Recent ibandronate (Boniva) review study (March 2007)
Clin. Ther. 2006 Apr;28(4):475-90. Once-monthly ibandronate for postmenopausal osteoporosis: review of a new dosing regimen. Pyon EY and others. PMID: 16750461. Background. Ibandronate 2.5 mg/d was approved by the FDA for the treatment and prevention of osteoporosis in women in May 2003. In March 2005, once-monthly ibandronate was approved for the same indication. This is a review which encompassed articles concerning ibandronate that were published between 1966 and 2005, with an emphasis on once-monthly oral dosing. Why intermittent therapy? Animal studies have shown that ibandronate is 2, 10, 50, and 500 times more potent than risedronate, alendronate, pamidronate, and clodronate, respectively, with the concentration in rat bone related more to the total cumulative dose administered rather than to dosing frequency. The half-life in rat bones ranged from 440 to 500 days. Thus the efficacy of bisphosphonates during intermittent therapy appears to be determined by the total cumulative dose over a given period rather than by dosing frequency. The ideal bisphosphonate to use for intermittent dosing appears to be one with high potency (the amount of drug required to get a therapeutic response) and good tolerability. Tolerability is important since higher one-time doses are required for intermittent therapy. Pharmacokinetics. Only 0.65% of ibandronate is absorbed when given orally with water and this small number is reduced by -90% if ibandronate is taken with a meal. (Editors note: Meaning you are totally wasting your time and money if you take a bisphosphonate with food. And, see below, there is added benefit to waiting 60 minutes compared to 30 minutes before eating.). Another study showed that women who waited for 60 minutes to eat after taking ibandronate gained 1.88% more bone mineral density (BMD) during a 48-week study when compared to women who only waited 30 minutes. Clinical trials. Pivotal trial. The very important aspect of treatment, antifracture efficacy, was tested in a Phase III study of 2,946 women with a history of 1 to 4 prevalent vertebral fractures and a T-score of -2.0 to -5.0 in at least one vertebra (L1-L4). This study used an intermittent dosing regimen of 20 mg every other day for 12 doses every 3 months. Clinical vertebral fractures were significantly lower in the ibandronate group when compared to placebo by about 50%. Hip fractures were only reduced significantly in a subgroup of women with a femoral neck BMD T-score of less than -3.0. See PMID: 15231010. Phase I trial. This trial by Reginster et al (see PMID: 15972582), tested the dosing possibilities for once-monthly ibandronate . One hundred forty-four women were randomized to receive three cycles of once-monthly 50 mg, 100 mg or 150 mg ibandronate. The primary endpoint of this study was changed concentration of biochemical markers of bone resorption. No serious adverse events were reported and there was a dose-response in biochemical markers during the 90-day study. There was an increased incidence of patients reporting self-limiting flu-like symptoms during the first few days after the first once-monthly dose. Phase III trial. (See PMID: 163329289 and PMID: 16007327). This study compared the 2.5 mg/day ibandronate dosage to three different dosing regimens: 50 mg, 100 mg or 150 mg once-monthly. Medications were taken first thing in the morning with no food for one hour after taking ibandronate. Additionally patients took 500 mg calcium and 400 IU vitamin D daily. BMD of the lumbar spine was the primary endpoint measured after one year of therapy. Additionally percent changes in lumbar spine and proximal femur BMD after two years of therapy were evaluated as secondary efficacy endpoints. At one year, 1,363 patients completed therapy and 1,291 completed two years. Results of lumbar spinal BMD increase at one year showed 3.9%, 4.3%, 4.1%, and 4.9% improvement over baseline for the 2.5 mg/day, 50 mg/month, 100 mg/month and 150 mg/month dosages, respectively. Only the 150 mg/month dose was statistically greater than the 2.5 mg/day dosage. After two years of therapy the following increases from baseline were noted: 5.0%, 4.8%, 5.6%, and 6.6% for 2.5 mg/day, 50 mg/month, 100 mg/month and 150 mg/month, respectively. All monthly dosages were as effective as the daily dose. Total hip improvements were at least as good when comparing the once-monthly dosing to the daily dose. Also the 100 and 150 mg/monthly dosing were significantly better regarding hip BMD than either the 2.5 mg/daily or the 50 mg/monthly doses. Adverse events were similar and unremarkable for all four regimens. Comparative efficacy. There are currently no published clinical trials comparing once-monthly ibandronate with other bisphosphonates to treat osteoporosis. Adverse events. The daily oral ibandronate dosage safety profile was evaluated in 3,900 patients in clinical trials of up to three years duration. Results showed it similar to placebo. Additionally, those studies cited above using the intermittent dosage showed similar adverse events findings across all dosages. The flu-like symptoms that occurred with the first once-monthly dosage of ibandronate did occur more commonly in the higher dosage regimens. Contraindications and precautions. Contraindications to the use of ibandronate include uncorrected hypocalcemia and the inability to stand or sit upright for at least 60 minutes after taking the pill. It is also contraindicated in patients with severe renal impairment (creatinine clearance <30 ml/min). Dosage and administration. Ibandronate 150 mg is taken once monthly, on the same date every month. It should be taken with 6 to 8 ounces of water in the morning on an empty stomach. Patients should remain upright standing or sitting for 60 minutes after taking the medication and they should take no supplement, medication, food or beverage other than water during that 60-minute wait period. Note that the 60-minute wait period differs from the 30-minute minimum wait required for risedronate (Actonel) or alendronate (Fosamax). Compliance and adherence. Compliance rates for those taking osteoporosis medications, although variable, is not very good overall. Twelve-month adherence rates in one study of Actonel and Fosamax ranged from 54% to 61%. In another study, one-year compliance rates were <25% for all osteoporosis therapies investigated, while another study showed about 70% compliance. The reasons given for noncompliance include adverse effects, inconvenient dosing, and inadequate understanding of the condition. In a study that compared once-monthly ibandronate dosing to once-weekly alendronate, 71.4% vs. 28.5%, respectively, preferred the once-monthly dosing comparing ibandronate to alendronate. Pharmacoeconomic considerations. Medication costs are similar with the average wholesale price for three months of therapy being about $230 for ibandronate, alendronate or risedronate. One study considered the cost of fracture care based upon patient persistence with taking the osteoporosis medication. These authors concluded that ibandronate would decrease costs by decreasing fractures due to the higher persistence patients have in taking the once-monthly dose of ibandronate when compared with more frequent dosing regimens of other osteoporosis medications. Discussion. One study comparing alendronate and risedronate concerning fracture reduction showed that valid results would require a study population of >50,000 people to detect a difference between the two medications ability to reduce fractures. Thus the increase in BMD is often used as a surrogate marker for fracture reduction. With that in mind, whatever osteoporosis medication is being considered, fracture reduction is often estimated by the increase in BMD rather than proven fracture reduction. Ibandronate, either daily or once-monthly, improves BMD in a similar range to other bisphosphonates that have been shown to decrease fractures. An interesting comparison of the dose of ibandronate used to treat osteoporosis is shown by comparing it to that used to treat metastatic bone disease. For that condition up to 50 mg/day or 6 mg IV each four weeks have been used. Editor's comments. The authors don't mention osteonecrosis of the jaws as a potential side effect. I did a PubMed search and could only find one instance of that condition occurring with metastatic bone disease treatment using ibandronate. Ibandronate has not been used as long as other bisphosphonates such as Fosmax and Actonel, so one can only conjecture if there will be cases being reported in the future with either the oral or IV ibandronate dosages used to treat osteoporosis. It would appear that the dose is small enough when treating osteoporosis to keep the risk of osteonecrosis low. Still one would be prudent to follow the guidelines as mentioned in my previous update on this topic. The very high noncompliance rates for people taking osteoporosis medications is a problem. I wonder if people were required to see a short video showing what is involved to treat a hip or vertebral fracture if it wouldn't improve compliance rates. I know that since I saw a video clip during citizens' police academy training showing what happens to you in an accident when you don't wear your seat belt, it permanently cured me of not wearing my seat belt. Perhaps something similar would have equal results for osteoporosis patients regarding taking their medications. I don't know the answer, but I know something needs to be done.