Consequences of Inhibition of the Mevalonate Pathway by Bisphosphonates at the Cellular and Mitochondrial Levels

Nitrogen-containing bisphosphonates (N-BPs) are commonly used drugs in the treatment of bone diseases due to their potent inhibition of the mevalonate pathway, leading to disrupted protein prenylation and reduced osteoclast activity. Although N-BPs are effective in reducing bone resorption, increasing evidence indicates their side effects on various non-skeletal cells. At the cellular level, N-BPs may reduce viability, modulate inflammatory responses, trigger apoptosis, disrupt cytoskeletal organization and influence signaling and energy metabolism. N-BPs may also impair prenylation of proteins essential for mitochondrial dynamics and quality control, and may disrupt Ca2+ homeostasis. By inhibiting the mevalonate pathway, N-BPs may lead to the reduction of key components of the mitochondrial respiratory chain, such as coenzyme Q (CoQ) and a-heme. These effects can contribute to impaired mitochondrial respiratory function, increased oxidative stress and mitochondria-dependent apoptosis, effecting cellular energy metabolism and viability. These findings underscore the multifaceted impact of N-BPs beyond bone, emphasizing the importance of mitochondrial health and energy metabolism in understanding their broader biological effects and potential adverse outcomes.