Journal Facts

Journal
BoneKEy Knowledge Environment
ISSN
1533-4368
Volume
Year
2002

Article Facts

Title
Yearly bisphosphonate infusions for the management of osteoporosis?
DOI
10.1138/2002035
Author

Online Date
04/08/2002

Article Links

BoneKEy-Osteovision | Commentary

Yearly bisphosphonate infusions for the management of osteoporosis?


DOI:10.1138/2002035

Bisphosphonates are widely used in the treatment of osteoporosis and daily oral alendronate and risedronate decrease the rate of bone turnover, increase BMD, and reduce the risk of vertebral and non-vertebral fractures including those of the hip (). Because of the inconvenience way of daily intake, alternative ways of bisphosphonate administration have been explored. On the basis of principles of bisphosphonate pharmacology and bone remodelling (), a weekly regimen providing a bisphosphonate dose equal to the total of seven daily doses was developed for alendronate and more recently for risedronate. These weekly regimens had the same efficacy as their respective daily regimens and a study with alendronate showed that weekly administration was preferred to the daily by a vast majority of osteoporotic patients (reported during the last ASBMR meeting).

Reid et al. recently reported fascinating results of a phase II clinical study with short (15 min) intravenous infusions of the very potent bisphosphonate zoledronate* in women with low bone mass (). Using total doses between 1 and 4 mg and dosing intervals between 3 months and 1 year they demonstrated significant reductions in the rate of bone turnover and increases in BMD. More importantly, the pattern of both the suppression of bone resorption and the increase in BMD were very similar to that obtained with orally administered bisphosphonates. The observation, in particular, that a single infusion of 4 mg zoledronate maintained the suppression of bone resorption for one year raises hopes for the development of a simplified, easy to comply with, annual bisphosphonate regimen for the management of osteoporosis.

There have been previous attempts to give bisphosphonates parenterally at infrequent intervals to increase adherence to treatment and avoid the gastrointestinal toxicity that may accompany the daily oral use. These include intravenous infusions of pamidronate 30 mg or alendronate 10 mg and intravenous injections of ibandronate up to 2 mg every 3 months (). These regimens generally decreased the rate of bone resorption and increased BMD to levels similar to those achieved by daily oral bisphosphonate — leading, in some cases, to off label use of intravenous bisphosphonates in the management of osteoporotic patients. However, the first placebo-controlled study with intravenous bisphosphonate and fracture endpoints did not meet expectations. Intravenous ibandronate injections, 0.5 or 1.0 mg every 3 months for 3 years, induced a moderate increase in BMD and a small but not significant decrease in the incidence of new osteoporotic fractures (reported at the World Congress of Osteoporosis but not yet published in a peer-reviewed Journal). These results demonstrated that doses and dosing intervals need to be assessed carefully before conclusions about the potential antifracture efficacy of intravenous bisphosphonate regimens are reached. This notion was supported by measurements of bone resorption markers that tended to return towards basal level by the time of the next ibandronate injection a pattern of response thus different from that obtained with oral or weekly bisphosphonate therapy. In contrast, the 12-month study of Reid et al. () showed that such responses may be possible even with a single short infusion of zoledronate.

Apart from the justified excitement, the zoledronate study also raises a number of questions. In-depth discussion of pharmacokinetic/pharmacodynamic issues related to continuous and intermittent bisphosphonate therapies lies beyond the scope of this short commentary but I will highlight a couple of issues that, in my view, require further consideration. Firstly, the responses of all outcomes of the Reid study (bone turnover, BMD, histology) did not differ among doses and regimens. Thus, the least effective dose (or interval) and consequently the appropriate regimen for phase III studies cannot be deduced from the results presented. Secondly, and perhaps more importantly, there is no information about the resolution of the effect of zoledronate, as has been the case with other bisphosphonates, and oral zoledronate has not been developed to allow pharmacodynamic comparisons. This is not the first time that responses to an annual infusion of bisphosphonate have been followed over a long period of time. Khan et al. () reported earlier that 30 mg alendronate infused over 4 consecutive days (equivalent roughly to 430 days of treatment with 10 mg oral alendronate daily) increased spine BMD by 5.3 % after one year but kept bone turnover suppressed for a longer period. It may, therefore, be that annual administration, as suggested in the publication, may not be the optimal choice of interval and may suppress further an already very low bone turnover (decrease in activation frequency by up to 84 % after one year) particularly with the 4 mg dose. The possible consequences of a forced further suppression of bone turnover (as opposed to the constant suppression with the low oral doses) for skeletal integrity, the clinical endpoint of any antiosteoporotic therapy, are currently unknown and need to be addressed in appropriately designed studies.

* In this commentary the term zoledronate rather than zoledronic acid has been used arbitrarily to be in line with the nomenclature of the other bisphosphonates. Furthermore, the chemical formula is not mentioned in the NEJM publication.

Creative Commons License This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 United States License.