Postmenopausal Osteoporosis and Osteopenia Management with a Combination of Once-Monthly Oral Ibandronate and Cholecalciferol—A Systematic Review

Postmenopausal osteoporosis and osteopenia are chronic and uncurable conditions that invariably lead to an increased risk of vertebral, hip, and femoral neck fracture if left untreated. Clinical guidelines establish, in general, pharmacological combinations allied to lifestyle changes as the mainstay of their management, and also increasing bone marrow density, lowering fracture risk, and improving quality of life are their main therapeutic goals. The objective of this systematic review was to analyze the available data in the scientific medical literature regarding the role of the ibandronate and cholecalciferol combination in postmenopausal osteoporosis and osteopenia management. Based on our results, we concluded that the above combination is safe and feasible for the clinical control of both conditions.

Prevalence of Non-Responders to Both Oral Bisphosphonate Monotherapy and Intravenous Ibandronate in Patients with Postmenopausal Osteoporosis

Objectives: Although bisphosphonates (BPs) are effective for the majority of patients with osteoporosis, some individuals do not adequately respond to these drugs. The objective of this study was to estimate the prevalence of true BP non-responders who showed insufficient response after both oral BPs and intravenous ibandronate. Methods: Among 146 consecutive patients with postmenopausal osteoporosis who received oral BP monotherapy for more than 12 months, insufficient responders to oral BP monotherapy were switched to intravenous ibandronate injection and followed for more than 12 months. Serum N-terminal telopeptide of type I collagen (NTX) and bone alkaline phosphatase (BAP) concentrations were measured. Patients who also showed insufficient response to intravenous ibandronate were defined as true BP non-responders. Insufficient response to BP therapy was evaluated based on the serum NTX reduction cut-off for minimum significant change. Results: Sixty-one patients (41.8%) were diagnosed as oral BP non-responders. Fourteen patients who switched to intravenous ibandronate and had complete data available were used for final analysis. After switching to intravenous ibandronate, both NTX and BAP decreased significantly (p Conclusion: These results estimated that as few as 9% - 15% (i.e., 21.4% - 35.7% of 41.8%) or as many as 24% - 27% (i.e., 57.1% - 64.3% of 41.8%) of patents might be true BP non-responders.

Prevention of Femoral Head Deformity after Ischemic Necrosis Using Ibandronate Acid and Growth Factor in Immature Pigs

Background: Femoral head deformity is the most severe sequela of ischemic necrosis in skeletally immature patients. Development of severe deformity shortens useful survival time of the joint due to the appearance of early degenerative changes. Preservation of the trabecular architecture through inhibition of osteoclastic bone resorption may minimize the development of the deformity in an animal model of ischemic necrosis of the femoral head. Aims: To determine if a highly potent antiabsorptive agent, ibandronate, would inhibit bone resorption during necrotic femoral head repair to avoid subsequent flattening and deformity, to determine if the use of platelet-rich plasma stimulates bone repair and neovascularization of the damaged femoral head, and to evaluate if the combination of both therapies can preserve the femoral head while stimulating new bone formation in an animal model of ischemic necrosis. Methods: Ischemic necrosis of the femoral head was induced by surgical ligature of the circumflex vessels in 10 Landrace pigs. The animals were divided into four different groups and were administered ibandronate acid, platelet-rich plasma, or both. The contralateral, untreated femoral heads with surgical ligature of the circumflex vessels served as the control group. All animals were killed three months after surgery and the femoral head was evaluated both radiographically and histologically. The femur length was measured on radiographs and compared among the groups.Results: Final femoral length was significantly longer in the group treated with a combination of both therapies (platelet-rich plasma-ibandronate acid) compared to the others groups, with a significant difference between groups. The histological findings showed increased osteoblastic activity and thickened trabiculae, a higher rate of neovascularization, and focal hyperplasia greater bone resorption and neovascularization. Only slight changes (femoral length) were observed in the animals that received platelet-rich plasma in situ favoring revascularization that was, however, only seen in the first months of administration. Conclusions: Radiographic and histological studies showed that a combination of both therapies (platelet-rich plasma and ibandronate acid) preserved the trabecular architecture and prevented femoral head deformity in the early phase of ischemic necrosis repair in immature pigs, coinciding with reports by other authors. Clinical Relevance: These findings support the concept that a combination of antiresorptive and anabolic agents can significantly improve bone healing and decrease femoral head deformity following ischemic necrosis in the fragmentation stage. Further studies would be necessary to determine the optimal dose and longterm effectiveness for the use in pediatric patients.

Bones and Crohn’s:No benefit of adding sodium fluoride or ibandronate to calcium and vitamin D

AIM: To compare the effect of calcium and cholecalciferol alone and along with additional sodium fluoride or ibandronate on bone mineral density (BMD) and fractures in patients with Crohn's disease (CD). METHODS: Patients (n =148) with reduced BMD (T-score < -1) were randomized to receive cholecalciferol (1000 IU) and calcium citrate (800 mg) daily alone(group A, n = 32) or along with additional sodium fluoride (25 mg bid) (group B, n = 62) or additional ibandronate (1 mg iv/3-monthly) (group C, n = 54). Dual energy X-ray absorptiometry of the lumbar spine (L1-L4) and proximal right femur and X-rays of the spine were performed at baseline and after 1.0, 2.25 and 3.5 years. Fracture-assessment included visual reading of X-rays and quantitative morphometry of vertebral bodies (T4-L4).RESULTS: One hundred and twenty three (83.1%) patients completed the first year for intention-to-treat (ITT) analysis. Ninety two (62.2%) patients completed the second year and 71 (47.8%) the third year available for per-protocol (PP) analysis. With a significant increase in T-score of the lumbar spine by +0.28 ± 0.35 [95% conf idence interval (CI): 0.162-0.460, P < 0.01], +0.33 ± 0.49 (95% CI: 0.109-0.558, P < 0.01), +0.43 ± 0.47 (95% CI: 0.147-0.708, P < 0.01) in group A, +0.22 ± 0.33 (95% CI: 0.125-0.321, P < 0.01); +0.47 ± 0.60 (95% CI: 0.262-0.676, P < 0.01), +0.51 ± 0.44 (95% CI: 0.338-0.682, P < 0.01) in group B and +0.22 ± 0.38 (95% CI: 0.111-0.329, P < 0.01), +0.36 ± 0.53 (95% CI: 0.147-0.578, P < 0.01), +0.41 ± 0.48 (95% CI: 0.238-0.576, P < 0.01) in group C, respectively, during the 1.0, 2.25 and 3.5 year periods (PP analysis), no treatment regimen was superior in any in- or between-group analyses. In the ITT analysis, similar results in all in- and between-group analyses with a significant in-group but non-significant between-group increase in T-score of the lumbar spine by 0.38 ± 0.46 (group A, P < 0.01), 0.37 ± 0.50 (group B, P < 0.01) and 0.35 ± 0.49 (group C, P < 0.01) was observed. Follow-up in ITT analysis was still 2.65 years. One vertebral fracture in the sodium fluoride group was detected. Study medication was safe and well tolerated. CONCLUSION: Additional sodium fluoride or ibandronate had no benefit over calcium and cholecalciferol alone in managing reduced BMD in CD.

A candidate identification questionnaire for postmenopausal osteoporosis patients switched from daily or weekly bisphosphonate to once-monthly ibandronate: An open, prospective, multicenter study—BONCURE study

A candidate identification questionnaire (CIQ) was tested to determine its predictive value for patient-reported satisfaction in patients switched from once-weekly or once-daily treatment with a bisphosphonate to once-monthly dosing. This was a prospective, open-label, multicenter international study in patients with postmenopausal osteoporosis who had been receiving once-daily or once-weekly alendronate or risendronate for at least 3 months. Patients completed a CIQ, then commenced 150 mg monthly ibandronate for 6 months. Patients completed the Osteoporosis Patient Satisfaction Questionnaire (OPSAT-QTM) at baseline for 6 months. Scores were converted to composite satisfaction scores (CSS, scale 0-100). Totally 677 patients completed a CIQ, 645 were enrolled in the treatment phase and comprised the intent-to-treat (ITT) population, and 630 completed the study. In the ITT population, 68.1% patients answered “yes” to one or more CIQ questions. OPSAT-Q scores increased for the convenience, quality of life and overall satisfaction domains (p scores for the side effects domains were significant (p < 0.001) in the CIQ “yes” group, but not for the degree of bother (decrease in mean of 0.1 points, p = 0.50) or duration (no change, p = 0.84) of non-gastrointestinal side effects. Of 638 patients who completed the preference questionnaire, 93.0% of patients preferred the once-monthly dosing schedule and 563 patients (90.7%) found it more convenient. The most common adverse events were dyspepsia (1.9%), nausea (1.1%), and upper abdominal pain (0.9%). Patients are likely to prefer treatment with monthly ibandronate to a weekly or monthly bisphosphonate irrespective of their stated preference before switching treatment.

Randomized Double-Blind Clinical Comparison of Sodium Ibandronate and Pamidronate Disodium for Treatment of 141 Patients with Malignant Tumor Ostealgia

OBJECTIVE To evaluate the therapeuticeffect and potential adverse ef- fects of sodium ibandronate(SI)in patients with malignant tumor ostealgia. METHODS Patients were randomly classified into two groups.Group A(SI)of 68 patients who received 4 mg SI i.v.,and 73 patients in Group B (pamidronate disodium[PD])who received 60 mg PD i.v.A randomized, double-blind method,with PD as a positive drug control,was used to assess changes in bone pain and adverse effects over a three-week period. RESULTS A total of 141 patients were enrol ed in the study,with 136 cases of appraisable efficacy.The effective rate was 72.3%(47/65)in Group A,and 63.4%(45/71)in Group B.There was no significant difference in ef- ficacy or adverse effects between the 2 groups. CONCLUSION The SI injection,with a pronounced effect,can relieve bone pain caused by osseous metastasis from a malignant tumor.The cura- tive and adverse effects were similar compared to PD.

双膦酸盐类骨质疏松症药物

美国FDA近日发布公告，着重提示接受双膦酸盐类骨质疏松症药物（商品名和通用名分别为：Actonel／risedronate，利塞膦酸钠；Actonel＋Ca／risedronate，利塞膦酸钠＋钙；Aredia／pamidronate Disodium，帕米膦酸钠；Boniva／ibandronate，伊拜膦酸钠；Didronel／Etridronatedisodium，依替膦酸钠；Fosamax。

长效骨质疏松药物的探索

华盛顿特区——于3月份，食品与药品管理局（the Food and Drug Administration，FDA）批准了每月服用一次的ibandronate，这项工作显著改善病人坚持骨质疏松治疗的能力。在临床试验中，检验骨质疏松药物的药物公司需要减少用药频率的趋势，已成为4月份第六次国际骨质疏松专题讨论会的最重要的内容。

Benefit of infusions with ibandronate treatment in children with osteogenesis imperfecta

Background Osteogenesis imperfecta （OI） is a rare bone disease and its effective treatment is relatively deficient. We tried to assess the effects of new bisphosphonate, ibandronate on children with OI.Methods In this open-label, prospective, controlled study, 30 children with OI were enrolled. They received either infusions of ibandronate （2 mg） in every three months or oral calcitriol 0.25 μg daily for 24 months. All patients took 500 mg calcium plus 200 U vitamin D daily together. The endpoints were the change of annual new fracture rate （observed by case history and X ray films of spine）, bone mineral density （BMD, measured by dual energy X-ray absortiometry）, serum concentration of carboxy-telopeptide cross-links of type Ⅰ collagen （CTX, bone resorption marker） and alkaline phosphatase （ALP, bone formation marker） during the follow-up.Results After the cyclic infusions of ibandronate, the annual new fracture rate was significantly decreased from 1.9 to 0.13 time, obviously lower than that of calcitriol group, which decreased from 1.8 to 1.0 time after the treatment （P 〈0.001）.The significant increase of BMD at the lumbar spine, femoral neck, trochanter, total hip was found in the group of ibandronate by 59.0%, 42.0%, 47.5% and 36.6% in time dependent manner （compared with the baseline, P 〈0.001）. The increase of BMD in ibandronate group was greater than that of calcitriol group （P 〈0.001）. The concentrations of ALP and CTX were obviously decreased in ibandronate group, and the reduction of CTX was more significant than that of ALP （P 〈0.001）. The tolerance of the children to ibandronate was quite well. Mild fever and muscle pain were found in 9 cases within 1-3 days after the first infusion of ibandronate, which could relieve after 1-2 days without special management.Conclusions The benefits of cyclic infusions of ibandronate to children with OI are significant because ibandronate could significantly reduce annual bone fracture rate, increase lumbar and hip BMD, preserve vertebral morphometry of patients through inhibition of bone resorption.

In vitro osteoclast-suppressing effect of sodium ibandronate

Background Bisphosphonates （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. Methods Mouse 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. Results OCL 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. Conclusions Sodium 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.

Chugai Pharmaceutical公司提交了ibandronate sodium hydrate的新药申请

Taisho Pharmaceutical公司的合作伙伴Chugai Pharmaceutical公司向日本厚生劳动省提交了ibandronate sodium hydrate（RG-484；CT-064）的新药申请（NDA）。本品是Taisho Pharmaceutica忪司和Chugai Pharmaceutical公司联合开发的一种二膦酸盐骨吸收抑制剂注射制剂，