Zoledronic acid is effective for osteoporosis at a single annual intravenous dose. It usually causes few adverse effects; the most common are related to acute phase reactions. We reported the case of a 64-year-old woman who presented flare-up of hand osteoarthritis after zoledronic acid infusions. Despite the fact that arthralgia is a common side effect of intravenous bisphosphonates, development of inflammatory signs in osteoarthritic joints is a rare event. We hypothesized that this side effect is caused by a release of cytokines secondary to activation of gamma-delta T lymphocytes.