Clinical and pathogenetic features of low bone mass in postmenopausal women

Background. Low bone mass (LBM) in the form of osteopenia (Op) and osteoporosis (OP) is one of the most pres sing public health problems. Рostmenopausal period in women is considered the main risk factor for the development of the pathological process. Objective of the research was to assess the clinical and pathogenetic features of LBM in women with menopause. Materials and methods. 261 non-menstruating women with an average age of 48 years were observed, physiological menopause occurred in 91 % of cases, and pathological in the rest. Exclusion criteria were women with inflammatory rheumatic diseases of the joints, oncological pathology, diseases of the blood system and thyroid gland, who received glucocorticoid hormones and anticonvulsants. In 133 (51 %) women, LBM (main group) was established in the ratio Op and ОР 4 : 1; diagnosis being made by the methods of conventional radiography and densitometry. Among the markers of bone metabolism, the following were used: blood levels of parathyrin (parathyroid hormone), calcitonin, osteocalcin, osteopontin, alkaline phosphatase, and osteo-associated chemical elements. During the examination, biochemical, enzyme immunoassay, atomic emission and atomic absorption methods were used. Results. The age of women correlates with the parameters of bone mineral density, and the LBM in all ca ses is associated with high blood levels of osteocalcin, in 1/2 of them — osteopontin, depends on the presence of comorbid primary arterial hypertension, type 2 diabetes mellitus, and leukocytoclastic vasculitis. OP formation significantly differs from Op in higher blood levels of parathyrin (by 47 %), alkaline phosphatase (by 19 %), phosphorus (by 9 %) and lead (by 27 %), but lower calcium values (by 4 %), moreover, the acti vity of alkaline phosphatase has predictive negative significance in relation to the severity of the LBM. Calcitonin, magnesium, strontium and zinc also participate in the pathogenetic constructions of the latter. Conclusions. LBM develops in every second postmenopau sal woman, and the further development of pathogenetic therapy should be aimed at correcting the concentration of osteocalcin and osteopontin in the body, and inhibition of alkaline phosphatase activity may be a criterion for the effectiveness of therapeutic measures.

Abstract. Background. Low bone mass (LBM) in the form of osteopenia (Op) and osteoporosis (OP) is one of the most pres sing public health problems. Рostmenopausal period in women is considered the main risk factor for the development of the pathological process. Objective of the research was to assess the clinical and pathogenetic features of LBM in women with menopause. Materials and methods. 261 non-menstruating women with an average age of 48 years were observed, physiological menopause occurred in 91 % of cases, and pathological in the rest. Exclusion criteria were women with inflammatory rheumatic diseases of the joints, oncological pathology, diseases of the blood system and thyroid gland, who received glucocorticoid hormones and anticonvulsants. In 133 (51 %) women, LBM (main group) was established in the ratio Op and ОР 4 : 1; diagnosis being made by the methods of conventional radiography and densitometry. Among the markers of bone metabolism, the following were used: blood levels of parathyrin (parathyroid hormone), calcitonin, osteocalcin, osteopontin, alkaline phosphatase, and osteo-associated chemical elements. During the examination, biochemical, enzyme immunoassay, atomic emission and atomic absorption methods were used. Results. The age of women correlates with the parameters of bone mineral density, and the LBM in all ca ses is associated with high blood levels of osteocalcin, in 1/2 of them -osteopontin, depends on the presence of comorbid primary arterial hypertension, type 2 diabetes mellitus, and leukocytoclastic vasculitis. OP formation significantly differs from Op in higher blood levels of parathyrin (by 47 %), alkaline phosphatase (by 19 %), phosphorus (by 9 %) and lead (by 27 %), but lower calcium values (by 4 %), moreover, the acti vity of alkaline phosphatase has predictive negative significance in relation to the severity of the LBM. Calcitonin, magnesium, strontium and zinc also participate in the pathogenetic constructions of the latter. Conclusions. LBM develops in every second postmenopau sal woman, and the further development of pathogenetic therapy should be aimed at correcting the concentration of osteocalcin and osteopontin in the body, and inhibition of alkaline phosphatase activity may be a criterion for the effectiveness of therapeutic measures.

Materials and methods
The study was cross-sectional, recruiting 261 nonmenstruating women aged 34-72 years (mean age -48.4±0.54 years). For 90.8 % women, the menopause was physiological, for 3.1 %, it was an early-onset menopause; while for 3.5 %, it was a late-onset menstruation and amenorrhea, for 2.7 %, ovariectomy was performed at the earlier stages, and 4.6 % women were infertile. The exclusion criteria were rheumatic bone and articular disorders, thyroid and blood circulation disorders, malignant tumors, chronic renal diseases of stage 2-4, glucocorticoid and anticonvulsant treatment, i.e. all those factors affecting the bone metabolism and associated with LBM.
The examined women were divided into two groups: 133 (51.0 %) women with LBM (main group) and 128 (49%) women with normal bone density (comparison group). The control group was made by 30 actually healthy, menstruating women aged 23-48 years (mean age -35.5±2.31 years). 79.0% women with LBM were diagnosed with Op, the remaining 21.1 % (or 10.7 % out of the total number) -with OP. Обязательно добавить одобрение ЛЭК и согласие пациентов на участие в исследовании. This study was approved by Local Ethic Committee, all women signed the inform consent for participation in the study.
The statistic processing of the obtained findings is performed by means of computer variational, non-parametric, correlation, one-way (ANOVA) and multivariate (ANOVA/MANOVA) dispersive analysis (Microsoft Excel and Statistica). The mean indices (M), standard errors (SE) and standard deviations (SD), the parametric Pearson correlation (r) and non-parametric Kendall correlation (t The LBM women have the BMD correlating with PT, CT, OC, OP, AP, Ca, Mg and Pb blood levels (T-score and W index are differently directed towards BN and R indices). Moreover, the BN index is reversely cor-related to Cu (r = -0.343, p=0.008) blood levels, and the R index is reversely correlated to Со (r=-0.437, p=0.001), while the W index is directly correlated with Sr (r=+0.28, p=0.047). While comparing women with Op and OP, we revealed that OP is associated with the significantly higher (by 47.4%) blood levels of РТ (t=6.41, p<0.001), by 19.0% of АР (t=4.27, p<0.001), by 9.4% of Р (t=4.97, p<0.001) and by 26.9% of Pb (t=2.58, p=0.011), but with a lower Ca concentration by 4.3% (t=5.16, p<0.001).

Discussion
With LBM, the BMM develop a single homeostatic mechanism of Са and Р metabolism regulation in postmenopausal women [8]. The PT has a negative impact on bone structure [9], while the reduced Ca concentrations may lead to an increased PT secretion in the LBM women. The osteoclasts accelerate the bonecontained mineral compounds' dissolution. In case of hypocalcaemia, CT secretion usually drops down, affecting osteoblasts and leading to the elevated calcitriol production; as a result, Са and Р's mobilization from bone intensifies. OC, being the Y-carboxylated protein, is synthesized by osteoblasts, while the bone mineralization is regulated by Vitamin D [10]. In the non-menstruating LBM women, the importance of OC association with osteoblasts via osteoclastogenesis and intensified synthesis of anti-inflammatory interleukin-6 [11], insulin-like growth factor (IGF), osteoprotegerin, nuclear factor NF-κB [12,13], C-telopeptide of collagen [14] is confirmed for the LBM pathogenesis.
The changes in Sr concentrations observed in the menopausal women's blood serum belong to the LBM-Практична медицина / Practical Medicine inducing factors. Strontium produces an anti-resorptive effect on bone, reduces osteoclast differentiation, and stimulates bone formation via pre-osteoclast proliferation. It is worthy of note that, according to our data, LBM in the non-menstruating women is attended by the increased strontiemia, prevailing in the OP cases. In this light, it should be observed that the increased Sr ion concentration may cause bone fragility by replacing Са ions present in the bone. For the matrix metalloproteinases (MMPs) to be able to perform their destructive functions in the LBM subjects, Zn ions should also be present. Empowered by Zn, aggrecanase, gelatinase, collagenase, elastase intervene into the bone pathology and disrupt aggrecan, biglycan, verzikan, decorin, fibronectin, fibromodullin ratio. It should also be mentioned that women with LBM demonstrate the reduced Zn concentrations, probably due to the protein binding.
By contrast, Со, Mn and Pb have no effect on BMD formation, while Cr and Se are associated with W index exclusively (D=2.00, p=0.003 and D=1.46, p=0.049 respectively). By means of variation, dispersion and correlation analyses, we've managed to make a practical conclusion: АР activity index >158 U/l (>M+SD for the OP women) reflects severe LBM presence (PPV=76.0%).

Conclusions
LBM (the Op and OP ratio is 4:1) develops in every one in two non-menstruating women; its development being associated with high ОС concentrations, half of them -OP concentrations. It depends on a history of primary arterial hypertension, diabetes mellitus and leukocytoclastic vasculitis comorbidities. The OP development is significantly different from the Op development due to the higher PT, P, Pb and АР concentrations (negative predictive value), though lower Са concentrations. The LBM pathogenesis also involves СТ, Mg, Sr and Zn.

Conflicts of interests.
Authors declare the absence of any conflicts of interests and their own financial interest that might be construed to influence the results or interpretation of their manuscript.