Haloperidol-induced experimental osteoporosis and its correction with dimephosphone

Abstract

BACKGROUND: There are reports of the negative impact of neuroleptics long-term use on bone metabolism. Dimephosphone is a drug with proven antirachitic effect.

AIM: To study under experimental conditions the effect of haloperidol on the microelement composition of the bone of experimental rats and the possibilities of its correction with dimephosphone.

MATERIAL AND METHODS: Wistar rats were divided into groups (10 animals in each): the first was the control group; the second group consisted of animals that were administered haloperidol; the third group used haloperidol with dimephosphone. Rats of the second and third groups were administered haloperidol intraperitoneally for 90 days, starting with 15 mg/day and reducing the dose to 5 mg/day. Rats of the third group were administered orally a 15% dimephosphone solution at a dose of 208 mg/kg/day. After the animals were withdrawn from the experiment, the lumbar vertebrae were dissected and the teeth were removed. The content of calcium, magnesium, strontium, zinc and copper ions in bone and teeth was determined by atomic absorption spectrophotometry. Statistical processing was performed using the SPSS 13.0 program.

RESULTS: Long-term use of therapeutic doses of haloperidol in the experiment caused a decrease in the content of calcium and zinc ions by 1.5 times, copper — by 1.7 times in the bones of animals, an increase in the concentration of strontium ions by 1.1 times, which indicated the resorptive effect of the neuroleptic. With the combined use of haloperidol and dimephosphone, the content of calcium ions (by 1.2 times), copper (by 1.4 times) and zinc ions (by 1.1 times) significantly increased; the amount of strontium ions decreased (by 1.1 times) only in bone tissue.

CONCLUSION: Dimephosphone reduces the negative effect of long-term haloperidol administration on the microelement composition of rat bones.

Keywords

haloperidol / osteoporosis / bone tissue / dimephosphone / microelements

References

[1] Tyler MW, Zaldivar-Diez J, Haggarty SJ. Classics in chemical neuroscience: Haloperidol. ACS Chem Neurosci. 2017;8(3):444–453. doi: 10.1021/acschemneuro.7b00018

[2] Tyler M.W., Zaldivar-Diez J., Haggarty S.J. Classics in chemical neuroscience: Haloperidol // ACS Chem Neurosci. 2017. Vol. 8, N. 3. P. 444–453. doi: 10.1021/acschemneuro.7b00018

[3] Oosthuizen PP, Emsley RA, Maritz JS, Turner JA, Keyter N. Incidence of tardive dyskinesia in first-episode psychosis patients treated with low-dose haloperidol. J Clin Psychiatry. 2003;64(9):1075–1080. doi: 10.4088/jcp.v64n0913

[4] Oosthuizen P.P., Emsley R.A., Maritz J.S., et al. Incidence of tardive dyskinesia in first-episode psychosis patients treated with low-dose haloperidol // J Clin Psychiatry. 2003. Vol. 64, N. 9. P. 1075–1080. doi: 10.4088/jcp.v64n0913

[5] Liu F, Wu Y, Chen J, Zou T, Qin Y, Teng Z, Su Y, Wu R, Huang J. Risk factors for osteoporosis in chronic schizophrenia on long-term treatment with antipsychotics: A cross-sectional study. BMC Psychiatry. 2023;23(1):454–461. doi: 10.1186/s12888-023-04951-1

[6] Liu F., Wu Y., Chen J., et al. Risk factors for osteoporosis in chronic schizophrenia on long-term treatment with antipsychotics: A cross-sectional study // BMC Psychiatry. 2023. Vol. 23, N. 1. P. 454–461. doi: 10.1186/s12888-023-04951-1

[7] De Hert M, Detraux J, Stubbs B. Relationship between antipsychotic medication, serum prolactin levels and osteoporosis/osteoporotic fractures in patients with schizophrenia: A critical literature review. Expert Opin Drug Saf. 2016;15(6):809–823. doi: 10.1517/14740338.2016.1167873

[8] De Hert M., Detraux J., Stubbs B. Relationship between antipsychotic medication, serum prolactin levels and osteoporosis/osteoporotic fractures in patients with schizophrenia: A critical literature review // Expert Opin Drug Saf. 2016. Vol. 15, N. 6. P. 809–823. doi: 10.1517/14740338.2016.1167873

[9] Kunimatsu T, Kimura J, Funabashi H, Inoue T, Seki T. The antipsychotics haloperidol and chlorpromazine increase bone metabolism and induce osteopenia in female rats. Regul Toxicol Pharmacol. 2010;58(3):360–368. doi: 10.1016/j.yrtph.2010.08.001

[10] Kunimatsu T., Kimura J., Funabashi H., et al. The antipsychotics haloperidol and chlorpromazine increase bone metabolism and induce osteopenia in female rats // Regul Toxicol Pharmacol. 2010. Vol. 58, N. 3. P. 360–368. doi: 10.1016/j.yrtph.2010.08.001

[11] Yokoyama S, Wakamoto S, Tanaka Y, Nakagawa C, Hosomi K, Takada M. Association between antipsychotics and osteoporosis based on real-world data. Ann Pharmacother. 2020;54(10):988–995. doi: 10.1177/1060028020913974

[12] Yokoyama S., Wakamoto S., Tanaka Y., et al. Association between antipsychotics and osteoporosis based on real-world data // Ann Pharmacother. 2020. Vol. 54, N. 10. P. 988–995. doi: 10.1177/1060028020913974

[13] Liang Y, Su YA, Zhao ZG, Gao N, Huang JZ, Tang MQ, Li KQ, Yang FD, Yu X, Si TM. Acute effects of haloperidol, amisulpride, and quetiapine on bone turnover markers in patients with schizophrenia. J Clin Psychopharmacol. 2015;35(5):583–586. doi: 10.1097/JCP.0000000000000379

[14] Liang Y., Su Y.A., Zhao Z.G., et al. Acute effects of haloperidol, amisulpride, and quetiapine on bone turnover markers in patients with schizophrenia // J Clin Psychopharmacol. 2015. Vol. 35, N. 5. P. 583–586. doi: 10.1097/JCP.0000000000000379

[15] Vizel' AO, Garaev RS. Novyi aspekt farmakologicheskogo podkhoda k soedineniyam fosfora. Dimefosfon. (New aspect of the pharmacological approach to phosphorus compounds. Dimephosphone.) Kazan: Pechat'-Servis-XXI vek; 2011. 189 р. (In Russ.)

[16] Визель А.О., Гараев Р.С. Новый аспект фармакологического подхода к соединениям фосфора. Димефосфон. Казань: Печать-Сервис-ХХI век, 2011. 189 с.

[17] Ziganshina LE, Lepahin VK, Petrov VI, Habriev RU, editors. Bol'shoi meditsinskii spravochnik. (Large reference book of drugs.) Moscow: GEOTAR-Media; 2011. 3344 р. (In Russ.) EDN: QLYWQP

[18] Большой справочник лекарственных средств / Под ред. Л.Е. Зиганшиной, В.К. Лепахина, В.И. Петрова, Р.У. Хабриева. М.: ГЭОТАР-Медиа, 2011. 3344 с. EDN: QLYWQP

[19] Ziganshina LE, Burnasheva ZA, Valeeva IH. Comparative study of the effectiveness of dimephosphone and xydiphone in steroid osteoporosis in rats. Experimental and clinical pharmacology. 2000;63(6):39–42. (In Russ.) EDN: NKDNDP

[20] Зиганшина Л.Е., Бурнашева З.А., Валеева И.Х. Сравнительное изучение эффективности димефосфона и ксидифона при стероидном остеопорозе у крыс // Экспериментальная и клиническая фармакология. 2000. Т. 63, № 6. С. 39–42. EDN: NKDNDP

[21] Ilyina RYu, Ziganshina LE. Mineral spectrum of the bone tissue of the centers of odontogenous infections at mentally sick patients treated by dimephosphon. Pacific medical journal. 2014;(3):25–28. (In Russ.) EDN: SYDRUH

[22] Ильина Р.Ю., Зиганшина Л.Е. Минеральный спектр костной ткани очагов одонтогенной инфекции у психически больных на фоне терапии димефосфоном // Тихоокеанский медицинский журнал. 2014. № 3. С. 25–28. EDN: SYDRUH

[23] Saghazadeh A, Mahmoudi M, Shahrokhi S, Mojarrad M, Dastmardi M, Mirbeyk M, Rezaei N. Trace elements in schizophrenia: A systematic review and meta-analysis of 39 studies (N|=| 5151 participants). Nutr Rev. 2020;78(4):278–303. doi: 10.1093/nutrit/nuz059

[24] Saghazadeh A., Mahmoudi M., Shahrokhi S., et al. Trace elements in schizophrenia: A systematic review and meta-analysis of 39 studies (N = 5151 participants) // Nutr Rev. 2020. Vol. 78, N. 4. P. 278–303. doi: 10.1093/nutrit/nuz059

[25] Chen X, Li Y, Zhang T, Yao Y, Shen C, Xue Y. Association of serum trace elements with schizophrenia and effects of antipsychotic treatment. Biol Trace Elem Res. 2018;181(1);22–30. doi: 10.1007/s12011-017-1039-6

[26] Chen X., Li Y., Zhang T., et al. Association of serum trace elements with schizophrenia and effects of antipsychotic treatment // Biol Trace Elem Res. 2018. Vol. 181, N. 1. P. 22–30. doi: 10.1007/s12011-017-1039-6

[27] Kołodziejska B, Stępień N, Kolmas J. The influence of strontium on bone tissue metabolism and its application in osteoporosis treatment. Int J Mol Sci. 2021;22(12):6564–6538. doi: 10.3390/ijms22126564

[28] Kołodziejska B., Stępień N., Kolmas J. The influence of strontium on bone tissue metabolism and its application in osteoporosis treatment // Int J Mol Sci. 2021. Vol. 22, N. 12. P. 6564–6538. doi: 10.3390/ijms22126564

[29] Anchikova LI, Valeeva IH, Studentsova IA. To the mechanism of the effect of domestic medication dimephosphone. Kazan Medical Journal. 2005;86(2):18–22. (In Russ.) EDN: HRTZQZ

[30] Анчикова Л.И., Валеева И.Х., Студенцова И.А. К механизму действия отечественного препарата димефосфона // Казанский медицинский журнал. 2005. Т. 86, № 2. С. 18–22. EDN: HRTZQZ

[31] Вelaya ZhE, Rozhinskaya LYa. Surrogate markers in assessment of bisphosphonate effectiveness in osteoporosis treatment (bone mineral density, bone turnover markers). Osteoporosis and Bone Diseases. 2023;26(4):20–25. (In Russ.) doi: 10.14341/osteo13166

[32] Белая Ж.Е., Рожинская Л.Я. Суррогатные маркёры в оценке эффективности лечения остеопороза бисфосфонатами (минеральная плотность кости, маркёры костного обмена) // Остеопороз и остеопатии. 2023. Т. 26, № 4. С. 20–25. doi: 10.14341/osteo13166

RIGHTS & PERMISSIONS

Eco-Vector