prevented by the formation of a raft. MATERIALS AND METHODS: The nanostructured raft was developed through the use of nanosized citrus pectin (NCP). The particle size of NCP was measured by zeta sizer and SEM. The percentage of NCP and the neutralization profile of raft was studied. The ibandronate, polymers, and the developed formulation were characterized by FTIR, XRD, TGA, and DSC. The release of ibandronate was studied in 0.1 N HCl, 0.5 N HCl, 1 N HCl, and simulated gastric fluid (SGF) and a cell viability study was performed using Caco-2 cells. The PPR5 formulation and Bonish 150 mg tablets were selected as test and reference formulations, respectively, for pharmacokinetic study. Twelve healthy albino rats were taken and divided into two groups using a Latin square crossover design, and the blood samples were collected for 24 hours. RESULTS: The SEM image showed that the particle size of NCP was 159 nm. The raft of PPR5 showed 94% NCP and 45 minutes duration of neutralization. The FTIR and XRD showed chemical stability and a uniform distribution of ibandronate in the raft. The TGA and DSC indicated the thermal stability of formulation. The release of 99.87% ibandronate at 20 minutes was observed in the SGF. The values of C max for the reference and test formulations were 493±0.237 ng/mL and 653±0.097 ng/mL, respectively. The AUC(0-t) of the reference and test formulations was 3708.25±3.418 ng/mL.h and 6899.25±3.467 ng/mL.h, respectively. CONCLUSION: The NCP has been successfully prepared from citrus pectin and has shown effective porous raft formation. The bioavailability of the ibandronate from newly developed PPR5 was higher than the already marketed formulation.

Effects of Injected Antiosteoporotic Medication Versus Oral Bisphosphonates on Rates of Repeated Vertebroplasty or Kyphoplasty.

PURPOSE: Vertebral compression fractures can recur within a few years after percutaneous vertebroplasty (PVP) or kyphoplasty. METHODS: We conducted a population-based study using data from the Taiwan National Health Insurance Research Database to investigate the efficacy of various antiosteoporotic treatments in reducing the prevalence rate of repeated PVP or kyphoplasty in patients hospitalized from January 1, 1997, to December 31, 2004. We included patients with vertebral compression fractures after PVP or kyphoplasty who received oral bisphosphonates (OB group; n = 6141) or injected drug therapies (injection group; n = 4308). FINDINGS: The incidence rate of repeated PVP or kyphoplasty was significantly lower in the I/Z/D (denosumab monotherapy or ibandronate or zoledronate with or without denosumab) group than in the OB group (crude subdistribution hazard ratio [sHR], 0.79; 95% CI, 0.70-0.90; P < 0.05; adjusted sHR, 0.77; 95% CI, 0.68-0.87; P < 0.0001). The analysis revealed a significantly lower incidence rate of repeated PVP or kyphoplasty in the I/Z group compared with that in the OB group (crude sHR, 0.82; 95% CI, 0.72-0.94; P = 0.0038; adjusted sHR, 0.80; 95% CI, 0.70-0.91; P = 0.0011). The denosumab group also exhibited a significantly lower incidence rate of repeated PVP or kyphoplasty than did the OB group (crude sHR, 0.61; 95% CI, 0.46-0.80; P = 0.0005; adjusted sHR, 0.58; 95% CI, 0.44-0.77; P = 0.0001). Although the teriparatide group had higher fracture frequency than did the OB group, the analysis revealed no significant difference between the OB and teriparatide groups with respect to the incidence rate of repeated PVP or kyphoplasty (adjusted sHR, 1.08; 95% CI, 0.92-1.26; P = 0. 3747). IMPLICATIONS: Injected antiosteoporotic medication was associated with lower rates of repeated vertebroplasty and kyphoplasty than was OB application.

Phase III Randomized Trial of Bisphosphonates as Adjuvant Therapy in Breast Cancer: S0307.

BACKGROUND: Adjuvant bisphosphonates, when given in a low-estrogen environment, can decrease breast cancer recurrence and death. Treatment guidelines include recommendations for adjuvant bisphosphonates in postmenopausal patients. SWOG/Alliance/Canadian Cancer Trials Group/ECOG-ACRIN/NRG Oncology study S0307 compared the efficacy of three bisphosphonates in early-stage breast cancer. METHODS: Patients with stage I-III breast cancer were randomly assigned to 3 years of intravenous zoledronic acid, oral clodronate, or oral ibandronate. The primary endpoint was disease-free survival (DFS) with overall survival as a secondary outcome. All statistical tests were two-sided. RESULTS: A total of 6097 patients enrolled. Median age was 52.7 years. Prior to being randomly assigned, 73.2% patients indicated preference for oral vs intravenous formulation. DFS did not differ across arms in a log-rank test (P = .49); 5-year DFS was 88.3% (zoledronic acid: 95% confidence interval [CI] = 86.9% to 89.6%), 87.6% (clodronate: 95% CI = 86.1% to 88.9%), and 87.4% (ibandronate: 95% CI = 85.6% to 88.9%). Additionally, 5-year overall survival did not differ between arms (log rank P = .50) and was 92.6% (zoledronic acid: 95% CI = 91.4% to 93.6%), 92.4% (clodronate: 95% CI = 91.2% to 93.5%), and 92.9% (ibandronate: 95% CI = 91.5% to 94.1%). Bone as first site of recurrence did not differ between arms (P = .93). Analyses based on age and tumor subtypes showed no treatment differences. Grade 3/4 toxicity was 8.8% (zoledronic acid), 8.3% (clodronate), and 10.5% (ibandronate). Osteonecrosis of the jaw was highest for zoledronic acid (1.26%) compared with clodronate (0.36%) and ibandronate (0.77%). CONCLUSIONS: We found no evidence of differences in efficacy by type of bisphosphonate, either in overall analysis or subgroups. Despite an increased rate of osteonecrosis of the jaw with zoledronic acid, overall toxicity grade differed little across arms. Given that patients expressed preference for oral formulation, efforts to make oral agents available in the United States should be considered.

Development and application of a urine drug concentration method for the evaluation of oral absorption of ibandronate in clinical patients.

Aim: A urine drug concentration method was developed for the evaluation of oral ibandronte absorption based on the fact that ibandronate is excreted unchanged by the kidneys. Methodology: Ibandronate was isolated from the urine matrix by coprecipitated with 2.5 M CaCl2 and 1 M K2HPO4 in basic conditions. After a liquid-liquid extraction, the analytes were derivatized with trimethylsilydiazomethane prior to detection. Results: The calibration curves exhibited excellent linearity (r > 0.99) between 1 and 250 ng/ml in human urine. Ibandronate was recovered >86.5% with the inter- and intraday relative standard deviations less than 15%. Conclusion: The method is selective, accurate, practical and was successfully applied to study the influence of vitamin D3 on the absorption of ibandronate.

Effectiveness of monthly intravenous ibandronate on the low responders to oral bisphosphonate: the MOVEMENT study.

The MOVEMENT study was designed to assess the effectiveness of monthly intravenous ibandronate on bone mineral density (BMD) in daily clinical practice in Japanese patients with primary osteoporosis whose lumbar spine BMD did not increase despite oral bisphosphonate therapy. This study was a multicenter, prospective, interventional study (52 sites; August 2015 to March 2018). Patients aged ≥ 50 years with primary osteoporosis, evaluated as low responders to oral bisphosphonate treatment for 1-3 years, continued on their existing oral bisphosphonate or switched to monthly intravenous ibandronate (1 mg) for 12 months. The primary endpoint was change in lumbar spine BMD from baseline to 12 months in the intravenous ibandronate group (IV IBN). A total of 240 and 141 patients were enrolled in the IV IBN and oral bisphosphonate groups (OBP), respectively. At 12 months, a significant increase in mean percent change from baseline in lumbar spine BMD was observed in the IV IBN (2.70%). This change was also significant at 6 months (1.92%). Similarly, the change in total hip BMD showed a significant increase at 12 months (0.78%). In the IV IBN, the responder rate, percentage of patient whose change from baseline of lumbar spine BMD has greater than 0%, for lumbar spine BMD was high at both 6 (72.3%, 141/195 patients) and 12 (78.0%, 145/186 patients) months. No new safety concerns were observed in either treatment group. Treatment with intravenous ibandronate significantly increased lumbar spine BMD without any new safety concerns in Japanese patients with osteoporosis who showed low response to existing oral bisphosphonates.

Fracturas vertebrales múltiples postsuspensión de denosumab: revisión del tema a partir de dos casos clínicos / Discontinuation of denosumab and multiple vertebral fractures: report of two cases and review of the literature

Los tratamientos para osteoporosis se indican por tiempo variable dependiendo del tipo de droga, anabólica o anticatabólica, y de la gravedad de la enfermedad. Denosumab es un anticuerpo monoclonal totalmente humano que inhibe a RANK-L evitando de esa manera la interacción entre RANKL-RANK, con la consiguiente inhibición de la formación de los osteoclastos, su activación y sobrevida. Disminuye la resorción ósea cortical y trabecular. Su administración subcutánea de 60 mg cada 6 meses al cabo de 3 años ha demostrado reducción de la resorción ósea, incremento de la densidad mineral ósea y disminución de las fracturas vertebrales, no vertebrales y de cadera. Está indicado para el tratamiento de la osteoporosis con alto riesgo de fractura. Su mecanismo de acción es reversible. Se han descripto pérdida de la DMO y elevación de los marcadores de remodelado óseo postsuspensión. Una situación clínica grave son las fracturas vertebrales múltiples postsuspensión. Este evento es infrecuente y se lo atribuye a un rebote del remodelado óseo, postulándose se postula una predisposición especial, probablemente relacionada con microRNA. Se escriben dos mujeres con osteoporosis que presentaron este cuadro. Las fracturas ocurrieron entre 7 y 10 meses posteriores a la última dosis de denosumab. Registraron elevación de C-telopéptidos y disminución de la DMO conjuntamente con las fracturas vertebrales agudas en cascada. (AU)

The duration of osteoporosis treatments depends on the drug type, anabolic or anticatabolic, and the severity of the disease. Denosumab is a fully human monoclonal antibody that inactivates RANK-L, inhibiting the RANKL-RANK interaction . This inhibits osteoclast formation, activation, and survival. It also reduces cortical and trabecular bone resorption. Subcutaneous administration of 60 mg every 6 months for 3 years has reduced bone resorption, increased bone mineral density (BMD) and decreased vertebral, non-vertebral and hip fractures. It is indicated for the treatment of osteoporosis with high risk of fracture. Denosumab mechanism of action is reversible. After discontinuation, loss of BMD and elevation of bone turnover markers have been observed. In addition, multiple vertebral fractures after the suspension of the drug have been reported. These rebound-associated vertebral fractures are rare. A special genetic predisposition related to miRNA has been proposed. Two women with this clinical presentation are described. Fractures occurred between 7 and 10 months respectively after the last dose of denosumab. They presented with an increase in circulating C-telopeptid levels and a decrease inBMD with acute multiple vertebral fractures. (AU)

Comparison of the efficacy between once-monthly oral ibandronate and risedronate among Korean women with osteoporosis: a nationwide population-based study.

Using a nationwide database from the Korean National Health Insurance Service, this study showed that once-monthly oral ibandronate (150 mg) had better anti-fracture efficacy than once-monthly oral risedronate (150 mg), as seen on assessing overall and non-vertebral fractures among Korean elderly women with osteoporosis. INTRODUCTION: Once-monthly oral bisphosphonates have been used widely without appropriate comparison. Therefore, we aimed to compare the anti-fracture efficacy of once-monthly ibandronate (150 mg) and once-monthly risedronate (150 mg). METHODS: We conducted a retrospective cohort study among Korean women aged ≥ 60 years from 2006 to 2015 using a nationwide database from the National Health Insurance Service Senior Cohort. The primary outcome was the first occurrence of fracture related to osteoporosis after the initial prescription of bisphosphonates. A Cox proportional model was used to estimate the incidence rate ratios (IRRs) and 95% confidence intervals (CIs) for overall and site-specific fractures between the two treatments, after adjusting for possible confounding factors. RESULTS: After propensity score matching, the ibandronate and risedronate groups, with 3454 patients each, were assembled from 36,701 new once-monthly ibandronate or risedronate users. After 4 years of follow-up, the ibandronate group had significantly lower incidence rates of overall and non-vertebral fractures than the risedronate group (IRR 0.822, 95% CI 0.698-0.968, P = 0.919 and IRR 0.798, 95% CI 0.647-0.985, P = 0.036, respectively). CONCLUSIONS: Once-monthly ibandronate (150 mg) shows better anti-fracture efficacy than once-monthly risedronate (150 mg). However, further large-scale studies are required to confirm our findings and to determine site-specific differences, especially regarding the vertebral and hip areas.

Comparison of clinical effect in treatment of bone tumor between zoledronic acid needle and ibandronate needle.

To observe and analyze the clinical effect of zoledronic acid needle and ibandronate needle in treatment of bone tumor. 100 patients who have been treated in our hospital for bone tumor were selected as research objects. They were randomly divided into research group and control group, each containing 50 patients. The research group was applied with ibandronate needle therapy, while the control group was given with zeledronic acid needle therapy. After treatment, the clinical effects of the two groups were observed and analyzed. Through comparing the pain relief rate after treatment between the two groups, it can be known that the pain relief rate of research group was relatively higher, P<0.05; the rate of adverse effect in research group was relatively lower, P<0.05; the quality of life score (QLS) of research group was significantly superior to that of control group, P<0.05. theibandronate needle therapy is a more reliable and superior method in treatment of bone tumor compared with zoledronic acid needle therapy, which should be promoted in clinical treatment.

Effects of discontinuing oral bisphosphonate treatments for postmenopausal osteoporosis on bone turnover markers and bone density.

The antiresorptive potency varies between different bisphosphonates. We investigated the effect of stopping oral bisphosphonate treatment for postmenopausal osteoporosis (ibandronate, alendronate, risedronate) on BTMs and BMD. After stopping treatment, all three groups showed an increase in BTMs and a decrease in hip BMD; however, none returned to pre-treatment baseline values. INTRODUCTION: Bisphosphonates (BPs) continue to suppress bone turnover markers (BTMs) after treatment has stopped, leading to the suggestion that a pause in treatment could be considered for low-risk patients. Indirect comparisons suggest that after cessation of treatment, the effects on bone may differ between drugs. We investigated the effects of stopping oral BP treatments for postmenopausal osteoporosis on BTMs and bone mineral density (BMD). METHODS: We studied postmenopausal osteoporotic women who had previously taken part in a 2-year randomised study of three oral BPs (ibandronate, alendronate, or risedronate). At the end of the study, women with hip BMD T-score > - 2.5 and considered clinically appropriate to discontinue treatment were invited to participate in a further 2-year observational study. Biochemical response was assessed using BTMs, and BMD was measured by dual-energy X-ray absorptiometry. RESULTS: All BTMs increased after treatment withdrawal but remained below the pre-treatment baseline with less suppression of BTMs for the risedronate group compared to alendronate and ibandronate up to 48 weeks. There was no difference between the BP groups 96 weeks after stopping treatment. The change in BMD during the 96 weeks after stopping treatment was - 1.6% (95% CI - 1.9 to - 1.2, P < 0.001) for the total hip and - 0.6% (95% CI - 1.1 to - 0.2, P = 0.17) at the lumbar spine with no difference between the three BP groups (P = 0.85 and P = 0.48, respectively). CONCLUSION: For all treatment groups, there was an increase in BTMs and a decrease in hip BMD after stopping BPs for 2 years; however, none returned to pre-treatment baseline values.

Effects of an oral bisphosphonate and three intravenous bisphosphonates on several cell types in vitro.

OBJECTIVE: To analyze the influence of an oral bisphosphonate and compare the potency to intravenous bisphosphonates on various cell types as regards the rarity of bisphosphonate-associated osteonecrosis of the jaw (BP-ONJ) caused by oral bisphosphonate. MATERIALS AND METHODS: A viability assay (MTT), a migration assay (Boyden chamber), and an apoptosis assay (Caspase-Glo® 3/7) were performed to analyze the effect of bisphosphonates on human fibroblasts, umbilical vein endothelial cells (HUVEC), and osteoblasts. RESULTS: Alendronate and intravenous bisphosphonates suppressed cell viability and migration, and induced apoptosis in all tested cell types. Alendronate had a greater impact than ibandronate on the characteristics in fibroblasts and osteoblasts but not as strong as zoledronate. CONCLUSIONS: The incidence of BP-ONJ in oral bisphosphonate treatment is reported to be much lower than that in intravenous bisphosphonates. However, the influences of alendronate on human cells were at least as strong as ibandronate, although it was lower than zoledronate. CLINICAL RELEVANCE: Alendronate showed strong enough effects to suppress human somatic cells and was comparable to certain intravenous bisphosphonates in potency. This study suggests that the lower incidence of BP-ONJ in alendronate treatment is not originated by its potency, but might be due to the low bioavailability of alendronate, lower dosing on a daily basis, and having no additional therapies.

Does Local Ibandronate and/or Pamidronate Delivery Enhance Osseointegration? A Systematic Review.

PURPOSE: To our knowledge from indexed literature, the present study is the first one to systematically review the influence of local delivery of pamidronate (PAM) and/or ibandronate (IBA) on osseointegration enhancement. The aim of the present systematic review was to assess the efficacy of IBA and/or PAM local delivery (topically or coating on implants surfaces) in promoting osseointegration. MATERIALS AND METHODS: To address the focused question, "Does local IBA and/or PAM delivery enhances osseointegration?," indexed databases were searched without time or language restrictions up to and including May 2016 using various combinations of the following keywords: "pamidronate," "ibandronate," "bisphosphonates," "osseointegration," and "topical administration." Letters to the Editor, historic reviews, commentaries, case series, and case reports were excluded. RESULTS: Fifteen studies were included. Fourteen studies were performed in animals and 2 were clinical trials. One study reported an experimental model and a clinical trial in the same publication. Results from 12 experimental studies and 2 clinical studies reported improved biomechanical properties and/or osseointegration around implants with PAM and/or IBA. Two experimental studies showed that PAM and/or IBA did not improve osseointegration. CONCLUSIONS: On experimental grounds, local IBA and/or PAM delivery seems to enhance osseointegration; however, from a clinical perspective, further randomized control trials are needed to assess the effectiveness of IBA and PAM in promoting osseointegration around dental implants.