Zmiany w tkance kostnej w chorobach nowotworowych (przegląd literatury i analiza własnych danych)

Oleh V. Syniachenko1, Yurii V. Dumanckyi1, Yelyzaveta D. Yehudina2, Tetiana B. Bevzenko3, Tetiana I. Yarmola4

1DONETSK NATIONAL MEDICAL UNIVERSITY, LYMAN, UKRAINE

2 SE “DNEPROPETROVSK MEDICAL ACADEMY”, DNIPRO, UKRAINE

3SHUPYK NATIONAL ACADEMY OF POSTGRADUATE EDUCATION, KYIV, UKRAINE

4HIGHER STATE EDUCATIONAL ESTABLISHMENT OF UKRAINE, UKRAINIAN MEDICAL STOMATOLOGICAL ACADEMY, POLTAVA, UKRAINE

 

ABSTRACT

A review of the current literature and our own researches data are presented. Malignant tumors all over the world cause a huge medical social and economic damage, being one of the main causes of people death in all countries. Involving bones in the pathological process occurs in every other patient with cancer. Osteoporosis in patients with malignant tumors is often formed due to disorders of the reproductive and calcium-regulating hormones, we demonstrated the existence of close connection between malignant tumors and bone metabolism disorders. The latter manifests by increase in the synthesis of osteocalcin and osteopontin, the activation of alkaline phosphatase, imbalance of osteo-associated macro elements (calcium, magnesium, phosphorus) and microelements (cobalt, manganese, copper, strontium, chromium, zinc, and others), involving in the pathogenetic constructions of cancer and osteoporosis. We established our data, on the study of osteopontin and other markers of bone metabolism in patients with lung cancer. We found that lung cancer occurs with severe disturbances of bone metabolism, Changes in bone metabolism are aggravated by ongoing chemotherapy and radiation therapy of cancer. These data necessitate the development of anticancer therapy medical technology, which has protective effect toward bone metabolism, and creating of antiosteoporotic treatment, simultaneously directed to the tumor process.

 

Wiad Lek 2018, 71, 6, -1266

 

INTRODUCTION

Malignant tumors all over the world cause a huge medical social and economic damage, being one of the main causes of people death in all countries [1, 2]. There is an increase in the cancer patient number not only in cities, but also in rural regions, which was not observed earlier. According to prognosis, patient deaths from cancer will be recorded up to 11-12 million per year by 2030 [3].

Involving bones in the pathological process occurs in every other patient with cancer, it happened in the form of osteoporosis and metastases [4]. The underlying mechanisms of the bone tissue lesion in different localization cancer are very complex and arise from interactions of the tumor and bone. Osteoporosis in patients with malignant tumors is often formed due to disorders of the reproductive and calcium-regulating hormones, more often in cases of the prostate, uterus, ovaries and breast cancer [5]. In lung cancer there are changes in bone mineral density, and the prevalence of osteoporotic vertebral fractures according to clinical sectional studies is 30-40% of the such patients number [6].

Tumors can be accompanied by the disorders of calcium metabolism with osteocalcin hyperproduction [7]. It should be noted that in patients with cancer, hypocalcemia is considered to be a predictor of bone metastases [8]. Magnesium low blood level in case of tumors can increase calcium absorption, and a high level of phosphorus activates this process. Normally, phosphorus absorption is inhibited by alkaline phosphatase, and magnesium being a natural calcium antagonist plays a significant role in the metabolism of bone tissue. Excess magnesium entails the stimulation of osteoclasts and the lesion of the structural and functional bone state, which may manifest with hypercalcemia, a decrease in the osteoclast number, and the revealed hypocalcemia is accompanied by the development of osteodeficit in the form of osteopenia / osteoporosis. W. Wulaningsih et al. [9] revealed that a high level of phosphatemia is considered to be a risk factor for lung cancer.

REVIEW AND DISCUSSION

In oncological patients there is an imbalance in the parameters of osteo-associated microelements (iron, cobalt, manganese, copper, chromium, zinc) in blood [10, 11]. In turn, the nature of the cancer course largely depends on the body level of these substances [12]. It should be noted that the oncoprotein micronutrients include copper [13] and zinc [14, 15], and cancer-inducing – cobalt and chromium [16, 17]. In mice experiment, it was shown that toxic concentrations of manganese significantly reduce deoxyribonucleic acid synthesis in cells, and zinc is antagonist in this process, having a cofactor role in the catalytic mechanisms of this acid polymerization [18].

C. Ostheimer et al. [19] attach special importance to osteopontin (sialoprotein) – a glycoprotein rich in aspartic and glutamic acids, a pro-inflammatory cytokine belonging to the class of matrix-cellular proteins that participates in the processes of bone tissue reconstruction [20] and determines the development of osteoporosis in patients with lung cancer [21]. Osteopontin, as one of the main products of the active osteoblast synthetic function, involved in the binding of osteoclasts on the bone surface, stimulating the interleukin-17 synthesis, which has prognostic significance with respect to the tumor stage and metastasis rate [22]. N.B.Bauer et al. [23] proved that in the first stages of osteoporosis formation the osteocalcin blood content increases in an experiment on rats with a tumor model, whereas later stages of the pathological process in the bone are accompanied by an increase in the osteopontin concentration. It should be emphasized that lung cancer naturally proceeds with an elevated level of osteopontin in blood [24].

According to C.G. Kang et al. [25] and Y. Li et al. [26], the glycoprotein blood content is directly associated with the metastases presence in such patients. However, as suggested by X. L. Zou et al. [27], the role of osteopontin in the development of non-small cell lung cancer and osteoporosis remains controversial.

Our data, on the study of osteopontin and other markers of bone metabolism in patients with lung cancer, are reflected in the table. It was found that lung cancer occurs with severe disturbances of bone metabolism, which are accompanied by an increase in phosphorus, osteocalcin, osteopontin, lithium, lead, strontium, alkaline phosphatase and cobalt blood level, against the background of a decrease in calcium, magnesium and manganese, that respectively observed in 100%, 78%, 75%, 66%, 47%, 44%, 31%, 3%, 100%, 100% and 6% of the patients’ number. These elements’ content is associated with a morphological variant (cobalt) and stage of the disease (calcium, magnesium, manganese, strontium), the development of osteoporosis (osteopontin, osteocalcin, alkaline phosphatase, strontium, zinc), which is more often observed in women and is noted in every second patient. The osteodensitometric T-value depends on the age of the patients, directly correlates with the values of osteopontin and osteocalcin, and conversely – with the concentration of zinc. Generalized data on the relationship between tumor and osteoporosis are reflected in the figure 1.

Chemo- and radiation therapy of malignant tumors often induces the development of osteoporosis [4] by affecting the functioning of osteoblasts [28]. Osteoporotic rib fractures occurred in 15-20% of the lung cancer patients number receiving radiation therapy, it happened on average 1.5 years after the onset of chest radiation exposure [29]. Y.B. Cihan et al. [30] showed that radiation exposure is accompanied by an imbalance of osteo-associated macro- and microelements levels in an experiment on Sprague-Dawley rats. As S.Siva et al. [31] is considered that the individual medical technology of radiation therapy for lung cancer should be improved, aimed at reducing the number of bone complications. At the same time, there are no reliable biomarkers in cancer allowing to predict the effectiveness of chemotherapy and the development of osteoporosis [32,33].

Bisphosphonates (inhibitors of farnesyl pyrophosphate synthase activity) have been used in the world practice for the treatment of primary osteoporosis for more than 40 years, they regulate the activity of osteoclasts [34]. In an experiment on the cancer cell culture Stachnik and college showed that bisphosphonates inhibit colony formation by HER1 (ΔE746-A750), MB231 and SW620, in conjunction with the activation of the tyrosine kinase inhibitors, bisphosphonates in vitro inhibit the reception of epidermal growth factor, thereby decreasing the viability of tumor cells [35].

It should be noted that the bisphosphonates using is a risk factor for the development of esophageal cancer in humans (less often malignant tumors of the lung, breast, liver, colon and prostate) [36], although some oncologists have previously questioned this information [37] and large-scale special studies completely refuted data in oncoinduced action of bisphosphonates against esophageal cancer [38, 39].

It is believed that the benefits of using bisphosphonates for the treatment of osteoporosis and the prevention of life-threatening bone fractures in cancer patients significantly outweigh the risk of bone complications of such therapy [40, 41]. Moreover, bisphosphonates are widely used in patients with bone metastases and with a plasmacytoma [34]. By the way, rare cases of esophageal cancer formation referred to using the first (etidronate) and second (alendronate, pamidronate) bisphosphonates for treatment patients with osteoporosis, whereas the third generation (zoledronate, risedronate) drugs, having a certain cytostatic effect, were applied just in patients with some forms of esophageal cancer [42].

CONCLUSIONS

Thus, malignant tumors have a close link with bone metabolism disorders, which is manifested by an increase in the synthesis of osteopontin and osteocalcin, an imbalance of osteo-associated macro- (calcium, magnesium, phosphorus) and microelements (cobalt, manganese, copper, strontium, chromium, zinc, etc.), involving in the pathogenetic constructions of cancer and osteoporosis. Such patients can even have bones fractures. Changes in bone metabolism can be exacerbated by cancer chemotherapy and radiation therapy, and the existing information about bisphosphonate oncoinduced action, widely used in the treatment of osteoporosis, is currently questioned. The presented data dictate the need to develop medical technology for antitumor therapy, which has a protective effect on bone metabolism, as well as the creation of anti-osteoporotic treatment, simultaneously directed to the tumor process.

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Authors’ contributions:

According to the order of the Authorship.

Conflict of interest:

The Authors declare no conflict of interest.

CORRESPONDING AUTHOR

Tetiana I. Yarmola

Higher state educational establishment,

Ukrainian medical stomatological academy,

23 Shevchenko Str., Poltava 36004, Ukraine

tel: +380505667005

e-mail: e-mail: tyarmola@gmail.com

Received: 08.04.2018

Accepted: 14.07.2018

Table I. Markers of bone metabolism in healthy people and patients with lung cancer (M±m)

Indices

Patients’ group

healthy

Patients without metastases

without osteoporosis

With osteoporosis

Alkaline phosphatase, U/l

90,0±5,25 *

108,1±9,31

135,0±9,53 **

Osteopontin, ng/ml

22,0±0,86 *

35,4±1,26

44,9±1,45 **

Osteocalcin, ng/ml

5,3±0,40 *

12,1±0,97

15,7±0,88 **

Ca (calcium), mg/l

100,0±0,57 *

54,5±1,57

53,0±2,07

Co (cobalt), mcg/l

6,6±0,40 *

8,1±0,15

8,4±0,14

Cu (copper), mcg/l

1,0±0,03

1,0±0,03

1,0±0,04

Fe (iron), mg/l

439,9±3,45

438,1±38,25

353,8±22,43

Li (lithium), mcg/l

2,3±0,04 *

3,8±0,42

4,2±0,44

Mg (magnesium), mg/l

412,2±5,79 *

35,9±0,38

35,9±0,55

Mn (manganese), mcg/l

18,4±2,18 *

12,5±0,73

12,7±0,99

P (phosphorus), mg/l

27,8±0,37 *

396,6±3,11

400,5±4,50

Pb (lead), mcg/l

39,5±2,58 *

62,0±6,77

66,8±6,67

Sr (strontium), mcg/l

32,4±1,54 *

41,9±3,01

59,1±5,15 **

Zn (zinc), mg/l

6,1±0,11

6,7±0,22

5,9±0,23 **

* Differences between similar indices in healthy and all patients with lung cancer are statistically significant

** Differences between similar indices in lung cancer patients with and without osteoporosis are statistically significant (p <0.05).

Fig.1. Interconnection of a tumorous process with osteoporosis.