The atypical anti-psychotic clozapine decreases bone mass in rats in vivo

Schizophr Res. 2011 Mar;126(1-3):291-7. doi: 10.1016/j.schres.2010.11.024. Epub 2010 Dec 23.


Background: Fracture risk is increased in patients with schizophrenia, who often receive long-term therapy with anti-psychotic drugs. The mechanisms by which skeletal fragility is increased in patients with psychosis include increased risk of falling, but direct skeletal toxicity of anti-psychotic drugs is a possibility that has not been investigated.

Methods: We examined the skeletal effects, in vivo and in vitro, of a typical anti-psychotic drug, haloperidol, which primarily inhibits dopaminergic signaling, and an atypical anti-psychotic drug, clozapine, which predominantly inhibits serotonergic signaling.

Results: In growing rats, 42 days of clozapine treatment reduced whole body bone mineral density by 15% (P<0.01 vs vehicle), and trabecular and cortical bone volume, as assessed by microcomputed tomography, by 29% and 15%, respectively (P<0.05 vs vehicle for each). Treatment with haloperidol did not affect bone density. Clozapine, but not haloperidol, transiently increased levels of serum corticosterone, and decreased levels of serum testosterone. In vitro, clozapine dose-dependently decreased osteoblast mitogenesis, osteoblast differentiation and osteoclastogenesis, while haloperidol did not affect any of these parameters.

Conclusions: These data demonstrate that clozapine, but not haloperidol, exerts adverse skeletal effects in rodents, and that this effect may be attributable to direct actions to reduce osteoblast growth and function. Long-term administration of clozapine may therefore negatively affect bone health, and clinical studies to investigate this possibility are warranted.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Absorptiometry, Photon / methods
  • Analysis of Variance
  • Animals
  • Antipsychotic Agents / pharmacology*
  • Bone Density / drug effects*
  • Bone Resorption / chemically induced
  • Bone and Bones / cytology
  • Bone and Bones / drug effects*
  • Cell Differentiation / drug effects
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Clozapine / pharmacology*
  • Haloperidol / pharmacology
  • Male
  • Osteoblasts / drug effects
  • Rats
  • Rats, Sprague-Dawley
  • Testosterone / blood
  • Thymidine / metabolism
  • Time Factors
  • Tritium / metabolism


  • Antipsychotic Agents
  • Tritium
  • Testosterone
  • Clozapine
  • Haloperidol
  • Thymidine