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Prevention and Management of Osteonecrosis of the Jaw Associated with Bisphosphonate Therapy
Supportive Cancer Therapy
research in brief Prevention and Management of Osteonecrosis of the Jaw Associated with Bisphosphonate Therapy
Rationale • Recently, bisphosphonate use has been associated with an increased incidence of osteonecrosis of the jaw. In the initial report of Migliorati, 5 patients presented with intraoral bone necrosis while receiving pamidronate or zoledronate.1 Three of the patients presented with spontaneous bone necrosis of the mylohyoid plate, and 2 presented with necrosis in the molar region after a tooth extraction. • In a later report, 63 cases of osteonecrosis of the jaw were reported by Ruggiero et al over a 2-year period.2 Previously, the rate of refractory osteomyelitis accounted for 1 or 2 cases per year, occurring mainly in patients treated with radiation therapy. However, none of the reported 63 patients had received radiation therapy, and only 56 of the 63 were oncology patients. Bisphosphonate treatment with pamidronate or zoledronate was the only common treatment agent for all 63 patients. Twenty-four patients had maxillary bone involvement, and 40 had mandibular bone involvement. The condition typically presented as pain and exposed bone at the site of a previous tooth extraction, although 9 patients had no recent history of a dentovascular procedure. On microscopic examination, all specimens consisted of necrotic bone with bacterial debris and granulation tissue. • Pain from the necrotic area can prevent patients from eating, speaking, and per-
forming adequate oral hygiene. Both reports stated that antibiotic treatment was ineffective.1,2 Surgical and hyperbaric oxygen treatments were also unsuccessful. Most patients in the study by Ruggiero et al required surgical procedures to remove the involved bone.2 Despite the presence of vascularized bone at the resection margins, however, progressive necrosis continued. Withdrawal from bisphosphonate treatment did not appear to reverse the process. • Although no direct causal relationship exists between zoledronate or pamidronate use and osteonecrosis of the jaw, bisphosphonate use is the common element in the increased occurrence reported. Novartis assembled an expert panel to discuss prevention, diagnosis, and treatment of osteonecrosis of the jaw in June 2004.3 A “post-marketing experience” section was added to the zoledronate and pamidronate labels to advise patients and physicians of the increased incidences of jaw osteonecrosis.4 The recommendations from the expert panel are discussed later in this article.
Bisphosphonate Treatment and Bone Physiology The necrosis of alveolar bone appears to result from a combination of poor blood supply and impaired bone remodeling or healing. Although the inhibition of osteoclasts by bisphosphonates reduces the incidence of pathologic fractures and treats hypercalcemia of malig-
nancy, it also suppresses the natural process of bone remodeling. In an experimental animal model, the nitrogencontaining bisphosphonates alendronate and risedronate suppressed trabecular bone remodeling with an associated increase in microdamage in beagles.5 Microdamage is hypothesized to underlie the development of stress fractures and to play a role in increased bone fragility associated with osteoporosis and aging. The report by Ruggiero et al suggested that the most likely cause of the osteonecrotic process in these patients was localized vascular insufficiency.2 Zoledronate and pamidronate have also demonstrated antiangiogenic properties in preclinical trials, although zoledronate was a much more potent antiangiogenic agent than pamidronate.6-10
A Retrospective Analysis to Identify Risk Factors and Guidelines Previously identified risk factors for osteonecrosis include radiation therapy to the head and neck, chemotherapy, immunotherapy, or other cancer treatments; female sex; and several comorbid conditions.3 A retrospective analysis was performed to identify risk factors for osteonecrosis and establish guidelines for management of osteonecrosis of the maxilla and mandible, and was presented at 40th Annual Meeting of the American Society of Clinical Oncology in June 2004.11 To achieve this objective, the medical and dental
Prepared by: Nancy Price, PhD Reviewed by: Alan Lipton, MD, Vinay K. Jain, MD, Salvatore Ruggiero, DMD, MD Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by Cancer Information Group, ISSN #1543-2912, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.
14
Volume 2, Number 1 • October 2004
Table 1 Characteristics of Patients in the Retrospective Analysis Who Developed Osteonecrosis of the Jaw11 Variable
Value
Type of Cancer Breast
15 (n = 297)
Multiple myeloma
6 (n = 139)
Prostate
2 (n = 83)
Site of Osteonecrosis Mandible
15
Maxilla
7
Both
1
Area Near tooth extraction
12
Spontaneous
10
Both
1
I.V. Bisphosphonate Pamidronate
8
Zoledronate
2
Pamidronate and zoledronate
12
Sex Male
6
Female
17
records of all patients with multiple myeloma, breast cancer, and prostate cancer who were provided with dental service at Memorial Sloan-Kettering Cancer Center between January 1996 and May 2004 were reviewed. Patients who presented with exposed bone in the maxilla or mandible were further evaluated for various clinical and pathologic characteristics (Table 1).11 Thirteen clinical and pathologic characteristics were considered, including tumor type, history of bisphosphonate therapy, corticosteroid use, tobacco use, oral hygiene, history of dental extraction in the osteonecrotic area, and comorbid conditions.
A total of 530 patients were reviewed, including 297 patients with breast cancer, 139 patients with multiple myeloma, and 83 patients with prostate cancer. The 23 patients who developed osteonecrosis included 15 with metastatic breast cancer, 6 with multiple myeloma, and 2 with prostate cancer. Seventeen of the 23 were women. The median age was 63 years. Twenty-two of the 23 patients received intravenous bisphosphonates. Eight patients had received pamidronate, 2 had received zoledronate, and 12 had received both. The median time of zoledronate therapy at the time of the diagnosis of osteonecrosis was 35 months (range, 194 months). The mandible was the site of 15 of the osteonecrotic areas, the maxilla was the site of 7, and 1 patient had lesions in both the mandible and maxilla. The site of osteonecrosis was located at tooth extractions in 12 patients. Osteonecrosis was spontaneous in 10 patients, and 1 patient had a spontaneous lesion and an osteonecrotic site near a previous tooth extraction. Osteonecrosis was not symptomatic in 14 patients. The retrospective analysis concluded that advanced cancer, chemotherapy, steroid use, bisphosphonate use, and comorbid conditions might be contributing causes. Nineteen patients (83%) had ≥ 1 comorbid condition, and 13 patients (57%) had > 2 comorbid conditions that included diabetes (n = 6), asthma (n = 2), arthritis (n = 4), osteoporosis (n = 1), anemia (n = 3), and renal disease (n = 4). Treatments used for the management of osteonecrosis in these patients included chlorhexidine rinses and antibiotics, conservative sequestrectomy or curettage, and surgical debridement (Table 2).11 Only 4 patients had a resolution and, of these, only 2 did not have progression or additional osteonecrotic lesions.
15
Table 2 Management and Outcome in the Retrospective Analysis11 Variable
Cases
Management Surgical debridement
1
Chlorhexidine rinse and antibiotics
16
Sequestrectomy or curettage
8
Outcomes Resolution
4
– Without progression
2
– Resolution with subsequent development of draining neck fistula
1
– Resolution of tooth extraction–related osteonecrosis but later development of a spontaneous osteonecrotic lesion
1
Lost to follow-up
4
Progression
3
No change
6
Deceased
2
Prevention of Osteonecrosis in Patients with Cancer Receiving Bisphosphonate Therapy Two of the 5 patients in the report by Migliorati1 and most of the patients in the report by Ruggiero et al2 presented with exposed bone at the site of a previous tooth extraction. Considering the coincidental occurrence of tooth extraction and the development of osteonecrosis after bisphosphonate use, the Novartis expert panel recommended that any procedure that would require bone healing should be completed before beginning bisphosphonate therapy. Patients should maintain excellent dental health and avoid injury to soft tissue or bone in the oral cavity. The expert panel’s recommendations for prevention of osteonecrosis of the jaw are listed in Table 3.3 A dental examination, including a panoramic jaw radiograph, is encouraged before beginning bisphosphonate thera-
Supportive Cancer Therapy
research in brief
Table 3 Preventive Measures Recommended Before Bisphosphonate Therapy3 Avoid any elective jaw procedure that will require bone to heal Patients should receive a routine clinical dental examination that may include a panoramic jaw radiograph to detect potential dental and periodontal infections If possible without risk to patient, delay bisphosphonate therapy until teeth with a poor prognosis are treated and healing is complete. This would include teeth in need of extraction or other dental surgery Suggested preventive dentistry should include: – Removal of abscessed and nonrestorable teeth and involved periodontal tissues – Functional rehabilitation of salvageable dentition, including endodontic therapy – Dental prophylaxis, caries control, and restorative dental care – Examine dentures to ensure proper fit – Education on oral self-care and hygiene – Prophylactic antibiotics are not recommended before routine dentistry, unless otherwise required for prophylaxis of bacteremia in patients at risk Education of patients on the importance of good dental hygiene and of promptly reporting symptoms; depending on risk, frequent oral assessments Oncologists are encouraged to perform a baseline assessment of the oral cavity, with visual examinations at every follow-up visit
py. Any extractions or other dental surgeries should be completed before the initiation of bisphosphonate therapy. It is suggested that patients receive treatment with preventive dentistry before the initiation of cancer treatments with or without bisphosphonates.
Management of Osteonecrosis of the Jaw The expert panel recommends consultations with an oral surgeon or oral pathologist for presenting patients (Table 4).3 Nonsurgical options, if available, may prevent further osseous injury. Limited surgery, including minimal bone debridement to reduce sharp edges on protruding bone that could cause trauma to surround-
Table 4 Management Recommendations from the Expert Panel3 Consultation with oral surgeon or oral pathologist Nonsurgical approaches to treatment to prevent further osseous injury Continuous or intermittent antibiotic therapy to prevent secondary soft-tissue infection 0.12% chlorhexidine gluconate oral rinses or minocycline hydrochloride periodontal pockets Adjustment or removal of dentures at night so that there is minimal soft-tissue trauma or irritation Monitoring at a minimum of every 3 months, or more often if symptoms continue or worsen Cessation or interruption of bisphosphonate therapy in severe cases
ing or opposing tissues, or a removable appliance to cover and protect the exposed area, is recommended. A protective stent could be beneficial to patients who have exposed bone that causes trauma to adjacent tissues and to patients in whom the area around the osteonecrotic site is repeatedly traumatized during normal oral function. Biopsies of the site should be performed only if metastasis to the jaw is suspected. Antibiotics might be used continuously or intermittently to prevent secondary soft tissue infections. The use of antibiotics in this setting is not yet defined, but the strategy appears to control pain and disease. The decision to use antibiotics should be made in consultation with an oral surgeon or oral pathologist. Cultures from the infected site may help in choosing the appropriate antibiotic regimen. Dental rinses that include 0.12% chlorhexidine gluconate can be used. Patients may retain their dentures, but it is recommended that dentures be adjusted to minimize damage to soft tissue and that they be removed at night.
16
Cessation or interruption of bisphosphonate therapy can be considered in severe cases but must be considered in light of the skeletal benefits of bisphosphonate therapy. At this time, no benefit of cessation of treatment has been observed. However, if surgery is required in patients with ongoing osteonecrosis, cessation of bisphosphonate therapy should be more thoughtfully considered. The decision to stop bisphosphonate treatment should be determined by an oncologist. Hyperbaric oxygen has not been effective and is not recommended. The placement of dental implants is contraindicated, as it will require significant bone healing. Frequent patient monitoring at intervals of ≤ 3 months is recommended, with more frequent monitoring if symptoms continue or worsen.
Conclusion The occurrence of osteonecrosis of the jaw in patients receiving bisphosphonate therapy is infrequent. However, the problem has just been recognized and the true occurrence rate cannot yet be determined, nor can the future rate of occurrence be predicted. Other unknown factors related to occurrence of osteo-necrosis of the jaw could include the type of bisphosphonate therapy (N-bisphosphonates vs. non–nitrogen-containing bisphosphonates) and the duration of treatment with bisphosphonates. The loss of normal bone remodeling along with the potential for increased bone density and microdamage combined with the antiangiogenic properties of N-bisphosphonates may all contribute to the increased incidence of osteonecrosis of the jaw in patients treated with bisphosphonates. Further investigations into the causes and treatments of osteonecrosis of the jaw are warranted. A retrospective analysis of patients treated with bisphosphonates during the past 10 years is being
Volume 2, Number 1 • October 2004
research in brief
conducted at M. D. Anderson Cancer Center (A. Hoff, MD, personal communication, October 5, 2004). Until more information is available, preventive measures are highly recommended.
References 1. Migliorati CA. Bisphosphanates and oral cavity avascular bone necrosis. J Clin Oncol 2003; 21: 4253-4254. 2. Ruggiero SL, Mehrotra B, Rosenberg TJ, et al. Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg 2004; 62:527-534.
3. Expert panel recommendations for the prevention, diagnosis, and treatment of osteonecrosis of the jaws. Hanover, NJ: Novartis, June 2004. 4. Zometa [package insert]. Hanover, NJ: Novartis, 2004. 5. Mashiba T, Turner CH, Hirano T, et al. Effects of suppressed bone turnover by bisphosphonates on microdamage accumulation and biomechanical properties in clinically relevant skeletal sites in beagles. Bone 2001; 28:524-531. 6. Fournier P, Boissier S, Filleur S, et al. Bisphosphonates inhibit angiogenesis in vitro and testosterone-stimulated vascular regrowth in the ventral prostate in castrated rats. Cancer Res 2002; 62:6538-6544. 7. Li J, Mori S, Kaji Y, et al. Effect of bisphos-
17
8. 9. 10.
11.
phonate (incadronate) on fracture healing of long bones in rats. J Bone Miner Res 1999; 14:969-979. Wood J. Novel antiangiogenic effects of the bisphosphonate compound zoledronic acid. J Pharmacol Exp Ther 2002; 302:1055-1061. Kapitola J, Zak J. Effect of pamidronate on bone blood flow in oophorectomized rats. Physiol Res 1998; 47:237-240. Kapitola J, Zak J, Lacinova Z, et al. Effect of growth hormone and pamidronate on bone blood flow, bone mineral and IGF-I levels in the rat. Physiol Res 2000; 49(suppl 1):S101-S106. Estilo CL. Osteonecrosis of the maxilla and mandible in patients treated with bisphosphonates: a retrospective study. J Clin Oncol 2004; 22:8088.
research in brief Prevention and Management of Osteonecrosis of the Jaw Associated with Bisphosphonate Therapy
Rationale • Recently, bisphosphonate use has been associated with an increased incidence of osteonecrosis of the jaw. In the initial report of Migliorati, 5 patients presented with intraoral bone necrosis while receiving pamidronate or zoledronate.1 Three of the patients presented with spontaneous bone necrosis of the mylohyoid plate, and 2 presented with necrosis in the molar region after a tooth extraction. • In a later report, 63 cases of osteonecrosis of the jaw were reported by Ruggiero et al over a 2-year period.2 Previously, the rate of refractory osteomyelitis accounted for 1 or 2 cases per year, occurring mainly in patients treated with radiation therapy. However, none of the reported 63 patients had received radiation therapy, and only 56 of the 63 were oncology patients. Bisphosphonate treatment with pamidronate or zoledronate was the only common treatment agent for all 63 patients. Twenty-four patients had maxillary bone involvement, and 40 had mandibular bone involvement. The condition typically presented as pain and exposed bone at the site of a previous tooth extraction, although 9 patients had no recent history of a dentovascular procedure. On microscopic examination, all specimens consisted of necrotic bone with bacterial debris and granulation tissue. • Pain from the necrotic area can prevent patients from eating, speaking, and per-
forming adequate oral hygiene. Both reports stated that antibiotic treatment was ineffective.1,2 Surgical and hyperbaric oxygen treatments were also unsuccessful. Most patients in the study by Ruggiero et al required surgical procedures to remove the involved bone.2 Despite the presence of vascularized bone at the resection margins, however, progressive necrosis continued. Withdrawal from bisphosphonate treatment did not appear to reverse the process. • Although no direct causal relationship exists between zoledronate or pamidronate use and osteonecrosis of the jaw, bisphosphonate use is the common element in the increased occurrence reported. Novartis assembled an expert panel to discuss prevention, diagnosis, and treatment of osteonecrosis of the jaw in June 2004.3 A “post-marketing experience” section was added to the zoledronate and pamidronate labels to advise patients and physicians of the increased incidences of jaw osteonecrosis.4 The recommendations from the expert panel are discussed later in this article.
Bisphosphonate Treatment and Bone Physiology The necrosis of alveolar bone appears to result from a combination of poor blood supply and impaired bone remodeling or healing. Although the inhibition of osteoclasts by bisphosphonates reduces the incidence of pathologic fractures and treats hypercalcemia of malig-
nancy, it also suppresses the natural process of bone remodeling. In an experimental animal model, the nitrogencontaining bisphosphonates alendronate and risedronate suppressed trabecular bone remodeling with an associated increase in microdamage in beagles.5 Microdamage is hypothesized to underlie the development of stress fractures and to play a role in increased bone fragility associated with osteoporosis and aging. The report by Ruggiero et al suggested that the most likely cause of the osteonecrotic process in these patients was localized vascular insufficiency.2 Zoledronate and pamidronate have also demonstrated antiangiogenic properties in preclinical trials, although zoledronate was a much more potent antiangiogenic agent than pamidronate.6-10
A Retrospective Analysis to Identify Risk Factors and Guidelines Previously identified risk factors for osteonecrosis include radiation therapy to the head and neck, chemotherapy, immunotherapy, or other cancer treatments; female sex; and several comorbid conditions.3 A retrospective analysis was performed to identify risk factors for osteonecrosis and establish guidelines for management of osteonecrosis of the maxilla and mandible, and was presented at 40th Annual Meeting of the American Society of Clinical Oncology in June 2004.11 To achieve this objective, the medical and dental
Prepared by: Nancy Price, PhD Reviewed by: Alan Lipton, MD, Vinay K. Jain, MD, Salvatore Ruggiero, DMD, MD Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by Cancer Information Group, ISSN #1543-2912, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.
14
Volume 2, Number 1 • October 2004
Table 1 Characteristics of Patients in the Retrospective Analysis Who Developed Osteonecrosis of the Jaw11 Variable
Value
Type of Cancer Breast
15 (n = 297)
Multiple myeloma
6 (n = 139)
Prostate
2 (n = 83)
Site of Osteonecrosis Mandible
15
Maxilla
7
Both
1
Area Near tooth extraction
12
Spontaneous
10
Both
1
I.V. Bisphosphonate Pamidronate
8
Zoledronate
2
Pamidronate and zoledronate
12
Sex Male
6
Female
17
records of all patients with multiple myeloma, breast cancer, and prostate cancer who were provided with dental service at Memorial Sloan-Kettering Cancer Center between January 1996 and May 2004 were reviewed. Patients who presented with exposed bone in the maxilla or mandible were further evaluated for various clinical and pathologic characteristics (Table 1).11 Thirteen clinical and pathologic characteristics were considered, including tumor type, history of bisphosphonate therapy, corticosteroid use, tobacco use, oral hygiene, history of dental extraction in the osteonecrotic area, and comorbid conditions.
A total of 530 patients were reviewed, including 297 patients with breast cancer, 139 patients with multiple myeloma, and 83 patients with prostate cancer. The 23 patients who developed osteonecrosis included 15 with metastatic breast cancer, 6 with multiple myeloma, and 2 with prostate cancer. Seventeen of the 23 were women. The median age was 63 years. Twenty-two of the 23 patients received intravenous bisphosphonates. Eight patients had received pamidronate, 2 had received zoledronate, and 12 had received both. The median time of zoledronate therapy at the time of the diagnosis of osteonecrosis was 35 months (range, 194 months). The mandible was the site of 15 of the osteonecrotic areas, the maxilla was the site of 7, and 1 patient had lesions in both the mandible and maxilla. The site of osteonecrosis was located at tooth extractions in 12 patients. Osteonecrosis was spontaneous in 10 patients, and 1 patient had a spontaneous lesion and an osteonecrotic site near a previous tooth extraction. Osteonecrosis was not symptomatic in 14 patients. The retrospective analysis concluded that advanced cancer, chemotherapy, steroid use, bisphosphonate use, and comorbid conditions might be contributing causes. Nineteen patients (83%) had ≥ 1 comorbid condition, and 13 patients (57%) had > 2 comorbid conditions that included diabetes (n = 6), asthma (n = 2), arthritis (n = 4), osteoporosis (n = 1), anemia (n = 3), and renal disease (n = 4). Treatments used for the management of osteonecrosis in these patients included chlorhexidine rinses and antibiotics, conservative sequestrectomy or curettage, and surgical debridement (Table 2).11 Only 4 patients had a resolution and, of these, only 2 did not have progression or additional osteonecrotic lesions.
15
Table 2 Management and Outcome in the Retrospective Analysis11 Variable
Cases
Management Surgical debridement
1
Chlorhexidine rinse and antibiotics
16
Sequestrectomy or curettage
8
Outcomes Resolution
4
– Without progression
2
– Resolution with subsequent development of draining neck fistula
1
– Resolution of tooth extraction–related osteonecrosis but later development of a spontaneous osteonecrotic lesion
1
Lost to follow-up
4
Progression
3
No change
6
Deceased
2
Prevention of Osteonecrosis in Patients with Cancer Receiving Bisphosphonate Therapy Two of the 5 patients in the report by Migliorati1 and most of the patients in the report by Ruggiero et al2 presented with exposed bone at the site of a previous tooth extraction. Considering the coincidental occurrence of tooth extraction and the development of osteonecrosis after bisphosphonate use, the Novartis expert panel recommended that any procedure that would require bone healing should be completed before beginning bisphosphonate therapy. Patients should maintain excellent dental health and avoid injury to soft tissue or bone in the oral cavity. The expert panel’s recommendations for prevention of osteonecrosis of the jaw are listed in Table 3.3 A dental examination, including a panoramic jaw radiograph, is encouraged before beginning bisphosphonate thera-
Supportive Cancer Therapy
research in brief
Table 3 Preventive Measures Recommended Before Bisphosphonate Therapy3 Avoid any elective jaw procedure that will require bone to heal Patients should receive a routine clinical dental examination that may include a panoramic jaw radiograph to detect potential dental and periodontal infections If possible without risk to patient, delay bisphosphonate therapy until teeth with a poor prognosis are treated and healing is complete. This would include teeth in need of extraction or other dental surgery Suggested preventive dentistry should include: – Removal of abscessed and nonrestorable teeth and involved periodontal tissues – Functional rehabilitation of salvageable dentition, including endodontic therapy – Dental prophylaxis, caries control, and restorative dental care – Examine dentures to ensure proper fit – Education on oral self-care and hygiene – Prophylactic antibiotics are not recommended before routine dentistry, unless otherwise required for prophylaxis of bacteremia in patients at risk Education of patients on the importance of good dental hygiene and of promptly reporting symptoms; depending on risk, frequent oral assessments Oncologists are encouraged to perform a baseline assessment of the oral cavity, with visual examinations at every follow-up visit
py. Any extractions or other dental surgeries should be completed before the initiation of bisphosphonate therapy. It is suggested that patients receive treatment with preventive dentistry before the initiation of cancer treatments with or without bisphosphonates.
Management of Osteonecrosis of the Jaw The expert panel recommends consultations with an oral surgeon or oral pathologist for presenting patients (Table 4).3 Nonsurgical options, if available, may prevent further osseous injury. Limited surgery, including minimal bone debridement to reduce sharp edges on protruding bone that could cause trauma to surround-
Table 4 Management Recommendations from the Expert Panel3 Consultation with oral surgeon or oral pathologist Nonsurgical approaches to treatment to prevent further osseous injury Continuous or intermittent antibiotic therapy to prevent secondary soft-tissue infection 0.12% chlorhexidine gluconate oral rinses or minocycline hydrochloride periodontal pockets Adjustment or removal of dentures at night so that there is minimal soft-tissue trauma or irritation Monitoring at a minimum of every 3 months, or more often if symptoms continue or worsen Cessation or interruption of bisphosphonate therapy in severe cases
ing or opposing tissues, or a removable appliance to cover and protect the exposed area, is recommended. A protective stent could be beneficial to patients who have exposed bone that causes trauma to adjacent tissues and to patients in whom the area around the osteonecrotic site is repeatedly traumatized during normal oral function. Biopsies of the site should be performed only if metastasis to the jaw is suspected. Antibiotics might be used continuously or intermittently to prevent secondary soft tissue infections. The use of antibiotics in this setting is not yet defined, but the strategy appears to control pain and disease. The decision to use antibiotics should be made in consultation with an oral surgeon or oral pathologist. Cultures from the infected site may help in choosing the appropriate antibiotic regimen. Dental rinses that include 0.12% chlorhexidine gluconate can be used. Patients may retain their dentures, but it is recommended that dentures be adjusted to minimize damage to soft tissue and that they be removed at night.
16
Cessation or interruption of bisphosphonate therapy can be considered in severe cases but must be considered in light of the skeletal benefits of bisphosphonate therapy. At this time, no benefit of cessation of treatment has been observed. However, if surgery is required in patients with ongoing osteonecrosis, cessation of bisphosphonate therapy should be more thoughtfully considered. The decision to stop bisphosphonate treatment should be determined by an oncologist. Hyperbaric oxygen has not been effective and is not recommended. The placement of dental implants is contraindicated, as it will require significant bone healing. Frequent patient monitoring at intervals of ≤ 3 months is recommended, with more frequent monitoring if symptoms continue or worsen.
Conclusion The occurrence of osteonecrosis of the jaw in patients receiving bisphosphonate therapy is infrequent. However, the problem has just been recognized and the true occurrence rate cannot yet be determined, nor can the future rate of occurrence be predicted. Other unknown factors related to occurrence of osteo-necrosis of the jaw could include the type of bisphosphonate therapy (N-bisphosphonates vs. non–nitrogen-containing bisphosphonates) and the duration of treatment with bisphosphonates. The loss of normal bone remodeling along with the potential for increased bone density and microdamage combined with the antiangiogenic properties of N-bisphosphonates may all contribute to the increased incidence of osteonecrosis of the jaw in patients treated with bisphosphonates. Further investigations into the causes and treatments of osteonecrosis of the jaw are warranted. A retrospective analysis of patients treated with bisphosphonates during the past 10 years is being
Volume 2, Number 1 • October 2004
research in brief
conducted at M. D. Anderson Cancer Center (A. Hoff, MD, personal communication, October 5, 2004). Until more information is available, preventive measures are highly recommended.
References 1. Migliorati CA. Bisphosphanates and oral cavity avascular bone necrosis. J Clin Oncol 2003; 21: 4253-4254. 2. Ruggiero SL, Mehrotra B, Rosenberg TJ, et al. Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg 2004; 62:527-534.
3. Expert panel recommendations for the prevention, diagnosis, and treatment of osteonecrosis of the jaws. Hanover, NJ: Novartis, June 2004. 4. Zometa [package insert]. Hanover, NJ: Novartis, 2004. 5. Mashiba T, Turner CH, Hirano T, et al. Effects of suppressed bone turnover by bisphosphonates on microdamage accumulation and biomechanical properties in clinically relevant skeletal sites in beagles. Bone 2001; 28:524-531. 6. Fournier P, Boissier S, Filleur S, et al. Bisphosphonates inhibit angiogenesis in vitro and testosterone-stimulated vascular regrowth in the ventral prostate in castrated rats. Cancer Res 2002; 62:6538-6544. 7. Li J, Mori S, Kaji Y, et al. Effect of bisphos-
17
8. 9. 10.
11.
phonate (incadronate) on fracture healing of long bones in rats. J Bone Miner Res 1999; 14:969-979. Wood J. Novel antiangiogenic effects of the bisphosphonate compound zoledronic acid. J Pharmacol Exp Ther 2002; 302:1055-1061. Kapitola J, Zak J. Effect of pamidronate on bone blood flow in oophorectomized rats. Physiol Res 1998; 47:237-240. Kapitola J, Zak J, Lacinova Z, et al. Effect of growth hormone and pamidronate on bone blood flow, bone mineral and IGF-I levels in the rat. Physiol Res 2000; 49(suppl 1):S101-S106. Estilo CL. Osteonecrosis of the maxilla and mandible in patients treated with bisphosphonates: a retrospective study. J Clin Oncol 2004; 22:8088.