Bisphosphonates: molecular mechanisms of action and effects on bone cells, monocytes and macrophages

Curr Pharm Des. 2010;16(27):2950-60. doi: 10.2174/138161210793563635.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Bone Density Conservation Agents / metabolism
  • Bone Density Conservation Agents / pharmacokinetics
  • Bone Density Conservation Agents / pharmacology*
  • Bone Density Conservation Agents / therapeutic use
  • Bone Resorption / drug therapy
  • Bone and Bones / drug effects*
  • Bone and Bones / metabolism
  • Calcium / metabolism
  • Chelating Agents / metabolism
  • Chelating Agents / pharmacokinetics
  • Chelating Agents / pharmacology
  • Chelating Agents / therapeutic use
  • Diphosphonates / metabolism
  • Diphosphonates / pharmacokinetics
  • Diphosphonates / pharmacology*
  • Diphosphonates / therapeutic use
  • Drug Design*
  • Humans
  • Macrophages / drug effects*
  • Macrophages / metabolism
  • Monocytes / drug effects*
  • Monocytes / metabolism
  • Organ Specificity
  • Tissue Distribution


  • Bone Density Conservation Agents
  • Chelating Agents
  • Diphosphonates
  • Calcium