Skip to main content

Advertisement

SpringerLink
Log in

Molecular Bases of Osteoporosis in HIV: The Role of the Virus and Antiretroviral Therapy

  • Original Paper
  • Published:
Clinical Reviews in Bone and Mineral Metabolism Aims and scope Submit manuscript

Abstract

In addition to immune system, HIV infection can determine the onset of functional dysfunctions of several organs and tissues such as central nervous system, cardiovascular system, kidney, and bone. It is noteworthy that HIV-infected individuals show an increased risk of bone mass loss with subsequent osteopenia and osteoporosis development. Interestingly, antiretroviral therapy is not able to tackle the bone derangement but, on the contrary, it can induce a progressive bone mass loss, especially when specific antiretroviral drugs are used. In this report, we summarized the HIV and antiretroviral-related mechanisms involved in the osteopenia and osteoporosis induction.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Lohse N, Hansen AB, Pedersen G, et al. Survival of persons with and without HIV infection in Denmark, 1995–2005. Ann Intern Med. 2007;146:87–95.

    PubMed  Google Scholar 

  2. Levy JA. HIV pathogenesis: 25 years of progress and persistent challenges. AIDS. 2009;23:147–60.

    Article  PubMed  Google Scholar 

  3. Borderi M, Gibellini D, Vescini F, et al. Metabolic bone disease in HIV infection. AIDS. 2009;23:1297–310.

    Article  PubMed  Google Scholar 

  4. Womack JA, Goulet JL, Gibert C, et al. Increased risk of fragility fractures among HIV infected compared to uninfected male veterans. PLoS ONE. 2011;6:e17217.

    Article  PubMed  CAS  Google Scholar 

  5. Dempster DW. Anatomy and functions of the adult skeleton, primer on the metabolic bone diseases and disorders of mineral metabolism. The American Society for Bone and Mineral Research; 2006. p. 7–11.

  6. Matsuo K, Irie N. Osteoclast-osteoblast communication. Arch Biochem Bioph. 2008;473:201–9.

    Article  CAS  Google Scholar 

  7. Sims NA, Gooi JH. Bone remodeling: multiple cellular interactions required for coupling of bone formation and resorption. Semin Cell Dev Biol. 2008;19:444–51.

    Article  PubMed  CAS  Google Scholar 

  8. Takayanagi H. Osteoimmunology and the effects of the immune system on bone. Nat Rev Rheumatol. 2009;5:667–76.

    Article  PubMed  CAS  Google Scholar 

  9. Agrawal M, Arora S, Li J, Rahmani R, Sun L, Steinlauf AF, Mechanick JI, Zaidi M. Bone, inflammation, and inflammatory bowel disease. Curr Osteoporos Rep. 2011;9:251–7.

    Article  PubMed  Google Scholar 

  10. Baker-LePain JC, Nakamura MC, Lane NE. Effects of inflammation on bone: an update. Curr Opin Rheumatol. 2011;23:389–95.

    Article  PubMed  Google Scholar 

  11. Manolagas SC. Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. Endocr Rev. 2000;21:115–37.

    Article  PubMed  CAS  Google Scholar 

  12. NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy. Osteoporosis prevention, diagnosis, and therapy. JAMA. 2001;285:785–95.

    Article  Google Scholar 

  13. Sambrook P, Cooper C. Osteoporosis. Lancet. 2006;367:2010–8.

    Article  PubMed  CAS  Google Scholar 

  14. Haskelberg H, Carr A, Emery S. Bone turnover markers in HIV disease. AIDS Rev. 2011;13:240–50.

    PubMed  Google Scholar 

  15. World Health Organization. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. WHO technical report series 843. Geneva: WHO; 1994.

  16. Kanis JA, McCloskey EV, Johansson H, et al. Reference standard for the description of osteoporosis. Bone. 2008;42:467–75.

    Article  PubMed  CAS  Google Scholar 

  17. Nguyen ND, Eisman JA, Center JR, et al. Risk factors for fracture in nonosteoporotic men and women. J Clin Endocrinol Metab. 2007;92:955–62.

    Article  PubMed  CAS  Google Scholar 

  18. Brainsky A, Glick H, Lydick E, et al. The economic cost of hip fractures in community-dwelling older adults: a prospective study. J Am Geriatr Soc. 1997;45:281–7.

    PubMed  CAS  Google Scholar 

  19. Lewis JR, Hassan SK, Wenn RT, et al. Mortality and serum urea and electrolytes on admission for hip fracture patients. Injury. 2006;37:698–704.

    Article  PubMed  CAS  Google Scholar 

  20. Black DM, Palermo L, Nevitt MC, et al. Comparison of methods for defining prevalent vertebral deformities: the study of osteoporotic fractures. J Bone Miner Res. 1995;10:890–902.

    Article  PubMed  CAS  Google Scholar 

  21. Burge R, Dawson-Hughes B, Solomon DH, et al. Incidence and economic burden of osteoporosis-related fractures in the United States, 2005–2025. J Bone Miner Res. 2007;22:465–75.

    Article  PubMed  Google Scholar 

  22. Stone B, Dockrell D, Bowman C, et al. HIV and bone disease. Arch Biochem Biophys. 2010;503:66–77.

    Article  PubMed  CAS  Google Scholar 

  23. Brown TT, Qaqish RB. Antiretroviral therapy and the prevalence of osteopenia and osteoporosis: a meta-analytic review. AIDS. 2006;20:2165–74.

    Article  PubMed  Google Scholar 

  24. Brown TT, McComsey GA. Osteopenia and osteoporosis in patients with HIV: a review of current concepts. Curr Inf Dis Reports. 2006;8:162–70.

    Article  Google Scholar 

  25. Ofotokun I, McIntosh E, Weitzmann MN. HIV: inflammation and bone. Curr HIV/AIDS Rep. 2012;9:16–25.

    Article  PubMed  Google Scholar 

  26. Serrano S, Marinoso M, Soriano J, et al. Bone remodelling in human immunodeficiency virus-1-infected patients. A histomorphometric study. Bone. 1995;16:185–91.

    Article  PubMed  CAS  Google Scholar 

  27. Mondy K, Yarasheski K, Powderly WG, et al. Longitudinal evolution of bone mineral density and bone markers in human immunodeficiency virus-infected individuals. Clin Infect Dis. 2003;36:482–90.

    Article  PubMed  Google Scholar 

  28. Aukrust P, Haug CJ, Ueland T, et al. Decreased bone formative and enhanced resorptive markers in human immunodeficiency virus infection: indication of normalization of the bone-remodeling process during highly active antiretroviral therapy. J Clin Endocrinol Metab. 1999;84:145–50.

    Article  PubMed  CAS  Google Scholar 

  29. Teichmann J, Stephan E, Discher T, et al. Changes in calciotropic hormones and biochemical markers of bone metabolism in patients with human immunodeficiency virus infection. Metabolism. 2000;49:1134–9.

    Article  PubMed  CAS  Google Scholar 

  30. Murray AB, Schmidt J, Rieke L. Retrovirus-induced osteopetrosis in mice. Ultrastructural evidence of early virus production in osteoblasts and osteocytes. Am J Pathol. 1986;124:319–23.

    Google Scholar 

  31. Foster RG, Lian JB, Stein G, et al. Replication of an osteopetrosis-inducing avian leukosis virus in fibroblasts, osteoblasts, and osteopetrotic bone. Virology. 1994;205:179–87.

    Article  PubMed  CAS  Google Scholar 

  32. Labat ML. Retroviruses and bone diseases. Clin Orthopaed. 1996;326:287–308.

    Article  Google Scholar 

  33. Centers for Disease Control. Transmission of HIV through bone transplantation. JAMA. 1988;260:2487–8.

    Article  Google Scholar 

  34. Roder W, Muller H, Muller WEG, et al. HIV infection in human bone. J Bone Joint Surg Br. 1992;74:179–80.

    PubMed  CAS  Google Scholar 

  35. Buck BE, Resnick L, Shah SM, et al. Human immunodeficiency virus cultured from bone. Implications for transplantation. Clin Orthop Relat Res. 1990;251:249–53.

    PubMed  Google Scholar 

  36. Mellert W, Kleinschmidt A, Schmidt J, et al. Infection of human fibroblasts and osteoblast-like cells with HIV-1. AIDS. 1990;4:527–35.

    Article  PubMed  CAS  Google Scholar 

  37. Fessel WJ, Hurley LB. Is HIV sequestered in bone? Possible implications of virological and immunological findings in some HIV-infected patients with bone disease. AIDS. 2003;17:255–7.

    Article  PubMed  Google Scholar 

  38. Nacher M, Serrano S, Gonzalez A, et al. Osteoblasts in HIV-infected patients: HIV-1 infection and cell function. AIDS. 2001;15:2239–43.

    Article  PubMed  CAS  Google Scholar 

  39. Gibellini D, De Crignis E, Ponti C, et al. HIV-1 triggers apoptosis in primary osteoblasts and HOBIT cells through TNFalpha activation. J Med Virol. 2008;80:1507–14.

    Article  PubMed  CAS  Google Scholar 

  40. Wang L, Mondal D, La Russa VF, et al. Suppression of clonogenic potential of human bone marrow mesenchymal stem cells by HIV type 1: putative role of HIV type 1 Tat protein and inflammatory cytokines. AIDS Res Hum Retrovir. 2002;18:917–31.

    Article  PubMed  CAS  Google Scholar 

  41. Cotter EJ, Chew N, Powderly WG, et al. HIV type 1 alters mesenchymal stem cell differentiation potential and cell phenotype ex vivo. AIDS Res Hum Retrov. 2011;27:187–99.

    Article  CAS  Google Scholar 

  42. Gibellini D, Alviano F, Miserocchi A, et al. HIV-1 and recombinant gp120 affect the survival and differentiation of human vessel wall derived mesenchymal stem cells. Retrovirology. 2011;8:40.

    Article  PubMed  Google Scholar 

  43. Cotter EJ, Ip HSM, Powderly WG, et al. Mechanism of HIV protein induced modulation of mesenchymal stem cell osteogenic differentiation. BMC Musculoskel Disord. 2008;9:33.

    Article  CAS  Google Scholar 

  44. Cotter EJ, Malizia AP, Chew N, et al. HIV proteins regulate bone marker secretion and transcription factor activity in cultured human osteoblasts with consequent potential implications for osteoblast function and development. AIDS Res Hum Retrovir. 2007;23:1521–30.

    Article  PubMed  CAS  Google Scholar 

  45. Cotter EJ, Mallon PW, Doran PP. Is PPARγ a prospective player in HIV-1 associated bone disease? PPAR Res. 2009;2009:421376.

  46. Perfettini JL, Castedo M, Roumier T, et al. Mechanisms of apoptosis induction by the HIV-1 envelope. Cell Death Differ. 2005;12:S916–23.

    Article  CAS  Google Scholar 

  47. Herbeuval JP, Shearer GM. Are blockers of gp120/CD4 interaction effective inhibitors of HIV-1 immunopathogenesis? AIDS Rev. 2006;8:3–8.

    PubMed  Google Scholar 

  48. Gibellini D, Vitone F, Buzzi M, et al. HIV-1 negatively affects the survival/maturation of cord blood CD34(+) hematopoietic progenitor cells differentiated towards megakaryocytic lineage by HIV-1 gp120/CD4 membrane interaction. J Cell Physiol. 2007;210:315–24.

    Article  PubMed  CAS  Google Scholar 

  49. Cummins NW, Klicpera A, Sainski AM, et al. Human immunodeficiency virus envelope protein Gp120 induces proliferation but not apoptosis in osteoblasts at physiologic concentrations. PLoS ONE. 2011;6:e24876.

    Article  PubMed  CAS  Google Scholar 

  50. Burger EH, Van der Meer JW, Van de Gevel JS, et al. In vitro formation of osteoclasts from long-term cultures of bone marrow mononuclear phagocytes. J Exp Med. 1982;156:1604–14.

    Article  PubMed  CAS  Google Scholar 

  51. Vaananem HK, Laitala-Leinonen T. Osteoclast lineage and function. Arch Biochem Biophys. 2008;473:132–8.

    Article  CAS  Google Scholar 

  52. Kudo O, Sabokbar A, Pocock A, et al. Interleukin-6 and interleukin-11 support human osteoclast formation by a RANKL-independent mechanism. Bone. 2003;32:1–7.

    Article  PubMed  CAS  Google Scholar 

  53. Gruber MF, Weih KA, Boone EJ, et al. Endogenous macrophage CSF production is associated with viral replication in HIV-1-infected human monocyte-derived macrophages. J Immunol. 1995;154:5528–35.

    PubMed  CAS  Google Scholar 

  54. Kalter DC, Nakamura M, Turpin JA, et al. Enhanced HIV replication in macrophage colony stimulating factor treated monocytes. J Immunol. 1991;146:298–306.

    PubMed  CAS  Google Scholar 

  55. Bergamini A, Perno CF, Dini L, Capozzi M, et al. Macrophage colony-stimulating factor enhances the susceptibility of macrophages to infection by HIV and reduces the activity of compounds that inhibit virus binding. Blood. 1994;84:3405–12.

    PubMed  CAS  Google Scholar 

  56. Wang J, Roderiquez G, Oravecz T, et al. Cytokine regulation of human immunodeficiency virus type 1 entry and replication in human monocytes/macrophages through modulation of CCR5 expression. J Virol. 1998;72:7642–7.

    PubMed  CAS  Google Scholar 

  57. Haine V, Fischer-Smith T, Rappaport J. M-CSF in the pathogenesis of HIV infection: potential target for therapeutical intervention. J Neuroimmune Pharmacol. 2006;1:32–40.

    Article  PubMed  Google Scholar 

  58. Yamada N, Tsujimura T, Ueda H, et al. Down-regulation of osteoprotegerin production in bone marrow macrophages by macrophage colony-stimulating factor. Cytokine. 2005;31:288–97.

    Article  PubMed  CAS  Google Scholar 

  59. Gibellini D, Borderi M, De Crignis E, et al. RANKL/OPG/TRAIL plasma levels and bone mass loss evaluation in antiretroviral naive HIV-1-positive men. J Med Virol. 2007;79:1446–54.

    Article  PubMed  CAS  Google Scholar 

  60. Konishi M, Takahashi K, Yoshimoto E, et al. Association between osteopenia/osteoporosis and the serum RANKL in HIV-infected patients. AIDS. 2005;19:1240–1.

    Article  PubMed  Google Scholar 

  61. Mora S, Zamproni I, Cafarelli L, et al. Alterations in circulating osteoimmune factors may be responsible for high bone resorption rate in HIV-infected children and adolescents. AIDS. 2007;21:1129–35.

    Article  PubMed  CAS  Google Scholar 

  62. Fakruddin JM, Laurence J. HIV envelope gp120-mediated regulation of osteoclastogensis via receptor activator of nuclear factor kb ligand (RANKL) decretion and its modulation by certain HIV protease inhibitors through interferon-gamma/RANKL cross-talk. J Biol Chem. 2003;278:48251–8.

    Article  PubMed  CAS  Google Scholar 

  63. Fakruddin JM, Laurence J. HIV-1 Vpr enhances production of receptor of activated NF-kB ligand (RANKL) via potentiation of glucocorticoid receptor activity. Arch Virol. 2005;150:67–78.

    Article  PubMed  CAS  Google Scholar 

  64. Gibellini D, De Crignis E, Ponti C, et al. HIV-1 Tat protein enhances RANKL/M-CSF-mediated osteoclast differentiation. Biochem Biophys Res Commun. 2010;401:429–34.

    Article  PubMed  CAS  Google Scholar 

  65. Weitzmann MN, Pacifici R. The role of T lymphocytes in bone metabolism. Immunol Rev. 2005;208:154–68.

    Article  PubMed  CAS  Google Scholar 

  66. Weitzmann MN, Pacifici R. T cells: unexpected players in the bone loss induced by estrogen deficiency and in basal bone homeostasis. Ann NY Acad Sci. 2007;116:360–75.

    Article  CAS  Google Scholar 

  67. Buonaguro L, Barillari G, Chang HK, et al. Effects of the human immunodeficiency virus type 1 Tat protein on the expression of inflammatory cytokines. J Virol. 1992;66:7159–67.

    PubMed  CAS  Google Scholar 

  68. Gibellini D, Zauli G, Re MC, et al. Recombinant human immunodeficiency virus type 1 (HIV-1) Tat protein sequentially upregulates IL-6 and TGFb1 mRNA expression and protein synthesis in peripheral blood monocytes. British J Haematol. 1994;88:261–7.

    Article  CAS  Google Scholar 

  69. Scala G, Ruocco MR, Ambrosino C, et al. The expression of the interleukin 6 gene is induced by the human immunodeficiency virus 1 TAT protein. J Exp Med. 1994;179:961–71.

    Article  PubMed  CAS  Google Scholar 

  70. Hill PA, Tumber A, Meikle MC. Multiple extracellular signals promote osteoblast survival and apoptosis. Endocrinology. 1997;138:849–58.

    Google Scholar 

  71. Jilka RL, Weinstein RS, Bellido T, et al. Osteoblast programmed cell death (apoptosis): modulation by growth factors and cytokines. J Bone Miner Res. 1998;13:793–802.

    Article  PubMed  CAS  Google Scholar 

  72. Poli G, Kinter A, Justement JS, et al. Tumor necrosis factor alpha functions in an autocrine manner in the induction of human immunodeficiency virus expression. Proc Natl Acad Sci USA. 1990;87:782–5.

    Article  PubMed  CAS  Google Scholar 

  73. Clerici M, Shearer GM. A TH1 → TH2 switch is a critical step in the etiology of HIV infection. Immunol Today. 1993;14:107–11.

    Article  PubMed  CAS  Google Scholar 

  74. Takayanagi H, Ogasawara K, Hida S, et al. T-cell-mediated regulation of osteoclastogenesis by signalling cross-talk between RANKL and IFN-gamma. Nature. 2000;408:600–5.

    Article  PubMed  CAS  Google Scholar 

  75. 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 USA. 2010;107:13848–53.

    Article  PubMed  CAS  Google Scholar 

  76. Martin JL, Brown CE, Matthews-Davis N, et al. Effects of antiviral nucleoside analogs on human DNA polymerases and mitochondrial DNA synthesis. Antimicrob Agents Chemother. 1994;38:2743–9.

    Article  PubMed  CAS  Google Scholar 

  77. Brinkman K, Hofstede HJ, Burger DM, et al. Adverse effects of reverse transcriptase inhibitors: mitochondrial toxicity as common pathway. AIDS. 1998;12:1735–44.

    Article  PubMed  CAS  Google Scholar 

  78. Walker UA, Setzer B, Venhoff N. Increased long-term mitochondrial toxicity in combinations of nucleoside analogue reverse-transcriptase inhibitors. AIDS. 2002;16:2165–73.

    Article  PubMed  CAS  Google Scholar 

  79. Lewis W, Dalakas MC. Mitochondrial toxicity of antiviral drugs. Nat Med. 1995;1:417–22.

    Article  PubMed  CAS  Google Scholar 

  80. Boubaker K, Flepp M, Sudre P, et al. Hyperlactatemia and antiretroviral therapy: the swiss HIV cohort study. Clin Infect Dis. 2001;33:1931–7.

    Article  PubMed  CAS  Google Scholar 

  81. Moyle GJ, Datta D, Mandalia S, et al. Hyperlactatæmia and lactic acidosis during antiretroviral therapy: relevance, reproducibility and possible risk factors. AIDS. 2002;16:1341–9.

    Article  PubMed  Google Scholar 

  82. Pan G, Wu X, McKenna MA, et al. AZT enhances osteoclastogenesis and bone loss. AIDS Res Hum Retrovir. 2004;20:608–20.

    Article  PubMed  CAS  Google Scholar 

  83. Pan G, Yang Z, Ballinger SW, et al. Pathogenesis of osteopenia/osteoporosis induced by highly active anti-retroviral therapy for AIDS. Ann NY Acad Sci. 2006;1068:297–308.

    Article  PubMed  CAS  Google Scholar 

  84. Carr A, Miller J, Eisman JA, et al. Osteopenia in HIV-infected men: association with asymptomatic lactic acidemia and lower weight pre-anti-retroviral therapy. AIDS. 2001;15:703–9.

    Article  PubMed  CAS  Google Scholar 

  85. Birkus G, Hitchcock MJ, Cihlar T. Assessment of mitochondrial toxicity in human cells treated with tenofovir: comparison with other nucleoside reverse transcriptase inhibitors. Antimicrob Agents Chemoter. 2002;46:716–23.

    Article  CAS  Google Scholar 

  86. Venhoff N, Setzer B, Melkaoui K, et al. Mitochondrial toxicity of tenofovir, emtricitabine and abacavir alone and in combination with additional nucleoside reverse transcriptase inhibitors. Antivir Ther. 2007;12:1075–85.

    PubMed  CAS  Google Scholar 

  87. Grigsby IF, Pham L, Mansky LM, et al. Tenofovir treatment of primary osteoblasts alters gene expression profiles: implications for bone mineral density loss. Biochem Biophys Res Commun. 2010;394:48–53.

    Article  PubMed  CAS  Google Scholar 

  88. Grigsby IF, Pham L, Gopalakrishnan R, et al. Downregulation of Gnas, Got2 and Snord32a following tenofovir exposure of primary osteoclasts. Biochem Biophys Res Commun. 2010;391:1324–9.

    Article  PubMed  CAS  Google Scholar 

  89. Bodine PV, Stauffer B, Ponce-de-Leon H, et al. A small molecule inhibitor of the Wnt antagonist secreted frizzled-related protein-1 stimulates bone formation. Bone. 2009;44:1063–8.

    Article  PubMed  CAS  Google Scholar 

  90. Tarantal AF, Marthas ML, Shaw JP, et al. Administration of 9-(2-(R)-(phosphonomethoxy)propyl) adenine (PMPA) to gravid and infant Rhesus macaques (Macaca mulatta): safety and efficacy studies. J Acquir Immun Defic Syndr Hum Retrovirol. 1999;20:323–33.

    Article  CAS  Google Scholar 

  91. Izzedine H, Hulot JS, Vittecoq D, et al. Long-term renal safety of tenofovir disoproxil fumarate in antiretroviral naive HIV-1-infected patients. Data from a double-blind randomized active-controlled multicentre study. Nephrol Dial Transpl. 2005;20:743–6.

    Article  CAS  Google Scholar 

  92. Barrios A, Garcia Benayas T, Gonzalez-Lahoz J, et al. Tenofovir-related nephrotoxicity in HIV-infected patients. AIDS. 2004;18:960–3.

    Article  PubMed  CAS  Google Scholar 

  93. Labarga P, Barreiro P, Martin-Carbonero L, et al. Kidney tubular abnormalities in the absence of impaired glomerular function in HIV patients treated with tenofovir. AIDS. 2009;23:689–96.

    Article  PubMed  CAS  Google Scholar 

  94. Parsonage MJ, Wilkins EG, Snowden N, et al. The development of hypophosphataemic osteomalacia with myopathy in two patients with HIV infection receiving tenofovir therapy. HIV Med. 2005;6:341–6.

    Article  PubMed  CAS  Google Scholar 

  95. Brim NM, Cu-Uvin S, Hu SL, et al. Bone disease and pathologic fractures in a patient with tenofovir-induced Fanconi syndrome. AIDS Read. 2007;17:322–8.

    PubMed  Google Scholar 

  96. Callens S, De Roo A, Colebunders R. Fanconi-like syndrome and rhabdomyolysis in a person with HIV infection on highly active antiretroviral treatment including tenofovir. J Infect. 2003;47:262–3.

    Article  PubMed  Google Scholar 

  97. Creput C, Gonzalez-Canali G, Hill G, et al. Renal lesions in HIV-1-positive patient treated with tenofovir. AIDS. 2003;17:935–7.

    Article  PubMed  Google Scholar 

  98. Rollot F, Nazal EM, Chauvelot-Moachon L, et al. Tenofovir-related Fanconi syndrome with nephrogenic diabetes insipidus in a patient with acquired immunodeficiency syndrome: the role of lopinavir-ritonavir-didanosine. Clin Infect Dis. 2003;37:e174–6.

    Article  PubMed  Google Scholar 

  99. Karras A, Lafaurie M, Furco A, et al. Tenofovir-related nephrotoxicity in human immunodeficiency virus–infected patients: three cases of renal failure, Fanconi syndrome, and nephrogenic diabetes insipidus. Clin Infect Dis. 2003;36:1070–3.

    Article  PubMed  Google Scholar 

  100. Schooley RT, Ruane P, Myers RA, et al. Tenofovir DF in antiretroviral-experienced patients: results from a 48-week, randomized, double-blind study. AIDS. 2002;16:1257–63.

    Article  PubMed  CAS  Google Scholar 

  101. Squires K, Pozniak AL, Pierone JG, et al. Tenofovir disoproxil fumarate in nucleoside-resistant HIV-1 Infection a randomized trial. Ann Intern Med. 2003;139:313–20.

    PubMed  CAS  Google Scholar 

  102. Izzedine H, Isnard-Bagnis C, Hulot JS, et al. Renal safety of tenofovir in HIV treatment experienced patients. AIDS. 2004;18:1074–6.

    Article  PubMed  CAS  Google Scholar 

  103. Mouly S, Lown KS, Kornhauser D, et al. Hepatic but not intestinal CYP3A4 displays dose-dependent induction by efavirenz in humans. Clin Pharmacol Ther. 2002;72:1–9.

    Article  PubMed  CAS  Google Scholar 

  104. 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;292:191–201.

    Article  PubMed  CAS  Google Scholar 

  105. Brown TT, McComsey GA. Association between initiation of antiretroviral therapy with efavirenz and decreases in 25-hydroxyvitamin D. Antivir Ther. 2010;15:425–9.

    Article  PubMed  CAS  Google Scholar 

  106. Arora S, Agrawal M, Sun L, et al. HIV and bone loss. Curr Osteoporos Rep. 2010;8:219–26.

    Article  PubMed  Google Scholar 

  107. 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 A5202. J Infect Dis. 2011;203:1791–801.

    Article  PubMed  CAS  Google Scholar 

  108. Jain RG, Lenhard JM. Select HIV protease inhibitors alter bone and fat metabolism ex vivo. J Biol Chem. 2002;277:19247–50.

    Article  PubMed  CAS  Google Scholar 

  109. Malizia AP, Cotter E, Chew N, et al. HIV protease inhibitors selectively induce gene expression alterations associated with reduced calcium deposition in primary human osteoblasts. AIDS Res Hum Retrovir. 2007;23:243–50.

    Article  PubMed  CAS  Google Scholar 

  110. Wong BR, Besser D, Kim N, et al. RANCE, a TNF family member, activates Akt/PKB through a signaling complex involving TRAF6 and c-Src. Mol Cell. 1999;4:1041–9.

    Article  PubMed  CAS  Google Scholar 

  111. Wang MW, Wei S, Faccio R, et al. The HIV protease inhibitor ritonavir blocks osteoclastogenesis and function by impairing RANKL-induced signaling. J Clin Invest. 2004;114:206–13.

    PubMed  CAS  Google Scholar 

  112. Baron R, Rawadi G. Minireview: targeting the Wnt/b-catenin pathway to regulate bone formation in the adult skeleton. Endocrinology. 2007;148:2635–43.

    Article  PubMed  CAS  Google Scholar 

  113. Goldring SR, Goldring MB. Eating bone or adding it: the Wnt pathway decides. Nat Med. 2007;13:113–4.

    Article  CAS  Google Scholar 

  114. Modarresi R, Xiang Z, Yin M, et al. WNT/beta-catenin signaling is involved in regulation of osteoclast differentiation by human immunodeficiency virus protease inhibitor ritonavir: relationship to human immunodeficiency virus-linked bone mineral loss. Am J Pathol. 2009;174:123–35.

    Article  PubMed  CAS  Google Scholar 

  115. Santiago F, Oguma J, Brown AM, et al. Noncanonical Wnt signaling promotes osteoclast differentiation and is facilitated by the human immunodeficiency virus protease inhibitor ritonavir. Biochem Biophys Res Commun. 2012;417:223–30.

    Article  PubMed  CAS  Google Scholar 

  116. Butler JS, Murray DW, Hurson CJ, et al. The role of Dkk1 in bone mass regulation: correlating serum Dkk1 expression with bone mineral density. J Orthop Res. 2011;29:414–8.

    Article  PubMed  Google Scholar 

  117. Whitfield GK, Hsieh JC, Jurutka PW, et al. Genomic actions of 1,25-dihydroxyvitamin D3. J Nutr. 1995;125:1690S–4S.

    PubMed  CAS  Google Scholar 

  118. Cozzolino M, Vidal M, Arcidiacono MV, et al. HIV-protease inhibitors impair vitamin D bioactivation to 1,25-dihydroxyvitamin D. AIDS. 2003;17:513–20.

    Article  PubMed  CAS  Google Scholar 

  119. Eagling VA, Back DJ, Barry MG. Differential inhibition of cytochrome P450 isoforms by the protease inhibitors, ritonavir, saquinavir and indinavir. Br J Clin Pharmacol. 1997;44:190–4.

    Article  PubMed  CAS  Google Scholar 

  120. Von Moltke LL, Greenblatt DJ, Grassi JM, et al. Protease inhibitors as inhibitors of human cytochromes P450: high risk associated with ritonavir. J Clin Pharmacol. 1998;38:106–11.

    Google Scholar 

  121. Haug CJ, Aukrust P, Haug E, et al. Severe deficiency of 1,25-dihydroxyvitamin D3 in human immunodeficiency virus infection: association with immunological hyperactivity and only minor changes in calcium homeostasis. J Clin Endocrinol Metab. 1998;83:3832–8.

    Article  PubMed  CAS  Google Scholar 

  122. Ramayo E, Gonzalez-Moreno MP, Macıas J, et al. Relationship between osteopenia, free testosterone, and vitamin D metabolite levels in HIV-infected patients with and without highly active antiretroviral therapy. AIDS Res Hum Retrovir. 2005;21:915–21.

    Article  PubMed  CAS  Google Scholar 

  123. Tomazic J, Ul K, Volcansek G, Gorensek S, et al. Prevalence and risk factors for osteopenia/osteoporosis in an HIV-infected male population. Wien Klin Wochenschr. 2007;119:639–46.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Haematology and Oncological Sciences, Microbiology Section, University of Bologna, Bologna, Italy

    D. Gibellini, A. Clò, S. Morini & M. C. Re

  2. Department of Internal Medicine, Aging and Nephrology, Infectious Diseases Section, University of Bologna, Bologna, Italy

    M. Borderi, E. Vanino, L. Calza & Pl. Viale

Authors
  1. D. Gibellini
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. Borderi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. E. Vanino
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A. Clò
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S. Morini
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. L. Calza
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M. C. Re
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Pl. Viale
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M. Borderi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gibellini, D., Borderi, M., Vanino, E. et al. Molecular Bases of Osteoporosis in HIV: The Role of the Virus and Antiretroviral Therapy. Clinic Rev Bone Miner Metab 10, 236–245 (2012). https://doi.org/10.1007/s12018-012-9133-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12018-012-9133-y

Keywords

Search

Navigation