Bisphosphonates: Molecular Mechanisms of Action and Effects on Bone Cells, Monocytes and Macrophages

Abstract

Bisphosphonates are widely used in the treatment of diseases involving excessive bone resorption, such as osteoporosis, cancer-associated bone disease, and Paget's disease of bone. They target to the skeleton due to their calcium-chelating properties, where they primarily act by inhibiting osteoclast-mediated bone resorption. The simple bisphosphonates, clodronate, etidronate and tiludronate, are intracellularly metabolised to cytotoxic ATP analogues, while the more potent, nitrogen-containing bisphosphonates act by inhibiting the enzyme FPP synthase, thereby preventing the prenylation of small GTPases that are necessary for the normal function and survival of osteoclasts. In recent years, these concepts have been refined, with an increased understanding of the exact mode of inhibition of FPP synthase and the consequences of inhibiting this enzyme. Recent studies further suggest that the R2 side chain, as well as determining the potency for inhibiting the target enzyme FPP synthase, also influences bone mineral binding, which may influence distribution within bone and duration of action. While bisphosphonates primarily affect the function of resorbing osteoclasts, it is becoming increasingly clear that bisphosphonates may also target the osteocyte network and prevent osteocyte apoptosis, which could contribute to their anti-fracture effects. Furthermore, increasing evidence implicates monocytes and macrophages as direct targets of bisphosphonate action, which may explain the acute phase response and the anti-tumour activity in certain animal models. Bone mineral affinity is likely to influence the extent of any such effects of these agents on non-osteoclast cells. While alternative anti-resorptive therapeutics are becoming available for clinical use, bisphosphonates currently remain the principle drugs used to treat excessive bone resorption.

Role of IL-1 receptor-associated kinase-M (IRAK-M) in priming of immune and inflammatory responses by nitrogen bisphosphonates

“…During this time, the intracellular level of IRAK-M, an inhibitor of TLR and IL-1 signaling, decreases progressively. The NBPs are established inhibitors of the mevalonate biosynthetic pathway, which controls the formation of FPP, and the prenylation of multiple proteins (1). Inhibition of prenylation most likely is required for the immune stimulatory effects of NBPs, as the addition of exogenous FPP to cultured mononuclear leukocytes abrogates the increase in cytokine production caused by NBP pretreatment.…”

“…Bisphosphonates bind to the bone surface, where they prevent osteoclast-mediated bone degradation through inhibition of the mevalonate pathway, which leads to altered protein prenylation (1). Several types of inflammatory reactions have been observed in patients treated with NBPs, including flu-like symptoms, esophageal irritation, and osteonecrosis of the jaw (2).…”

“…These side effects might be attributable to the immune-modulating effects of NBPs (3). Inhibition of the mevalonate pathway by NBPs causes isopentenyl-5-pyrophosphate accumulation in monocytes, augmenting γδ T-cell activation in vitro (4), but additional effects likely contribute to the in vivo inflammatory responses to NBPs (1). Pretreatment of mice with NBPs increases IL-1 production in response to bacterial LPS (5), a Toll-like receptor 4 (TLR4) ligand.…”

Treatment and pattern of bone metastases in 1094 patients with advanced breast cancer – Results from the prospective German Tumour Registry Breast Cancer cohort study

“…The main types of bone-targeted agents are bisphosphonates and the RANK-ligand (RANKL) inhibitor denosumab. Bisphosphonates induce apoptosis of osteoclasts and thus inhibit bone resorption [15] and reduce the skeletal morbidity rate [16]. The synthetic antibody denosumab specifically inhibits the maturation of osteoclasts and was shown to be superior to zoledronic acid in reducing skeletal-related events (SREs) such as surgery or radiotherapy to the bone, pathological fracture, spinal cord compression or hypercalcaemia [17].…”

2-Alkylaminoethyl-1,1-Bisphosphonic Acids Are Potent Inhibitors of the Enzymatic Activity of Trypanosoma cruzi Squalene Synthase

“…Substitution at the bridge has produced a large number of compounds (27). Bisphosphonates such as pamidronate (compound 6), alendronate (compound 7), risedronate (compound 8), and ibandronate (compound 9) are in clinical use for the treatment of different bone disorders (Fig.…”