Men's Osteoporosis Support Group

Fosamax and Actonel don't cause reflux or GERD

Shortly after Fosamax (alendronate) was approved by the FDA for treatment of osteoporosis case reports of esophageal adverse events started showing up in the literature. This has led to the widespread belief that the bisphosphonates, in general, and Fosamax and Actonel (risedronate), specifically, are gastric troublemakers. I've decided to research this topic to see if this reputation is warranted. I've not done an exhaustive investigation of the literature, but tried to find representative studies, including review articles.

Clinical trial results

Drug Saf. 2007;30(9):755-63. Safety considerations with bisphosphonates for the treatment of osteoporosis. Strampel W, Emkey R, Civitelli R. PMID: 17722968. This review article notes that, "UGI (upper gastrointestinal) AEs (adverse events), including severe events such as oesophageal ulcer, oesophagitis and erosive oesophagitis, have been reported at similar frequencies in placebo- and active-treatment arms." But they also note that after the bisphosphonates were approved and widely marketed, then gastric adverse events started being reported. This is explained as, "These studies show that a significant portion of patients are less compliant with administration instructions outside strict clinical trial supervision, and when oral bisphosphonates are not administered as directed, patients are more likely to experience UGI AEs." Thus, in a controlled environment, where people are closely observed and given exacting instructions, the active medication group and the placebo group had similar results. It is only when patients are not getting careful advice as to how to take the medications that problems occur.

Arch Intern Med. 2000 Feb 28;160(4):517-25. Upper gastrointestinal tract safety profile of alendronate: the fracture intervention trial. Bauer DC and others. PMID: 10695692. This study involved only postmenopausal women were were treated for two years with 5 mg Fosamax/day and then for about 1.8 years with 10 mg/day. They were interviewed quarterly to determine the occurrence of UGI AEs. There was no statistically significant difference between the active-ingredient group and placebo group regarding UGI AEs. What was noteworthy was that roughly 46% of women in both groups reported an incidence of UGI AEs. The incidence of more serious events such as perforations, ulcers, etc., was also similar in each group. The authors note, "In these older women, upper GI tract complaints, particularly dyspepsia and abdominal pain, were common, but alendronate treatment was not associated with an increased incidence of upper GI tract events, even in high-risk subgroups." So, almost 50% of women in this age group report GI tract events whether taking Fosamax once-daily or placebo.

Mayo Clin Proc. 2002 Oct;77(10):1044-52. Tolerability of once-weekly alendronate in patients with osteoporosis: a randomized, double-blind, placebo-controlled study. Greenspan S and others. PMID: 12374248. This three-month study involved 224 men and women who took 70 mg Fosamax once a week and were compared to 226 who took placebo. Its sole purpose was to evaluate UGI tolerability of once-weekly Fosamax. Total adverse events were 11% and 13% in the Fosamax and placebo group, respectively, with 3% of Fosamax and 1% of placebo patients discontinuing therapy. The authors conclude: "In this 3-month study, the incidence of upper GI tract adverse events in patients treated with once-weekly alendronate, 70 mg, was comparable to that with placebo."

Curr Med Res Opin. 2004 Dec;20(12):2031-41. Response to therapy with once-weekly alendronate 70 mg compared to once-weekly risedronate 35 mg in the treatment of postmenopausal osteoporosis. Sebba AI and others. PMID: 15706659. This was a head-to-head trial comparing efficacy and tolerability of once-weekly 70 mg Fosamax and 35 mg Actonel in postmenopausal women. Evaluation included medication tolerability in a subgroup of women with a history of UGI disorders. They reported, "The tolerability profiles of the two medications were similar." Not mentioned here, but one of the initial "selling points" for Actonel was that it was purportedly superior to Fosamax in GI tolerability. This study did not show superiority for Actonel over Fosamax if both medications were taken in the once-weekly dosage.

Clin Ther. 2000 Dec;22(12):1433-42. Rechallenge of patients who had discontinued alendronate therapy because of upper gastrointestinal symptoms. Miller PD and others, PMID: 11192135. The authors note that a large percentage of patients in the active and placebo groups develop UGI symptoms, which is suggestive that this group of people who have osteoporosis are prone to gastric discomfort. This study involved rechallenge of 172 women in the group of people who had previously discontinued treatment with 10 mg/day Fosamax. The rechallenge was for 8 weeks with the same dose regimen. After rechallenge 16.7% in the placebo group and 14.8% in the Fosamax group discontinued treatment due to UGI AEs. The authors conclude: "The results of this study suggest that many UGI adverse experiences reported during therapy with alendronate may reflect a high background incidence of UGI complaints and an increased sensitivity to detection of such complaints, rather than a causal relationship to therapy."

Transit times of Actonel

Aliment Pharmacol Ther. 2001 Jan;15(1):115-21. Oesophageal transit, disintegration and gastric emptying of a film-coated risedronate placebo tablet in gastro-oesophageal reflux disease and normal control subjects. Perkins AC and others. PMID: 11136284. There are at least three other similar studies by Perkins and others. Go to PubMed and type in "Perkins AC film-coated" without the quotes to see them. This study was designed to compare esophageal transit, disintegration and gastric emptying of the film-coated Actonel tablet in placebo form in subjects with or without gastro-esophageal reflux disease (GERD). They found the film-coated tablet transited the esophagus, disintegrated, and emptied from the stomach rapidly in both groups. They concluded: "The oval shape and film-coating on the commercial risedronate tablet promotes rapid oesophageal transit and minimizes oesophageal contact, even in the high-risk GERD population." To sum up the findings in the various studies on this topic: 1) There is no significant difference between GERD and non-GERD subjects when the film-coated Actonel tablet is used. 2) There is no significant difference in transit time of the film-coated tablets if 50 mL or 120 mL of water are used when swallowing the pills in kyphotic subjects. 3) A round, flat non-coated tablet was found to be inferior to the film-coated oval tablet, was much slower to transiting the esophagus, took greater than 20 seconds often, and remained in the esophagus for 10 minutes in three subjects. 4) The oval film-coated tablet had a mean transit time in the esophagus of 3.3 seconds compared to 23.8 seconds for a gelatin capsule. In summary, these studies show that the oval film-coated tablet has superior properties when considering a pill that needs to transit the esophagus quickly and dissolve readily in the stomach with a fairly short and complete exit time from there.

According to the package insert, Fosamax is not film-coated, but may be wax-coated. The 35 and 70 mg tablets are oval-shaped which appears to positively influence esophageal transit time. I could find no studies for Fosamax similar to those above with Actonel regarding transit times, dissolution, etc.. There is some literature indicating that generic brands of alendronate may be susceptible to breakage in the esophagus, so further investigation of this is warranted if you are considering switching to a generic brand. I find the 70 or 35 mg oval Fosamax tablet to be quite smooth and presumably would transit the esophagus in similar times as indicated in 4) above, which is certainly insufficient time to lodge in or disintegrate in the esophagus.

Alendronate esophageal injury studies

Mod Pathol. 1999 Dec;12(12):1152-7. Alendronate-associated esophageal injury: pathologic and endoscopic features. Abraham SC and others. PMID: 10619269. This study reports on ten patients with erosive or ulcerative esophagitis after ingesting 5 mg/day Fosamax. They described the histology of the inflamed tissues, with the significant finding that 6/10 patients had crystalline material present in the biopsy specimen which the investigators classified as remnants of the Fosamax pills. Re-biopsy was done in four patients. Two who had stopped taking Fosamax were healed and two who continued on the medication still had esophageal ulcers. The most common symptom was dysphagia which was reported in 7/10 patients. The authors state the source of irritation is probably multifactorial, with one cause being physical contact of the esophagus by the pill which causes "pill esophagitis" which means esophageal inflammation caused by a pill. Additionally they noted, "A second mechanism that may lead to even more severe injury by alendronate occurs when the tablet is dissolved and the medication is exposed to the esophageal mucosa in an acidic environment. Alendronate exists as a monosodium salt at pH more than 3.5; however, at pH less than 2 it is primarily in a free acid form that is more irritating to the mucosa. This suggests a specific toxicity from the medication itself, related to reflux of acidic gastric fluid containing dissolved alendronate in patients who do not remain upright for the required period of time after ingestion of the tablet. This form of injury may play an important role in the patients in whom tablet material is not detected in the biopsy (40% of our series)." In summary, the injury to the esophagus comes from either pill contact, most likely due to ingesting inadequate water so that it lodges in the esophagus, or due to not remaining upright after taking the pill until eating as the directions state. Both of these are problems with patient compliance with stated instructions on how to take the pills.

Endoscopy. 2005 Aug;37(8):740-4. Pill-induced esophageal injury: endoscopic features and clinical outcomes. Abid S and others. PMID: 16032493. This is five-year study of patients who reported to a hospital with esophageal injury that was determined to come from pill esophagitis. Several pills can cause such problems, including anti-inflammatory medications, tetracycline, bisphosphonates and others. Of note is that only 9% of the patients in this group took Fosamax, which was presumably the 5 mg variety since the study period involved 1997 to 2003. The authors note the most common site was the middle third of the esophagus. This means the pill had to be taken with insufficient water which didn't flush it into the stomach which is able to handle it.

I searched PubMed for "alendronate esophagitis" restricted to the last three years and found no case reports or new articles other than the Abid and others study which was published in 2005 but the patients visited the hospital from 1997 to 2003. My interpretation of this is that alendronate-caused esophageal gastritis no longer occurs because most people are taking the once-weekly dosing. Even were a person to take the pill incorrectly and, for instance, lie back down or not drink enough water, the once-weekly dosing doesn't contact the esophagus long or often enough to allow serious damage to occur.

Editor's comments: Based upon my understanding of the literature cited above and other sources, I conclude the following:

1. Bisphosphonates such as Fosamax and Actonel do not and have never caused acid reflux or GERD.

2. The source of the reputation for bisphosphonates causing UGI AEs was the round 10 mg Fosamax tablet that was taken once-daily before once-weekly dosing was approved. The combination of this tablet taken day after day and people not following directions by either lying down or not flushing the pill down with adequate water caused the esophagitis. It is possible that pre-existing acid reflux or GERD magnified the problem, but were not caused by the pills. The lack of esophagitis case reports after daily Fosamax dosing went out of favor is circumstantial evidence for this statement.

3. Thus UGI AEs, if they occur, are not from taking a bisphosphonate if you are taking one of the bisphosphonates using a once-weekly or once-monthly regimen and following the directions carefully. You need to look for the true cause of the gastric symptoms you are having for they come from something else.

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