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Hypophosphatemic osteomalacia induced by tenofovir in HIV-infected patients

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Abstract

Tenofovir disoproxil fumarate (TDF) is an adenine analogue reverse transcription inhibitor widely used in first-line treatment of human immunodeficiency virus (HIV) infection and also in hepatitis B virus infection. Its use has been linked to sporadic Fanconi syndrome, renal failure and bone disease. We present the clinical characteristics of tenofovir-induced osteomalacia, discuss bone biopsy findings, describe predisposing factors and compare our results with other reported cases. We describe five cases of hypophosphatemic osteomalacia induced by TDF and recorded at the rheumatology service of a university hospital between 2010 and 2014. We also report the characteristics of bone biopsies of this pathology, which have not been previously described. We include a review of published cases of proximal renal tubulopathy (PRT) and osteomalacia induced by TDF (PubMed 1995–2014; keywords: osteomalacia, tenofovir, Fanconi syndrome, hypophosphatemic osteomalacia, proximal renal tubulopathy, bone biopsy). Five HIV patients who developed hypophosphatemic osteomalacia under TDF treatment (>5 years) presented increasing bone pain and a progressive inability to walk without assistance as a result of multiple insufficiency fractures. Bone biopsy performed in three patients after tetracycline labelling showed increased osteoid thickness, confirming osteomalacia. A literature review retrieved 17 publications on this condition, including 53 cases: 26 patients developed isolated PRT, 25 presented PRT and with multiple insufficiency fractures and two presented isolated bone disease, including osteomalacia and osteoporosis. Rheumatologists should be alert to this complication in patients receiving tenofovir. The main complaint reported by these patients is diffuse pain, predominantly in the lower limbs, indicating multiple stress fractures. Serum phosphate and appropriate screening for abnormal proximal tubule function should be monitored. Bone scintigraphy should be carried out in cases of limb pain before the occurrence of more severe complications.

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References

  1. Bruera D, Luna N, David DO, Bergoglio LM, Zamudio J (2003) Decreased bone mineral density in HIV-infected patients is independent of antiretroviral therapy. AIDS 17(13):1917–1923

    Article  PubMed  Google Scholar 

  2. Brown TT, Qaqish RB (2006) Antiretroviral therapy and the prevalence of osteopenia and osteoporosis: a meta-analytic review. AIDS 20(17):2165–2174

    Article  PubMed  Google Scholar 

  3. Cotter AG, Powderly WG (2011) Endocrine complications of human immunodeficiency virus infection: hypogonadism, bone disease and tenofovir-related toxicity. Best Pract Res Clin Endocrinol Metab 25(3):501–515

    Article  CAS  PubMed  Google Scholar 

  4. Bonjoch A, Figueras M, Estany C, Perez-Alvarez N, Rosales J, del Rio L et al (2010) High prevalence of and progression to low bone mineral density in HIV-infected patients: a longitudinal cohort study. AIDS 24(18):2827–2833

    Article  PubMed  Google Scholar 

  5. Izzedine H, Hulot JS, Vittecoq D, Gallant JE, Staszewski S, Launay-Vacher V et al (2005) 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 Transplant 20(4):743–746

    Article  CAS  PubMed  Google Scholar 

  6. Zimmermann AE, Pizzoferrato T, Bedford J, Morris A, Hoffman R, Braden G (2006) Tenofovir-associated acute and chronic kidney disease: a case of multiple drug interactions. Clin Infect Dis 42(2):283–290

    Article  CAS  PubMed  Google Scholar 

  7. Saidenberg-Kermanac’h N, Souabni L, Prendki V, Prie D, Boissier MC (2011) Normal plasma FGF23 levels kinetic in tenofovir-related hypophosphatemic osteomalacia in an HIV-infected patient with von Recklinghausen disease. Joint Bone Spine 78(3):306–308

    Article  PubMed  Google Scholar 

  8. Haverkort ME, van der Spek BW, Lips P, Slieker WA, ter Heine R, Huitema AD et al (2011) Tenofovir-induced Fanconi syndrome and osteomalacia in two HIV-infected patients: role of intracellular tenofovir diphosphate levels and review of the literature. Scand J Infect Dis 43(10):821–826

    Article  CAS  PubMed  Google Scholar 

  9. Labarga P, Barreiro P, Martin-Carbonero L, Rodriguez-Novoa S, Solera C, Medrano J et al (2009) Kidney tubular abnormalities in the absence of impaired glomerular function in HIV patients treated with tenofovir. AIDS 23(6):689–696

    Article  CAS  PubMed  Google Scholar 

  10. Kinai E, Hanabusa H (2009) Progressive renal tubular dysfunction associated with long-term use of tenofovir DF. AIDS Res Hum Retrovir 25(4):387–394

    Article  CAS  PubMed  Google Scholar 

  11. Gallant JE, Staszewski S, Pozniak AL, DeJesus E, Suleiman JM, Miller MD et al (2004) Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial. JAMA 292(2):191–201

    Article  CAS  PubMed  Google Scholar 

  12. Coca S, Perazella MA (2002) Rapid communication: acute renal failure associated with tenofovir: evidence of drug-induced nephrotoxicity. Am J Med Sci 324(6):342–344

    Article  PubMed  Google Scholar 

  13. Woodward CL, Hall AM, Williams IG, Madge S, Copas A, Nair D et al (2009) Tenofovir-associated renal and bone toxicity. HIV Med 10(8):482–487

    Article  CAS  PubMed  Google Scholar 

  14. Peyriere H, Reynes J, Rouanet I, Daniel N, de Boever CM, Mauboussin JM et al (2004) Renal tubular dysfunction associated with tenofovir therapy: report of 7 cases. J Acquir Immune Defic Syndr 35(3):269–273

    Article  PubMed  Google Scholar 

  15. Izzedine H, Isnard-Bagnis C, Hulot JS, Vittecoq D, Cheng A, Jais CK et al (2004) Renal safety of tenofovir in HIV treatment-experienced patients. AIDS 18(7):1074–1076

    Article  CAS  PubMed  Google Scholar 

  16. Jhaveri MA, Mawad HW, Thornton AC, Mullen NW, Greenberg RN (2010) Tenofovir-associated severe bone pain: I cannot walk! J Int Assoc Phys AIDS Care (Chic) 9(5):328–334

    Article  Google Scholar 

  17. Perrot S, Aslangul E, Szwebel T, Caillat-Vigneron N, Le Jeunne C (2009) Bone pain due to fractures revealing osteomalacia related to tenofovir-induced proximal renal tubular dysfunction in a human immunodeficiency virus-infected patient. J Clin Rheumatol 15(2):72–74

    Article  PubMed  Google Scholar 

  18. Gutmann H, Fricker G, Drewe J, Toeroek M, Miller DS (1999) Interactions of HIV protease inhibitors with ATP-dependent drug export proteins. Mol Pharmacol 56(2):383–389

    CAS  PubMed  Google Scholar 

  19. Bonjoch A, Echeverria P, Perez-Alvarez N, Puig J, Estany C, Clotet B et al (2012) High rate of reversibility of renal damage in a cohort of HIV-infected patients receiving tenofovir-containing antiretroviral therapy. Antiviral Res 96(1):65–69

    Article  CAS  PubMed  Google Scholar 

  20. Earle KE, Seneviratne T, Shaker J, Shoback D (2004) Fanconi’s syndrome in HIV + adults: report of three cases and literature review. J Bone Miner Res 19(5):714–721

    Article  PubMed  Google Scholar 

  21. Parsonage MJ, Wilkins EG, Snowden N, Issa BG, Savage MW (2005) The development of hypophosphataemic osteomalacia with myopathy in two patients with HIV infection receiving tenofovir therapy. HIV Med 6(5):341–346

    Article  CAS  PubMed  Google Scholar 

  22. De la Prada FJ, Prados AM, Tugores A, Uriol M, Saus C, Morey A (2006) Acute renal failure and proximal renal tubular dysfuntion in a patient with acquired immunodeficiency syndrome treated with tenofovir. Nefrologia 26(5):626–630

    PubMed  Google Scholar 

  23. Torres Isidro MV, Garcia Benayas T, del Val Gomez Martinez M, Gonzalez Gallardo F, Gambi Pisonero N, Castilla Miguel S et al (2006) Role of bone gammagraphy in the diagnosis of secondary osteomalacia in a patient treated with tenofovir. Rev Esp Med Nucl 25(2):103–106

    Article  CAS  PubMed  Google Scholar 

  24. Rosello L, Gort A, Planella R, Cabau J (2007) Hypophosphatemia and multiple fractures in patient with human immunodeficiency virus infection treated with tenofovir. Med Clin (Barc) 129(5):197

    Article  Google Scholar 

  25. Brim NM, Cu-Uvin S, Hu SL, O’Bell JW (2007) Bone disease and pathologic fractures in a patient with tenofovir-induced Fanconi syndrome. AIDS Read 17(6):322–328, C3

    PubMed  Google Scholar 

  26. Di Biagio A, Rosso R, Monteforte P, Russo R, Rovetta G, Viscoli C (2009) Whole body bone scintigraphy in tenofovir-related osteomalacia: a case report. J Med Case Rep 3:8136

    Article  PubMed  PubMed Central  Google Scholar 

  27. Wanner DP, Tyndall A, Walker UA (2009) Tenofovir-induced osteomalacia. Clin Exp Rheumatol 27(6):1001–1003

    CAS  PubMed  Google Scholar 

  28. Izzedine H, Thibault V, Valantin MA, Peytavin G, Schneider L, Benhamou Y (2010) Tenofovir/probenecid combination in HIV/HBV-coinfected patients: how to escape Fanconi syndrome recurrence? AIDS 24(7):1078–1079

    Article  PubMed  Google Scholar 

  29. Perez-Rivera AA, Saez P, Leon E, Lozano de Leon-Naranjo F (2011) HIV infected women with intense bone and muscular pain and general weakness. Enferm Infecc Microbiol Clin 29(4):308–310

    Article  PubMed  Google Scholar 

  30. De Socio GV, Fabbriciani G, Massarotti M, Messina S, Cecchini E, Marasini B (2012) Hypophosphatemic osteomalacia associated with tenofovir: a multidisciplinary approach is required. Mediterr J Hematol Infect Dis 4(1):e2012025

    Article  PubMed  PubMed Central  Google Scholar 

  31. Lucey JM, Hsu P, Ziegler JB (2013) Tenofovir-related Fanconi’s syndrome and osteomalacia in a teenager with HIV. BMJ Case Rep 9:2013

    Google Scholar 

  32. Koenig KF, Kalbermatter S, Menter T, Graber P, Kiss D (2014) Recurrent bone fractures due to tenofovir-induced renal phosphate wasting. Scand J Infect Dis 46(3):221–224

    Article  PubMed  Google Scholar 

  33. Gómez Martinez MV, Gallardo FG, Pirogova T, García-Samaniego J (2014) Bone scintigraphy and secondary osteomalacia due to nephrotoxicity in a chronic hepatitis B patient treated with tenofovir. Rev Esp Med Nucl Imagen Mol 33(2):103–105

    PubMed  Google Scholar 

  34. Hamnvik OP, Becker CB, Levy BD, Loscalzo J (2014) Wasting away. N Engl J Med 370:959–966

    Article  PubMed  Google Scholar 

  35. Hall AM, Hendry BM, Nitsch D, Connolly JO (2011) Tenofovir-associated kidney toxicity in HIV-infected patients: a review of the evidence. Am J Kidney Dis 57(5):773–780

    Article  CAS  PubMed  Google Scholar 

  36. Gupta SK, Eustace JA, Winston JA, Boydstun II, Ahuja TS, Rodriguez RA et al (2005) Guidelines for the management of chronic kidney disease in HIV-infected patients: recommendations of the HIV Medicine Association of the Infectious Diseases Society of America. Clin Infect Dis 40(11):1559–1585

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Rheumatology Service, University Hospital Germans Trias i Pujol, Carretera del Canyet s/n, Badalona, Barcelona, 08916, Spain

    Lourdes Mateo, Susana Holgado & Alejandro Olivé

  2. Pathology Service, Hospital del Mar, Barcelona, Spain

    Maria Luisa Mariñoso

  3. Radiology Service, University Hospital Germans Trias i Pujol, Carretera del Canyet s/n, Badalona, Barcelona, 08916, Spain

    Ricard Pérez-Andrés

  4. Lluita Contra la SIDA Foundation, University Hospital Germans Trias i Pujol, Carretera del Canyet s/n, Badalona, Barcelona, 08916, Spain

    Anna Bonjoch

  5. Internal Medicine Department, University Hospital Germans Trias i Pujol, Carretera del Canyet s/n, Badalona, Barcelona, 08916, Spain

    Anna Bonjoch & Joan Romeu

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  1. Lourdes Mateo
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  2. Susana Holgado
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  3. Maria Luisa Mariñoso
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  4. Ricard Pérez-Andrés
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  5. Anna Bonjoch
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  7. Alejandro Olivé
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Correspondence to Lourdes Mateo.

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Mateo, L., Holgado, S., Mariñoso, M.L. et al. Hypophosphatemic osteomalacia induced by tenofovir in HIV-infected patients. Clin Rheumatol 35, 1271–1279 (2016). https://doi.org/10.1007/s10067-014-2627-x

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  • DOI: https://doi.org/10.1007/s10067-014-2627-x

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