@rwdlaw

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“ When amino-bisphosphonates (N-BPs) are administered IV, resulting in a high systemic exposure (unlike when taken orally, where the very low oral bioavailability results in a quite low systemic exposure), phagocytic cells other than just osteoclasts can encounter the N-BP, Up to 30% of patients can experience an APR (acute phase reaction) after their initial infusion of zoledronic acid. This APR, which starts usually about 6 hours post-infusion, and can last several days, consists of a mild fever associated with muscle and joint pains, similar to the symptoms with a bad viral infection such as the flu. And it turns out that the cause is very similar, as well. When a special category of phagocytic T-cells, called gamma-delta T-cells, encounter the zoledronic acid, they engulf it, just like an osteoclast will engulf alendronate or zoledronic bound to the bone surface. And just like an osteoclast that engulfs a N_BP undergoes apoptosis (programmed cell death), the gamma-delta T-cells that engulfs a N-BP also undergoes apoptosis. The difference is, when a gamma-delta T-cell undergoes apoptosis, it releases inflammatory cytokines, such as IL-1, IL-6, and TNF-alpha, just like when it encounters a flu virus. And these inflammatory cytokines mediate the temperature rise and myalgias, just as with a flu infection."