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Monthly ibandronate as effective as more frequent bisphosphonate dosing in osteoporosis

Monthly ibandronate as effective as more frequent bisphosphonate dosing in osteoporosis


Without treatment, an estimated one in three women will experience an osteoporosis-related fracture during their lifetime
Last Updated: 27-Aug-2010

Without treatment, an estimated one in three women will experience an osteoporosis-related fracture during their lifetime (1). The risk of fracture can be substantially reduced by oral nitrogen-containing bisphosphonates such as alendronate (Fosamax) and risedronate (Actonel).  However, although these are widely prescribed, they are not widely adhered to by patients. At least half to three quarters of women stop treatment within one year (2). 

Reasons for poor adherence are generally ascribed to inconvenience and, in part, to upper gastro-intestinal (GI) side effects which are thought to affect around one in five.  Dosing is complicated. Tablets have to be taken with water first thing in the morning, on an empty stomach.  No food or drink is permitted for half to one hour afterwards.  To minimise the risk of upper GI  complications patients need to remain upright for at least 30 minutes.

Attempts to improve adherence led first to the development of bisphosphonate therapies that could be administered weekly rather than daily. But whilst this has helped to some extent, adherence has remained poor (2). Patients say they prefer dosing to be less frequent than weekly, so bisphosphonate research in osteoporosis continues to focus on the development of formulations that can be administered with longer intervals between doses without compromising efficacy in fracture prevention or increasing the incidence of side effects. 

Women prefer less frequent dosing

The first oral bisphosphonate administered at monthly intervals, ibandronate, was launched in the in March 2005 as Boniva and six months later in as Bonviva.  The drug, co-marketed by Roche and GlaxoSmithKline, involves a single monthly dose of 150mg.  It has proved more popular than alendronate (Fosamax) with patients according to Roche/GSK-sponsored research (3,4). The BALTO II study randomised over 300 patients to receive treatment first with monthly therapy for three months, then crossing over to a weekly therapy for 12 weeks or vice versa (4).   Over 90 per cent of women expressed a preference for one or other treatment and, of these, a highly significant 70 per cent opted for monthly therapy.  Women said it fitted better with their lifestyle.  Interestingly, the same proportion of each group, 17 per cent, experienced a treatment-related adverse event. (4)


Women may prefer a monthly therapy but critics were concerned the long interval between doses would be less effective than daily therapy in reducing bone resorption and improving bone mineral density (BMD).  These concerns have now been addressed by two-year data from another Roche/GSK-sponsored investigation, the (Monthly Oral Ibandronate in Ladies) study involving 1609 postmenopausal women receiving ibandronate either as 2.5mg daily or as a monthly dose of either 100mg or 150mg (5).  The data were presented recently in at the 33rd European Symposium on Calcified Tissues (ECTS).

Effects of monthly treatment on BMD and bone turnover

At two years, substantial increases in lumbar spine BMD were seen in all treatment arms but were significantly greater in patients receiving 150mg monthly (5).  At the hip, BMD was again substantially increased in each treatment arm but gains in the monthly-dosing arms were significantly greater at all hip sites (total hip, femoral neck and trochanter) (5).  Data published in 2004 has previously shown intermittently-administered ibandronate achieved a highly significant three-year vertebral fracture risk reduction of 50 per cent (6).

BMD increases over the two years studied in were accompanied by clinically meaningful decreases in serum CTX , a marker of bone resorption predictive of hip fracture, say investigators (7).  At two years more than 80 per cent of patients in all treatment arms achieved decreases in sCTX of more than 30 per cent .  In all treatment arms, between 60 and 80 per cent of participants more than halved sCTX .  The greatest response was observed in the treatment arm receiving the highest monthly dose, 150mg.

Activation frequency, a direct tissue-level measure of surface-based bone remodelling activity, has proved similar in a study, also presented at ECTS in May 2006, involving US women receiving daily (2.5mg) or intermittent ibandronate ( 20mg every other day for 12 doses every 3 months  dosing interval more than two months.) (8) The levels were comparable to those seen in healthy premenopausal women but were significantly reduced in comparison to placebo among healthy and osteoporotic postmenopausal women (9).

Upper GI effects no worse than for daily therapy

“Another concern of monthly therapy was that the high dose necessary would adversely affect upper GI tolerability,” said Professor Claus Christiansen, Professor of Medicine at of and an investigator of the study. Two-year data from MOBILE, however, show tolerance to the once-monthly dose was similar to tolerance seen with the much smaller 2.5mg dose administered daily (10).  Between 19 and 25 per cent experienced upper GI problems across both treatment groups.  But the lowest incidence of adverse events in patients with a history of upper GI disorders was seen with monthly 150mg treatment  (27.1 per cent vs 45.2-48.9 per cent). In all subgroups, the lowest incidence of upper GI adverse events was consistently associated with the 150mg monthly dose (10).  “Women might get the same level of side effects with monthly as with daily therapy but with monthly treatment they get them a lot less often, ” Professor Christiansen commented.

What about fracture prevention?

Critics complain all the above are merely surrogate markers and do not answer the real question of efficacy as to whether or not monthly therapy compares to weekly or daily bisphosphonate treatments in preventing non-vertebral fractures.   “This is a very difficult question to answer,” remarked Professor Jan Stepan, Professor of Biochemistry and Medicine at .  Studies of new drugs in postmenopausal osteoporosis start with women who have just developed the disease who are in their 60s, he noted.  “Women are unlikely to experience a hip fracture until they are much older so no bisphosphonate has demonstrated a reduction in this younger age group.”  Furthermore hip fracture rates are not corrected for falls, he noted.  “You can’t design a study where patients experience the same conditions that might or might not cause them to fall and fracture.  Yet most hip fractures are the result of falls.”  With the increasing availability of medicines to treat osteoporosis, it would now be unethical to conduct a placebo-controlled trial in older women to demonstrate protection against the likelihood of hip fracture, he added.

Adherence in the real-world

Whatever the comparative efficacy of weekly and monthly bisphophonates in clinical trials, their effectiveness will depend on whether patients in real-world clinical practice take them as directed. 

Whether or not monthly ibandronate results in greater adherence in real-life clinical practice will probably be best judged from databases using pharmacy prescription dispensing data.  One UK open-label study, PERSIST, is comparing adherence among 1000 women randomised to either monthly ibandronate 150mg  or weekly alendronate 70mg (11).  Each woman receives a prescription at monthly intervals and takes it to a participating pharmacy to be filled.


Since alendronate would not normally be dispensed at monthly intervals, the study protocol contains a “fultility” analysis to assess whether patients receiving alendronate after four months compare to persistence rates demonstrated by DIN-LINK, a database collating medical information from approximately 100 general practices that provides real-life data on prescription refills.  If the adherence rates in the alendronate group had appeared higher than expected, according to DIN-LINK, the trial would be stopped because adherence in the clinical trial setting would obviously be exaggerated and unrepresentative of real-life.  Results suggest adherence to alendronate has not been exaggerated by the clinical trial which has therefore continued for its full six months.

Women receiving monthly ibandronate are offered the option of a patient support programme available to all monthly ibandronate users in the and some other countries.  This allows them to receive nurse support and reminders to take their medication by telephone.  Such a programme is not on offer to users of other bisphosphonates so it could be argued PERSIST will not provide a valid comparison of real-world adherence.  Dr Alun Cooper, the , UK-based GP with a special interest in osteoporosis who is leading PERSIST disagrees.  “In the real world of the , if you are prescribed ibandronate you also get access to the support programme.  And so far as I know, that level of support is going to be available for several years at least, if not indefinitely.”  If adherence to monthly ibandronate is greater than to weekly therapy, does it matter which aspect of the treatment is responsible for greater adherence so long as the end result is the effective prevention of osteoporotic fractures?


1.       Melton LJ et al.  J Bone Miner Res 1992; 7: 1005-1010.

2.       Cramer JA et al.  Curr Res Med Opin 2005; 21: 1453-60.

3.       Emkey R et al. Curr Res Med Opin 2005; 21: 1895-903.

4.       Benhamou C-L. Calcif Tiss Int 2006; 78 (suppl 1):S127-8 (abst)

5.       Reginster J-Y et al.  Ann Rheum Dis 2006; 65: 654-61.

6.       Chestnut CH et al.  J Bone Miner Res 2004; 19: 1241-9

7.       Lorenc R et al. Calcif Tiss Int 2006; 78 (suppl 1): S145 (abst)

8.       Recker R et al. J Bone Miner Res 2004; 19: 1628-33.

9.       Recker R et al. Calcif Tiss Int 2006; 78 (suppl 1):S155-6.

10.    Stone M et al. Calcif Tiss Int 2006; 78 (suppl 1): S160-1

11.   Cooper A et al. Calcif Tiss Int 2006; 78 (suppl 1):S131-2