In general, there is a good safety profile for bisphosphonates. The most common tolerability issues have been upper gastrointestinal symptoms, influenza-like illnesses, and rarely, ONJ and uveitis. Atrial fibrillation has been reported both with zolendronic acid and alendronate, but not with risedronate to date.
Taggart and colleagues pooled nine multicenter, randomized placebo controlled studies of risedronate to review the frequency of upper GI events with risedronate. Sixty percent of patients had a history of GI tract disease, 38.7% had active GI tract disease, and 20.5% used antisecretory drugs during the studies. Sixty-three percent used aspirin and/or nonsteroidal anti-inflammatory drugs during the studies. Upper GI adverse events were reported by 29.6% of patients in the placebo arm compared with 29.8% in the risedronate arm. In addition, endoscopy performed in 349 patients demonstrated no significant difference among the two treatment groups.38
Harris and colleagues did a study comparing daily and weekly risedronate and similar prevalence of gastrointestinal adverse events among treatment groups.39
Osteonecrosis of the jaw is defined as the presence of nonhealing exposed bone in the maxillofacial region which has not healed within eight weeks and in whom there was no history of radiation therapy to the area. Only the maxilla and mandible appear to be susceptible. Pazianis and colleagues performed a literature review to help further clarify the connection between bisphosphonate use and risk of ONJ. Of the eleven publications reported in the review only 26 cases of ONJ were reported.40
Etminam and colleagues studied a cohort of 87,837 elderly cardiovascular patients who were each on an oral bisphosphonate. The adjusted RR for ONJ among all bisphosphonate users was 2.87 (95% CI 1.71–5.05). The adjusted RR for alendronate, etidronate, and risedronate were 2.87 (95% CI 1.46–5.67), 2.43 (95% CI 1.05–5.62), and 3.34 (95% CI 1.04–10.67). Of interest, is that there were no significant differences in RR of ONJ among current users (recent drug exposure within 90 days) and past users (drug exposure between 91–365 days before diagnosis).41
Marx and colleagues in the Journal of Oral and Maxillofacial Surgery
compared details from 30 consecutive cases of ONJ from oral bisphosphonates with 116 cases from intravenous bisphosphonates. In both groups, 50% occurred spontaneously and 50% resulted from an oral surgical procedure, mostly tooth removals. There was a direct exponential relation between the size of the exposed bone and the duration of oral bisphosphonate use. Notably, oral bisphosphonate-induced osteonecrosis was less frequent, less severe, and more responsive to treatment than intravenous-induced osteonecrosis.42
According to the American Society for Bone and Mineral Research Task Force on Bisphosphonate-Associated ONJ43
and the American Dental Association Council on Scientific Affairs,44
actions that may reduce the risk of ONJ in patients about to begin or are currently using bisphosphonates include maintenance of good oral hygiene and regular dental care.
Renal side effects have also been studied, given that bisphosphonates are cleared by the kidney. Miller and colleagues pooled results from nine clinical trials, revealing no significant differences in incidences of renal toxicity between daily risedronate and placebo with baseline renal function being the same between the two groups. Risedronate was found to have no effect on specific renal function or general adverse events across mild, moderate, and severe age-related renal dysfunction.43
Case reports of uveitis and scleritis have been reported with bisphophonates, mostly alendronate. The ocular events occurred rapidly after treatment and resolved upon cessation.44
Finally, viral-like illness has been associated with all the bisphosphonates. These symptoms are generally self-limiting, lasting up to 2–3 days and do not recur with subsequent dosing.45