Mayo Clin Proc, October 2002, Vol 77 Editorial 1029

Mayo Clin Proc. 2002;77:1029-1030 1029 © 2002 Mayo Foundation for Medical Education and Research

Mayo ClinicProceedings

October 2002Volume 77Number 10

Editorial

Address reprint requests and correspondence to William J.Tremaine, MD, Division of Gastroenterology and Hepatology, MayoClinic, 200 First St SW, Rochester, MN 55905 (e-mail: tremaine.william@mayo.edu).

Bisphosphonates and the Upper Gastrointestinal Tract:Skeletal Gain Without Visceral Pain?

I n 1996, after a postmarketing surveillance study inwhich 51 of 470,000 patients who received alendronate

developed serious or severe esophageal adverse effects, thedose instructions for alendronate were revised to reduce thechance of esophageal injury.1,2 Today, both of the oralbisphosphonates available by prescription in the UnitedStates—alendronate and risedronate—have precautionsand warnings for physicians, pharmacists, and patients.These drugs must be swallowed with 6 to 8 ounces ofwater, the patient must not lie down for at least 30 minutesand not until after eating the first food of the day, and thetablets should not be chewed or sucked. With these preven-tive measures, far fewer reports of adverse esophagealevents have been reported, as noted by Cryer and Bauer3

in this issue of the Mayo Clinic Proceedings. Despitethis reduction in esophageal injury, upper gastrointestinaladverse events were reported in 11% to 47% of patientswho received an oral bisphosphonate in multiple studies,as noted by Cryer and Bauer3 and by Greenspan et al4 inthis issue of the Mayo Clinic Proceedings. The physician,pharmacist, and patient can take some reassurance fromthese current studies that show that the frequency and typesof upper gastrointestinal symptoms are no different com-pared with placebo when these medications are taken asprescribed.3,4

The physician should remember the ancient caveat forclinicians, Primum non nocere (First, do no harm), beforeinitiating a bisphosphonate in an asymptomatic patient whohas abnormal results on a bone density test. Bisphos-phonates have the potential to irritate the upper gastrointes-

tinal tract,4 and some previously asymptomatic patientswho take a bisphosphonate experience gastrointestinalsymptoms. Evidence-based data from clinical trials areinadequate to answer every clinical question, and for bis-phosphonates, lack of proof of harm to the upper gas-trointestinal tract is not proof of lack of harm.

See also pages 1031 and 1044.

Are the benefits of oral bisphosphonates worth the risksof adverse effects? Epidemiological studies show that os-teoporotic fractures are a major health problem. In theUnited States, the estimated lifetime risk of hip fracturesfor white women and men aged 50 years and older is 17%and 6%, respectively.5 In comparison, the probability ofwhite women and men aged 50 years or older developinginvasive breast or prostate cancer is 12.7% and 17.2%,respectively.6 As with cancer, osteoporosis has an addedrisk of mortality: 10% to 20% more women die than ex-pected for their age group within the first year after a hipfracture, and mortality is even higher in men.7 Addition-ally, osteoporotic fractures occur in people of other races,although less often, and the variation due to race is lessafter correction for differences in skeletal size.8,9 Finally,the use of bisphosphonates is likely to increase in post-menopausal women in light of the recently published re-sults of the Women’s Health Initiative study, which foundthat, although the combination of conjugated estrogens andmedroxyprogesterone reduced the risk of hip fracture andof colon cancer, this reduction was associated with anincrease in the risk of breast cancer, deep venous thrombo-sis, and cardiovascular events.10

Physicians must always weigh the potential for benefitagainst the potential risks when initiating a new therapy.The studies in this issue of the Mayo Clinic Proceedings

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

Editorial Mayo Clin Proc, October 2002, Vol 771030

show that bisphosphonates are safe for the gastrointestinaltract in patients viewed as a group, but physicians must bevigilant for the chance of adverse gastrointestinal effects inthe individual patient.

William J. Tremaine, MDDivision of Gastroenterology and Hepatology

and Internal Medicine

Sundeep Khosla, MDDivision of Endocrinology, Diabetes, Metabolism,

Nutrition, and Internal MedicineMayo ClinicRochester, Minn

1. de Groen PC, Lubbe DF, Hirsch LJ, et al. Esophagitis associatedwith the use of alendronate. N Engl J Med. 1996;335:1016-1021.

2. Fosamax (alendronate sodium tablets) [package insert]. WestPoint, Pa: Merck & Co, Inc; 1996.

3. Cryer B, Bauer DC. Oral bisphosphonates and upper gastrointesti-nal tract problems: what is the evidence? Mayo Clin Proc. 2002;77:1031-1043.

4. Greenspan S, Field-Munves E, Tonino R, et al. Tolerability ofonce-weekly alendronate in patients with osteoporosis: a random-ized, double-blind, placebo-controlled study. Mayo Clin Proc. 2002;77:1044-1052.

5. Melton LJ III. Who has osteoporosis? a conflict between clinicaland public health perspectives. J Bone Miner Res. 2000;15:2309-2314.

6. Feuer EJ, Wun LM. DEVCAN: Probability of Developing or Dyingof Cancer [computer program]. Version 4.1. Bethesda, Md: Na-tional Cancer Institute; 1999.

7. Melton LJ III, Cooper C. Magnitude and impact of osteoporosisand fractures. In: Marcus R, Feldman D, Kelsey J, eds. Osteoporo-sis. Vol 1. 2nd ed. San Diego, Calif: Academic Press; 2001:557-567.

8. Marquez MA, Melton LJ III, Muhs JM, et al. Bone density in animmigrant population from Southeast Asia. Osteoporos Int. 2001;12:595-604.

9. Melton LJ III, Marquez MA, Achenbach SJ, et al. Variations inbone density among persons of African heritage. Osteoporos Int.2002;13:551-559.

10. Women’s Health Initiative Investigators. Risks and benefits ofestrogen plus progestin in healthy postmenopausal women: princi-pal results from the Women’s Health Initiative randomized con-trolled trial. JAMA. 2002;288:321-333.

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.