Letters to the Editor

Multiple osteonecrosis of the , oral therapy and refractory rheumatoid arthritis (Pathological fracture associated with ONJ and BP use for )

Sirs, Osteonecrosis of the (ONJ) is a recent- ly described adverse side effect of bisphos- phonate therapy (1). Patients with multiple myeloma and metastatic carcinoma to the skeleton who are receiving intravenous, nitrogen-containing are at greatest risk for osteonecrosis of the jaws. There may be contributing comorbid fac- tors such as jaw infection, ill-fi tting den- tures, dental decay, poor dental hygiene and , dentoalveolar surgery, and immunosuppressive agents and, recently proposed, diabetes (2- 4). But we have not found any case with the association of ONJ, oral bisphosphonate and refractory rheumatoid arthritis (RA) as the patient we describe below. A 64-year-old white female patient present- ed in February 2004 with irregularity of the . She was admitted to evaluate a possible versus osteonecrosis complication of . She had a long history of aggressive and refractory RA. RA had set in at the age of 49. She was Fig. 1. Ortopantomography evolution of multiple ONJ in a RA patient treated with oral bisphosphonates treated initially with non-steroidal anti- for osteoporosis: A. May 17, 2006 Rx – Osteonecrotic lesions at both branches of mandible. B. October 11, 2006. – Fracture of right branch of mandible and its coronoid process. infl ammatory drugs, low doses of corti- coids and parenteral gold salts. Due to a negative response to the treatment, she re- moment, the diagnosis of ONJ associated open for discussion. Some authors related ceived successively a combination of oral to bisphosphonates was made, and the alen- ONJ more with malignancy and its thera- gold salts, methotrexate, chloroquine and dronate and the corticoids treatment were py than with bisphosphonates use, and do cyclosporine. In October 1996, she began withdrawn. The patient was sent for treat- not recommended their interruption (5). treatment with 150 mg/day of oral cyclo- ment in a hyperbaric chamber. At present Moreover, a favourable response of diffuse phosphamide, low doses of corticoids and a she is free of infection. Figure 1 shows the sclerosing osteomyelitis of the mandible to supplement of calcium and vitamin D. Cy- sequential evolution of lesions. alendronate was recently published (8), and clophosphamide was withdrawn due to he- Osteonecrosis of the jaw is characterized experimental alendronate use in amputated maturia 6 months later but her arthritis had clinically by an area of exposed in the rat molar seems useful and not complicated improved. Later, she was treated with lefl u- mandible, , or that typically with ONJ (9). But the growing number of nomide and chloroquine with control of the heals poorly or does not heal over a period reports regarding this complication sug- infl ammatory activity of RA until today. of 6 to 8 weeks. The diagnosis is primarily gests a bisphosphonates biological infl u- She was in a “burned RA” situation. She a clinical one, but imaging studies such as ence on the microtraumatic lesions self-re- began with 70 mg of weekly alendronate in computed tomography can be helpful. It is storative ability of the jaw bone. This site February 2002 for osteoporosis. a well-known but rare situation related to may be affected because the jawbones are She was evaluated by a maxillofacial sur- radiotherapy and chemotherapy for malig- in constant use and are characterized by ac- geon in March 2004. A cranial CT showed nancy (5). tive remodelling. For this reason, bisphos- lesions with detached bone in the mandible, This condition in connection with bisphos- phonates might accumulate preferentially therefore surgical cleaning was carried out. phonate use was fi rst reported in 2003; it in the jaw, resulting in concentrations that In June of 2006 she again had pain in the was rarely seen before then. Most of the exceed those found elsewhere in the skel- mandible, and an x-ray image of mandible reported cases (95%) have been associated eton. The possible antiangiogenic effects of osteonecrosis was obtained. A new CT was with or pamidronate given nitrogen-containing bisphosphonates and made that showed several osteonecrosis intravenously to control metastatic bone the effects of these agents on T-cell func- lesions. In October of 2006 she suffered disease (1, 2). The reported incidence of tion have also been hypothesized. acute pain and infection. A fracture of the osteonecrosis of the jaw in these cases has Osteonecrosis of the jaw has developed right part of the jaw was detected. Surgical ranged from 1.3% (6, 7) to 7% (1). Myel- far less often among patients who have re- cleaning of the mandible was done, the jaw oma and breast are by far the most ceived oral bisphosphonates at the lower was blocked with the superior dental pros- common associated with intrave- doses used for osteoporosis. Among several thesis and systemic antibiotics were admin- nous bisphosphonate use and ONJ. million patients who have received oral istered. Histological studies showed “bone The cause-effect relationship between bis- treatment for osteoporosis, fewer than 50 tissue ” without infection. At this phosphonates therapy and ONJ remains cases of osteonecrosis of the jaw have been

384 Letters to the Editor reported to date (1). Some authors believe Juan Canalejo University Hospital Complex, Related Jaw Osteonecrosis. J Clin Endocrinol Metab that 1 in 100,000 patient-years is a reason- Coruña, Spain. 2006 Dec 19; [Epub ahead of print]. able estimate of the incidence for this com- Address correspondence to: Dr. Jenaro Graña, 5. LENZ JH, STEINER-KRAMMER B, SCHMIDT W, Juan Canalejo University Hospital Complex, FIETKAU R, MUELLER PC, GUNDLACH KK: Does plication (3, 10) of the jaws in cancer patients Rheumatoid arthritis patients can be asso- Xubias de Arriba 84, 15006 A Coruña, Spain. E-mail: [email protected] only occur following treatment with bisphospho- ciated with poor mouth health and loose nates? J Craniomaxillofac Surg 2005; 33: 395-403. teeth, particularly patients with Sjögren’s Competing interests: none declared. [Epub 2005 Oct 25]. syndrome, and they are also often treated 6. HOFF AO, TOTH B, ALTUNDAG K et al.: Osteo- necrosis of the jaw in patients receiving intravenous with corticosteroids and immunosuppres- References bisphosphonate therapy. J Bone Miner Res 2005; 20 sive agents. This may increase the risk of 1. WOO SB, HELLSTEIN JW, KALMAR JR: Narrative (Suppl. 1): 1218 (abstract). developing ONJ during treatment with ami- [corrected] review: bisphosphonates and osteo- 7. POLIZZOTTO MN, COUSINS V, SCHWARER AP: nobisphosphonates. necrosis of the jaws. Ann Intern Med 2 2006;006; 1 144:44: Bisphosphonate-associated osteonecrosis of the To the best of our knowledge, this is the 753-61. Review. Erratum in: Ann Intern Med 22006;006; auditory canal. Br J Haematol 22006;006; 1132:32: 1114.14. 145: 235. Comment in: Ann Intern Med 2006; 145: fi rst published case of multiple ONJ, refrac- 8. HINO S, MURASE R, TERAKADO N, SHINTANI 791-2; author reply 792. Ann Intern Med 2006;2006; 145:145: S, HAMAKAWA H: Response of diffuse sclerosing tory RA and oral use of BP. The degree of 791; author reply 792. osteomyelitis of the mandible to alendronate: fol- risk for osteonecrosis in these patients tak- 2. MELO MD, OBEID G: Osteonecrosis of the jaws in low-up study by Tc-99m scintigraphy. Intl J Oral ing oral bisphosphonates for osteoporosis is patients with a history of receiving bisphosphonate Maxillofacial Surg 2005; 34: 576-8. uncertain and warrants careful monitoring. therapy. Strategies for prevention and early recogni- 9. CENGIZ SB, BATIRBAYGIL Y, ONUR MA et al.: tion. JADA 2005; 136: 1675-81. Histological comparison of alendronate, calcium 3. BILEZIKIAN JP: Osteonecrosis of the jaw – Do hydroxide and formocresol in amputated rat molar. J. GRAÑA, MD, PhD, Rheumatologist bisphosphonates pose a risk? N Engl J Med 2006; Dental Traumatol 2005; 21: 281-8. I. VAZQUEZ MAHIA, MD, Maxillofacial Surgeon 355: 2278-81. 10. BOLLAND MJ, GREY A, REID IR: Osteonecrosis M.-O. SÁNCHEZ MEIZOSO, MD, Documentalist 4. KHAMAISI M, REGEV E, YAROM N et al.: Possible of the jaw and bisphosphonates. BMJ 2006;2006; 333:333: T. VÁZQUEZ, MD, Training Rheumatologist Association Between Diabetes and Bisphosphonate- 1122-3.

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