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POSTMENOPAUSAL OSTEOPOROSIS/OSTEOPOROZA U POSTMENOPAUZI.

Abbreviations

DXA  - dual-energy X-ray absorptiometry
QCT  - quantitative computed tomography
WHO  - World Health Organization
BMD  - bone mass density
BBI  - bone balance index


Introduction

Menopause is an inevitable and irreversible part of the general aging of the woman's reproductive system, followed by the permanent loss of menstruation. Menopause occurs as a result of losing ovarian sensitivity to stimulation with gonadotropins, with a consequent failure of folliculogenesis and steroidogenesis [1]. Changes in the number and quality of ovarian follicles start about 20 to 25 years after menarche. It is thought that the disturbed ovarian function in perimenopause, with the consequent oscillating changes in the estrogen level, and not only reduced production of estrogen, is the main cause of the menopausal syndrome. The syndrome is typically associated with a decline in the ovarian function, including vasomotor symptoms, psychic complaints, depressions, lowered concentration and insomnia, increase in body mass, urogenital disturbances and decline of the libido, as well as the skin and hair changes [2]. The shortage of estrogen leads to an increased osteoclast activity and bone resoprtion, while bone formation shows a decrease. Hence, postmenopausal women are at a great risk for the development of osteoporosis and bone fractures [3].

Osteoporosis is a common metabolic bone disorder which causes damages to the overall health, with physical, psychosocial and economic consequences. It is a chronic, progressive, and multifactorially conditioned disease. Most often it is diagnosed in older Caucasian women, although it also affects both genders, all races and all ages. Osteoporosis is a systemic bone disease which is characterized by a decrease in bone mass and decay of the microarchitecture of bone tissue, leading to an increase in bone fragility. Unfortunately, it is often detected only after a bone fracture.

Although osteoporosis is a disease of the elderly. its significance is often neglected. Namely, it should be kept in mind that osteopenia, as a state which is a consequence of menopause, can be prevented.

The World Health Organization (WHO) considers bone density measured by dual-energy X-ray absoptiometry (DXA) to be a criterion for the bone tissue status. The results are expressed via T-score or Z-score. The T-score is obtained by comparing the person's DXA density to that of control subjects at the moment of the highest bone mass density (BMD), whereas the Z-score, as the number of standard deviations in the BMD, compares these values of the given subjects with those of the subjects of the corresponding gender and age [4].

According to the WHO recommendations, the diagnostic classification is related to postmenopausal women and man above the age of 50. In this classification, osteoporosis is defined as the BMD which is equal to or lower than 2.5 standard deviations compared to the maximum BMD (T-score). On the other hand, osteopenia is characterized by a BMD in the range of 1.0 - 2.49 SD below the T-score.

A decrease in the BMD occurs due to bone resorption, as a consequence of an accelerated degradation of bones, whereas the level of bone building remains within the premenopausal ranges. In the postmenopause, the bone degradation is accelerated by about 20% compared to that at younger age.

Pathophysiology of osteoporosis

As already said, the main cause of osteoporosis is the disbalance between the degradation and formation of bones. In physiological states, these two processes are balanced. Osteoporosis occurs when this balance is disturbed. i.e. when degradation is accelerated or when formation is decreased. It is important to point out that osteoporosis can be a consequence of reduced bone formation during the life and achieving full bone density in an earlier stage of life. The two main factors causing osteoporosis are aging and loss of the gonadal function. Postmenopausal osteoporosis is primarily the consequence of estrogen deficiency, whereas senile osteoporosis is related to the natural aging process [5].

Aging. After the age of 30, the process of bone resorption surpasses that of bone formation, which may lead to osteopenia/osteoporosis. Women lose about 40% of bone cortex and men about 15 - 20%. Also. trabecular bone loss in women is about 50%, compared with 25 - 30% in men. Age-related bone loss is characterized by a reduced supply of osteoblasts compared to the needs, whereas in the postmenopausal women it is associated with increased activity of osteoclasts [6].

Estrogen deficiency. It causes a decrease in BMD in women, but also in men, since osteoblasts, osteoclasts and osteocytes possess estrogen receptors. Besides, estrogens affect bones in an indirect way, via cytokines and growth factor. In the states of estrogen shortage, T-cells accelerate osteoclast recruitment, inhibit their differentiation, and extend their lifespan via interleukin-1, interleukin-6, and tumor necrosis factor alpha. Also, T-cells cause premature apoptosis of osteoblasts via interleukin-7. In the states of estrogen shortage, bones are more sensitive to the action of parathormone [7].

Calcium deficiency. Calcium, vitamin D, and parathormone maintain bone homeostasis. Calcium-poor diet or reduced calcium absorption, due to aging or some disease, may cause secondary hyperparathyroidism, which leads to increased absorption of calcium from bones by calcium excretion via kidneys [8].

Vitamin D deficiency. Vitamin D controls concentrations of calcium and phosphate, needed for healthy bones and teeth. Besides maintaining BMD. it is thought that this important biogenic element plays a role in prevention and development of cardiovascular, inflammatory and malignant diseases. Vitamin D is supplied in two ways - by the synthesis in the skin and through food. In the latter case, we differ vitamin D2 (ergocalciferol) of plant origin, and D3 (cholecalciferol) of animal origin. Still, the main source of vitamin D is its synthesis in the skin under influence of ultraviolet B light [9].

The primary function of vitamin D is to regulate calcium absorption from the intestine and stimulation of its resorption from bones, to maintain the calcium serum level. The shortage of vitamin D leads to reduction of calcium absorption from the intestine and increased production of osteoclasts. which mobilize bone calcium. Due to its inadequate intake, vitamin D interacts with osteoblast receptors, causing an increase in the formation of osteoclasts.

Risk factors for the onset of osteoporosis [10-12]:

1. 50-plus years of age,

2. female gender,

3. Caucasian race,

4. genetic predisposition,

5. short stature,

6. undernourishment,

7. physical inactivity,

8. amenorrhea,

9. late menarche. early menopause,

10. deficiency of estrogen and androgen,

11. alcohol consumption,

12. cigarette smoking,

13. calcium-poor diet,

14. some drugs (steroids, insulin, anticonvulsants, chemotherapeutics, heparin).

Osteoporosis complications

Osteoporosis is the main cause of bone fractures in elderly people (more than 80% of cases in persons of 50-plus years of age). If not treated successfully, it leads to chronic painful conditions, limitation of movements, and in some cases to death (fractures of the spine and hip joints) [13].

Biochemical indicators of bone metabolism

There are markers of bone formation and markers of bone resorption. Bone formation markers are: total and bone-specific alkaline phosphatase (serum), osteocalcin (serum), C- and N-terminal propeptides of procollagen type 1, procollagen 1 carboxyterminal propeptide (PICP, serum), procollagen type 1N-terminal propeptide (P1NP, serum), and other non-collagen bone proteins. Bone resorption markers are: tartrate-resistant acid phosphatase (plasma), calcium (urine), hydroxyproline (urine), pyridinium crosslinks (urine), collagen type 1 telopeptide beta-crosslaps (urine, serum), C-terminal type-1 collagen telopeptide (ICTP - serum), collagen type 1 cross-linked 1 N-telopeptide (NTX, urine). The bone balance index (BBI) represents the relative values of the ratio of (osteocalcin/crosslaps x 1000). It indicates the degree of deviation of the ratios of the physiological processes of bone remodeling (formation and degradation of bones) from an ideally balanced state. In healthy population, the BBI is about 90 [14].

Diagnostics

Bone densitometry measures the difference in the absorption of gamma- or X-rays, ultrasound or laser in the bone and in the soft tissue. It is possible to measure the bone mineral content (g), and indirectly the bone density (g/[cm.sup.2]).

The DXA is a very widespread method, which is characterized by extremely high resolution and precision. The measurement time is short, i.e. the method allows rapid measurement of the whole-body mineral content in a safe and reliable way, with very good reproducibility, while reducing the problem of superposition with the adjacent soft tissues. The apparatus uses X-rays as source of energy. The DXA measurements of the hip and spine are a worldwide standard in diagnosing osteoporosis [15]. Measurements by dual X-ray absorptiometry and laser technique (DXL) of the heel bone are an alternative to DXA. The technique has been developed with the aim of avoiding measurement errors of DXA due to the influence of the adjacent soft tissue [16].

The quantitative computed tomography measures thin layers by cross-sectional scans. The computer analysis provides data for BMD and estimates density of the trabecular and cortical bones [17].

Ultrasound densitometry is a method whose advantages are avoidance of irradiation and easily portable apparatus, but the measurements are not as precise as the ones obtained by other imaging techniques [18].

Drug treatment of osteoporosis

Modern treatment of osteoporosis includes application of [19-21]:

1. bisphosphonates (alendronate, etidronate, ibandronate, risedronate, zoledronic acid),

2. selective estrogen receptor modulators (raloxifene, lasofoxifene, arzoxifene),

3. calcium preparations,

4. vitamin D,

5. monoclonal antibodies,

6. hormonal therapy,

7. estrogens,

8. phytoestrogens.

Prevention

Lifestyle changes and non-pharmacological measures are most important for healthy bones. Physical activity, nutrition rich in calcium and vitamin D, avoidance of smoking and alcohol consumption are of crucial importance for people of all ages, and especially for the older ones [22]. The application of these measures also shows results in patients with osteoporosis. These subjects have enhanced bone strength and lower risk of bone fracture.

The prevention strategy includes optimal development of the skeletal system and achievement of maximal bone mass at the time of skeletal maturity; prevention of secondary causes for bone mass loss; preservation of the structural integrity of bones, and fracture prevention.

A balanced and healthy diet ensures adequate intake of calcium and vitamin D. Malnutrition, anorexia and excessive aerobic activity of young girls leads to a later menarche and lower bone mass compared with those of the same age. A similar situation is also observed with the adults practicing restrictive diets and reducing body mass by surgery. The balanced protein intake (recommended daily intake is about 0.8 g/kg of body mass) can contribute to the minimization of the bone loss even in patients with advanced osteoporosis [23].

The main factor in the prevention of osteoporosis and its treatment is calcium. For women over the age of 50, the daily intake of calcium should be 1200 mg (diet + supplementation if necessary). If the diet does not supply sufficient amounts of calcium, its supplementation is indispensable. However, the pertinent data show that the daily diet intake in the majority of patients is only about 600 mg, which makes in fact only half of the necessary daily dose. In case of supplementation, to ensure optimal resorption, the calcium dose should not exceed 500 mg. It has been proved that calcium increases the BMD, but there are no scientific confirmations that its application without application of vitamin D decreases the risk of bone fracture [24]. Calcium supplementation is safe for the users. The risk of nephrolithiasis with these patients is minimal compared to general population (2.5% risk for development of nephrolithiasis in supplementation patients compared to 2.1 in general population).

Thus, apart from calcium, it is necessary to administer vitamin D. Many, apparently healthy persons, have a significantly lower serum 25-hydroxy-vitamin D level compared to the optimum. This is primarily a consequence of inappropriate nutrition, since vitamin D is not so widely present in the foodstuffs. It is found in fish oil, cereals, and bread, Vitamin D is formed in the skin. According to the recommendations of the American National Academy of Sciences the daily intake of vitamin D should be 400 IU for healthy younger persons. For persons over 50 years of age, the recommendation is 800 to 1000 IU a day. However, some experts recommend even significantly higher daily doses of 1000 - 2000 mg of calcium. The correct recommendation for minimal 25-hydroxyvitamin D levels are 30-32 ng/ml, whereas the upper limit is up to 60 ng/ml. Some meta-analytic studies showed that postmenopausal women are at lower risk of fracture even if the daily supplementation dose is 700 - 800 IU. In the patients with severe vitamin D deficiency, the daily supplementation dose should be up to 2000 IU [25].

Increased alcohol consumption has negative effects on bones, since it increases the risk of bone fracture. The way how alcohol affects bones is complex and multifactorial, leading to an increased risk of accidental falls, deficiency of calcium, and liver overload. Also, it is not recommended to drink more than 1 - 2 cups of coffee a day, since some studies showed the existence of a positive relationship between caffeine and bone fracture, most probably due to a lower calcium intake.

Cigarette smoking also affects the bone health. The exact mechanism is not fully resolved yet, but it is thought that it increases the metabolism of estrogen and direct effect of cadmium on bone metabolism [26].

Regular physical activity, for example, everyday 30 minute walk and exercising for about 10 min several times a week contribute to the maintenance of healthy bone system. Studies have shown that muscle power in younger women is in a positive correlation with their BMD. Nevertheless, physical activity of older women should be individually adapted to the age, as well as to the general state of the subject [27].

Also, an important issue is education aimed at prevention of falls and consequent fractures. It is important to point out that phytoestrogens represent an option for preventing osteoporosis in women since there are indications that they have a positive effect on the bone health. Soybean isoflavon shows a functional activity similar to that of 17 beta-estradiol on osteoblasts and osteoclasts via genomic and non-genomic mechanisms [28]. Besides, they also exhibit a favorable effect on BMD and mechanical durability in postemenopausal women, contributing to bone formation via estrogen receptors on the cell surface.

References

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Artur BJELICA (1,2), Viktorija VUCAJ CIRILOVIC (1,3), Snezana TOMASEVIC TODOROVIC (1,4) and Karmela FILIPOVIC (1,5)

University of Novi Sad, Faculty of Medicine Novi Sad Department of Obstetrics and Gynecology (1)

Clinical Center of Vojvodina, Novi Sad Clinic of Gynecology and Obstetrics (2)

Oncology Institute of Vojvodina, Department for Diagnostic Imaging, Sremska Kamenica (3)

Clinical Center of Vojvodina, Novi Sad, Department of Medical Rehabilitation (4)

Special Hospital for Rheumatic Diseases, Novi Sad (5)

Corresponding Author: Prof. dr Artur Bjelica, Klinika za ginekologiju i akuserstvo, 21000 Novi Sad, Branimira Cosica 37, E-mail: artur.bjelica@mf.uns.ac.rs

https://doi.org/10.2298/MPNS1806201B
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Title Annotation:SEMINAR FOR PHYSICIANS/SEMINAR ZA LEKARE U PRAKSI
Author:Bjelica, Artur; Cirilovic, Viktorija Vucaj; Todorovic, Snezana Tomasevic; Filipovic, Karmela
Publication:Medicinski Pregled
Date:May 1, 2018
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