Improving measurements of persistence on Actonel treatment
J Clin Endocrinol Metab. 207 Apr;92(4):1296-304. Effect of monitoring bone turnover markers on persistence with risedronate treatment of postmenopausal osteoporosis. Delmas and others. PMID: 17244788. Definitions: Persistence is the time in days from the date of the first dose of risedronate until discontinuation of treatment as assessed by electronic monitoring. Compliance is the percentage of drug taken since first intake until discontinuation. Adherence is the average daily percentage of patients who were both persistent (continued risedronate treatment) and compliant (took drug properly on that particular day). Persistence and compliance when taking osteoporosis medications are very important. I've alluded to several studies which show that compliance for those needing to take osteoporosis medications can be extremely poor, possibly resulting in increased risk of fracture for those individuals. This one-year study's goal was to see if physicians could reinforce the need to persist taking Actonel (risedronate) during the study. The reinforcement tool was each patient's response in bone turnover markers (BTMs) using urinary N-terminal cross-linking telopeptide of type I collagen (uNTX) as the measured marker of bone turnover. See a previous Update on this site for more information on biochemical markers of bone turnover. The physicians applied reinforcement (RE+) to the test group of women at the 13 and 25 week periods, while providing no reinforcement to the control group of women. The patient's own BTM results were used as the reinforcement tool. Three categories were established for BTM results: good (>30% decrease), stable (-30% to +30% change), poor (> 30% increase). Note that risedronate and other bisphosphonates function by decreasing the rate of bone remodeling and resorption. Thus a positive response to bisphosphonates would show a decrease in the NTX products in the urine. Participants were postmenopausal women aged 64-80 years from 171 osteoporosis centers in 21 countries. All 2382 women had a T-score of -2.5 or less or a T-score of -1.0 or less with low-trauma fracture who took 500 mg/day of calcium and 400 IU/day of vitamin D. Electronic drug monitors were used to measure persistence. This study involved women taking daily risedronate, not the weekly, monthly, quarterly or yearly regimens that are now available for some bisphosphonates. Results: Overall persistence was high in both groups: RE+=80% and RE-=77%. If patients had a good BTM response and were reinforced with that information, they had a statistically significant improvement in persistence compared to RE- patients who had no reinforcement. If, however, reinforcement was based upon stable or lower BTM scores, persistence was unchanged or lower, respectively. Also note that reinforcement was associated with a lower incidence of new vertebral fractures as determine by X-ray.
Editor's comments: This was a very complex and difficult study to assess, even with the full printed study to read. Thus please forgive me should I miss important points, or fail to correctly evaluate aspects of the study. I find the results somewhat opposite of what I would expect. That is, women who performed poorly on the BTM score, thus showing they weren't improving in spite of taking the medication, almost assuredly because they weren't complying properly, did worse. I would expect them to buck up and try to comply by taking their medications at the proper time each day in order to decrease their chance of fracture. The exact opposite happened in that they got worse in the degree to which they persisted in the study. Conversely you might think that women who got good BTM scores might slack off a bit and relax thinking they had some leeway in view of their good scores. How these results might apply when evaluating other studies. It would be helpful when looking at the results of other studies using bisphosphonates to see the correlation of bone density results as related to that patient's compliance with the drug regimen. Instead we see only a mean (average) score for all participants. As a person who takes my Fosamax (alendronate) once weekly like clockwork, I would like to know that, not only should I, e.g., expect an increased bone mineral density (BMD) equal to the mean of the study population, but perhaps well above that if that study found that people who were strict compliers indeed had better results. That is, have the authors break out the results in terms of compliance as well as just the mean result for all participants, not based upon compliance whatsoever. This could be a form of reinforcement that could then be used with all people taking that form of bisphosphonate: take your medication exactly as prescribed and you'll get better results than those who take it haphazardly--if indeed that is the study's finding. How individuals might use these results: If your care provider agrees, having a baseline uNTX and at least one follow up at perhaps 13 to 25 weeks, could be helpful to show that the medication and dosing regimen are working. Thus you would feel confident that waiting a full two years for a bone density test would be all right. If, however, you weren't responding according to the uNTX results, then you might want to consider another medication, different dosing method or get a bone density test in one year. Study limitations: The authors point out that participants were highly motivated, thus the high persistence rates were probably abnormal. Virtually no one currently takes a daily bisphosphonate medication, so it is unknown how much these results might apply to weekly or longer dosing periods. I could imagine even more problematic results in individuals who don't comply with proper dosing methods if they take once-weekly medications. For instance, if they fail to wait for 1/2-1 hour before eating, or take the bisphosphonate with meals, they will get almost no benefit. Whereas were they taking the medication daily, and sometimes taking it properly, then they might have more benefit than with the poor compliance on a once-weekly dose. The future: IV medications are becoming increasingly more available as reported in a recent Update. The once-quarterly dosing method with IV ibandronate, done in the doctor's office, virtually eliminates compliance issues, other than for those who simply refuse to go there for the medication. And there is a new medication approved for treatment of Paget's disease, but not yet for osteoporosis, that uses once-yearly 5-mg IV dosing. This is zoledronate (Reclast), which gives equal, or even more effective, results compared to shorter dosing methods as shown in a phase-III clinical trial. Bottom Line: Reinforcement via explaining BTM results to patients is beneficial by improving persistence in patients taking daily risedronate. BTM reinforcement results could be even more important in patients taking oral bisphosphonates at longer intervals.