Bisphosphonates: Mode of Action and Pharmacology

Abstract

The profound effects of the bisphosphonates on calcium metabolism were discovered over 30 years ago, and they are now well established as the major drugs used for the treatment of bone diseases associated with excessive resorption. Their principal uses are for Paget disease of bone, myeloma, bone metastases, and osteoporosis in adults, but there has been increasing and successful application in pediatric bone diseases, notably osteogenesis imperfecta. Bisphosphonates are structural analogues of inorganic pyrophosphate but are resistant to enzymatic and chemical breakdown. Bisphosphonates inhibit bone resorption by selective adsorption to mineral surfaces and subsequent internalization by bone-resorbing osteoclasts where they interfere with various biochemical processes. The simpler, non-nitrogen-containing bisphosphonates (eg, clodronate and etidronate) can be metabolically incorporated into nonhydrolysable analogues of adenosine triphosphate (ATP) that may inhibit ATP-dependent intracellular enzymes. In contrast, the more potent, nitrogen-containing bisphosphonates (eg, pamidronate, alendronate, risedronate, ibandronate, and zoledronate) inhibit a key enzyme, farnesyl pyrophosphate synthase, in the mevalonate pathway, thereby preventing the biosynthesis of isoprenoid compounds that are essential for the posttranslational modification of small guanosine triphosphate (GTP)-binding proteins (which are also GTPases) such as Rab, Rho, and Rac. The inhibition of protein prenylation and the disruption of the function of these key regulatory proteins explains the loss of osteoclast activity. The recently elucidated crystal structure of farnesyl diphosphate reveals how bisphosphonates bind to and inhibit at the active site via their critical nitrogen atoms. Although bisphosphonates are now established as an important class of drugs for the treatment of many bone diseases, there is new knowledge about how they work and the subtle but potentially important differences that exist between individual bisphosphonates. Understanding these may help to explain differences in potency, onset and duration of action, and clinical effectiveness.www.pediatrics.org/cgi

Zoledronic acid determines S-phase arrest but fails to induce apoptosis in cholangiocarcinoma cells

“…In the present study, we examined the commonly used biphosphonate molecule ZOL, because of its high biological activity in inducing inhibition of proliferation and apoptosis in several cancer cell lines [20]. We here reported that ZOL, the most potent nitrogen containing BP, causes The ability to form a colony from a single cell, may be seen as a surrogate of the invasive ability of the tumor cell [43].…”

“…The antiproliferative effect of pamidronate in human and rat osteosarcoma cells has recently been demonstrated in vitro [18,19]. BPs can be divided into two distinct pharmacological classes based on their molecular mechanisms of action [20]. Non-nitrogencontaining BPs, such as clodronate and etidronate, are metabolized intracellularly as cytotoxic analogues of ATP and thus inhibit osteoclast activity [21].…”

Cell therapy of a patient with type III <i>osteogenesis imperfecta</i> caused by mutation in <i>COL1A2</i> gene and unstable collagen type I

“…Conventional management for patients with OI consisted of supplementation with vitamin D and minerals, or administration of bisphosphonates [8,[12][13][14][15]. However, these methods did not ameliorate the symptoms of OI [12].…”

Impact of alendronate and VEGF-antisense combined treatment on highly VEGF-expressing A431 cells

“…BPs are widely used to inhibit osteoclastic activity in benign and malignant bone diseases, such as Paget's disease, osteoporosis or osteolytic tumor bone metastases [1][2][3]. The nitrogen containing-BPs (N-BPs) are more effective and are able to interfere with the metabolism of mevalonate, leading to inhibition of the prenylation of small GTP-binding proteins (Ras, Rho…) [4,5].…”