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Bisphosphonate-Associated Osteonecrosis of Mandibular and Maxillary Bone An Emerging Oral Complication of Supportive Cancer Therapy

Cesar A. Migliorati, D.D.S., M.S., Ph.D.1 Mark M. Schubert, D.D.S., M.S.D.2,3 Douglas E. Peterson, D.M.D., Ph.D.4,5 Luis Marcelo Seneda, D.D.S.6

BACKGROUND. The current report presented 17 patients with cancer with bone metastases and 1 patient with osteopenia who received treatment with bisphosphonates and who subsequently developed osteonecrosis of the mandible and/or maxilla. METHODS. The authors reviewed information on 18 patients who were referred to oral

1

Department of Diagnostic Sciences, College of Dental Medicine, Nova Southeastern University, Fort Lauderdale, Florida.

2

Department of Oral Medicine, School of Dentistry, University of Washington, Seattle, Washington.

3

Oral Medicine Service, Seattle Cancer Care Alliance and Fred Hutchinson Cancer Research Center, Seattle, Washington.

4

Department of Oral Health and Diagnostic Sciences, School of Dental Medicine, University of Connecticut Health Center, Farmington, Connecticut.

5

Cancer Center, University of Connecticut Health Center, Farmington, Connecticut.

6

Oral Medicine Clinic, Oncology Center-Hospital Sirio Libaneˆs, Sa˜o Paulo, Brazil.

The authors acknowledge the role of Jeffrey Kingsbury, D.D.S., M.D., who was responsible for documenting the data of patients managed at the University of Connecticut Health Center. Address for reprints: Cesar Augusto Migliorati, D.D.S., M.S., Ph.D., Department of Diagnostic Sciences, Nova Southeastern University College of Dental Medicine, 3200 S. University Drive, Fort Lauderdale, FL 33328-2018; Fax: (954) 262-1782; E-mail: [email protected] Received October 25, 2004; revision received January 29, 2005; accepted February 9, 2005.

medicine or oral surgery specialists for evaluation and treatment of mandibular and/or maxillary bone necrosis from June 2002 to September 2004. To be included in the current review, patients must have been treated with either pamidronate or zoledronic acid to control or prevent metastatic disease, or with alendronate for osteoporosis. All patients with cancer had received chemotherapy while receiving bisphosphonate management. RESULTS. The 17 patients with cancer were receiving active medical care for a malignancy. Cancer treatment included a variety of chemotherapeutic agents. They presented with metastatic disease to bone and were treated intravenously with the bisphosphonates pamidronate or zoledronic acid for a mean time of 25 months (range, 4 – 41 mos). There were 14 females and 4 males with a mean age of 62 years (range, 37–74 yrs). Malignancies included breast carcinoma (n ⫽ 10), multiple myeloma (n ⫽ 3), prostate carcinoma (n ⫽ 1), ovarian carcinoma (n ⫽ 1), prostate carcinoma/lymphoma (n ⫽ 1), and breast/ovarian carcinoma (n ⫽ 1). One female patient with osteopenia received alendronate. The most common clinical osteonecrosis presentations included infection and necrotic bone in the mandible. Associated events included dental extractions, infection, and trauma. Two patients appeared to develop disease spontaneously, without any clinical or radiographic evidence of local pathology. Despite surgical intervention, antibiotic therapy, hyperbaric oxygen therapy, and topical use of chemotherapeutic mouth rinses, most of the lesions did not respond well to therapy. Discontinuation of bisphosphonate therapy did not assure healing. However, 1 patient with cancer healed after discontinuation of bisphosphonate therapy for 4 months. CONCLUSIONS. The findings in the patient population combined with recent literature reports suggested that bisphosphonates may contribute to the pathogenesis of the oral lesions. The risk factors and precise mechanism involved in the formation of the osteonecrosis are not known. This condition represents a new oral complication in patients with cancer and can be termed bisphosphonate-associated osteonecrosis. Lesions in patients with osteoporosis are worrisome and need to be further evaluated. Cancer 2005;104:83–93. © 2005 American Cancer Society.

KEYWORDS: osteonecrosis, bisphosphonates, jaws, cancer metastasis, skeletal metastasis, oral complication, osteoporosis.

© 2005 American Cancer Society DOI 10.1002/cncr.21130 Published online 31 May 2005 in Wiley InterScience (www.interscience.wiley.com).

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isphosphonates, potent inhibitors of osteoclastmediated bone resorption, have been utilized clinically for the past 30 years.1 These compounds produce marked inhibition of bone resorption, particularly when administered by intravenous infusion. Bisphosphonates have become the standard of care in the management of patients with advanced-stage cancer involving skeletal metastasis and hypercalcemia of malignancy.2,3 Although several other compounds have been used, pamidronate and zoledronic acid have been the most frequently used in patients with cancer.1,4 The Food and Drug Administration have approved pamidronate and zoledronic acid for the treatment of hypercalcemia of malignancy, multiple myeloma, and for the treatment of patients with documented bone metastasis from solid tumors (breast, prostate, and lung) in conjunction with standard antineoplastic therapy. In addition, zoledronic acid is currently being used for the prevention of bone metastasis from breast or prostate carcinoma. Currently, zoledronic acid is considered to be one of the most potent antiresorptive bisphosphonates.1,5 Bisphosphonates are synthetic analogs of inorganic pyrophosphate that have a high affinity for calcium. They are rapidly cleared from the circulation, and bind to bone mineral, selectively concentrating in bone.6 All bisphosphonate compounds accumulate over extended periods of time in mineralized bone matrix.7 During bone resorption, they are released from the bone surface and may be reincorporated into newly formed bone or internalized into osteoclasts.8 The latter process results in loss of the ability of osteoclasts to resorb bone and promote apoptosis.1,6,8 Common adverse reactions of bisphosphonates include flu-like symptoms, fatigue, gastrointestinal reactions, anemia, dyspnea, and edema.9 Elevation of creatinine levels may result from altered renal function, especially when bisphosphonates are administered in high doses and in patients with previous renal impairment.10 Bisphosphonates can cause mucosal ulceration in the esophagus and several recent reports have described patients who have developed oral cavity mucosal ulcerations while receiving alendronate for osteoporosis.11,12 Marx and Stern13 suggested that patients with multiple myeloma who receive pamidronate might develop avascular necrosis of the jaw bones. Several recent publications have reported on patients who had sought treatment for intraoral bone necrosis that occurred either spontaneously or after dental extractions or oral trauma.14 –17 These patients presented with a history of a primary malignancy, including multiple myeloma, breast carcinoma, or prostate carcinoma, and were all being treated with intravenous pamidronate or zoledronic acid to control skeletal

complications of advanced-stage cancer. In most patients, there was also a history of treatment with a variety of cancer chemotherapy protocols (Table 1). These patients had never received radiotherapy to the head and neck, which has been identified as one of the causes of osteonecrosis of the mandible, and rarely, the maxilla.18 No common etiologic factor for osteonecrosis could be identified. The current multicenter report delineates the clinical, radiographic, and histopathologic aspects of these lesions that we are calling bisphosphonate-associated osteonecrosis. The possible pathogenic mechanisms are discussed. We believe that this oral lesion represents a new and significant complication associated with the use of bisphosphonates in patients receiving supportive cancer therapy.

MATERIALS AND METHODS We reviewed data for 18 patients referred to either an oral and maxillofacial surgeon or an oral medicine specialist for the management of clinically apparent chronic oral osteonecrosis of unknown etiology. Of these 18 patients, 17 had cancer. All had received cancer chemotherapy simultaneously with bisphosphonate management. The patients were referred to oral medicine and oral surgery clinics in the United States and Brazil for diagnosis and/or management. The first concern for the 17 patients with a history of advanced-stage cancer was to eliminate the possibility of metastatic bone disease to the oral cavity. Table 1 shows patient information, primary malignancy, oncologic treatment, and use of bisphosphonates. There were 14 females and 4 males with a mean age of 62 years (range, 37–74 yrs). Malignancies included breast carcinoma (n ⫽ 10), multiple myeloma (n ⫽ 3), ovarian carcinoma (n ⫽ 1), prostate carcinoma (n ⫽ 1), ovarian/breast carcinoma (n ⫽ 1), and prostate carcinoma/lymphoma (n ⫽ 1). The mean time of receipt of bisphosphonate therapy until 1 of the authors first examined the patient was 24 months (range, 4 –37 mos). One female patient (Patient 18) was being treated with alendronate for osteopenia. She was 61 years old and was receiving treatment with bisphosphonate for 3 years. The majority of patients presented to clinics complaining of pain, discomfort, or numbness either in the mandible or the maxilla. Because of the similarity among the patients, we present a summary description of the common history, clinical, radiographic, and histopathologic findings, and patient management.

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TABLE 1 Demographics of 18 Patients with Oral Cavity Bisphosphonates-Associated Osteonecrosis

Patient no.

Age

Gender

Tumor

1

67

Female

Ovarian

2

67

Female

Breast

3

57

Female

4

74

5

Chemotherapeutic agents

Time used (mos)a

Oral manifestation (type/location)

Therapy

Histopathology

Pamidronate, zoledronic acid

NAb

Infection, osteonecrosis

Sequestrectomy, antibiotics

Osteonecrosis

Bisphosphonates

Zoledronic acid

NAb

Infection, osteonecrosis

Sequestrectomy, antibiotics

ND

Breast

Tamoxifen, letrosol, anastrozole, fulvestrant, doxorubicin Tamoxifen, letrosol, anastrozole, fulvestrant, doxorubicin Doxorubicin

Zoledronic acid

NAb

Breast

N/Aa

Pamidronate

NAb

44

Female

Breast

Doxorubicin, bleomycin

Zoledronic acid

NAb

6

53

Female

Breast

Doxorubicin

Zoledronic acid

NAb

7

66

Female

Breast/ovarian

Exemestane

Zoledronic acid

16

Sequestrectomy, antibiotics Sequestrectomy, antibiotics Sequestrectomy, antibiotics Sequestrectomy, antibiotics Sequestrectomy, antibiotics

Osteonecrosis

Female

8

62

Male

Prostate, mantel cell lymphoma

Zoledronic acid

5

Sequestrectomy, antibiotics

ND

9

58

Male

Multiple myeloma

Palmidronate, zoledronic acid

24

Infection, None osteonecrosis (mandible, postextraction)

10

56

Male

Multiple myeloma

Pamidronate, zoledronic acid

37

Infection, Hyperbaric ND osteonecrosis oxygen (mandible, therapy, postextraction) sequestrectomy, antibiotics

11

69

Female

Breast

Bicalutamide, leuprolide, vincristine, doxorubicin, dexamethasone, radiotherapy (breast) Vincristine, doxorubicin, dexamethasone, autotransplant (bussulphanmelphalan-thiotepa), Idiotype immunization with GM-CSF, genasense Vincristine, doxorubicin, dexamethasone, anabolic steroids, thalidomide, cyclophosphamide, CC-5013 Trastuzumab, cisplatin, dexamethasone

Infection, osteonecrosis Infection, osteonecrosis Infection, osteonecrosis Infection, osteonecrosis Infection, osteonecrosis (mandible, postextraction) Infection, osteonecrosis

Zoledronic acid (discontinued for 3 mos, lesion persisted)

31

12

37

Female

Breast

AC, paclitaxel, radiotherapy (lumbar), fulvestrant

Pamidronate, zoledronic acid

31

13

72

Female

Breast

Trastuzumab, vinorelbine, paclitaxel

Pamidronate, zoledronic acid

16

Infection, Sequestrectomy, osteonecrosis antibiotics (R mandible, posttrauma, L mandible, spontaneous) Infection, Sequestrectomy, osteonecrosis antibiotics, (R and L Endodontics, mandible) flap surgery Infection, Sequestrectomy, osteonecrosis antibiotics (L maxilla, postextraction)

Osteonecrosis Osteonecrosis ND Osteonecrosis

ND

Osteonecrosis

Osteonecrosis

Osteonecrosis

continued

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TABLE 1 (continued)

Bisphosphonates

Time used (mos)a

Oral manifestation (type/location) Infection, osteonecrosis (L mandible, spontaneous) Infection, osteonecrosis (L mandible, postextraction) Infection, osteonecrosis (R and L maxilla, R mandible) Infection, osteonecrosis (L mandible, postimplant failure)

Patient no.

Age

Gender

Tumor

Chemotherapeutic agents

14

74

Female

Multiple myeloma

Vincristine, doxorubicin, dexamethasone

Pamidronate

26

15

73

Male

Prostate

Goserelin, bicalutamide

Pamidronate

8

16

66

Female

Breast

Tamoxifen, trastuzumab

Pamidronate, zoledronic acid

41

17

54

Female

Breast

Zoledronic acid

34

18

61

Female

Osteopenia

Doxorubicin, cyclosphophamide, docetaxel, radiotherapy, letrozole, epothiolone, capecitabine, fulvestrant, exemestane Losartan, amlodipine, furosemide, esomeprazole, nexium, aspirin, potassium

Alendronate

36

Therapy

Histopathology

Sequestrectomy, antibiotics

Osteonecrosis

Sequestrectomy, antibiotics

Osteonecrosis

Antibiotics, rinses, local smoothing of bone surface

ND

Antibiotics, rinses, analgesics

Osteonecrosis

L maxilla, Periodontal flap postextraction, surgery, palatal curettage, torus, antibiotics postprosthetic trauma

Osteonecrosis

GM-CSF: granulocyte-macrophage—colony-stimulating factor; AC: xxx; NA: not available; R: right; L: left; ND: not done. a Length of time bisphosphonates was received reflects the time from start of therapy to the first clinical detection of osteonecrosis. b Unable to obtain information about the chemotherapeutic agents being used by patient or length of time that bisphosphonate therapy was received.

RESULTS History of the Lesions In most patients, the lesions initially occurred after dental extraction. In other instances, accidental trauma by the patient to the involved area was identified. Some patients, however, could not recall a possible causative event. The involved areas were often secondarily infected. Some patients already had been treated with local surgical procedures and antibiotic therapy, following the same protocol used in the treatment of osteomyelitis. At the time of onset of osteonecrosis, all patients with cancer were receiving chemotherapy for the treatment of a primary malignancy. All of these patients developed lesions while actively receiving bisphosphonates (e.g., pamidronate and zoledronic acid) in addition to cancer chemotherapy, because they had advanced-stage disease with known skeletal metastasis. The primary reason for

referral for oral care was to rule out the possibility of bone metastasis to the oral cavity, although in several patients, osteonecrosis was viewed as a nonhealing surgical site, with osteomyelitis. Pain and oral discomfort were common complaints. There was no observed correlation of the intraoral lesions with myelosuppression secondary to antineoplastic therapy. At the time of consultation, other potential etiologic risk factors for osteonecrosis were investigated and could not be identified. These factors included dental and family history, social lifestyle, tobacco or alcohol use, or radiotherapy to the head and neck. Although some patients had been or were currently taking corticosteroids, this was not observed in all patients.

Clinical Examination and Findings The most common clinical finding was an area of ulcerated mucosa and exposed devitalized bone. The exposed bone had a yellow-white discoloration, and

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FIGURE 1. Patient 11: Spontaneous necrotic bone at the mylohyoid plate present for months in a patient with metastatic breast carcinoma taking zoledronic acid. (A) Initial presentation on the left mandible. (B) Initial presentation on the right mandible. (C) Progress of bone exposure 1 year later. Bone necrosis and secondary infection on the left mandible are present after extraction of tooth 18 and part of the fixed bridge. (D) Left mandible 1 month before patient’s death.

the surrounding soft tissue areas were often inflamed due to secondary mucosal infection and were painful. Probing of the bone was asymptomatic, and bleeding did not result. These findings were consistent with avascular osteonecrosis. The exposed bone surface in the early stage of the process was smooth. However, with progression of necrosis, some patients developed an irregular rough, bony surface that was likely due to fracture of the necrotic bone during mastication. Pain appears to have resulted from either secondary infection of surrounding soft tissue areas or from trauma to opposing soft tissue areas (e.g., lateral tongue). The most common site of bone necrosis was the posterior/lingual mandible, in the area of the mylohyoid ridge (Fig. 1). Bone necrosis was typically progressive and, with the subsequent involvement of adjacent teeth, often led to compromised oral hygiene of the dentition con-

tiguous to the lesion. This impaired oral hygiene, in turn, may have facilitated local infection leading to advanced bone necrosis, and subsequent increased tooth mobility and loss (Fig. 1). Past dental history for many of the patients revealed recent tooth extraction, with subsequent osteonecrosis of the alveolar socket and delayed or nonhealing of the extraction site. This process was observed in both the mandible and the maxilla (Fig. 2). The irregular osseous margins caused further trauma to adjacent soft tissue. It was not uncommon to observe traumatic mucosal ulceration in areas opposed to the necrotic bone due to rubbing of the soft tissue against the rough bone surface. The posterolateral border of the tongue opposing areas of exposed lingual mandibular bone was one of the most commonly presenting ulcerative sites (Fig. 3). Discomfort generated by the tongue ulcers required that the patients be treated for palliation and pain control.

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FIGURE 3. Patient 11. A patient taking zoledronic acid for the control of bone metastases of breast carcinoma presented with necrotic alveolar bone and tongue pain. (A) Traumatic ulceration of the lateral border of the tongue. The area is directly in contact with the exposed necrotic bone on the left posterior mandible. (B) Stint protecting area of exposed bone.

Injury to contiguous neural tissue also may have occurred. Two patients with a mandibular lesion presented with progressive numbness of the lips and face, suggesting neural involvement and necessitating both extraction of the involved tooth adjacent to the necrotic area and aggressive control of local infection. Although this therapy corrected the neurologic symptoms and infection, osteonecrosis persisted.

FIGURE 2. Patient 13. Nonhealing alveolus with bone necrosis in a patient with breast carcinoma treated with pamidronate and zoledronic acid after the extraction of tooth 14. (A) Initial radiographic presentation of tooth 14 showing recurrent decay and endodontic treatment failure. (B) Exposed necrotic alveolar bone. (C) Radiographic evidence of compromised bone in the area of tooth 14 and the endodontic involvement of tooth 13.

Radiographic and Imaging Findings Depending on the stage of development of osteonecrosis, radiographic evaluation did not add substantive value to the clinical database. Progressive periodontal involvement resulted in bone loss around the involved teeth. However, no other specific radiographic changes associated with this necrotic process

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were documented in the patients, perhaps because, unlike patients with osteomyelitis, active bone resorption or sequestration did not occur in the early stages of development of osteonecrosis (Fig. 4). Scintigraphy in 1 patient with breast carcinoma showed areas of uptake of the radioactive markers at the areas of osteonecrosis, but differentiation between inflammation and metastasis could not be established (Fig. 4).

Histopathologic Findings An important initial clinical concern for all patients was the possibility of oral cavity osseous metastasis of the primary malignancy. However, the presence of tumor has not been identified yet in any of the patients by either clinical and/or histopathologic means. Histopathology typically demonstrated areas of chronic inflammation represented by a mixed cellular infiltration and capillaries. Bone osteoblasts or vascularization were not prominent, and the diagnosis was consistent with necrosis (Fig. 5).

Management Management of patients with bisphosphonate-associated osteonecrosis has been difficult and challenging.19 Although there are currently no scientific data to support any specific treatment protocol for the management of patients with bisphosphonate-associated oral osteonecrosis, we are following recommendations published by the manufacturer of the drugs (Novartis, East Hanover, NJ).19 These recommendations are presented in Table 2. In the current study, responses to treatment varied. Although some patients demonstrated partial healing responses when their medical oncologist discontinued bisphosphonates, most did not respond. Early in our experience, the most common type of therapy was local surgical debridement and sequestrectomy. Aggressive osseous surgery was attempted in several patients with the objective of removing necrotic bone to establish vital bone margins to initiate healing. However, in most patients, a larger necrotic bone defect developed, and no healing occurred. In several patients, conservative osteoplasty to smooth the exposed bone surface was beneficial in minimizing traumatic ulceration of adjacent soft tissue. Several patients were provided with soft vinyl splints to cover the necrotic area, to mitigate further trauma. Hyperbaric oxygen therapy was administered in one patient in an attempt to treat osteonecrosis, but similar to reports in the literature, no benefit was seen.11,13 Systemic antibiotic therapy to control secondary infection and pain has been useful and should be administered whenever active infection is present.

FIGURE 4. Patient 12. Exposed necrotic bone on the posterior right lingual aspect of the mandible in a patient with breast carcinoma taking zoledronic acid. (A) Exposed area at the right posterior lingual aspect of the mandible. (B) Radiographic view of the area shows furcation involvement of tooth 31, but no sequestration. Tooth 31 was retreated endodontically and the area treated with periodontal flap surgery twice. (C) Scintographic examination shows a “hot spot” at the posterior right mandible.

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CANCER July 1, 2005 / Volume 104 / Number 1 TABLE 2 Management recommendations Management of acute symptoms: pain and infection Oral hygiene (brushing and flossing) Topical antibiotics (e.g., chlorhexidine, tetracycline) Systemic antibiotics active against common oral/dental bacterial infections Pain medications Management of exposed bone Early—conservative removal of exposed bone, primary closure when possible Later—conservative protection of site, bone recontouring, prevention of infection Protective—covering of symptomatic osteonecrosis (e.g., vinyl guards, stints) Prophylactic recommendation Routine oral examination and care to stabilize oral disease and prevent oral trauma/irritation before administering bisphosphonate therapy to the patient Discontinuation of bisphosphonates There are no scientific data to support this indication. Interruption or discontinuation of therapy needs to be considered on a patient-by-patient basis. Risks and benefits should be discussed with patient’s physician.

tissues and vital bone. Several of the reported patients responded symptomatically to this type of therapy. However, if surgery is being considered, timing for surgical intervention must be discussed with the patient’s oncology team. Decisions to proceed will be based on the patient’s overall status, with attention directed to the patient’s immune and hematologic status due to chemotherapy, and on the general surgical risks for the patient. Patients should be informed of the possibility of impaired healing and/or exacerbation of the lesion after surgery. In addition, we cannot overemphasize that when the evaluation of a patient’s prebisphosphonate therapy is possible, detailed examination of the entire dentition is critical. Sources of potential dental infection and advancing dental disease should be treated aggressively, particularly dental extractions, in ways comparable to managing patients scheduled to undergo radiotherapy involving the mandible and/or maxilla.

DISCUSSION

FIGURE 5. Patient 12. Extracted tooth 31 and histopathologic findings. (A) Granulation tissue adhered to the cervical and furcation areas and part of the necrotic bone was removed. (B) Acantholitic epithelium and mononuclear inflammatory cell infiltrate. (C) Necrotic avascular and acellular bone. (Courtesy A. Camara Lopes.)

Topical antibacterial mouth rinses also may be of benefit. However, because the affected bone is avascular, systemic antibiotics will only control infection in soft

The current article describes bony lesions occurring in 17 patients with cancer and in 1 patient with osteopenia managed at several institutions. The lesions represent an emerging oral complication of bisphosphonate therapy, especially in patients with cancer with skeleton metastasis. Marx and Stern13 were the first to describe avascular necrosis of the bone associated with the use of pamidronate in patients with multiple myeloma. Subsequent reports in the medical and dental literature described a total of 120 patients with a similar condition.14 –17,20 The bisphosphonates pamidronate and zoledronic acid have been the most common drugs

Bisphosphates Associated Oral Osteonecrosis/Migliorati et al.

involved. However, the long-term effect of other less potent bisphosphonates used to prevent and treat osteoporosis on bone metabolism, resorption, and neoformation has not been well defined. Although most of the patients with cancer with metastatic disease were affected by bisphosphonate therapy,13,17 8 patients did not have cancer and were taking bisphosphonate (alendronate) to prevent or treat osteoporosis. We describe one patient with osteopenia who received bisphosphonate therapy. Wang et al.20 believed that osteonecrosis in the patients in their study was caused by chemotherapy with docetaxel and paclitaxel. However, all of their patients were also taking pamidronate, the probable cause of the necrosis.21 Additional evidence suggests that excessive doses of bisphosphonates may compromise skeletal quality in growing patients despite concomitant increases in bone density.22,23 If this new type of oral osteonecrosis is fundamentally associated with the use of bisphosphonates, patients with cancer with bone metastasis or who are at risk of developing bone metastasis, and patients receiving protocols for prevention or treatment of osteoporosis, may be at risk for bisphosphonate-associated osteonecrosis. In past years, thousands of patients have been treated with a variety of bisphosphonates, but osteonecrosis has only recently been reported. The rate of reported occurrence is actually low. However, as awareness grows, the recognition and reporting of osteonecrotic jaw lesions in patients being treated with bisphosphonates could well become more common, especially as there is wider use of more potent agents. Bisphosphonates are osteoclast inhibitors. The intravenous use of these medications produces a potent inhibitory effect on bone resorption, making them the standard of care in the management of patients with advanced-stage cancer involving skeletal metastasis.2,3,24,25 Internalization of the drug in active osteoclasts disrupts the cytoskeleton and vesicular trafficking, leading to cessation of resorption and induction of apoptosis.1,6,8 In addition to the antibone resorptive effect of bisphosphonates, an antiangiogenic effect has recently been described in animal studies.26,27 Zoledronic acid decreases endothelial cell proliferation and induces apoptosis.27 In rats, zoledronic acid can inhibit testosterone-stimulated vascular regrowth in the ventral prostate.26,27 In the current series, all 17 patients with cancer were treated with intravenous bisphosphonates, either pamidronate or zoledronic acid, for metastatic skeletal carcinoma. In addition to bisphosphonate therapy, they received chemotherapy, and some re-

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FIGURE 6. Pathobiologic model for the development of bisphosphonateassociated osteonecrosis. Bisphosphonates alone or in association with oral cavity infection and trauma or systemic chemotherapy may lead to cell necrosis and apoptosis. The sequence of events would include a decrease in bone resorption, decrease of activation of bone multicellular units, leading to decreased bone cellularity and reduced blood flow. All of these events would predispose the jaw bones to osteonecrosis.

ceived glucocorticoids. All patients had some degree of local oral infection. However, none of them received radiotherapy to the head and neck region as part of their cancer therapy. One patient with osteopenia who received alendronate for 3 years developed oral osteonecrosis after undergoing several dental extractions and preparing for dental implant placement. This patient has discontinued alendronate for 3 months but, unfortunately, the oral osteonecrosis is progressing. Bisphosphonate-associated osteonecrosis of the jaws is an important new complication of supportive therapy in patients with malignancy. Detailed pathologic studies are not yet available and, hence, one can only speculate on the pathogenic mechanisms. We propose a scheme that might explain both the phenomenon and its localization (Fig. 6). Bisphosphonates are potent antiresorptive agents that first bind to bone and then are taken up by osteoclasts, resulting in their inactivation and apoptotic cell death.1,6,8 The consequence is a marked reduction in the rate of formation of new bone multicellular units (BMU), also termed activation frequency. The BMU is a compartmentalized bone-remodeling unit that includes blood vessels as well as osteoclasts and osteoblasts.28 Osteoblasts are critical for bone formation. They also interact with hematopoietic precursors to induce osteoclast

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formation and may produce vascular endothelial growth factor to enhance the local blood supply.29 The decrease in bone cellularity and blood flow resulting from bisphosphonate therapy could lead to a generalized impairment of bone remodeling and of the response to skeletal injury. Although prolonged use of oral bisphosphonates has not increased skeletal fragility or impaired fracture healing in osteoporotic patients, a loss of forearm bone density has been described after intravenous pamidronate treatment in patients with Paget disease.30 Aseptic necrosis of bone at typical sites such as the head of the femur or humerus has not been reported as a complication of bisphosphonate therapy. Indeed, bisphosphonates have been used to treat this condition, although no clear benefit has been established. Why, then, is there an association between bisphosphonate therapy and osteonecrosis of the jaws? In the past, osteonecrosis has been associated with radiotherapy, which is not only known to injure cells, but it also can occur at sites of local damage, for example, under fixed partial denture pontics.31 In addition, radiotherapy-induced vascular damage renders the tissues relatively more ischemic than nonradiated tissue. The emerging complication of bisphosphonate-associated osteonecrosis of the jaws may be attributable to the finding that the marked inhibition of bone remodeling that occurs with high doses of bisphosphonates predisposes patients to osteonecrosis when there are additional demands on the bone that require remodeling or growth to maintain vitality.32,33 The oral cavity is never “aseptic” and, hence, the necrosis observed in these patients probably may also involve the effects of host– bacterial interactions, including infection. Bacterial products have been shown to increase bone resorption and to decrease bone formation. Moreover, the bones of the jaws are constantly undergoing impact loading, which may require a remodeling response, and are frequently the site of trauma such as tooth extraction. There may be an additional component of bone cell death due to the chemotherapy that many of the patients with this condition have received or may be concurrently receiving. We believe that changes in normal bone remodeling and some alteration of the intraosseous blood circulation could be occurring in the mandible and maxilla of patients with cancer being treated with bisphosphonates. There might also be genetic differences that produce a unique response in susceptible individuals. The potential for polymorphisms accounting for an increased risk of bisphosphonate-associated osteonecrosis in specific groups of patients should be considered. It remains important that cofactors continue to be investigated, given the many

patients treated with bisphosphonates and the relatively few reported to have this condition so far. The contribution of various other drugs (e.g., steroids, cancer chemotherapy) will also need to be pursued. Bisphosphonates are becoming the standard of care for patients with various malignancies characterized by metastatic or malignancy-related bone disease. The positive benefits of bisphosphonate therapy on the course and outcome of these cancer therapies are becoming increasingly apparent. Therefore, even though there is considerable uncertainty relative to what is the most effective way to manage patients with oral osteonecrosis, if the lesions can be kept stable and the patients made comfortable, bisphosphonate therapy should likely be continued. Currently, there is no effective therapy for bisphosphonate-associated osteonecrosis of the jaws. Therefore, preventive measures are warranted. Aggressive dental management, particularly dental extractions of teeth in patients with a poor prognosis, with resolution of any major problems before the initiation of bisphosphonate therapy should be done whenever possible. Therefore, communication between professionals prescribing bisphosphonates and the dental professionals may improve prevention and early detection of bisphosphonates-associated osteonecrosis. Although we agree that the evidence available associating bisphosphonates with osteonecrosis is far from conclusive, a certain number of patients with cancer taking bisphosphonates are at risk for developing this oral complication.13–17 Although only a few cases of bisphosphonate-associated osteonecrosis in patients with osteoporosis have been observed, this group of individuals has to be carefully followed. The scientific investigation of the mechanisms leading to bisphosphonate-associated osteonecrosis has to be pursued.

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