Table 9Adverse Health Outcomes From Medication Studies

Adverse OutcomeEvidence (Risk Ratio; 95% CI; trials, n*)
WithdrawalsNo differences with placebo for alendronate162, etidronate163, risedronate,161 zoledronic acid,174, 175 and ibandronate168, 194, 195
Gastrointestinal events
  • Mild upper gastrointestinal events (acid reflux, esophageal irritation, nausea, vomiting, and heartburn) were associated with etidronate and pamidronate in meta-analyses of trials;187 however, several trials were conducted before current preventive dosing measures were widely practiced and may not be relevant. No associations with alendronate, ibandronate, risedronate, or zoledronic acid
  • Serious events including esophageal ulcerations have been reported for all bisphosphonates, although some trials predate preventive measures196 and another uses a noncomparable control group197
  • Esophageal adenocarcinoma was reported by the FDA in 54 cases of bisphosphonate users199
Atrial fibrillation
  • Data from the HORIZON trial of zoledronic acid,174 the FIT trial of alendronate,200 and a meta-analysis of risedronate trials190 suggest associations with severe atrial fibrillation
  • Observational studies of alendronate and etidronate reported conflicting results189, 191
  • A report from the FDA based on data from nearly 20,000 patients treated with bisphosphonates in placebo-controlled trials found no associations with atrial fibrillation192
Musculoskeletal symptoms
  • Zoledronic acid was associated with increased muscular and joint pain, arthritis, and muscle cramps (4.52; 3.48–5.43; 3 trials)187
  • Severe reversible musculoskeletal pain has been reported for all bisphosphonates
Osteonecrosis of the jawA report from the FDA described 151 case reports of osteonecrosis of the jaw through 2003.193 Of these, 139 occurred in cancer patients using high-dose intravenous pamidronate or zoledronic acid and 12 in patients using alendronate
Parathyroid Hormone
CancerNo association (0.49; 0.27–0.90; 3 trials)187
Mild gastrointestinal eventsNo association (1.39; 0.98–2.00; 2 trials)187
Acute coronary syndromeNo association (0.98; 0.07–13.7; 3 trials)187
CancerNo association187
Mild gastrointestinal eventsNo association (0.96; 0.63–1.48; 15 trials)187
Thromboembolic eventsIncreased (1.60; 1.15–2.23; 2 trials)156
Coronary heart diseaseNo association (0.95; 0.84–1.06; 2 trials)156
StrokeNo association (0.96; 0.67–1.38; 2 trials)156
Breast cancerReduced risk for invasive breast cancer in older women without preexisting cancer 0.44 (0.27–0.71; 2 trials)156
Endometrial cancerNo association (1.14; 0.65–1.98; 2 trials)156
OthersIncreased vasomotor symptoms and leg cramps156
Thromboembolic eventsIncreased with E+P (2.06; 1.57–2.70)212; results for E-alone were not statistically significant when all events were combined (1.32; 0.99–1.75),213 but were increased for DVT (1.47; 1.06–2.06) and PE (1.37; 1.12–4.40) when evaluated separately in the WHI213
Coronary heart diseaseIncreased with E+P (1.24; 1.00–1.54)208 but not with E-alone (0.95;0.79–1.16)211 in the WHI. Women starting E+P within 10 years from the onset of menopause had reduced risk compared with those starting later209
StrokeIncreased with E+P (1.31; 1.02–1.68)214 and E-alone (1.39; 1.10–1.77)158 in the WHI
Breast cancerIncreased with E+P (1.24; 1.01–1.54)207 but not with E-alone (0.80; 0.62–1.04)210 in the WHI
Endometrial cancerNo association with E+P (0.81; 0.48–1.36)215 in the WHI
OthersDecreased colon cancer with E+P (0.54; 0.36–00.82),235 but not E-alone (1.08; 0.75–1.55)158 in the WHI. Increased vaginal bleeding

Abbreviations: CI = confidence interval; DVT= deep vein thrombosis; E-alone = estrogen without concomitant use of progestin; E+P = estrogen and concomitant use of progestin; FDA = U. S. Food and Drug Administration; FIT = Fracture Intervention Trial; HORIZON = Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly trial; WHI = Women’s Health Initiative.


If meta-analysis.

Adjusted CI = 0.97–1.60.

Adjusted CI = 0.97–1.99.

From: 3, Results

Cover of Screening for Osteoporosis
Screening for Osteoporosis: Systematic Review to Update the 2002 U.S. Preventive Services Task Force Recommendation [Internet].
Evidence Syntheses, No. 77.
Nelson HD, Haney EM, Chou R, et al.

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.