Bisphosphonate induced osteonecrosis of jaw in breast cancer patients: A systematic review.

INTRODUCTION

Bisphosphonates are analogues of inorganic pyrophosphates, which are commonly used in the treatment of osteoporosis, metastatic osteolytic bone disease and primary resorptive malignancies of bone like multiple myeloma.[ 1 ] Breast and lung cancers usually metastasize to the bone and produce osteolytic lesions. The indications of bisphosphonate therapy in patients with metastatic breast cancer are to reduce the resorption of bone and to correct hypercalcemia of malignancy.[ 2 ] These drugs improve the quality of life of the breast cancer patients by decreasing the pain and skeletal-related events (pathologic fracture, spinal cord compression and the need for surgery or radiation therapy) by 30-40%.[ 3 4 ]

Bisphosphonate-induced osteonecrosis of jaw (BONJ) is a potential complication associated with long term use of bisphosphonates, especially pamidronate and zoledronate and was first described by Marx in 2003.[ 5 ] BONJ is a condition characterized by hypocellularity, tissue dehiscence, chronic bone necrosis and osteolytic radiographic features.[ 6 ] The prevalence of BONJ has not been well established and the underlying pathogenesis still remains to be fully elucidated. Knowledge about the prevalence and pathogenesis of BONJ will help in patient education and development of appropriate management guidelines. The aim of the present study is to estimate the overall prevalence of BONJ in breast cancer patients with bone metastasis. The paper also highlights the proposed guidelines for diagnosis, staging and management of BONJ.

MATERIALS AND METHODS

A systematic literature search was conducted in Pubmed database for articles published between 2003 and 2009. The Pubmed search terms used were bisphosphonate, osteonecrosis, jaws and breast cancer. All the articles containing original data on the prevalence of BONJ in breast cancer patients were identified. Articles involving randomized controlled clinical trials, case-control studies and retrospective studies were included. Articles with anecdotal information, case reports and literature reviews were not included. Specific information collected also included the type of bisphosphonate and study design along with the prevalence of BONJ.

RESULTS

A total of 126 potentially relevant articles containing information on BONJ in breast cancer patients were identified from Pubmed database, of which 115 articles were excluded after assessing the title and abstract. Eleven articles which fulfilled the inclusion criteria were retrieved in full text. Of the 2490 breast cancer patients, 69 developed BONJ with the overall prevalence rate of 2.8%. Majority of the patients with BONJ had received a combination of zoledronate and pamidronate (63.6%), while 27.2% and 9.2% of them had only zoledronate or pamidronate respectively. Table 1 lists the published studies on the prevalence of BONJ in breast cancer patients from 2003 to 2009.[ 7 – 17 ]

DISCUSSION

Bisphosphonates are analogs of pyrophosphate in which carbon replaces the oxygen molecule thereby forming a phosphate-carbon-phosphate (P-C-P) structural backbone. Different bisphosphonates were designed by changing the two side chains on the carbon atom in P-C-P structure. The binding affinity of bisphosphonates to mineralized structure and their effectiveness is due to the phosphate ends of P-C-P structure, while the two side chains determine the anti resorptive potential of individual bisphosphonates.[ 18 ] Bisphosphonates have increased affinity for hydroxyapatite crystals and they remain unmetabolized for prolonged duration of time. This property of bisphosphonates is because of the attachment of phosphate ends to calcium ions, forming both insoluble and soluble complexes.[ 19 ]

Bisphosphonates act directly on the osteoclasts, reducing recruitment and proliferation of osteoclast precursors and also inducing osteoclast apoptosis. They inhibit “receptor activator of nuclear factor κ B ligand (RANKL) expression and increase osteoproterin production by bone marrow stromal cells and osteoblasts so that RANK-RANKL interaction is disrupted. These synergistic actions result in the suppression of osteoclast recruitment and decrease the bone resorption.[ 20 ] Bisphosphonates also exhibit anti-angiogenic activity by inhibiting vascular endothelial growth factor and formation of new blood vessels.[ 21 ]

Currently, seven bisphosphonates have been approved for clinical use in the USA by FDA: alendronate, pamidronate, risedronate, zoledronate, ibandronate, etidronate and tiludronate. Five of them have been approved for oral administration while pamidronate and zoledronate are for intravenous use.[ 6 ] The intravenous bisphosphonates are approved for patients with multiple myeloma, metastatic breast cancer and for bone metastases from any solid tumor. The intravenous bisphosphonates are pamidronate (Aredia) that is administered at a dose 90 mg every 3-4 weeks and zoledronate (zometa) administered at a dose of 4 mg every 3-4 weeks.[ 1 ] When compared to pamidronate, zoledronate is more potent and effective in reducing the skeletal complication and hypercalcemia of malignancy.[ 22 ] The oral bisphosphonates such as alendronate and residronate are commonly used for the treatment of postmenopausal and glucocorticoid induced osteoporosis. The treatment protocol is alendronate 70 mg given once weekly and risedronate 35 mg once weekly. Ibandronate is the most recent bisphosphonate to receive FDA approval in March 2005 for the treatment of osteoporosis and is given as monthly regimen.[ 1 ] Etidronate and tiludronate are approved by the FDA to treat Paget's disease.[ 6 ]

The most common side effects of bisphosphonates include gastrointestinal intolerance, flu like symptoms, nausea, vomiting, dizziness and headaches.[ 6 ] BONJ is a recently described complication, which was first reported by Marx in 2003. He had reported painful exposure of maxilla, mandible or both in 36 patients receiving bisphosphonates for malignancy.[ 5 ] In the same year, Migliorati reported 5 cases of mandibular osteonecrosis, while Wang et al described osteonecrosis in 3 patients receiving intravenous bisphosphonates for metastatic breast cancer.[ 23 24 ]

Long-term use of pamidronate and zoledronic acid have been associated with up to 600 cases of BONJ.[ 1 ] Woo et al , after reviewing 368 cases of bisphosphonate associated osteonecrosis, have reported that 97% of the cases were treated with pamidronate or zoledronate or both, which similar to our study where 63.6% of the patients had pamidronate and zoledronate.[ 25 ] The strong association of these two drugs to BONJ may be due to higher bioavailability of intravenous bisphosphonates as compared with oral formulations. Approximately 50% intravenous bisphosphonates are available for incorporation into the bone matrix compared to an average of 1% of oral bisphosphonates absorbed by the gastrointestinal tract.[ 26 ] About 170 cases of alendronate, 12 cases of risedronate and only one case of ibandronate-induced osteonecrosis have been reported world wide.[ 27 ] There are currently no reported cases of etidronate and tiludronate related osteonecrosis.

Jaw susceptibility

It has been proposed that the jaw bones are highly susceptible to osteonecrosis based on certain anatomical and physiological factors. Bisphosphonates are highly concentrated in the jaw rather than other skeleton because of high vascularity and bone turnover of the jaws. The forces of mastication and periodontal ligament around numerous teeth ensure rapid bone turnover around the periodontium and can induce microfractures in bisphosphonate-induced acellular and avascular bone. The thin oral mucosa can be easily traumatized during surgical procedures, allowing oral microbes to enter into the necrotic bone.[ 28 ]

Risk factors

It has been suggested that BONJ could be caused by a combination of environmental and genetic risk factors. Various retrospective studies have identified the potential risk factors which include use of oral vs. intravenous bisphosphonates, duration of bisphosphonate therapy, concomitant use of chemotherapy or glucocorticoids, pre existing dental or periodontal diseases, advanced age of the patient and presence of co-morbid conditions such as obesity, tobacco and alcohol abuse.[ 1 ]

Of all these environmental factors, dental trauma is considered to be the most common precipitating factor for the development of BONJ.[ 29 ] In a review of 368 cases by Woo et al , 60% of the cases occurred after dental extraction.[ 25 ] Of the 119 BONJ cases reported by Marx et al , 37.8% occurred following tooth removal, 28.6% had periodontitis, and 25.2% occurred spontaneously, 11.2% after periodontal surgery, 3.4% after dental implants and 0.8% following root canal surgery.[ 28 ]

The more potent intravenous bisphosphonates such pamidronate and zoledronate have significantly higher risk of producing BONJ than the oral bisphosphonates.[ 8 ] The duration of bisphosphonate therapy is also associated with the development of osteonecrosis with longer duration of treatment related to greater risk of developing the disease. The incidence of BONJ increased from 1.5% treated for 4-12 months to 7.7% when treated for 37-48 months.[ 7 ] The synergistic effect of the combination of bisphosphonate-induced stress of bone marrow stromal cells, chemotherapy, cancer-related co-morbid factor, reduced vascularity, bone microfractures and tracking or oral microbes through the periodontium may act together to produce “band wagon” effect which increases the disease burden and decreases the susceptibility threshold in favor of BONJ. The median time of treatment with bisphosphonates in patients with metastatic breast cancer before developing BONJ was 72 months for pamidronate and 18 months for zoledronate.[ 6 ]

As only few patients using bisphosphonates develop osteonecrosis, it is possible that individual genetic variations in the drug metabolism or bone homeostasis may confer susceptibility or resistance in the development of BONJ. Polymorphic variations in CYP2C8 gene are associated with increased risk of BONJ in patients with multiple myeloma; specifically single nucleotide polymorphism in intron 8 of CYP2C8 was significantly associated with BONJ when the T allele was present.[ 30 ]

Clinical features

BONJ may be asymptomatic for weeks, months or years and become symptomatic when the surrounding tissues are inflamed or infected. Prior to the development of clinically detectable osteonecrosis, patient may complain of pain, erythema, ulceration, tooth mobility and altered sensation of the affected area. In patients with maxillary involvement, chronic maxillary sinusitis with or without oral-antral fistula can be present secondary to osteonecrosis. In cases of extensive bone involvement, mottled bone similar to diffuse osteomyelitis and widening of periodontal ligament space are noted radiographically.[ 1 ]

Staging

Ruggiero et al [ 1 ] have implemented a staging system to stratify the patients with BONJ.

Stage 1: The disease is characterized by exposed necrotic bone which is asymptomatic without any evidence of soft tissue inflammation or infection.

Stage 2: The disease is characterized by exposed necrotic bone associated with pain and soft tissue inflammation or infection

Stage 3: The disease is characterized by exposed necrotic bone associated with pain, soft tissue inflammation or infection, pathologic fracture, extra oral fistula formation or osteolysis extending to the inferior border.

Management protocol

Patients about to start bisphosphonate therapy

Majority of the patients receiving bisphosphonates are affected with BONJ following extraction, dental implant placement or apical surgery. Hence, optimizing the dental health should be the primary goal in patients receiving bisphosphonates. The teeth which cannot be restored and those with poor prognosis should be extracted. The bisphosphonate therapy should be delayed by atleast 4-6 weeks after extraction to ensure complete healing. The patients should be educated about the importance of maintaining good oral hygiene and regular dental evaluations.

Patients receiving bisphosphonates without any evidence of osteonecrosis

Maintaining good oral hygiene is of paramount importance to prevent dental disease and thereby to avoid dento alveolar surgery. Placement of dental implants should be avoided in patients receiving potent intravenous bisphosphonates. If the tooth is non restorable, the crown portion can be removed and the endodontically treated roots can be left behind.

Patients with established BONJ

A thorough history and clinical examination along with radiographs helps in establishing the diagnosis of BONJ. The associated oral infectious agents can be identified and the appropriate antibiotics can be selected using microbial cultures. Stage 1 dictates daily use of oral antimicrobial rinses with 0.12% chlorhexidine and regular clinical follow-up. Stage 2 necessitates the use of antimicrobial therapy along with analgesics and daily oral antimicrobial rinses. Stage 3 disease represents the most difficult group to treat as they are refractory to antibiotic therapy. These patients require surgical debridement in addition to analgesics and oral antimicrobial rinses.

CONCLUSION

BONJ is a significant complication occurring in 2.8% of the breast cancer patients receiving bisphosphonates for metastatic bone disease. The prevalence of BONJ can vary depending on the type and duration of bisphosphonate therapy, with the combination of pamidronate and zoledronate yielding the highest prevalence. BONJ can be distressing to patients, causing severe pain and discomfort lasting for several months, requiring frequent visits to the dental office, surgical interventions and antibiotic use. Patients treated with these drugs should be aware of the potential complications in the jaws and importance of maintaining good oral hygiene should be emphasized in these patients to prevent osteonecrosis. As the patient's medical history and thorough oral examination is the most effective method to detect BONJ, dentists are in a unique position to identify the disease process early and manage the patients appropriately.

Source of Support: Nil.

Conflict of Interest: None declared.

REFERENCES

1 Ruggiero SL Fantasia J Carlson E Bisphosphonate related osteonecrosis of the jaw: Background and guidelines for diagnosis, staging and management Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2006 102 433 41 16997108 10.1016/j.tripleo.2006.06.004

2 Ruggiero SL Mehrotra B Rosenberg TJ Engroff SL Osteonecrosis of the jaws associated with the use of bisphosphonates: A review of 63 cases J Oral Maxillofac Surg 2004 62 527 34 15122554 10.1016/j.joms.2004.02.004

3 Lipton A Theriault RL Hortobagyi GN Simeone J Knight RD Mellars K Pamidronate prevents skeletal complications and is effective palliative treatment in women with breast carcinoma and osteolytic bone metastasis: Long tern follow up of two randomized placebo controlled trials Cancer 2000 88 1082 90 10699899 10.1002/(sici)1097-0142(20000301)88:5<1082::aid-cncr20>3.0.co;2-z

4 Jagdev SP Purohito P Heatley S Herling C Coleman RE Comparison of the effect of intravenous pamidronate and oral clodronate on symptoms and bone resorption in patients with metastatic bone disease Ann Oncol 2001 12 1433 38 11762816 10.1023/a:1012506426440

5 Marx RE Pamidronate and zoledronate induced avascular necrosis of jaws: A growing epidemic J Oral Maxillofac Surg 2003 61 1115 17 12966493 10.1016/s0278-2391(03)00720-1

6 Sarin J De Rossi SS Akintoye SO Updates on bisphosphonates and potential pathobiology of bisphosphonate induced jaw osteonecrosis Oral Dis 2008 14 277 85 18336375 10.1111/j.1601-0825.2007.01381.x

7 Bamias A Kastritis E Bamia C Moulopoulos LA Melakopoulos I Bozas G Osteoecrosis of the jaw in cancer after treatment with bisphosphonates: incidence and risk factors J Clin Oncol 2005 23 8580 87 16314620 10.1200/JCO.2005.02.8670

8 Durie BG Katz M Crowley J Osteonecrosis of the jaw and bisphosphonates N Engl J Med 2005 353 99 102 16000365 10.1056/NEJM200507073530120

9 Guarneri V Donati S Nicolini M Giovannelli S D’Amico R Conte PF Renal safety and efficacy of intravenous bisphosphonates in patients with skeletal metastasis treated for up to 10 years Oncologist 2005 10 842 48 16314295 10.1634/theoncologist.10-10-842

10 Sanna G Preda L Bruschini R Rocca MC Ferretti S Adamoli L Bisphosphonates and jaw osteonecrosis in patients with advanced breast cancer Ann Oncol 2006 17 1512 16 16936182 10.1093/annonc/mdl163

11 Aguiar Bujanda D Bohn Sarmiento U Cabrera Suarez MA Aguiar Morales J Assessment of renal toxicity and osteonecrosis of the jaws in patients receiving zoledronic acid for bone metastasis Ann Oncol 2007 18 556 60 17082512 10.1093/annonc/mdl408

12 Wang EP Kaban LB Strewler GJ Raje N Troulis MJ Incidence of osteonecrosis of jaw in patients with multiple myeloma and breast or prostrate cancer on intravenous bisphosphonate therapy J Oral Maxillofac Surg 2007 65 1328 32 17577497 10.1016/j.joms.2007.03.006

13 Ibrahim T Barbanti F Marrano GG Mercatali L Ronconi S Vicini C Osteonecrosis of the jaw in patients with bone metastasis treated with bisphosphonates: A retrospective study Oncologist 2008 13 330 36 18378544 10.1634/theoncologist.2007-0159

14 Hoff AO Toth BB Altundag K Johnson MM Warneke CL Hu M Frequency and risk factors associated with osteonecrosis of jaw in cancer patients treated with intravenous bisphosphonates J Bone Miner Res 2008 23 826 36 18558816 10.1359/JBMR.080205 PMC2677083

15 Boonyapakorn T Schirmer I Reichert PA Sturm I Massenkeil G Bisphosphonate induced osteonecrosis of the jaws: Prospective study of 80 patients with multiple myeloma and other malignancies Oral Oncol 2008 44 857 69 18282788 10.1016/j.oraloncology.2007.11.012

16 Walter C Al-Nawas B duBois A Buch L Harter P Grotz KA Incidence of bisphosphonate associated osteonecrosis of the jaws in breast cancer patients Cancer 2009 115 1631 37 19156913 10.1002/cncr.24119

17 Fehm T Beck V Banys M Lipp HP Hairass M Reinert S Bisphosphonate induced osteonecrosis of the jaw:Incidence and risk factors in patients with breast cancer and gynecological malignancies Gynecol Oncol 2009 112 605 09 19136147 10.1016/j.ygyno.2008.11.029

18 Rodan GA Fleisch HA Bisphosphonates: mechanisms of action J Clin Invest 1996 97 2692 96 8675678 10.1172/JCI118722 PMC507360

19 Fleisch H Bisphosphonates: mechanisms of action Endocri Rev 1998 19 8 100 10.1210/edrv.19.1.0325 9494781

20 Viereck V Emons G Lauck V Frosch KH Blaschke S Grundker C Bisphosphonates pamidronate and zoledronic acid stimulate osteoprotegrin production by primary human Osteoblasts Biochem Biophy Res Commun 2002 291 680 86 10.1006/bbrc.2002.6510 11855844

21 Ferretti G Fabi A Carlini P Papaldo P Cordiali FP Di Cosimo S Zoledronic acid induced circulating level of modifications of angiogenic factor, metalloproteinases and proinflammatory cytokines in metastatic breast cancer patients Oncology 2005 69 35 43 16088233 10.1159/000087286

22 Berenson JR Hillner BE Kyle RA Anderson K Lipton A Yee GC American society of clinical oncology clinical practice guidelines: The role of bisphosphonates in multiple myeloma J Clin Oncol 2002 20 3719 36 12202673 10.1200/JCO.2002.06.037

23 Migliorati CA Bisphosphonates and oral cavity avascular bone necrosis J Clin Oncol 2003 21 4253 54 14615459 10.1200/JCO.2003.99.132

24 Wang J Goodger NM Pogrel MA Osteonecrosis of the jaws associated with cancer chemotherapy J Oral Maxillofac Surg 2003 61 1104 07 12966490 10.1016/s0278-2391(03)00328-8

25 Woo SB Hellstein JW Kalmar JR Narrative (corrected) review: Bisphosphonates and osteonecrosis of the jaws Ann Intern Med 2006 144 753 61 16702591 10.7326/0003-4819-144-10-200605160-00009

26 Ezra A Golomb G Administration routes and delivery systems of bisphosphonates for the treatment of bone resorption Adv Drug Deliv Rev 2000 42 175 95 10963835 10.1016/s0169-409x(00)00061-2

27 American Dental Association Council on Scientific Affairs. Dental management of patients receiving oral bisphosphonate therapy: Expert panel recommendations J Am Dent Assoc 2006 137 1144 50 16873332 10.14219/jada.archive.2006.0355

28 Marx RE Sawatari Y Fortin M Broumand V Bisphosphonate induced exposed bone (osteonecrosis/osteopetrosis) of the jaws: Risk factors, recognition, prevention and treatment J Oral Maxillofac Surg 2005 63 1567 75 16243172 10.1016/j.joms.2005.07.010

29 Sarasquete ME Gonzalez M San Miguel JF Garcia-Sanz R Bisphosphonate related osteonecrosis: genetic and acquired risk factors Oral Dis 2009 15 382 87 19413677 10.1111/j.1601-0825.2009.01568.x

30 Sarasquete ME Garcia-Sanz R Marin L Alcoceba M Chillon MC Balanzategui A Bisphosphonate related osteonecrosis of the jaw is associated with polymorphisms of cytochrome P450 CYP2C8 in multiple myeloma: A genome wide single nucleotide polymorphism analysis Blood 2008 112 2709 12 18594024 10.1182/blood-2008-04-147884