Bulhões, Camila Nobre

Franco, André Silva

Freitas, Thiago Quadrante

Pereira, Rosa Maria Rodrigues

English

Cadernos Espinosanos (E-Journal)

Rev Med (São Paulo). 2018 May-June;97(3):372-3.372doi: http://dx.doi.org/10.11606/issn.1679-9836.v97i3p372-373Letter to the editorBone impairment in HIV-infected patients and tenofovir-induced osteomalacia as a differential diagnosisThiago Quadrante Freitas1, André Silva Franco1,  Camila Nobre Bulhões1, Rosa Maria Rodrigues Pereira1Award Panels Case COMU 2017 - XXXVI Congresso Médico Universitário da FMUSP, São Paulo, 6-8 out. 2017.1. Bone Metabolism Laboratory, Rheumatology Division, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, BR.Corresponding address: Av. Dr. Arnaldo, 455, 3rd floor, room 3193. Sao Paulo, SP, Brazil.  CEP: 1246-903. E-mail: thiago.f@fm.usp.br.Bone impairment is well described in people living with HIV and taking antiretrovirals due to direct and indirect effects of both the virus and the medications on bone and immune cells1,2. Osteopenia and osteoporosis have a prevalence of up to 67% in this population3, and is frequent even in antiretroviral-naïve patients2.Such finding could suggest that unchecked viremia affects bone metabolism through its persistent systemic inflammatory properties1. However, an in vitro study showed that HIV promotes direct osteoblast apoptosis through TNF-alpha activation4, providing evidence that bone impairment may be explained by viremia itself.Hence, the use of antiretrovirals with a goal of undetectable viral load should lead to higher bone mineral density, but some of them may also affect bone metabolism. Indeed, a meta-analysis found that osteoporosis had an odds ratio of 2.5 in patients treated with antiretrovirals, compared to those without treatment3, which suggests that such medications are responsible for another component of bone loss in HIV patients.Protease inhibitors are the antiretrovirals that most frequently affect bone homeostasis: reduced bone mineral density is significantly more common in patients treated with such medications, compared to those in other treatment schemes3. However, tenofovir alone was also associated with increase in bone turnover markers and accelerated bone mineral density loss5,6, even when used in the absence of HIV infection7.In addition to affecting bone resorption, tenofovir may also induce proximal renal tubular toxicity and hypophosphatemic osteomalacia8, another factor that could contribute to bone alterations in HIV patients. Increased tenofovir concentrations in proximal renal tubule cells induces mitochondrial dysfunction, which leads to phosphate depletion9. Tenofovir-induced proximal renal tubular acidosis has an estimated prevalence of 17% in HIV-infected patients taking the drug8, and may appear years after treatment initiation10. Approximately 0.5% develop hypophosphatemic osteomalacia, especially if its use is concomitant with ritonavir-boosted protease inhibitors and non-steroidal anti-inflammatories11. 373Freitas TQ, et al. Bone impairment in HIV-infected patients and tenofovir-induced osteomalacia.The most common clinical finding is diffuse bone pain due to multiple stress fractures11, and should be suspected whenever low phosphate serum levels, increased alkaline phosphatase and increased fractional excretion of phosphate are found, which rule out osteoporosis, that presents without electrolyte laboratory alterations12. Making the right diagnosis prevents inappropriate treatment with bisphosphonates, which depletes even more phosphorus, leaving no substrate with which to mineralize the bone, worsening pain and fractures.Therefore,  cl inicians should be aler t  to hypophosphatemic osteomalacia in patients with low BMD receiving tenofovir, since it can be easily mistaken and incorrectly treated as osteoporosis, worsening bone pain, fractures and hypophosphatemia.REFERENCES1.  Kruger MJ, Nell TA. Bone mineral density in people living with HIV: a narrative review of the literature. AIDS Res Ther. 2017;14(1):35. doi: 10.1186/s12981-017-0162-y.2.  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. 2008;22(3):395-402. oi: 10.1097/QAD.0b013e3282f423dd.3.  Brown TT, Qaqish RB. Antiretroviral therapy and the prevalence of osteopenia and osteoporosis: a meta-analytic review. AIDS. 2006;20(17):2165-74. doi: 10.1097/QAD.0b013e32801022eb.4.  Gibellini D, De Crignis E, Ponti C, Cimatti L, Borderi M, Tschon M, et al. HIV-1 triggers apoptosis in primary osteoblasts and HOBIT cells through TNFα activation. J Med Virol. 2008;80(9):1507-14. doi: 10.1002/jmv.21266. 5.  Negredo E, Diez-Perez A, Bonjoch A, Domingo P, Perez-Alvarez N, Gutierrez M, et al. Switching from tenofovir to abacavir in HIV-1-infected patients with low bone mineral density: changes in bone turnover markers and circulating sclerostin levels. J Antimicrob Chemother. 2015;70(7):2104-7. doi: 10.1093/jac/dkv063.6.  Bloch M, Tong W, Hoy J, Baker D, Lee F, Richardson R, et al. Switch from tenofovir to raltegravir increases low bone mineral density and decreases markers of bone turnover over 48 weeks. HIV Med. 2014;15(6):373-80. doi: 10.1111/hiv.12123.7.  Mulligan K, Glidden D V, 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. Clin Infect Dis. 2015;61(4):572-80. doi: 10.1093/cid/civ324. 8.  Saidenberg-Kermanac’h N, Souabni L, Prendki V, Prie D, Boissier M-C. Normal plasma FGF23 levels kinetic in tenofovir-related hypophosphatemic osteomalacia in an HIV-infected patient with von Recklinghausen disease. Jt Bone Spine. 2011;78(3):306-8. doi: 10.1016/j.jbspin.2010.11.007. 9.  Perazella MA. Tenofovir-induced kidney disease: an acquired renal tubular mitochondriopathy. Kidney Int. 2010;78(11):1060-3. doi: 10.1038/ki.2010.344.10.  Haverkort ME, van der Spek BW, Lips P, Slieker WA, ter Heine R, Huitema AD, et al. 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. 2011;43(10):821-6. doi: 10.3109/00365548.2011.577805.11.  Perrot S, Aslangul E, Szwebel T, Caillat-Vigneron N, Le Jeunne C. Bone pain due to fractures revealing osteomalacia related to Tenofovir-induced proximal renal tubular dysfunction in a human immunodeficiency virus-infected patient. JCR J Clin Rheumatol. 2009;15(2):72-4. doi: 10.1097/RHU.0b013e31819c20d8.12.  Morgan DB. Osteomalacia and osteoporosis. Postgrad Med J. 1968;44(514):621-5. Available from: https://pmj.bmj.com/content/44/514/621.long.Submitted for publication: June 18, 2018Accepted in: June 21, 2018

Bone impairment in HIV-infected patients and tenofovir-induced osteomalacia as a differential diagnosis

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Bone impairment in HIV-infected patients and tenofovir-induced osteomalacia as a differential diagnosis

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