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Myeloma patients: genes increase risk for osteonecrosis of the jaw

Anti-resorptive medications such as bisphosphonates are widely used agents in the setting of both malignant and nonmalignant pathology of bone turnover. From an oncological perspective, anti-resorptive agents are integral in the management of both osteolytic and osteoblastic bony involvement. Malignant cells in many solid tumors release various factors such as plateletderived growth factor and fibroblast growth factor that stimulate osteoblasts proliferation and bony generation. Alternatively, malignant plasma cells in multiple myeloma release factors such as interleukins and transforming growth factor beta that stimulate osteoclasts indirectly via the upregulation RANK ligand on osteoblasts. Osteoclastic stimulation ultimately leads to bone resorption and hypercalcemia [1]. Bisphosphonates inhibit maturation of osteoclastic precursors and therein leads to apoptosis of osteoclasts [1,2]. Bisphosphonates, such as zoledronic acid, are essential in the management of myeloma-related bony complications such as hypercalcemia and pathologic fractures [2]. Although these agents are generally considered safe, one of the feared complications includes bisphosphonate-related osteonecrosis of the jaw (BRONJ) [2,3]. The precise pathologic mechanism for the development of this complication remains largely unknown, but development has been linked to intravenous route of administration, the length of treatment duration, and periodontal and odontogenic diseases [3,4]. Additional risk factors include poorlyfitting dentures, diabetes mellitus and chronic corticosteroid use [3–5]. Given the complexity in the pathogenesis, both environmental and genetic factors likely contribute to the development of BRONJ [5]. Several genetic polymorphisms have been linked to increased risk of osteonecrosis of the jaw. These include polymorphisms in cytochrome P4502C8 (CYP2C8 rs1934951), which plays a role in vasculature homeostasis and peroxisome proliferator-activated receptor gamma (PPARG rs1152003), which is important in angiogenesis and bone turnover [5–7]. In this edition of Leukemia and Lymphoma, Kastritis et al. reports on the correlation between high-risk single nucleotide polymorphisms (SNPs) and the development of BRONJ [8] in 140 patients with symptomatic myeloma treated with zoledronic acid who had available DNA for testing. Overall, about 25% of the patients in this cohort developed BRONJ after a median follow-up of five years. According to study results, about a third of the patients (35%) were heterozygous and 25% were homozygous for PPARG rs1152003. An additional 25% of patients were heterozygous and one patient homozygous for CYP2C8 rs 1934951. In this study, patients with high-risk SNPs in both PPARG and CYP2C8 genes had a 70% cumulative incidence of BRONJ after 24 infusions of zoledronic acid compared to only 17% for patients with SNPs in one of the genes and 0% in patients who had no high-risk SNPs. Other factors that contributed to BRONJ were history of prior dental extraction, poor oral hygiene and higher cumulative doses of zoledronic acid among others. It is important to note that the contribution of genetic factors was an independent predictor of development of BRONJ. In this rather large prospective study of the use of zoledronic acid and relationship to genetic factors in multiple myeloma, the authors validate previous studies suggesting that a link exists between certain genetic polymorphisms and risk of development of BRONJ. Indeed, the risk of developing BRONJ amongst