Alendronate-related oral mucosa ulcerations

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1 Case report Alendronate-related oral mucosa ulcerations Miguel Angel Gonzalez-Moles 1 Jose Vicente Bagan-Sebastian 2 1 School of Dentistry, University of Granada, Granada, and 2 School of Dentistry, University of Valencia and Valencia General Hospital, Valencia, Spain Abstract: Alendronate is widely used in the treatment of osteoporosis and other bone diseases. Although it is considered a well-tolerated drug, there are numerous reports of adverse effects on the mucosa in the upper aerodigestive tract, with oesophagitis as the most common complication. The strict regulations for the proper administration of the drug indicate that these side effects might well be the result of a direct, irritant mechanism on the upper aerodigestive tract. We present two clinical cases of patients who developed extensive palatal ulcers as a result of taking alendronate. We discuss possible mechanisms implicated in the production of the ulcers and some clinical factors of interest. Key words: adverse drug reaction; alendronate; mouth J Oral Pathol Med 2000: 29: Correspondence to: Miguel Angel Gonzalez Moles Oral Medicine, School of Dentistry, University of Granada Colegio Maximo, s/n, Campus de Cartuja, E Granada, Spain Accepted for publication November 20, 1999 Copyright C Munksgaard 2000 J Oral Pathol Med. ISSN Printed in Denmark. All rights reserved Alendronate (Fosamax A ) is a drug belonging to the diphosphonate family (4-amino-1-hydroxybutylidene 1,1-diphosphonate) that has recently been used in the treatment of osteoporosis (1 4). It has been demonstrated that this drug induces a progressive and significant increase in bone mineral density in women with osteoporosis (5) and with both hyperthyroidism and osteoporosis (6). Alendronate has also proven to be effective in the treatment of glucocorticoidinduced osteoporosis (7). On the other hand, the administration of this drug to patients with Paget s disease induced a noticeable reduction in the urinary excretion of hydroxiproline, followed by a fall in the serum activity of alkaline phosphatase and in bone turnover rates (8). The high prevalence of diseases in which alendronate has proven to be effective has led to its increasing use. Though it has been affirmed to be a well-tolerated drug (5, 9), adverse side effects on the mucosa in the upper aerodigestive tract have been reported, with oesophagitis as the commonest complication (10 24). We describe two clinical cases in which extensive ulcers related to taking alendronate appeared on the oral mucosa. 514

2 Alendronate-related oral mucosa ulcers Case reports Case no. 1 In June 1998, a 79-year-old woman with an ulcer on her palate of 5 months duration (since March, 1998) attended the Oral Medicine Outpatients Department at the School of Dentistry of the University of Granada. The patient was fitted with a full upper dental prosthesis and reported intense pain in the palate that prevented her from wearing it. There was no family case history of interest. She suffered from chronic anaemia and severe osteoporosis, for which she was receiving treatment with a mixture of ferrous sulphate (Ferro-semar A, 3 tablets/d), a vitamin compound (Hydroxyl B1-B6- B12 A, 3 tablets/d) and alendronate (Fosamax A, 10 mg/d). She re- ported that she habitually kept the drug on her tongue for a few seconds whilst she went for a glass of water. The clinical intraoral examination showed the presence of an ulcer with irregular margins, measuring 3 4 cm, that affected the hard palate and the alveolar ridge (Fig. 1A). Biopsies were taken from the border of the lesion for histopathological, Mycobacterium tuberculosis culture and direct immunofluorescence (IgG, IgM, IgA, C3) studies. The histopathological study demonstrated the existence of an ulcer with a chronic inflammatory lymphoplasmocytic bandlike infiltration and chronic granulation tissue (Fig. 2A). Both the direct immunofluorescence and the tissue culture results were negative. The base of the ulcer was scraped with a swab and the material obtained was used for detecting viral antigens of the herpes simplex virus, cytomegalovirus and Epstein-Barr virus, with negative re- Fig. 1. Case no. 1: Large ulcer of hard palate (A); after treatment (B). Fig. 2. Ulcers showing chronic inflammatory lymphoplasmocytic infiltration. Case no. 1 (A). Case no. 2 (B) (H&E, 40). J Oral Pathol Med 29:

3 Gonzalez-Moles & Bagan-Sebastian Fig. 3. Case no. 2: Large ulcer of hard palate (A); after treatment (B). sults in each case. Diagnostic tests for HIV infection and syphilis were both negative. Complete haematological analyses only demonstrated the presence of a discrete anaemia (3,000,000 erythrocytes/ mm). The patient s previous medication was suspended and she was treated with deflazacort (30 mg/d/5 d) followed by clobetasol propionate at 0.05%πnystatin 100,000 UI/cc in orabase (3 applications a day using the prosthesis as a support). At the first checkup after 20 days (end of July, 1998) no change was observed in the lesion. She was told to continue with the local corticoid at the same rate and to take no other drug orally. At the second check-up (beginning of September, 1998) no improvement in the lesion was observed. However, the patient reported that she had restarted treatment with alendronate. This drug was again suspended and she was told to continue with the local corticoid treatment. The patient was then monitored every 15 days. At the check-up on October 15, 1998 a minor improvement in the lesion was noted. The improvement in the ulcer was progressive until the almost complete disappearance of the lesion (January, 1999) (Fig. 1B). At follow-up 7 months later (August, 1999) complete healing of the lesion was observed. A full haematologic analysis was also performed (August, 1999) that showed no significant changes in the anaemia ( erythrocytes/mm). est. She suffered from severe osteoporosis for which she had been treated with alendronate (Fosamax A, 10 mg/d) for over a year. The patient reported that she sucked the tablet until it completely dissolved in her mouth. Intraoral examination revealed the presence of an extensive ulcer on the hard palate, with irregular margins and surrounded by an erythematous halo (Fig. 3A). Furthermore, a large ulcer was found on the dorsum of the tongue and another ulcer on the right side of the lower lip (Figs. 4 & 5). Biopsies were taken from the lesion on the palate for histopathological and direct immunofluorescence studies (IgG, IgM, IgA, C3). The histopathological analysis revealed the presence of an ulcer with a band-like subepithelial inflammatory infiltration (Fig. 2B). From December, 1997, the alendronate treatment was suspended and the patient was treated with clobetasol propionate at 0.05%πnystatin (100,000 UI/cc) in orabase applied on the palate surface of the prosthesis and on a swab Case no. 2 In November, 1997, a 67-year-old woman fitted with a partial upper prosthesis attended the Oral Medicine Outpatients Department at the School of Dentistry of the University of Valencia to complain of three ulcers located on the palate, tongue and lower lip, all of one month s duration. The ulcers caused intense pain and prevented her from using the prosthesis. There was no family case history of inter- Fig. 4. Ulcer of dorsum of tongue in case no J Oral Pathol Med 29: 514 8

4 Alendronate-related oral mucosa ulcers Fig. 5. Ulcer of lip in case no. 2. placed on the tongue and lip lesions. At follow-up in January, 1998, an improvement was observed in the palate and lip lesions without any change in the tongue lesion. By April, 1998, all the lesions had disappeared (Fig. 3B). ance as oral ulcers that arise from immunity disorder-related diseases, such as pemphigoid and lichen planus. The reports revealed that the response to corticoid treatment was poor and that the ulcers remitted slowly over long periods of time after withdrawal of the drug. This slowness of response had created diagnostic uncertainty in the two present cases, since drug-related oral ulcers normally remit more speedily after withdrawal of the medication causing the process. On the other hand, it is known that in skin allergic responses to drugs, healing can take many months. It is difficult to categorically identify the mechanism by which alendronate produced the oral lesions in the clinical cases presented here. It has been demonstrated that alendronate may cause gastric ulcers in rabbits through a direct irritant effect and that it increases the rate and the size of indomethacin-induced ulcers (25). However, some clinical factors make it difficult to accept a direct irritant effect of the drug as the exclusive mechanism for the production of the oral ulcers in the cases described. Both patients used upper prostheses that they did not remove when taking the drug. Furthermore, although neither patient followed the correct administration procedure, one patient (case no. 1) suffered no ulcers on the back of her tongue or at any other location, despite keeping the pill on her tongue for a time before swallowing it. Moreover, both patients had taken alendronate for long periods of time (5 months and 1 year, respectively) before the appearance of the ulcers. It is of interest to understand this phenomenon, since it may well create confusion in the diagnosis of conditions with similar symptoms. Discussion Alendronate is widely used for treating osteoporosis and other bone diseases (1 4). Although it is deemed to be a well-tolerated drug (5, 9), there have been frequent reports of adverse effects on the mucosa in the upper aerodigestive tract, with oesophagitis as the commonest complication (10 24). The correct procedure is for the patient to take the medication with a full glass of water, avoiding any chewing or sucking of the tablet, and to maintain an upright posture for at least 30 minutes afterwards. All these preventive measures indicate that the adverse effects of alendronate on the upper aerodigestive mucosa may be the result of a direct irritant mechanism (25). Both of the patients described in the present report developed extensive ulcers on the palate and one of them also had ulcers on the tongue and lower lip. These lesions disappeared slowly after withdrawal of the drug. Another two case reports of mucosal ulcerations of the mouth have also been reported in the medical literature (23, 24). Interestingly, the palatal ulcers reported were of considerable size and were similar to each another, with the same appear- References 1. Skorey K, Ly HD, Kelly J, et al. How does alendronate inhibit proteintyrosine phosphatases? J Biol Chem 1997; 272: Selby P. Alendronate treatment for osteoporosis: a review of the clinical evidence. Osteoporos Int 1996; 6: Sankaran SK. Osteoporosis prevention and treatment. Pharmacological management and treatment implications. Drugs Aging 1996; 9: Tucci JR, Tonino RP, Emkey RD, Peverly CA, Kher U, Santora AC. Effect of three years of oral alendronate treatment in postmenopausal women with osteoporosis. Am J Med 1996; 101: Devogelaer JP, Broll H, Correa-Rotter-R, et al. Oral alendronate induces progressive increases in bone mass of the spine, hip, and total body over 3 years in postmenopausal women with osteoporosis. Bone 1996; 18: Lupoli G, Nuzzo V, Di-Carlo C, et al. Effects of alendronate on bone loss in pre- and postmenopausal hyperthyroid women treated with methimazole. Gynecol Endocrinol 1996; 10: Saag KG, Emkey R, Schnitzer TJ, et al., Glucocorticoid-Induced Osteoporosis Intervention Study Group. Alendronate for the prevention and J Oral Pathol Med 29:

5 Gonzalez-Moles & Bagan-Sebastian treatment of glucocorticoid-induced osteoporosis. N Engl J Med 1998; 339: Khan SA, Vasikaran S, McCloskey EV, et al., Fracture Intervention Trial Research Group. Alendronate in the treatment of Paget s disease of bone. Bone 1997; 20: Black DM, Cummings SR, Karpf DB, et al. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet 1996; 348: Weihrauch TR. Arzneimittelinduzierte Osophagitis (AIO): Konnen stringente Anwendungshinweise dieses Krankheitsbild vermeiden helfen? Z Gastroenterol 1997; 35: Lilley LL, Guanci R. Avoiding alendronate-related esophageal irritation. Am J Nurs 1997; 97: Pizzani E, Valenzuela G. Esophagitis associated with alendronate sodium. Va Med Q 1997; 124: Girelli CM, Reguzzoni G, Rocca F. Esofagite da alendronato. Descrizione di due casi. Recenti Prog Med 1997; 88: Levine J, Nelson D. Esophageal stricture associated with alendronate therapy. Am J Med 1997; 102: Colina RE, Smith M, Kikendall JW, Wong RK. A new probable increasing cause of esophageal ulceration: alendronate. Am J Gastroenterol 1997; 92: Sorrentino D, Trevisi A, Bernardis V, Debiase F, Labombarda A, Bartoli E. Esophageal ulceration due to alendronate. Endoscopy 1996; 28: Rimmer DE, Rawls DE. Improper alendronate administration and a case of pill esophagitis (letter). Am J Gastroenterol 1996; 91: Naylor G, Davies MH. Oesophageal stricture associated with alendronic acid (letter). Lancet 1996; 348: Mackay FJ, Wilton LV, Pearce GL, Freemantle SN, Mann RD. United Kingdom experience with alendronate and oesophageal reactions. Br J Gen Pract 1998; 48: Tursi A, Cuoco L, Cammarota G, et al. Ulcerative oesophagitis due to alendronate (letter). Ital J Gastroenterol Hepatol 1997; 29: Ryan JM, Kelsey P, Ryan BM, Mueller PR. Alendronate-induced esophagitis: case report of a recently recognized form of severe esophagitis with esophageal stricture-radiographic features. Radiology 1998; 206: Cameron RB. Esophagitis dissecans superficialis and alendronate: case report. Gastrointest Endosc 1997; 46: Spreux A, Ampelas M, Bolla G, Baldin B. Ulcerations muqueuses topographiquement atypiques avec l alendronate. Therapie 1998; 53: Mundy GR, Guise TA. Hypercalcemia of malignancy. Am J Med 1997; 103: Elliott SN, McKnight W, Davies NM, MacNaughton WK, Wallace JL. Alendronate induces gastric injury and delays ulcer healing in rodents. Life Sci 1998; 62: J Oral Pathol Med 29: 514 8