Abstract
Summary
We evaluated the impact of high dose of zoledronic acid on the superficial vascular network parameters of a membranous bone site. During a 5-day follow-up, significant reduction of the vascular density is observed only in the treated group.
Introduction
The superficial vascularization is of great importance in membranous bone-healing process. A new rat calvarium intravital model was developed to study the short-term effect of a single high dose of zoledronic acid infusion on the superficial vascularization.
Methods
Optical bone chambers were implanted in the bone tissue surface of Sprague-Dawley rats' calvarium. Nine rats were injected i.v. with 400 µg/kg of zoledronic acid (Z group), and nine rats were injected with vehicle (PSS group). A 5-day follow-up of the vascular network was made by the use of pictures analysis method.
Results
The vascular density significantly decreases only in Z group but there was no significant difference between groups at individual time points. The total length of the vascular network decreases significantly in Z group only (p = 0.003) with a significant higher decrease at D3 (p = 0.04) and D5 (p = 0.02) compared with control. The vascular density related to the smaller vessels (width, 5–10 µm) decreases significantly between T0 and D5 in Z group only (p = 0.002).
Conclusions
With the help of an original intravital animal model a significant modifications on the total length of the vascular network and the vascular density of small vessels are highlighted on a membranous bone site.
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References
Brown JE, Ellis SP, Lester JE, Gutcher S, Khanna T, Purohit OP et al (2007) Prolonged efficacy of a single dose of the bisphosphonate zoledronic acid. Clin Cancer Res 13:5406–5410
Aapro M, Abrahamsson PA, Body JJ, Coleman RE, Colomer R, Costa L et al (2008) Guidance on the use of bisphosphonates in solid tumours: recommendations of an international expert panel. Ann Oncol 19:420–432
Reid IR, Miller P, Lyles K, Fraser W, Brown JP, Saidi Y et al (2005) Comparison of a single infusion of zoledronic acid with risedronate for Paget's disease. N Engl J Med 353:898–908
Black DM, Delmas PD, Eastell R, Reid IR, Boonen S, Cauley JA et al (2007) Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 356:1809–1822
Green JR (2003) Antitumor effects of bisphosphonates. Cancer 97:840–847
Gnant M, Mlineritsch B, Schippinger W, Luschin-Ebengreuth G, Pöstlberger S, Menzel C et al (2009) Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Engl J Med 360:679–691
Daubine F, Le Gall C, Gasser J, Green J, Clezardin P (2007) Antitumor effects of clinical dosing regimens of bisphosphonates in experimental breast cancer bone metastasis. J Natl Cancer Inst 99:322–330
Stresing V, Daubine F, Benzaid I, Monkkonen H, Clezardin P (2007) Bisphosphonates in cancer therapy. Cancer Lett 257:16–35
Wood J, Bonjean K, Ruetz S, Bellahcene A, Devy L, Foidart JM et al (2002) Novel antiangiogenic effects of the bisphosphonate compound zoledronic acid. J Pharmacol Exp Ther 302:1055–1061
Wood J, Schnell C, Green JR (2000) Zoledronic acid, a potent inhibitor of bone resorption, inhibits proliferation and induces apoptosis in human endothelial cells in vitro and is antiangiogenic in a murine growth factor implant model. Proc Am Soc Clin Oncol 19:664
Streeten EA, Brandi ML (1990) Biology of bone endothelial cells. Bone Miner 10:85–94
Shenker NG, Jawad AS (2007) Bisphosphonates and osteonecrosis of the jaw. Rheumatology (Oxford) 46:1049–1051
Ruggiero SL, Drew SJ (2007) Osteonecrosis of the jaws and bisphosphonate therapy. J Dent Res 86:1013–1021
Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL (2004) Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg 62:527–534
Somerman MJ (2006) Bisphosphonates: saccrificing the jaw to save the skeleton? BoneKEy-Osteovision 3:12–18
Khosla S, Burr D, Cauley J, Dempster DW, Ebeling PR, Felsenberg D et al (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
Penel G, Delfosse C, Descamps M, Leroy G (2005) Composition of bone and apatitic biomaterials as revealed by intravital Raman microspectroscopy. Bone 36:893–901
Fournier P, Boissier S, Filleur S, Guglielmi J, Cabon F, Colombel M et al (2002) Bisphosphonates inhibit angiogenesis in vitro and testosterone-stimulated vascular regrowth in the ventral prostate in castrated rats. Cancer Res 62:6538–6544
Gasser JA, Ingold P, Venturiere A, Shen V, Green JR (2008) Long-term protective effects of zoledronic acid on cancellous and cortical bone in the ovariectomized rat. J Bone Miner Res 23:544–551
Desmons S, Heger M, Delfosse C, Falgayrac G, Sarrazin T, Delattre C et al (2009) A preliminary investigation into the effects of X-rays radiation on superficial cranial vascularization. Calcif Tissue Int 84:379–387
Thompson HJ, McGinley JN, Knott KK, Spoelstra NS, Wolfe P (2002) Vascular density profile of rat mammary carcinomas induced by 1-methyl-1-nitrosourea: implications for the investigation of angiogenesis. Carcinogenesis 23:847–854
Verbeke G, Molenberghs G (2000) Linear Mixed Models for longitudinal data. Springer Verlag, New York
Chen T, Berenson J, Vescio R, Swift R, Gilchick A, Goodin S et al (2002) Pharmacokinetics and pharmacodynamics of zoledronic acid in cancer patients with bone metastasis. J Clin Pharmacol 42:1228–1236
Santini D, Vincenzi B, Dicuonzo G, Avvisati G, Massacesi C, Battistoni F et al (2003) Zoledronic acid induces significant and long-lasting modifications of circulating angiogenic factors in cancer patients. Clin Cancer Res 9:2893–2897
Santini D, Vincenzi B, Tonini G, Scarpa S, Baldi A (2003) Zoledronic acid exhibits inhibitory effects on osteoblastic and osteolytic metastases of prostate cancer. Clin Cancer Res 9:3215; author reply 3216
Santini D, Vincenzi B, Galluzzo S, Battistoni F, Rocci L, Venditti O et al (2007) Repeated intermittent low-dose therapy with zoledronic acid induces an early, sustained, and long-lasting decrease of peripheral vascular endothelial growth factor levels in cancer patients. Clin Cancer Res 13:4482–4486
Tas F, Duranyildiz D, Oguz H, Camlica H, Yasasever V, Topuz E (2008) Effect of zoledronic acid on serum angiogenic factors in patients with one metastases. Med Oncol 25:346–349
Colleran PN, Wilkerson MK, Bloomfield SA, Suva LJ, Turner RT, Delp MD (2000) Alterations in skeletal perfusion with simulated microgravity: a possible mechanism for bone remodeling. J Appl Physiol 89:1046–1054
Laroche M (2002) Intraosseous circulation from physiology to disease. Joint Bone Spine 69:262–269
Hansen T, Kunkel M, Weber A, James Kirkpatrick C (2006) Osteonecrosis of the jaws in patients treated with bisphosphonates—histomorphologic analysis in comparison with infected osteoradionecrosis. J Oral Pathol Med 35:155–160
Hansen T, Kunkel M, Springer E, Walter C, Weber A, Siegel E et al (2007) Actinomycosis of the jaws—histopathological study of 45 patients shows significant involvement in bisphosphonate-associated osteonecrosis and infected osteoradionecrosis. Virchows Arch 451:1009–1017
Kapitola J, Zak J (1998) Effect of pamidronate on bone blood flow in oophorectomized rats. Physiol Res 47:237–240
Kapitola J, Zak J, Lacinova Z, Justova V (2000) Effect of growth hormone and pamidronate on bone blood flow, bone mineral and IGF-I levels in the rat. Physiol Res 49(Suppl 1):S101–S106
Selby PL, Davie MW, Ralston SH, Stone MD (2002) Guidelines on the management of Paget's disease of bone. Bone 31:366–373
Acknowledgments
This work was realised with a research grant from the French Society of Rheumatology. Zoledronic acid was kindly provided by Novartis Pharma AG, Basel, Switzerland.
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Julien Paccou and Marie H. Vieillard contributed equally to this work.
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Vieillard, M.H., Paccou, J., Cortet, B. et al. Effects of high dose of zoledronic acid on superficial vascular network of membranous bone sites: an intravital study on rat calvarium. Osteoporos Int 21, 1919–1925 (2010). https://doi.org/10.1007/s00198-009-1146-0
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DOI: https://doi.org/10.1007/s00198-009-1146-0