Tolerability of Different Dosing Regimens of Bisphosphonates for the Treatment of Osteoporosis and Malignant Bone Disease

Abstract

Bisphosphonates are the primary pharmacological agents used for the management of osteoporosis and hypercalcaemia of malignant bone disease. The efficacy of these agents in these two conditions has been demonstrated in many well designed trials published over the past 2 decades. The variety of bisphosphonates currently available to us provides a wide range of tolerability and dosing profiles thus necessitating a thorough comparison of the most recent oral and intravenous bisphosphonates to differentiate the clinical context in which they should be used. Despite the fact that bisphosphonates are generally well accepted, their tolerability is dependent on complications which encompass gastrointestinal (GI) and renal toxicity. Other adverse events include osteonecrosis of the jaw, arthralgias, flu-like symptoms and uveitis. Studies have shown that various dosing regimens are able to modulate these rates of toxicity. To maximise tolerability, the direction of future therapy will likely fall into a pattern of decreasing the frequency of administration of bisphosphonates, whether it is oral or intravenous formulations, thus improving patient adherence. To review the literature on different dosing regimens of various bisphosphonates and their associated tolerability, we searched MEDLINE for articles from 1975 to 2006. Oral bisphosphonates, in particular alendronate and risedronate, have been systematically evaluated with regards to GI toxicity. Overall tolerability with these oral formulations has found GI toxicity to be the primary adverse event of interest. Both alendronate and risedronate have been found to have similar rates of GI toxicity when compared with placebo. Mounting evidence has developed validating the use of intravenous ibandronate and zoledronic acid for the purpose of treating hypercalcaemia secondary to malignancy. Unique to all other bisphosphonates, ibandronate also has an oral form which has a similar GI-toxicity profile to placebo. In addition, no significant differences in renal toxicity have been observed between those receiving intravenous ibandronate compared with placebo. Because of its potency and mode of administration, zoledronic acid has been widely accepted for the treatment of hypercalcaemia secondary to malignancy. However, a decrease in renal function, albeit rare, remains a significant complication of zoledronic acid; therefore, regular renal monitoring is recommended.

Cost Effectiveness of Denosumab Compared with Oral Bisphosphonates in the Treatment of Post-Menopausal Osteoporotic Women in Belgium

“…In addition, we have not included adverse effects with oral bisphosphonates. Although oral bisphosphonates are generally well tolerated, they are likely to be associated with upper gastrointestinal adverse events, [73] which may require additional costs.…”

Bisphosphonate-associated adverse events

“…9 Risedronate and ibandronate seem to have a GI tolerability similar to that of alendronate. 9,10 Current evidence, as presented above, should be reassuring to practitioners and patients in that the use of oral bisphosphonates for treatment of osteoporosis does not increase the likelihood of upper GI adverse events on condition that the patients adhere to the rules of correct dosing and mode of intake of these drugs. With regard to upper GI tract safety, women were excluded from participating in the FIT study 5 if they had had upper GI tract bleeding within the past five years requiring hospitalization or transfusion; documented recurrent or recent ulcer disease (two episodes in the preceding five years or one episode in the preceding 12 months); experienced esophageal or gastric varices; or used medication daily for dyspepsia.…”

Corrigendum: A systematic review and economic evaluation of bisphosphonates for the prevention of fragility fractures

“…Fourteen reviews summarising evidence for AEs across studies in bisphosphonates were identified. [112][113][114][115][116][117][118][119][120][121][122][123][124][125] A summary of these reviews and their findings is presented in Table 48, Appendix 5.…”

“…[112][113][114][115][116][117][118][119][120][121][122][123][124][125] One review considered any antresorptive therapy, 123 10 considered any bisphosphonate therapy 112,114,[117][118][119][120][121][122]124,125 and three reported on AEs associated with specific bisphosphonates (two in risedronic acid 113,115 and one in alendronic acid or risedronic acid 116 ). Four reviews included evidence from both observational studies and RCTs 112,116,117,125 and seven included only observational studies. [118][119][120][121][122][123][124] Five reviews reported on any AE, [112][113][114][115] whereas nine reported on specific AEs (four in jaw osteonecrosis, [117][118]…”

“…Four reviews included evidence from both observational studies and RCTs 112,116,117,125 and seven included only observational studies. [118][119][120][121][122][123][124] Five reviews reported on any AE, [112][113][114][115] whereas nine reported on specific AEs (four in jaw osteonecrosis, [117][118][119][120] two in atypical fracture, 121,122 two in oesophogeal cancer 123,124 and one in atrial fibrillation 125 ). Four reviews pooled data across studies in a meta-analysis.…”