Clinical, Radiographic, and Biochemical Characterization of Multiple Myeloma Patients with Osteonecrosis of the Jaw

Abstract

Purpose: Osteonecrosis of the jaw (ONJ) has been reported in patients with a history of aminobisphosphonate use. This study was conducted in order to define ONJ clinically and radiographically and gain insights into its pathophysiology. Experimental Design: Eleven multiple myeloma (MM) patients with ONJ were included in the study. Patients underwent clinical, biochemical, radiographic, and molecular profiling. Ten MM patients on aminobisphosphonates without ONJ and five healthy volunteers were used as controls for biochemical and molecular studies. Results: MM patients with ONJ were treated with either pamidronate (n = 3), zoledronate (n = 4), or both agents sequentially (n = 4) for a mean of 38.7 months. Radiographic studies showed bone sclerosis and fragmentation on plain films and computerized tomography. Quantitative regional analysis of NaF-PET and FDG-PET scans confirmed an increased standardized uptake value (SUVmax) in areas of ONJ. The target to background ratio of SUVmax was significantly greater for NaF-PET compared with FDG-PET scan. Biochemical bone marker data and transcriptional profiling studies showed that genes and proteins involved in osteoblast and osteoclast signaling cascades were significantly down-regulated in patients with ONJ. Conclusions: ONJ was associated with a mean duration of 38.7 months of aminobisphosphonate exposure. Radiographic and functional imaging confirmed sites of clinically established ONJ. Gene and protein studies are consistent with altered bone remodeling, evidenced by suppression of both bone resorption and formation.

Bisphosphonate-associated osteonecrosis of the jaw: A key role of inflammation?

“…preceded oral bone exposure. Recently, Raje et al reported in clinically unaffected sides of the jaws of ONJ patients imaging abnormalities similar to the affected sides [17], a feature shown here in Fig. 1 (patient 3).…”

“…Our observation is in keeping with the pronounced boneseeking-isotope uptake, pointing to the persistence of an effective blood supply to the affected site. Accordingly, no differences in genes associated with angiogenesis were reported in multiple myeloma patients with NBPs related ONJ [17]. Thus, defective local circulation is unlikely to be responsible for the necrosis, contrary to previous deductions [19,30].…”

“…NBP soft tissue toxicity would thus be the trigger leading to necrosis of the mucosa and bone [13][14][15]. Genetic variations may also constitute a risk factor; it was recently shown that ONJ is associated with gene polymorphisms in multiple myeloma patients [16,17]. Moreover, the primary disease is probably a predisposing factor as frequency of ONJ is 2 fold higher in multiple myeloma than in breast cancers despite similar NBPs treatments [6].…”

Regular dental check-ups could be of benefit for patients receiving intravenous bisphosphonates. Regarding ‘risks and benefits of bisphosphonates’

“…This fact has also been emphasised by other authors, especially in regard to the Greek and US population (Raje et al, 2008). We have suggested that it could be an issue of differential susceptibility to ONJ in the Greek population , although careful pretreatment, dental assessment and avoidance of invasive dental procedures, as suggested by the author (Coleman, 2008), could partly account for this difference.…”

In�silico analysis identifies CRISP3 as a potential peripheral blood biomarker for multiple myeloma: From data modeling to validation with RT-PCR

“…Gene expression profiling is a powerful way of understanding the molecular basis of diseases, and has been applied to explore the unique gene expression patterns and distinctly expressed genes of MM from different samples including peripheral blood, bone marrow and isolated cells (9)(10)(11). A number of potential biomarkers pertaining to disease classifications and therapy responses have been identified (5).…”