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Bonviva (ibandronic acid): a new, once-monthly bisphosphonate

Michael Stone BA, DM, FRCP and Zahed Ikram MRCP(UK) Bonviva is a new formulation

PRODUCT PROFILE
Proprietary name: Bonviva Constituents: ibandronic acid Indication: treatment of osteoporosis in postmenopausal women at increased risk of fracture Dosage and method of administration: adults: 150mg once monthly; elderly no dosage adjustment required; children not applicable Contraindications: patients hypersensitive to ibandronic acid or its excipients; hypocalcaemia Precautions: hypocalcaemia must be corrected and other disturbances of bone and mineral metabolism should be treated before initiating Bonviva therapy; risk of developing osteonecrosis of the jaw while on bisphosphonate therapy; dental examination with appropriate preventive dentistry should be considered prior to initiating bisphosphonate treatment in patients with concomitant risk factors (eg cancer, chemotherapy, radiotherapy, corticosteroids, poor oral hygiene); avoid dental procedures during treatment; discontinue in patients with symptoms of oesophageal irritation such as new or worsening dysphagia, pain on swallowing, retrosternal pain or heartburn; not recommended in patients with a creatinine clearance below 30ml per minute; patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take Bonviva Pregnancy and lactation: not recommended during pregnancy or lactation Interactions: patients should fast and also not take other oral medicinal products for at least 6 hours before taking and for 1 hour following intake of Bonviva; exercise caution in co-administration with NSAIDs Side-effects: common: gastritis, gastro-oesophageal reflux disease, oesophagitis, diarrhoea, abdominal pain, dyspepsia, nausea; headache; influenza-like illness (eg myalgia, arthralgia, fever, chills, fatigue, nausea, loss of appetite, bone pain); muscle cramp, musculoskeletal pain, arthralgia, myalgia, musculoskeletal stiffness; rash Presentation/cost: 150mg film-coated tablets; 1, 21.45; 3, 64.35

of ibandronic acid that is taken once a month to treat osteoporosis. This New products review examines the trial data for its efficacy and how compliance may be improved.

ral bisphosphonates remain the mainstay of osteoporosis treatments. However, the efficacy of daily and weekly regimens is compromised by poor therapeutic adherence, and less frequent dosing may prove more convenient for patients and provide adherence benefits. Ibandronic acid (Bonviva) is a new highly potent
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aminobisphosphonate available both as a unique once-monthly tablet and as a solution for intravenous injection once every three months. This article will focus mainly on the oral formulation.
Mechanism of action

Ibandronic acid is a highly potent aminobisphosphonate and has

high bone affinity. Like all aminobisphosphonates, ibandronic acid reduces bone resorption and enhances mineralisation resulting in an increase in bone mineral density (BMD). In addition, the reduction in bone turnover reduces the risk of further disruption to the microarchitecture of bone such as loss of connectivity
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in trabecular bone as a result of trabecular perforation. The increase in BMD as well as the preser vation of bone microarchitecture contributes to increased bone strength relative to placebo. In tandem with reduced bone turnover, biochemical markers of bone resorption and bone formation are also decreased and these correlate well with

efficacy in terms of fracture reduction.1

What have the main clinical trials shown?

Extensive preclinical testing in animals with ibandronic acid established equivalent efficacy between daily and intermittent dosing in terms of increased bone strength, using extended intervals (up to 11 weeks) between

doses. Taking advantage of the high potency and high bone affinity of ibandronic acid provided the opportunity for the development of both the monthly oral dose and the three-monthly iv formulation.2 Fracture efficacy The pivotal fracture trial for ibandronic acid is the oral iBandronate Osteoporosis vertebral

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fracture trial in North America and Europe (BONE) study.3 This was a trial powered to show reductions in vertebral fracture rates comparing placebo with both daily ibandronic acid (2.5mg) and an intermittent regimen (20mg ever y other day for 12 doses followed by a nine-week treatmentfree interval). There were nearly 3000 postmenopausal women recruited to the study who were

all required to have at least one prevalent vertebral fracture at baseline together with a lumbar spine T-score -2.0. The primary end-point was the rate of new vertebral fractures at three years. The average T-score at the spine was low at -2.8 and there was a highly significant 62 per cent reduction in the relative risk of new vertebral fractures at three years for daily ibandronate. The

relative risk reduction in vertebral fracture was remarkably consistent at the end of year 1, year 2 and year 3 both for all vertebral fractures as well as for moderate and severe vertebral fractures that are probably of greater clinical significance.4 The intermittent regimen showed a 50 per cent reduction in the incidence of vertebral fractures the first time that such an

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Change (per cent) 7 daily (2.5mg) 6 5 4 3 2 1 0 monthly (150mg)

*

p<0.001

*p=0.002 vs daily vs daily

1 Year

Figure 1. Monthly ibandronate achieved greater gains in spinal bone density over two years than daily ibandronate6

extended treatment-free interval between doses of an oral bisphosphonate had demonstrated a significant reduction in fracture risk. The BONE study was never expected to show an overall reduction in nonvertebral fractures in a low-risk population with relatively high hip BMDs (total hip T-score -1.7) and this was indeed the case. However, in post-hoc analyses, there was a significant 69 per cent reduction in the incidence of lowtrauma nonvertebral fractures in a high-risk subgroup that had a femoral neck BMD of 3.0. A similar interaction between baseline hip BMD and relative risk reduction in nonvertebral fractures was also seen in the second Fracture Inter vention Trial with alendronic acid but this was a preplanned analysis.5 Dosage regimen Having confirmed fracture efficacy with once-daily and intermittent ibandronic acid, the next stage in the development of this
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bisphosphonate was to create a more convenient dosing regimen in the form of once-monthly oral ibandronic acid at the dose of 150mg. The noninferiority bridging study between once-daily and once-monthly oral ibandronic acid was similar to the therapeutic equivalence studies bridging the gap between once-daily and onceweekly bisphosphonates. The Monthly Oral iBandronate In LadiEs (MOBILE) study compared 2.5mg ibandronic acid once daily with either 100mg or 150mg once monthly over two years in postmenopausal women with osteoporosis (see Figure 1). 6 Both once-monthly doses showed noninferiority in terms of the primar y outcome measure, which was the increase in lumbar spine BMD from baseline but, in a preplanned analysis, superiority of the 150mg dose was also demonstrated. In other words, 150mg oral ibandronic acid once monthly resulted in significantly greater rises in bone density both at the spine and hip

in comparison with once-daily ibandronic acid. Reduction in bone markers was also greater with the 150mg once-monthly dose. Safety and tolerability for once-daily ibandronic acid was good with an overall adverse effect profile similar to placebo. Likewise, once-monthly oral ibandronic acid had a tolerability profile ver y similar to that of daily ibandronic acid. Patients were permitted to take concomitant NSAIDs and were not excluded unless dyspepsia symptoms were uncontrolled. In a six-month crossover preferability study comparing alendronic acid 70mg once weekly with ibandronic acid 150mg once monthly, 70 per cent of patients expressed a preference for ibandronic acid.7 Compliance with treatment It is increasingly recognised that adherence to and persistence with treatment is important in determining outcome. For example, we know from observational studies of prescription databases that lower fracture rates are seen in patients who have better persistence with bisphosphonates. 8 Once-weekly bisphosphonates have greater persistence rates than once-daily but remain suboptimal. The PERSIST study (PERsistence Study of Ibandronate verSus alendronaTe) was a six-month, prospective, randomised, openlabel study of 1000 women with postmenopausal osteoporosis comparing persistence with ibandronic acid 150mg once monthly with that of once-weekly alendronic acid performed in primary care in the UK (see Figure 2). Patients randomised to ibandronate also received a monthly telephone call to remind them to
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take their tablet as part of the patient support programme, which is available free of charge to all patients taking the drug in the UK. After six months, 57 per cent of patients receiving ibandronic acid were still taking their treatment compared with 39 per cent on alendronic acid (p<0.0001).9
Intravenous formulation

Persistence probability 1.0

0.5

Ibandronic acid is also available as an iv injection given once ever y three months using a prefilled syringe containing 3mg. This can be administered rapidly (15 to 30 seconds) offering an advantage over currently used iv bisphosphonates. Ibandronic acid is the only iv bisphosphonate to be licensed for the treatment of osteoporosis (most centres use iv pamidronate off-licence). The bridging study (Dosing IntraVenous Administration, DIVA) showed superiority for the licensed dose of iv ibandronic acid compared with the 2.5mg once daily dose in terms of BMD.10
Ibandronic acid vs alendronic acid

monthly ibandronate + PSP weekly alendronate 0 0 60 120 180 240 Time from randomisation (days)
PSP = patient support programme Figure 2. Significantly improved treatment persistence with monthly ibandronate plus a patient support programme vs weekly alendronate9

Alendronic acid is the goldstandard oral bisphosphonate against which all others have to be compared. In addition, now that alendronic acid is available as a generic drug, cost advantages also exist. The vertebral fracture data are ver y good for ibandronic acid. However, the nonvertebral fracture data are considered less robust since they are post-hoc analyses, but this high-risk subgroup analysis is similar to that used for alendronic acid in the Fracture Inter vention Trial. Ibandronic acid also lacks hip fracture data, but only a head-to-head trial of active treatments though
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impractical due to the very large numbers of subjects required would now be ethical. Reductions in bone turnover and increases in hip and spine bone density (accepted as surrogate markers of efficacy by the regulator y authorities) are broadly similar between these two bisphosphonates. A noninferiority trial comparing the changes in hip bone density for weekly alendronic acid and monthly ibandronic acid is well underway. Once-monthly ibandronate may improve adherence and persistence compared to daily or weekly treatment and, while alenKey points

dronate will remain a first-line option for many clinicians, oncemonthly ibandronate would appear to offer a reasonable alternative.
Conclusion

Once-monthly oral ibandronic acid is a potent bisphosphonate with similar efficacy to existing bisphosphonates. Patients prefer the monthly dosing regimen to weekly and this also results in improved persistence. Intravenous ibandronic acid is a welcome new alternative for those patients who cannot tolerate, have poor compliance with or

ibandronic acid is a highly potent aminobisphosphonate now licensed for use in the treatment of osteoporosis it has similar efficacy to other aminobisphosphonates it is available as a unique once-monthly oral formulation once-monthly ibandronic acid has better compliance than once-weekly alendronic acid also available as an iv formulation given by rapid injection every three months only iv bisphosphonate licensed for treatment of osteoporosis

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who are unable to take oral bisphosphonates.

References

1. Hochberg MC, Greenspan S, Wasnich RD, et al. Changes in bone density and turnover explain the reductions in incidence of nonvertebral fractures that occur during treatment with antiresorptive agents. J Clin Endocrinol Metab 2002;87:1586-92. 2. Bauss F, Russell RG. Ibandronate in osteoporosis: preclinical data and

rationale for intermittent dosing. Osteoporos Int 2004;15:423-33. 3. Chesnut III CH, Skag A, Christiansen C, et al; Oral Ibandronate Osteoporosis Vertebral Fracture Trial in North America and Europe (BONE). Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis. J Bone Miner Res 2004; 19(8):1241-9. 4. Felsenberg D, Miller P, Armbrecht G, et al. Oral ibandronate signifi-

cantly reduces the risk of vertebral fractures of greater severity after 1, 2, and 3 years in postmenopausal women with osteoporosis. Bone 2005; 37(5):651-4. 5. Cummings SR, Black DM, Thompson DE, et al. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Inter vention Trial. JAMA 1998;280:2077-82. 6. Reginster JY, Adami S, Lakatos P, et

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al. Efficacy and tolerability of oncemonthly oral ibandronate in postmenopausal osteoporosis: 2 year results from the MOBILE study. Ann Rheum Dis 2006;65:654-61. 7. Emkey R, Koltun W, Beusterien K, et al. Patient preference for oncemonthly ibandronate versus onceweekly alendronate in a randomized, open-label, cross-over trial: the Bonviva Alendronate Trial in Osteoporosis (BALTO). Curr Med Res Opin 2005;21:1895-903.

8. Huybrechts KF, Ishak KJ, Caro JJ. Assessment of compliance with osteoporosis treatment and its consequences in a managed care population. Bone 2006;38(6):922-8. 9. Cooper A, Drake J, Brankin E; the PERSIST investigators. Treatment persistence with once-monthly ibandronate and patient support vs once-weekly alendronate: results from the PERSIST study. Int J Clin Pract 2006;60(8):896-905. 10. Delmas PD, Adami S, Strugala C,

et al. Intravenous ibandronate injections in postmenopausal women with osteoporosis: one-year results from the Dosing Intravenous Administration Study. Arthritis Rheum 2006;54:1838-46.

Dr Ikram is specialist registrar in care of the elderly and Dr Stone is consultant physician and director of bone research at Cardiff University Academic Centre, Llandough Hospital, Penarth

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