Extreme hypocalcaemia and hyperparathyroidism following denosumab. Is this drug safe in chronic kidney disease?
Hipocalcemia e hiperparatiroidismo extremos tras denosumab. ¿Es seguro este fármaco en la enfermedad renal crónica?
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Is this drug safe in chronic kidney disease?" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "542" "paginaFinal" => "544" ] ] "autores" => array:1 [ 0 => array:3 [ "autoresLista" => "Ana E. Sirvent, Ricardo Enríquez, María Sánchez, César González, Isabel Millán, Francisco Amorós" "autores" => array:6 [ 0 => array:4 [ "nombre" => "Ana E." "apellidos" => "Sirvent" "email" => array:1 [ 0 => "anaesipe@gmail.com" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "affa" ] ] ] 1 => array:3 [ "nombre" => "Ricardo" "apellidos" => "Enríquez" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "affa" ] ] ] 2 => array:3 [ "nombre" => "María" "apellidos" => "Sánchez" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "affa" ] ] ] 3 => array:3 [ "nombre" => "César" "apellidos" => "González" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "affa" ] ] ] 4 => array:3 [ "nombre" => "Isabel" "apellidos" => "Millán" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "affa" ] ] ] 5 => array:3 [ "nombre" => "Francisco" "apellidos" => "Amorós" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "affa" ] ] ] ] "afiliaciones" => array:1 [ 0 => array:3 [ "entidad" => " Servicio de Nefrología, Hospital General Universitario de Elche, Alicante, " "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "affa" ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Hipocalcemia e hiperparatiroidismo extremos tras denosumab. ¿Es seguro este fármaco en la enfermedad renal crónica?" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig1" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "12383_16025_60197_en_f112383.jpg" "Alto" => 986 "Ancho" => 1384 "Tamanyo" => 332962 ] ] "descripcion" => array:1 [ "en" => "Evolution of biochemical parameters" ] ] ] "textoCompleto" => "<p class="elsevierStylePara"><span class="elsevierStyleBold">To the Editor,</span></p><p class="elsevierStylePara"><span class="elsevierStyleItalic">Nefrología </span>has recently published a case of post-denosumab hypocalcaemia and we would like to contribute to this subject<span class="elsevierStyleSup">1</span>. Denosumab is an anti-RANKL (receptor activator of nuclear factor<span class="elsevierStyleItalic">-κ</span> B ligand) monoclonal antibody used in osteoporosis treatment as an antiresorptive agent. Unlike bisphosphonates, denosumab does not appear to be nephrotoxic<span class="elsevierStyleSup">2</span>, nor does it require dosage adjustments in kidney failure due to its favourable pharmacokinetic and pharmacodynamic profile<span class="elsevierStyleSup">1,3</span>. However, the qualitative bone changes in osteoporosis patients are not comparable with the wide spectrum of alterations in bone turnover that accompanies chronic kidney disease (CKD)<span class="elsevierStyleSup">4</span>. For this reason and in relation to the changes in mineral metabolism caused by denosumab, its safety in this population could be questioned. We describe a patient with advanced CKD with extreme hypocalcaemia and hyperparathyroidism following continuous administration of denosumab.</p><p class="elsevierStylePara">The patient is a 75-year-old female who sought treatment for tremors, muscle spasms and paraesthesia in the limbs. Stage 5 CKD, probably secondary to nephroangiosclerosis and diabetes mellitus, stands out in her medical history. She is allergic to penicillin and is treated with insulin, doxazosin, nifedipine GITS, torsemide, acetylsalicyclic acid, oral iron, erythropoietin, paricalcitol and calcifediol. She was treated, until 7 months before, with 70mg alendronic acid, which was suspended on starting six-monthly subcutaneous 60mg denosumab. Her nephrologist was unaware of the prescription of this drug. She presented the following analysis: creatinine 3.6mg/dl, total corrected calcium 10.06mg/dl, ionic calcium 5.1mg/dl, phosphate 5.1mg/dl, alkaline phosphatase 157U/l, bicarbonate 27.6mmol/l, parathyroid hormone (PTH) 436pg/ml, 25-vitamin D 30.2ng/ml. The evolution of the biochemical parameters until the last analysis 14 days after denosumab is shown in Figure 1. The patient did not attend this last evaluation due to not feeling well. Six days later, she was examined in the Emergency Department: urea 154mg/dl, creatinine 6mg/dl, total corrected calcium 4.36mg/dl, ionic calcium 2.4mg/dl, phosphate 6.7mg/dl, magnesium 1.3mg/dl, alkaline phosphatase 59U/l, bicarbonate 18.6mmol/l, PTH 1900pg/ml. Electrocardiogram (ECG): 440ms corrected QT (QTc). Oral and intravenous calcium replacement and intravenous calcitriol were started, with the disappearance of symptoms. After 15 days of parenteral replacement, the analytical parameters had normalised (Figure 1): ECG: QTc 402ms. PTH remained 1858pg/ml.</p><p class="elsevierStylePara">The recommendations for the use of denosumab in kidney failure are based on a clinical trial involving very few patients, over a 16 week follow-up period and following only one dose of the drug<span class="elsevierStyleSup">3</span>. In addition, the authors excluded, in part of the study, those subjects with 1.25-dihydroxyvitamin D levels <30pg/ml, severe renal failure and PTH ≥110pg/ml or kidney failure and PTH ≥300pg/ml. Even so, 22%-25% of the cases with moderate-severe renal failure or patients on dialysis presented hypocalcaemia. The authors recommend calcium and vitamin D supplements for its prevention. In another clinical trial carried out over 36 months in post-menopausal women with CKD and estimated glomerular filtration rate >15ml/min, cases of hypoparathyroidism, hyperparathyroidism, hypercalcaemia and hypovitaminosis D were excluded; PTH levels were not monitored in the study<span class="elsevierStyleSup">2</span>.</p><p class="elsevierStylePara">In recent months, cases of hypocalcaemia in chronic nephropathies have continued to be reported<span class="elsevierStyleSup">1,5-8</span>. Non previous biphosphonate use and kidney failure are risk factors for developing hypocalcaemia<span class="elsevierStyleSup">8</span>. Consequently, our patient may only have developed hypocalcaemia following the second dose, since she had previously been treated with alendronate.</p><p class="elsevierStylePara">Denosumab reduces the number of osteoclasts and bone formation rate. Hypocalcaemia would be related to the rapid mineral deposit of calcium in the new bone matrix, which would behave similarly to a hungry bone following parathyroidectomy<span class="elsevierStyleSup">3</span>. However, as occurred in this case, PTH was not suppressed, but hyperstimulated. In addition to sudden hypocalcaemia following the second denosumab dose, PTH levels were progressively increasing to very high levels following the first dose, despite vitamin D supplements; we also observed a reduction of alkaline phosphatase. For some experts, this inhibition of osteoclastogenesis could favour adynamic bone disease in CKD<span class="elsevierStyleSup">4,5</span>.</p><p class="elsevierStylePara">The monitoring of calcium levels 8-14 days after treatment has been advised<span class="elsevierStyleSup">7</span>. However, this does not guarantee its prevention, since it is not known when the nadir is reached<span class="elsevierStyleSup">7</span>.</p><p class="elsevierStylePara">Denosumab can cause potentially fatal short-term adverse effects, as well as other unknown long-term effects, on the bone of CKD patients. For these reasons, some authors recommend not using denosumab in CKD patients or only using it if a bone biopsy has previously been carried out<span class="elsevierStyleSup">4,6</span>.</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">Conflicts of interest</span></p><p class="elsevierStylePara">The authors declare that they have no conflicts of interest related to the contents of this article.</p><p class="elsevierStylePara"><a href="grande/12383_16025_60197_en_f112383.jpg" class="elsevierStyleCrossRefs"><img src="12383_16025_60197_en_f112383.jpg" alt="Evolution of biochemical parameters"></img></a></p><p class="elsevierStylePara">Figure 1. Evolution of biochemical parameters</p>" "pdfFichero" => "P1-E572-S4663-A12383-EN.pdf" "tienePdf" => true "multimedia" => array:1 [ 0 => array:8 [ "identificador" => "fig1" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "12383_16025_60197_en_f112383.jpg" "Alto" => 986 "Ancho" => 1384 "Tamanyo" => 332962 ] ] "descripcion" => array:1 [ "en" => "Evolution of biochemical parameters" ] ] ] "bibliografia" => array:2 [ "titulo" => "Bibliography" "seccion" => array:1 [ 0 => array:1 [ "bibliografiaReferencia" => array:8 [ 0 => array:3 [ "identificador" => "bib1" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Martín-Baez IM, Blanco-García R, Alonso-Suárez M, Cossio-Aranibar C, Beato-Coo LV, Fernández-Fleming F. Severe hypocalcaemia post-denosumab. 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J Bone Miner Res 2012;27:1471-9. <a href="http://www.ncbi.nlm.nih.gov/pubmed/22461041" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 3 => array:3 [ "identificador" => "bib4" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Ott SM. Therapy for patients with CKD and low bone mineral density. Nat Rev Nephrol 2013;9:681-92. <a href="http://www.ncbi.nlm.nih.gov/pubmed/24100401" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 4 => array:3 [ "identificador" => "bib5" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Torregrosa JV. Dramatic increase in parathyroid hormone and hypocalcemia after denosumab in a kidney transplant patient. Clin Kidney J 2013;6:122." 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| 2017 June | 122 | 17 | 139 |
| 2017 May | 128 | 14 | 142 |
| 2017 April | 136 | 40 | 176 |
| 2017 March | 97 | 19 | 116 |
| 2017 February | 114 | 16 | 130 |
| 2017 January | 102 | 13 | 115 |
| 2016 December | 115 | 10 | 125 |
| 2016 November | 137 | 9 | 146 |
| 2016 October | 198 | 16 | 214 |
| 2016 September | 234 | 8 | 242 |
| 2016 August | 236 | 11 | 247 |
| 2016 July | 278 | 10 | 288 |
| 2016 June | 186 | 0 | 186 |
| 2016 May | 199 | 0 | 199 |
| 2016 April | 144 | 0 | 144 |
| 2016 March | 118 | 0 | 118 |
| 2016 February | 149 | 0 | 149 |
| 2016 January | 138 | 0 | 138 |
| 2015 December | 136 | 0 | 136 |
| 2015 November | 114 | 0 | 114 |
| 2015 October | 122 | 0 | 122 |
| 2015 September | 116 | 0 | 116 |
| 2015 August | 93 | 0 | 93 |
| 2015 July | 125 | 0 | 125 |
| 2015 June | 74 | 0 | 74 |
| 2015 May | 86 | 0 | 86 |
| 2015 April | 13 | 0 | 13 |
Show all
