High Body Surface Area (BSA) Is An Independent Risk Factor for Developing Bisphosphonate-Induced Osteonecrosis of the Jaw (ONJ)
Authors: Ailawadhi Sikander , Elefante Angie , O’Connor Tracey L. , Wilding Gregory E. , Tan Wei , Kossoff Ellen , McCuthcheon Stephanie , Miller Kena C. , Sher Taimur , Patel Mehul , Lee Kelvin , Chanan-Khan Asher A. 
Published: April 2020

Abstract
Background: Osteolytic bone disease and associated complications of pathological fractures is a major complication in patients with multiple myeloma (MM) and metastatic breast cancer (MBC). This is due to tumor cell mediated increase in osteoclastic activity. Bisphosphonates (BP) are effective in preventing skeletal events associated with osteolytic bone destruction. Improved survival of MM and MBC patients has resulted in prolonged exposure to BP therapy, which is reported to be associated with an increased incidence of osteonecrosis of the jaw (ONJ). ONJ involves destruction and necrosis of the maxillary and/or mandibular bone, etiology of which remains unclear. As treatment is usually not helpful, prevention becomes an important strategy and in this context identification of validated risk factors for development of OJN is critical. Several investigators have reported possible risk factors (including invasive dental procedures, prolonged BP therapy and renal dysfunction) that are associated with increased likelihood of ONJ development. We asked if specific patient biometric profile renders enhanced risk of ONJ development? Thus we investigated patient demographic profiles in a large cohort of patients and correlated with development of ONJ.
Methods: Patients with MM or MBC with bone lesions treated with intravenous (iv) BP (zoledronic acid; Zometañ) between November 2002–December 2006 were identified using the RPCI database. Demographic, laboratory biochemical, BP-related and ONJ-related data was collected and compared between cases and controls.
Results: Complete data was available for 160 patients, of whom 36 (22.5%) patients had ONJ. The remaining 124 (77.5%) patients served as controls. Of all the patients, 122 (76.2%) had MBC and 38 (23.8%) had MM. Median age for all patients was 58 years (range 35–87) while the median age at diagnosis of ONJ was 59.5 years (range 40–81). The median number of cycles with BP for the control group was 15 (range 1–80) and for the ONJ group was 23.5 (range 1–80). Cumulative median BP dose in the control and ONJ groups was 58 mg (range 2–316 mg) and 94 mg (range 4–297 mg) respectively, while the median body surface area (BSA) amongst the control group was 1.66 m2 (range 0.93–2.4) and in the ONJ group was 1.81 m2 (range 1.44–2.5). Other variables studied between cases and controls included percent deviation from ideal body weight, body mass index (BMI) serum creatinine at baseline, creatinine clearance (CrCl) at baseline and at time of diagnosis of ONJ, baseline serum calcium and baseline serum alkaline phosphatase. Amongst the variables tested, BSA was the only factor that was significantly different between the two groups (p=0.004; Wilcoxon). There was no significant difference between CrCl at baseline and at ONJ diagnosis (p=0.73; Sign test). A logistic regression model showed that BSA was significantly different between the cases and controls on univariate analysis (p=0.009) as well as a multivariate analysis incorporating BSA, cumulative BP dose, age at initiation of BP, BMI and baseline creatinine clearance (p=0.028). Using a normal adult BSA of 1.71 m2 as the cut-off, the odds ratio for developing ONJ was 2.85 times (univariate) and 2.54 times (multivariate) higher in the higher than normal BSA group (BSA 3 1.71 m2) when compared with the lesser BSA group (BSA &lt;1.71 m2).
Conclusions: ONJ is a serious complication of BP therapy. Patient’s biometric profile has not been implicated as a potential risk factor in ONJ development so far. Our study, for the first time suggests that patient’s BSA may be an important and independent risk factor for BP associated ONJ. Our findings warrant further investigation in prospective studies and emphasize close monitoring of patients with high BSA who are on BP treatment with careful periodic assessment of risk-benefit for BP continuation.
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