Advances in Clinical and Experimental Medicine

Title abbreviation: Adv Clin Exp Med
JCR Impact Factor (IF) – 2.1 (5-Year IF – 2.0)
Journal Citation Indicator (JCI) (2023) – 0.4
Scopus CiteScore – 3.7 (CiteScore Tracker 3.8)
Index Copernicus  – 171.00; MNiSW – 70 pts

ISSN 1899–5276 (print)
ISSN 2451-2680 (online)
Periodicity – monthly

Download original text (EN)

Advances in Clinical and Experimental Medicine

2020, vol. 29, nr 11, November, p. 1265–1275

doi: 10.17219/acem/127684

Publication type: original article

Language: English

License: Creative Commons Attribution 3.0 Unported (CC BY 3.0)

Download citation:

  • BIBTEX (JabRef, Mendeley)
  • RIS (Papers, Reference Manager, RefWorks, Zotero)

Effects of efavirenz and tenofovir on bone tissue in Wistar rats

Agnieszka Matuszewska1,A,B,C,D,E,F, Beata Nowak1,A,B,C,D,E,F, Anna Nikodem2,B,C,E,F, Diana Jędrzejuk3,C,F, Danuta Szkudlarek4,C,F, Krzysztof Zduniak4,C,F, Jarosław Filipiak2,C,E,F, Marta Sznadruk-Bender1,C,E,F, Tomasz Tomkalski5,C,E,F, Ireneusz Ceremuga6,B,C,E,F, Marek Bolanowski3,E,F, Adam Szeląg1,E,F

1 Department of Pharmacology, Wroclaw Medical University, Poland

2 Division of Biomedical Engineering and Experimental Mechanics, Wroclaw University of Technology, Poland

3 Department of Endocrinology, Diabetes and Isotope Therapy, Wroclaw Medical University, Poland

4 Department of Pathology, Wroclaw Medical University, Poland

5 Department of Endocrinology, T. Marciniak Lower Silesian Specialist Hospital, Poland

6 Department of Medical Biochemistry, Wroclaw Medical University, Poland

Abstract

Background. Clinical trials indicate an increased risk of osteoporosis and bone fractures in people infected with human immunodeficiency virus (HIV). The pathogenesis of bone disturbances in HIV-positive patients is unknown, but it is suggested that antiretroviral drugs may be involved.
Objectives. To assess the effects of efavirenz (EF) and tenofovir (T) on bone remodeling in rats.
Material and Methods. The study involved 36 male Wistar rats divided into 3 groups, receiving normal saline (control group – group C), efavirenz (group EF) or tenofovir disoproxil (group T).
Results. After 24 weeks of the study, the following observations were made: In blood serum of the EF group compared to group C, there were increased levels of tartrate-resistant acid phosphatase form 5b (TRAP) and inorganic phosphorus. In the densitometric examination, group T showed a lower total body (TB) bone mineral density (BMD) than group C. In the immunohistochemical assessment, group EF showed a higher intensity and extension of anti-tartrate resistant acid phosphatase antibodies (abTRAP) compared to group C. In the histopathological examination of the second lumbar vertebra (L2), group EF showed a lower bone surface/volume ratio (BS/BV) and higher trabecular thickness (Tb.Th) than the control group. In the histopathological examination of the femur, a lower bone surface/tissue volume (BS/TV) and lower trabecular number (Tb.N) were found in group T compared to in group C. A lower value of the Young’s modulus was observed in the four-point bending trial in groups EF and T compared to group C.
Conclusion. The results of this study indicate that EF affects bone microarchitecture and leads to impaired biomechanical properties of bones in rats. Additionally, the negative effect of T on bone tissue was confirmed.

Key words

bone, rat model, efavirenz, tenofovir, antiretroviral drug

References (50)

  1. UNAIDS. 2017 Global HIV Statistics. Fact sheet. Geneva, Switzerland: The Joint United Nations Programme on HIV and AIDS; 2017.
  2. Shiau S, Yin MT, Strehlau R, et al. Decreased bone turnover in HIV-infected children on antiretroviral therapy. Arch Osteoporos. 2018;13(1):40. doi:10.1007/s11657-018-0452-6
  3. Zuccotti G, Viganò A, Gabiano C, et al. Antiretroviral therapy and bone mineral measurements in HIV-infected youths. Bone. 2010;46(6):1633–1638. doi:10.1016/j.bone.2010.02.029
  4. Margossian R, Williams PL, Yu W, et al; Pediatric HIV/AIDS Cohort Study (PHACS). Markers of bone mineral metabolism and cardiac structure and function in perinatally HIV-infected and HIV-exposed but uninfected children and adolescents. J Acquir Immune Defic Syndr. 2019;81(2):238–246. doi:10.1097/QAI.0000000000002007
  5. Jacobson DL, Stephensen CB, Miller TL, et al; Pediatric HIV/AIDS Cohort Study. Associations of low vitamin D and elevated parathyroid hormone concentrations with bone mineral density in perinatally HIV-infected children. J Acquir Immune Defic Syndr. 2017;76(1):33–42. doi:10.1097/QAI.0000000000001467
  6. Manavalan JS, Arpadi S, Tharmarajah S, et al. Abnormal bone acquisition with early-life HIV infection: Role of immune activation and senescent osteogenic precursors. J Bone Miner Res. 2016;31(11):1988–1996. doi:10.1002/jbmr.2883
  7. Eckard AR, Mora S. Bone health in HIV-infected children and adolescents. Curr Opin HIV AIDS. 2016;11(3):294–300. doi:10.1097/COH.0000000000000270
  8. Vikulina T, Fan X, Yamaguchi M, et al. Alterations in the immuno-skeletal interface drive bone destruction in HIV-1 transgenic rats. Proc Natl Acad Sci U S A. 2010;107(31):13848–13853. doi:10.1073/pnas.1003020107
  9. Ofotokun I. Deciphering how HIV-1 weakens and cracks the bone. Proc Natl Acad Sci U S A. 2018;115(11):2551–2553. doi:10.1073/pnas.1801555115
  10. Biver E, Calmy A, Rizzoli R. Bone health in HIV and hepatitis B or C infections. Ther Adv Musculoskelet Dis. 2016;9(1):22–34. doi:10.1177/1759720X16671927
  11. Brown TT, Qaqish RB. Antiretroviral therapy and the prevalence of osteopenia and osteoporosis: A meta-analytic review. AIDS. 2006;20(17):2165–2174. doi:10.1097/QAD.0b013e32801022eb
  12. Madeddu G, Spanu A, Solinas P, et al. Different impact of NNRTI and PI-including HAART on bone mineral density loss in HIV-infected patients. Eur Rev Med Pharmacol Sci. 2015;19(23):4576–4589.
  13. Tebas P, Kumar P, Hicks C, et al. Greater change in bone turnover markers for efavirenz/emtricitabine/tenofovir disoproxil fumarate versus dolutegravir + abacavir/lamivudine in antiretroviral therapy-naive adults over 144 weeks. AIDS. 2015;29(18):2459–2464. doi:10.1097/QAD.0000000000000863
  14. Ofotokun I, Titanji K, Vunnava A, et al. Antiretroviral therapy induces a rapid increase in bone resorption that is positively associated with the magnitude of immune reconstitution in HIV infection. AIDS. 2016;30(3):405–414. doi:10.1097/QAD.0000000000000918
  15. Yin MT, Chan ES, Brown TT, et al. Vitamin D does not modulate immune-mediated bone loss during ART initiation. Antivir Ther. 2019;24(5):355–362. doi:10.3851/IMP3316
  16. McComsey GA, Kitch D, Daar ES, et al. Bone mineral density and fractures in antiretroviral-naive persons randomized to receive abacavir-lamivudine or tenofovir disoproxil fumarate-emtricitabine along with efavirenz or atazanavir-ritonavir: AIDS Clinical Trials Group A5224s, a substudy of ACTG. J Infect Dis. 2011;203(12):1791–1801. doi:10.1093/infdis/jir188
  17. Aurpibul L, Puthanakit T. Review of tenofovir use in HIV-infected children. Pediatr Infect Dis J. 2015;34(4):383–391. doi:10.1097/INF.0000000000000571
  18. Arpadi SM, Shiau S, Strehlau R, et al. Efavirenz is associated with higher bone mass in South African children with HIV. AIDS. 2016;30(16):2459–2467. doi:10.1097/QAD.0000000000001204
  19. Dave JA, Cohen K, Micklesfield LK, Maartens G, Levitt NS. Antiretroviral therapy, especially efavirenz, is associated with low bone mineral density in HIV-infected South Africans. PLoS One. 2015;10(12):e0144286. doi:10.1371/journal.pone.0144286
  20. Gafni RI, Hazra R, Reynolds JC, et al. Tenofovir disoproxil fumarate and an optimized background regimen of antiretroviral agents as salvage therapy: Impact on bone mineral density in HIV-infected children. Pediatrics. 2006;118(3):e711–e718. doi:10.1542/peds.2005-2525
  21. Viganò A, Zuccotti GV, Puzzovio M, et al. Tenofovir disoproxil fumarate and bone mineral density: A 60-month longitudinal study in a cohort of HIV-infected youths. Antivir Ther. 2010;15(7):1053–1058. doi:10.3851/IMP1650
  22. Unsal AB, Mattingly AS, Jones SE, et al. Effect of antiretroviral therapy on bone and renal health in young adults infected with HIV in early life. J Clin Endocrinol Metab. 2017;102(8):2896–2904. doi:10.1210/jc.2017-00197
  23. Hernandez CJ, Beaupré GS, Carter DR. A theoretical analysis of the changes in basic multicellular unit activity at menopause. Bone. 2003;32(4):357–363. doi:10.1016/s8756-3282(03)00037-1
  24. Compston J. HIV infection and bone disease. J Intern Med. 2016;280(4):350–358. doi:10.1111/joim.12520
  25. Goffinet C, Allespach I, Keppler OT. HIV-susceptible transgenic rats allow rapid preclinical testing of antiviral compounds targeting virus entry or reverse transcription. Proc Natl Acad Sci. 2007;104(3):1015–1020. doi:10.1073/pnas.0607414104
  26. Watkins ME, Wring S, Randolph R, et al. Development of a novel formulation that improves preclinical bioavailability of tenofovir disoproxil fumarate. J Pharm Sci. 2017;106(3):906–919. doi:10.1016/j.xphs.2016.12.003
  27. Dempster DW, Compston JE, Drezner MK, et al. Standardized nomenclature, symbols, and units for bone histomorphometry: A 2012 update of the report of the ASBMR Histomorphometry Nomenclature Committee. J Bone Miner Res. 2013;28(1):2–17. doi:10.1002/jbmr.1805
  28. Torlakovic EE, Francis G, Garratt J, et al; International Ad Hoc Expert Panel. Standardization of negative controls in diagnostic immunohistochemistry: Recommendations from the international ad hoc expert panel. Appl Immunohistochem Mol Morphol. 2014;22(4):241–252. doi:10.1097/PAI.0000000000000069
  29. Tandon N, Fall CHD, Osmond C, et al. Growth from birth to adulthood and peak bone mass and density data from the New Delhi Birth Cohort. Osteoporos Int. 2012;23(10):2447–2459. doi:10.1007/s00198-011-1857-x
  30. Filus A, Zdrojewicz Z. Insulin-like growth factor-1 (IGF-1) – structure and the role in the human body [in Polish]. Pediatr Endocrinol Diabetes Metab. 2014;20(4):161–169. doi:10.18544/PEDM-20.04.0016
  31. Datta HK, Ng WF, Walker JA, Tuck SP, Varanasi SS. The cell biology of bone metabolism. J Clin Pathol. 2008;61(5):577–587. doi:10.1136/JCP.2007.048868
  32. Hlaing TT, Compston JE. Biochemical markers of bone turnover: Uses and limitations. Ann Clin Biochem. 2014;51(Pt 2):189–202. doi:10.1177/0004563213515190
  33. Vescini F, Cozzi-Lepri A, Borderi M, et al; Icona Foundation Study Group. Prevalence of hypovitaminosis D and factors associated with vitamin D deficiency and morbidity among HIV-infected patients enrolled in a large Italian cohort. J Acquir Immune Defic Syndr. 2011;58(2):163–172. doi:10.1097/QAI.0b013e31822e57e9
  34. Conesa-Botella A, Florence E, Lynen L, Colebunders R, Menten J, Moreno-Reyes R. Decrease of vitamin D concentration in patients with HIV infection on a non-nucleoside reverse transcriptase inhibitor-containing regimen. AIDS Res Ther. 2010;7:40. doi:10.1186/1742-6405-7-40
  35. Welz T, Childs K, Ibrahim F, et al. Efavirenz is associated with severe vitamin D deficiency and increased alkaline phosphatase. AIDS. 2010;24(12):1923–1928. doi:10.1097/QAD.0b013e32833c3281
  36. Guryev O, Carvalho RA, Usanov S, Gilep A, Estabrook RW. A pathway for the metabolism of vitamin D3: Unique hydroxylated metabolites formed during catalysis with cytochrome P450scc (CYP11A1). Proc Natl Acad Sci U S A. 2003;100(25):14754–14759. doi:10.1073/pnas.2336107100
  37. Horst RL, Omdahl JA, Reddy S. Rat cytochrome P450C24 (CYP24) does not metabolize 1,25-dihydroxyvitamin D 2 to calcitroic acid. J Cell Biochem. 2003;88(2):282–285. doi:10.1002/jcb.10359
  38. Purdy JB, Gafni RI, Reynolds JC, Zeichner S, Hazra R. Decreased bone mineral density with off-label use of tenofovir in children and adolescents infected with human immunodeficiency virus. J Pediatr. 2008;152(4):582–584. doi:10.1016/j.jpeds.2007.12.020
  39. Castillo AB, Tarantal AF, Watnik MR, Bruce Martin R. Tenofovir treatment at 30 mg/kg/day can inhibit cortical bone mineralization in growing rhesus monkeys (Macaca mulatta). J Orthop Res. 2002;20(6):1185–1189. doi:10.1016/S0736-0266(02)00074-8
  40. Conradie MM, van de Vyver M, Andrag E, Conradie M, Ferris WF. A direct comparison of the effects of the antiretroviral drugs stavudine, tenofovir and the combination lopinavir/ritonavir on bone metabolism in a rat model. Calcif Tissue Int. 2017;101(4):422–432. doi:10.1007/s00223-017-0290-3
  41. Gallant JE, Staszewski S, Pozniak AL, et al. Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients: A 3-year randomized trial. JAMA. 2004;292(2):191–201. doi:10.1001/jama.292.2.191
  42. Stellbrink H, Orkin C, Arribas JR, et al; ASSERT Study Group. Comparison of changes in bone density and turnover with abacavir‐lamivudine versus tenofovir‐emtricitabine in HIV‐infected adults: 48‐week results from the ASSERT study. Clin Infect Dis. 2010;51(8):963–972. doi:10.1086/656417
  43. Hamzah L, Tiraboschi JM, Iveson H, et al. Effects on vitamin D, bone and the kidney of switching from fixed-dose tenofovir disoproxil fumarate/emtricitabine/efavirenz to darunavir/ritonavir monotherapy: A randomized, controlled trial (MIDAS). Antivir Ther. 2016;21(4):287–296. doi:10.3851/IMP3000
  44. Ramalho J, Martins CSW, Galvão J, et al. Treatment of human immunodeficiency virus infection with tenofovir disoproxil fumarate-containing antiretrovirals maintains low bone formation rate, but increases osteoid volume on bone histomorphometry. J Bone Miner Res. 2019;34(9):1574–1584. doi:10.1002/jbmr.3751
  45. Venter WDF, Kambugu A, Chersich MF, et al. Efficacy and safety of tenofovir disoproxil fumarate versus low-dose stavudine over 96 weeks: A multicountry randomized, noninferiority trial. J Acquir Immune Defic Syndr. 2019;80(2):224–233. doi:10.1097/QAI.0000000000001908
  46. Bagger YZ, Rasmussen HB, Alexandersen P, Werge T,Christiansen C, Tankó LB; PERF study group. Links between cardiovascular disease and osteoporosis in postmenopausal women: Serum lipids or athero­sclerosis per se? Osteoporos Int. 2007;18(4):505–512. doi:10.1007/s00198-006-0255-2
  47. Grigsby IF, Pham L, Mansky LM, Gopalakrishnan R, Mansky KC. Tenofovir-associated bone density loss. Ther Clin Risk Manag. 2010;6(1):41–47. doi:10.2147/TCRM.S8836
  48. Casado JL. Renal and bone toxicity with the use of tenofovir: Understanding at the end. AIDS Rev. 2016;18(2):59–68.
  49. Nowak B, Matuszewska A, Filipiak J, et al. The influence of bexarotene, a selective agonist of the retinoid receptor X (RXR), and tazarotene, a selective agonist of the retinoid acid receptor (RAR), on bone metabolism in rats. Adv Med Sci. 2016;61(1):85–89. doi:10.1016/j.advms.2015.09.001
  50. Markiewicz-Górka I, Kuropka P, Januszewska L, et al. Influence of physical training on markers of bone turnover, mechanical properties, morphological alterations, density and mineral contents in the femur of rats exposed to cadmium and/or alcohol. Toxicol Ind Health. 2019;35(4):277–293. doi:10.1177/0748233719831534
© Wroclaw Medical University