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Published in: Clinical and Translational Oncology 6/2015

01-06-2015 | Research Article

Effects of zoledronate on the radiation-induced collagen breakdown: a prospective randomized clinical trial

Authors: M. Gierloff, M. Reutemann, A. Gülses, P. Niehoff, J. Wiltfang, Y. Açil

Published in: Clinical and Translational Oncology | Issue 6/2015

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Abstract

Background

A negative side effect of therapeutic irradiation is the radiation-induced bone loss which can lead, in long term, to pathological fractures. Until today, the detailed mechanism is unknown. If osteoclasts would mainly contribute to the pathological bone loss, bisphosphonates could potentially counteract the osteolytic process and possibly help to prevent long-term complications. The aim of this study was to evaluate the effect of zoledronic acid on the early radiation-induced degradation of bone collagen fibrils by monitoring the urinary excretion of hydroxylysylpyridinoline and lysylpyridinoline under radiotherapy.

Patients and methods

A total of 40 patients with skeletal metastases were assigned for a local radiotherapy and bisphosphonate treatment. The patients were prospectively randomized into two treatment groups: group A (n = 20) received the first zoledronate administration after and group B (n = 20) prior to the radiotherapy. Urine samples were collected from each patient on the first day, in the middle, and on the last day of the radiation therapy. Measurement of the bone metabolites hydroxylysylpyridinoline and lysylpyridinoline was performed by high-performance liquid chromatography. Statistical analysis was performed using the Mann–Whitney U test.

Results

The hydroxylysylpyridinoline and lysylpyridinoline excretion decreased significantly in the combined bisphosphonate and radiotherapy group (p = 0.02, p = 0.08). No significant change of the hydroxylysylpyridinoline and lysylpyridinoline excretion was determined in the patients that received solely irradiation.

Conclusion

The results indicate the ability of zoledronate to prevent the early radiation-induced bone collagen degradation suggesting that the radiation-induced bone loss is mainly caused by osteoclastic bone resorption rather than by a direct radiation-induced damage.
Literature
1.
go back to reference Freundt K, Meyners T, Bajrovic A, Basic H, Karstens JH, Adamietz IA, et al. Radiotherapy for oligometastatic disease in patients with spinal cord compression (MSCC) from relatively radioresistant tumors. Strahlenther Onkol. 2010;186:218–23.CrossRefPubMed Freundt K, Meyners T, Bajrovic A, Basic H, Karstens JH, Adamietz IA, et al. Radiotherapy for oligometastatic disease in patients with spinal cord compression (MSCC) from relatively radioresistant tumors. Strahlenther Onkol. 2010;186:218–23.CrossRefPubMed
2.
go back to reference Sauer N, Leising D, Wild B, Treiber M, Henningsen P, Jakobsen T. Pain and quality of life following palliative radiotherapy of bone metastases. Strahlenther Onkol. 2006;182:550–6.CrossRefPubMed Sauer N, Leising D, Wild B, Treiber M, Henningsen P, Jakobsen T. Pain and quality of life following palliative radiotherapy of bone metastases. Strahlenther Onkol. 2006;182:550–6.CrossRefPubMed
3.
go back to reference van Oorschot B, Schuler M, Simon A, Schleicher U, Geinitz H. Patterns of care and course of symptoms in palliative radiotherapy: a multicenter pilot study analysis. Strahlenther Onkol. 2011;187:461–6.CrossRefPubMed van Oorschot B, Schuler M, Simon A, Schleicher U, Geinitz H. Patterns of care and course of symptoms in palliative radiotherapy: a multicenter pilot study analysis. Strahlenther Onkol. 2011;187:461–6.CrossRefPubMed
4.
go back to reference Mose S, Pfitzner D, Rahn A, Nierhoff C, Schiemann M, Bottcher HD. Role of radiotherapy in the treatment of multiple myeloma. Strahlenther Onkol. 2000;176:506–12.CrossRefPubMed Mose S, Pfitzner D, Rahn A, Nierhoff C, Schiemann M, Bottcher HD. Role of radiotherapy in the treatment of multiple myeloma. Strahlenther Onkol. 2000;176:506–12.CrossRefPubMed
5.
go back to reference Ogino I, Okamato N, Ono Y, Kitamura T, Nakayama H. Pelvic insuffiency fractures in postmenopausal woman with advanced cervical cancer treated by radiotherapy. Radiother Oncol. 2003;68:61–7.CrossRefPubMed Ogino I, Okamato N, Ono Y, Kitamura T, Nakayama H. Pelvic insuffiency fractures in postmenopausal woman with advanced cervical cancer treated by radiotherapy. Radiother Oncol. 2003;68:61–7.CrossRefPubMed
6.
go back to reference Schmeler KM, Jhingran A, Iyer RB, Sun CC, Eifel PJ, Soliman PT, et al. Pelvic fractures after radiotherapy for cervical cancer: implications for survivors. Cancer. 2010;116:625–30.CrossRefPubMed Schmeler KM, Jhingran A, Iyer RB, Sun CC, Eifel PJ, Soliman PT, et al. Pelvic fractures after radiotherapy for cervical cancer: implications for survivors. Cancer. 2010;116:625–30.CrossRefPubMed
7.
go back to reference Stanic S, Bolke TP, Rule WG, Timmermann RD. Rib fracture following stereotactic body radiotherapy: a potential pitfall. Clin Nucl Med. 2011;36:168–70.CrossRef Stanic S, Bolke TP, Rule WG, Timmermann RD. Rib fracture following stereotactic body radiotherapy: a potential pitfall. Clin Nucl Med. 2011;36:168–70.CrossRef
8.
go back to reference Dudziak ME, Saadeh PB, Mehrara BJ, Steinbrech DS, Greenwald JA, Gittes GK, et al. The effects of ionizing radiation on osteoblast-like cells in vitro. Plast Reconstr Surg. 2000;106:1049–61.CrossRefPubMed Dudziak ME, Saadeh PB, Mehrara BJ, Steinbrech DS, Greenwald JA, Gittes GK, et al. The effects of ionizing radiation on osteoblast-like cells in vitro. Plast Reconstr Surg. 2000;106:1049–61.CrossRefPubMed
9.
go back to reference Ural AU, Avcu F, Baran Y. Bisphosphonate treatment and radiotherapy in metastatic breast cancer. Med Oncol. 2008;25:350–5.CrossRefPubMed Ural AU, Avcu F, Baran Y. Bisphosphonate treatment and radiotherapy in metastatic breast cancer. Med Oncol. 2008;25:350–5.CrossRefPubMed
10.
go back to reference Szymcyk KH, Shapiro IM, Adams CS. Ionizing radiation sensitizes bone cells to apoptosis. Bone. 2004;34:148–56.CrossRef Szymcyk KH, Shapiro IM, Adams CS. Ionizing radiation sensitizes bone cells to apoptosis. Bone. 2004;34:148–56.CrossRef
11.
go back to reference Willey JS, Lloyd SA, Robbins ME, Bourland JD, Smith-Sielicki H, Bowman LC, et al. Early increase in osteoclast number in mice after whole-body irradiation with 2 Gy X rays. Radiat Res. 2008;170:388–92.CrossRefPubMedCentralPubMed Willey JS, Lloyd SA, Robbins ME, Bourland JD, Smith-Sielicki H, Bowman LC, et al. Early increase in osteoclast number in mice after whole-body irradiation with 2 Gy X rays. Radiat Res. 2008;170:388–92.CrossRefPubMedCentralPubMed
12.
go back to reference Williams HJ, Davies AM. The effect of X-rays on bone: a pictorial review. Eur Radiol. 2006;16:619–33.CrossRefPubMed Williams HJ, Davies AM. The effect of X-rays on bone: a pictorial review. Eur Radiol. 2006;16:619–33.CrossRefPubMed
13.
go back to reference Jereczek-Fossa BA, Orecchia R. Radiotherapy-induced mandibular bone complications. Cancer Treat Rev. 2002;28:65–74.CrossRefPubMed Jereczek-Fossa BA, Orecchia R. Radiotherapy-induced mandibular bone complications. Cancer Treat Rev. 2002;28:65–74.CrossRefPubMed
14.
go back to reference Açil Y, Springer IN, Niehoff P, Gassling V, Warnke PH, Açmaz S, et al. Proof of direct radiogenic destruction of collagen in vitro. Strahlenther Onkol. 2007;183:374–9.CrossRefPubMed Açil Y, Springer IN, Niehoff P, Gassling V, Warnke PH, Açmaz S, et al. Proof of direct radiogenic destruction of collagen in vitro. Strahlenther Onkol. 2007;183:374–9.CrossRefPubMed
15.
go back to reference Inoue Y, Miki C, Ojima E, Nomoto J, Kusunoki M. Pelvic insufficiency factures after preoperative radiotherapy for rectal carcinoma. Int J Clin Oncol. 2003;8:336–9.CrossRefPubMed Inoue Y, Miki C, Ojima E, Nomoto J, Kusunoki M. Pelvic insufficiency factures after preoperative radiotherapy for rectal carcinoma. Int J Clin Oncol. 2003;8:336–9.CrossRefPubMed
16.
go back to reference Niehoff P, Wiltfang J, Springer IN, Weppner N, Kimmig B, Açil Y. Increased excretion of collagen crosslinks in irradiated patients indicates destruction of collagen. Int J Radiat Biol. 2006;82:503–9.CrossRefPubMed Niehoff P, Wiltfang J, Springer IN, Weppner N, Kimmig B, Açil Y. Increased excretion of collagen crosslinks in irradiated patients indicates destruction of collagen. Int J Radiat Biol. 2006;82:503–9.CrossRefPubMed
17.
go back to reference Springer ING, Terheyden H, Dunsche A, Czech N, Tiemann M, Hedderich J, et al. Collagen crosslink excretion and staging of oral cancer. Br J Cancer. 2003;88:1105–10.CrossRefPubMedCentralPubMed Springer ING, Terheyden H, Dunsche A, Czech N, Tiemann M, Hedderich J, et al. Collagen crosslink excretion and staging of oral cancer. Br J Cancer. 2003;88:1105–10.CrossRefPubMedCentralPubMed
18.
go back to reference Burr DB. The contribution of the organic matrix to bone’s material properties. Bone. 2002;31:8–11.CrossRefPubMed Burr DB. The contribution of the organic matrix to bone’s material properties. Bone. 2002;31:8–11.CrossRefPubMed
19.
go back to reference Kini U, Nandeesh BN. Physiology of boneformation, remodelling and metabolism. In: Fogelman I, Gnanasegaran G, van der Wall H, editors. Radionuclideand hybrid bone imaging, vol. XIV. 2012. p. 29–57.CrossRef Kini U, Nandeesh BN. Physiology of boneformation, remodelling and metabolism. In: Fogelman I, Gnanasegaran G, van der Wall H, editors. Radionuclideand hybrid bone imaging, vol. XIV. 2012. p. 29–57.CrossRef
20.
go back to reference Rogers MJ, Crockett JC, Coxon FP, Mönkkönen J. Biochemical and molecular mechanisms of action of bisphosphonates. Bone. 2011;49:34–41.CrossRefPubMed Rogers MJ, Crockett JC, Coxon FP, Mönkkönen J. Biochemical and molecular mechanisms of action of bisphosphonates. Bone. 2011;49:34–41.CrossRefPubMed
21.
go back to reference Coleman RE. Metastatic bone disease: clinical features, pathophysiology, and treatment strategies. Cancer Treat Rev. 2001;27:165–76.CrossRefPubMed Coleman RE. Metastatic bone disease: clinical features, pathophysiology, and treatment strategies. Cancer Treat Rev. 2001;27:165–76.CrossRefPubMed
22.
23.
go back to reference Goldhahn J, Feron JM, Kanis J, Papaloulos S, Reginster JY, Rizzoli R, et al. Implications for fracture healing of current and new osteoporosis treatments: an ESCEO consensus paper. Calcif Tissue Int. 2012;90:343–53.CrossRefPubMed Goldhahn J, Feron JM, Kanis J, Papaloulos S, Reginster JY, Rizzoli R, et al. Implications for fracture healing of current and new osteoporosis treatments: an ESCEO consensus paper. Calcif Tissue Int. 2012;90:343–53.CrossRefPubMed
24.
go back to reference Rauch F, Travers R, Plotkin H, Glorieux FH. The effects of intravenous pamidronate on the bone tissue of children and adolescent with osteogenesis imperfecta. J Clin Invest. 2002;110:1293–9.CrossRefPubMedCentralPubMed Rauch F, Travers R, Plotkin H, Glorieux FH. The effects of intravenous pamidronate on the bone tissue of children and adolescent with osteogenesis imperfecta. J Clin Invest. 2002;110:1293–9.CrossRefPubMedCentralPubMed
25.
go back to reference Hoskin PJ. Bisphosphonates and radiation therapy for palliation of metastatic bone disease. Cancer Treat Rev. 2003;29:321–7.CrossRefPubMed Hoskin PJ. Bisphosphonates and radiation therapy for palliation of metastatic bone disease. Cancer Treat Rev. 2003;29:321–7.CrossRefPubMed
26.
go back to reference Willey JS, Livingston EW, Robbings ME, Bourland JD, Tirado-Lee L, Smith-Sielicki H, et al. Risedronate prevents early radiation-induced osteoporosis in mice at multiple skeletal locations. Bone. 2010;46:101–11.CrossRefPubMedCentralPubMed Willey JS, Livingston EW, Robbings ME, Bourland JD, Tirado-Lee L, Smith-Sielicki H, et al. Risedronate prevents early radiation-induced osteoporosis in mice at multiple skeletal locations. Bone. 2010;46:101–11.CrossRefPubMedCentralPubMed
27.
go back to reference Açil Y, Gierloff M, Behrens C, Möller B, Gassling V, Niehoff P, et al. Effects of zoledronate on irradiated bone in vivo: analysis of the collagen types I, V and their crosslinks lysylpyridinoline, hydroxylysylpyridinoline and hydroxyproline. Calcif Tissue Int. 2013;92:251–60.CrossRefPubMed Açil Y, Gierloff M, Behrens C, Möller B, Gassling V, Niehoff P, et al. Effects of zoledronate on irradiated bone in vivo: analysis of the collagen types I, V and their crosslinks lysylpyridinoline, hydroxylysylpyridinoline and hydroxyproline. Calcif Tissue Int. 2013;92:251–60.CrossRefPubMed
28.
go back to reference Springer ING, Wiltfang J, Dunsche A, Lier GC, Bartsch M, Warnke PH, et al. A new method of monitoring osteomyelitis. Int J Oral Maxillofac Surg. 2007;36:527–32.CrossRefPubMed Springer ING, Wiltfang J, Dunsche A, Lier GC, Bartsch M, Warnke PH, et al. A new method of monitoring osteomyelitis. Int J Oral Maxillofac Surg. 2007;36:527–32.CrossRefPubMed
29.
go back to reference Hoskin PJ, Stratford MR, Folkes LK, Regan J, Yarnold JR. Effect of local radiotherapy for bone pain on urinary markers of osteoclast activity. Lancet. 2000;355:1428–9.CrossRefPubMed Hoskin PJ, Stratford MR, Folkes LK, Regan J, Yarnold JR. Effect of local radiotherapy for bone pain on urinary markers of osteoclast activity. Lancet. 2000;355:1428–9.CrossRefPubMed
30.
go back to reference Theriault RL, Theriault RL. Biology of bone metastases. Cancer Control. 2012;19:92–101.PubMed Theriault RL, Theriault RL. Biology of bone metastases. Cancer Control. 2012;19:92–101.PubMed
31.
go back to reference Arrington SA, Fisher ER, Willick GE, Mann KA, Allen MJ. Anabolic and antiresorptive drugs improve trabecular microarchitecture and reduce fracture risk following radiation therapy. Calcif Tissue Int. 2010;87:263–72.CrossRefPubMed Arrington SA, Fisher ER, Willick GE, Mann KA, Allen MJ. Anabolic and antiresorptive drugs improve trabecular microarchitecture and reduce fracture risk following radiation therapy. Calcif Tissue Int. 2010;87:263–72.CrossRefPubMed
32.
go back to reference Hui SK, Fairchild GR, Kidder LS, Sharma M, Bhattacharya M, Jackson S, et al. Skeletal remodeling following clinically relevant radiation-induced bone damage treated with zoledronic acid. Calcif Tissue Int. 2012;90:40–9.CrossRefPubMed Hui SK, Fairchild GR, Kidder LS, Sharma M, Bhattacharya M, Jackson S, et al. Skeletal remodeling following clinically relevant radiation-induced bone damage treated with zoledronic acid. Calcif Tissue Int. 2012;90:40–9.CrossRefPubMed
33.
go back to reference Krempien R, Huber PE, Harms W, Treiber M, Wannenmacher M, Krempien B. Combination of early bisphosphonate administration and irradiation leads to improved remineralization and restabilization of osteolytic bone metastases in an animal tumor model. Cancer. 2003;98:1318–24.CrossRefPubMed Krempien R, Huber PE, Harms W, Treiber M, Wannenmacher M, Krempien B. Combination of early bisphosphonate administration and irradiation leads to improved remineralization and restabilization of osteolytic bone metastases in an animal tumor model. Cancer. 2003;98:1318–24.CrossRefPubMed
Metadata
Title
Effects of zoledronate on the radiation-induced collagen breakdown: a prospective randomized clinical trial
Authors
M. Gierloff
M. Reutemann
A. Gülses
P. Niehoff
J. Wiltfang
Y. Açil
Publication date
01-06-2015
Publisher
Springer Milan
Published in
Clinical and Translational Oncology / Issue 6/2015
Print ISSN: 1699-048X
Electronic ISSN: 1699-3055
DOI
https://doi.org/10.1007/s12094-014-1257-8

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