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
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.
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
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
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
Ruggiero et al
] 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.
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.