Bisphosphonate drugs have actions in the lung and inhibit the mevalonate pathway in alveolar macrophages.

Bisphosphonates drugs target the skeleton and are used globally for the treatment of common bone disorders. Nitrogen-containing bisphosphonates act by inhibiting the mevalonate pathway in bone-resorbing osteoclasts but, surprisingly, also appear to reduce the risk of death from pneumonia. We overturn the long-held belief that these drugs act only in the skeleton and show that a fluorescently labelled bisphosphonate is internalised by alveolar macrophages and large peritoneal macrophages in vivo. Furthermore, a single dose of a nitrogen-containing bisphosphonate (zoledronic acid) in mice was sufficient to inhibit the mevalonate pathway in tissue-resident macrophages, causing the build-up of a mevalonate metabolite and preventing protein prenylation. Importantly, one dose of bisphosphonate enhanced the immune response to bacterial endotoxin in the lung and increased the level of cytokines and chemokines in bronchoalveolar fluid. These studies suggest that bisphosphonates, as well as preventing bone loss, may boost immune responses to infection in the lung and provide a mechanistic basis to fully examine the potential of bisphosphonates to help combat respiratory infections that cause pneumonia

Mechanisms of action of bisphosphonates: similarities and differences and their potential influence on clinical efficacy.

UNLABELLED: Bisphosphonates (BPs) are well established as the leading drugs for the treatment of osteoporosis. There is new knowledge about how they work. The differences that exist among individual BPs in terms of mineral binding and biochemical actions may explain differences in their clinical behavior and effectiveness. INTRODUCTION: The classical pharmacological effects of bisphosphonates (BPs) appear to be the result of two key properties: their affinity for bone mineral and their inhibitory effects on osteoclasts. DISCUSSION: There is new information about both properties. Mineral binding affinities differ among the clinically used BPs and may influence their differential distribution within bone, their biological potency, and their duration of action. The antiresorptive effects of the nitrogen-containing BPs (including alendronate, risedronate, ibandronate, and zoledronate) appear to result from their inhibition of the enzyme farnesyl pyrophosphate synthase (FPPS) in osteoclasts. FPPS is a key enzyme in the mevalonate pathway, which generates isoprenoid lipids utilized for the post-translational modification of small GTP-binding proteins that are essential for osteoclast function. Effects on other cellular targets, such as osteocytes, may also be important. BPs share several common properties as a drug class. However, as with other families of drugs, there are obvious chemical, biochemical, and pharmacological differences among the individual BPs. Each BP has a unique profile that may help to explain potential clinical differences among them, in terms of their speed and duration of action, and effects on fracture reduction

Bisphosphonates: Mechanisms of Action

The bisphosphonates are a class of drugs used in various diseases of calcium metabolism. This chapter describes the history of the development, chemistry, biological actions, and molecular mechanisms of action of bisphosphonates. It also highlights the newer developments in the field of study of bisphosphonates. Great progress has been made over the past two decades in understanding the mechanism of action of the bisphosphonates. Bisphosphonates are widely used in the treatment of osteoporosis, Paget's disease, tumor-associated bone disease, with potential uses in several other skeletal conditions. Owing to their bone-binding characteristics, bisphosphonates target to the skeleton, where they primarily act by inhibiting osteoclastic bone resorption. Whether they directly affect other cell types such as osteoblasts, osteocytes, and tumor cells in vivo, is still a matter of debate. The simple bisphosphonates, clodronate, etidronate and tiludronate, are intracellularly metabolized to cytotoxic analogues of ATP, whereas 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. With emerging differences between bisphosphonates in bone affinity and enzyme inhibitory potency, it is becoming apparent that each bisphosphonate may have a unique pharmacological profile. Unraveling the exact molecular mechanisms underlying differences in efficacy and adverse effects may help to expand the utility of bisphosphonates and ensure their overall safe use in the treatment of a variety of bone diseases. © 2008 Elsevier Inc. All rights reserved