Use of bisphosphonates in chronic kidney disease
Uso de bifosfonatos en la enfermedad renal crónica
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They were developed in the middle of this last century as growth inhibitors and subsequently they were found to decrease bone resorption too. Pyrophosphates, in turn, are organic compounds composed of two phosphoric acids linked by esterification to a molecule of oxygen (P-O-P structure) (Figure 1). They are detected in the blood and urine because they are byproducts of various physiological reactions.</p><p class="elsevierStylePara">Bisphosphonates differ from the pyrophosphates in that the oxygen molecule has been replaced by a carbon (P-C-P structure) (Figure 1), making them difficult to break down and, moreover, giving them a high affinity for hydroxyapatite crystals. The central carbon is also joined by two side chains that vary for each type of bisphosphonate and determine their potency, duration of action, side effects, and other clinical or bone parameters (Figure 1). The most potent bisphosphonates have a hydroxyl group on one of their side chains that increase their ability to bind to calcium.</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">DISTRIBUTION </span></p><p class="elsevierStylePara">Bisphosphonates, since they are not biodegradable, are absorbed, stored and excreted by the body without being metabolised. While the bioavailability of an intravenous dose is 100%, the bioavailability of an oral dose is only 1 to 5%. Absorption is achieved through passive diffusion in the stomach and intestine, and decreases when the drug is administered with meals, especially in the presence of calcium, so it is recommended that its administration occurs at least 30 minutes before breakfast (although it can also be administered 2-3 hours after a meal), and only with water.</p><p class="elsevierStylePara">Approximately 50-80% of available bisphosphonate is taken up by bone. The remaining 30-50% is excreted in urine without being metabolised. The uptake of bisphosphonate by bone increases with high bone turnover or low renal excretion. The half-life in plasma is approximately 1-2 hours, while bisphosphonate in the bone usually persists for many years.<span class="elsevierStyleSup">1 </span>In bone, bisphosphonates are bound with high affinity to the hydroxyapatite crystals on bone surfaces, inhibiting its breakdown. From there it is absorbed quickly and directed primarily to areas of active remodelling, acting as potent inhibitors of bone resorption. Bisphosphonates also prevent the formation of calcium phosphate crystals and inhibit apoptosis of osteocytes and osteoblasts.</p><p class="elsevierStylePara">In experimental models, they have been shown to inhibit soft-tissue calcification, prevent calcification induced by vitamin D in the aorta and the renal arteries, and other forms of ectopic calcification.<span class="elsevierStyleSup">1,2 </span><span class="elsevierStyleBold"> </span></p><p class="elsevierStylePara"><span class="elsevierStyleBold"> </span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">MECHANISM OF ACTION </span></p><p class="elsevierStylePara">We have proposed two basic molecular mechanisms responsible for the effects of these drugs on osteoclast function (Table 1) that allow their classification: Bisphosphonates that do not contain nitrogen (etidronate, clodronate and tiludronate), considered “first-generation” bind ATP which, when incorporated in osteoclasts, are cytotoxic to these cells, disrupting cell function and causing apoptosis.</p><p class="elsevierStylePara">Nitrogenous bisphosphonates, called “second and third generation” (pamidronate, alendronate, ibandronate, risedronate and zolendronate) are more potent than their predecessors. They inhibit farnesyl pyrophosphatase synthase and other final steps of the intracellular mevalonate pathway whose end product is cholesterol. Depending on the different side groups, bisphosphonates vary in their affinity for mineral, farnesyl pyrophosphate synthase inhibition, and hydroxyapatite binding capacity, all of which determine its potency and effects. If we regard etidronate as having a potency of 1, pamidronate has a potency of 100; alendronate 1,000; risedronate 5,000; ibandronate 10,000; and zolendronate 20,000.</p><p class="elsevierStylePara">Theoretically, the greater the drug potency, the lower the dose and frequency of administration should be, although the risk of accumulation and the possible toxicity and side effects are also increased.</p><p class="elsevierStylePara"><span class="elsevierStyleBold"> </span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">BISPHOSPHONATES IN CHRONIC KIDNEY DISEASE </span></p><p class="elsevierStylePara">In patients with impaired renal function, caution should be used when administering these drugs, mainly because bisphosphonates, in their renal elimination, are freely filtered by the glomerulus and actively secreted in the tubule. This does not mean they are contraindicated in these patients.<span class="elsevierStyleSup">3 </span></p><p class="elsevierStylePara">Experimental studies in animals have shown that high doses of bisphosphonates can cause decreased glomerular filtration rate and abnormalities in renal histology.<span class="elsevierStyleSup">4 </span></p><p class="elsevierStylePara"> However, not all bisphosphonates behave the same. In experimental animals, administration of high doses of ibandronate (1mg/kg) produced no deterioration of renal function, whereas a slight deterioration was observed with the administration of zolendronic acid (1mg/kg).<span class="elsevierStyleSup">5 </span>In these same studies, higher and repeated administration of zolendronic acid yielded renal histological abnormalities with the presence of degeneration and tubular atrophy, findings that were evident only with repeated doses of ibandronate.<span class="elsevierStyleSup">5 </span><span class="elsevierStyleBold"> </span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">Clinical experience </span></p><p class="elsevierStylePara">On review of the studies published so far on intravenous bisphosphonate administration, a slight deterioration of renal function is seen in 6-10% of all patients, except in the case of ibandronate in which the percentage is only 2-3%.<span class="elsevierStyleSup">6-10 </span>Oral forms have not been reported as a cause of impairment of renal function.</p><p class="elsevierStylePara">In cancer patients, intravenous administration of high doses of bisphosphonates has been associated with some degree of renal toxicity. Pamidronate, when administered at well above recommended doses, has resulted in nephrotic range proteinuria and collapsing glomerulonephritis in some cases.<span class="elsevierStyleSup">11-14 </span>Cases of acute tubular necrosis with high-dose intravenous zolendronic acid have also been published.<span class="elsevierStyleSup">15 </span>Side effects with intravenous ibandronate have not been reported.<span class="elsevierStyleSup">16 </span>In terms of oral bisphosphonate administration, although some cases of renal involvement have been reported, these occurred in patients with previously established nephrotic syndrome and confirmed renal disease and in whom the association between deterioration of renal function and bisphosphonates cannot be wellestablished.<span class="elsevierStyleSup">17</span></p><p class="elsevierStylePara">Pathophysiologically, differences in renal toxicity of these drugs may be due to various factors such as:</p><p class="elsevierStylePara"> 1. Their different protein-binding capacity, with ibandronate having the highest percentage (87%).</p><p class="elsevierStylePara"> 2. Their distinct half-life in renal tissue, which is low with ibandronate (24 days) when compared with the 150-200 days of zolendronic acid.</p><p class="elsevierStylePara"> 3. The difference in cumulative renal toxicity, which is also lower in the case of ibandronate.<span class="elsevierStyleSup">9 </span>Taking all this into account, and in general, it must be noted that toxicity is usually secondary to excessive doses and rapid administration of the drug. <span class="elsevierStyleBold"> </span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">Dosing </span></p><p class="elsevierStylePara">There have been no prospective trials in patients with impaired renal function, although it has been observed that, in general, at recommended doses, these drugs do not cause impairment of renal function. No dose adjustment is necessary in patients with mild or moderate renal failure (Cl<span class="elsevierStyleSup">cr </span>greater than or equal to 30ml/min), although there may be increased risk of renal toxicity in elderly patients or in patients simultaneously receiving other nephrotoxic drugs.<span class="elsevierStyleSup">18-20 </span></p><p class="elsevierStylePara">In patients with clearance rates below 30ml/min renal elimination is decreased, the concentration being approximately two times higher than in patients with normal renal function, so it is advisable to reduce the dose by half.<span class="elsevierStyleSup">15-21 </span></p><p class="elsevierStylePara">Curiously, in some patients with multiple myeloma, it has been observed that not only is there improvement of serum calcium but also of renal function with the administration of ibandronate.<span class="elsevierStyleSup">22 </span><span class="elsevierStyleBold"> </span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">Infusion Time </span></p><p class="elsevierStylePara">Although a recent study with ibandronate did not show any differences when comparing an infusion period of 60 minutes with a period of 15 minutes,<span class="elsevierStyleSup">23 </span>in general, the infusion rate may also determine renal toxicity, with less observed toxicity when the infusion is slower.<span class="elsevierStyleSup">24,25 </span><span class="elsevierStyleBold"> </span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">Elimination in chronic kidney disease </span></p><p class="elsevierStylePara">Renal clearance of bisphosphonates has a linear relationship with creatinine clearance.</p><p class="elsevierStylePara">In patients with normal renal function, bisphosphonates are rapidly eliminated from plasma during the first 2 hours after administration, renal excretion being the main route of elimination and bone being the tissue that retains it. Uptake in the skeleton is 47-82% and depends on bone remodelling. Therefore, more remodelling means increased uptake. In haemodialysis patients the elimination of various types of bisphosphonates is similar. No differences have been found between the clearance of these substances in haemodialysis patients as compared with a population with normal renal function.<span class="elsevierStyleSup">26-30 </span>If this fact is combined with the fact that the duration of the sessions is equivalent to the elimination period of bisphosphonate in patients with normal renal function, we believe these drugs should be administered in the early hours of dialysis.</p><p class="elsevierStylePara">In connection with peritoneal dialysis, there is little information, except a study with clodronate, in which no differences were observed in the action of the drug compared to patients on haemodialysis.<span class="elsevierStyleSup">31 </span><span class="elsevierStyleBold"> </span></p><p class="elsevierStylePara"><span class="elsevierStyleBold"> </span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">INDICATIONS IN PATIENTS WITH CHRONIC KIDNEY DISEASE </span></p><p class="elsevierStylePara">The method of administration and dosing varies between different types of bisphosphonates (Table 2). Possible indications for bisphosphonates, both for oral and intravenous administration, in patients with CKD are as follows (Table 3): <span class="elsevierStyleBold"> </span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">Prevention and treatment of bone loss after renal transplantation </span></p><p class="elsevierStylePara">Bisphosphonates have proven effective in preventing bone loss after transplantation. Intravenous pamidronate (60mg on day 0 and 30mg/month from months 1 through 6), IV ibandronate (1mg on day 0 and 2mg on months 3, 6 and 9), or oral risedronate (35mg/week) all prevent loss of bone mineral density (BMD) at different skeletal sites in the first 2 years after transplantation.<span class="elsevierStyleSup">32,33 </span></p><p class="elsevierStylePara"> However, this does not justify the indiscriminate use of bisphosphonates after transplantation. It seems that its use is recommended in patients with osteoporosis and/or other risk factors, such as: patients with type 1 diabetes, men over age 65 and women over age 45, those with preexisting stress fractures, and those with immunosuppression with high-dose steroids. <span class="elsevierStyleBold"> </span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">Treatment of decreased bone mass in chronic kidney disease stages 3-5 and dialysis </span></p><p class="elsevierStylePara">There are few data on these patients, which is paradoxical, considering that patients with CKD are at increased risk of fractures relative to the general population. Studies conducted in this population on patients with impaired renal function have demonstrated improvement in BMD and reduced fracture risk, independent of renal function.<span class="elsevierStyleSup">34 </span>Furthermore, in the few published studies of dialysis patients, an improvement in BMD has also been observed, especially when the patients had high parathyroid hormone (PTH) levels.<span class="elsevierStyleSup">35-38 </span></p><p class="elsevierStylePara"> It is unknown whether the accumulation in bone increases with deterioration of renal function. It should be considered in these patients whether the accumulation results in microfractures and bone quality deterioration. On the other hand, it is also true that in situations of low remodelling, bisphosphonate accumulation is lower.</p><p class="elsevierStylePara"> In summary, in patients with advanced CKD or on dialysis, bisphosphonates are indicated, especially in the presence of frank decrease in bone mass <span class="elsevierStyleItalic">(z-</span>score < 2.5) and the presence of risk factors for osteoporosis (bone fractures, type 1 diabetes, men over 65, and women over 45 years of age), along with high bone remodelling (PTH > 450pg/ml). In situations with PTH below 100, indicative of probable low remodelling, although to date the use of bisphosphonates has been highly discouraged, it is appropriate to treat on a case-by-case basis. One should consider and, in this case, assess the possibility of bone biopsy and treatment with parathyroid hormone. In situations with PTH between 100 and 450, one should also treat on a case-bycase basis, but one may be more lax.</p><p class="elsevierStylePara"><span class="elsevierStyleBold"> </span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">TREATMENT OF CALCIPHYLAXIS </span></p><p class="elsevierStylePara">Some studies have shown that bisphosphonates may have a beneficial effect in the treatment of calciphylaxis. Inhibition of bone resorption caused by bisphosphonates could reduce the concentration of calcium in blood, and thereby reduce the tendency of mineral nuclei to form and grow on arterial walls. On the other hand, bisphosphonates could inhibit the secretion of proinflammatory cytokines in the vascular wall and thus improve the overall situation.<span class="elsevierStyleSup">39 </span>Both intravenous (pamidronate) and oral (alendronate or risedronate) bisphosphonates have been used with similar results.<span class="elsevierStyleSup">40-42 </span><span class="elsevierStyleBold"> </span></p><p class="elsevierStylePara"> In our experience, seven cases of calciphylaxis have been resolved, five of them in patients on dialysis and two with functioning kidney transplantations, with the administration of alendronate over 6 months in one case, risedronate in three others, and ibandronate in the last two cases. <span class="elsevierStyleBold"> </span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">Treatment of hypercalcaemia </span></p><p class="elsevierStylePara">In CKD patients, one may encounter hypercalcaemia when using high doses of calcium salts as phosphorus binders, with high doses of vitamin D, hypercalcaemia of malignancy, multiple myeloma, and some cases of primary hyperparathyroidism. The administration of intravenous bisphosphonates may be useful as a complement to other strategies.</p><p class="elsevierStylePara"> Pamidronate is a bisphosphonate with which there is more experience in the treatment of hypercalcaemia, although zoledronate and ibandronate have also been used.<span class="elsevierStyleSup">43 </span>It should be administered for very short periods to prevent hypocalcaemia in the medium term. In our experience, and due to its margin of safety, we recommend IV ibandronate 6mg as a first option. <span class="elsevierStyleBold"> </span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">Prevention and treatment of vascular calcification </span></p><p class="elsevierStylePara">The mechanism by which bisphosphonates inhibit vascular calcification has not been elucidated. The various mechanisms proposed are: <span class="elsevierStyleItalic">a) </span>inhibition of bone resorption leading to a decrease in the calcium and phosphorus leaving bone which limits their availability and deposition in the vascular tree, <span class="elsevierStyleItalic">b) </span>modulation of the activity of the NaP cotransporter of smooth muscle cells, <span class="elsevierStyleItalic">c) </span>direct effect on the vascular wall preventing the formation of hydroxyapatite crystals, and <span class="elsevierStyleItalic">d) </span>positive effect on osteoprotegerin/RANK-L.<span class="elsevierStyleSup">44 </span></p><p class="elsevierStylePara"> Dialysis patients have lower serum pyrophosphate levels, which is one of the possible mechanisms contributing to higher rates of vascular calcification. The administration of bisphosphonates could reset the pyrophosphate levels.<span class="elsevierStyleSup">45 </span>There are very few studies in dialysis patients, each of which has a small number of patients. In most, low-dose bisphosphonates appear to have beneficial effects on vascular calcification, and improvement in coronary and aortic calcifications has been demonstrated.<span class="elsevierStyleSup">46-50 </span>It remains a promising alternative that requires larger prospective studies for validation.</p><p class="elsevierStylePara"><span class="elsevierStyleBold"> </span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">OSTEONECROSIS OF THE MANDIBLE </span></p><p class="elsevierStylePara">Mandibular osteonecrosis deserves special mention, although its incidence is very low. It is unusual for it to occur with oral bisphosphonates. The predisposing risk factors include the administration of intravenous bisphosphonates over long periods of time, high doses of steroids, alcohol and/or tobacco (snuff) abuse and especially local factors such as periodontal disease, tooth extraction and maxillofacial surgery.<span class="elsevierStyleSup">51-53 </span></p><p class="elsevierStylePara"> Prevention is important in patients with CKD, although no case has been reported to date. Basic guidelines have been developed for the treatment of this complication in patients treated with bisphosphonates<span class="elsevierStyleSup">54</span>:</p><p class="elsevierStylePara"> Before initiating treatment with bisphosphonates, teeth with poor prognosis should be extracted and surgical dental procedures performed.</p><p class="elsevierStylePara"> As a preventive measure, during treatment with bisphosphonates and in the case of dental surgery, administer antibiotics before and after the procedure for 10 days. It is essential in all cases to maintain good oral hygiene.</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"> <span class="elsevierStyleBold">KEY CONCEPTS </span></p><p class="elsevierStylePara"><span class="elsevierStyleBold"> </span>1. Bisphosphonates can be used at different stages of chronic kidney disease, including dialysis and renal transplantation.</p><p class="elsevierStylePara"> 2. In patients with glomerular filtration rates below 30ml/min, it is advisable to reduce the dose to half of that recommended for patients with normal renal function.</p><p class="elsevierStylePara"> 3. While very few negative effects on the kidney have been reported, it is important to maintain and even extend the infusion time to avoid side effects with intravenous administration. With ibandronate no renal effects have been reported to date.</p><p class="elsevierStylePara"> 4. Oral administration does not appear to alter renal function.</p><p class="elsevierStylePara"> 5. Patients on haemodialysis should be administered the drug during the session.</p><p class="elsevierStylePara"> 6. The indication for bisphosphonates must be weighed carefully in patients with suspected adynamic bone disease, in which case bone biopsy must be performed. </p><p class="elsevierStylePara"><a href="grande/10320_18030_5508_en_figure1.jpg" class="elsevierStyleCrossRefs"><img src="10320_18030_5508_en_figure1.jpg" alt="Molecular structure of bisphosphonates."></img></a></p><p class="elsevierStylePara">Figure 1. Molecular structure of bisphosphonates.</p><p class="elsevierStylePara"><a href="grande/10320_18030_5510_en_table1.jpg" class="elsevierStyleCrossRefs"><img src="10320_18030_5510_en_table1.gif" alt="Classification of bisphosphonates by their mechanism of action"></img></a></p><p class="elsevierStylePara">Table 1. Classification of bisphosphonates by their mechanism of action</p><p class="elsevierStylePara"><a href="grande/10320_18030_5512_en_figure2.jpg" class="elsevierStyleCrossRefs"><img src="10320_18030_5512_en_figure2.jpg" alt="Classification of bisphosphonates by their mechanism of action."></img></a></p><p class="elsevierStylePara">Figure 2. Classification of bisphosphonates by their mechanism of action.</p><p class="elsevierStylePara"><a href="grande/10320_18030_5513_en_table2.jpg" class="elsevierStyleCrossRefs"><img src="10320_18030_5513_en_table2.gif" alt="Bisphosphonates marketed in our country, route of administration, and brand name"></img></a></p><p class="elsevierStylePara">Table 2. Bisphosphonates marketed in our country, route of administration, and brand name</p><p class="elsevierStylePara"><a href="grande/10320_18030_5515_en_table3.jpg" class="elsevierStyleCrossRefs"><img src="10320_18030_5515_en_table3.gif" alt="Possible indications for bisphosphonates in nephrology"></img></a></p><p class="elsevierStylePara">Table 3. Possible indications for bisphosphonates in nephrology</p>" "pdfFichero" => "P1-E46-S1858-A10320-EN.pdf" "tienePdf" => true "PalabrasClave" => array:2 [ "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec437087" "palabras" => array:1 [ 0 => "Bifosfonatos; Enfermedad Renal Crónica; Revision" ] ] ] "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec437088" "palabras" => array:1 [ 0 => "Bisphosphonates; Chronic Renal Insufficiency; Review" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:1 [ "resumen" => "<p class="elsevierStylePara">Bisphosphonates are synthetic compounds similar to  organic pyrophosphates. The bioavailability of  intravenous preparations is 100%, whereas the  availability of oral therapy ranges from 1 to 5%. About  50% to 80% of free bisphosphonates are incorporated  into the bone. Because of their urinary elimination,  bisphosphonates must be carefully administered in  chronic kidney disease (CKD) patients. In spite of this,  bisphosphonates can safely be used at all CKD stages,  including dialysis and kidney transplant. Renal toxicity  seems different among these compounds, and it is  basically due to their protein binding and the average  lifespan of renal tissues. In practice, renal toxicity has  been associated with infusion speed and excessive  dosage. In patients with CKD, it is very relevant to  maintain infusion time and in haemodialysis patients we  recommend administration during the haemodialysis  session. When bisphosphonates are given to 4-5 CKD  patients it seems reasonable to reduce the dose to 50%.  No renal pathology has been associated to oral  administration.  The indications of bisphosphonates in CKD include:  hypercalcaemia episodes, preventing bone loss after  renal transplantation, treating low bone mineral  density in all CKD stages including transplantation.  They are also a promising therapy for calciphylaxis and  to prevent vascular calcifications. When suppressed  bone turnover is suspected, bone biopsy is mandatory  before bisphosphonates therapy.<span class="elsevierStyleBold">    <br /></span></p>" ] "es" => array:1 [ "resumen" => "<p class="elsevierStylePara">Los bifosfonatos son compuestos sintéticos análogos de los pirofosfatos. Mientras que la biodisponibilidad de una dosis endovenosa es del 100%, la biodisponibilidad oral es del 1 al 5%. Aproximadamente el 50-80% del bifosfonato disponible es captado por el hueso.</p> <p class="elsevierStylePara">En pacientes con deterioro de función renal debemos ser cautelosos fundamentalmente porque se eliminan a nivel renal (se filtran por el glomérulo y secretan en el túbulo). Su diferente toxicidad renal puede deberse a factores como: diferente capacidad de unión a proteínas, distinta vida media en tejido renal, y diferente toxicidad renal acumulada. No obstante, la toxicidad se debe a la administración rápida y a dosis excesivas. En pacientes con filtrado glomerular inferior a 30 ml/min es aconsejable reducir la dosis a la mitad. Con la administración endovenosa es importante mantener el tiempo de infusión y en hemodiálisis administrar durante la sesion. Con el ibandronato, hasta el momento actual, no se ha descrito patología renal y con las formas orales de cualquiera de ellos tampoco.</p> <p class="elsevierStylePara"><span class="elsevierStyleBold"> </span>Los bifosfonatos se han demostrado eficaces en la prevención de la pérdida ósea postrasplante, en tratamiento de calcifilaxis y prevención de las calcificaciones vasculares. En los pacientes con ERC avanzada ó en diálisis, los bifosfonatos estarían indicados, sobre todo, ante la presencia de franca disminución de la masa ósea y la existencia de factores de riesgo de osteoporosis junto a alto remodelado óseo. Se debe sopesar con cuidado su indicación en pacientes con sospecha de enfermedad ósea adinámica, siendo en este caso mandatoria la biopsia ósea.</p>" ] ] "multimedia" => array:5 [ 0 => array:8 [ "identificador" => "fig1" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "10320_18030_5508_en_figure1.jpg" "Alto" => 468 "Ancho" => 784 "Tamanyo" => 119170 ] ] "descripcion" => array:1 [ "en" => "Molecular structure of bisphosphonates." ] ] 1 => array:7 [ "identificador" => "tbl1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:1 [ "tablaImagen" => array:1 [ 0 => array:4 [ "imagenFichero" => "10320_18030_5510_en_table1.jpg" "imagenAlto" => 310 "imagenAncho" => 384 "imagenTamanyo" => 78940 ] ] ] ] ] "descripcion" => array:1 [ "en" => "Classification of bisphosphonates by their mechanism of action" ] ] 2 => array:8 [ "identificador" => "fig2" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "10320_18030_5512_en_figure2.jpg" "Alto" => 534 "Ancho" => 785 "Tamanyo" => 170696 ] ] "descripcion" => array:1 [ "en" => "Classification of bisphosphonates by their mechanism of action." ] ] 3 => array:7 [ "identificador" => "tbl2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:1 [ "tablaImagen" => array:1 [ 0 => array:4 [ "imagenFichero" => "10320_18030_5513_en_table2.jpg" "imagenAlto" => 278 "imagenAncho" => 791 "imagenTamanyo" => 134016 ] ] ] ] ] "descripcion" => array:1 [ "en" => "Bisphosphonates marketed in our country, route of administration, and brand name" ] ] 4 => array:7 [ "identificador" => "tbl3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:1 [ "tablaImagen" => array:1 [ 0 => array:4 [ "imagenFichero" => "10320_18030_5515_en_table3.jpg" "imagenAlto" => 174 "imagenAncho" => 384 "imagenTamanyo" => 84574 ] ] ] ] ] "descripcion" => array:1 [ "en" => "Possible indications for bisphosphonates in nephrology" ] ] ] "bibliografia" => array:2 [ "titulo" => "Bibliography" "seccion" => array:1 [ 0 => array:1 [ "bibliografiaReferencia" => array:54 [ 0 => array:3 [ "identificador" => "bib1" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Roelofs AJ, Thompson K, Gordon S, Rogers MJ. Molecular mechanisms of action of bisphosphonates: current status. Clin Cancer Res 2006; 12:6222-30." "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:1 [ "itemHostRev" => array:3 [ "pii" => "S1525861013000510" "estado" => "S300" "issn" => "15258610" ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib2" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Russell RGG, Watts NB, Ebetino FH, Rogers MJ. Mechanisms of action of bisphosphonates: similarities and differences and their potential influence on clinical efficacy. Osteoporosis Int 2008; 19:733-59." "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 2 => array:3 [ "identificador" => "bib3" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Courtney AE, Maxwell AP. Chronic kidney disease and bisphosphonate treatment: are prescribing guidelines unnecessarily restrictive? Postgrad Med J 2009; 85:327-30. <a href="http://www.ncbi.nlm.nih.gov/pubmed/19528309" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:1 [ "itemHostRev" => array:3 [ "pii" => "S1525861012004471" "estado" => "S300" "issn" => "15258610" ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib4" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Lühe A, Künkele KP, Haiker M, Schad K, Zihlmann C, Bauss F, Suter L, Pfister T. Preclinical evidence for nitrogen-containing bisphosphonate inhibition of farnesyl diphosphate synthase in the kidney: implications for renal safety. Toxicology 2008; 22:899-909." "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 4 => array:3 [ "identificador" => "bib5" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Pfister T, Atzpodien E, Bauss F. The renal effects of minimally nephrotoxic doses of ibandronate and zoledronate following single and intermittent intravenous administration. Toxicology 2003; 191:159-67. <a href="http://www.ncbi.nlm.nih.gov/pubmed/12965119" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 5 => array:3 [ "identificador" => "bib6" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Perazella MA, Markowitz GS. Bisphosphonate nephrotoxicity. Kidney International 2008; 74:1385-93. <a href="http://www.ncbi.nlm.nih.gov/pubmed/18685574" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 6 => array:3 [ "identificador" => "bib7" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Bergner R, Diel IJ, Henrich d, Hoffman M, Uppenkamp M. Differences in nephrotoxicity of intravenous bisphosphonates for the treatment of malignancy-related bone disease. Onkologie 2006; 29:534-40. <a href="http://www.ncbi.nlm.nih.gov/pubmed/17068390" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 7 => array:3 [ "identificador" => "bib8" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Hernández MV, Peris P, Monegal A, Reyes R, Muxi A, Gifre L, Guabañens N. Effects of intravenous pamidronate on renal function, bone mineral metabolism and bone mass in patients with severe osteoporosis. Am J Med Sci 2010; 339:225-9. <a href="http://www.ncbi.nlm.nih.gov/pubmed/20220332" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 8 => array:3 [ "identificador" => "bib9" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Bonen S, Sellmeyer DE, Lippuner K, Orlov-Morozov A, Abrams K, Mesenbrink P, Eriksen EF, Miller PD. Renal safety of annual zoledronic acid infusions in osteoporotic postmenopausal women. Kidney Int 2008; 74:641-8. \u{A0} <a href="http://www.ncbi.nlm.nih.gov/pubmed/18509324" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 9 => array:3 [ "identificador" => "bib10" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Diel IJ, Weide R, Köppler H, Neary M, Duh MS. Risk of renal impairment after treatment with ibandronate versus zoledronic acid: a retrospective medical records review. Support Care Cancer 2009; 17:719-25. <a href="http://www.ncbi.nlm.nih.gov/pubmed/19089462" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 10 => array:3 [ "identificador" => "bib11" "etiqueta" => "11" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Body JJ, Pfister T, Bausss F. Preclinical perspectives on biphosphonate renal safety. The oncologist 2005; 10:3-7. <a href="http://www.ncbi.nlm.nih.gov/pubmed/16264106" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 11 => array:3 [ "identificador" => "bib12" "etiqueta" => "12" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Barri YM, Munshi NC, Sukumalchantra S, Abulezz SR, Bonsib SM, Wallach J, Walker PD. Podocyte injury associated glomerulopathies induced by pamidronate. Kidney Int 2004; 65:634-41. <a href="http://www.ncbi.nlm.nih.gov/pubmed/14717935" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 12 => array:3 [ "identificador" => "bib13" "etiqueta" => "13" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Shreedhara M, Fenves AZ, Benavides D, Stone MJ. Reversibility of pamidronate-associated glomeruloesclerosis. Proc Bayl Univ Med Cent 2007; 20:249-53. <a href="http://www.ncbi.nlm.nih.gov/pubmed/17637879" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 13 => array:3 [ "identificador" => "bib14" "etiqueta" => "14" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Nagahama M, Sica DA. Pamidronate-induced kidney injury in a patient with metastatic breast cancer. Am J Med Sci 2009; 338:225-28." "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 14 => array:3 [ "identificador" => "bib15" "etiqueta" => "15" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Markowitz GS, Fine PL, Stack JI, Kunis CL, Radhakrishnan J, Palecki W, Park J, Nasr SH, Hoh S, Siegel DS, D¿Agati VD. Toxic acute tubular necrosis following treatment with zoledronate. Kidney Int 2003; 64:281-89." "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 15 => array:3 [ "identificador" => "bib16" "etiqueta" => "16" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Bergner R, Henrich DM, Hoffmann M, Honocker A, Mikus G, Nauth B, Nagel D, Uppenkamp M. Renal safety and pharmacokinetics of ibandronate in multiple myeloma patients with or without impaired renal function. J Clin Pharmacol 2007; 47:942-50 <a href="http://www.ncbi.nlm.nih.gov/pubmed/17615253" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 16 => array:3 [ "identificador" => "bib17" "etiqueta" => "17" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Miura N, Mizuno N, Aoyama R, Kitagawa W, Yamada H, Nishikawa K, Imai H. Massive proteinuria and acute renal failure after oral bisphosphonate (alendronate) administration in a patient with focal segmental glomerulosclerosis. Clin Exp Nephrol 2009; 13:85-8. <a href="http://www.ncbi.nlm.nih.gov/pubmed/18754075" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 17 => array:3 [ "identificador" => "bib18" "etiqueta" => "18" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Ersoy FF. Osteoporosis in the elderly with chronic kidney disease. Int Urol Nephrol 2007; 39:321-31. \u{A0} <a href="http://www.ncbi.nlm.nih.gov/pubmed/17103030" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:1 [ "itemHostRev" => array:3 [ "pii" => "S1525861013005677" "estado" => "S300" "issn" => "15258610" ] ] ] ] ] ] ] 18 => array:3 [ "identificador" => "bib19" "etiqueta" => "19" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Miller PD, Roux C, Boonen S, Barton IP, Dunlap LE, Burgio DE. Safety and efficacy of risedronate in patients with age-related reduced renal function as estimated by the Cockcroft and Gault method: a pooled analysis of nine clinical trials. J Bone Miner Res 2005; 20:2105-15. <a href="http://www.ncbi.nlm.nih.gov/pubmed/16294264" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:1 [ "itemHostRev" => array:3 [ "pii" => "S1525861013006063" "estado" => "S300" "issn" => "15258610" ] ] ] ] ] ] ] 19 => array:3 [ "identificador" => "bib20" "etiqueta" => "20" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Jamal SA, Bauer DC, Ensrud KE, Cauley JA, Hochberg M, Ishani A, Cummings SR. Alendronate treatment in women with normal to severely impaired renal function: an analysis of the fracture intervention trial. J Bone Miner Res 2007; 22:503-8. <a href="http://www.ncbi.nlm.nih.gov/pubmed/17243862" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 20 => array:3 [ "identificador" => "bib21" "etiqueta" => "21" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Jacksob GH. Renal safety of Ibandronate. The Oncologist 2005; 10:14-8. <a href="http://www.ncbi.nlm.nih.gov/pubmed/16264108" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 21 => array:3 [ "identificador" => "bib22" "etiqueta" => "22" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Henrich D, Hoffman M, Uppenkamp M, Bergner R. Ibandronate for the treatment of hypercalcemia or nephrocalcinosis in patients with multiple myeloma and acute renal failure: case reports. Acta Haematol 2006; 116:165-72. <a href="http://www.ncbi.nlm.nih.gov/pubmed/17016034" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 22 => array:3 [ "identificador" => "bib23" "etiqueta" => "23" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "von Moos R, Caspar CB, Thürlimann B, Angst R, Inauen R, Greil R, Bergstrom B, Schmieding K, Pecherstorfer M. Renal safety profiles of ibandronate 6 mg infused over 15 and 60 min: a randomized, open-label study. Ann Oncol 2008; 19:1266-70. \u{A0} <a href="http://www.ncbi.nlm.nih.gov/pubmed/18334511" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 23 => array:3 [ "identificador" => "bib24" "etiqueta" => "24" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Chantzichristos D, Andréasson B, Johansson P. Safe and tolerable one-hour pamidronate infusion for multiple myeloma patients. Therapeutics and Clinical Risk Management 2008; 4:1371-4. <a href="http://www.ncbi.nlm.nih.gov/pubmed/19337444" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 24 => array:3 [ "identificador" => "bib25" "etiqueta" => "25" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Sierra F, Román A, Barreda C, Moleón M, Pastor J, Navas A. Influencia del tiempo de perfusión de pamidronato sobre la función renal en pacientes con mieloma múltiple. Farm Hosp 2010; 34:23-6. <a href="http://www.ncbi.nlm.nih.gov/pubmed/20144818" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 25 => array:3 [ "identificador" => "bib26" "etiqueta" => "26" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Buttazzoni M, Rosa Diez GJ, Jager V, Crucelegui MS, Algranati SL, Plantalech L. Elimination and clearance of pamidronate by haemodialysis. Nephrology 2006; 11:197-200. <a href="http://www.ncbi.nlm.nih.gov/pubmed/16756631" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:1 [ "itemHostRev" => array:3 [ "pii" => "S0140673613623880" "estado" => "S300" "issn" => "01406736" ] ] ] ] ] ] ] 26 => array:3 [ "identificador" => "bib27" "etiqueta" => "27" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Ala-Houhala I, Saha H, Liukko-Sipi S, Ylitalo P, Pasternack A.Pharmacokinetics of clodronate in haemodialysis patients. Nephrol Dial Transplant 1999; 14: 699-705. <a href="http://www.ncbi.nlm.nih.gov/pubmed/10193822" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 27 => array:3 [ "identificador" => "bib28" "etiqueta" => "28" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Beigel AE, Rienhoff E, Olbricht CJ. Removal of clodronate by haemodialysis in end-stage renal disease patients. Nephrol Dial Transplant 1995; 10: 2266-8. <a href="http://www.ncbi.nlm.nih.gov/pubmed/8808223" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 28 => array:3 [ "identificador" => "bib29" "etiqueta" => "29" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Bergner R, Dill K, Boerner D, Uppenkamp M. Elimination of intravenously administered ibandronate in patients on haemodialysis: A monocentre open study. Nephrol Dial Transplant 2002; 17: 1281-5. <a href="http://www.ncbi.nlm.nih.gov/pubmed/12105253" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 29 => array:3 [ "identificador" => "bib30" "etiqueta" => "30" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Henrich DM, Hoffman M, Uppenkamp M, Bergner R. Tolerability on dose escalation of ibandronate in patients with multiple myeloma and end-stage renal disease:a case series. Onkologie 2009; 32:482-6. <a href="http://www.ncbi.nlm.nih.gov/pubmed/19745591" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:1 [ "itemHostRev" => array:3 [ "pii" => "S1525861013006713" "estado" => "S300" "issn" => "15258610" ] ] ] ] ] ] ] 30 => array:3 [ "identificador" => "bib31" "etiqueta" => "31" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Saha H et al. Skeletal deposition of clodronate is related to parathyroid function and bone turnover in dialysis patients. Clin Nephrol 2002; 58:47-53. <a href="http://www.ncbi.nlm.nih.gov/pubmed/12141406" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 31 => array:3 [ "identificador" => "bib32" "etiqueta" => "32" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Torregrosa JV, Fuster D, Monegal A, Gentil MA, Bravo J, Guirado L, Muxí A, Cubero J. Efficacy of low doses of pamidronate in osteopenic patients administered in the early post-renal transplant. Osteoporos Int 2010;" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:1 [ "itemHostRev" => array:3 [ "pii" => "S1525861013004702" "estado" => "S300" "issn" => "15258610" ] ] ] ] ] ] ] 32 => array:3 [ "identificador" => "bib33" "etiqueta" => "33" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Torregrosa JV, Fuster D, Gentil MA, Marcen R, Guirado L, Zarraga S, Bravo J, Burgos D, Monegal A, Muxi A, Garcia S. Open-label trial: effect of weekly risedronate inmediately after transplantation in kidney recipients. Transplantation 2010." "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:1 [ "itemHostRev" => array:3 [ "pii" => "S152586101200463X" "estado" => "S300" "issn" => "15258610" ] ] ] ] ] ] ] 33 => array:3 [ "identificador" => "bib34" "etiqueta" => "34" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Ste-Marie LG, Sod E, Johnson T, Chines A. Five years of treatment with risedronate an its effects on bone safety in women with postmenopausal osteoporosis. Calcif Tissue Int 2004; 75:469-76. <a href="http://www.ncbi.nlm.nih.gov/pubmed/15478000" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 34 => array:3 [ "identificador" => "bib35" "etiqueta" => "35" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Bergner R, Henrich D, Hoffmann M, Schmidt-Gayk H, Lenz T, Upperkamp M. Treatment of reduced bone density with ibandronate in dialysis patients. J Nephrol 2008; 21:510-5." "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 35 => array:3 [ "identificador" => "bib36" "etiqueta" => "36" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Miller PD. Is there a role for bisphosphonates in chronic kidney disease? Semin Dial 2007; 20:186-90. <a href="http://www.ncbi.nlm.nih.gov/pubmed/17555478" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 36 => array:3 [ "identificador" => "bib37" "etiqueta" => "37" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Torregrosa JV, Moreno A, Mas M, Ybarra J, Fuster D. Usefulness of pamidronate in severe secondary hyperparathyroidism in patients undergoing hemodialysis. Kidney Int 2003; 85:88-90." "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 37 => array:3 [ "identificador" => "bib38" "etiqueta" => "38" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Wetmore JB, Benet LZ, Kleinstuck D, Frassetto L. Effects of short-term alendronate on bone mineral density in haemodialysis patients. Nephrology 2005; 10:393-9. <a href="http://www.ncbi.nlm.nih.gov/pubmed/16109088" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:1 [ "itemHostRev" => array:3 [ "pii" => "S1525861013004258" "estado" => "S300" "issn" => "15258610" ] ] ] ] ] ] ] 38 => array:3 [ "identificador" => "bib39" "etiqueta" => "39" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Price PA. Omid N, Than TN, Williamson MK. The aminobisphosphonate ibandronate prevents calciphylaxis in the rat at doses that inhibit bone resoption. Calcif Tissue Int 2002; 71:356-63. <a href="http://www.ncbi.nlm.nih.gov/pubmed/12183764" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:1 [ "itemHostRev" => array:3 [ "pii" => "S1525861013000820" "estado" => "S300" "issn" => "15258610" ] ] ] ] ] ] ] 39 => array:3 [ "identificador" => "bib40" "etiqueta" => "40" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Monney P, Nguyen QV, Perroud H, Descombres E. Rapid improvement of calciphylaxis after intravenous pamidronate therapy in a patient with chronic renal failure. Nephrol Dial Transplant 2004; 19:2130-2. <a href="http://www.ncbi.nlm.nih.gov/pubmed/15252173" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 40 => array:3 [ "identificador" => "bib41" "etiqueta" => "41" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Shiraishi N, Kitamura K, Miyoshi T, Adachi M, Kohda Y, Nonoguchi H, Misumi S, Maekawa Y, Murayama T, Tomita M, Tomita K. Succesful treatment of a patients with severe calcifil uremic arteriolopathy (calciphylaxis) by etidronate disodium. Am J Kidney Dis 2006; 48:151-4. <a href="http://www.ncbi.nlm.nih.gov/pubmed/16797398" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:1 [ "itemHostRev" => array:3 [ "pii" => "S1525861013003836" "estado" => "S300" "issn" => "15258610" ] ] ] ] ] ] ] 41 => array:3 [ "identificador" => "bib42" "etiqueta" => "42" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Schliep S, Schuler G, Kiesewetter F. Sucessful treatment of calciphylaxis with pamidronate. Eur J Dermatol 2008; 18:554-6. <a href="http://www.ncbi.nlm.nih.gov/pubmed/18693159" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 42 => array:3 [ "identificador" => "bib43" "etiqueta" => "43" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Czosnowski LM, Hudson JQ, Canada RB. Hypercalcemia associated with tertiary hyperparathyroidism managed conservatively with pamidronate in a hemodialysis patient. Am J Med Sci 2009; 337:300-1. <a href="http://www.ncbi.nlm.nih.gov/pubmed/19365180" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 43 => array:3 [ "identificador" => "bib44" "etiqueta" => "44" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Fiore CE, Pennisi P, Pulvirenti I, Francucci CM. Bisphosphonates and atherosclerosis. J Endocrinol Invest 2009; 32:38-43. <a href="http://www.ncbi.nlm.nih.gov/pubmed/19724165" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 44 => array:3 [ "identificador" => "bib45" "etiqueta" => "45" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Lomashvili KA, Khawandi W, O¿Neil WC. Reduced plasma pyrophosphate levels in hemodialysis patients. J Am Soc Nephrol 2005; 16:2495-500. <a href="http://www.ncbi.nlm.nih.gov/pubmed/15958726" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 45 => array:3 [ "identificador" => "bib46" "etiqueta" => "46" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Hill JA, Goldin JG, Gjerston D, Emerick AM, Greaser LD, Yoon HC, Khorrami S, Aziz D, Adams JS. Progression of coronary artery calcification in patients taking alendronate for osteoporosis. Acad Radiol 2002; 9:1148-52. <a href="http://www.ncbi.nlm.nih.gov/pubmed/12385509" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 46 => array:3 [ "identificador" => "bib47" "etiqueta" => "47" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Tanko LB, Qin G, Alexandersen P, Bagger YZ, Christiansen C. Effective doses of ibandronate do not influence the 3-year progression of aortic calcification in elderly osteoporotic women. Osteoporosis Int 2005; 16:184-90." "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 47 => array:3 [ "identificador" => "bib48" "etiqueta" => "48" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Nitta K, Akiba T, Suzuki K, Uchida K, Watanabe R, Majima K, Aoki T, Nihei H. Effects of cyclic intermittent etidronate therapy on coronary artery calcification in patients receiving long-term hemodialysis. Am J Kidney Dis 2004; 44:680-8. <a href="http://www.ncbi.nlm.nih.gov/pubmed/15384019" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:1 [ "itemHostRev" => array:3 [ "pii" => "S1525861012004203" "estado" => "S300" "issn" => "15258610" ] ] ] ] ] ] ] 48 => array:3 [ "identificador" => "bib49" "etiqueta" => "49" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Hashiba H, Aizawa S, Tamura K, Kogo H. Inhibition of the progression of aortic calcification by etidronate treatment in hemodialysis patients: long-term effects. Ther Apher Dial 2006; 10:59-64. <a href="http://www.ncbi.nlm.nih.gov/pubmed/16556138" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 49 => array:3 [ "identificador" => "bib50" "etiqueta" => "50" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Ariyoshi T, Eishi K, Sakamoto I, Matsukuma S, Odate T. Effect ofetidronic acid on arterial calcification in dialysis patients. Clin Drug Investig 2006; 26:215-22. <a href="http://www.ncbi.nlm.nih.gov/pubmed/17163254" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 50 => array:3 [ "identificador" => "bib51" "etiqueta" => "51" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Sung EC, Chan SM, Sakurai K, Chung E. Osteonecrosis of the maxilla as a complication to chemotherapy: a case report. Spec Care Dentist 2002; 22:142-6. <a href="http://www.ncbi.nlm.nih.gov/pubmed/12449457" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 51 => array:3 [ "identificador" => "bib52" "etiqueta" => "52" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Merigo E, Manfredi M, Meleti M, Guidotti R, Ripasarti A, Zanzucchi E, D¿Aleo P, Corradi D, Corcione L, Sesenna E, Ferrari S, Poli T, Bonaninil M, Vescovi P. Bone necrosis of the jaws associated with bisphosphonate treatment: a report of twenty-nine cases. Acta Biomed 2006; 77:109-17. <a href="http://www.ncbi.nlm.nih.gov/pubmed/17172192" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 52 => array:3 [ "identificador" => "bib53" "etiqueta" => "53" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Migliorati CA, Schubert MM, Peterson DE, Seneda LM et al. Bisphosphonate-associated osteonecrosis of mandibular and maxillary bone. Cancer 2005; 104:83-93. <a href="http://www.ncbi.nlm.nih.gov/pubmed/15929121" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 53 => array:3 [ "identificador" => "bib54" "etiqueta" => "54" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Khosla S et al. Bisphosphonate associated osteonecrosis of the jaw: Report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 2007; 22:1479-91. \u{A0} <a href="http://www.ncbi.nlm.nih.gov/pubmed/17663640" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/20132514/0000003000000003/v0_201502091603/X2013251410035792/v0_201502091603/en/main.assets" "Apartado" => array:4 [ "identificador" => "35445" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Short Reviews" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/20132514/0000003000000003/v0_201502091603/X2013251410035792/v0_201502091603/en/P1-E46-S1858-A10320-EN.pdf?idApp=UINPBA000064&text.app=https://revistanefrologia.com/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X2013251410035792?idApp=UINPBA000064" ]
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| 2024 November | 40 | 11 | 51 |
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| 2020 December | 155 | 43 | 198 |
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| 2020 April | 103 | 20 | 123 |
| 2020 March | 160 | 26 | 186 |
| 2020 February | 263 | 39 | 302 |
| 2020 January | 186 | 33 | 219 |
| 2019 December | 119 | 33 | 152 |
| 2019 November | 177 | 40 | 217 |
| 2019 October | 141 | 21 | 162 |
| 2019 September | 172 | 38 | 210 |
| 2019 August | 104 | 26 | 130 |
| 2019 July | 90 | 23 | 113 |
| 2019 June | 112 | 38 | 150 |
| 2019 May | 134 | 34 | 168 |
| 2019 April | 185 | 50 | 235 |
| 2019 March | 144 | 46 | 190 |
| 2019 February | 89 | 35 | 124 |
| 2019 January | 199 | 29 | 228 |
| 2018 December | 190 | 57 | 247 |
| 2018 November | 202 | 25 | 227 |
| 2018 October | 205 | 16 | 221 |
| 2018 September | 304 | 23 | 327 |
| 2018 August | 194 | 34 | 228 |
| 2018 July | 160 | 20 | 180 |
| 2018 June | 150 | 15 | 165 |
| 2018 May | 159 | 15 | 174 |
| 2018 April | 154 | 10 | 164 |
| 2018 March | 147 | 8 | 155 |
| 2018 February | 110 | 8 | 118 |
| 2018 January | 108 | 8 | 116 |
| 2017 December | 141 | 15 | 156 |
| 2017 November | 116 | 25 | 141 |
| 2017 October | 106 | 6 | 112 |
| 2017 September | 99 | 21 | 120 |
| 2017 August | 122 | 23 | 145 |
| 2017 July | 130 | 10 | 140 |
| 2017 June | 156 | 21 | 177 |
| 2017 May | 185 | 12 | 197 |
| 2017 April | 125 | 13 | 138 |
| 2017 March | 172 | 4 | 176 |
| 2017 February | 194 | 18 | 212 |
| 2017 January | 110 | 16 | 126 |
| 2016 December | 140 | 12 | 152 |
| 2016 November | 256 | 18 | 274 |
| 2016 October | 285 | 30 | 315 |
| 2016 September | 376 | 11 | 387 |
| 2016 August | 506 | 12 | 518 |
| 2016 July | 253 | 8 | 261 |
| 2016 June | 183 | 0 | 183 |
| 2016 May | 194 | 0 | 194 |
| 2016 April | 180 | 0 | 180 |
| 2016 March | 165 | 0 | 165 |
| 2016 February | 165 | 0 | 165 |
| 2016 January | 141 | 0 | 141 |
| 2015 December | 152 | 0 | 152 |
| 2015 November | 138 | 0 | 138 |
| 2015 October | 129 | 0 | 129 |
| 2015 September | 125 | 0 | 125 |
| 2015 August | 107 | 0 | 107 |
| 2015 July | 111 | 0 | 111 |
| 2015 June | 34 | 0 | 34 |
| 2015 May | 42 | 0 | 42 |
| 2015 April | 6 | 0 | 6 |
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