The relationship between the chemistry and biological activity of the bisphosphonates

Pyrophosphate: a key inhibitor of mineralisation

“…Like pyrophosphate, BPs bind strongly to bone mineral and inhibit the formation and propagation of hydroxyapatite crystals [107]. The binding affinity of the different BPs for hydroxyapatite, and hence their uptake and persistence, is influenced by their R1 and R2 groups [104,108] (Figure 1). Despite the similarities, there are some critical differences between pyrophosphate and BPs.…”

Potent Triazole Bisphosphonate Inhibitor of Geranylgeranyl Diphosphate Synthase

“…1 One prominent therapeutic objective has been inhibition of the enzyme farnesyl diphosphate synthase (FDPS), which is addressed by the nitrogenous bisphosphonates that are used for treatment of osteoporosis and other diseases of the bone including zoledronate (1, Figure 1), risedronate (2), and pamidronate (3). These compounds all lead to reduced levels of the C 15 isoprenoid farnesyl diphosphate (FPP), 2 but there is increasing evidence that the effect of these drugs may be expressed through their impact on cellular levels of the downstream C 20 isoprenoid geranylgeranyl diphosphate (GGDP). 3 This C 20 isoprenoid is produced from FPP and isopentenyl diphosphate by the enzyme geranylgeranyl diphosphate synthase (GGDPS), and among other functions, it is used as a substrate for the geranylgeranyl transferases that mediate protein geranylgeranylation.…”

Low concentrations of zoledronic acid are better at regulating bone formation and repair

“…However, there is no experimental evidence that BPs can reduce the number of mature OCs (23). Nitrogen-containing BPs can act by inhibiting the mevalonate pathway and nitrogen-free BPs can act by interfering with the process of energy conversion inside a cell (24,25).…”