Haloperidol for modelling osteoporosis in rats
Authors
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Roza Ju. Ilyina
Kazan State Medical Academy
https://orcid.org/0000-0001-8534-1282
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Liliya E. Ziganshina
Kazan State Medical University
https://orcid.org/0000-0003-1999-0705
DOI:
https://doi.org/10.18413/rrpharmacology.12.1272Abstract
Introduction: Various experimental models of osteoporosis are well-known and presented in the literature, yet we did not find a description in the available literature of the possibility of using antipsychotics to induce osteoporosis in rats. The aim of the study: We aimed to develop a “haloperidol model” of osteoporosis and to evaluate its efficiency in rats.
Materials and Methods: Wistar rats were divided into 2 groups (20 animals each): control (saline) and experimental (haloperidol). Haloperidol was administered intraperitoneally for 90 days according to the regimen from 15 mg/kg/day to 5 mg/kg/day as 1 mL per 100 mg of rat body weight of saline solutions in corresponding concentrations. We performed blood tests for total calcium, alkaline phosphatase, and urine tests for oxyproline to demonstrate that bone metabolism changes in rats were consistent with osteoporosis. After 90 days, we finalized the experiment and performed a histomorphometry assessment of the bone tissue of rats’ vertebrae (the average diameter of the spongy trabecula, the thickness of the cortical plate and the area of the intertrabecular space were evaluated) and microelement analysis (Ca, Sr, Zn, Cu).
Results: We found that haloperidol induced a decrease in the level of total calcium by 2.2 times and alkaline phosphatase by 1.6 times in the blood, an increase in oxyproline in the urine by 1.7 times; a reduction in the average diameter of trabeculae by 2.2 times and the thickness of the cortical layer by 2 times, an increase in the area of the intertrabecular space by 2 times; a deficiency in the content of Ca, Zn and Cu, and an increase in the content of Sr, as compared with such in the control group.
Conclusion: Prolonged administration of haloperidol to rats intraperitoneally for 90 days according to the regimen from 15 mg/kg/day to 5 mg/kg/day causes the bone metabolism changes with all characteristics of bone destruction, detected by biochemical, histomorphometry and microelement analyses of bone tissue and blood. Haloperidol could be used to model experimental osteoporosis and the “haloperidol model” could be used to study potential of new antiresorptive agents.
Graphical Abstract
Keywords:
antipsychotics, haloperidol, experimental osteoporosis, experimental ratsReferences
Al Jumaili W, Jain SB (2022) Atypical antipsychotic effect on bone mineral density. In: StatPearls, 6–10. https://www.ncbi.nlm.nih.gov/books/NBK572154/ [PubMed]
Andreassen OA, Jørgensen HA (1995) The rat model of tardive dyskinesia: relationship between vacuous chewing movements and gross motor activity during acute and long-term haloperidol treatment. Life Sciences 57(24): 2263– https://doi.org/10.1016/0024-3205(95)02219-9 [PubMed]
Berezancev AYu, Burygina LA, Levin ME (2020) Some current trends in the use of long-acting injectable antipsychotics in the context of the modernization of the psychiatric service.Korsakov Journal of Neurology and Psychiatry [Zhurnal Nevrologii i Psikhiatrii im. S.S. Korsakova] 120(6): 61–67. https://doi.org/10.17116/jnevro202012006261 [in Russian]
Blouin S, Libouban H, Moreau MF, Chappard D (2008) Orchidectomy models of osteoporosis.Methods in Molecular Biology 455: 125–134. https://doi.org/10.1007/978-1-59745-104-8_9[PubMed]
Bressan GN, Rodrigues T, da Silva ME, Schetinger MR, Scussel R, Machado-de-Ávila RA, Abel JDS, Fachinetto R (2024) Effects of acute haloperidol treatment on dopaminergic markers, GAD67, and A2A receptors in rats with high and low VCMs. Neurochemical Research 50(1): 4. https://doi.org/10.1007/s11064-024-04275-w [PubMed]
Bricker B, Sampson D, Ablordeppey SY (2014) Evaluation of the potential of antipsychotic agents to induce catalepsy in rats: Assessment of a new, commercially available, semi-automated instrument. Pharmacology Biochemistry and Behavior 120: 109– https://doi.org/10.1016/j.pbb.2014.02.013 [PubMed] [PMC]
Chen Y, Zhang Y, Fan K, Xu W, Teng C, Wang S, Tang W, Zhu X (2021) Association between gonadal hormones and osteoporosis in schizophrenia patients undergoing risperidone monotherapy: A cross-sectional study. PeerJ 9: e11332. https://doi.org/10.7717/peerj.11332 [PubMed] [PMC]
De Hert M, Detraux J, Stubbs B (2016) Relationship between antipsychotic medication, serum prolactin levels and osteoporosis/osteoporotic fractures in patients with schizophrenia: A critical literature review. Expert Opinion in Drug Safety 15(6): 809– https://doi.org/10.1517/14740338.2016.1167873 [PubMed]
Di Filippo L, Doga M, Resmini E, Giustina A (2020) Hyperprolactinemia and bone. Pituitary 23(3): 314–321. https://doi.org/10.1007/s11102-020-01041-3 [PubMed]
Drinkenburg WH, Keith AB, Sahgal A, Andrews JS (1999) Haloperidol-induced within-session response decrement patterns and catalepsy in rats: Behavioural dissociation. Behavioral Pharmacology 10(1): 105– https://doi.org/10.1097/00008877-199902000-00010[PubMed]
Food and Drug Administration (2005) Estimating the Safe Starting Dose in Clinical Trials for Therapeutics in Adult Healthy Volunteers. Guidance for industry. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/estimating-maximum-safe-starting-dose-initial-clinical-trials-therapeutics-adult-healthy-volunteers
Gala J, Díaz-Curiel M, de la Piedra C, Calero J (2001) Short- and long-term effects of calcium and exercise on bone mineral density in ovariectomized rats. British Journal of Nutrition 86(4): 521– https://doi.org/10.1079/bjn2001428 [PubMed]
Huang HH, Wang YC, Wu CL, Hong CJ, Bai YM, Tsai SJ, Liou YJ (2011) TNF-α -308 G. A polymorphism and weight gain in patients with schizophrenia under long-term clozapine, risperidone or olanzapine treatment. Neuroscience Letters 504(3): 277–280.https://doi.org/10.1016/j.neulet.2011.09.046 [PubMed]
Huo J, Ding Y, Wei X, Chen Q, Zhao B (2022) Antiosteoporosis and bone protective effect of nimbolide in steroid-induced osteoporosis rats. Journal of Biochemical and Molecular Toxicology 36(12): e23209. https://doi.org/10.1002/jbt.23209 [PubMed]
Ilyina RY, Ziganshina LE, Mukhamedzhanova LR (2024) Haloperidol-induced experimental osteoporosis and its correction by dimephosphone. Kazan Medical Journal [Kazanskij Medicinskij Zhurnal] 5: 718– https://doi.org/10.17816/KMJ633502 [in Russian]
Kudo S, Ishizaki T (1999) Pharmacokinetics of haloperidol: an update. Clinical Pharmacokinetics 37(6): 435–456. https://doi.org/10.2165/00003088-199937060-00001[PubMed]
Lin S, Huang J, Zheng L, Liu Y, Liu G, Li N, Wang K, Zou L, Wu T, Qin L, Cui L, Li G (2014)Glucocorticoid-induced osteoporosis in growing rats. Calcified Tissue International 95(4): 362– https://doi.org/10.1007/s00223-014-9899-7 [PubMed]
Lin X, Siafis S, Tian J, Wu H, Qin M, Correll CU, Schneider-Thoma J, Leucht S (2025)Antipsychotic-related prolactin changes: a systematic review and dose-response meta-analysis. CNS Drugs 39(10): 937–947. https://doi.org/10.1007/s40263-025-01218-z[PubMed]
Matsumoto C, Inada M, Toda K, Miyaura C (2006) Estrogen and androgen play distinct roles in bone turnover in male mice before and after reaching sexual maturity. Bone 38(2): 220–22 https://doi.org/10.1016/j.bone.2005.08.019 [PubMed]
McGrane I, Spina E, Hiemke C, de Leon J (2022) Pharmacokinetic drug interactions with oral haloperidol in adults: dose correction factors from a combined weighted analysis. Expert Opinionj on Drug Metabolism and Toxicology 18(2): 135–149. https://doi.org/10.1080/17425255.2022.2057297 [PubMed]
Miroshnichenko II, Bajmeeva NV, Platova II, Kaleda VG (2023) Therapeutic drug monitoring of antipsychotic drugs in routine psychiatric practice. Korsakov Journal of Neurology and Psychiatry 123(5): 145–152. https://doi.org/10.17116/jnevro2023123051145
Nikolić T, Petronijević M, Sopta J, Velimirović M, Stojković T, Jevtić Dožudić G, Aksić M, Radonjić NV, Petronijević N (2017) Haloperidol affects bones while clozapine alters metabolic parameters - sex specific effects in rats perinatally treated with phencyclidine. BMC Pharmacology and Toxicology 18(1): 65. https://doi.org/10.1186/s40360-017-0171-4. [PubMed] [PMC]
Sananta P, Dradjat RS, Irsan II, Yudistira A, Anwar ARD (2026) An animal model in rat for secondary osteoporosis: the effect of gonadotropin-releasing hormone (GnRH) agonists, low calcium diet, and immobilization on tartrate-resistant acid phosphatase 5b (TRACP-5b) and procollagen type 1 N-terminal propeptide (PINP) levels. Med Glas (Zenica) 23(1): 180– https://doi.org/10.17392/2081-23-01 [PubMed]
Shekunova EV, Kovaleva MA, Makarova MN, Makarov VG (2020) Nonclinical dose selection: interspecific dose transfer statements of the scientific center for expertise of medical products Regulatory Research and Medicine Evaluation [Regulyatornye Issledovaniya i Ekspertiza Lekarstvennykh Sredstv] 10(1): 19– https://doi.org/10.30895/1991-2919-2020-10-1-19-28 [in Russian]
Siafis S, Wu H, Wang D, Burschinski A, Nomura N, Takeuchi H, Schneider-Thoma J, Davis JM, Leucht S (2023) Antipsychotic dose, dopamine D2 receptor occupancy and extrapyramidal side-effects: a systematic review and dose-response meta-analysis. Molecular Psychiatry 28 (8): 3267–3277. https://doi.org/10.1038/s41380-023-02203-y [PubMed]
Teófilo JM, Azevedo AC, Petenusci SO, Mazaro R, Lamano-Carvalho TL (2003) Comparison between two experimental protocols to promote osteoporosis in the maxilla and proximal tibia of female rats. Pesquisa Odontológica Brasileira 17(4): 302–30 https://doi.org/10.1590/s1517-74912003000400002 [PubMed]
Ziganshina LE, Burnasheva ZA, Valeeva IH (2000) Comparative study of the efficacy of dimephosphone and xymedone in steroid osteoporosis in rats. Experimental and Clinical Pharmacology 63(6): 39–42. [in PubMed]
Ziganshina LE, Lepakhin VK, Petrov VI, Khabriev RU, (2011) Great Directory of Medicinal Products. Moscow, GEOTAR-Media, 574–576 pp. [in Russian]
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