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Revista Española de Cirugía Oral y Maxilofacial

versión On-line ISSN 2173-9161versión impresa ISSN 1130-0558

Rev Esp Cirug Oral y Maxilofac vol.29 no.5 Madrid sep./oct. 2007




Bisphosphonate induced osteonecrosis of the jaws: prevention and therapeutic approach

Osteonecrosis de los maxilares inducida por bifosfonatos: prevención y actitud terapéutica



F.J. Barrientos Lezcano1, B. Peral Cagigal1, G. de la Peña Varela1, L.A. Sánchez Cuéllar2, J.M. García Cantera2, A. Serrat Soto2, A. Verrier Hernández3

1 Médico Residente.
2 Médico Adjunto.
3 Jefe de Servicio.
Servicio de Cirugía Oral y Maxilofacial.
Hospital Universitario Pio del Río Hortega. Valladolid, España





Introduction. Bisphosphonate-induced osteonecrosis of the jaws might reach epidemic proportions due to the widespread use of this therapy.
Materials and methods. A protocol for prevention and treatment of this pathology is shown. Three clinical cases are reported.
Results. It is quite difficult to reach restitutio ad integrum, but stopping the progress of the disease is possible.
Discussion. Surgical treatment and cessation of bisphosphonate therapy are of no use. Only antibiotics and oral chlorhexidine have shown some benefits.
Conclusions. An accurate preventive attitude is mandatory prior to undergoing bisphosphonate therapy. If osteonecrosis of the jaws is present, management should be conservative.

Key words: Osteonecrosis; Bisphosphonates; Avascular necrosis; Jaws; Mandible.


Introducción. La osteonecrosis maxilar o mandibular por bifosfonatos puede convertirse en una epidemia debido a la amplia difusión de estos fármacos entre la población.
Material y método. Se muestra un protocolo para la prevención y el tratamiento de esta enfermedad. Se presentan tres casos de osteonecrosis maxilar/mandibular.
Resultados. Es difícil lograr una curación completa; sin embargo es posible detener la progresión de la enfermedad.
Discusión. La cirugía y la suspensión de la terapia con bifosfonatos han demostrado poca utilidad. Los antibióticos y los enjuagues con clorhexidina son las únicas medidas eficaces.
Conclusiones. Es imprescindible una planificación adecuada previa a la instauración del tratamiento con bifosfonatos. Ante una osteonecrosis establecida, la actitud debe ser conservadora.

Palabras clave: Bifosfonatos; Osteonecrosis; Necrosis avascular; Maxilar; Mandíbula.



The exposure of necrotic maxillary o mandibular bone in patients treated with bisphosphonates is becoming increasingly questionable. Bisphosphonates1 (Table 1) are non-metabolizable pyrophosphate analogs, with a preference for bone tissue. They act on osteoclasts (through a membrane receptor or an intracellular enzyme),2 inhibiting chemotaxis, shortening their average life span, halting their activity and inducing apoptosis.3 As a result, bone resorption is stopped. Zoledronate and pamidronate also inhibit capillary neoangiogenesis of the tumor.4-6

Generally7 bisphosphonates are indicated for stabilizing the loss of bone mass in postmenopausal women with osteoporosis (and they are taken orally). Intravenous administration is reserved for cases of bone metastases (principally breast and prostrate) and for correcting bone resorption, or moderate-to-severe hypercalcemia in cases of multiple myeloma. It is also recommended for osteolytic lesions caused by any type of solid tumor.2,8 In 2003 Marx7 published a series of 36 maxillary or mandibular exposure cases due to bisphosphonates. From then on numerous cases have been reported, and many more are to be expected given the wide use of these drugs among the population.

The initial phase of the disease2,9 typically starts with post-extraction alveolitis (although there are spontaneous cases) refractory to treatment, which progresses towards osteomyelitis, with sequestrum, bone exposure, inflammation and suppuration. Biopsies are frequently carried out in order to rule out mandibular bone metastases or primary jaw bone tumors. Failure occurs when trying to cover these areas even though meticulous regularization or bone resection has been carried out together with closure with local mucosal flaps. Clinically and radiologically the lesions are like those from osteoradionecrosis with sequestrum (that form spontaneously or after invasive procedures) that can complicate due to secondary infections.2

Its pathogenesis lies in the interruption of osteoclastic remodeling activity and from bone cell turnover,7 which is aggravated by localized vascular insufficiency as a result of ischemic changes.2 This inhibition is partial in the case of oral bisphosphonates, as osteonecrosis rarely arises and only following high accumulated doses over long periods of time. If administered intravenously, osteoclastic inhibition is irreversible, and apoptosis will take place.7

This is a characteristic entity of the jaw bones. These drugs have a preference for them given their profuse vascular supply and the high cellular turnover (there is great bone remodeling activity around the periodontal ligament). Other factors include the limited thickness of the mandibular-maxillary mucosa and the frequent "aggressive behavior" suffered by the bone in the way of invasive surgical or dental procedures.

It predominates in the upper jaw (38-80.5%); while 14- 63% is located in the mandible and 5.5-23% in both.2,10


Material and method

Case report 1

Female patient, 37 years old, was referred (May 2005) to our department because of right-sided trigeminal neuropathic pain that had been evolving for a year and a half, and which had arisen 20 days after the incomplete extraction of the lower right wisdom tooth carried out (in 2004) by her dentist. Her medical history included breast cancer (2001) that had been treated with surgery and chemotherapy. Metachronic bone metastases was then diagnosed in the lumbar spine (in 2002) and brain (2003), both treated with radiotherapy. Due to hypercalcemia caused by the bone metastases, treatment with zoledronate was given (4mg infused per week) for a year and a half. This was suspended for six months and then started again. She was also given corticoid steroids (unknown dosage).

The oral examination revealed suppuration and gingivitis around the root remains of tooth 48. The differential diagnosis included chronic osteitis/osteomyelitis and bone metastasis (Fig. 1). Tooth 47 was affected clinically and radiologically and avulsion was carried out together with curettage and an ostectomy of the alveolar bed of tooth 48 before extraction of the root remains (Fig. 2). The histopathologic report ruled out neoplastic infiltration, and only granulation tissue was observed that contained bone spicules. Three months later bone exposure persisted. Bone regulation was carried out and the defect was closed using a local mucosal flap, and a bone tissue sample was once again sent away for analysis that indicated the presence of bacillary colonies of an actinomycotic type surrounded by compacted bone fragments, which were infiltrating the medullary areas. Initial treatment was prescribed with amoxicillin-clavulanate 875/125 every 8 hours for two weeks that was maintained with continuous amoxicillin 500 mg every 8 hours to date. The lesion was re-examined every two months and it continued to have the same clinical appearance, although radiologically bone rarefaction could be observed towards the symphysis (Fig. 3). The patient reported occasional self-limited bouts of vestibular-gingival swelling. The symptoms ceased considerably and she now only complains of slight discomfort from these bouts of infection.

Case report 2

Female patient, 68 years old with a history of multiple myeloma IgG stage III B (in 2003) who had been treated with chemotherapy (6 cycles of VBMCP/VBAD) with complete response. Later (in 2004) an autotransplant was carried out with hemopoietic progenitors from peripheral blood. She had multiple crushed vertebrae and focal bone lesions secondary to the myeloma and, as a result, she was being treated with constant alendronate (10mg taken orally every 24 hours), prednisone (50 mg every 2 days taken orally) and various analgesics. Between December 2004 and February 2005 all her teeth were extracted by her dentist (incisors, canines and upper and lower premolars) after which she was fitted with a removable complete prosthesis. She was referred to our department (in July 2005) because of bone exposure with necrosis in areas 1,2 and 3 (Figs. 4 and 5) and local discomfort. As there was a clinical and radiological suspicion (Fig. 6) of osteomyelitis, she was advised not to use the prosthesis temporarily. She was treated with clindamycin, 300mg every eight hours for a week, and a sequestrectomy was carried out together with bone regularization and direct closure of the defect, prior to raising a mucoperiosteal flap from the vestibular and palate side. The exposed bone was completely covered. No material was sent away to be studied histologically. A month later, during re-examination, the osteonecrotic areas appeared in the same location. As osteonecrosis was suspected due to bisphosphonates, 875/125 amoxicillin- clavulanate was administered every eight hours for a month, and oral rinses every 12 hours with chlorhexidine at 0.12%. She was told to delay using the prosthesis. A bone biopsy was not carried out in order to avoid any progression of the bone lesions. During previous monitoring (bi-monthly) the lesions showed no sign of remission, although they had not become any worse. The patient´s symptoms showed subjective improvement. She died recently due to a stroke secondary to carotid stenosis.

Case report 3

Female patient, 81 years old with schizophrenia and serious extrapyramidal symptoms secondary to her treatment, was referred to us (in May 2005) by the geriatrician of her residence as a result of maxillary bone exposure on the left side of 4-5 cm (Fig. 7). She was edentulous and did not have a prosthesis. As there was no patient collaboration, the time that had evolved, the subjective clinical data and possible triggering factors, could not be ascertained. She had a history of refractory multiple myeloma (Kappa IgG) in 1998 with evidence of progression (currently stage III-B) with long bone osteopenia and lumbar-back spondyloarthrosis and she had received intravenous infusions of zoledronic acid (4mg/month). Although maxillary osteonecrosis was suspected as a result of bisphosphonates, a biopsy was taken of a small bone fragment so that bone metastasis could be ruled out. The histopathological report ruled out any neoplasm and necrotic bone was reported with numerous inflammatory cells and colonies of the actinomyce-type bacillus. She was treated with amoxicillin clavulanate (875/125, every 8 hours for 2 weeks) metronidazole (500 mg taken orally every 8 hours for two weeks) and 0.12% chlorhexidine washes every 12 hours. She later received amoxicillin 500mg every 8 hours for 3 months. Her carers were advised to maintain strict oral hygiene. She was then re-examined every three months, but an improvement was not observed in the clinical appearance of the lesions although their growth had been halted. She did not receive any further antibiotic treatment.



Bisphosphonates are of undoubted value for oncological patients with bone metastases. Survival increases, skeletal complications and associated pain are reduced, and quality of life is improved.2

This "epidemic" of maxillary or mandibular osteonecrosis as a result of bisphosphonates, has generated confusion due to the difficulty for completely curing the disease. In 2004 a panel of experts on the disease11 gathered together because of the growing incidence of cases and a series of recommendations was published (Figs. 8 and 9) (Table 2).

In spite of these recommendations, the best treatment for osteonecrosis continues being controversial. One of the few effective measures is antibiotic treatment although the ideal duration has not yet been defined. Its use has been proposed10 in intermittent or continuous cycles so that osteomyelitis is avoided and further soft tissue infection is prevented. They are clinically efficient for controlling pain and the development of the disease.7,10 This has been corroborated in the three cases presented. The symptoms improved as soon as the antibiotics were administered, and there was no increase in bone exposure. Although clindamycin has been recommended given its efficiency against Gram flora – and because of its bone tissue preference,10,11 Marx does not advise its use on its own,7 and he recommends penicillin derivatives such as first choice drugs. The antibiotic administered should cover the Eikenella or Actinomyces-type germs that frequently colonize exposed bone (as occurred in both clinical cases in which a bone biopsy was carried out).7-10 They also advise minimally invasive procedures such as irrigation and antiseptic washes.2,7,10

Surgical procedures such as wound debridement are not advised nor are bone decortication or dental extraction.10 Carrying out extractions therefore does not appear to be very sensible, as this is precisely what typically triggers the disease (Cases 1 and 2). Both cases show how curettage and bone regularization failed and how the lesions recurred. The first case even worsened until a conservative approach was adopted, no doubt because initially the possibility of bisphosphonates being the cause of the lesion was not taken into account. Therefore carrying out a meticulous medical history should be stressed as should be making a note of the drugs being taken by the patient, together with the " tablet for the bones" which normally is not given much importance. There are cases in which antibiotics fail, possibly due to the difficulty of reaching a target subjected to ischemic surroundings. In these cases, if slight, some authors10 advise carrying out debridement and flap closure, but always with antibiotic cover. This approach failed in cases 1 and 2 in spite of completely closing the defect with mucoperiosteal flaps. Marx had already warned that these flaps were of little use.13

There are severe cases in which the magnitude of the exposed area of bone or the symptoms makes a total or subtotal resection necessary and secondary reconstruction using viable tissue.10 However, this approach increases the risk of experiencing pathological fractures as well as new area of osteonecrosis.10 In case Nº3, nearly half the maxilla was exposed. Fortunately, it was suspected from the start that Zoledronic acid was involved (also in case 1) and a conservative approach was adopted. In addition, the general state of the patient and her short life expectancy obviated surgical intervention. Ruggiero et al.2 carried out systematic sequestrectomies of the bone fragments that had not responded to conservative treatment, as they constituted a possible focus of additional infection. The problem in these cases is finding a viable surgical margin of bone, as bisphosphonates are deposited in all bone tissue, and not only in exposed necrotic bone, with ulterior exposure of the resection margin being possible.2,9

In symptomatic patients with pathologic fractures, segmental mandibular resection and reconstruction with a rigid plate2 could be attempted. Free flaps or vascularized grafts are strictly contraindicated given the possibility of developing necrosis in the margins.2

In short, surgical treatment should only be considered in symptomatic cases in which conservative treatment has failed,2 and it should be limited to sequestrectomies when needed.9 The least amount of bone as possible should be removed and the periosteum should be preserved so that the bone does not come into contact with oral flora.7

Another step that has led to certain controversy is suspending bisphosphonate therapy (with the risk that this entails for the oncological patient). This decision, if taken, should be made together with the oncologist.11,14 In none of the three clinical cases was this possibility contemplated as they all had neoplastic antecedents and, the last two had bone lesions with a clinical course that was being relatively controlled with bisphosphonates. Moreover, it has not been demonstrated that there is any benefit to be had from stopping bisphosphonates once the osteonecrosis has started. 10 This could be evaluated if the indication were not oncological, 7 but suspension is not advisable if being taken because of pain due to bone metastasis, pathological fractures or tumor-induced hypercalcemia. However, the worsening in quality of life that is sometimes produced by osteonecrosis is much greater than the improvement attributed to bisphosphonates. 2

Temporally suspending treatment has been proposed for patients that are going to undergo oral surgery. These measures are of no use, as bisphosphonates accumulate in the mineralized bone matrix (and they are directly related to the total accumulated dosage and treatment duration)10 and they remain here for long time periods,10,15 gradually being reincorporated into the circulation over months and years.5 In these cases carrying out cultures in the extraction area at the time of the intervention and administering antibiotics for at least 10 days is preferable.7

Hyperbaric oxygen, unlike with osteoradionecrosis, has not shown any uniform efficiency with regard to halting the progress of the disease.2

Implants are contraindicated, although one might think that if bone resorption is inhibited, the bisphosphonates will favor osseointegration. Failures have been reported in osteoporosis patients who were taking bisphosphonates orally.2

Stark16 reported a case of repeated dental implant failure due to etidronate. As the implants have no "epithelial anchorage" there is a greater tendency towards bone exposure.



All patients that are treated with bisphosphonates (especially intravenously) should be considered as being susceptible to osteonecrosis if they are subjected to invasive dental procedures, or maxillary or mandibular bone surgery. The key lies in proper planning before starting bisphosphonate treatment, as occurs with patients that are to undergo radiotherapy of the head and neck.2 Any dental problems that the patient may have in the short term should be anticipated and dealt with promptly so that the mucosa is intact once bisphosphonate therapy is started, and no bone is exposed.

Once osteonecrosis is established, a conservative approach should be adopted, as there is a possibility of iatrogenic worsening of the symptoms. The surgical procedures should also be conservative and they should be carried out only in the more symptomatic cases.



Dr. F.J. Barrientos
Hospital Universitario Pio del Rio Hortega
c/ Torquemada s/n
47010 Valladolid, España

Recibido: 24.04.06
Aceptado: 18.12.06




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11. Damato K, Gralow J, Hoff A, Huryn J, Marx R, Ruggiero S, y cols. ADA council on scientific affairs. Expert panel recommendations for the prevention, diagnosis and treatment of osteonecrosis of the jaws: June 2004. (        [ Links ]

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