Abstract
Purpose
Bisphosphonate-associated osteonecrosis (BON) is a recently recognized oral complication of bisphosphonate (BP) therapy. Currently, research into the pathogenesis of BON has been hampered by being deficient in studies capable of measuring the level of BP in saliva or at the bone–soft tissue interface. The objective of this current study was to develop a novel bioassay model representative of the oral levels of BPs in patients presenting with or at risk for BON.
Methods
Zoledronic acid (ZA) injectable was used to develop standardized MTS cell proliferation assay curves at concentrations of 0–10 μM, which were used either in a dilution in normal media, mimicking BP freed from bone or used to “spike” saliva individuals not taking BPs and mimicking BP levels being excreted. This bioassay was then used to estimate BP levels from samples of saliva and bone ex vivo from patients with and without BON.
Results
Saliva and bone from patients with existing BON showed levels of BP ranging from 0.4 to 4.6 μM, while patients receiving IV infusion of BP and naïve to BON showed levels in saliva ranging from 0.4 to 5 μM. All control specimens and patients naïve to BP showed levels at 0 μM.
Conclusions
Given the fact that BPs are poor candidates for detection using standard methods (HPLC), this bioassay provides us with the ability to estimate clinically relevant concentrations of BP capable of producing apoptosis and the inhibition cell proliferation of oral mucosal cells based on previous studies. Subsequently, apoptosis and the inhibition of proliferation could lead to BON, secondary to the exposure of the bone in the unique microenvironment of the oral cavity.
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References
Badros A, Terpos E, Katodritou E, Goloubeva O, Kastritis E, Verrou E, Zervas K, Baer MR, Meiller T, Dimopoulos MA (2008) Natural history of osteonecrosis of the jaw in patients with multiple myeloma. J Clin Oncol 26:5904–5909
Badros A, Weikel D, Salama A, Goloubeva O, Schneider A, Rapoport A, Fenton R, Gahres N, Sausville E, Ord R, Meiller T (2006) Osteonecrosis of the jaw in multiple myeloma patients: clinical features and risk factors. J Clin Oncol 24:945–952
Bagan JV, Jimenez Y, Murillo J, Hernandez S, Poveda R, Sanchis JM, Diaz JM, Scully C (2006) Jaw osteonecrosis associated with bisphosphonates: multiple exposed areas and its relationship to teeth extractions. Study of 20 cases. Oral Oncol 42:327–329
Bamias A, Kastritis E, Bamia C, Moulopoulos LA, Melakopoulos I, Bozas G, Koutsoukou V, Gika D, Anagnostopoulos A, Papadimitriou C, Terpos E, Dimopoulos MA (2005) Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: incidence and risk factors. J Clin Oncol 23:8580–8587
Bilezikian JP (2006) Osteonecrosis of the jaw—do bisphosphonates pose a risk? N Engl J Med 355:2278–2281
Cremers SC, Pillai G, Papapoulos SE (2005) Pharmacokinetics/pharmacodynamics of bisphosphonates: use for optimisation of intermittent therapy for osteoporosis. Clin Pharmacokinet 44:551–570
Dannemann C, Zwahlen R, Gratz KW (2006) Clinical experiences with bisphopsphonate induced osteochemonecrosis of the jaws. Swiss Med Wkly 136:504–509
Kanis JA (1995) Bone and cancer: pathophysiology and treatment of metastases. Bone 17:101S–105S
Khosla S, Burr D, Cauley J, Dempster DW, Ebeling PR, Felsenberg D, Gagel RF, Gilsanz V, Guise T, Koka S, McCauley LK, McGowan J, McKee MD, Mohla S, Pendrys DG, Raisz LG, Ruggiero SL, Shafer DM, Shum L, Silverman SL, Van Poznak CH, Watts N, Woo SB, Shane E (2007) Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 22:1479–1491
Klein KO, Baron J, Barnes KM, Pescovitz OH, Cutler GB Jr (1998) Use of an ultrasensitive recombinant cell bioassay to determine estrogen levels in girls with precocious puberty treated with a luteinizing hormone-releasing hormone agonist. J Clin Endocrinol Metab 83:2387–2389
Mavrokokki T, Cheng A, Stein B, Goss A (2007) Nature and frequency of bisphosphonate-associated osteonecrosis of the jaws in Australia. J Oral Maxillofac Surg 65:415–423
Noedl H, Teja-Isavadharm P, Miller RS (2004) Nonisotopic, semiautomated Plasmodium falciparum bioassay for measurement of antimalarial drug levels in serum or plasma. Antimicrob Agents Chemother 48:4485–4487
Rogers MJ, Watts DJ, Russell RG (1997) Overview of bisphosphonates. Cancer 80:1652–1660
Scheper MA, Badros A, Chaisuparat R, Cullen KJ, Meiller TF (2009) Effect of zoledronic acid on oral fibroblasts and epithelial cells: a potential mechanism of bisphosphonate-associated osteonecrosis. Br J Haematol 144:667–676
Skerjanec A, Berenson J, Hsu C, Major P, Miller WH Jr, Ravera C, Schran H, Seaman J, Waldmeier F (2003) The pharmacokinetics and pharmacodynamics of zoledronic acid in cancer patients with varying degrees of renal function. J Clin Pharmacol 43:154–162
Witvrouw M, Baba M, Balzarini J, Pauwels R, De Clercq E (1990) Establishment of a bioassay to determine serum levels of dextran sulfate and pentosan polysulfate, two potent inhibitors of human immunodeficiency virus. J Acquir Immune Defic Syndr 3:343–347
Woo SB, Hellstein JW, Kalmar JR (2006) Narrative [corrected] review: bisphosphonates and osteonecrosis of the jaws. Ann Intern Med 144:753–761
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Grant: supported by K12 RR023250.
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Scheper, M.A., Badros, A., Salama, A.R. et al. A novel bioassay model to determine clinically significant bisphosphonate levels. Support Care Cancer 17, 1553–1557 (2009). https://doi.org/10.1007/s00520-009-0710-7
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DOI: https://doi.org/10.1007/s00520-009-0710-7