A discussion of an email received
----- Original Message -----
From Name omitted To: _________ Sent: Friday, February 28, 2003 7:43 PM Subject: your final newsletter
Hi Jerry,
I came across your site, actually looking for a variety of information sources on strontium ranelate.
Having two generations of OP among both men and women in my (paternal) family, I enjoyed reading your newsletter. But I did find something that caused me a little concern. It deals with the dosing of bisphosphonates...allow me to explain.
I am not a man, and I have both primary OP (early menopausal) and secondary OP (hypercalciuria). Both OPs were tardy diagnoses, somewhat forgivable regarding the hypercalciuria, in that it is not easy to diagnose. Once the correct treatment was established (thiazides), I asked my endocrinologist to replace the calcitonin (Miacalcin) for risedronate (Actonel). By coincidence, around that time, I received from a doctor friend with upper GI disturbances, her 5mg Actonel which she could not tolerate. On my first day of taking it, I found a remarkable difference in physical (and mental) integrity which I had not had in a few years. Taking the daily dose produced a slight discomfort but only for the first two days or so. I have never taken Fosamax though I know of several women who have been unable to tolerate it.
My endocrinologist then put me onto the weekly dose of Actonel (30mg). The first dose was well tolerated; the second dose (2nd week) knocked me out cold. Perhaps it was caused by the renal difficulties (and there is a contraindication to the effect in the Actonel literature). Whatever the case, my endocrinologist suggested I not take the weekly dose - at least not until it is available in a time-release format. I'm back to the daily.
The bottom line is that the weekly dose may not be for everyone, so saying it is a passé mode of delivery is not the best way to put it. Just my humble opinion.
Otherwise, thanks for the info, and I hope this helps.
Kind regards,
Name omitted,
Thanks for the note. You've hit a bit of a "hot spot" with me, so I'll be glad to reply to your comments. Let me preface this by saying that I'm a firm believer in the scientific method and in the powers of logic and deductive reasoning. If someone can show me strong scientific research to back up an opinion or judgment, I love that and it definitely sways my viewpoint. In the absence of such research or a logical explanation, I'm forced to stick with my judgment. I'll discuss your email from several points. After some general review, I'll first discuss the scientific studies and how they relate to untoward reactions to two bisphosphonates, Fosamax and Actonel.
First my view of placebos in clinical trials. Placebos are given because they have ABSOLUTELY NO POTENTIAL to cause any kind of side effect. Thus, when you look at the results from a clinical trial and see such and such an untoward reaction in the placebo group, you know it wasn't caused by the placebo. You don't know for sure what caused it, but you know for certain it wasn't the placebo. If you see similar results in the placebo and test groups for that type of reaction, you realize that people in the study simply have that problem. It isn't caused by any medication, it is either there in people's minds, or is a physiological or pathological problem that they have in spite of the medications they are taking--NOT BECAUSE THEY TAKE THOSE MEDICATIONS.
Next my view on clinical trials to determine "scientific proof" of something. We will probably never be able to prove anything for certain, but good controlled double-blind randomized clinical trials are the best option we have. If you have a large group of participants and a high quality study, the results are quite dependable. If you have a small group, the chance of getting dependable results is not nearly as good. So, I depend upon large, controlled clinical trials to provide me with my evidence for a belief in something. I may also augment that belief with smaller studies if those studies corroborate the other evidence. That could be the effectiveness of a medication, its ability to cause side effects in people, or other results.
Now to look at some clinical trials to see what they found about the bisphosphonates and their side effects.
1. PMID: 12374248, by Greenspan S and others. With once-weekly Fosamax, gastric adverse events were similar in the test and placebo groups.
2. PMID: 11192135, a classic study showing that women who had stopped taking daily Fosamax due to gastric problems had virtually the same drop out rate compared to placebo when rechallenged by Fosamax. Understanding the results of this article is critical. They mean it wasn't the Fosamax that caused them to withdraw, it was their feelings about Fosamax, or some underlying problem unrelated to Fosamax.
3. PMID: 11820707, this study showed a slightly smaller drop out percentage of women taking Actonel compared to those taking placebo when rechallenged to placebo or Risedronate after stopping Fosamax. Note the very similar percentages of problems in this study compared to study #2.
4. PMID: 10695693, another study with large numbers of women receiving Fosamax or placebo for three years. Note the remarkable similarity between all types of gastric adverse events in both groups. Note the author's conclusions.
5. PMID: 11808969, showing the placebo group had more gastric ulcers compared to 70 mg Fosamax once weekly for a 10-week period. No ulcers were found in the Fosamax group.
6. PMID 12374247, a review study showing little or no increase in the risk of upper GI tract problems. Essentially summarizing what the above studies found.
7. PMID: 11888030, an analysis of nine studies on Actonel showing no adverse GI events with the 5-mg daily dosing.
8. PMID: 12122976, a review study indicating that in clinical trials there was no difference found between Actonel and Fosamax as concerns gastric events.
9. PMID: 12412806, the two-year results after 70-mg/week of Fosamax showing no difference between placebo and test groups.
10. PMID: 11095236, an endoscopic study showing no difference between Fosamax and Actonel when taken at 40-mg/day and 30-mg/day, respectively, for one month. NOTE: This dose wasn't taken once-weekly, it was taken daily.
11. PMID: 10335722, a study on patients with Paget's disease given 30-mg/day of Actonel for two months with that dosage "well tolerated."
12. PMID: 10527181, large numbers of women taking 2.5- and/or 5-mg/day of Actonel for three years found the therapy was well tolerated with gastrointestinal safety similar to placebo.
13. PMID:10999794, a seven-year study of alendronate showing similar safety and tolerability between Fosamax and placebo.
Summary to this point: Actonel and Fosamax don't cause gastric problems in patients in clinical trials, however, women in these trials do have gastric problems as evidenced by similar complaints in the placebo and test groups. Note that the incidence of all types of problems in the study and placebo groups is also similar.
The next question is can bisphosphonate cause gastric problems?
1. PMID: 107100500, was a one-month study using endoscopic evaluation of the gastric mucosa that found no evidence of irritation from 10-mg/day Fosamax dosage.
2. PMID: 9260798, in a four-day study of 40-mg day of Fosamax found gastric mucosal injury similar to what aspirin caused.
3. PMID: 11069316, found gastric ulcers in two individuals after 10-mg day of Fosamax for 14 days, but no esophageal injury.
4. PMID: 9625122, found no difference between 5- or 10-mg day of Fosamax and placebo in gastric injury. Note that 15% of the women had gastric problems when screened before the trial was done. Does that percentage sound familiar?
5. PMID: 10215737, found 38% of people had mucosal damage after 10-mg day of Fosamax for 7 and 14 days.
6. PMID: 10982755, found lower incidence of mucosal injury with Actonel than Fosamax in a two-week endoscopic study.
7. PMID: 11095326, using endoscopy found no difference between Fosamax 40-mg day and Actonel 30-mg day and placebo after 28 days of treatment. Note this is the same group that found mucosal injury with Fosamax in #6 above at much lower doses and for half the time. Why?
8. PMID: 11808969, used the 70-mg/week Fosamax dose for 10 weeks and found no endoscopic lesions while two developed in the placebo group.
Summary of this segment. About half the studies using endoscopy found evidence of mucosal damage from Fosamax, why this didn't occur in other studies is uncertain. But, Fosamax appears capable of GI injury. In fact, Merck acknowledged this and puts the warning with the medication to take it with a full glass of water and to remain upright for at least one-half hour or until eating to prevent gastric problems. Thus, if the pill is taken incorrectly and allowed to remain in the esophagus rather than being washed into the stomach, it can definitely cause gastric distress and mucosal damage. If it is taken correctly, however, it doesn't cause injury or damage during controlled clinical trials.
Now to examine your statements in your email to me:
1. "I received from a doctor friend with upper GI disturbances, her 5mg Actonel which she could not tolerate." This is interesting since the clinical studies have shown no capability of Actonel in any dose or form to cause gastric intolerance. How could she have been having problems taking Actonel? How did she determine that Actonel caused her problems? What do you think would be minimal objective evidence for any of us to accept her conclusion on this topic? What do you think the effect of her statement will be on her patients who also take Fosamax or Actonel? Do you think there is some conditioned response in people if they are told to expect some effect from something they are doing? Do you suppose that could be the cause of 30% or more of women having problems taking Fosamax when they weren't in clinical trials? Yet, these same people who drop out of clinical trials due to gastric intolerance develop problems at the same rate as the placebo group when rechallenged with Fosamax. This says in no uncertain terms the problem isn't the medication, it is the person taking it. Whether it is mental or physical we don't know.
2. "On my first day of taking it, I found a remarkable difference in physical (and mental) integrity which I had not had in a few years." How could Actonel modify your mental or physical integrity? What is in it that could possibly do that? Since clinical trials showed no difference between placebo and Actonel in any category, how could this medication affect anything but your BMD and fracture risk? How did you determine that it was the Actonel and not some other variable that caused your new-found feelings? Is it not possible that thinking that you are finally getting your osteoporosis under control could have been a tremendous relief of mental stress and strain that led to this feeling? Do you think that people should report your results and tell others to expect it when they take Actonel? Or, should we use a more rigorous set of criteria to judge cause and effect from medications?
3. "The first dose was well tolerated; the second dose (2nd week) knocked me out cold." Do you literally mean you passed out? Are you saying that because you were taking Actonel, there could be nothing else that could have contributed to your being "knocked out cold?" You have never gotten an unexplained flu or simply been down and out for no apparent reason? There are absolutely no case reports or clinical studies showing any negatives concerning either Fosamax or Actonel in the once-weekly dosage. I'm trying to figure out how, in spite of that, you have had to stop the once-weekly Actonel.
4. "The bottom line is that the weekly dose may not be for everyone, so saying it is a passé mode of delivery is not the best way to put it." The clinical studies have been done which show: a) Once-weekly dosing is as effective as the daily dose. b) Once-weekly dosing is many times more convenient than daily dosing (at least six times more convenient for certain). c) Once-weekly dosing is just as safe as daily dosing in that no clinical trials have found any difference between either dosing method and placebo. Thus, I will have to stick to my guns on this one since there is nothing in the literature to give any reason to take the daily dose unless you want a more inconvenient way to take it.
In review of my statements at the beginning of this email, I will say that I am open to sound logic that proves me wrong. There are ways you could "prove" that the once-weekly dose of Actonel somehow caused problems that weren't caused by the daily dose. But, that would take a rigorous randomly generated sequence of taking active and placebo medications each week for a year or so with you able to tell me exactly when you were taking the placebo and the active form. The same would go for your physician as concerns her response to daily Actonel. But, what I am hearing from you is, "I took Actonel, I got this or that symptom, therefore Actonel caused it." That is the equivalent of me saying, "I was born in Colorado, I have gray hair, therefore being born in Colorado causes gray hair." I hope you would demand that I furnish more rigorous proof of my statement that Colorado birth causes gray hair, since this is fallacious deductive logic. I will ask the same of you and will gladly publish your findings upon receiving verifiable proof that once-weekly Actonel causes your problems. And, I would suggest your physician publish a case report so others will know of this side effect.
On one other issue in your email, I agree with you about the difficulty of diagnosing resorptive hypercalciuria. I trust that you had those tests while in the fasting state, since to not do so could furnish improper results as I've outlined a couple of times in my newsletters. That is, only while fasting is it known that the calcium comes from the bones rather than just from excessive absorption through the GI tract. I always bring this up since I received an improper test one time, so I know it can happen.
Thanks for the email and for the chance to respond to it. As you can see this is a topic that interests me. I hope my response will be helpful, as it is intended to be.
Regards,
Jerry Donnelly