Case Report
Osteomalacia Induced by Adefovir in Patient With Hepatitis B
Osteomalacia inducida por adefovir en paciente con hepatitis B
Mayra Nathali Rivas Zavaleta
, Sonia Guayambuco Romero, Marcelo Calabozo Raluy, Fernando Pérez Ruiz
Corresponding author
Servicio de Reumatología, Hospital Cruces, Barakaldo, Vizcaya, Spain
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Among its adverse effects one finds nephrotoxicity, although this usually occurs when high doses (60–120<span class="elsevierStyleHsp" style=""></span>mg/day) are employed.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> The currently recommended dose is approximately 10<span class="elsevierStyleHsp" style=""></span>mg/day PO, which minimizes the risk of nephrotoxicity in patients without a history of renal disease.<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2–4</span></a> The case presented is that of a patient treated with adefovir at a dose of 10<span class="elsevierStyleHsp" style=""></span>mg/day which caused abnormalities in the proximal renal tubule, leading to<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5,6</span></a> hypophosphatemic osteomalacia.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Case Presentation</span><p id="par0010" class="elsevierStylePara elsevierViewall">The patient was an 81 year old male with a single kidney, with chronic hepatitis B treated with adefovir for four years approximately at a dose of 10<span class="elsevierStyleHsp" style=""></span>mg/day. The patient had poor overall condition, fatigue, weakness, bone pain, muscle atrophy and weight loss which had lasted for a year. He had elevated alkaline phosphatase (386<span class="elsevierStyleHsp" style=""></span>U/l; normal <140<span class="elsevierStyleHsp" style=""></span>U/l) and a bone scan showed multiple pathological uptake areas (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). With the presumptive diagnosis of Paget's disease, treatment was begun with bisphosphonates (etidronate 30<span class="elsevierStyleHsp" style=""></span>mg/day for 2 months), calcium and vitamin D, with no clinical improvement, so the patient was referred to the Rheumatology department. Laboratory results showed elevated alkaline phosphatase (329<span class="elsevierStyleHsp" style=""></span>U/L), hypoproteinemia (5.5<span class="elsevierStyleHsp" style=""></span>g/dl), hypoalbuminemia (3.3<span class="elsevierStyleHsp" style=""></span>g/dl), hypouricemia (1.5<span class="elsevierStyleHsp" style=""></span>mg/dl) with a fractional excretion of urate of 50% and hypophosphatemia <span class="elsevierStyleMonospace">(</span>1.2<span class="elsevierStyleHsp" style=""></span>mg/dl) with tubular reabsorption of phosphate 9% (normal >80%). PTH levels were normal as was 25-hydroxycholecalciferol. Regarding renal function, creatinine was 1.13<span class="elsevierStyleHsp" style=""></span>mg/dl and the estimated glomerular filtration rate was 53<span class="elsevierStyleHsp" style=""></span>ml/min. The patient had proteinuria (1178<span class="elsevierStyleHsp" style=""></span>mg/day) and glucosuria (>100<span class="elsevierStyleHsp" style=""></span>mg/day). A chest X-ray showed rib fractures on both sides and bone scintigraphy showed multiple foci of uptake in the ribs, right sacrum, knees and right tibia.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0015" class="elsevierStylePara elsevierViewall">A historical review of the analysis showed that the onset of disturbances, in particular decreasing phosphate levels, coincided with the beginning of the administration of adefovir (4 years prior). Adefovir was discontinued and the patient was treated with intravenous phosphate, presenting an increase in phosphate values to 4.1<span class="elsevierStyleHsp" style=""></span>mg/dl. He was discharged with oral phosphate at a dose of 7<span class="elsevierStyleHsp" style=""></span>g/day. In the next 6 months, there was a clear, albeit slow, clinical improvement.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Discussion</span><p id="par0020" class="elsevierStylePara elsevierViewall">In the case presented, laboratory abnormalities coincided with the start of the administration of adefovir and were associated with an improvement in phosphate values after drug withdrawal. Adefovir is associated with nephrotoxic effects, which are dose-dependent, leading to dysfunction of the proximal renal tubule and glomerular filtration rate.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> The lowering effect of the plasma phosphate levels of adefovir has been observed in 22%–50% of patients treated with doses of 30<span class="elsevierStyleHsp" style=""></span>mg/day for at least 6 months and manifests itself as a progressive increase in serum creatinine, hypophosphatemia or both.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> While use of 10<span class="elsevierStyleHsp" style=""></span>mg/day orally is not associated with significant renal dysfunction, in this case a low dose caused a decrease in tubular phosphate reabsorption and resulted in hypophosphatemia, leading to clinically manifested osteomalacia and bone pain, functional impairment and generalized muscle pain.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Predisposing factors were the presence of a single kidney, and a moderately low glomerular filtration rate which contributed to a greater impact of the drug on renal function, as seen in previous cases.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">The pathophysiology of renal proximal tubule dysfunction caused by adefovir is due to its concentration in the mitochondria, resulting in mitochondrial toxicity and inhibition of ATP-dependent transporters in proximal tubule cells, leading to altered phosphate reabsorption, decreasing its concentration in plasma and ultimately leading to<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10,11</span></a> osteomalacia.</p><p id="par0035" class="elsevierStylePara elsevierViewall">In conclusion, although low doses of adefovir are not usually associated with renal toxicity and hypophosphatemia due to renal phosphate loss, the comorbid conditions present in this case led to a situation of increased susceptibility.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Ethical Responsibilities</span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Protection of people and animals</span><p id="par0040" class="elsevierStylePara elsevierViewall">The authors state that no experiments were performed on humans or animals.</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Data confidentiality</span><p id="par0045" class="elsevierStylePara elsevierViewall">The authors declare that they have followed the protocols of their workplace regarding the publication of data from patients and all patients included in the study have received sufficient information and gave their written informed consent to participate in this study.</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Right to privacy and informed consent</span><p id="par0050" class="elsevierStylePara elsevierViewall">The authors state that no patient data appears in this article.</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Conflict of Interest</span><p id="par0055" class="elsevierStylePara elsevierViewall">The authors have no conflict of interest to declare.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:10 [ 0 => array:2 [ "identificador" => "xres326263" "titulo" => "Abstract" ] 1 => array:2 [ "identificador" => "xpalclavsec307743" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xres326262" "titulo" => "Resumen" ] 3 => array:2 [ "identificador" => "xpalclavsec307742" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Case Presentation" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Discussion" ] 7 => array:3 [ "identificador" => "sec0020" "titulo" => "Ethical Responsibilities" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0025" "titulo" => "Protection of people and animals" ] 1 => array:2 [ "identificador" => "sec0030" "titulo" => "Data confidentiality" ] 2 => array:2 [ "identificador" => "sec0035" "titulo" => "Right to privacy and informed consent" ] ] ] 8 => array:2 [ "identificador" => "sec0040" "titulo" => "Conflict of Interest" ] 9 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2012-06-22" "fechaAceptado" => "2013-01-10" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec307743" "palabras" => array:3 [ 0 => "Osteomalacia" 1 => "Adefovir" 2 => "Hypophosphatemia" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec307742" "palabras" => array:3 [ 0 => "Osteomalacia" 1 => "Adefovir" 2 => "Hipofosfatemia" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Osteomalacia is defined as a defect in mineralization of the bone matrix. We describe the case of a patient with chronic hepatitis B infection in whom treatment with adefovir induced renal phosphate loss with intense and sustained hypophosphatemia which derived in symptomatic osteomalacia.</p>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La osteomalacia se define como un defecto en la mineralización de la matriz ósea. Describimos el caso de un paciente con infección crónica por virus de la hepatitis B en el que el tratamiento con adefovir indujo una pérdida renal de fosfato con hipofosfatemia intensa y mantenida que derivó en osteomalacia sintomática.</p>" ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Rivas Zavaleta MN, et al. Osteomalacia inducida por adefovir en paciente con hepatitis B. Reumatol Clin. 2014;10:120–121.</p>" ] ] "multimedia" => array:1 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 741 "Ancho" => 1049 "Tamanyo" => 73382 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Bone scan with multiple foci of increased uptake on both sides of the thorax, right sacroiliac joint, pubis, both knees and right ankle.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:11 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Tubular transporters and clearance of adefovir" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "A. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 5 | 5 | 10 |
| 2024 October | 30 | 34 | 64 |
| 2024 September | 34 | 15 | 49 |
| 2024 August | 56 | 30 | 86 |
| 2024 July | 46 | 28 | 74 |
| 2024 June | 70 | 25 | 95 |
| 2024 May | 83 | 28 | 111 |
| 2024 April | 75 | 31 | 106 |
| 2024 March | 58 | 27 | 85 |
| 2024 February | 30 | 23 | 53 |
| 2024 January | 25 | 20 | 45 |
| 2023 December | 45 | 23 | 68 |
| 2023 November | 38 | 20 | 58 |
| 2023 October | 49 | 21 | 70 |
| 2023 September | 89 | 38 | 127 |
| 2023 August | 84 | 21 | 105 |
| 2023 July | 48 | 26 | 74 |
| 2023 June | 43 | 25 | 68 |
| 2023 May | 40 | 22 | 62 |
| 2023 April | 33 | 8 | 41 |
| 2023 March | 57 | 29 | 86 |
| 2023 February | 27 | 26 | 53 |
| 2023 January | 25 | 17 | 42 |
| 2022 December | 43 | 21 | 64 |
| 2022 November | 61 | 26 | 87 |
| 2022 October | 32 | 30 | 62 |
| 2022 September | 29 | 30 | 59 |
| 2022 August | 43 | 47 | 90 |
| 2022 July | 30 | 44 | 74 |
| 2022 June | 36 | 32 | 68 |
| 2022 May | 42 | 33 | 75 |
| 2022 April | 38 | 42 | 80 |
| 2022 March | 58 | 42 | 100 |
| 2022 February | 47 | 33 | 80 |
| 2022 January | 47 | 37 | 84 |
| 2021 December | 32 | 40 | 72 |
| 2021 November | 29 | 41 | 70 |
| 2021 October | 91 | 44 | 135 |
| 2021 September | 35 | 25 | 60 |
| 2021 August | 42 | 28 | 70 |
| 2021 July | 50 | 34 | 84 |
| 2021 June | 35 | 39 | 74 |
| 2021 May | 38 | 41 | 79 |
| 2021 April | 65 | 59 | 124 |
| 2021 March | 44 | 25 | 69 |
| 2021 February | 27 | 26 | 53 |
| 2021 January | 28 | 14 | 42 |
| 2020 December | 18 | 25 | 43 |
| 2020 November | 20 | 17 | 37 |
| 2020 October | 19 | 18 | 37 |
| 2020 September | 21 | 26 | 47 |
| 2020 August | 22 | 18 | 40 |
| 2020 July | 30 | 9 | 39 |
| 2020 June | 37 | 17 | 54 |
| 2020 May | 43 | 15 | 58 |
| 2020 April | 21 | 10 | 31 |
| 2020 March | 24 | 7 | 31 |
| 2018 May | 7 | 0 | 7 |
| 2018 April | 57 | 10 | 67 |
| 2018 March | 45 | 11 | 56 |
| 2018 February | 21 | 4 | 25 |
| 2018 January | 26 | 5 | 31 |
| 2017 December | 31 | 3 | 34 |
| 2017 November | 25 | 5 | 30 |
| 2017 October | 34 | 8 | 42 |
| 2017 September | 43 | 2 | 45 |
| 2017 August | 26 | 8 | 34 |
| 2017 July | 27 | 12 | 39 |
| 2017 June | 40 | 4 | 44 |
| 2017 May | 54 | 7 | 61 |
| 2017 April | 52 | 8 | 60 |
| 2017 March | 39 | 11 | 50 |
| 2017 February | 14 | 11 | 25 |
| 2017 January | 24 | 4 | 28 |
| 2016 December | 52 | 10 | 62 |
| 2016 November | 31 | 9 | 40 |
| 2016 October | 51 | 9 | 60 |
| 2016 September | 46 | 5 | 51 |
| 2016 August | 48 | 11 | 59 |
| 2016 July | 21 | 3 | 24 |
| 2015 December | 2 | 0 | 2 |
| 2015 September | 2 | 0 | 2 |
| 2015 August | 2 | 0 | 2 |
| 2015 July | 15 | 4 | 19 |
| 2015 June | 36 | 5 | 41 |
| 2015 May | 52 | 12 | 64 |
| 2015 April | 35 | 13 | 48 |
| 2015 March | 54 | 10 | 64 |
| 2015 February | 44 | 4 | 48 |
| 2015 January | 69 | 14 | 83 |
| 2014 December | 55 | 9 | 64 |
| 2014 November | 45 | 8 | 53 |
| 2014 October | 49 | 15 | 64 |
| 2014 September | 42 | 8 | 50 |
| 2014 August | 36 | 13 | 49 |
| 2014 July | 57 | 20 | 77 |
| 2014 June | 69 | 18 | 87 |
| 2014 May | 49 | 21 | 70 |
| 2014 April | 86 | 27 | 113 |
| 2014 March | 39 | 22 | 61 |
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