INFLUENCE OF ANTITUMOR CHEMOTHERAPEUTICS ON THE STRUCTURE AND PHOSPHORUS-CALCIUM METABOLISM OF INJURED LONG TUBULAR SKELETAL BONES

Keywords: reparative regeneration, scanning microscopy, spectral analysis, phosphorus-calcium metabolism, mineralization, anticancer chemotherapy

Abstract

The high frequency of fractures in cancer patients is due to a decrease in bone strength which is associated with bone metabolism disorders such as osteoporosis, metastatic bone disease, and pathological fractures. Anticancer chemotherapy is prescribed for long-term periods and affects bone metabolism, in particular mineralization of bony tissue.

Objective. To study the structure and macronutrient composition of long tubular bones in rats under the influence of antitumor chemotherapeutics.

Materials and methods. The study involved 96 white laboratory 7 month-old male rats weighing 230 ± 10 g that were cut by a ball-shaped dental burr to obtain a 2 mm diameter perforation defect to the medullary cavity in the middle third of the femoral shaft. The animals were divided into the control (n = 24) and three experimental groups (Group I, II, and III, n = 72), which were given intraperitoneal antitumor chemotherapeutics after the cut procedure: Group I (n = 24) – doxorubicin (60 mg/m²), Group II (n = 24) – 5-fluorouracil (600 mg/m²), Group III (n = 24) – methotrexate (40 mg/m²). The therapy was repeated every 21 days throughout the experiment. On the 15th, 30th, 45th, and 60th day after the injury, the animals were sacrificed with subsequent removal of the injured long tubular bones. The samples were studied using scanning electron microscopy and X-ray energy dispersive spectroscopy. Statistical analysis of the obtained digital values was performed with the help of MX Excel XP statistical computer program using the Student's t‑test. The difference was considered significant at p ˂ 0.05.

Results. Antitumor chemotherapy slows down the formation of bone regenerate in the area of the defect and causes disorders of phosphorus-calcium metabolism in the injured bone. This is manifested by a decrease in the intensity of newly formed organic matrix mineralization in the area of the defect and a decrease in the level of calcium and phosphorus in the native bone and on its border with the regenerate. Doxorubicin and methotrexate provide the most negative impact on mineralization process among antitumor chemotherapeutic agents.

Conclusions. The use of antitumor chemotherapeutic agents – doxorubicin, 5-fluorouracil and methotrexate – slows down the processes of reparative regeneration at all stages of recovery after injury and reduces the phosphorus-calcium metabolism of injured long tubular bones.

Author Biography

Tetiana V. Riabenko, Department of Morphology, Medical Institute, Sumy State University, Sumy, Ukraine

Assistant at the Department of Morphology, Sumy State University, 31 Sanatorna str, Sumy, Ukraine, 40000;

e-mail: t.riabenko@med.sumdu.edu.ua

phone: +38066 9362214

ORCID: https://orcid.org/0000-0003-2740-389X

References

1. Freeman AK, Sumathi VP, Jays L. Metastatic tumors of bone. Surgery (Oxford). 2018;36 (1):35–40. doi: 10.1016 /j.mpsur.2017.10.002
2. Shop AB, Kolb AD, Mukhopadhyay D, Bussard KM. Cancer Metastases with to Bone: Concepts, Mechanisms and Interactions with Bone Osteoblasts. Cancers. 2018;10(6):182. doi: 10.3390/cancers10060182
3. An J, Leeuwenburgh S, Wolke J, Jansen J. Mineralization processes in hard tissue. Bio mineralization and Biomaterials. 2016:129–146. doi: 10.1016/b978-1-78242-338-6.00005-3
4. Murshed M. Mechanism of Bone Mineralization. Cold Spring Harbor Perspectives in Medicine. 2018; 8(12):a031229. doi: 10.1101/cshperspect.a031229.
5. Hasegawa T. Ultrastructure and biological function of matrix vesicles in bone mineralization. Histochem Cell Biol. 2018; 149:289–304. doi: 10.1007/s00418-018-1646-0
6. Reznikov N, Hoac B, Buss DJ, Addison WN, Barros NMT, McKee MD. Biological stenciling of mineralization in the skeleton: Local enzymatic removal of inhibitors in the extracellular matrix. Bone. 2020; 138:115447. doi: 10.1016/j.bone.2020.115447
7. Upadhyay RK. Role of calcium bio-minerals in regenerative medicine and tissue engineering. J Stem Cell Res Ther. 2017; 2(6):166-175. doi: 10.15406/jsrt.2017.02.00081
8. Erben RG. Physiological Actions of Fibroblast Growth Factor-23. Frontiers in Endocrinology. 2018; 9. doi: 10.3389/fendo.2018.00267
9. Ciosek Ż, Kot K, Kosik-Bogacka D, Łanocha-Arendarczyk N, Rotter I. The Effects of Calcium, Magnesium, Phosphorus, Fluoride and Le ad on Bone Tissue. Biomolecules. 2021; 11(4):506. doi: 10.3390/biom11040506
10. Pylypchuk IS, Pylypchuk II. [Osteoporosis and women's quality of life in the XXI century]. Publishing House "Baltija Publishing. 2021:253-275. doi: 10.30525/978-9934-26-024-7-13
11. Stewart S, Bryant SJ, Ahn J, Hankenson KD. Bone Regeneration. Translational Regenerative Medicine. 2015:313–333. doi: 10.1016/b978-0-12-410396-2.00024-4
12. Shah FA, Ruscsák K, Palmquist A. 50 years of scanning electron microscopy of bone — a comprehensive overview of the important discoveries made and insights gained into bone material properties in health, disease and taphonomy. Bone Res. 2019; 7(1):1-15. doi: 10.1038/s41413-019-0053-z
13. Nisha Y, Dubashi B, Bobby Z, Sahoo JP, Kayal S. Effect of cytotoxic chemotherapy on bone health among breast cancer patients. Does it require intervention? Support Care Cancer. 2021:1-16. doi: 10.1007/s00520-021-06231-8
14. Fan J, Su YW, Hassanshahi M, Fan CM, Peymanfar Y, Piergentili A, Xian CJ. β ‐Catenin signaling is important for osteogenesis and hematopoiesis recovery following methotrexate chemotherapy in rats. Journal of Cellular Physiology. 2021;236(5):3740-3751. doi: 10.1002/jcp.30114
15. Georgiou KR, King TJ, Scherer MA, Zhou H, Foster BK, Xian CJ. Attenuated Wnt/β-catenin signaling mediates methotrexate chemotherapy-induced bone loss and marrow adiposity in rats. Bone. 2012; 50(6):1223–1233. doi: 10.1016/ j.bone.2012.03.027
16. King TJ, Georgiou KR, Cool JC, Scherer MA, Ang ES, Foster BK, Xian CJ. Methotrexate chemotherapy promotes osteoclast formation in the long bone of rats via increased pro-inflammatory cytokines and enhanced NF-κB activation. The American journal of pathology. 2012; 181(1):121-129. doi: 10.1016/j.ajpath.2012.03.037
17. Fan C, Georgiou KR, Morris HA, McKinnon RA, Keefe DMK, Howe PR, Xian CJ. Combination breast cancer chemotherapy with doxorubicin and cyclophosphamide damages bone and bone marrow in a female rat model. Breast cancer rese arch and treatment. 2017; 165(1):41–51. doi: 10.1007/s10549-017-4308-3
18. Xian CJ, Cool JC, Pyragius T, Foster BK. Damage and recovery of the bone growth mechanism in young rats following 5-fluorouracil acute chemotherapy. Journal of Cellular Biochemistry. 2006; 99(6):1688–1704. doi: 10.1002/jcb.20889
19. Raghu Nadhanan R, Abimosleh SM, Su Y-W, Scherer MA, Howarth GS, Xian CJ. Dietary emu oil supplementation suppresses 5-fluorouracil chemotherapy-induced inflammation, osteoclast formation, and bone loss. American Journal of Physiology-Endocrinology and Metabolism. 2012; 302(11):E1440 – E1449. doi: 10.1152/ajpendo.00587.2011
20. Vyas D, Laput G, Vyas A. Chemotherapy-enhanced inflammation may lead to the failure of therapy and Meta stasis. OncoTargets and Therapy. 2014; 7:1015. doi: 10.2147/ott.s60114
21. Wigner NA, Luderer HF, Cox MK, Sooy K, Gerstenfeld LC, Demay MB. Acute Phosphate Restriction Leads to Impaired Fracture Healing and Resistance to BMP2. Journal of Bone and Mineral Research. 2010; 25(4):724-733. doi: 10.1359/jbmr.091021
Published
2021-09-29
How to Cite
Tetiana V. Riabenko. (2021). INFLUENCE OF ANTITUMOR CHEMOTHERAPEUTICS ON THE STRUCTURE AND PHOSPHORUS-CALCIUM METABOLISM OF INJURED LONG TUBULAR SKELETAL BONES. Eastern Ukrainian Medical Journal, 9(3), 295-307. https://doi.org/10.21272/eumj.2021;9(3):295-307