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Lviv clinical bulletin 2019, 1(25): 51-62

https://doi.org/10.25040/lkv2019.01.051

Peculiarities of Calcium-Phosphorus Metabolism and Bone State in Patients with Rheumatoid Arthritis: Pathogenesis, Diagnosis and Principles of Differential Treatment (Literature Review and Clinical Case Description)

V. Chemes, O. Abrahamovych, U. Abrahamovych, L. Tsyhanyk, S. Guta

Danylo Halytsky Lviv National Medical University

Introduction. Rheumatoid diseases belong to those the most widely spread ones in the world. The abundance of Rheumatoid Arthritis (RA) in northern Europe and North America is 0,5–1,0 %, and is expected to grow together with the age rise [31, 32]. Specifically, in 2017 р. 8132 people fell ill with RA in Lviv region, it is almost 4 people per 1000 ones of the whole population. Women come down with RA 2–4 times more often than men in the proportion of 3:1 [32]. RA usually hits the people of able-bodied age. The peak of the disease for women is 41 year old, while it is 45 for men [2]. Each, out of four inhabitants of Euro Union will be 65 till the year of 2030 [37]. RA is a vast economic load for the society [25, 37, 50]. Well – developed countries of the world spend almost 39 billion dollars yearly on the cure of the patients with arthritis [73]. The majority of this money is destined to cure comorbid damages caused by RA. Considerable spread of reumatiod diseases, constant morbidity rise, able-bodied people affliction, late diagnostics, the treatment which is not always effective and a considerable economic damage caused by these diseases and their complications make medicine face the issues which demand quick solution.

The Aim of the Research. To review the sources and describe a clinical case with the aim of pathogenesis specificities discovery, diagnostics and the principles of differentiated treatment of calcium and phosphor interchange and also bone state for the patients ill at rheumatoid arthritis.

Data and Methods of ResearchWe have applied a content-analysis method, the system and comparative analysis, bibliosemantic method of the research of modern scientific investigation of the specificities of calcium and phosphor interchange and the state of bones for the patients ill at Reumatois Arthritis. We have also researched the pathogenesis, methods of diagnostics and the principles of differentiated treatment.  The search of the sources has been conducted in scientific medical information bases such as: PubMed-NCBI, Medline, CochraneLibrary, EMBASE, ResearchGate by the key words: RA, osteoporosis, densitometry, calcium, phosphor, vitamin D, pararthyroid hormone, denosumab. 81 sources in English and Ukrainian have been analysed. We have picked out the sources which describe the pathogenesis, methods of diagnostics with a proved high sensitivity and specificity, the principles of treatment. We have also described a clinical case (disease case № 24887).

The Results of the Research.

Sources Review. RA is a chronic autoimmune disease of unclerified etiology which damages joints, causes an early disability of able-bodied people. It is characterized by systemic damages, early death and considerable socio-economic expenses [6, 27].

Despite the fact that the first cases of RA were described among Northern American tribes in 1500 BC., the etiology has not been fully investigated yet [6].

Scientiests dwell upon a few factors of the RA risk. One of them is genetics [39]. It is known that the risk of RA is thrice higher for the people whose relatives of the first line suffered from this disease and genetic predisposition equally influences both – men and women [24, 39]. 

Many factors of the environment including smoking, professional damage are the triggers for the people inclined to RA development [3, 8]. The harm of smoking is the most proved among all the enumerated ones since it provokes the development of citrulline albumens. According to the recent research, the risk of RA development rises twice after 20 years of smoking for both men and women [62].

 A considerable number of researches are dedicated to the connection between RA and paradontitis development. J. Schmikler and his co-authors [56] proved the connection between RA and the existence of Porphyromonas Gingivalis in mouth cavity. The research proved that the patients with RA have a high level of IgG antibodies to Toxoplasma gondii [21]. A reversible correlation has been discovered between high titres of IgG antibodies to the virus of M.E. Epshten- I.Barr and paravirus B19 and the risk of seropositive RA development [60].

Pathogenesis of RA is the result of the interaction between genetic factors and the ones of the environment which cause the activation of congenital and acquired processes in the immune system. It eventually causes the disorder of immune tolerance, T and B lymphocytes activation and and abnormal production of inflammatory cytokines. The row of reactions finishes with the development of synovite with further subchondral destruction of bone tissue.

RA damages not only joints and bones. It can also damage skin, lungs, eyes and cardiovascular system. Deeper understanding of pathogenetic ways on the basis of RA will enable us to receive more adequate and safe treatment, improve the diagnostics at early stages and receive the control of the disease activity [13].

It is obvious that to have more predictable and favourable treatment of RA it is very important to diagnose it at early stages. Owing to the symptoms revealing throughout 12 weeks (optimal «therapeutic window») less joints are damaged and it is possible to achieve remission without basic anti-rheumatic medicines which modify the course of the diseas, – disease-modifying anti-rheumatic drugs (DMARDs) [16, 46].

Throughout 5–6 years of the first symptoms, if there is no relevant treatment, a patient with RA can become disabled which leads to the worse quality of life or partial or even whole loss of efficiency [3]. Optimal treatment of RA will enable us to avoid joint disability, frequent hospitalization and lower the expenses for recovery.

Comorbid damage makes a considerably negative impact on the patient’s condition with RA [20, 48]. Insufficient treatment of concomitant illnesses is a vast issue for the patients with RA [19] since they are under non sufficient therapy against RA [51].Each additional concomitant illness lowers the probability of remission for 28,00 % [52].

One of the most frequent comorbid damage for the patients with RA is osteoporosis (ОP), which develops more often in their state than in general population [18, 30, 61]. OP for the patients with RA belongs to derived metabolic osteopathies which develop as a result of immune deviations of bone tissue remodeling when the resorption prevails and it causes the lowering of mineral density of bone tissue (MDBT) and the higher risk of fractures. Osteoporosis is one of hardest RA complications which worsens the course and prediction of the disease [73]. About 50,00 % of women and 20,00 % of men suffer from fractures caused by OP [61]. In general population of Europe there were fixed 620 000 of the neck of thigh bone fractures and the same quantity of compressive spine ones [37, 50]. The fractures of the neck of thigh bone and compressive spine ones for the patients with RA are fixed twice more often than for the healthy people of such age [30]. As a result of numerous researches it has been discovered that  25,60 % of women at the age of 50–59 who suffers from RA, osteoporosis is found in a lumber spine section, while for 30,80 % it is on the level of the neck of a thigh bone; 33,40 % have osteoporosis in the bones of forearm [38]. Osteopenia and osteoporosis development are tightly associated with the activity, duration of RA and other general factors of risk such as age, low body mass index(<18,0), early menopause, low physical activity, smoking, alcohol consumption, vitamin D deficit, Calcium deficit, the concumption of glucocorticistiroids (GC) and the inclination to falling down [42].

Osteoclastogenesis is mostly regulated with the help of two cytokines: a receptor activator of nuclear factor kappa-B ligand (RANKL) and оsteoprotegerin (OPG) [55]. RANKL – is a glycoprotein which causes the maturation of osteoblasts (ОB) and belongs to the supra family of tumor necrosis factor (TNF) [64]. In case of RANKL expression rise the resorption grows and bone tissue is lost. The receptor activator of nuclear factor kappa-B (RANK) is a specific receptor situated on the surface of OB membrane. The rise of RANKL content and its interaction with RANK leads to the transformation in previous osteoclasts (OS), which in ist turn transforms into preosteoclasts an as a result of this mature OC make bone tissue resorption. During this process apoptosis of mature OC is slowed down [65]. The discovery of cytokine system of RANK / RANKL / OPG enabled us to understand the pathogenesis of OP to a better extent [62]. This system regulates osteoclastogenesis and takes part in the regulation of bone resorption processes.

There has been conducted a research with the help of mice. They were injected RANKL and to the end of the first 24 hours they had hypercalcemia and till the end of the third day there was bone mass loss. RANKL – effect is regulated by ОPG, which is also a member of supra family of TNF. ОРG is produced in many organs (bones, skin, liver, stomach, guts, lungs, kidneys, placenta).In bone tissue of ОРG OB is produced and is a false receptor for RANKL [62, 65].

As a result of ОРG-RANKL interaction in bone tissue there is a blocking of OC differentiation out of their previous ones and this way bone resorption is slowed down. A large number of cytokines, hormones and medicines may have stimulating or inhibitory effect on RANKL or ОРG. For instance, paratiroid hormone (PTH), interleikinі-11 and prostaglandins may produce RANKL expression on the surface of immature OB. GC and PTH reinforce the synthesis of RANKL and lower the synthesis of ОРG. Vitamin D3 reinforces the production of RANKL, while estrogens stimulate the synthesis of ОРG [55, 62, 65].

Numerous researches conducted on animals proved that hyper expression of ОРG gene for mice caused the rise of bone mass and is characterisedwith the lowering of number and activity of OC when the «exclusion» of ОРG gene led to MDBT lowering, OC rise and a higher risk of random fractures. These researches prove that the function of OPG lies in «exclusion» RANKL [45, 62].

In most available researches there is an assumption that the correlation between RANKL and OPG is an important link of bone resorption. It is obvious that the support of the correlation between RANKL and OPG is an important condition of balance preservation between resorption and bone tissue development. The balance of those two processes, a relevant content of RANKL and OPG in bone tissue are the most impostant determinants of bone mass and strength [45, 62].

Throughout recent years the part of immune system has been considered in the pathogenesis of OP [49]. Some scientiests claim that immune system plays an important part in the etiology of bone illnesses but it ruins the balance between OB which takes part in bone development and OC which are responsible for bone resorption [29].

We have conducted numerous researches which proved the commonness between bone and immune systems. Firstly, OB derives from the very myeloid progenitor-cells as macrophages and myeloid dendritic cells; secondly, OB has the same life cycles as dendritic cells which are regulated by different cytokines and inflammation mediators [13].

The mechanisms which damage the bone during autoimmune disease are complicated and different since they vary from direct bone damage and gristle by immune cells to indirect concequences of systemic bone remodeling deviation [13]. Through OP, nowadays, many researches are conducted to dwell upon an inflammation process in the pathogenesis of bone tisuue damage development which is observable. Inflammation mediators are important regulators of bone homeostasis [34].

Throughout a chronic inflammation the balance between the development and resorption of bone is deviated and it leads to OP and increases the risk of fractures [14]. It happens with the part of RANKL-immune produced cells (neutrophils, monocytes, dendritic cells and T-limphocytes), which induce OB differentiation [4, 62]. It is also known that theses cells provoke the synthesis of pro-inflammatory cytokines such as – interleukin lα (IЛ-lα) and β (IЛ-lβ), TNF-α, interleukine 11 (ІЛ-11), interleukine 17 (ІЛ-17) and colony stimulating factor of macrophages–macrophage colony-stimulating factor (M-CSF), which regulate the maturity, proliferation and the differentiation of osteoclasts. For the patients with RA these cytokines are produced by synovial tissues.

The impact of inflammation process on the tissue has been illustrated by the researches on animals. During the investigation with mice ill at RA anti-iflammatory cytokines of a type were discovered ІЛ-1β as well as TNF-α and interleukine 6 (ІЛ-6), which launch  signal transducer and activator of transcription 3 (STAT3) in OB fibreblasts [45].  STAT3 activation provokes the expression of RANKL [45]. A key role of RANKL in OP pathogenesis is proved by the research where there was conducted a genetic exclusion of RANKL or its RANK–receptor on the animals and they have discovered that their absence protects from bone tissue loss [7, 45]. The observetions proved the impact of inflammation process on OP and the correlation between the production of ІЛ-1, ІЛ-6 and TNF-α momcytes of perirheric blood and bone resorption [45]. 

Acording to J. Sokolov і D. Pisetsky [61], the existence of antibodies plays a crucial part in pathologic bone tissue loss.  Autoantobodies, such as rheumatoid factor (RF) and the antibodies to anti-cyclic citrullinated peptide (anti-CCP), are the factors of OP development [61], when positive RF occurs approximately for 50,00–90,00 % of patients with RA [33].

A large amount of researches have been conducted and according to their results we can assume that OP is s genetically determined disease [42].

Very often OP is diagnosed after fractures which is a late indicator and the result of slow and non-symptomatic bone damage. The fractures are mostly localized in the area of the neck of a thigh bone, lower part of forearm and spine section [57]. OP is also characterized by the pain in bones, in chest and lumber spine sections, growth deviation, teeth loss and nail fragility.

Laboratory methods of diagnostics enable us to exclude secondary reasons of the disease and diagnose it properly. They include the evaluation of hormones of thyroid gland and para-thyroid gland and also testosterone.  One more factor of PO development is the decrease of magnium amount in the blood [74].

Biochemical markers of bone tissue interchange are determined both in blood and urine. In a few researches it has been shown that women in postmenopausal period the amount of markers which characterize interchange processes in the bone, blood serum and their excrection with urine correlate with the risk of fracture occurrence. Other researches demonstrate that the amount of biochemical markers of female bone tissue metabolism in postmenopausal stage is higher than for those who are in premenopausalperiod and the risk of vertebra and the neck of a thigh bone fractures grows twice with no dependence on the age and average MDBT values [3].

Bone metabolism markers are divided into the markers of resorption and the markers of bone tissue development. Osteocalcin, bone alkaline phosphatase, Procollagen type I N propeptide (PІNP), Procollagen type I C-terminal propeptide (P1CP) are the markers responsible for the process of bone tissue development. Osteocalcin is a sensitive marker of the bone tissue and it reflects a metabolic activity of OB of bone tissue since it changes owing to the synthesis, but is not revealed during the bone resorptio [9]. Osteocalcin points to the speed of bone tissue remodeling [28]. P1NP, P1СP are produced in the skin, eye cornea, blood vessels, cartilage tissue and other organs, however only bone is the biggest source of its synthesis.

The markers of bone tissue resorption include beta-C-terminal telopeptide (β-СТх, β-СrossLaps). The concentration is researched in the blood serum and urine since there is no metabolism in liver and kidneys for it and it is withdrawn by the kidneys in unchanged state. To diagnose OP this marker is highly specific since its amount grows radically in case of diseases which provoke resorption of bone and throughout a few weeks it decreases quickly after antiresorptive treatment [6]. For instance, the efficiency of antiresorptive treatment with the help of β-crossLaps index may be evaluated through 3–6 months [3].

Bone metabolism markers are applied as a means of OP treatment monitoring [16, 47]. Although it has not been determined which markers exactly we should take and what the intervals of monitoring are to be used.

Vitamin D influences structural and functional state of bone tissue. During vitamin D hypovitaminosis hypocalcaemia occurs and as a result of which we get hyperparatirosis. The former stimulates bone tissue resorption and calcium relief out of bone depot. Secondary hyperparatirosis becomes the reason for osteopenia and osteoporosis. According to modern international recommendations (M. Holick and others., 2011), the deficit of vitamin D is determined if the index 25(OH) of vitamin D is lower than 20,00 ng/ml (50,00 nmoll/l), insufficiency of vitamin D in 25(OH) of vitamin D is 21,00–29,00 ng/ml (50,10–74,90 nmoll/l), norm in 25(ОН) is 75,00 nmoll/l.  Epidemilological researches conducted by the professor V.V. Povoroznyuk (2012) showed that only 4,60 % of inhabitants of Ukraine have 25 (ОН) of vitamin Dwithin the norm, while 13,60 % have insufficient amount of it and 81,80 % – deficit. Judging by the influence of vitamin D on MDBT, we observe that it is very important to research it in the blood serum of the patients with OP.

Paratiroid hormone is the hormone which regulates the amount of calcium and phosphor in blood. It influences the processes of bone tissue resorption and promotes calcium and phosphor withdrawal out of the bone and also increases calcium reabsorption, suppresses phosphates reabsorption in distal sections of nephron canals, activates α1-hydroxylase, reinforces the synthesis of calcitriol and calcium and phosphor absorption out of guts.

We should not omit determining such routine indexes as calcium and phosphor amount in blood serum. As hypercalciemia is a characteristic feature of primary and tertiary hyperparatirosis,  malignant tumors, some medicines intoxication (vitamin D medicines, lithium, thiazide diuretic), while hypophosphatemia occurs as a result of vitamin D deficit, hyperparatirosis, genetic hypophosphatemia, Fanconi Syndrome, paraneoplastic osteomalacia, in case of alcohol abusage, respiratory alkalosis, hard burns, diabetic ketoacidosis treatment. Hyperphosphatemia occurs as a result of hypoparaterosis, D – hyperavotaminosis, myeloma condition.

Instrumental methods of research include ultrasound density metrology which was first developed by C. M. Langton and his co-authors in 1984 р. They suggested using a broad band ultrasound attenuation (BUA) of the fifth bone since they claim that it is a potential indicator of thigh bone fractures. The sense of investigation is based on the fact that the speed of ultrasound wave depends on the density and elasticity of bone tissue structure through which it runs. BUA depends on the bone structure, namely the number and bone trabeculas thickness. The method of ultrasound density metrology allows receiving the information about the speed of ultrasound fluctuations which is the basis for conclusion.  Researches may be conducted in the area of radial bone, heel bone, finger phalanx and big shin bone.

The main advantages of the method are non-invasiveness, high accuracy, safety and therapidity of research conduct and results acquiring right after the end of examination. That is why US densitometry may be applied as a scrinning method for the bone state diagnostics for the patients with RA [3]. High specificity and sensitivity of ultrasound densitometry in comparison to Dual X-ray absorptometry (DXA) as a scrinning method of OP diagnostics in the research by U.O. Abrahamovytch [1].

Very often to diagnose OP the method of hand wrist X-ray steodensitometry is applied which is based on the use of X-ray of peripheric skeleton bones, metacarpal bones and computer densitometry of radiographs. The most important advantages of this method are accessibility and the speed of the investigation as not complicated equipment may be installed in any hospital with X-ray equipment [1].

DXA is «a gold standard» of OP diagnostics today. The examinations are held on the level of lumber spine section, in the area of radial bone and the neck of thigh bone [72].

Received indexes determine a standard deviation from MDBT peak and are called T-score. Standard deviation from average value of MDBT fort he patient’s age is called Z-score. According tot he reccommendations of International Community of Clinical Densitometry (ICCD), T-score is applied form en aged from 50 and more and the women in the stage of menopause, Z-score is applied for the men to 50 and the women in premenopausal stage.

DXA method is rather convenient as it provides us with the opportunity to determine MDBT of the whole skeleton and its separate sections, namely of those with the highest risk of fractures. MDBT is evaluated in the area under scanning. To spot the deformation of vertebras bodies we apply lateral pictures of spine which gives the possibility to diagnose fractures of vertebras bodies in case when T-index does not coincide to the value of OP. DXA has less irradiation than typical X-ray examination. The method is sensitive and and specific, with its help we can determine up to 90,00 % of fractures. Owing to a high level of safety this method has acquired a wide range of use in the world medical practice [1, 3].

As DXA determines only MDBT, it is sometimes a very serious limit as the results of the research do not point to the changes in bone structure which is extremely important in order to evaluate bone resistability to fractures.

In some cases, even having a compressive spine fracture as a result of OP, the indexes of MDBT may be in norm or falsly testify aobout osteopenia which does not coinside to the patient’s state and condition [72].

According to the reccommendations of ICCD, to diagnose OP for the patients with RA at the age from 30 to 50 it is necessary to conduct DXA on the level of lumber spine section. It is not advisable to expect that osteoporosis-caused changes for the patients of young age will be observed in the area of the neck of a thigh bone as it is known that MDBT loss in the area of a thigh bone begins at the age of 65. One should remember that the patients with RA should not experience the evaluation of MDBT in the area of distal end of a radial bone. This result will be characterized by abnormal OP manifestation as a result of RA and the inflammations caused by it which will provoke a local loss of MDBT [7].

Very often vertebra fractures are painless and are not timely diagnosed. Only about 30,00 % of these types of fractures are accompanied with pain syndrome. In such cases pain in the chest and the lumber spine section are mistaken for the inflammation of nerve radicals. The people who had at least one such fracture in the anamnesis, have a 5-7 times higher risk of fractures [2, 30].

Numerous researches prove a considerable growth of fractures for the patients with RA in comparison to healthy people of the same age [30].

In clinical research, in a research (191 patients with RA at a postmenopausal stage) and in a controlled (713 patients at a postmenopausal stage) groups (in both groups the patients at the age of 45–65 years old) we have evaluated the number of compressive fractures o the basis of X-rays. The patients with RA had compressive fractures twice more often than in a controlled group. Such researches prove the necessity of the evaluation of the state of MDBT of lumber spine section [30].

With the help of DXA it is not possible to diagnose compressive fractures in a lumber spine section [59].

One of the alternative methods of MDBT evaluation is a quantitative computer tomography (QCT). QCT is the largest and most precise method of MDBT evaluation in comparison to DXA [40]. One of the advantages of this research is the opportunity to receive 3 dimensional reflections. The largest advantage of QCT is the possibility to reflect bone structure and fulfill the differentiation between cortical and trabecular bones [40]. Owing to this it is possible to evaluate the volume of MDBT in a lumber spine section even for the patients with slight degenerate damage in this area. The results of QCT may be evaluated with the help of MDBT volume evaluation only on the sample of trabecular bone in which the development processes occur faster that in cortical one [40].

Insufficient differentiation of bone tissue during DXA leads to the OP disguise and false rise of MDBT caused by the degenerate changes and it demands considerable intrvals between the examinations in order to show the changes in MDBT.

A major limit concerning the number of QCT is a large dose of X-ray irradiance. It is 2500,00–3000,00 mczv on average when in DXA  it is about 13,00 mczv [41], which makes DXA a routine method of examination and is often used to control the treatment.

The most important task in the process of OP treatment is to minimize the risk of fractures for the patients with RA and the improvement of life quality.

Throughout recent years bisphosphonates are the best medicine for the treatment of OP. The major result of bisphosphonates lies in MDBT increase and the normalization of metabolic processes in bones. Bisphosphonates are effective in case of postmenopausal OP and OP induced by GC. The results of th research show that approximately 50,00 % of osteoporosis fractures may be prevented using bisphosphonates [38, 44, 59]. However, in clinical research the efficiency of this group of medicines is proved only under the circumstances of their long use [9, 50].

One more medicine for OP is PTG which protects OB from apoptosis and increases their activity [69, 70, 71]. The use of PTG has been researched for the women with RA in postmenopausal stage who took GC and estrogens. In this population, a daily use of teryparatid increased MDBT of spine and more or less of a thigh bone. PTG injection promotes a primary bone tissue development with a gradual increase of bone tissue resorption.

In 2007 there was conducted a multicenter, random, controlled research to compare the effects of teriparatide and alendronic acis for the patients who received a long treatment by GC and had a high risk of fractures. In this research we have evaluated MDBT in a lumber spine section [43, 44]. The results of the research showed that teriparatid was more effective than alendronic acid and it also provoked the same slight side effects as a local injection reaction, headache which testifies to a high level of danger.

The researchers have recently terminated the phase of clinical approbation for one more medicine – abaloparatide. Its function lies in a selective receptor activation of paratiroid hormone of I type [35]. The results of the research showed a higher efficiency of the medicine in comparison to placebo and teriparatide as the prevention of another osteoporosis vertebra fractures and also of hypercalcaemia development [43].

The prescription of calcium and vitamin D 3 has become a routine practice which is considered as a basic treatment of OP. However, one should not forget that these medicines are not sufficient to prevent from bone mass loo for the patients with a high risk of fractures occurence [17, 23].

Very often, the patients who take GC to cure the main disease are also recommended vitamin D and calcium which prevent from bone mass loss and renew the amount of calcium in blood serum [23]. Vitamin D increases oxygen resorption of calciaum and its reabsorption in distalic canals of kidneys as a result of which the amount of calcium in blood serum increases. Throughout a 2 year random research the patients with RA who took prednyzolon (average dose is 5,60 mg/24 hrs), showed the decrease of MDBT up to 0,90 % a year in a lumber spine section and in the neck of a thigh bone [23]. The patients randomly included in the research took calcium (1000,00 mg/24 hrs) and vitamin D (500,00 МО/ day),  had a yearly increase of MDBT up to 0,72 %in their spines and to 0,85 % in the neck of a thigh bone [10, 23]. We should note that the patients who take GC may be resistant to vitamin D. So, the patients should receive a sufficient amount of vitamin D to keep the amount of 25-hydroxyvitamin D considerably higher than minimal when a normal level is 30,00 ng/ml. Many experts recommend keeping the concentration of 25-hydroxyvitamin D >40,00 ng/ml or 110,00 nmoll/l [10, 11, 23]. The amount of vitamin D to achieve this goal is often 1000,00–2000,00 MO daily or an equivalent weekly use.

Some researchers doubt the efficiency of the medicines which contain calcium, others believe that it is absolutely enough to take vitamin D [15, 29, 54], one more category of researchers believe defend the fact that the prescription of calcium slightly increase MDBT, but it is not enough to prevent fractures [53, 63]. Some researchers claim that calcium should not be used regularly as they fear of negative impact on kidney, gastrointestinal track and cardiovascular system [15, 54]. It is probable that the reccommendations concerning calcium prescription advisability should be reconsidered [57].

О. V. Synenkiy investigated the manifestation of vitamin D deficit for the patients with RA.  He added an individual purposeful treatment of vitamin D deficit to the scheme of a basic antirheumatoid treatment with the aim of lessening of a pain syndrome [4].

Other class of medicines applied for OP treatment is represented by the selective modulators of estrogen receptors, but since 2012 this group of medicines ceased to be recommended by European Agency of Medicines for OP treatment because of a higher risk of cancer menace as a result of a long use [26].

In recent years it has become usual to apply strontium ranelate which provides antiresorptive and anabolic effect towards bone tissue and owing to this it is considered a medicine with double effect, though its mechanism has not been studied yet [12].

One more medicine as an option for OP treatment is denosumab. In the research [22, 58, 64, 75] the monotherapy by denosumab and the efficiency of the combination of calcium and vitamin D were studied. According to the results of research the amount of calcium in serum was decreasing only in the group of patients who took denosumab. After the addition of vitamin D and calcium to to the therapy percent changes in MDBT considerably increased. Many scientiests [59] recommend the combination of denosumab and vitamin D for the patients with OP who have a high risk of fracture occurrence in the area of the neck of a thigh bone.

The inhibitors yanus – kinasa which are used for RA treatment are at the stage of research now. Today many investigations are being held now which demonstrate that such selective inhibitors as Jakl and Jak2, as baricithinib, filgothinib slow down osteoclastogenesis suppressing the expression of RANKL in osteoblasts. Baritsitinib blocks the growth of X-ray changes for the patients with RAУ [66, 67], but the functional mechanism with the help of which it prevents from bone destruction under arthritis has not been fully studied yet.

Notwithstanding the fact that there are many medicines for OP cure, in practice there arise a lit of difficulties in choosing the ones, treatment duration, a correct shift of the treatment from one medicine to anther, doses. It especially concerns the patients with hard OP condition and a high risk of fracture occurrence, who have been taking the medicines for OP cure for a long time. Apart from this, a low compliance leads to the decrease of the efficiency of OP medicines and as a result it suppsesses the expected treatment effect. That is why the search of new schemes of treatment and new medicines still last, it will enable us to optimize the prevention and OP treatment.

Clinical Case Description. The patient, G.I., 1974of birth, applied with the complaints of distinctive pain in a lumber spine section which reinforces in the course of movement, periodical aching in small hand wrist and heel joints, radial-wrist and forearm joints, in a chest and lumber spine sections which increases while moving. The patient also complained of periodical swelling of small hand wrist joints, the feeling of morning constraint and up to 1 hour, periodical heartbeat, eyes redness, legs and arms stiffness, the swelling of legs and general weakness.

Out of the anamnesis: the patient claims being ill since June of 2013 when she first felt migrating pain in her joints. She consulted a local rheaumatologist. The doctor suspected RA and prescribed diclorber, dexamethasone and neurorubin. The treatment did not meet an expected effect. The patient was hhospitalized into a rheumatology unit of LRCH, where she was diagnosed «Rheumatoid Arthritis». After the treatment (medrol 24,00 mg, sulfasalazine 2,00 gr/24 hrs) the state improved. In 6 months the patient herself stopped taking sulfasalazine and reduced ady dose of GC to 8,00 mg/24 hrs, which worsened her state. Throughout the last two months there occurred the ache in a lumber spine section. The patient consulted neurologist and orthopaedist with a slight improvement.  The ache in a lumber spine section increased throughout the last three days. The patient was hospitalized into a rheumatology unit of LRCH because of her bad condition.

Out of her life anamnesis: in her childhood the patient suffered from smallpox, rubella and frequent aggravations of chronic tonsilitis. The patient rejects having tuberculosis, venereal illnesses, hepatitis, malaria, diabetis and other chronic diseases and traumas. She does not smoke and does not abuse hard drinks. Genetics: patient’s mother suffered from pancreas cancer, her father had lung cancer. In 1982 the patient suffered from appendectomy, in 2010 – thyroidectomy.

Objective examination: general state – average severity. Body weight– 63,00 kg. Height – 163,00 сm. Body weight index – 24,00 %. S-shaped scoliosis of neck and chest spine sections. Body constitution is normosthenic. Mucous membranes are pale pink, humid and clear. Skin is pale pink, humid; trophic ulcer of front left tibia. There were the swellings of para-orbital areas. Lymph nodes are available to palpation, not enlarged and painful.  There was a pastoralism of lower extremities more distinctive on the right. Respiratory organs: breath frequency (BF) – 19 per 1 min; percussionally there was a clear lung sound; auscultationally – the breath wasvesicular on the whole surface of lungs. The organs of cardio-vascular system: heart rate (HR) – 76 per 1 min; pulse – 76 per 1 min, it was of an average filling, tension was satisfactory; a pulse deficit – no; palpatedly: apical push localized in the fifth intercostal space on lin. med.-clav. sin., moderately resistant; auscultationally: heart tones were rhythmical, clear, sounding, blood pressure (BP) on the left – 120/80 mm. mr.pil., on the right – 120/80 mm. mer.pil. The organs of gastrointestinal system: the tongue is humid with white furring; belly is oval, there was an operation scar (аppendectomy); soft and painless during palaption; deep palpation: the gut is elastic, painless; lower ending of liver – +1,0 сm pierces out of the end of edge arc, painless, oval; spleen is not susceptible to palaption; liver size according to M.G. Kurlov is: 9,00–8,00–7,00 сm; auscultationally: threre are peristaltic noise. The organs of urinary system: the area of kidney is unchanged during the examinatio; kidneys are not susceptible to palpation, s-m of F.I. Pasternatskiy: left «+», right «+»; there are no dysuric manifesations. Joint-bone system: defiguration of small hand joints and feet; active and passive movements are abruptly limited in all the spine sections; not considerably limited in hand joints; hand wrist strength is considerably lowered; the tone of skeleton muscles is preserved; the pace is violated (through the pain in a lumber spine section). Endocrine system: exophthalmos, there is an operation scar on the front neck area (thyroidectomy).

The patient had laboratory and instrumental investigations: 1) general blood test – leukocytosis (leuk. /WBC/ – 16,10/17,90•109/l), normchromic anemia  (erythrocytes  – 3,55/3,63•1012/l, hemoglobin – 115,00/118,00 g/l), lymphopenia – lymphocytes (10,00/14,00 %), ESA (16,00/17,00 mm/hr.); 2) general urine test – b/о;  3) biochemical blood test– РФ – 68,10 (N < 14,0 UN/l), cholesterol – 5,80 mmoll/l (N < 5,20 mmoll/l), β-lipoproteins – 70,00 (N  35,00–55,00 mmoll/l), ionized calcium – 1,06 mmoll/l (N 1,15–1,27 mmoll/l), general calcium – 1,70 mmoll/l (N 2,12–2,52 mmoll/l); phosphor in blood serum – 1,09 mmoll/l (N 0,87–1,45 mmoll/l); β-сrossLaps – 0,27 ng/ml (N 0,57 ng/ml); P1NP – 20,20 ng/ml (N 15,00–59,00 ng/ml); osteocalcin – 14,75 ng/ml (N 11,0–43,0 ng/ml); parathormone – 3,97 pg/ml (N 15,00–65,00 pg/ml); vitamin D amount 57,19 ng/ml (N 30,00–100,00 ng/ml). 4)biochemical urine test: calcium in urine – 4,54 mmoll/24 hrs (N 1,00–8,80 mmoll/24 hrs); phosphor in urine – 32,76 mmoll/24 hrs (N 12,0–42,0 mmoll/24 hrs); creatinin in urine – 15,47 mmoll/24 hrs (N 5,30–13,30 mmoll/24 hrs). 5) immunological analysis – antinuclear anbodies increase – 1:100 (N < 1:100), the increase of the level of anti-CCР >500,00 Un/ml (N 0-17 un/ml); 6) blood test for AIDS,  hepatitis В and С markers, RW – negative.

In the results of instrumental research there are deviations: 1) Rtg-graphy of neck and chest spine section – there are OP changes, neck lordosis straightening, convergent deformation on the level С6-С7-Th1, S-shaped neck and chest scoliosis of І-ІІ stages, the increase of intervertebral discs С4–С6, the narrowing of relevant intervertebral holes, multiple sclerosis, the flattening of specific plates, angle, edge and apical ostephites. Conclusion: р-features of intervertebral oteochondrosis of chest and neck spine sections;

2) RTg-graphy of knee joints. It is visible on the Rtg-graphy of a right knee joint that they are determined by the narrowing of joint crack, subchondral sclerosis, area OP, by the medium outline of big tibia bone one can determine the sharpening(thyroid-shaped) of bone structure . Conclusions: the features of osteoarthrosis of І-ІІ types;

3) On Rtg –graphy of a chest spine section  (in two dimensions) the bodies of  Th3–Th8 are rotated, when Th7 is wedge-shapedly narrowed to the front up to 1/3 of vertebra height which differentiates hypercystitis of a chest spine section from a physiological one; intervertebral intervals from Th3 to Th11 are narrowed, occlusive plates are compacted, body sufaces are sharpened. Along with the shift to a lumber – sacrum spine section we can observe the straightening of physiological lordosis and  L5 body shift backwards from S1; all intervertebral intervals in a chest and lumber spine sections are narrowed (maximum L4–L5, L5–S1) with subchondric osteosclerosis and a slight sharpening of front surfaces of vertebra bodies. Conclusion: osteochondrosis of a chest and lumber spine sections.  Rtg-graphy of hand wrists is the narrowing of joint openings, subchondral sclerosis, epiphyseal osteoporosis; the deformation on the right in the area of interfail joints of І-ІІ type. Conclusion: the features of poliosteoarthrosoarthritis of ІІ-ІІІ type;

4) MRI of spine – degenerate spine changes; МR-features of OP; new compressive fracture of vertebra body of L1, of bodies Th10, Th11, Th12; compressive fractures with a slight decrease of vertebra bodies lowering of Th5, Th7, Th9; osteochondrosis of neck and chest spine sections; the protrusion of the С3–С4b С4–С5b С5–С6 discs; arthrosis of rib and vertebra joints; degenerate changes of ileosacral joints; slight size increase of spinal ganglia of lumber spine section. It needs a clinical correlation; there is the probability of ganglionitis previously;

5) spirographic: the violation of ventilating lung ability with restrictive type І, a slight decrease of bronchial patency the I restrictive type;

6) DЕXA – forearm – norm (T-score (-0,40), Z-score (0,30)), lumber spine section – osteopenia (T-score ( -1,20), Z-score (-0,90)), right thigh bone – osteopenia (T-score (-0,50), Z-score (-0,30));

7) ultrasound densitometry  (BQI – 73,90; T-Score –1,70; Z-Score –1,30; T-coefficient – 70,40 %; Z-coefficient– 74,60 %);

8) X-ray densitometry for the determination of the indexes of Е. Barnett – В. Nordin (T-Score –2,04; Z-Score –1,37; T-coefficient71,10 %; Z-coefficient 78,53 %).

The patient has also been consulted by neuropathologist and was diagnosed – thoraco lumbalgia on the ground of degenerate changes of chest and lumber spine sections, the deformation of Th5, Th7 vertebra bodies with the features of compression with sharp pain syndrom; orthopedist diagnosed new compressive fractures of L1, Th10–11, Th12 bodies, old fractures of Th5, Th7, Th9 ones, osteochondrosis;  a vascular surgeon diagnosed lymphostasis of both lower extremities; gynecologist diagnosed node leiomyoma of the uterus; ophthalmologist diagnosed endocrinic ophtalmopathy, retinal angiopathy;  cardiologist diagnosed arteria hypertension: ІІ stage (hypertensive retinal angiopathy ), І stage, the risk of ІІ, СН 0-І; otolaryngologist diagnosed chronic tonsilitis; the surgeon concluded umbilical retracting keel; endocrinologist diagnosed post operational hypotirosis (hard type) and medicine hypercorticism. 

Judging by patient’s complaints, the information out of anamnesis, the results of objective examination, laboratory and instrumental research the patient was give a clinical conclusion: «Rheumatois arthritis: seropositive (RF-, anti-MCV, anti-CCP-positiv); polyarthritis (along with small hand joints damage, radial and wrist, forearm and knee joints, X-ray stage of ІІ-ІІІ, functional insufficiency of joints of ІІ type); active phaseа (І-ІІ  type activity); complicated: osteoporosis of  mixed genesis – the main diseaseо + medicine like with compressive fractures of the bodies of L1, Th10–11, Th12, with consolidated fractures of Th5, Th7, Th9 and distinctice pain syndrom; arterial hypertension: mixed genesis (medicine + endocrinic): ІІ stage (hypertensive retinal angiopathy), І stage,  ІІ risk , СН 0-І (with preserved systolic function of left ventricle of FV 63,00 %), І FK according to NYHA.

Hypothirosis: post-operational (thyroidectomy for the reason of diffuse toxic goiter in 2010): of hard stage; at the stage of medicine compensation; complicated: metabolic and endocrinic miocardiopathy, dysmetabolic neuropathy of extremities, double-sided exophtalmos.

Spine ostheochondrosis: neck, chest and lumber sections; ІІІ stage (with disk С3–С4, С4–С5, С5–С6 protrusion); S-shaped scoliosis of neck and chest spine sections of І-ІІ stages.

Lymphostasis of both lower extremities. Manipulated umbilical keel. Node myleiomyoma of the uterus. Chronic tonsilitis. Post apendyctomy state (1982 р.). The functional class of a “therapeutic case II”.

The problem of OP for the patients with RA needs further investigation of pathogenetic mechanisms and the methods of early diagnostics which will enable us to justify new schemes of effective differentiated treatment of this category of patients.

Conclusions. The review of modern sources and clinical case description testify to the fact that the patients with rheumatoid arthritis are characterized by considerable deviations of calcium and phosphor interchange along with bone damage, however there is a lack of data about pathogenetic mechanisms, optimal diagnostic methods of osteoporosis and its treatment. Very often those data are insufficient and controversial which is the reason for further research in this field.

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