Analysis of Frequency and Risk Factors for Developing Bisphosphonate Associated Osteonecrosis of the Jaw.

Abstract

Although the evidence available associating bisphosphonates (BP) with osteonecrosis of the jaw (ONJ) is far from conclusive, the growing literature reports strongly suggest a strict relationship between them. The real frequency of this complication is unknown because of the recent observation of this condition, the bias related to retrospective studies and the wide-spread use of this supportive therapy. Aims of this research were to look for additional risk factors for developing ONJ and to determine the frequency of this event in the subgroup of patients affected by Multiple Myeloma (MM) treated with BP. We asked 49 GISL centers to participate in a retrospective multicenter study filling out a form containing several queries, including sex and age, anamnesis for smoke habit, anemia and thrombotic events, type and time of neoplasia diagnosis, treatment and neoplasia status, odonthoiatric anamnesis, type and duration of therapy with BP, microbial isolation in site of lesion, specific treatment for osteonecrosis, number of patients (pts) affected by MM treated with BP from 2002 to 2005. Fifteen centers decided to participate in the study and 12 had cases of osteonecrosis. ONJ was reported in 19 pts. Sixty % were females and the median age was 65 ys. Sixteen had MM, 1 breast cancer, 1 prostatic cancer, 1 osteoporosis steroid related. Median time from diagnosis of cancer was 54 months and median duration of treatment with BP was 34 months. Thirteen events manifested between 20 and 60 months. Of the 19 pts, 8 had received zolendronate, 2 pamidronate and 9 both drugs. None had radiotherapy on head and neck, while two received total body irradiation. In these two cases, ONJ was associated with necrosis of the pelvis. The 2 solid tumors were treated with ormonal therapy. All MM pts had received one or more line of treatment including, VAD, MP, steroids and thalidomide alone or in combination, as well as high dose melphalan, as part of autologous bone marrow transplant. ONJ involved the mandible in 14 pts, the maxilla in 3 and both in 2. Symptoms included local pain and discomfort. In 17 cases CT scan was the strumental procedure used to identifiy the lesion. In 14 pts biopsy was performed excluding localization of neoplasia in 11 cases. Microbiological evaluation of the lesion was positive in 11 pts, with 6 cases of Actynomices. In 12 patients ONJ was apparently spontaneous; in 7 occurred after dental procedures. Parodonthopaties were present in 10 pts. In 11 cases ONJ was complicated by fistula, exposed bone or abscess. BP were stopped in 17 pts. Antibiothic therapy was administered in 17 cases; 7 pts underwent hyperbaric oxygen therapy and 8 surgical debridement. Several pts improved but none were cured. Considering only the MM subgroup 16 cases of ONJ were identified among 888 pts treated with BP between 2002 and 2005, with a frequency of 1.8%. Utilizing the data collected by our retrospective study a fine statistical analysis is not applicable. However, in MM pts the frequency of steroid treatment, parodonthopaties and anemia was particularly high, respectively 100%, 56%, and 56%, supporting the idea that these are additional risk factors for developing ONJ.

Bisphosphonate-Associated Osteonecrosis of the Jaw: Report of a Task Force of the American Society for Bone and Mineral Research

“…Mand (2) Max (1) Carter et al (48) 3 P (3) A (1), P (2) Max (3) Pozzi et al (49) the FDA for use in patients with cancer involving bone are pamidronate and zoledronic acid. Clodronate and ibandronate have been licensed for use in malignant bone disease in other countries.…”

Osteonecrosis of the jaw complicating bisphosphonate treatment for bone disease in multiple myeloma: an overview with recommendations for prevention and treatment

“…of 4000 patients at the MD Anderson Cancer Centre 36 to 15% in the report by Dimopoulos et al. 37 with many other retrospective reviews quoting figures within this range 31,38–43 . Complicating analysis of these studies are variations of definition and methods, population denominators and length of follow up as the incidence is time dependent.…”

“…Estimates range from 1.2% in a review by Hoff et al of 4000 patients at the MD Anderson Cancer Centre 36 to 15% in the report by Dimopoulos et al 37 with many other retrospective reviews quoting figures within this range. 31,[38][39][40][41][42][43] Complicating analysis of these studies are variations of definition and methods, population denominators and length of follow up as the incidence is time dependent. Although the published work is dominated by descriptions of patients with myeloma, substantial numbers of cases of ONJ have been reported in patients with breast and prostate cancer.…”

American Association of Oral and Maxillofacial Surgeons Position Paper on Bisphosphonate‐Related Osteonecrosis of the Jaw – 2009 Update

“…IV bisphosphonate exposure in the setting of managing malignancy remains the major risk factor for BRONJ. Based on case series, case‐controlled and cohort studies, estimates of the cumulative incidence of BRONJ range from 0.8% to 12% (37–45).…”