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Bone Loss in HIV Infection

  • HIV Medicine (CJ Yoon, Section editor)
  • Published:
Current Treatment Options in Infectious Diseases Aims and scope Submit manuscript

Opinion Statement

Human immunodeficiency virus (HIV) infection is an established risk factor for low bone mineral density (BMD) and subsequent fracture, and treatment with combination antiretroviral therapy (cART) leads to additional BMD loss, particularly in the first 1–2 years of therapy. The prevalence of low BMD and fragility fracture is expected to increase as the HIV-infected population ages with successful treatment with cART. Mechanisms of bone loss in the setting of HIV infection are likely multifactorial, and include viral, host, and immune effects, as well as direct and indirect effects of cART, particularly tenofovir disoproxil fumarate (TDF), and the protease inhibitors (PIs). Emerging data indicate that BMD loss following cART initiation can be mitigated by prophylaxis with either long-acting bisphosphonates or vitamin D and calcium supplementation. In addition, newer antiretrovirals, particularly the integrase strand transfer inhibitors and tenofovir alafenamide (TAF), are associated with less intense bone loss than PIs and TDF. However, further studies are needed to establish optimal bone sparing cART regimens, appropriate screening intervals, and preventive measures to address the rising prevalence of fragility bone disease in the HIV population.

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References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Harrison KM, Song R, Zhang X. Life expectancy after HIV diagnosis based on national HIV surveillance data from 25 states, United States. Journal of acquired immune deficiency syndromes (1999). 2010;53(1):124–30.

    Article  Google Scholar 

  2. Aberg JA. Aging, inflammation, and HIV infection. Topics in antiviral medicine. 2012;20(3):101–5.

    PubMed  Google Scholar 

  3. Smit M, Brinkman K, Geerlings S, Smit C, Thyagarajan K, Sighem A, et al. Future challenges for clinical care of an ageing population infected with HIV: a modelling study. Lancet Infect Dis. 2015;15(7):810–8.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Cosman F, de Beur SJ, LeBoff MS, Lewiecki EM, Tanner B, Randall S, et al. Clinician's guide to prevention and treatment of osteoporosis. Osteoporosis international: a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. 2014;25(10):2359–81.

    Article  CAS  Google Scholar 

  5. Rey D, Treger M, Sibilia J, Priester M, Bernard-Henry C, Cheneau C, et al. Bone mineral density changes after 2 years of ARV treatment, compared to naive HIV-1-infected patients not on HAART. Infectious diseases (London, England). 2015;47(2):88–95.

    Article  CAS  Google Scholar 

  6. Ofotokun I, McIntosh E, Weitzmann MN. HIV: inflammation and bone. Current HIV/AIDS reports. 2012;9(1):16–25.

    Article  PubMed  PubMed Central  Google Scholar 

  7. McComsey GA, Tebas P, Shane E, Yin MT, Overton ET, Huang JS, et al. Bone disease in HIV infection: a practical review and recommendations for HIV care providers. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2010;51(8):937–46.

    Article  Google Scholar 

  8. Finkelstein JS, Brockwell SE, Mehta V, Greendale GA, Sowers MR, Ettinger B, et al. Bone mineral density changes during the menopause transition in a multiethnic cohort of women. J Clin Endocrinol Metab. 2008;93(3):861–8.

    Article  CAS  PubMed  Google Scholar 

  9. Triant VA, Brown TT, Lee H, Grinspoon SK. Fracture prevalence among human immunodeficiency virus (HIV)-infected versus non-HIV-infected patients in a large U.S. healthcare system. J Clin Endocrinol Metab. 2008;93(9):3499–504.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Guerri-Fernandez R, Vestergaard P, Carbonell C, Knobel H, Aviles FF, Castro AS, et al. HIV infection is strongly associated with hip fracture risk, independently of age, gender, and comorbidities: a population-based cohort study. Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research. 2013;28(6):1259–63.

    Article  Google Scholar 

  11. Bonjoch A, Figueras M, Estany C, Perez-Alvarez N, Rosales J, del Rio L, et al. High prevalence of and progression to low bone mineral density in HIV-infected patients: a longitudinal cohort study. AIDS (London, England). 2010;24(18):2827–33.

    Article  Google Scholar 

  12. Escota GV, Mondy K, Bush T, Conley L, Brooks JT, Onen N, et al. High prevalence of low bone mineral density and substantial bone loss over 4 years among HIV-infected persons in the era of modern antiretroviral therapy. AIDS Res Hum Retrovir. 2016;32(1):59–67.

    Article  CAS  PubMed  Google Scholar 

  13. Cazanave C, Dupon M, Lavignolle-Aurillac V, Barthe N, Lawson-Ayayi S, Mehsen N et al. Reduced bone mineral density in HIV-infected patients: prevalence and associated factors. AIDS (London, England). 2008;22(3):395–402.

  14. Battalora L, Buchacz K, Armon C, Overton ET, Hammer J, Patel P et al. Low bone mineral density and risk of incident fracture in HIV-infected adults. Antivir Ther. 2015.

  15. Young B, Dao CN, Buchacz K, Baker R, Brooks JT. Increased rates of bone fracture among HIV-infected persons in the HIV Outpatient Study (HOPS) compared with the US general population, 2000–2006. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America. 2011;52(8):1061–8.

    Article  Google Scholar 

  16. Womack JA, Goulet JL, Gibert C, Brandt C, Chang CC, Gulanski B, et al. Increased risk of fragility fractures among HIV infected compared to uninfected male veterans. PLoS One. 2011;6(2):e17217.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Sharma A, Shi Q, Hoover DR, Anastos K, Tien PC, Young MA et al. Increased fracture incidence in middle-aged HIV-infected and HIV-uninfected women: updated results from the Women's Interagency HIV Study. Journal of acquired immune deficiency syndromes (1999). 2015;70(1):54–61.

  18. Prieto-Alhambra D, Guerri-Fernandez R, De Vries F, Lalmohamed A, Bazelier M, Starup-Linde J, et al. HIV infection and its association with an excess risk of clinical fractures: a nationwide case-control study. Journal of acquired immune deficiency syndromes (1999). 2014;66(1):90–5.

    Article  Google Scholar 

  19. Loi F, Cordova LA, Pajarinen J, Lin TH, Yao Z, Goodman SB. Inflammation, fracture and bone repair. Bone. 2016;86:119–30.

    Article  CAS  PubMed  Google Scholar 

  20. Xiong J, Onal M, Jilka RL, Weinstein RS, Manolagas SC, O'Brien CA. Matrix-embedded cells control osteoclast formation. Nat Med. 2011;17(10):1235–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Nakashima T, Hayashi M, Fukunaga T, Kurata K, Oh-Hora M, Feng JQ, et al. Evidence for osteocyte regulation of bone homeostasis through RANKL expression. Nat Med. 2011;17(10):1231–4.

    Article  CAS  PubMed  Google Scholar 

  22. • Titanji K, Vunnava A, Sheth AN, Delille C, Lennox JL, Sanford SE, et al. Dysregulated B cell expression of RANKL and OPG correlates with loss of bone mineral density in HIV infection. PLoS Pathog. 2014;10(10):e1004497. This immuno-skeletal profiling of HIV-uninfected and cART-naïve HIV-infected adults provides evidence that B cell dysfunction in the setting of HIV infection is associated with dysregulated RANKL and OPG expression, which is correlated with BMD loss, thus providing an immuno-centric mechanism for HIV-induced bone loss.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Li Y, Toraldo G, Li A, Yang X, Zhang H, Qian WP, et al. B cells and T cells are critical for the preservation of bone homeostasis and attainment of peak bone mass in vivo. Blood. 2007;109(9):3839–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. •• Ofotokun I, Titanji K, Vikulina T, Roser-Page S, Yamaguchi M, Zayzafoon M, et al. Role of T-cell reconstitution in HIV-1 antiretroviral therapy-induced bone loss. Nat Commun. 2015;6:8282. This study is a proof of concept that immune reconstitution/regeneration, as occurs in HIV-infected subjects initiating cART, can promote significant bone loss, thus providing a mechanism by which all cART classes contribute to bone loss.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Ofotokun I, Weitzmann MN. HIV and bone metabolism. Discov Med. 2011;11(60):385–93.

    PubMed  PubMed Central  Google Scholar 

  26. Carr A, Grund B, Neuhaus J, Schwartz A, Bernardino JI, White D, et al. Prevalence of and risk factors for low bone mineral density in untreated HIV infection: a substudy of the INSIGHT Strategic Timing of AntiRetroviral Treatment (START) trial. HIV medicine. 2015;16(Suppl 1):137–46.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Kooij KW, Wit FW, Bisschop PH, Schouten J, Stolte IG, Prins M, et al. Low bone mineral density in patients with well-suppressed HIV infection: association with body weight, smoking, and prior advanced HIV disease. The Journal of infectious diseases. 2015;211(4):539–48.

    Article  PubMed  Google Scholar 

  28. Lo Re 3rd V, Volk J, Newcomb CW, Yang YX, Freeman CP, Hennessy S, et al. Risk of hip fracture associated with hepatitis C virus infection and hepatitis C/human immunodeficiency virus coinfection. Hepatology (Baltimore, Md). 2012;56(5):1688–98.

    Article  Google Scholar 

  29. O'Neill TJ, Rivera L, Struchkov V, Zaheen A, Thein HH. The effect of HIV-hepatitis C co-infection on bone mineral density and fracture: a meta-analysis. PLoS One. 2014;9(7):e101493.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Cotter AG, Sabin CA, Simelane S, Macken A, Kavanagh E, Brady JJ, et al. Relative contribution of HIV infection, demographics and body mass index to bone mineral density. AIDS (London, England). 2014;28(14):2051–60.

    Article  Google Scholar 

  31. Takeda K, Adhikari R, Yamada KM, Dhawan S. Hemin activation of innate cellular response blocks human immunodeficiency virus type-1-induced osteoclastogenesis. Biochem Biophys Res Commun. 2015;464(1):7–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Hileman CO, Labbato DE, Storer NJ, Tangpricha V, McComsey GA. Is bone loss linked to chronic inflammation in antiretroviral-naive HIV-infected adults? A 48-week matched cohort study. AIDS (London, England). 2014;28(12):1759–67.

    Article  CAS  Google Scholar 

  33. Short CE, Shaw SG, Fisher MJ, Walker-Bone K, Gilleece YC. Prevalence of and risk factors for osteoporosis and fracture among a male HIV-infected population in the UK. Int J STD AIDS. 2014;25(2):113–21.

    Article  PubMed  Google Scholar 

  34. Masyeni S, Utama S, Somia A, Widiana R, Merati TP. Factors influencing bone mineral density in ARV-naive patients at Sanglah Hospital, Bali. Acta medica Indonesiana. 2013;45(3):175–9.

    PubMed  Google Scholar 

  35. Grijsen ML, Vrouenraets SM, Steingrover R, Lips P, Reiss P, Wit FW, et al. High prevalence of reduced bone mineral density in primary HIV-1-infected men. AIDS (London, England). 2010;24(14):2233–8.

    Article  Google Scholar 

  36. Ruan A, Tobin NH, Mulligan K, Rollie A, Li F, Sleasman J, et al. Brief report: macrophage activation in HIV-infected adolescent males contributes to differential bone loss by sex: Adolescent Trials Network Study 021. Journal of acquired immune deficiency syndromes (1999). 2016;72(4):372–5.

    Article  CAS  Google Scholar 

  37. Kong YY, Feige U, Sarosi I, Bolon B, Tafuri A, Morony S, et al. Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature. 1999;402(6759):304–9.

    Article  CAS  PubMed  Google Scholar 

  38. D'Amelio P, Grimaldi A, Di Bella S, Brianza SZ, Cristofaro MA, Tamone C, et al. Estrogen deficiency increases osteoclastogenesis up-regulating T cells activity: a key mechanism in osteoporosis. Bone. 2008;43(1):92–100.

    Article  PubMed  CAS  Google Scholar 

  39. Gazzola L, Bellistri GM, Tincati C, Ierardi V, Savoldi A, Del Sole A, et al. Association between peripheral T-Lymphocyte activation and impaired bone mineral density in HIV-infected patients. J Transl Med. 2013;11:51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Kendall MA, Tassiopoulos K, McComsey GA, Yin MT. Fractures are not associated with CD8(+) T cell activation: an analysis of the ACTG ALLRT study. AIDS Res Hum Retrovir. 2015;31(8):769–71.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Vikulina T, Fan X, Yamaguchi M, Roser-Page S, Zayzafoon M, Guidot DM, 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):13848–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Butler JS, Dunning EC, Murray DW, Doran PP, O'Byrne JM. HIV-1 protein induced modulation of primary human osteoblast differentiation and function via a Wnt/beta-catenin-dependent mechanism. Journal of orthopaedic research : official publication of the Orthopaedic Research Society. 2013;31(2):218–26.

    Article  CAS  Google Scholar 

  43. Cotter EJ, Malizia AP, Chew N, Powderly WG, Doran PP. 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(12):1521–30.

    Article  CAS  PubMed  Google Scholar 

  44. Fakruddin JM, Laurence J. HIV envelope gp120-mediated regulation of osteoclastogenesis via receptor activator of nuclear factor kappa B ligand (RANKL) secretion and its modulation by certain HIV protease inhibitors through interferon-gamma/RANKL cross-talk. J Biol Chem. 2003;278(48):48251–8.

    Article  CAS  PubMed  Google Scholar 

  45. Modarresi R, Xiang Z, Yin M, Laurence J. 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(1):123–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Beaupere C, Garcia M, Larghero J, Feve B, Capeau J, Lagathu C. The HIV proteins Tat and Nef promote human bone marrow mesenchymal stem cell senescence and alter osteoblastic differentiation. Aging Cell. 2015;14(4):534–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Brown TT, Qaqish RB. Antiretroviral therapy and the prevalence of osteopenia and osteoporosis: a meta-analytic review. AIDS (London, England). 2006;20(17):2165–74.

    Article  Google Scholar 

  48. Brown TT, McComsey GA, King MS, Qaqish RB, Bernstein BM, da Silva BA. Loss of bone mineral density after antiretroviral therapy initiation, independent of antiretroviral regimen. Journal of acquired immune deficiency syndromes (1999). 2009;51(5):554–61.

    Article  CAS  Google Scholar 

  49. de Menezes Barbosa EG, de Paula FJ, Machado AA, de Assis PF, Barbosa Junior F, Navarro AM. Impact of antiretroviral therapy on bone metabolism markers in HIV-seropositive patients. Bone. 2013;57(1):62–7.

    Article  PubMed  CAS  Google Scholar 

  50. Briot K, Kolta S, Flandre P, Boue F, Ngo Van P, Cohen-Codar I, et al. Prospective one-year bone loss in treatment-naive HIV+ men and women on single or multiple drug HIV therapies. Bone. 2011;48(5):1133–9.

    Article  CAS  PubMed  Google Scholar 

  51. Bolland MJ, Wang TK, Grey A, Gamble GD, Reid IR. Stable bone density in HAART-treated individuals with HIV: a meta-analysis. J Clin Endocrinol Metab. 2011;96(9):2721–31.

    Article  CAS  PubMed  Google Scholar 

  52. Grund B, Peng G, Gibert CL, Hoy JF, Isaksson RL, Shlay JC, et al. Continuous antiretroviral therapy decreases bone mineral density. AIDS (London, England). 2009;23(12):1519–29.

    Article  CAS  PubMed Central  Google Scholar 

  53. Grant PM, Kitch D, McComsey GA, Collier AC, Koletar SL, Erlandson KM, et al. Long-term bone mineral density changes in antiretroviral-treated HIV-infected individuals. The Journal of infectious diseases. 2016;214(4):607–11.

    Article  PubMed  Google Scholar 

  54. • Grant PM, Kitch D, McComsey GA, Dube MP, Haubrich R, Huang J, et al. Low baseline CD4+ count is associated with greater bone mineral density loss after antiretroviral therapy initiation. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2013;57(10):1483–8. This study shows that lower CD4 nadir is associated with more robust cART-induced bone loss, supporting an immune regeneration component to cART bone loss.

  55. •• Ofotokun I, Titanji K, Vunnava A, Roser-Page S, Vikulina T, Villinger F, 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 (London, England). 2016;30(3):405–14. This study demonstrates that early bone loss after cART initiation is associated with the degree of immune reconstitution, thus providing a mechanism by which all cART classes contribute to bone loss.

    Article  CAS  Google Scholar 

  56. Franco JM, Rubio A, Martinez-Moya M, Leal M, Merchante E, Sanchez-Quijano A, et al. T-cell repopulation and thymic volume in HIV-1-infected adult patients after highly active antiretroviral therapy. Blood. 2002;99(10):3702–6.

    Article  CAS  PubMed  Google Scholar 

  57. Stellbrink HJ, Orkin C, Arribas JR, Compston J, Gerstoft J, Van Wijngaerden E, et al. 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. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2010;51(8):963–72.

    Article  Google Scholar 

  58. McComsey GA, Kitch D, Daar ES, Tierney C, Jahed NC, Tebas P, 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(12):1791–801.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Huang JS, Hughes MD, Riddler SA, Haubrich RH. The ACTGAST. Bone mineral density effects of randomized regimen and nucleoside reverse transcriptase inhibitor (NRTI) selection from ACTG A5142. HIV clinical trials. 2013;14(5):224–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Brown TT, Ross AC, Storer N, Labbato D, McComsey GA. Bone turnover, osteoprotegerin/RANKL and inflammation with antiretroviral initiation: tenofovir versus non-tenofovir regimens. Antivir Ther. 2011;16(7):1063–72.

    Article  CAS  PubMed  Google Scholar 

  61. Wohl DA, Bhatti L, Small CB, Edelstein H, Zhao HH, Margolis DA, et al. The ASSURE study: HIV-1 suppression is maintained with bone and renal biomarker improvement 48 weeks after ritonavir discontinuation and randomized switch to abacavir/lamivudine + atazanavir. HIV medicine. 2016;17(2):106–17.

    Article  CAS  PubMed  Google Scholar 

  62. Mulligan K, Glidden DV, Anderson PL, Liu A, McMahan V, Gonzales P, et al. Effects of emtricitabine/tenofovir on bone mineral density in HIV-negative persons in a randomized, double-blind, placebo-controlled trial. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2015;61(4):572–80.

    Article  Google Scholar 

  63. Kasonde M, Niska RW, Rose C, Henderson FL, Segolodi TM, Turner K, et al. Bone mineral density changes among HIV-uninfected young adults in a randomised trial of pre-exposure prophylaxis with tenofovir-emtricitabine or placebo in Botswana. PLoS One. 2014;9(3):e90111.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Mirembe BG, Kelly CW, Mgodi N, Greenspan S, Dai JY, Mayo A, et al. Bone mineral density changes among young, healthy African women receiving oral tenofovir for HIV preexposure prophylaxis. Journal of acquired immune deficiency syndromes (1999). 2016;71(3):287–94.

    Article  CAS  Google Scholar 

  65. Grigsby IF, Pham L, Gopalakrishnan R, Mansky LM, Mansky KC. Downregulation of Gnas, Got2 and Snord32a following tenofovir exposure of primary osteoclasts. Biochem Biophys Res Commun. 2010;391(3):1324–9.

    Article  CAS  PubMed  Google Scholar 

  66. Grigsby IF, Pham L, Mansky LM, Gopalakrishnan R, Carlson AE, Mansky KC. Tenofovir treatment of primary osteoblasts alters gene expression profiles: implications for bone mineral density loss. Biochem Biophys Res Commun. 2010;394(1):48–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Labarga P, Barreiro P, Martin-Carbonero L, Rodriguez-Novoa S, Solera C, Medrano J, et al. Kidney tubular abnormalities in the absence of impaired glomerular function in HIV patients treated with tenofovir. AIDS (London, England). 2009;23(6):689–96.

    Article  CAS  Google Scholar 

  68. Ray AS, Fordyce MW, Hitchcock MJ. Tenofovir alafenamide: a novel prodrug of tenofovir for the treatment of human immunodeficiency virus. Antivir Res. 2016;125:63–70.

    Article  CAS  PubMed  Google Scholar 

  69. Casado JL. Renal and bone toxicity with the use of tenofovir: understanding at the end. AIDS Rev. 2016;18(2):59–68.

    PubMed  Google Scholar 

  70. Lucey JM, Hsu P, Ziegler JB. Tenofovir-related Fanconi's syndrome and osteomalacia in a teenager with HIV. BMJ Case Rep. 2013;2013.

  71. Hamzah L, Samarawickrama A, Campbell L, Pope M, Burling K, Walker-Bone K, et al. Effects of renal tubular dysfunction on bone in tenofovir-exposed HIV-positive patients. AIDS (London, England). 2015;29(14):1785–92.

    Article  CAS  Google Scholar 

  72. Masia M, Padilla S, Robledano C, Lopez N, Ramos JM, Gutierrez F. Early changes in parathyroid hormone concentrations in HIV-infected patients initiating antiretroviral therapy with tenofovir. AIDS Res Hum Retrovir. 2012;28(3):242–6.

    Article  CAS  PubMed  Google Scholar 

  73. Casado JL, Santiuste C, Vazquez M, Banon S, Rosillo M, Gomez A, et al. Bone mineral density decline according to renal tubular dysfunction and phosphaturia in tenofovir-exposed HIV-infected patients. AIDS (London, England). 2016;30(9):1423–31.

    Article  CAS  Google Scholar 

  74. Lee WA, He GX, Eisenberg E, Cihlar T, Swaminathan S, Mulato A, et al. Selective intracellular activation of a novel prodrug of the human immunodeficiency virus reverse transcriptase inhibitor tenofovir leads to preferential distribution and accumulation in lymphatic tissue. Antimicrob Agents Chemother. 2005;49(5):1898–906.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Ruane PJ, DeJesus E, Berger D, Markowitz M, Bredeek UF, Callebaut C, et al. Antiviral activity, safety, and pharmacokinetics/pharmacodynamics of tenofovir alafenamide as 10-day monotherapy in HIV-1-positive adults. Journal of acquired immune deficiency syndromes (1999). 2013;63(4):449–55.

    Article  CAS  Google Scholar 

  76. Sax PE, Wohl D, Yin MT, Post F, DeJesus E, Saag M, et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate, coformulated with elvitegravir, cobicistat, and emtricitabine, for initial treatment of HIV-1 infection: two randomised, double-blind, phase 3, non-inferiority trials. Lancet (London, England). 2015;385(9987):2606–15.

    Article  CAS  Google Scholar 

  77. Mills A, Crofoot Jr G, McDonald C, Shalit P, Flamm JA, Gathe Jr J, et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate in the first protease inhibitor-based single-tablet regimen for initial HIV-1 therapy: a randomized phase 2 study. Journal of acquired immune deficiency syndromes (1999). 2015;69(4):439–45.

    Article  CAS  Google Scholar 

  78. Mills A, Arribas JR, Andrade-Villanueva J, DiPerri G, Van Lunzen J, Koenig E, et al. Switching from tenofovir disoproxil fumarate to tenofovir alafenamide in antiretroviral regimens for virologically suppressed adults with HIV-1 infection: a randomised, active-controlled, multicentre, open-label, phase 3, non-inferiority study. Lancet Infect Dis. 2016;16(1):43–52.

    Article  CAS  PubMed  Google Scholar 

  79. Kinai E, Nishijima T, Mizushima D, Watanabe K, Aoki T, Honda H, et al. Long-term use of protease inhibitors is associated with bone mineral density loss. AIDS Res Hum Retrovir. 2014;30(6):553–9.

    Article  CAS  PubMed  Google Scholar 

  80. Tebas P, Powderly WG, Claxton S, Marin D, Tantisiriwat W, Teitelbaum SL, et al. Accelerated bone mineral loss in HIV-infected patients receiving potent antiretroviral therapy. AIDS (London, England). 2000;14(4):F63–7.

    Article  CAS  Google Scholar 

  81. Zuccotti G, Vigano A, Gabiano C, Giacomet V, Mignone F, Stucchi S, et al. Antiretroviral therapy and bone mineral measurements in HIV-infected youths. Bone. 2010;46(6):1633–8.

    Article  PubMed  Google Scholar 

  82. Bedimo R, Maalouf NM, Zhang S, Drechsler H, Tebas P. Osteoporotic fracture risk associated with cumulative exposure to tenofovir and other antiretroviral agents. AIDS (London, England). 2012;26(7):825–31.

    Article  CAS  Google Scholar 

  83. Tebas P, Umbleja T, Dube MP, Parker RA, Mulligan K, Roubenoff R et al. Initiation of ART is associated with bone loss independent of the specific ART regimen. The results of ACTG A5005s. 14th Conference on Retroviruses and Opportunistic Infections; 2007; Los Angeles, CA.

  84. Duvivier C, Kolta S, Assoumou L, Ghosn J, Rozenberg S, Murphy RL, et al. Greater decrease in bone mineral density with protease inhibitor regimens compared with nonnucleoside reverse transcriptase inhibitor regimens in HIV-1 infected naive patients. AIDS (London, England). 2009;23(7):817–24.

    Article  Google Scholar 

  85. Rockstroh JK, DeJesus E, Henry K, Molina JM, Gathe J, Ramanathan S et al. A randomized, double-blind comparison of coformulated elvitegravir/cobicistat/emtricitabine/tenofovir DF vs ritonavir-boosted atazanavir plus coformulated emtricitabine and tenofovir DF for initial treatment of HIV-1 infection: analysis of week 96 results. Journal of acquired immune deficiency syndromes (1999). 2013;62(5):483–486.

  86. Brown TT, Moser C, Currier JS, Ribaudo HJ, Rothenberg J, Kelesidis T, et al. Changes in bone mineral density after initiation of antiretroviral treatment with tenofovir disoproxil fumarate/emtricitabine plus atazanavir/ritonavir, darunavir/ritonavir, or raltegravir. The Journal of infectious diseases. 2015;212(8):1241–9.

    Article  PubMed  PubMed Central  Google Scholar 

  87. Gibellini D, Borderi M, de Crignis E, Clo A, Miserocchi A, Viale P, et al. Analysis of the effects of specific protease inhibitors on OPG/RANKL regulation in an osteoblast-like cell line. The new microbiologica. 2010;33(2):109–15.

    CAS  PubMed  Google Scholar 

  88. Malizia AP, Cotter E, Chew N, Powderly WG, Doran PP. HIV protease inhibitors selectively induce gene expression alterations associated with reduced calcium deposition in primary human osteoblasts. AIDS Res Hum Retrovir. 2007;23(2):243–50.

    Article  CAS  PubMed  Google Scholar 

  89. Hernandez-Vallejo SJ, Beaupere C, Larghero J, Capeau J, Lagathu C. HIV protease inhibitors induce senescence and alter osteoblastic potential of human bone marrow mesenchymal stem cells: beneficial effect of pravastatin. Aging Cell. 2013;12(6):955–65.

    Article  CAS  PubMed  Google Scholar 

  90. Yin MT, Modarresi R, Shane E, Santiago F, Ferris DC, McMahon DJ, et al. Effects of HIV infection and antiretroviral therapy with ritonavir on induction of osteoclast-like cells in postmenopausal women. Osteoporosis international: a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. 2011;22(5):1459–68.

    Article  CAS  Google Scholar 

  91. Santiago F, Oguma J, Brown AM, Laurence J. Noncanonical Wnt signaling promotes osteoclast differentiation and is facilitated by the human immunodeficiency virus protease inhibitor ritonavir. Biochem Biophys Res Commun. 2012;417(1):223–30.

    Article  CAS  PubMed  Google Scholar 

  92. Guaraldi G, Zona S, Cossarizza A, Vernacotola L, Carli F, Lattanzi A, et al. Switching to darunavir/ritonavir monotherapy vs. triple-therapy on body fat redistribution and bone mass in HIV-infected adults: the Monarch randomized controlled trial. Int J STD AIDS. 2014;25(3):207–12.

    Article  PubMed  CAS  Google Scholar 

  93. Haskelberg H, Mallon PW, Hoy J, Amin J, Moore C, Phanuphak P, et al. Bone mineral density over 96 weeks in adults failing first-line therapy randomized to raltegravir/lopinavir/ritonavir compared with standard second-line therapy. Journal of acquired immune deficiency syndromes (1999). 2014;67(2):161–8.

    Article  CAS  Google Scholar 

  94. Bedimo RJ, Drechsler H, Jain M, Cutrell J, Zhang S, Li X, et al. The RADAR study: week 48 safety and efficacy of RAltegravir combined with boosted DARunavir compared to tenofovir/emtricitabine combined with boosted darunavir in antiretroviral-naive patients. Impact on bone health. PLoS One. 2014;9(8):e106221.

    Article  PubMed  PubMed Central  Google Scholar 

  95. Cihlar T, Ray AS, Laflamme G, Vela JE, Tong L, Fuller MD, et al. Molecular assessment of the potential for renal drug interactions between tenofovir and HIV protease inhibitors. Antivir Ther. 2007;12(2):267–72.

    CAS  PubMed  Google Scholar 

  96. Kearney BP, Mathias A, Mittan A, Sayre J, Ebrahimi R, Cheng AK. Pharmacokinetics and safety of tenofovir disoproxil fumarate on coadministration with lopinavir/ritonavir. Journal of acquired immune deficiency syndromes (1999). 2006;43(3):278–83.

    Article  CAS  Google Scholar 

  97. Baxi SM, Greenblatt RM, Bacchetti P, Scherzer R, Minkoff H, Huang Y, et al. Common clinical conditions—age, low BMI, ritonavir use, mild renal impairment—affect tenofovir pharmacokinetics in a large cohort of HIV-infected women. AIDS (London, England). 2014;28(1):59–66.

    Article  CAS  Google Scholar 

  98. Reid IR, Bolland MJ, Grey A. Effects of vitamin D supplements on bone mineral density: a systematic review and meta-analysis. Lancet (London, England). 2014;383(9912):146–55.

    Article  CAS  Google Scholar 

  99. Pinzone MR, Di Rosa M, Celesia BM, Condorelli F, Malaguarnera M, Madeddu G, et al. LPS and HIV gp120 modulate monocyte/macrophage CYP27B1 and CYP24A1 expression leading to vitamin D consumption and hypovitaminosis D in HIV-infected individuals. European review for medical and pharmacological sciences. 2013;17(14):1938–50.

    CAS  PubMed  Google Scholar 

  100. Hileman CO, Overton ET, McComsey GA. Vitamin D and bone loss in HIV. Curr Opin HIV AIDS. 2016;11(3):277–84.

    Article  CAS  PubMed  Google Scholar 

  101. Havers FP, Detrick B, Cardoso SW, Berendes S, Lama JR, Sugandhavesa P, et al. Change in vitamin d levels occurs early after antiretroviral therapy initiation and depends on treatment regimen in resource-limited settings. PLoS One. 2014;9(4):e95164.

    Article  PubMed  PubMed Central  Google Scholar 

  102. Cervero M, Agud JL, Garcia-Lacalle C, Alcazar V, Torres R, Jusdado JJ, et al. Prevalence of vitamin D deficiency and its related risk factor in a Spanish cohort of adult HIV-infected patients: effects of antiretroviral therapy. AIDS Res Hum Retrovir. 2012;28(9):963–71.

    Article  CAS  PubMed  Google Scholar 

  103. Hidron AI, Hill B, Guest JL, Rimland D. Risk factors for vitamin D deficiency among veterans with and without HIV infection. PLoS One. 2015;10(4):e0124168.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  104. Cozzolino M, Vidal M, Arcidiacono MV, Tebas P, Yarasheski KE, Dusso AS. HIV-protease inhibitors impair vitamin D bioactivation to 1,25-dihydroxyvitamin D. AIDS (London, England). 2003;17(4):513–20.

    Article  CAS  Google Scholar 

  105. • Brown TT, Hoy J, Borderi M, Guaraldi G, Renjifo B, Vescini F, et al. Recommendations for evaluation and management of bone disease in HIV. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2015;60(8):1242–51. This evidence-based guideline is a useful resource for clinicians in diagnosing and treating bone disease in HIV-infected patients.

    Article  Google Scholar 

  106. European AIDS Clinical Society (EACS) Guidelines, version 8.0. European AIDS Clinical Society. 2015. http://www.eacsociety.org/files/guidelines_8.0-english-revised_20160610.pdf. Accessed October 13 2016.

  107. Hillier TA, Cauley JA, Rizzo JH, Pedula KL, Ensrud KE, Bauer DC, et al. WHO absolute fracture risk models (FRAX): do clinical risk factors improve fracture prediction in older women without osteoporosis? Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2011;26(8):1774–82.

    Article  Google Scholar 

  108. Yin MT, Shiau S, Rimland D, Gibert CL, Bedimo RJ, Rodriguez-Barradas MC, et al. Fracture prediction with modified-FRAX in older HIV-infected and uninfected men. Journal of acquired immune deficiency syndromes (1999). 2016;72(5):513–20.

    Google Scholar 

  109. Stephens KI, Rubinsztain L, Payan J, Rentsch C, Rimland D, Tangpricha V. Dual-energy X-ray absorptiometry and calculated FRAX risk scores may underestimate osteoporotic fracture risk in vitamin D-deficient veterans with HIV infection. Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. 2016;22(4):440–6.

    Article  Google Scholar 

  110. Short CE, Shaw SG, Fisher MJ, Gilleece YC, Walker-Bone K. Comparison of peripheral forearm DXA and clinical risk factor screening using FRAX(R) to assess the risk of HIV-associated low bone mass: a cross-sectional study. Arch Osteoporos. 2014;9:181.

    Article  PubMed  PubMed Central  Google Scholar 

  111. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach. World Health Organization. 2016. http://apps.who.int/iris/bitstream/10665/208825/1/9789241549684_eng.pdf?ua=1. Accessed October 12 2016.

  112. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents—A Working Group of the Office of AIDS Research Advisory Council (OARAC). 2016. https://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. Accessed October 12 2016.

  113. Bech A, Van Bentum P, Telting D, Gisolf J, Richter C, De Boer H. Treatment of calcium and vitamin D deficiency in HIV-positive men on tenofovir-containing antiretroviral therapy. HIV Clin Trials. 2012;13(6):350–6.

    Article  CAS  PubMed  Google Scholar 

  114. • Overton ET, Chan ES, Brown TT, Tebas P, McComsey GA, Melbourne KM, et al. Vitamin D and calcium attenuate bone loss with antiretroviral therapy initiation: a randomized trial. Ann Intern Med. 2015;162(12):815–24. This ACTG clinical trial demonstrates that HIV-associated bone loss can be mitigated by calcium and vitamin D supplementation initiated at the start of cART. Vitamin D and calcium supplementation is therefore a potential strategy to prevent BMD loss in high-risk HIV-infected patients.

    Article  PubMed  PubMed Central  Google Scholar 

  115. Yamaguchi M, Weitzmann MN. High dose 1,25(OH)2D3 inhibits osteoblast mineralization in vitro. Int J Mol Med. 2012;29(5):934–8.

    CAS  PubMed  Google Scholar 

  116. Waldman T, Sarbaziha R, Merz CN, Shufelt C. Calcium supplements and cardiovascular disease: a review. Am J Lifestyle Med. 2015;9(4):298–307.

    Article  PubMed  Google Scholar 

  117. Black DM, Rosen CJ. Clinical Practice. Postmenopausal osteoporosis. N Engl J Med. 2016;374(3):254–62.

    Article  CAS  PubMed  Google Scholar 

  118. Rozenberg S, Lanoy E, Bentata M, Viard JP, Valantin MA, Missy P, et al. Effect of alendronate on HIV-associated osteoporosis: a randomized, double-blind, placebo-controlled, 96-week trial (ANRS 120). AIDS Res Hum Retrovir. 2012;28(9):972–80.

    CAS  PubMed  Google Scholar 

  119. Bolland MJ, Grey AB, Horne AM, Briggs SE, Thomas MG, Ellis-Pegler RB, et al. Annual zoledronate increases bone density in highly active antiretroviral therapy-treated human immunodeficiency virus-infected men: a randomized controlled trial. J Clin Endocrinol Metab. 2007;92(4):1283–8.

    Article  CAS  PubMed  Google Scholar 

  120. Pepe J, Isidori AM, Falciano M, Iaiani G, Salotti A, Diacinti D, et al. Effect of risedronate in osteoporotic HIV males, according to gonadal status: a pilot study. Endocrine. 2014;47(2):456–62.

    Article  CAS  PubMed  Google Scholar 

  121. Pinzone MR, Moreno S, Cacopardo B, Nunnari G. Is there enough evidence to use bisphosphonates in HIV-infected patients? A systematic review and meta-analysis. AIDS Rev. 2014;16(4):213–22.

    PubMed  Google Scholar 

  122. •• Ofotokun I, Titanji K, Lahiri CD, Vunnava A, Foster A, Sanford SE, et al. A single-dose zoledronic acid infusion prevents antiretroviral therapy-induced bone loss in treatment-naive HIV-infected patients: a phase IIb trial. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2016;63(5):663–71. In this clinical trial, a single zoledronic acid infusion prevented cART-induced bone loss up to 48 weeks after administration thus potentially providing a simple pharmacologic strategy for preventing cART-associated bone loss. Long term follow-up data are needed.

    Article  Google Scholar 

  123. Wheeler AL, Tien PC, Grunfeld C, Schafer AL. Teriparatide treatment of osteoporosis in an HIV-infected man: a case report and literature review. AIDS (London, England). 2015;29(2):245–6.

    Article  Google Scholar 

  124. Moshiri A, Sharifi AM, Oryan A. Role of Simvastatin on fracture healing and osteoporosis: a systematic review on in vivo investigations. Clin Exp Pharmacol Physiol. 2016;43(7):659–84.

    Article  CAS  PubMed  Google Scholar 

  125. Erlandson KM, Jiang Y, Debanne SM, McComsey GA. Effects of 96 weeks of rosuvastatin on bone, muscle, and fat in HIV-infected adults on effective antiretroviral therapy. AIDS Res Hum Retrovir. 2016;32(4):311–6.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, 49 Jesse Hill Jr Drive, Atlanta, GA, 30303, USA

    Caitlin A. Moran MD & Ighovwerha Ofotokun MD, MSc

  2. Grady Healthcare System, Atlanta, GA, USA

    Caitlin A. Moran MD & Ighovwerha Ofotokun MD, MSc

  3. Atlanta Department of Veterans Affairs Medical Center, Decatur, GA, USA

    M. Neale Weitzmann PhD

  4. Division of Endocrinology, Metabolism and Lipids, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA

    M. Neale Weitzmann PhD

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  1. Caitlin A. Moran MD
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Correspondence to Ighovwerha Ofotokun MD, MSc.

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The authors’ research activities are supported by the National Institute on Aging (NIA) under Award Number R01AG040013 and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) under Award Numbers R01AR059364, R01AR068157, and R01AR070091 to M.N.W. and I.O. M.N.W. is also supported by a grant from the Biomedical Laboratory Research and Development Service of the VA Office of Research and Development (5I01BX000105). C.A.M. is supported by National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR000454. The authors gratefully acknowledge services provided by the Emory Center for AIDS Research (CFAR) funded though NIAID (P30AI050409) and the Atlanta Clinical and Translational Science Institute (ACTSI), funded though the National Center for Advancing Translational Sciences (UL1TR000454).

Conflicts of Interest

Dr. Caitlin A. Moran declares that she has no conflict of interest. Dr. M. Neale Weitzmann declares that he has no conflict of interest. Dr. Ighovwerha Ofotokun declares that he has no conflict of interest.

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Moran, C.A., Neale Weitzmann, M. & Ofotokun, I. Bone Loss in HIV Infection. Curr Treat Options Infect Dis 9, 52–67 (2017). https://doi.org/10.1007/s40506-017-0109-9

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