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Background
The National Osteoporosis Foundation Consensus Development Conference (NOF, 1993) defined osteoporosis as a disease characterized by low bone mass and microarchitectural deterioration of bone tissue, leading to enhanced bone fragility and a consequent increase in fracture risk. Osteoporosis is the most common bone disease in humans.
Peak bone mass in adults is achieved by age 25-30 years, and is largely determined by genetic factors; however, nutrition, endocrine status, physical activity, and health during growth also play a contributing role. Bone loss occurs when bone resorption begins to outpace bone formation. This imbalance occurs with menopause and advancing age. After menopause, women experience an accelerated bone loss of 1-5% per year for the first 5-7 years. The end result is a decrease in trabecular bone and an increased risk of Colles and vertebral fractures (Hobar, 2005).
Ibandronate sodium (Boniva) (Hoffmann-La Roche Inc., Nutley, NJ) is a nitrogen-containing bisphosphonate that inhibits osteoclast-mediated bone resorption. It has been developed as a once-monthly oral tablet and as an intravenous (IV) injection. Both forms have been approved by the U.S. Food and Drug Administration (FDA) in the treatment of postmenopausal osteoporosis.
The FDA approval of Boniva injection was based on results from the one year Dosing Intravenous Administration (DIVA) study, a multinational, randomized, double-blind, active control multicenter study involving approximately 1,300 women with postmenopausal osteoporosis between ages 55 and 80 years. The study compared the efficacy, safety, and tolerability of once-daily oral ibandronate sodium 2.5 mg regimen with two IV ibandronate sodium regimens: 2 mg every two months and 3 mg every three months, with lumbar spine bone mineral density (BMD) at one year as the primary endpoint. The results showed that the average increase in lumbar spine BMD at one year in patients treated with ibandronate sodium injection (3 mg once every three months) was statistically superior to that in patients treated with the daily oral tablets (4.5% vs. 3.5% for the two treatments, respectively, p < 0.001). The study also showed that patients treated with ibandronate sodium injection had consistently higher BMD increases in the total hip and other skeletal sites (femoral neck and trochanter) than patients treated with oral daily ibandronate sodium.
The two-year findings from the DIVA study were presented at the 2005 Annual Scientific Meeting of the American College of Rheumatology in November 2005. For patients who received the 3 mg ibandronate sodium injection every 3 months, BMD at the lumbar spine increased more than in the daily oral dosing group (6.3% vs. 4.8%); substantial increases in bone density at the hip were also observed in the IV group than in the oral daily regimen (3.1% vs. 2.2%); clinically relevant decreases in bone breakdown (measured by the biochemical marker of bone resorption, serum CTX) were observed in all treatment groups.
The IV regimen was reported to be well tolerated. The most common side effects were arthralgia, back pain, influenza / influenza-like symptoms, hypertension, abdominal pain and nasopharyngitis.
The FDA-approved dosing for Boniva injection in the treatment of postmenopausal osteoporosis is 3 mg every 3 months administered IV over a period of 15 to 30 seconds by a health care professional. It is intended as an alternative for patients who have difficulty with oral bisphophonate dosing requirements, including an inability to sit upright for 30 to 60 minutes and/or difficulty in swallowing a pill. It may also be useful in women who have esophagitis, gastritis, or esophageal or gastric ulcers prohibiting the use of oral bisphosphonates.
Guay (2006) stated that ibandronate is an experimental IV bisphosphonate under study for skeletal complications of bone metastases, as well as hypercalcemia of malignancy.
Intravenous ibandronate has been shown to be effective in treatment of hypercalcemia of malignancy. Ralston, et al. (1997) studied the efficacy and safety of intravenous ibandronate in a multicenter study of 147 patients with severe cancer-associated hypercalcemia which had been resistant to treatment with rehydration alone. Of 131 randomized patients who were eligible for evaluation, 45 were allocated to receive 2 mg ibandronate, 44 patients to receive 4 mg ibandronate, and 42 patients to receive 6 mg ibandronate. The investigators reported that serum calcium values fell progressively in each group from day 2, reaching a nadir at day 5, and in some patients normocalcemia was maintained for up to 36 days after treatment. The investigators found the 2-mg dose significantly less effective than the 4-mg or 6-mg dose in correcting hypercalcemia, as the number of patients who achieved serum calcium values below 2.7 mmol/L (10.8 mg/dL) after treatment was 50% in the 2-mg group compared with 75.6% in the 4-mg group and 77.4% in the 6-mg group (P < 0.05; 2 mg vs others). The investigators reported that ibandronate was generally well tolerated and no serious drug-related adverse events were observed. The investigators concluded that ibandronate is a safe, well tolerated and effective treatment for cancer-associated hypercalcemia.
Pecherstorfer, et al. (2003) compared the efficacy and safety of ibandronate and pamidronate in patients with hypercalcemia of malignancy. Seventy-two patients with hypercalcemia of malignancy (serum calcium > 2.7 mmol/L) were treated with a single infusion of ibandronate (2 or 4 mg) or pamidronate (15, 30, 60, or 90 mg) on day 0. The dose was dependent on the severity of hypercalcemia (baseline serum calcium level). Serum calcium was assessed daily until day 4, then at intervals until day 28. The primary endpoint was lowering of serum calcium at day 4. Secondary endpoints included the number of patients responding and time to reincrease following response. Using the serum calcium baseline approach, the most frequently administered doses were 4 mg ibandronate (78.4%) and 60 mg pamidronate (50.0%). Mean lowering of serum calcium at day 4 was 0.6 mmol/L for ibandronate and 0.41 mmol/L for pamidronate. The 95% confidence interval for the difference ibandronate pamidronate had a lower limit of 0.05 mmol/l, indicating that ibandronate was as effective as pamidronate. The number of patients responding to the two agents was also similar; 76.5% of ibandronate patients and 75.8% of pamidronate patients were rated as responders after the first dose of study medication. The median time to reincrease after response was longer for ibandronate (14 days) than pamidronate (4 days) (p = 0.0303). In the subgroup of 17 patients with high baseline serum calcium (> 3.5 mmol/L), ibandronate appeared to be more effective than pamidronate. The safety profile of both agents was similar. The investigators concluded that ibandronate is at least as effective as pamidronate in the treatment of hypercalcemia of malignancy. Furthermore, in patients with higher baseline serum calcium, ibandronate appears to be more effective than pamidronate. The duration of response is significantly longer with ibandronate than pamidronate.
Pecherstorfer, et al. (1997) conducted a Phase IIb clinical trial to evaluate the hypocalcemic effect and safety of three different doses of ibandronate in hypercalcemia of malignancy. One hundred seventy-four cancer patients with a serum calcium level greater than 2.7 mmol/L (10.8 mg/dL) were enrolled onto the trial. If hypercalcemia persisted after fluid repletion, patients were randomly assigned to treatment with 0.6 mg, 1.1 mg, and 2.0 mg of ibandronate. Response, defined as restoration of normocalcemia, was evaluated by an intent-to-treat analysis. One hundred seventy-three (99%) patients were assessable for toxicity and 151 (87%) for efficacy. The administration of 0.6 mg (group A), 1.1 mg (group B), or 2.0 mg (group C) of ibandronate led to response rates of 44%, 52%, and 67%, respectively. Significantly more patients in group C responded than in group A (p = 0.0276). Of the various parameters examined, only the initial serum calcium level (p < .0001; odds ratio, 0.083) and the dose of ibandronate (p = .0162; odds ratio, 2.094) correlated with response. One hundred ninety-five adverse events were reported, 99 classified as serious and 96 as nonserious. Three serious and sixteen nonserious adverse events were considered related to ibandronate treatment. The three serious adverse events were one case with thrombocytopenia, one with nausea, and one with fever. The investigators concluded that ibandronate therapy led to a dose-dependent reduction in serum calcium levels. The response to ibandronate treatment correlated negatively with the initial serum calcium level and positively with the dose administered. A dose of 2 mg was necessary to achieve a response rate comparable to that in previous studies with pamidronate and clodronate. The investigators noted that, because the incidence of drug-associated adverse events was low, a dose escalation of ibandronate can be recommended for further clinical trials.
Ibandonate has been found to be effective in treatment of bone metastases in advanced breast cancer. In a phase III randomized, double-blind, placebo-controlled trial in patients with bone metastases due to breast cancer, 466 women were randomized to receive placebo (n = 158), 2 mg ibandronate (n = 154) or 6 mg ibandronate (n = 154) for up to 96 weeks (Body, et al., 2003; Diel, et al., 2004). Treatment was administered intravenously at 3- or 4-weekly intervals. The primary efficacy parameter was the number of 12-week periods with new bone complications, expressed as the skeletal morbidity period rate (SMPR). Other clinical endpoints included analgesic use, the incidence of adverse events, quality of life (assessed using the European Organisation for the Research and Treatment of Cancer (EORTC) Quality of Life Scale -Core 30 questionnaire (QLQ-C30)), and bone pain (assessed on a 5-point scale from 0 = none to 4 = intolerable). Ibandronate was generally well tolerated. SMPR was lower in both ibandronate groups compared with the placebo group; the difference was statistically significant for the ibandronate 6 mg group (p = 0.004 versus placebo). Consistent with the SMPR, ibandronate 6 mg significantly reduced the number of new bone events (by 38%) and increased time to first new bone event. Patients on ibandronate 6 mg also experienced decreased bone pain scores and analgesic use. Compared with baseline measurements, the bone pain score was increased at the last assessment in both the placebo and 2 mg ibandronate groups, but was significantly reduced in the patients receiving 6 mg ibandronate (-0.28 +/- 1.11, p < 0.001). A significant improvement in quality of lifewas demonstrated forpatients treated with ibandronate (p < 0.05) for all global health status. Overall, at the last assessment, the 6 mg ibandronate group showed significantly better functioning compared with placebo (p = 0.004), and had significantly better scores on the domains of physical, emotional, and social functioning, and in global health status (p < 0.05). Significant improvements in the symptoms of fatigue and pain were also observed in the 6 mg ibandronate group. The investigators concluded that intravenous ibandronate is effective and safe in the palliative treatment of bone metastases from breast cancer. The investigators found that treatment with ibandronate leads to significant improvements in quality oflife and is well-tolerated.
Ibandonate has been found to be poorly effective in multiple myeloma. Menssen, et al. (2002) reported on a double-blind, randomized, placebo-controlled study to assess the efficacy of ibandronate in preventing skeletal-related events (SREs) in advanced-stage multiple myeloma patients. Patients with multiple myeloma stage II or III were randomly assigned to receive either ibandronate 2 mg or placebo as a monthly intravenous (IV) bolus injection for 12 to 24 months in addition to conventional chemotherapy. SREs such as peripheral pathologic or vertebral fractures, hypercalcemia, severe bone pain, and bone radiotherapy or surgery were analyzed. Bone-turnover markers were also studied. Finally, post hoc analyses of bone morbidity and survival were performed. Ninety-nine patients per treatment group were assessable for efficacy analysis. The investigators reported that the occurrence of SRE per patient year and the time to first SRE were not significantly different between the two treatment groups. In overall evaluation, no differences were found between the treatment groups regarding bone pain, analgesic drug use, quality of life, and median survival (33.1 versus 28.2 months, respectively). The investigators concluded that monthly injections of ibandronate 2 mg IV neither reduced bone morbidity nor prolonged survival in the overall population of stage II/III multiple myeloma patients.
Ibandronate has been found to be less effective than pamidronate in multiple myeloma. Terpos, et al. (2003) reported on the results of a randomized trial to compare the efficacy of pamidronate and ibandronate in bone turnover and disease activity in multiple myeloma patients. Patients with stage II or III multiple myeloma were randomly assigned to receive either pamidronate 90 mg (n = 23) or ibandronate 4 mg (n = 21) as a monthly intravenous infusion in addition to conventional chemotherapy. Skeletal events, such as pathologic fractures, hypercalcaemia, and bone radiotherapy were analyzed. Bone resorption markers were also studied. The investigators reported that, in both groups, the combination of chemotherapy with either pamidronate or ibandronate produced a reduction in bone resorption and tumour burden from the second month of treatment, having no effect on bone formation. However, there was a greater reduction in most markers of bone turnover in the pamidronate group than in the ibandronate group, that being continued throughout the 10-month follow-up of this study. The investigators reported that there was no difference in skeletal events during this period. The investigators concluded that a monthly dose of 90 mg of pamidronate was more effective than 4 mg of ibandronate in reducing bone resorption and possibly tumor burden in multiple myeloma.
Guidelines from Cancer Care Ontario have concluded that ibandronate should not be used for treatment of multiple myeloma (Imrie, et al., 2004).
Studies of IV ibandronate as an adjunctive treatment for other cancers that tend to metastasize to bone are under way (Guay, 2006). Whether IV ibandronate will be a therapeutic advance is best answered by randomized, controlled trials.
According to the FDA approved labeling, ibandronate sodium injection is contraindicated in persons with uncorrected hypocalcemia and in persons with known hypersensitivity to ibandronate sodium injection or to any of its excipients.
Kreck and colleagues (2008) stated that osteoporosis is a frequent complication in patients with inflammatory bowel disease. Recent studies have shown bisphosphonates to considerably reduce fracture risk in patients with osteoporosis, and preventing fractures with bisphosphonates has been reported to be cost effective in older populations. However, no studies of the cost effectiveness of these agents in preventing fractures in patients with inflammatory bowel disease are available. These researchers examined the cost effectiveness of ibandronate combined with calcium/colecalciferol ("ibandronate") in patients with osteopenia or osteoporosis due to inflammatory bowel disease. Treatment strategies used for comparison were sodium fluoride combined with calcium/colecalciferol ("fluoride") and calcium/colecalciferol ("calcium") alone. A cost-utility analysis was conducted using data from a randomized controlled trial (RCT). Changes in BMD were adjusted and predicted for a standardized population receiving each respective treatment. A Markov model was developed, with probabilities of transition to fracture states consisting of BMD-dependent and BMD-independent components. The BMD-dependent component was assessed using predicted change in BMD from the RCT. The BMD-independent component captured differences in bone quality and micro-architecture resulting from prevalent fractures or treatment with anti-resorptive drugs. The analysis was conducted for a population with a mean age of the RCT patients (women aged 36 years, men aged 38 years) with osteopenia (T-score about -2.0 at baseline), a population of the same age with osteoporosis (T-score of -3.0 at baseline) and for an older population (both sexes aged 65 years) with osteoporosis (T-score of -3.0). Outcomes were measured as costs per quality-adjusted life year (QALY) gained from a societal perspective. The treatment duration in the RCT was 42 months. A 5-year period was assumed to follow, during which the treatment effects linearly declined to 0. The simulation time was 10 years. Prices for medication and treatment were presented as year 2004 values; costs and effects were discounted at 5 %. To test the robustness of the results, uni-variate and probabilistic sensitivity analyses (Monte Carlo simulation) were conducted. The "calcium" strategy dominated the "fluoride" strategy. When the "ibandronate" strategy was compared with the "calcium" strategy, the base-case cost-effectiveness ratios (costs per QALY gained) were between Euro 407,375 for an older female population with osteoporosis and Euro 6,516,345 for a younger female population with osteopenia. Uni-variate sensitivity analyses resulted in variations between 4 % of base-case results and dominance of calcium. In Monte Carlo simulations, conducted for the various populations, the probability of an incremental cost-effectiveness ratio of ibandronate below Euro 50,000 per QALY was never greater than 20.2 %. The authors concluded that the "ibandronate" strategy is unlikely to be considered cost effective by decision makers in men or women with characteristics of those in the target population of the RCT, or in older populations with osteoporosis.
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