Q U I N T E S S E N C E I N T E R N AT I O N A L

ORAL MEDICINE

Dale A. Baur

Osteonecrosis of the jaw in a patient on raloxifene: A case report Dale A. Baur, DDS, MD1/Mehmet Ali Altay, DDS, PhD2/Sorin Teich, DMD, MBA 3/Meghan Schmitt Oswald, DMD 4/ Faisal A. Quereshy, MD, DDS, FACS 5 Osteonecrosis of jaws (ONJ) is a chronic disease characterized by necrotic bone from any number of causes. ONJ can also occur due to several systemic and local factors which compromise blood flow within the bone. Among anti-resorptive medications, a very low risk of ONJ development is associated with oral bisphosphonates used for the management of osteopenia, osteoporosis, and Paget’s disease. Raloxifene is a nonsteroidal benzothiophene which is classified as a selective estrogen receptor modulator (SERM). It is commonly used for the prevention and the treatment of osteoporosis in postmenopausal

women and was recently approved to reduce the risk of breast cancer. Raloxifene is regarded as a safe alternative in the management of osteoporosis in terms of ONJ development. This report presents a case of ONJ in a patient receiving raloxifene, who presented with existing comorbidities and a history of discontinued oral bisphosphonates use. The clinical report is followed by a discussion aimed to clarify how the general practitioner should consider similar cases. (Quintessence Int 2015;46:423–428; doi: 10.3290/j.qi.a32918)

Key words: jaw, mandible, osteonecrosis, raloxifene

Osteonecrosis of the jaw (ONJ) is a chronic disease characterized by necrotic bone from any number of causes. ONJ can also occur due to several systemic and local factors which compromise the blood flow within 1

Associate Professor and Chair, Department of Oral and Maxillofacial Surgery, School of Dental Medicine, Case Western Reserve University, Cleveland, OH, USA.

2

Doctor, Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Akdeniz University, Antalya, Turkey; and Research Fellow, Department of Oral and Maxillofacial Surgery, School of Dental Medicine, Case Western Reserve University, Cleveland, OH, USA.

3

Associate Professor, Associate Dean of Clinical Operations, Department of Comprehensive Care, School of Dental Medicine, Case Western Reserve University, Cleveland, OH, USA.

4

Intern, Department of Oral and Maxillofacial Surgery, School of Dental Medicine, Case Western Reserve University, Cleveland, OH, USA.

5

Associate Professor, Residency Program Director, Department of Oral and Maxillofacial Surgery, School of Dental Medicine, Case Western Reserve University, Cleveland, OH, USA.

Correspondence: Dr Dale A. Baur, Department of Oral and Maxillofacial Surgery, School of Dental Medicine, Case Western Reserve University, 2124 Cornell Road, Cleveland, OH, 44106-4905, USA. Email: dale. [email protected]

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the bone. These include chronic infections such as osteomyelitis, hematologic, rheumatologic, and metabolic disorders, chemotherapy, radiotherapy, and corticosteroid therapy, and/or a combination of above factors all with the common thread that immunity is impaired and healing is compromised.1 The American Association of Oral and Maxillofacial Surgeons (AAOMS) recently coined the term “medication-related osteonecrosis of the jaw” (MRONJ).2 MRONJ is defined as an area of exposed bone or bone that can be probed through an intraoral or extraoral fistula(e) in the maxillofacial region that has persisted for more than 8 weeks in a patient who was exposed to anti-resorptive or anti-angiogenic agents and has no history of radiation therapy to the jaws or obvious metastatic disease to the jaws.2 Among anti-resorptive medications, a very low grade risk of MRONJ development (from 0.01% to

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Fig 1 Intraoral view at presentation; note poor extraction site healing and necrotic area on the left.

Fig 2

0.04%) is associated with oral bisphosphonates used for the management of osteopenia, osteoporosis, and Paget’s disease, and the majority of cases are commonly observed in patients who were treated with these drugs for years.3 The mean duration of oral bisphosphonate treatment prior to MRONJ development has been previously reported to be as high as 4.6 years.4 However, there have been some reports that it may develop after shorter use of oral bisphosphonates. Diniz-Freitas et al5 recently reported MRONJ development in a period shorter than 3 years in 7 of 20 patients receiving oral bisphosphonates. Controversy remains on the efficacy of a “drug holiday” and it is not clear if cessation of oral bisphosphonate therapy ensures a favorable outcome when an invasive dental surgery is to be undertaken. Although in 2009, the AAOMS position paper6 on bisphosphonate-related osteonecrosis of the jaw (BRONJ) recommended drug holidays of 3 months preand post-operatively, this statement has been revised in 2014 due to lack of clinical data which prove that interruption of oral bisphosphonate treatment reduces the risk of MRONJ. The guideline also mentions comorbidities such as rheumatoid arthritis, prior or current glucocorticoid exposure, diabetes, and smoking, which may contribute to development of osteonecrosis in these patients.2 Raloxifene (Evista, Eli Lilly and Company) is a nonsteroidal benzothiophene which is classified as a selective estrogen receptor modulator (SERM). It is commonly used for the prevention and the treatment of

osteoporosis in postmenopausal women and is recently approved to reduce the risk of breast cancer. Raloxifene is regarded as a safe alternative in the management of osteoporosis in terms of association with MRONJ development as reported in a limited number of studies.7,8 The aim of this report is to present a case of ONJ in a patient receiving raloxifene, with past history of discontinued oral bisphosphonates, and to discuss and clarify how the general practitioner should consider similar cases.

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Panoramic radiograph at presentation.

CASE REPORT A 67-year-old woman was referred to the Department of Oral and Maxillofacial Surgery at Case Western Reserve University School of Dental Medicine for an evaluation of a possible pathologic fracture of her mandible. The patient’s chief complaint was numbness of her lower lip, jaw pain, and areas of exposed mandibular bone. She had a significant medical history of hypertension, hyperlipidemia, hypothyroidism, and type 2 diabetes mellitus, rheumatoid arthritis, cirrhosis, and osteoporosis. Medications at the time of presentation included metoprolol, levothyroxine, acetylsalicylic acid, folic acid, and raloxifene (Evista, 60 mg/day). The patient had been on anti-resorptive therapy with raloxifene for 18 months. She also had a history of oral alendronic acid use (Fosamax, Merck & Co, 70 mg/ week) prior to raloxifene for approximately 2 years,

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a Figs 3a to 3c

b

CT reconstruction: (a) right, (b) front, (c) left. Note bilateral areas of pathology in the body of mandible.

a Figs 4a and 4b

c

b (a) Preoperative CT posterior reconstruction. (b) Excised surgical specimen, posterior view.

which was discontinued for unclear reasons 3 years prior to her presentation to our clinic. The dental history of the patient was significant for multiple teeth extractions performed 9 months earlier with the intent to have full upper and lower dentures fabricated. The patient had been on raloxifene for 10 months prior to extractions. The patient had previously been placed on oral clindamycin and chlorhexidine mouth rinse for a week-long course prior to her presentation to our facility. On physical examination, two necrotic appearing lesions of exposed bone were noted bilaterally in the posterior parts of the mandible. Soft tissues surrounding the exposed sites were free of signs of infection (Fig 1). No active drainage or tenderness to palpation was noted. Poor healing of extraction sites was clinically visible but no signs of a mandibular fracture were evident upon palpation. Initial radiographic evaluation of the patient was carried out with a panoramic radiograph (Fig 2), which

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revealed multiple nonhealing extraction sockets and irregular bony changes of a moth-eaten appearance bilaterally of the body of the mandible, and an area highly suspicious for a pathologic fracture. A medical computed tomograph (CT) scan was obtained with three-dimensional (3D) reconstruction, which confirmed the initial radiographic findings and further revealed extensive involvement of the mandible (Fig 3). Clinical and radiologic evaluation of the patient when assessed together with her history of anti-resorptive therapy with alendronic acid and more recently raloxifene, was strongly suggestive of a diagnosis of MRONJ. In addition, the patient had significant medical comorbidities such as diabetes mellitus, rheumatoid arthritis, and cirrhosis, which are well known to impair immunity and healing. The lesion could be classified as an AAOMS Stage III MRONJ2 lesion due to invasion of the inferior border of the mandible and a possible pathologic fracture. The treatment of the patient comprised resection of the diseased segment (Fig 4) and

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reconstruction with a plate. The patient has remained asymptomatic in the post-operative period and will further be evaluated for future reconstruction of her mandible with autogenous bone to be harvested from an extraoral donor site.

DISCUSSION MRONJ is a disease of poor healing capacity, which may develop as a result of several systemic, iatrogenic, or infectious factors. It has been reported as having an association to anti-resorptive therapy. However recent reports have shown that MRONJ has been associated with several other medications, which include vascular endothelial growth factor (VEGF), tyrosine kinase (TK), platelet-derived growth factor (PDGF), and receptor activator of nuclear factor κ-B ligand (RANK-L) inhibitors.1,2,9,10 It is of paramount importance to recognize that both prevention and management of MRONJ require a multidisciplinary approach. Dental professionals have a significant role in raising awareness among patients about this medication-related complication. The significance of preventive measures in avoiding MRONJ onset have been pointed out several times in the literature and considerable reduction in the number of new cases has been achieved with dental screening and appropriate dental care.11-14 However, it should be taken into consideration that MRONJ can also develop spontaneously or after a minor trauma even with proper maintenance of good oral hygiene and dental care.2 When a MRONJ lesion is suspected, a dental professional should refer the patient to an oral and maxillofacial surgeon taking into consideration that the differential diagnosis of MRONJ includes metastatic jaw lesions in addition to other common clinical conditions such as alveolar osteoitis, sinusitis, periapical pathologies, periodontal disease, and osteomyelitis. Once the lesion has formed, its management similarly requires a team approach involving the patient’s dentist, oral and maxillofacial surgeon, and other medical specialists who manage the systemic treatments. SERMs are synthetic agents that have been approved for the management and the treatment of

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postmenopausal women’s health disorders, including osteoporosis and estrogen-sensitive breast cancer. Raloxifene, a second generation SERM with estrogen agonistic effects on bone, has been reported to significantly increase bone mineral density (BMD), reducing the risk of skeletal fractures.15-17 Although reported to have variable results, long-term raloxifene therapy has also been shown to reduce invasive breast cancer.18 Although not yet fully elucidated, the mechanism of action of raloxifene on bone metabolism has been the subject of a number of experimental and clinical studies, the majority of which target osteoclasts.19 In vitro, raloxifene has been shown to modulate bone homeostasis by inhibiting osteoclastogenesis, and bone resorption with dose-dependent activity.20,21 Luvizuto et al22 investigated the expression of bone turnover markers during alveolar healing in ovariectomized rats and reported inhibitory effects of raloxifene therapy on osteoclasts. Similar results were obtained in Michael et al’s study,23 in which the authors examined the effects of different types of SERMs on osteoclast formation and function and reported inhibition of osteoclast differentiation with raloxifene. The present article reports development of an extensive ONJ lesion in a patient who has been receiving anti-resorptive therapy with raloxifene. The patient had existing comorbidities and a history of discontinued oral alendronic acid use. Although previous studies have shown that oral alendronic acid use is less likely to be associated with ONJ unless the treatment is continued for several years, current evidence of MRONJ development in patients with a limited history of oral bisphosphonate use necessitates clinical awareness by both the patient and the dental professional.2,3 When treating patients with comorbid risk factors such as rheumatoid arthritis, prior or current glucocorticoid exposure, diabetes, smoking, or greater cumulative bisphosphonate exposure (> 4 years), caution should be taken and the patient should be referred to an oral and maxillofacial surgeon for appropriate surgical management.1-3 It is important to note that the patient had a history of diabetes and rheumatoid arthritis, which are reported to increase the risk of MRONJ (odd ratio 2

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and 4.56, respectively) in patients treated with alendronic acid or raloxifene.7 Due to its commonly reported cumulative effect and long half-life,24,25 prior oral alendronic acid use may be considered as a contributing factor, although the patient in this case had received it for a relatively short duration and the treatment had been terminated long before the onset of symptoms. However, whether or not the MRONJ in this case is related to the previous medications, or to raloxifene therapy, must be questioned in a patient with significant medical comorbidities. It is important for the clinician to be aware that the authors have seen many cases of ONJ in patients without a history of exposure to medications commonly associated with MRONJ.26 MRONJ has been previously reported in patients treated with raloxifene in only one study by Chiu et al.7 The study, which aimed to evaluate a possible association between ONJ and oral alendronic acid or raloxifene used for osteoporosis, included 1,884 osteoporotic women using raloxifene among which 16 cases of ONJ were identified. However, 12 of these patients had developed ONJ prior to raloxifene exposure during oral alendronic acid therapy and ONJ was confirmed after initiation of raloxifene therapy in only four patients. SERMs, however, are drugs with side effects and the “ideal SERM” still remains a goal of contemporary research. It should be noted that the clinical development of another SERM, arzoxifene, was discontinued by the manufacturer due to significantly higher incidence of adverse events, including osteonecrosis.27 The goal of this work is to report an extensive case of MRONJ in a physiologically challenged patient receiving raloxifene, with several comorbidities and history of oral alendronic acid use. Although there are several significant systemic and local factors that make it hard to determine the inciting event in this case, further studies and clinical observations need to be performed to ascertain MRONJ’s association with raloxifene therapy.

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ACKNOWLEDGMENTS Dr Baur is a consultant for Novartis and Checkpoint Surgical LLC. Dr Altay has provided consultancy for Checkpoint LLC in 2014. This study followed the Declaration of Helsinki on medical protocol and ethics. No ethical approval was required.

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17. Maricic M, Adachi JD, Sarkar S, Wu W, Wong M, Harper KD. Early effects of raloxifene on clinical vertebral fractures at 12 months in postmenopausal women with osteoporosis. Arch Intern Med 2002;162:1140–1143. 18. Vogel VG, Qu Y, Wong M, Mitchell B, Mershon JL. Incidence of invasive breast cancer in postmenopausal women after discontinuation of long-term raloxifene administration. Clin Breast Cancer 2009;9:45–50. 19. Yan MZ, Xu Y, Gong YX, et al. Raloxifene inhibits bone loss and improves bone strength through an Opg-independent mechanism. Endocrine 2010;37: 55–61. 20. Messalli EM, Scaffa C. Long-term safety and efficacy of raloxifene in the prevention and treatment of postmenopausal osteoporosis: an update. Int J Womens Health 2010;1:11–20. 21. Taranta A, Brama M, Teti A, et al. The selective estrogen receptor modulator raloxifene regulates osteoclast and osteoblast activity in vitro. Bone 2002;30:368–376.

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Osteonecrosis of the jaw in a patient on raloxifene: a case report.

Osteonecrosis of jaws (ONJ) is a chronic disease characterized by necrotic bone from any number of causes. ONJ can also occur due to several systemic ...
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