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DOI: 10.1055/s-0041-1728734
Proximal Femur Fracture (31-A3.2) Associated with the Use of Tenofovir by an HIV-positive Patient: Case Report
Article in several languages: español | EnglishAbstract
We present the first case report of a human immunodeficiency virus (HIV)-positive adult patient with a fragility fracture of the proximal femur associated with antiretroviral therapy (ART) with tenofovir disoproxil fumarate (TDF) in Chile. Currently, patients diagnosed with HIV start ART early, resulting in more years of exposure to these drugs. The accumulated exposure time to TDF has been associated with a decreased bone mineral density and progressive renal failure, potentially leading to acquired Fanconi syndrome, osteomalacia, and an increased risk of fracture. We present a case of a 44-year-old, HIV-positive man assessed at the emergency room after a fall from standing height which resulted in a proximal femoral pathological fracture. Laboratory findings at admission revealed hypokalemia, hypocalcemia, hypophosphatemia, and hypovitaminosis D. Multidisciplinary management was performed, with TDF discontinuation, ART change, and supplementation with calcium and vitamin D. Closed reduction and fixation with a long cephalomedullary nail was successful, with early motor rehabilitation, functional recovery, and bone consolidation at 12 weeks. Musculoskeletal pain in HIV-positive patients on ART must raise the clinical suspicion of an adverse drug effect; the follow-up of these subjects must include serial monitoring of renal function and serum calcium and phosphorus levels. Screening and suspicion of such complications would enable an early intervention, improving the patients' condition and preventing pathological fractures.
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Introduction
Patients infected with the human immunodeficiency virus (HIV) can present multiple complications, some immunological, based on the level of CD4 cells, and others associated with the treatment. It has been shown that HIV-positive patients have higher osteoporosis rates[1] and a higher frequency of osteoporotic fractures[2] compared to the general population; the etiology of the fractures is multifactorial.
Several studies[3] have reported the association of tenofovir disoproxil fumarate (TDF) with a greater reduction in bone mineral density compared to other antiretroviral agents. In addition, progressive renal failure has been associated to the excretion of TDF by the kidneys, particularly at the proximal tubule (Fanconi syndrome); this increases the urinary excretion of phosphorus and inhibits vitamin D hydroxylation in the kidneys,[4] inhibiting calcitriol synthesis and resulting in osteomalacia.[5]
According to Bedimo et al.,[6] HIV-positive patients treated with TDF present a 12% increase in the risk of osteoporotic fracture by year of exposure compared to HIV-positive patients not treated with TDF.
The present case report discusses the management and warns about the potential adverse effects and increased risk of fractures in HIV-positive patients submitted to antiretroviral therapy (ART) with TDF.
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Clinical Case
A 44-year-old male patient diagnosed as HIV-positive 11 years ago and with class-A chronic liver damage according to the Child-Pugh classification was transferred to an emergency service after a fall from standing height resulting in a left hip injury. The physical examination revealed left-sided muscle deformity, left hip functional impairment, and ecchymosis at the proximal third of the anterior muscle. The patient also referred generalized muscle and bone pain for 1 month.
The laboratory tests revealed mild chronic anemia, thrombocytopenia, hypokalemia, hypocalcemia, and hypophosphatemia, in addition to hypoalbuminemia, hypoproteinemia, severe vitamin D deficit, and preserved renal function. The patient reported treatment with TDF for 5 years, and had no history of previous fractures.
Anteroposterior (AP) hip radiographs and AP and lateral left femur radiographs showed a proximal femur fracture classified as 31-A3.2 in the AO Foundation/Orthopaedic Trauma Association (AO/OTA) classification ([Figure 1]).
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This fragility fracture in a HIV-positive patient treated with TDF was managed multidisciplinary with discontinuation of the TDF, a change in the ART, and calcium and vitamin D supplementation.
The left femur fracture was treated with closed reduction and osteosynthesis with a wide cephalomedullary nail, ensuring a complete segment and avoiding stress areas. The surgery was uneventful ([Figure 2]). Rehabilitation with load as tolerated started at the first postoperative day.
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The patient evolved favorably, with no complications. Serial follow-up evaluations were carried out at 3, 6 and 12 weeks. Twelve weeks after surgery, the radiographs showed signs of consolidation ([Figure 3]), and the functional assessment revealed a Harris score of 92 points. The laboratory tests showed preserved renal function and normalization of bone metabolism, with the following findings: creatinine: 0.74 mg/dL (normal range: 0.70 mg/dL to 1.2 mg/dL); calcium: 8.7 mg/dL (normal range: 8.4 mg/dL to 10.4 mg/dL); phosphorus: 3.2 mg/dL (normal range: 2.7 mg/dL to 4.5 mg/dL); total protein: 7.1 mg/dL (normal range: 6.0 mg/dL to 8.0 mg/dL); potassium: 3.9 mg/dL (normal range: 3.5 mg/dL to 5.1 mg/dL); and vitamin D: 39.2 ng/mL (normal range: 20.0 ng/mL to 100.0 ng/mL).
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Discussion
Bone metabolism disorders are common in HIV-positive patients, and many subjects present premature osteoporosis and an increased risk of fracture.[7] [8]
In an international cohort including 11,820 HIV-positive patients on ART, Borges et al.[9] noted that exposure to TDF was an independent risk factor for fracture.
Another side effect of TDF is renal proximal tubulopathy, but it is less frequently described.[8] Nephrotoxicity has been reported in 1% to 2% of HIV-positive patients treated with TDF.[10] It is known that high intracellular TDF levels interact with mitochondrial DNA;[11] renal proximal tubular injury is associated with this toxic effect on mitochondrial DNA.[12] Renal proximal tubular dysfunction due to TDF may result in increased urinary excretion of phosphorus and inhibition of the 1a-hydroxylation of vitamin D in the kidneys. The inhibition of 1a-hydroxylase in the kidney inhibits the synthesis of 1,25-dihydroxyvitamin D3, leading to osteoporosis secondary to osteomalacia.
The present clinical report describes the first case of a proximal femur fracture associated with the use of TDF in an HIV-positive adult patient in Chile. We have previously reported[13] a case of bilateral hip fracture associated with TDF treatment in a pediatric patient.
The international literature has limited case reports of fragility fractures in patients on ART. The first case was published by Rebolledo et al.[14] in 2011: that of a 54-year-old female patient with bilateral hip fracture who developed Fanconi syndrome after 5 years of TDF treatment.
In HIV-positive patients undergoing treatment with TDF, the presence of musculoskeletal symptoms, such as pain in the muscles or bones, must result in a high index of suspicion of changes in bone metabolism and adverse reactions to drugs. The usual follow-up laboratory tests must include bone metabolism, renal function, and hydric and electrolytic balance tests.
Bone density scan is a useful tool for the early detection of osteoporosis; currently, it is recommended for all HIV-positive patients older than 50 years of age.[8] We also recommend it in patients with bone and muscle symptoms or abnormal findings on bone metabolism laboratory tests, regardless of age.
With laboratory test results showing signs of renal proximal tubulopathy or bone metabolism alterations, as well as bone density scans revealing severe osteoporosis, physicians must consider the discontinuation of the TDF treatment and a change in the ART to manage the complications and reduce the risk of fracture.
Some publications have shown that bisphosphonates can be effective in preventing bone loss due to ART[15] or treating osteoporosis[16] in HIV-positive patients. However, there are no clear guidelines on their use.
The surgical management of these patients is not different from the usual treatment of fragility fractures; in addition, there are no reports of significant differences in terms of infectious complications or consolidation.[17]
In conclusion, the careful evaluation of the patients and the suspicion of drug-related complications are essential for the proper management and prevention of fractures in HIV-positive patients under ART.
It is important to treat these patients with a multidisciplinary team, to change the ART regimen in favor of drugs with milder effects on bone quality, to correct metabolic disturbances, and to provide a timely surgical treatment that enables early movement and rehabilitation to avoid further complications.
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Conflicto de Intereeses
Los autores declaran no haber conflictos de intereeses.
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Referencias
- 1 Tebas P, Powderly WG, Claxton S. et al. Accelerated bone mineral loss in HIV-infected patients receiving potent antiretroviral therapy. AIDS 2000; 14 (04) F63-F67
- 2 Womack JA, Goulet JL, Gibert C. et al; Veterans Aging Cohort Study Project Team. Increased risk of fragility fractures among HIV infected compared to uninfected male veterans. PLoS One 2011; 6 (02) e17217
- 3 Gallant JE, Staszewski S, Pozniak AL. et al; 903 Study Group. Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial. JAMA 2004; 292 (02) 191-201
- 4 Van Rompay KKA, Brignolo LL, Meyer DJ. et al. Biological effects of short-term or prolonged administration of 9-[2-(phosphonomethoxy)propyl]adenine (tenofovir) to newborn and infant rhesus macaques. Antimicrob Agents Chemother 2004; 48 (05) 1469-1487
- 5 Wanner DP, Tyndall A, Walker UA. Tenofovir-induced osteomalacia. Clin Exp Rheumatol 2009; 27 (06) 1001-1003
- 6 Bedimo R, Maalouf NM, Zhang S, Drechsler H, Tebas P. Osteoporotic fracture risk associated with cumulative exposure to tenofovir and other antiretroviral agents. AIDS 2012; 26 (07) 825-831
- 7 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 2014; 28 (12) 1759-1767
- 8 Shiau S, Arpadi SM, Yin MT. Bone Update: Is It Still an Issue Without Tenofovir Disoproxil Fumarate?. Curr HIV/AIDS Rep 2020; 17 (01) 1-5
- 9 Borges ÁH, Hoy J, Florence E. et al; for EuroSIDA. Antiretrovirals, Fractures, and Osteonecrosis in a Large International HIV Cohort. Clin Infect Dis 2017; 64 (10) 1413-1421
- 10 Hall AM, Hendry BM, Nitsch D, Connolly JO. Tenofovir-associated kidney toxicity in HIV-infected patients: a review of the evidence. Am J Kidney Dis 2011; 57 (05) 773-780
- 11 Lebrecht D, Venhoff AC, Kirschner J, Wiech T, Venhoff N, Walker UA. Mitochondrial tubulopathy in tenofovir disoproxil fumarate-treated rats. J Acquir Immune Defic Syndr 2009; 51 (03) 258-263
- 12 Duarte-Rojo A, Heathcote EJ. Efficacy and safety of tenofovir disoproxil fumarate in patients with chronic hepatitis B. Therap Adv Gastroenterol 2010; 3 (02) 107-119
- 13 Marco P, Cristian A, Isabel GM, Veronica V, Juan H. Bilateral Hip Fracture in Adolescents With Antiretroviral Treatment. J Am Acad Orthop Surg Glob Res Rev 2017; 1 (01) e005
- 14 Rebolledo BJ, Unnanuntana A, Lane JM. Bilateral pathologic hip fractures associated with antiretroviral therapy: a case report. J Bone Joint Surg Am 2011; 93 (14) e78
- 15 Carr A, Kerr SJ, Richardson R. et al; ZEST study Investigators. Prolonged Effect of Zoledronic Acid on Bone Mineral Density and Turnover in HIV-Infected Adults on Tenofovir: A Randomized, Open-Label Study. J Bone Miner Res 2019; 34 (12) 2192-2197
- 16 Bolland MJ, Grey A, Horne AM. et al. Effects of intravenous zoledronate on bone turnover and bone density persist for at least five years in HIV-infected men. J Clin Endocrinol Metab 2012; 97 (06) 1922-1928
- 17 Wijesekera MP, Graham SM, Lalloo DG, Simpson H, Harrison WJ. Fracture management in HIV positive individuals: a systematic review. Int Orthop 2016; 40 (12) 2429-2445
Address for correspondence
Publication History
Received: 25 May 2020
Accepted: 21 January 2021
Article published online:
02 June 2021
© 2021. Sociedad Chilena de Ortopedia y Traumatologia. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commecial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)
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Referencias
- 1 Tebas P, Powderly WG, Claxton S. et al. Accelerated bone mineral loss in HIV-infected patients receiving potent antiretroviral therapy. AIDS 2000; 14 (04) F63-F67
- 2 Womack JA, Goulet JL, Gibert C. et al; Veterans Aging Cohort Study Project Team. Increased risk of fragility fractures among HIV infected compared to uninfected male veterans. PLoS One 2011; 6 (02) e17217
- 3 Gallant JE, Staszewski S, Pozniak AL. et al; 903 Study Group. Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial. JAMA 2004; 292 (02) 191-201
- 4 Van Rompay KKA, Brignolo LL, Meyer DJ. et al. Biological effects of short-term or prolonged administration of 9-[2-(phosphonomethoxy)propyl]adenine (tenofovir) to newborn and infant rhesus macaques. Antimicrob Agents Chemother 2004; 48 (05) 1469-1487
- 5 Wanner DP, Tyndall A, Walker UA. Tenofovir-induced osteomalacia. Clin Exp Rheumatol 2009; 27 (06) 1001-1003
- 6 Bedimo R, Maalouf NM, Zhang S, Drechsler H, Tebas P. Osteoporotic fracture risk associated with cumulative exposure to tenofovir and other antiretroviral agents. AIDS 2012; 26 (07) 825-831
- 7 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 2014; 28 (12) 1759-1767
- 8 Shiau S, Arpadi SM, Yin MT. Bone Update: Is It Still an Issue Without Tenofovir Disoproxil Fumarate?. Curr HIV/AIDS Rep 2020; 17 (01) 1-5
- 9 Borges ÁH, Hoy J, Florence E. et al; for EuroSIDA. Antiretrovirals, Fractures, and Osteonecrosis in a Large International HIV Cohort. Clin Infect Dis 2017; 64 (10) 1413-1421
- 10 Hall AM, Hendry BM, Nitsch D, Connolly JO. Tenofovir-associated kidney toxicity in HIV-infected patients: a review of the evidence. Am J Kidney Dis 2011; 57 (05) 773-780
- 11 Lebrecht D, Venhoff AC, Kirschner J, Wiech T, Venhoff N, Walker UA. Mitochondrial tubulopathy in tenofovir disoproxil fumarate-treated rats. J Acquir Immune Defic Syndr 2009; 51 (03) 258-263
- 12 Duarte-Rojo A, Heathcote EJ. Efficacy and safety of tenofovir disoproxil fumarate in patients with chronic hepatitis B. Therap Adv Gastroenterol 2010; 3 (02) 107-119
- 13 Marco P, Cristian A, Isabel GM, Veronica V, Juan H. Bilateral Hip Fracture in Adolescents With Antiretroviral Treatment. J Am Acad Orthop Surg Glob Res Rev 2017; 1 (01) e005
- 14 Rebolledo BJ, Unnanuntana A, Lane JM. Bilateral pathologic hip fractures associated with antiretroviral therapy: a case report. J Bone Joint Surg Am 2011; 93 (14) e78
- 15 Carr A, Kerr SJ, Richardson R. et al; ZEST study Investigators. Prolonged Effect of Zoledronic Acid on Bone Mineral Density and Turnover in HIV-Infected Adults on Tenofovir: A Randomized, Open-Label Study. J Bone Miner Res 2019; 34 (12) 2192-2197
- 16 Bolland MJ, Grey A, Horne AM. et al. Effects of intravenous zoledronate on bone turnover and bone density persist for at least five years in HIV-infected men. J Clin Endocrinol Metab 2012; 97 (06) 1922-1928
- 17 Wijesekera MP, Graham SM, Lalloo DG, Simpson H, Harrison WJ. Fracture management in HIV positive individuals: a systematic review. Int Orthop 2016; 40 (12) 2429-2445
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