This retrospective study aimed to evaluate the role of bisphosphonates in jaw osteomyelitis. 29 patients were included: 18 had been treated with bisphosphonates (12 with multiple myelomas, 3 with breast carcinomas, 2 with prostate carcinomas, and 1 with osteoporosis). Of 11 control patients, 2 had breast carcinomas, 2 had bronchial carcinomas, and 7 had no cancer. Descriptive and statistical evaluations were conducted to investigate the influence of chemotherapy, corticosteroids, stem cell transplantation, and bisphosphonates on the development and clinical picture of osteomyelitis. Both groups had similar disease histories, clinical pictures, treatment methods, and outcome. Wound dehiscence frequencies were also similar (Mann–Whitney rank sum test 1.66 ± 1.5 vs. 1.45 ± 2.0 p = 0.393). Chemotherapy, steroid therapy, stem cell transplantation, or bisphosphonate administration did not correlate with the clinical picture. Neither the duration of therapy nor the type of bisphosphonate influenced the clinical picture (negative Fisher’s tests). The bisphosphonate group showed a characteristic settlement of Actinomyces in the exposed bone (positive Fisher’s test, p = 0.021). These results suggested that osteomyelitis developed as a consequence of the simultaneous, cumulative action of many factors. Bisphosphonates played a role comparable to other predisposing features. Coating the jaws with bisphosphonates could promote the settlement of Actinomyces.
Owing to their unique ability to inhibit bone resorption, bisphosphonates (BPs) have been used for several years for treating osteoporosis, Paget’s disease, and fibrous dysplasia. Recently, they have become part of chemotherapeutic protocols for managing bone invading tumours. The beneficial effects of BPs include significant reductions in pain, pathological fractures, osteolytic lesion size, and the need for subsequent bone surgery. A growing number of studies have recognized the crucial role of BPs in provoking heavy, chronic, therapy-resistant osteonecrosis of the jaws (ONJ). BPs are thought to influence ONJ by reducing bone metabolism, reducing osteoclast recruitment, inducing osteoclast-inhibiting factor production, and impairing angiogenesis.
Jaws are particularly subject to infection, due to their contact with the external environment, their susceptibility to trauma, their rich saprophytic flora, and the presence of teeth. The jaws are protected by a high rate of oral epithelium regeneration and a substantial blood supply. Serious bony complications are seldom triggered by potentially infectious conditions, such as open fractures, neglected teeth, periodontal abscesses, ill-fitting dentures, injuries to the mucosa, and facial wounds. The development of osteomyelitis and ONJ requires conditions that alter the healthy processes of immunity, blood supply, or cellular activity, and destroy natural defences. For example, diabetes mellitus, metabolic bone disorders, anti-cancer therapy, or neoplasmatic infiltration can contribute to the development of ONJ. Diabetes mellitus is associated with microvascular ischaemia, endothelial cell dysfunction, osteocyte apoptosis, and reduced bone turnover. Anti-cancer therapy, combined with cytostatics, corticosteroids, and stem cell transplantation, leads to general immunosuppression, bone marrow degeneration, vasculitis, reduced blood flow, and osteopenia. Multiple myelomas that develop in bone marrow and cancers that metastasise to the skeletal system (breast, prostate, kidney, lung) weaken bone structure by increasing osteoclast numbers and enhancing their resorptive activity. For example, in patients with multiple myelomas, A ndersen et al. demonstrated that osteolytic lesions contained 30% of malignant, hyperactive, polynuclear osteoclasts that originated from hybrid fusions between myeloma cells and normal osteoclasts.
Until recently, BPs were considered safe drugs with only a few side effects. BPs are pyrophosphate analogues, in which the oxygen atom in the basic chain (P–O–P) is substituted with carbon (P–C–P). BPs possess a high affinity for hydroxyapatite and are resistant to hydrolysis by bone phosphatases. This contributes to extended bone deposition, over several years. The mechanism of action underlying the antiresorptive potential of a BP is determined by whether it has a nitrogen molecule in the side chain. Non-nitrogen BPs (etidronate, clodronate, tiludronate) are phagocytosed by osteoclasts and metabolised to non-hydrolysable cytotoxic ATP analogues; this handicaps the mitochondrial function of the cell and results in apoptosis. In contrast, the more potent, nitrogen-containing BPs (aledronate, pamidronate, zoledronate, risedronate) can inhibit osteoclasts by interrupting the mevalonate pathway of cholesterol synthesis.
BPs were shown to exert a protective effect on bone tissue in avascular necrosis of the long bones and chronic sclerosing osteomyelitis of the jaws. Zoledronate had a beneficial influence on new bone formation during distraction osteogenesis. Several reports describe ONJ in patients who were treated for a long time with BPs due to bone metabolic disorders such as Paget’s disease or fibrous dysplasia.
These data raised the question of whether BPs might play a role in ONJ. To address this question, the authors undertook a retrospective analysis of a group of patients who had been treated with BPs for maxillary and mandibular osteomyelitis that did not have a directly associated pathological condition.
Materials and methods
The authors retrospectively reviewed the records of patients treated for ONJ from 1 January 2003 to 31 December 2006. The records included anamnesis, local status at admission and during treatment, surgery reports, and accessible panoramic X-rays. The authors evaluated bone infections of uncertain aetiology with delayed wound healing, bone sequestration, abscess formation, and recurrent wound dehiscence; clear cases of osteoradionecrosis or open fractures were excluded.
The 29 patients included in this study had a mean age of 62 ± 13 years and a male to female ratio of 14:15. The patients were divided into two groups. The first consisted of 18 patients that had received BPs, including 12 with multiple myeloma, 3 with breast carcinoma, 2 with prostate carcinoma, and 1 with osteoporosis. The second group (controls) consisted of 11 patients with no history of bisphosphonate administration, but with similar anamnesis and clinical symptoms, including 2 with breast carcinoma, 2 with bronchial carcinoma, and 7 without cancer. The presence of tumour metastases in the affected areas was ruled out by bone biopsy.
A descriptive method was used for comparisons between groups of the location of the infection, clinical picture, treatment method, pattern of wound healing, and co-morbidity. A Mann–Whitney rank sum test was used to evaluate differences in the mean number of wound dehiscences between study groups. Fisher’s exact test was used to evaluate the relationship between the following independent categorical variables: chemotherapy, corticosteroids, stem cell transplantation, BP administration, time of BP administration, type of drug (pamidronate vs. zoledronate), number of wound dehiscences, and Actinomyces colonisation.
Statistical significance was defined as p < 0.05.
The clinical characteristics of the patients treated with BPs and controls are given in Tables 1 and 2 , respectively. Surgical procedures usually preceded the onset of symptoms. These affected 12/18 (67%) of the patients treated with BPs and 9/11 (73%) of the control subjects, and included, respectively, teeth extractions (8/18; 6/11), cystectomies (2/18; 1/11), implant insertions (2/18; 1/11), or dentoalveolar trauma (0/18; 1/11) The most common clinical findings were swelling and pain that accompanied a mucosa injury and an area of exposed and devitalised bone. Areas of bone necrosis were situated predominantly in the postero-lateral part of the mandible (BP-treated: 13/18 and controls: 10/11; not significantly different). In all patients, a bone biopsy ruled out malignancy at the site of infection. In two patients with multiple myelomas showing an extremely high wound dehiscence rate, malignant plasmatic cells were found 1 year after primary surgery. Surgical treatment was provided to 25/29 patients (16/18; 9/11). The method of treatment was independent of receiving BP administration.
|Sex||Age a||Diagnosis||Cytostatics||Steroids||Stem cell transpl.||Bisphosphonate||Time of b administr.||Location of osteomyelitis||Therapy||Recurrences c||Actionomycosis|
|1||♀||65||BC d||–||+||−||−||Zometa e||35||Maxilla left||Bone shaving||2||−|
|2||♀||64||BC||–||+||−||−||Zometa||12||Mandible corps left||Bone shaving||1||+|
|3||♀||78||BC||–||+||+||−||Pamidronate f||34||Mandible corps left||Bone shaving||3||+|
|4||♀||70||–||Bronchial asthma, Anaemia||−||+||−||Fosamax g||60||Mandible corps bil.||Decortication||2||+|
|5||♂||70||PC h||Liver metastases||+||−||−||Zometa||12||Mandible corps right||Incision||1||−|
|6||♂||67||PC||–||+||−||−||Zometa||24||Mandible corps right||Teeth extr.||0||−|
|7||♂||69||MM i||Venous insufficiency||+||+||+||Zometa||23||Maxilla bilateral||Bone shaving||2||+|
|8||♂||71||MM||–||−||+||−||Zometa||33||Mandible corps left||Bone shaving||2||Candida|
|9||♀||58||MM||Atopic asthma, Diabetes||+||+||+||Pamidronate||16||Mandible corps left||Bone shaving||2||−|
|10||♀||75||MM||Hypertension||+||+||−||Pamidronate||26||Mandible corps bil.||Bone shaving||1||+|
|11||♂||65||MM||Anaemia, generalised Herpes||+||+||+||Pamidronate||18||Maxilla right||Bone shaving||0||+|
|12||♀||78||MM||Diabetes, Hypertension||+||+||+||Pamidronate||15||Maxilla right||Bone shaving||4||+|
|13||♀||63||MM||Renal insufficiency, Coxarthrosis bil.||+||+||+||Pamidronate||84||Mandible bil.||Bone shaving||6||+|
|14||♀||58||MM||–||+||+||−||Zometa||48||Mandible corps left||Incision||0||+|
|15||♂||46||MM||–||+||+||+||Zometa||46||Mandible corps right||Bone shaving||1||−|
|16||♀||75||MM||Renal insufficiency||+||+||+||Pamidronate||58||Mandible corps bil||Bone shaving||1||−|
|17||♂||53||MM||–||+||+||+||Pamidronate||48||Mandible corps left, maxilla||Decortication||2||+|
|18||♀||77||MM||–||+||+||−||Zometa||36||Maxilla right, mandible front||Bone shaving||0||+|
|67 ± 8.9 j||34.9 ± 19.5||1.66 ± 1.5|
|Nr||Sex||Age a||Diagnosis||Cytostatics||Steroids||Location of osteomyelitis||Therapy||Recurrences b||Actionomycosis|
|1||♀||66||BC c||Pleurocarcinosis||+||−||Mandible bilateral||Decortication||0||+|
|2||♀||48||BC||–||+||+||Mandible corps front||Bone shaving||1||−|
|3||♂||66||BrC d||–||+||−||Mandible corps front||Decortication||1||−|
|4||♂||56||BrC||–||+||−||Mandible corps right||Decortication||0||−|
|5||♂||56||–||–||−||−||Mandible corps right||Bone shaving||1||−|
|6||♀||66||–||Coronary insufficiency||−||−||Mandible corps left||Decortication||7||−|
|7||♂||54||–||Heart infarct, Artificial heart valve||−||−||Mandible corps right||Decortication||1||−|
|9||♀||61||–||–||−||−||Mandible corps left||Bone shaving||3||−|
|10||♂||48||–||–||−||−||Mandible corps right||Antibiotics||0||−|
|11||♂||45||–||Alkoholism, Cachexia||−||−||Mandible corps right||Incision||0||+|
|62 ± 13 e||1.45 ± 2.0|