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Possible Ocular Adverse Effects Attributable to Bisphosphonate

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Possible Ocular Adverse Effects Attributable to Bisphosphonate r e v c o l o m b r e u m a t o l . 2 0 1 7;2 4(1):54–59 w ww.elsevier.es/rcreuma Case report Possible ocular adverse effects attributable to ଝ bisphosphonate therapy: Two case reports a b,∗ Luis Guillermo Gómez Escobar , Deyanira González Devia a Facultad de Medicina, Universidad de los Andes, Bogotá, Colombia b Medicina Interna, Endocrinología, Hospital Universitario Fundación Santa Fe de Bogotá, Bogotá, Colombia a r t i c l e i n f o a b s t r a c t Article history: Bisphosphonates are used in the management of diseases characterized by an increase in Received 16 June 2015 bone resorption such as osteoporosis, metatasic bone disease, malignant hypercalcemia Accepted 6 June 2016 among others. It has been reported that the use of IV bisphosphonates as zoledronate and Available online 30 April 2017 pamidronate generate ocular adverse effects by an acute phase reaction mediated by an increase of interleukin 6 (IL-6) and tumoral necrosis factor (TNF-␣). We present 2 cases, a Keywords: woman 71 years old and a 67 years old man that received therapy with bisphosphonates Uveitis and 24–72 h later they presented an anterior uveitis. Bisphosphonates © 2016 Asociacion´ Colombiana de Reumatologıa.´ Published by Elsevier Espana,˜ S.L.U. All Zoledronic acid rights reserved. Adverse effect Posibles efectos adversos oculares de los bifosfonatos. Reporte de 2 casos r e s u m e n Palabras clave: Los bifosfonatos se utilizan para el manejo de enfermedades con incremento de la resor- Uveítis ción ósea como la osteoporosis, la enfermedad metastásica ósea y la hipercalcemia maligna, Bifosfonatos entre otras patologías. En los últimos anos˜ se ha reportado que el uso de bifosfonatos intra- Ácido zoledrónico venosos como el zoledronato y el pamidronato pueden generar efectos adversos oculares, Efecto adverso ocasionados por una reacción de fase aguda mediada por la interleucina-6 (IL-6) y factor de necrosis tumoral alfa (TNF-␣). Se reportan 2 casos (una mujer de 71 anos˜ y un hombre de 67 anos)˜ que entre las 24 a 72 h después de recibir terapia con zoledronato presentaron una uveítis anterior. © 2016 Asociacion´ Colombiana de Reumatologıa.´ Publicado por Elsevier Espana,˜ S.L.U. Todos los derechos reservados. PII of original article: S0121-8123(16)30040-8 ଝ Please cite this article as: Gómez Escobar LG, Devia DG. Posibles efectos adversos oculares de los bifosfonatos. Reporte de 2 casos. Rev Colomb Reumatol. 2017;24:54–59. ∗ Corresponding author. E-mail address: [email protected] (D.G. Devia). 2444-4405/© 2016 Asociacion´ Colombiana de Reumatologıa.´ Published by Elsevier Espana,˜ S.L.U. All rights reserved. r e v c o l o m b r e u m a t o l . 2 0 1 7;2 4(1):54–59 55 that required management with osteosynthesis; café-au-lait Introduction spots; and in this context the McCune-Albright syndrome is suspected, with a negative mutation for the GNAS gene, Bisphosphonates have been used in subjects with confirmed to which is pending to carry out the whole gene sequenc- 1 diagnosis of osteoporosis, Paget’s disease, neoplastic diseases ing. The patient has presented drug allergy to dapsone. As with bone metastases, malignant hypercalcemia and other concomitant medication the patient was receiving levothyrox- 2 pathologies such as osteogenesis imperfecta. In the world, ine, cholecalciferol and calcium carbonate. After the adverse the prescription of this family of drugs has increased; an event, the patient was taken to the medical board, where it example of this is that from 2002 to 2007 the use of thera- was decided to control the decrease in bone mass with deno- pies with oral bisphosphonates reached 52.7 million formulas, sumab 60 mg subcutaneously, every 6 months, but the patient and with intravenous bisphosphonates, in the United States, did not accept; at the present time she continues under close 3 from 2002 to 2010 it increased by 561,000 doses. In Spain surveillance with bone alkaline phosphatase, densitometries it has been also observed an increase in the prescription of and clinical examinations. 4 bisphosphonates up to double between 1998 and 2003. It has been reported that the use of intravenous and oral Case #2 bisphosphonates can generate ocular adverse effects by a transient increase in pyrogenic cytokines and an increased A 67-year-old man who enters the emergency department production of interleukin-6 (IL-6) and tumor necrosis factor 5 with a clinical picture of 72 h of evolution consisting in bilat- alpha (TNF-␣) mediated by ␥/␦ T lymphocytes. The most com- eral eye pain, red eye, photophobia without alteration of visual mon adverse effects are anterior uveitis, episcleritis, scleritis 6 acuity following the application of zoledronic acid (4 mg) and orbital inflammatory disease. for the management of polyostotic disease associated with The objective of this publication is to report 2 cases of pos- prostate carcinoma. The ophthalmological exam reported sible secondary effects of bisphosphonates at the ocular level, generalized conjunctival hyperemia, intraocular pressure of especially of zoledronic acid. 14 mmHg, positive Tyndall and Flare (++/+), round papillae with well-defined edges and a healthy macula. In addition, he reported hyperthermia of 38 degrees during 2 days, dys- Case presentation pnea, myalgias and arthralgias with limitation of movement, unsteady gait and prostration that lasted for a month. It Case #1 was diagnosed a bilateral AAU and topical cyclopentolate and prednisolone F were prescribed. The patient recovered within A 74-year-old woman with presence of high bone alkaline a month without sequelae. phosphatase despite the correction of the 25 OH-vitamin D As relevant antecedents the patient has a stage IV prostate deficiency, normal calcemia, normal phosphatemia, normal carcinoma diagnosed in October 2014, with metastatic bone 1,25-dihydroxyvitamin D, normal PTH, dietary and supple- involvement (spine and hip) managed with hormonal block- mental calcium intake; ruling out clinically and radiologically ade, bilateral phakectomy with intraocular lenses, retinal an osteomalacia and considering another metabolic bone dis- detachment in left eye, primary hypothyroidism, low bone ease. With DXA densitometry compatible with osteoporosis mass and dyslipidemia. As concomitant medication the according to the criteria of the World Health Organization patient was receiving cholecalciferol and goserelin acetate. (WHO), it was prescribed zoledronic acid, 5 mg intravenously, The patient has no history of allergies to any medication. After to be applied during 15 min. 48 h after having received the infu- the adverse event the prescription was changed for deno- sion, the patient presented pain in the right eye accompanied sumab, in part because the patient refused to use the drug by conjunctival hyperemia with dilated episcleral vessels. At again. the ophthalmological examination the patient presented pos- itive Tyndall and Flare (++), nuclear sclerosis and a decrease in visual acuity in the right eye 20/200. In the fundus of Discussion the eye were observed excavated oval papillae, a macula with slight decrease in brightness without the presence of Bisphosphonates decrease the rhythm of bone resorption 7 infection foci, and an ocular pressure of 12 mmHg; it was and delay the bone loss by 2 mechanisms: (1) Non-nitrogen diagnosed an acute anterior uveitis (AAU) of the right eye containing bisphosphonates have similarity to pyrophos- and it was prescribed prednisolone acetate, tropicamide and phate, being incorporated into the molecule of adenosine drops of hydroxypropyl-methylcellulose. The symptomato- triphosphate (ATP), producing non-hydrolizable ATP, which logy improved after treatment within the following 8 days and accumulates and inhibits multiple ATP-dependent cellular did not leave any sequels. processes and, finally, causes toxicity. (2) Nitrogen containing As relevant antecedents, the patient has controlled high bisphosphonates inhibit the enzyme farnesyl pyrophosphate blood pressure, hyperthyroidism due to toxic multinodular (FPP) synthase, involved in the mevalonate pathway, which goiter managed with iodine 131 mCI with successful response, is necessary for the construction of the cytoskeleton and the 8 type 1 gastric neuroendocrine tumor with histological grade survival of the osteoclast. 2 according to the WHO classification, recurrent, associ- Among the options of management with bisphosphonates, ated with autoimmunity, managed with subtotal gastrectomy; intravenous bisphosphonates have emerged as an interest- 9–11 monostotic dysplasia with involvement of the frontal bone ing choice due to their posology and potency. Zoledronic 56 r e v c o l o m b r e u m a t o l . 2 0 1 7;2 4(1):54–59 HMG-CoA Osteoclast effect Apoptosis/Inactivation Mevalonate Bisphosphonate molecules Zoledronate Pamidronate Inhibition of resorption Bone INFα IPP DMAPP κ-6 Activation Systemic IPP INFγ administration of γ/δ Self-limited Ocular effect local bisphosphonates inflammation GPP DMAPP Alendronate γ γ/δ /δ Etidronate Proliferation γ/δ Interaction macrophage/lymphocyte FPP INFα Self-limited Systemic effect Activation κ-6 systemic inflammation γ Protein prenylation Squalene INF Interaction macrophage/lymphocyte Fig. 1 – Mechanism of action of nitrogen-containing bisphosphonates and their relationship with the ocular adverse event. The systemic nitrogen-containing bisphosphonates lead to alteration in the mevalonate pathway generating the apoptosis of the osteoclast; this causes inhibition of bone resorption which is the expected
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