Safety and tolerability of zoledronic acid and other bisphosphonates in osteoporosis management

Luca Dalle Carbonare, Mirko Zanatta, Adriano Gasparetto, Maria Teresa Valenti, Luca Dalle Carbonare, Mirko Zanatta, Adriano Gasparetto, Maria Teresa Valenti

Abstract

Bisphosphonates (BPs) are widely used in the treatment of postmenopausal osteoporosis and other metabolic bone diseases. They bind strongly to bone matrix and reduce bone loss through inhibition of osteoclast activity. They are classified as nitrogen- and non-nitrogen-containing bisphosphonates (NBPs and NNBPs, respectively). The former inhibit farnesyl diphosphate synthase while the latter induce the production of toxic analogs of adenosine triphosphate. These mechanisms of action are associated with different antifracture efficacy, and NBPs show the most powerful action. Moreover, recent evidence indicates that NBPs can also stimulate osteoblast activity and differentiation. Several randomized control trials have demonstrated that NBPs significantly improve bone mineral density, suppress bone turnover, and reduce the incidence of both vertebral and nonvertebral fragility fractures. Although they are generally considered safe, some side effects are reported (esophagitis, acute phase reaction, hypocalcemia, uveitis), and compliance with therapy is often inadequate. In particular, gastrointestinal discomfort is frequent with the older daily oral administrations and is responsible for a high proportion of discontinuation. The most recent weekly and monthly formulations, and in particular the yearly infusion of zoledronate, significantly improve persistence with treatment, and optimize clinical, densitometric, and antifracture outcomes.

Keywords: bisphosphonates; osteoporosis; safety; tolerability; zoledronic acid.

Figures

Figure 1
Figure 1
Molecular structure of pyrophosphate and of the most common nitrogen-containing bisphosphonates.
Figure 2
Figure 2
Farnesyl pyrophosphate synthase enzyme inhibition potency (IC50) of nitrogen-containing bisphosphonates (inhibition of 50% of maximum enzyme activity). Note that zoledronic acid shows the higher affinity for the mineral matrix combined with the higher inhibition potency of farnesyl pyrophosphate synthase. Abbreviations: ALN, alendronate; IBN, ibandronate; RIS, risendronate; ZOL, zolendronic acid.
Figure 3
Figure 3
Reduction of new vertebral A) and femoral B) fractures after treatment with several common bisphosphonates.
Figure 4
Figure 4
Effects on bone density and turnover between zoledronate and risedronate in glucocorticoid-induced osteoporosis. Note that zoledronate induces a rapid and higher suppression of resorption markers with respect to risedronate. This can explain the higher increase of bone density with zoledronate in this particular setting.

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