General Information

Boniva (ibandronate sodium) is a nitrogen-containing bisphosphonate that inhibits osteoclast-mediated bone resorption. In osteoporosis, where osteoclasts break down bone too quickly, inhibition of this pathway has been shown to slow bone turnover, leading to not only an attenuation of turnover but also a mean increase in bone mass.

Boniva is specifically indicated for the treatment and prevention of osteoporosis in postmenopausal women. The recommended dose of Boniva is 2.5 mg (oral tablet) once daily.

Boniva is approved as a once-daily oral tablet, with a recommended dosage of 2.5 mg.

Update: In March 2005, Boniva received approval in a new formulation, as a once-monthly oral tablet, with a recommended dosage of 150 mg on the same date each month. This approval made Boniva the first ever once-monthly oral treatment for any chronic disease.

Clinical Results

Treatment Study
FDA approval of Boniva for the treatment of osteoporosis was based on a three-year, randomized, double blind, placebo-controlled, multinational pivotal phase III trial, called BONE. The study enrolled 2,946 post-menopausal women between age 55 and 80 years with osteoporosis. Subjects were treated with either placebo or one of two oral ibandronate schedules: daily (2.5 mg) or intermittent (20 mg) taken every other day for 24 days followed by a between-dose interval of greater than two months. All participants received daily oral calcium (500 mg) and vitamin D (400 IU) supplementation. The main outcome measure was the occurrence of new radiographically diagnosed fractured of the vertebrae after 3 years of treatment.

Results showed that 2.5mg daily of ibandronate reduced the risk of new vertebral fractures by 62% compared with placebo. In addition, data demonstrated an intermittent (20mg) dose of oral ibandronate taken every other day for 24 days reduced the risk of new vertebral fractures by 50% compared with placebo. The cumulative incidence of vertebral fractures in the placebo group was 9.6% over three years, 4.7% in the 2.5mg daily group and 4.9% in the 20mg intermittent group. In the study, ibandronate demonstrated a favorable tolerability profile, with the most commonly reported adverse events being upper respiratory tract infection, back pain, arthralgia, dyspepsia and bronchitis. The percentage of subjects who withdrew from the study due to adverse events was approximately 18% in each of the three groups.

Prevention Study FDA approval of Boniva for the prevention of osteoporosis was based on a randomized, double blind, placebo controlled, two year trial. The study enrolled 653 postmenopausal women aged 41 to 82 years of age without osteoporosis. Subjects were given Boniva at .5 mg, 1.0 mg and 2.5 mg or placebo. All subjects were given 500 mg of supplemental calcium daily. The primary endpoint was the change in bone mineral density (BMD) of the lumbar spine after two years of treatment.

Results showed that treatment with 2.5 mg daily of Boniva achieved a mean increase in lumbar spine BMD of 3.1% compared with placebo after two years of treatment. Data also showed that Boniva (2.5 mg daily) achieved an increase in hip BMD by 1.8%, the femoral neck by 2.0% and the trochanter by 2.1%.

Update: Once-Monthly Dosing Study
Approval of the once-monthly dosing formulation was based on a 12-month, double-blind, placebo controlled noninferiority study which compared the safety and efficacy of the 150 mg once-monthly dose of Boniva to the approved 2.5 mg once-daily dose. The trial enrolled 1602 postmenopausal women with low BMD due to confirmed osteoporosis, who were randomized to receive one of the two regimens. Primary efficacy data indicated that the once-monthly dose produced a mean increase in BMD of 4.85%, vs. an increase of 3.86% for the daily dose. This 0.99% relative increase exceeded the non-inferiority endpoint, establishing the once-monthly regimen's statistical superiority in improving BMD (p=0.002).

Side Effects

Adverse events associated with the use of Boniva may include (but are not limited to) the following:

• 
  
• Dyspepsia
• Diarrhea
• Tooth Disorder
• Vomiting
• Gastritis
• Allergic Reaction
• Infection

Update: Results from a 1 year trial comparing the safety of once monthly Boniva to the approved daily regimen produced similar tolerability profiles. Serious events occurred in 7.1% or subjects in the once-monthly group, compared to 4.8% in the daily group. Overall adverse events which may occur more often with once-monthly dosing vs. once daily include, but are not limited to, the following:

• 
  
• Constipation
• Influenza-like Illness
• Pain in the extremities

Mechanism of Action

Boniva has a high binding affinity for hydroxypatite, a calcium compound which is part of the mineral matrix of bone. Binding to the site allows the drug to be taken up by mature osteoclasts during the resorption process, and it appear to act intracellularly as an isoprenoid diphosphate lipid analogue, disrupting the farnesylation and geranylgeranylation of small GTPase signaling proteins and potentiating selective osteoclast apoptosis.

Literature References

Muller R, Hannan M, Smith SY, Bauss F. Intermittent ibandronate preserves bone quality and bone strength in the lumbar spine after 16 months of treatment in the ovariectomized cynomolgus monkey. Journal of Bone Mineral Research. 2004 Nov;19(11):1787-96. Epub 2004 Aug 16.

Rogers MJ. New insights into the molecular mechanisms of action of bisphosphonates. Current Pharmaceutical Design. 2003;9(32):2643-58

Coleman RE, Purohit OP, Black C, Vinholes JJ, et al. Double-blind, randomised, placebo-controlled study of oral ibandronate in patients with metastatic bone disease. Annals of Oncology 1999;10:311-16

Pecherstorfer M, Herrmann Z, Body JJ, Manegold C, et al. Randomized phase II trial comparing different doses of the bisphosphonate ibandronate in the treatment of hypercalcemia of malignancy. Journal of Clinical Oncology 1996;14:268-76

Ralston SH, Thiebaud D, Herrmann Z, et al. Dose-response study of ibandronate in treatment of cancer-associated hypercalcaemia. British Journal of Cancer 1997;73:293-300

Additional Information

For additional information regarding Boniva or osteoporosis, please visit the Boniva web page.