Abstract
The symptoms of acute phase response (APR) following the first infusion of zoledronic acid (ZA) are attenuated after re-administration. We investigated the reasons for this attenuation, focusing on the changes in several hormones, bone markers and markers of inflammation occurring after the second ZA injection in patients who had experienced a severe APR after their first ZA infusion. Twenty-two postmenopausal women with osteoporosis and severe symptoms of APR following the first ZA infusion were included in the study (group A1). A year later, the same women (possibly with a residual activity of ZA) were subjected to ZA re-administration (group A2). Urine NTx (uNTx), white blood cells, parathyroid hormone, serum calcium, phosphorus and several serum markers of inflammation were measured before (0) and at 1 and 2 days following the first as well as the second infusion. In group A1, the APR was associated with a significant increase in serum C-reactive protein (CRP), high-sensitive interleukin 6 (hsIL-6), high-sensitive tumor necrosis factor alpha (hsTNF-α) and cortisol within 24 h after the infusion. The majority of the patients in group A2 did not experience an APR and serum calcium, phosphorus, CRP, hsIL-6, hsTNF-α, and cortisol remained essentially unchanged throughout the study. In group A2, on day 0, the uNTx were significantly lower than in group A1. In group A1 the uNTx decreased by 69 and 78 % from baseline on days 1 and 2, whereas in group A2, they decreased by 48 and 53 % (p < 0.01), respectively. A positive correlation was found between the degree of uNTx decline from the baseline levels (Δ-uNTx) and hsTNF-α and between Δ-uNTx and CRP. The Δ-uNTx, reflecting the osteoclast-mediated bone resorption, may play some role in the APR appearance, although it must be excluded if the relationships of the changes between uNTx and hsTNF-α/CRP are coincidental effects and not causal.
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Black DM, Delmas PD, Eastell R, Reid IR, Boonen S, Cayley JA, Cosman F, Lakatos P, Leung PC, Man Z, Mautalen C, Mesenbrink P, Hu TF, Sellmeyer D, Eriksen EF, Cummings SR (2007) HORIZON Pivotal Fracture Trial. Once-year zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 356:1809–1822
Reid IR, Gamble GD, Mesenbrink P, Lakatos P, Black DM (2010) Characterization of and risk factors for the acute-phase response after zoledronic acid. J Clin Endocrinol Metab 95:4380–4387
Thiebaud D, Sauty A, Burckhardt P, Leunberger P, Sitzler ZI, Green JR, Kandra A, Zieschang J, Ibarra de Palacios P (1997) An in vivo and in vitro study of cytokines in the acute-phase response associated with bisphosphonates. Calcif Tissue Int 61:386–392
Roelofs A, Thompston K, Gordon S, Rogers M (2006) Molecular mechanisms of action of bisphosphonates: current status. Clin Cancer Res 12:6222s–6230s
Weinstein RS, Roberston PK, Manolagas SC (2009) Giant osteoclast formation and long-term oral bisphosphonate therapy. N Engl J Med 360:53–62
Rossini M, Silvaro A, Ombreta V, Ortolani R, Vella A, Fracassi E, Gatti D (2012) Circulating γδT cells and the risk of acute-phase response after zoledronic acid administration. J Bone Miner Res 27:227–230
Hewitt RE, Lissina A, Green A, Slay ES, Price DA, Sewell AK (2005) The bisphosphonate acute phase response: rapid and copious production of proinflammatory cytokines by peripheral blood γδ T cells in response to aminobisphosphonates is inhibited by statins. Clin Exp Immunol 139:101–111
Karga H, Giagourta I, Papaioannou G, Katsichti P, Pardalakis A, Kassi G, Zagoreou A, Triantaphyllopoulou M, Zerva C (2011) Transient changes in thyroid functions tests after zoledronic acid infusion. Endocr J 58:969–977
Karga H, Papaioannou G, Polymeris A, Papamichael K, Karpouza A, Samouilidou E, Papaioannou P (2010) The effect of recombinant human TSH on bone turnover in patient after thyroidectomy. J Bone Miner Metab 28:35–41
Dicuonzo G, Vincenzi B, Santini D, Avvisari G, Rocci L, Battistoni F, Gavasci M, Borzomati D, Coppolo R, Tomini G (2003) Fever after zoledronic acid administration is due to increase in TNF-a and IL-6. J Interferon Cytokine Res 23:649–654
Berdoldo F, Pancheri S, Zenari S, Boldini S, Giovanazzi B, Zanatta M, Valenti MT, Carbonate LC, Cascio VL (2010) Serum 25-hydroxyvitamin D levels modulate the acute-phase response associated with the first nitrogen-containing bisphosphonate infusion. J Bone Miner Res 25:447–454
Penna G, Roncari A, Armuchastegui S, Daniel KC, Berti E, Colonna M, Adorini L (2005) Expression of the inhibitory receptor IL T3 on dendritic cells is dispensable for induction of CD4 + Foxp3 + regulatory T cells by 1,25-dihydroxyvitamin D3. Blood 106:3490–3497
Anastasilakis A, Polyzos S, Sakellariou G, Bisbinas I, Gkiomisi A, Delaroudis S, Gerou S, Ballaouris Z (2012) Acute phase response following intravenous zoledronate in postmenopausal women with low bone mass. Bone 50:1130–1134
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Sykiotis, A., Papaioannou, G., Mavropoulos, J. et al. Markers of inflammation after zoledronic acid redosing. J Bone Miner Metab 32, 72–77 (2014). https://doi.org/10.1007/s00774-013-0467-4
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DOI: https://doi.org/10.1007/s00774-013-0467-4