Ibandronate Sodium (Boniva) Injection

Number: 0727

Policy

Aetna considers ibandronate sodium (Boniva) injection medically necessary for the following indications:

• Treatment of bone metastases or bone pain presumed due to bone metastases from breast cancer; or
• Treatment of hypercalcemia of malignancy; or
• Treatment of osteoporosis in post-menopausal women.

Aetna considers ibandronate therapy contraindicated and experimental and investigational in persons with severe renal impairment (persons with serum creatinine greater than 200 uM/L (2.3 mg/dL)) or creatinine clearance less than 30 ml/min.

Aetna considers ibandronate sodium injection experimental and investigational for the following indications (not an all-inclusive list) because its effectiveness for these indications has not been established.

• Giant cell tumor of the spine
• Inflammatory bowel disease-related osteoporosis
• Knee osteoarthrosis
• Multiple myeloma
• Osteogenesis imperfecta
• Osteonecrosis of the knee
• Osteoporosis in men
• Prevention of postmenopausal osteoporosis
• Primary biliary cirrhosis-related osteoporosis
• Solid organ transplantation-related osteoporosis

Aetna considers local administration of ibandronate experimental and investigational for enhancement of fracture healing and osseointegration because the effectiveness of this approach has not been established.

Note: The World Health Organization (WHO) osteoporosis diagnostic classification assessment (1994) defines osteoporosis as a T score of 2.5 or more standard deviations (SDs) below the mean (i.e., less than -2.5).

Background

The National Osteoporosis Foundation Consensus Development Conference (NOF, 2003) 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 to 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 1to 5 % per year for the first 5 to 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. The action of ibandronate on bone tissue is based on its affinity for hydroxyapatite, which is part of the mineral matrix of bone. In postmenopausal women, it reduces the elevated rate of bone turnover, leading to, on average, a net gain in bone mass. 

Ibandronate 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 1-year Dosing Intravenous Administration (DIVA) study, a multinational, randomized, double-blind, active control multi-center study involving approximately 1,300 women with post-menopausal 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 2 IV ibandronate sodium regimens: 2 mg every 2 months and 3 mg every 3 months, with lumbar spine bone mineral density (BMD) at 1 year as the primary endpoint.  The results showed that the average increase in lumbar spine BMD at 1 year in patients treated with ibandronate sodium injection (3 mg once every 3 months) was statistically superior to that in patients treated with the daily oral tablets (4.5 % versus 3.5 % for the 2 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 2-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 % versus 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 % versus 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.

Ibandronate sodium is available as:

• Boniva Injection as a 3mg/3mL single‐use, clear glass prefilled syringe
• Ibandronate sodium 3 mg/3ml vial solution for injection
• Ibandronate sodium 3 mg/3ml syringe for injection

The FDA-approved dosing for Boniva injection in the treatment of post-menopausal 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 mins 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.

Information regarding administration of Boniva:

• Patients must be adequately supplemented with calcium and vitamin D if dietary intake is not sufficient. The current recommended daily intake of calcium is at least 1200 mg in divided doses and 800‐1000 IU daily of vitamin D.
• Serum creatinine must be measured prior to each dose.

The U.S. Food and Drug Administration has warned patients and health care providers about the possible risk of atypical thigh bone (femoral) fracture in patients who take bisphosphonates. While it is not clear whether bisphosphonates are the cause, atypical femur fractures, a rare (<1%) but serious type of thigh bone fracture, have been predominantly reported in patients taking bisphosphonates. The optimal duration of bisphosphonate use for osteoporosis is unknown, and the FDA is highlighting this uncertainty because these fractures may be related to use of bisphosphonates for longer than five years.

The FDA recommends that health care professionals be aware of the possible risk in patients taking bisphosphonates and consider periodic reevaluation of the need for continued bisphosphonate therapy for patients who have been on bisphosphonates for longer than five years.

Boniva Injection (ibandronate sodium) therapy is not considered medically necessary for patients with the following concomitant conditions:

• Ibandronate therapy is considered contraindicated in patients with uncorrected hypocalcemia or known hypersensitivity to ibandronate sodium or any of its excipients.
• Hypocalcemia, hypovitaminosis D, and other disturbances of bone and mineral metabolism must be effectively treated before starting therapy.
• Withhold future doses of Boniva Injection. If severe incapacitating bone, joint, or muscle pain symptoms occur.
• An oral exam by the prescriber is performed prior to treatment. Osteonecrosis of the jaw has been reported rarely in postmenopausal osteoporosis patients treated with bisphosphonates, including ibandronate sodium.

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 versus 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 greater than 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 (CI) 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 2 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 (greater than 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. A total of 174 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.  A total of 173 (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.  A total of 195 adverse events were reported, 99 classified as serious and 96 as non-serious; 3 serious and 16 non-serious adverse events were considered related to ibandronate treatment.  The 3 serious adverse events were 1 case with thrombocytopenia, 1 with nausea, and 1 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. S MPR 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 life was 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.  A total of 99 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 2 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 tumor 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.

Klause et al (2011) compared the effect of calcium and cholecalciferol alone and along with additional sodium fluoride or ibandronate on BMD and fractures in patients with Crohn's disease (CD).  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 to 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 to L4).  A total of 123 (83.1 %) patients completed the 1st year for intention-to-treat (ITT) analysis; 92 (62.2 %) patients completed the 2nd year; and 71 (47.8 %) the 3rd year available for per-protocol (PP) analysis.  With a significant increase in T-score of the lumbar spine by +0.28 ± 0.35 [95 % CI: 0.162 to 0.460, p < 0.01], +0.33 ± 0.49 (95 % CI: 0.109 to 0.558, p < 0.01), +0.43 ± 0.47 (95 % CI: 0.147 to 0.708, p < 0.01) in group A, +0.22 ± 0.33 (95 % CI: 0.125 to 0.321, p < 0.01); +0.47 ± 0.60 (95 % CI: 0.262 to 0.676, p < 0.01), +0.51 ± 0.44 (95 % CI: 0.338 to 0.682, p < 0.01) in group B and +0.22 ± 0.38 (95 % CI: 0.111 to 0.329, p < 0.01), +0.36 ± 0.53 (95 % CI: 0.147 to 0.578, p < 0.01), +0.41 ± 0.48 (95 % CI: 0.238 to 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.  The authors concluded that additional sodium fluoride or ibandronate had no benefit over calcium and cholecalciferol alone in managing reduced BMD in CD.

Patients with chronic kidney disease have significant abnormalities of bone remodeling and mineral homeostasis and are at increased risk of fracture.  The fracture risk for kidney transplant recipients is 4 times that of the general population and higher than for patients on dialysis.  Ebeling (2007) noted that organ transplant candidates should be evaluated and pre-transplantation bone disease should be treated.  Preventive therapy initiated in the immediate post-transplantation period is indicated in patients with osteopenia or osteoporosis, as further bone loss will occur in the first several months following transplantation.  Long-term organ transplant recipients should also have bone mass measurement and treatment of osteoporosis.  Bisphosphonates are the most promising approach for the management of transplantation osteoporosis.  Active vitamin D metabolites may have additional benefits in reducing hyper-parathyroidism, particularly following kidney transplantation.  The author stated that large, multi-center treatment trials with oral or parenteral bisphosphonates and calcitriol are needed.

In a Cochrane review, Palmer et al (2007) assessed the use of interventions for treating bone disease following kidney transplantation.  Randomized controlled trials and quasi-RCTs comparing different treatments for kidney transplant recipients of any age were selected.  All other transplant recipients, including kidney-pancreas transplant recipients were excluded.  Two authors independently evaluated trial quality and extracted data.  Statistical analyses were performed using the random effects model and the results expressed as relative risk (RR) with 95 % CI for dichotomous variables and mean difference (MD) for continuous outcomes.  A total of 24 trials (n = 1,299) were included.  No individual intervention (bisphosphonates, vitamin D sterol or calcitonin) was associated with a reduction in fracture risk compared with placebo.  Combining results for all active interventions against placebo demonstrated any treatment of bone disease was associated with a reduction in the RR of fracture (RR 0.51, 95 % CI: 0.27 to 0.99).  Bisphosphonates (any route), vitamin D sterol, and calcitonin all had a beneficial effect on the BMD at the lumbar spine.  Bisphosphonates and vitamin D sterol also had a beneficial effect on the BMD at the femoral neck.  Bisphosphonates were more effective in preventing BMD loss when compared head-to-head with vitamin D sterols.  Few or no data were available for combined hormone replacement, testosterone, selective estrogen receptor modulators, fluoride or anabolic steroids.  Other outcomes including all-cause mortality and drug-related toxicity were reported infrequently.  The authors concluded that treatment with bisphosphonates, vitamin D sterol or calcitonin after kidney transplantation may protect against immunosuppression-induced reductions in BMD and prevent fracture.  However, they state that adequately powered clinical studies are needed to ascertain if bisphosphonates are better than vitamin D sterols for fracture prevention in this population.  Moreover, the optimal route, timing, and duration of administration of these interventions remains unknown.

Fahrleitner-Pammer et al (2009) stated that bone loss and fractures are common complications following cardiac transplantation (CTP).  These investigators examined if intravenous ibandronate is an effective preventive option.  A total of 35 male cardiac transplant recipients received either ibandronate (IBN) 2 mg intravenously every 3 months or matching placebo (CTR) in addition to 500 mg calcium carbonate and 400 IE vitamin D(3).  Sera were collected at CTP and every 3 months thereafter.  At baseline and 6 and 12 months, standardized spinal X-rays and BMD measurements were taken.  Bone biopsies were taken at CTP and after 6 months from 6 patients.  In the IBN group, 13 % of the patients sustained a new morphometric vertebral fracture compared with 53 % in the CTR group (absolute risk reduction, 40 %; relative risk reduction, 75 %; p = 0.04).  Bone mineral density remained unchanged with IBN treatment but in the CTR group decreased at the lumbar spine by 25 % and at the femoral neck by 23 % (both p < 0.0001) over the 1-year period.  Serum bone resorption markers carboxy-terminal telopeptide region of type I collagen and tartrate-resistant acid phosphatase 5b were significantly increased in the CTR group and decreased in the IBN group at all time points compared with baseline.  In contrast, both osteocalcin and bone-specific alkaline phosphatase levels showed, after a similar decrease over the first 3 months in both groups, a marked rise in the CTR subjects and steadily declining levels in the IBN patients throughout the remainder of the study period.  Three paired biopsies were available from each group.  Despite the small sample size, a difference in the relative change of eroded surface (68 % in the CTR versus -23 % in the IBN group, p < 0.05) could be shown.  The authors concluded that intravenous IBN reduced fractures, preserved bone mass, and prevented uncoupling of bone formation and resorption after CTP.  This was a small study; its findings need to be validated by further investigation, and comparisons with other alternatives, including oral bisphosphonates.

Spinal giant cell tumors are a rare clinical entity with a high recurrence rate following surgical resection.  Furthermore, complete resection of such lesions remains a challenging surgical problem.  Zhang et al (2011) present 3 complicated cases of giant cell tumor of the spine treated with sodium ibandronate.  One patient with a recurrent giant cell tumor of the 7th thoracic vertebra, 1 patient with a 5th lumbar vertebral giant cell tumor, and 1 patient with recurrent giant cell tumor of the sacrum were treated with sodium ibandronate either post-operatively or upon recurrence of the tumor.  The 1st patient with recurrent thoracic giant cell tumor recovered both clinically and radiologically after treatment with sodium ibandronate without re-operation at 6-years follow-up.  The 2nd patient also recovered with no recurrence of the tumor at 4-years follow-up.  In the 3rd case, although not fully recovered, the recurrent sacral tumor was under control after treatment with sodium ibandronate at 2-years follow-up.  The authors concluded that these case studies demonstrated the potential promise of using sodium ibandronate in the treatment of primary and recurrent giant cell tumors of the spine.  They stated that clinical evaluation should be performed in future studies.

1.  zoledronic acid,
2.  pamidronate disodium, or
3. ibandronate sodium. 

The median (interquartile-range) age of patients at osteoporosis diagnosis was 62.2 (56.4 to 67.9) and 94 % were women.  After treatment, percent change of lumbar spine-BMD (LS-BMD) and proximal femur-BMD (PF-BMD) of patients with PBC was 2.9% and 0.4%, respectively. Eight patients (47%) showed a greater LS-BMD and/or PF-BMD with percent change of LS-BMD and PF-BMD of 8.7 % and 0.8 %, respectively.  No serious adverse events were found.  In PBC patients with osteoporosis, parenteral bisphosphonates can stabilize BMD for 47 % of patients.  The authors concluded that more prospective studies are needed to evaluate the effectiveness of specific parenteral bisphosphonates in patients with PBC and osteoporosis.

In a Cochrane review, Rudic et al (2012) evaluated the beneficial and harmful effects of bisphosphonates for osteoporosis in PBC.  The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, LILACS, clinicaltrials.gov, the WHO International Clinical Trials Registry Platform, and full text searches were conducted until November 2011.  Manufacturers and authors were contacted for additional studies during the conductance of the review.  All RCTs of bisphosphonates in PBC compared with placebo or no intervention, or another bisphosphonate, or any other drug were selected for review.  Two authors extracted data.  RevMan Analysis was used for statistical analysis of dichotomous data with risk ratio (RR) or risk difference (RD) and of continuous data with mean difference (MD) or standardised mean difference (SMD), all with 95 % CI.  Methodological components were used to assess risk of systematic errors (bias).  Trial sequential analysis was also used to control for random errors (play of chance).  A total of 6 trials were included for analysis: 3 trials with 106 participants, of which 2 trials with high-risk of bias, did not demonstrate significant effects of bisphosphonates (etidronate or alendronate) versus placebo or no intervention regarding mortality (RD 0.00; 95 % CI: -0.12 to 0.12, I^² = 0 %), fractures (RR 0.87; 95 % CI: 0.29 to 2.66, I^² = 0 %), or adverse events (RR 1.00; 95 % CI: 0.49 to 2.04).  Two trials with 62 participants with high-risk of bias compared 1 bisphosphonate (etidronate or alendronate) versus another (alendronate or ibandronate) and found no significant difference regarding mortality (RD -0.03; 95 % CI: -0.14 to 0.07, I^² = 0 %), fractures (RR 0.95; 95 % CI: 0.18 to 5.06, I^² = 0 %), or adverse events (RR 1.00; 95 % CI: 0.49 to 2.04, I^² = 0 %).  Bisphosphonates had no significant effect on liver-related mortality, liver transplantation, or liver-related morbidity compared with placebo or no intervention, or another bisphosphonate.  Bisphosphonates had no significant effect on BMD compared with placebo or no intervention, or another bisphosphonate.  Bisphosphonates compared with placebo or no intervention seem to decrease the urinary amino telopeptides of collagen I (NTx) concentration (MD -16.93 nmol bone collagen equivalents/mmol creatinine; 95 % CI: -23.77 to -10.10; 2 trials with 88 patients; I^² = 0 %) and serum osteocalcin (SMD -0.81; 95 % CI: -1.22 to -0.39; 3 trials with 100 patients; I^² = 34 %) concentration.  The former result was supported by trial sequential analysis, but not the latter.  Alendronate compared with another bisphosphonate (ibandronate) had no significant effect on serum osteocalcin concentration (MD -3.61 ng/ml, 95 % CI: -9.41 to 2.18; 2 trials with 47 patients; I^² = 82 %) in a random-effects meta-analysis, but it significantly decreased serum osteocalcin (MD -4.40 ng/ml, 95 % CI: -6.75 to -2.05; 2 trials with 47 patients; I^² = 82 %), the procollagen type I N-terminal propeptide (MD -8.79 ng/ml, 95 % CI: -15.96 to -1.63; 2 trials with 47 patients; I^² = 38 %), and NTx concentration (MD -14.07 nmol bone collagen equivalents/mmol creatinine, 95 % CI: -24.23 to -3.90; 2 trials with 46 patients; I^² = 0 %) in a fixed-effect model.  The latter 2 results were not supported by trial sequential analyses.  There was no statistically significant difference in the number of patients having bisphosphonates withdrawn due to adverse events compared with placebo or no intervention (RD -0.04; 95 % CI: -0.21 to 0.12; 2 trials with 46 patients; I^² = 0 %), or another bisphosphonate (RR 0.56; 95 % CI: 0.14 to 2.17; 2 trials with 62 patients; I^² = 0 %).  One trial with 32 participants and with high-risk of bias compared etidronate versus sodium fluoride without finding significant difference regarding mortality, fractures, adverse events, or BMD.  Etidronate compared with sodium fluoride significantly decreased serum osteocalcin, urinary hydroxyproline, and parathyroid hormone concentration.  Th authors concluded that they did not find evidence to support or refute the use of bisphosphonates for patients with primary biliary cirrhosis.  The data seem to indicate a possible positive intervention effect of bisphosphonates on decreasing urinary amino telopeptides of collagen I concentration compared with placebo or no intervention with no risk of random error.  They stated that there is need for more RCTs assessing the effects of bisphosphonates for osteoporosis on patient-relevant outcomes in PBC.

In a pilot study, Alekseeva et al (2013) evaluated the effectiveness and tolerance of ibandronic acid in patients with osteoporosis (OP) concurrent with osteoarthrosis (OA) in the knee joints (KJ).  A total of 20 female outpatients aged 56 to 77 years with post-monopausal OP and primary KJ OA were examined.  All the patients took ibandronic acid in a dose of 150 mg monthly during a year.  During the treatment, the patients showed a significant reduction in the values of all components of the Western Ontario and McMasters Universities Osteoarthritis Index (WOMAC) (pain intensity from 51.7 +/- 11.6 to 34.6 +/- 20.7 mm, stiffness from 96.0 +/- 55.6 to 78.5 +/- 46.6 mm, and functional failure from 783.6 +/- 333.2 to 657.8 +/- 360.9 mm according to a visual analog scale), the Oswestry disability index, as well as in the concentration of markers for bone resorption and cartilage degradation.  The need for non-steroidal anti-inflammatory drugs was stated to decrease.  The authors concluded that ibandronic acid therapy resulted in a significant reduction in pain, KJ stiffness, and locomotor functional failure in patients with gonoarthrosis.  These preliminary findings need to be validated by well-designed studies.

Migliore et al (2013) stated that bisphosphonates are considered as a 1st-line therapy for the prevention and treatment of OP, showing in double-blind, randomized, controlled trials a significant reduction of incidence of new vertebral fractures compared to placebo.  Recently, denosumab has also been shown to reduce the appearance of new vertebral fractures by blocking RANK.  There are no head-to-head comparative studies between the above mentioned drugs.  Mixed treatment comparison, an extension of traditional meta-analysis, is able to compare simultaneously several drugs across a range producing a synthetic evidence of efficacy and a range of probability as to the best treatment.  These investigators simultaneously compared alendronate, risedronate, ibandronate, zolendronate and denosumab in the prevention of OP vertebral fractures in a Bayesian meta-analysis for assessing indirect comparisons.  A search for RCTs involving alendronate, risedronate, ibandronate, zolendronate and denosumab was conducted using several databases.  Randomized controlled trials with a double-blind treatment period of at least 3 years were included.  Men and glucocorticoid-induced osteoporosis, RCTs having as primary or secondary end-points continuous values as BMD and studies comparing different dosing regimens of the same agent, which are not used in clinical practice, were excluded.  Only fully published reports were considered.  A total of 9 RCTs were identified providing data on 31,393 participants.  Zolendronate had the highest probability (52 %) of being the most effective treatment towards placebo, followed by denosumab (46 % probability), ibandronate, alendronate, and risedronate against placebo.  The authors concluded that although the mixed treatment comparisons among alendronate, risedronate, ibandronate, zolendronate and denosumab did not show a statistically significant difference, this analysis suggested that zolendronate, compared to placebo, is expected to provide the highest rate of reduction in vertebral fractures affecting osteoporosis affected patients.

In a randomized, multi-centered, open label, non-inferiority, phase III clinical trial, Barrett-Lee and colleagues (2014) compared oral ibandronic acid with IV zoledronic acid for the treatment of metastatic breast cancer to bone.  Eligibility criteria included at least 1 radiologically confirmed bone metastasis from a histologically confirmed breast cancer.  Patients with ECOG performance status 0 to 2 and clinical decision to treat with bisphosphonates within 3 months of randomization were randomly assigned to receive 96 weeks of treatment with either IV zoledronic acid at 4 mg every 3 to 4 weeks or oral ibandronic acid 50 mg daily.  Randomization (1:1) was done via a central computerized system within stratified block sizes of 4.  Randomization was stratified on whether patients had current or planned treatment with chemotherapy; current or planned treatment with hormone therapy; and whether they had a previous skeletal-related event within the last 3 months or had planned radiotherapy treatment to the bone or planned orthopedic surgery due to bone metastases.  The primary non-inferiority end-point was the frequency and timing of skeletal-related events over 96 weeks, analyzed using a per-protocol analysis.  Between Jan 13, 2006, and Oct 4, 2010, a total of 705 patients were randomly assigned to receive ibandronic acid and 699 to receive zoledronic acid; 3 patients withdrew immediately after randomization.  The per-protocol analysis included 654 patients in the ibandronic acid group and 672 in the zoledronic acid group.  Annual rates of skeletal-related events were 0·499 (95 % CI: 0·454 to 0·549) with ibandronic acid and 0·435 (0·393 to 0·480) with zoledronic acid; the rate ratio for skeletal-related events was 1·148 (95 % CI: 0·967 to 1·362).  The upper CI was greater than the margin of non-inferiority of 1·08; therefore, these investigators could not reject the null hypothesis that ibandronic acid was inferior to zoledronic acid.  More patients in the zoledronic acid group had renal toxic effects than in the ibandronic acid group (226 [32 %] of 697 versus 172 [24 %] of 704) but rates of osteonecrosis of the jaw were low in both groups (9 [1 %] of 697 versus 5 [less than 1 %] of 704).  The most common grade 3 or 4 adverse events were fatigue (97 [14 %] of 697 patients allocated zoledronic acid versus 98 [14 %] of 704 allocated ibandronic acid), increased bone pain (91 [corrected] [13 %] versus 85 [corrected] [12 %]), joint pain (41 [corrected] [6 %] versus 38 [5 %]), infection (31 [5 %] versus 23 [corrected] [3 %]), and nausea or vomiting (38 [5 %] versus 41 [6 %]).  The authors concluded that these findings suggested that zoledronic acid is preferable to ibandronic acid in preventing skeletal-related events caused by bone metastases.  However, both drugs have acceptable side-effect profiles and the oral formulation is more convenient, and could still be considered if the patient has a strong preference or if difficulties occur with IV infusions.

1. ibandronate 150 mg/month,
2. alendronate 70 mg/week or
3. risedronate 35 mg/week, plus calcium (1,200 mg/day) and vitamin D (800 IU/day), for 2 years.

Pre-menopausal women (aged 33 to 40 years, n = 226) were studied to monitor device stability.  These researchers measured central BMD of the lumbar spine, total hip, total body and forearm using dual-energy X-ray absorptiometry (DEXA).  They measured calcaneus BMD (using DEXA plus laser), radius and tibia BMD (using peripheral quantitative computed tomography), finger BMD (using radiographic absorptiometry), and phalangeal and calcaneal ultrasound variables (using quantitative ultrasound).  Mixed effects regression models were used to evaluate effects of time and treatment allocation on BMD change.  By 2 years, there were significant increases (p < 0.05) in central BMD sites (lumbar spine, total hip).  In the peripheral skeleton, only significant changes in calcaneus BMD, 33 % total radius BMD and quantitative ultrasound (QUS)-2 broadband ultrasound attenuation (BUA) were evident for women receiving oral bisphosphonates.  The authors concluded that increases in lumbar spine and total body BMD were greater with ibandronate and alendronate than with risedronate.  Treatment effects on peripheral measurements did not differ between the 3 bisphosphonates.

In a randomized, double-blind, placebo-controlled trial, Meier and associates (2014) examined the effect of ibandronate on clinical and radiological outcome in patients with spontaneous osteonecrosis (ON) of the knee over and above anti-inflammatory medication.  A total of 30 patients (mean age of 57.3 ± 10.7 years) with ON of the knee were assigned to receive either ibandronate (cumulative dose, 13.5 mg) or placebo intravenously (divided into 5 doses 12 weeks).  All subjects received additional treatment with oral diclofenac (70 mg) and supplementation with calcium carbonate (500 mg) and vitamin D (400 IU) to be taken daily for 12 weeks.  Patients were followed for 48 weeks.  The primary outcome was the change in pain score after 12 weeks.  Secondary endpoints included changes in pain score, mobility, and radiological outcome (MRI) after 48 weeks.  At baseline, both treatment groups (ibandronate, n = 14; placebo, n = 16) were comparable in relation to pain score and radiological grading (bone marrow edema, ON).  After 12 weeks, mean pain score was reduced in both ibandronate- (mean change, -2.98; 95 % CI: -4.34 to -1.62) and placebo- (-3.59; 95 % CI: -5.07 to -2.12) treated subjects (between-group comparison adjusted for age, sex, and ON type, p = ns).  Except for significant decrease in bone resorption marker (CTX) in ibandronate-treated subjects (p < 0.01), adjusted mean changes in all functional and radiological outcome measures were comparable between treatment groups after 24 and 48 weeks.  The authors concluded that in patients with spontaneous ON of the knee, bisphosphonate treatment (i.e., IV ibandronate) has no beneficial effect over and above anti-inflammatory medication.

Hou et al (2015) performed a meta-analysis on the effectiveness of ibandronate by evaluating the effect sizes of different dosing regimens.  Major electronic databases were searched from 1985 to February 2015.  A random effects meta-analysis was performed in STATA.  Data from 34 studies (13,639 patients) were included in this meta-analysis.  Ibandronate treatment significantly improved lumbar spine BMD as shown by the percent change from baseline (4.80 %, p < 0.0001, 95 % CI: [4.14 to 5.45]).  The respective effect sizes for oral intake and IV infusion were 4.57 % and 5.22 % (p < 0.0001, CIs: 3.71 to 5.42] and [4.37 to 6.07]), respectively.  All doses led to a significant increase in BMD except 2 oral dose regimens (1 mg/d: 4.65 %, p = 0.285, 95 % CI: -3.87 to 13.18 and 0.5 mg/d: 3.60 %, p = 0.38, 95 % CI: -4.43 to 11.64].  Ibandronate treatment (overall as well as dose wise) also significantly improved the total hip BMD-2.30 % overall, 2.13 % oral, and 2.63 % IV (p < 0.0001, 95 % Cis: 1.96 to 2.64], [1.70 to 2.55], and [2.07 to 3.20]), respectively.  Ibandronate administration significantly decreased serum markers of bone resorption to -46.53 % for C-terminal telopeptide of type 1 collagen, -24.03 % for bone-specific alkaline phosphatase, and -50.17 % for procollagen type I N-terminal propeptide (p < 0.0001, 95 % Cis: -53.16 to -39.91], [-31.28 to -16.77], and [-64.13 to -36.20]), respectively.  Parathyroid hormone levels remained unaffected by ibandronate treatment (3.03 %, p = 0.439, 95 % CI: -5.06 to 11.66]).  The authors concluded that there was no significant difference in the effectiveness of ibandronate between oral or IV administration.  Predominant dose regimens for IV administration were 1 to 3 mg/3 mo and 150 mg/mo oral and 2.5 mg/d for oral ibandronate treatment.

Enhancement of Fracture Healing

Guo and co-workers (2017) stated that non-union is a major clinical problem in the healing of fractures, especially in patients with osteoporosis.  The systemic administration of drugs is time consuming and large doses are demanding and act slowly, whereas local release acts rapidly, increases the quality and quantity of the bone tissue.  These researchers hypothesized that local delivery demonstrated better therapeutic effects on an osteoporotic fracture.  These investigators examined the effect of the local application of ibandronate loaded with a collagen sponge on regulating bone formation and remodeling in an osteoporotic rat model of fracture healing.  They found that the local delivery of ibandronate exhibited excellent effects on improving the bone micro-architecture and suppressed effects on bone remodeling.  At 4 weeks, more callus formation and improvement of mechanical character and microstructure were observed in a local delivery via micro-computed tomography, mechanical test, histological research and serum analysis.  The suppression of bone remodeling was compared with a systemic treatment at 12 weeks, and the structural mechanical properties and microarchitecture were also improved with local delivery.  The authors concluded that this research identified an earlier, safer and integrated approach for local delivery of ibandronate with collagen and provided a better strategy for the treatment of osteoporotic fracture in rats.  These researchers noted that more work is needed to enhance the stability of the collagen scaffold on the premise of reducing its suppression effect on bone remodeling.  These preliminary findings need to be further investigated in human subjects.

Enhancement of Osseointegration

Kellesarian and colleagues (2018) systematically reviewed the influence of local delivery of pamidronate (PAM) and/or ibandronate (IBA) on enhancement of osseointegration. These investigators evaluated the efficacy of IBA and/or PAM local delivery (topically or coating on implants surfaces) in promoting osseointegration.  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.  A total of 15 studies were included; 14 studies were performed in animals and 2 were clinical trials; 1 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.  The authors concluded that on experimental grounds, local IBA and/or PAM delivery appeared to enhance osseointegration; however, from a clinical perspective, further RCTs are needed to examine the effectiveness of IBA and PAM in promoting osseointegration around dental implants.

The above policy is based on the following references: