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FDA Drug Safety Communication: Ongoing safety review of oral osteoporosis drugs (bisphosphonates) and potential increased risk of esophageal cancer

 

Safety Announcement
Additional Information for Patients
Additional Information for Healthcare Professionals
Data Summary

 

Safety Announcement

[07-21-2011] The U.S. Food and Drug Administration (FDA) is continuing to review data from published studies to evaluate whether use of oral bisphosphonate drugs is associated with an increased risk of cancer of the esophagus (esophageal cancer). There have been conflicting findings from studies evaluating this risk.

 

Facts about oral bisphosphonates

  • Commonly used for the prevention and treatment of osteoporosis as well as to treat other bone diseases such as Paget's disease. Osteoporosis is a disease that makes bones weak and more likely to break.
  • Include: Fosamax (alendronate), Actonel (risedronate), Boniva (ibandronate), Atelvia (risedronate delayed release), Didronel (etidronate), and Skelid (tiludronate).
  • May cause irritation of the esophagus. Irritation of the esophagus can lead to esophagitis (inflammation) or esophageal ulcers (sores), which may bleed. The risk of these esophageal events is low when oral bisphosphonates are prescribed appropriately and the specific directions for use are followed by patients.

At this time, FDA believes that the benefits of oral bisphosphonate drugs in reducing the risk of serious fractures in people with osteoporosis continue to outweigh their potential risks.

FDA's review is ongoing and the Agency has not concluded that patients taking oral bisphosphonate drugs have an increased risk of esophageal cancer. It is also important to note that esophageal cancer is rare, especially in women.

The largest studies that FDA has reviewed, thus far, are two epidemiologic studies using one patient database (the U.K. General Practice Research Database or GPRD). One study found no increase in the risk of esophageal cancer.1 The second study found a doubling of the risk of esophageal cancer among patients who had 10 or more prescriptions of the drugs, or who had taken the drugs over 3 years.2 Other external researchers investigating this issue, using different patient databases, have reported no increase in risk, or a reduced risk.3 [See Data Summary for additional information on the studies]

Patients should talk with their healthcare professionals about the benefits and risks of taking oral bisphosphonates. Patients who take oral bisphosphonates should pay particular attention to the directions for use to minimize any potential adverse events.

FDA will continue to evaluate all available data supporting the safety and effectiveness of bisphosphonate drugs and will update the public when more information becomes available.

 

Additional Information for Patients

  • There is conflicting information on whether oral bisphosphonate drugs can affect your chance of developing esophageal cancer.
  • Directions for use of the oral bisphosphonate drug should be followed carefully. All oral bisphosphonate drugs, except Atelvia, should be taken first thing in the morning after awakening, with a full glass of plain water. Atelvia should be taken immediately following breakfast. Do not lie down or eat or drink anything for at least 30 to 60 minutes after taking any oral bisphosphonate drug.
  • Talk to your healthcare professional if you develop swallowing difficulties, chest pain, new or worsening heartburn, or have trouble or pain when you swallow. These may be signs of problems of the esophagus.
  • You should not take oral bisphosphonates if you have esophageal conditions that delay emptying of the esophagus, or if you cannot stand or sit upright for at least 30 to 60 minutes, or have low calcium levels in your blood.
  • Talk to your healthcare professional about the benefits and risks of taking oral bisphosphonates and how long you should expect to take them.
  • Discuss any questions or concerns about your oral bisphosphonate drug with your healthcare professional.
  • Report any side effects you experience to the FDA MedWatch program using the information in the "Contact Us" box at the bottom of the page.

 

Additional Information for Healthcare Professionals

  • FDA has not concluded that taking an oral bisphosphonate drug increases the risk of esophageal cancer and there are conflicting data on this risk.
  • There are insufficient data to recommend endoscopic screening of asymptomatic patients.
  • Esophagitis and other esophageal events have been reported, particularly in patients who do not follow the specific directions for use of oral bisphosphonates.
  • Instruct patients to carefully follow the directions for use of the oral bisphosphonate drug they are prescribed.
  • Report adverse events involving bisphosphonate drugs to the FDA MedWatch program, using the information in the "Contact Us" box at the bottom of the page.

 

Data Summary

In January 2009, a case series was published describing reports submitted to the FDA of esophageal cancer in patients prescribed oral bisphosphonates.4 Since then, several epidemiological studies looking at the association between oral bisphosphonates and esophageal cancer have been published, with discrepant findings. The two largest published studies used data from the U.K.'s General Practice Research Database (GPRD).

One study compared the rate of esophageal cancer in patients taking an oral bisphosphonate to patients not taking an oral bisphosphonate. This study found no increase in the risk of esophageal cancer.1 Using the same database, a second study found a doubling of the risk of esophageal cancer among patients who had 10 or more prescriptions of oral bisphosphonates, or who had taken the drugs over 3 years.2

Other investigators are researching this issue. In a large cohort of Danish patients with fractures, investigators found that bisphosphonate users (who had taken them for a median of 1.5 years) had a significantly reduced risk for esophageal cancer compared to patients with fractures who had not taken any bisphosphonate.3 Longer term follow-up of alendronate (Fosamax) users and non-alendronate users showed that alendronate users had a higher frequency of endoscopic examination of the esophagus, no greater incidence of esophageal cancer, and no increase in esophageal cancer deaths.5

Differences in methodologies in these studies may account for the discrepant findings. Also, since these studies are observational rather than randomized, they are subject to bias and confounding. For example, it is possible that the gastrointestinal side effects of bisphosphonates increase a patient's likelihood of undergoing an endoscopy, which could lead to earlier detection of a cancer or drug discontinuation. At this time, there is not enough information to make definitive conclusions about a possible association. FDA's safety review is ongoing. Additional studies conducted in different databases may be warranted.

 

References

  1. Cardwell CR, Abnet CC, Cantwell MM, Murray LJ. Exposure to oral bisphosphonates and risk of esophageal cancer. JAMA 2010;304:657-63.
  2. Green J, Czanner G, Reeves G, Watson J, Wise L, Beral V. Oral bisphosphonates and risk of cancer of the oesophagus, stomach, and colorectum: case-control analysis within a UK primary care cohort. BMJ 2010;341:doi:10.1136/bmj.c4444.
  3. Abrahamsen B, Eiken P, Eastell R. More on reports of esophageal cancer with oral bisphophonate use. N Engl J Med 2009; 360:1789.
  4. Wysowski DK. Reports of esophageal cancer with oral bisphosphonate use. N Engl J Med 2009;360:89-90.
  5. Abrahamsen B, et. al. The risk of oesophageal and cancer incidence and mortality in alendronate users: a national cohort study. 3rd Joint Meeting of the European Calcified Tissue Society and the International Bone and Mineral Society, May 2011.

 

 

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