The antipsychotics haloperidol and chlorpromazine increase bone metabolism and induce osteopenia in female rats.
The main objective of this study was to evaluate the effects of the antipsychotic drugs haloperidol (HAL) and chlorpromazine (CPZ) on bone mineral density (BMD) in female rats and to examine the relationship between the effects on bone and reproductive organs or hormone concentrations. Female rats were orally administered HAL (2 or 10 mg/kg) or CPZ (25 or 50 mg/kg) once daily (7 days/week) for 6 months resulting in a significant increase in prolactin. Hyperprolactinemia resulted in enlarged corpora lutea in the ovary, because prolactin has a luteotropic activity. Thus, atrophy in the uterus, epithelial mucification in the vagina and continuous diestrus stages were observed. These events in the reproductive organs induced a decrease in estradiol, elevation of biochemical markers of bone metabolism, significant reductions of BMD in trabecular bone of the femur and decreased trabecular bone in the femur. The bone loss is associated with an increase in bone resorption due to decreased estradiol derived from the luteotropic activity of prolactin. The mechanism of dopamine blockers to induce bone loss in female rats is considered to be rodent specific because the luteotropic effects of prolactin are confined primarily to rodents. Also, it appears that chronic hyperprolactinemia and maintained corpora lutea leading to bone loss are commonly inducible in female rats receiving long-term treatment with antipsychotic drugs possessing dopamine D2 receptor antagonist activity.
Kunimatsu
Takeshi
T
Safety Research Laboratories, Dainippon Sumitomo Pharma, Osaka, Japan. takeshi-kunimatsu@ds-pharma.co.jp
Kimura
Juki
J
Funabashi
Hitoshi
H
Inoue
Tadashi
T
Seki
Takaki
T
D000596:Amino Acids / Q000652:urine; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology / Q000633:toxicity*; D015519:Bone Density / Q000187:drug effects; D001851:Bone Diseases, Metabolic / Q000139:chemically induced* / Q000378:metabolism; D001842:Bone and Bones / Q000187:drug effects* / Q000378:metabolism; D002746:Chlorpromazine / Q000494:pharmacology / Q000633:toxicity*; D018492:Dopamine Antagonists / Q000494:pharmacology / Q000633:toxicity; D004958:Estradiol / Q000097:blood; D030762:Estrous Cycle / Q000187:drug effects; D005260:Female; D006220:Haloperidol / Q000494:pharmacology / Q000633:toxicity*; D006966:Hyperprolactinemia / Q000139:chemically induced; D015675:Osteocalcin / Q000097:blood; D011388:Prolactin / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley
D000596:Amino Acids; D014150:Antipsychotic Agents; D018492:Dopamine Antagonists; D015675:Osteocalcin; D004958:Estradiol; D011388:Prolactin; C036020:deoxypyridinoline; D006220:Haloperidol; D002746:Chlorpromazine