Abstract: Bisphosphonates are chemically and metabolically stable analogs of pyrophosphates and have become indispensable in the treatment of bone-related diseases such as osteoporosis and bone metastases. They potently inhibit osteoclast-mediated bone resorption, however, their clinical utility is limited by poor bioavailability. This limitation arises from their multiple negative charges, which restrict membrane permeability, as well as their strong affinity for calcium and magnesium ions, leading to the formation of insoluble complexes. Recently, the monoanionic pentafluorophosphate moiety (–PF5) has emerged as a powerful phosphate bioisostere that significantly enhances the drug-like properties of compounds and exhibits strong binding to phosphatases. In this work, we report the synthesis of pentafluorophosphate-analogs of bisphosphonates as isosters of natural pyrophosphates and investigate their physico-chemical characteristics and first biological interactions. A novel protocol for the pentafluorination of phosphonates was developed using the HF:pyridine complex (Olah´s reagent) as an efficient fluorinating system. A variety of phosphonate and bisphosphonate esters were smoothly converted into their corresponding PF5 analogs in a single step. Quenching with methoxy-trimethylsilane greatly simplified the work-up and facilitated the isolation of these charged, highly polar compounds. Infrared spectroscopic analysis revealed disruption of the bulk water network through specific fluorine-water interactions, producing dangling water peaks, while RP-HPLC analysis demonstrated a substantial increase in the hydrophobicity of the pentafluorinated derivatives. Modification of the clinically approved drug risedronate with the PF5 moiety enhanced its drug-like properties, and molecular modelling suggested potential interactions with farnesyl pyrophosphate synthase. However, enzyme assays have not yet provided conclusive evidence for such interactions, and further studies are required to elucidate the biological effects of pentafluorophosphato bisphosphonates and to identify their potential protein targets.