Endocrinologist O.V. Danilenko
Associate professor, Ph.D. L.P. Churilov
St. Petersburg State University, St. Petersburg
Professor, Dr.Med. S.A. Varzin
St. Petersburg State Polytechnic University, St. Petersburg
Professor, Dr.Med. K.J. van Zwieten
University of Hasselt, Diepenbeek, Belgium

Keywords: connective tissue dysplasia, marfanoid phenotype, trauma, spine, bones, osteopenia, osteoporosis, sport.

Introduction. Increased flexibility and plasticity of the ligament-articular apparatus are among the main criteria for qualifying future athletes. However, high incidence of spinal injuries, early articular diseases and their complications in athletes are a major problem which often turns into a tragedy: retirement from sport at the beginning of successful sports career. Joint hypermobility syndrome and a high risk of injuries and lesions of the musculoskeletal system are interrelated: most often they occur against the background of connective tissue dysplasia.

Undifferentiated connective tissue dysplasia (UCTD) is a widespread, polygenic, hereditary, multi-syndrome state, against the background of a metabolic disturbance and self-assembly of connective tissue, particularly collagen, elastin and associated proteins and proteoglycans [7]. Marfanoid, Ehlers-like and mixed (dysplastic) phenotypes are distinguished in the structure of UCTD. One is attributed to one of these phenotypes based on the presence of particular features of habitus, internal organs and flexibility tests according to the rating criteria [7, 12].

Generally, children and young people of mixed (dysplastic) phenotype have the greatest potential for sport [1]. On the other hand, sports potential may reduce the presence of evident signs of UCTD, particularly of joint hypermobility [4, 9].

UCTD is not a disease but a constitutionally determined prenosological state, which predisposes to a number of clinical syndromes and chronic diseases [3]. Instability in mesenchymal derivatives, including the locomotor system, to energy and plastic deprivation caused by hypercorticism, which is typical for training-competitive stress, is expressed in such individuals by early development of linear atrophy and is typical for any variant of UCTD [1].

Osteopenia, early osteoporosis and related complications, occurring at a relatively early age, are a major concern of persons of the dysplastic phenotype [3]. Our own clinical experience and the data obtained by many authors [8, 10] have shown that their signs may be detected in case of UCTD as early as at the age of 13-17. Mostly, it is local osteoporosis of the 2^nd lumbar vertebra.

Materials and methods. We observed a total of 243 individuals of dysplastic phenotype (151 women among them) of young adulthood and juvenile age of 14-25 (18,1±0,5 years on the average) for osteopenia and osteoporosis based on the methodology of integrated diagnostics of low bone mass and osteoporosis in children and young adults [5]. About 55% of them were engaged in professional and semiprofessional sport, the rest attended health and fitness sections. The signs of UCTD were verified on a point scale in accordance with the modified Ghent criteria [7]. Bone mineral density was determined by densimetric method, primarily in L1-L4 lumbar parts of the spine. The indices of the bone tissue metabolism and regulation measured in blood plasma using the standard immunoenzyme and biochemical methods were as follows [6]: osteocalcin (OC), calcitriol - vitamin D3 (D(ON) 1,25), marker of bone resorption - product  of cleavage (depolymerization) of mature type I collagen, the main structure bone proteins (В-CrossLaps); marker of osteogenesis (P1PN); parathyreocrin, or parathormone (PTH), calcium to phosphorus ratio (Ca/P). The control group consisted of individuals of both sexes and similar age of 14-25, of normosthenic somatotype (F:M=2:1, 18,1±0,4 years), who had no signs of UCTD, 65% of which were involved in sports. The data were processed using the parametric methods of variation statistics, the Student-Fisher t-test and the Pearson’s linear correlation coefficient (r).

Results and discussion. Such complications as cervical osteochondrosis, radiculitis, sciatic neuralgia, spinal compression fractures, which are closely associated with early osteoporosis, are observed in most individuals with UCTD by the age of 35. In terms of extra load on the locomotor system and sport stress, these complications were detected even earlier - at the age of 15-25 [7]. Within the examined group, in 4 cases we observed Schmorl's node of the sacral spine (protrusions of the intervertebral discs) in the girls of 12-14 years, and Osgood-Schlatter disease (radio-carpal joint hernia) in the young tennis-player aged 15. During densitometry of L1-L4 lumbar parts of the spine, low bone mineral density (BDM) was registered, within the range of minus 10-14% in 89% of the examined. Osteopenia to UCTD ratio was high (r=0,91). No gender differences were observed in bone mineralization (p<0,1), however, the correlation of UCTD and bone mass deficit was equally high in males and females (r=0,96). Taking into account the examined quantity, and involvement of male and female individuals, it can be stated that moderately low bone mineral density is constitutionally typical for individuals with UCTD. The presence of UCTD-associated osteopenia, within reasonable limits, should not be interpreted as a contraindication to sports activities: in past medical history of people of dysplastic phenotype, occurrence of traumatic fractured limbs was almost three times as low compared with normosthenic people (р<0,05). Probably, the low risk of fractures is specifically due to moderately low mineralization, which makes bones, as composite material, less brittle and more elastic. However, against the background of UCTD-osteopenia, under training-competitive stress, occurrence of early osteoporosis and related complications increases significantly (р<0,001). Bone mass deficit is growing with age [6] in any contingent of people. But in case of UCTD against the background of the initial BMD-10-14%, this deficit, which is typical for osteoporosis, starts forming earlier compared with normosthenic people. Thus, in case of UCTD, average mineralization deficit amounts to: 10% - at the age of 15 BMDL1-L4, 16% - at the age of 20, 20% - at the age of 25, 24-26% - at the age of 30, while at the age of 15 in individuals without UCTD BMDL1-L4 is within normal limits, and at the age of 30 it amounts only to 15%.

The characteristic feature of UCTD-associated osteopenia was the low level of OC - less than 2 ng/ml (norm – 3-11 ng/ml), observed in 89% of the examined. At the same time, the UCTD carriers had an insufficient level of calcitriol - within the range of 11-19 ng/ml. These indices never fell under 10 ng/ml, that is, we never observed absolute deficit of vitamin D, but we did not observe normal values either - above 30 ng/ml. Rickets in young children is accompanied by a decay of the concentration of vitamin D and osteocalcin in the blood, increase of Ca/P and PTH. Changes in the indices of bone tissue metabolism are observed also in case of the hormone-driven (cortisone-excessive or steroid-deficit), not associated with UCTD, osteopenia [6]. В-CrossLaps is a sensible biochemical marker of low bone density. The most expressed bone density disorders, typical for women of pre- and postmenopausal age, are accompanied by an increase of В-CrossLaps, PTH and OC. It is well-known that the P1NP value is in direct proportion to the content of newly-synthesized tissue-inbuilt collagen, and in case of osteogenesis disorders and osteoporosis, the P1NP level decreases [6]. UCTD-associated osteopenia differs from UCTD-nonassociated one (rachitic, hypoestrogenic, in case of hypercorticism) as there are no signs of imbalance between osteogenesis and osteolysis: the В-CrossLaps, P1PN, PTH, Са/Р levels, against the background of BMD-10-14%, in individuals with UCTD were within the physiological standard. UCTD-osteopenia is constitutional and is not associated with abnormalities of regulation, which depends on the above-mentioned hormones. It is commonly known, that OC is formed of osteoblasts and odontoblasts when stimulated by calcitriol. Most probably, the low level of OC in case of UCTD is predetermined by vitamin D metabolic disorders. OC serves as the most specific marker of osteoblastic activity during the normal bone formation [6]. Consequently, the OC level <2 ng/ml indicates low activity of osteoblasts, which leads to low bone tissue mineralization and constitutionally determined osteopenia. Vitamin D metabolic disorders might be the key unit of pathogenesis of formation of UCTD-associated osteopenia and early osteoporosis tendency. Moreover, in case of UCTD they are not driven by its exogenous deficit. The contingent of people with UCTD is prone to autoimmune thyroiditis (AIT) and early development of autoimmune disorders [12]. We assume that the reason might be the insufficient sensibility of nuclear VDR-receptors of calcitriol, which is typical for a number of autoimmune diseases associated with chronic long-lasting infections [2]. This causes osteopenia and later - osteoporosis against the background of UCTD. Further on, worsening AIT and hypothyroidism slow down bone tissue regeneration more and more [6, 12]. More than 50% of the examined individuals from the UCTD group turned out to be the carriers of the Epstein-Barr virus, according to immunologic and virologic screening (conducted in cooperation with professor A.A. Yakovlev) [5]. This virus, according to T.G. Marshall, is able to interrupt vitamin D - VDR interaction [2]. The peculiarities of the UCTD-osteopenia explain the low effectiveness of conventional prevention techniques and treatment options for UCTD-associated osteoporosis (preparations of calcium, calcitriol, calcitonin, bisphosphonates) compared to biological preparations (chondroitin, glucozamin, peptide therapy) [5, 10].

Conclusion. Most people with UCTD have an associated mild osteopenia (BMD - 10-14%). The latter, along with lack of inefficiency of vitamin D and a relatively low osteoblast activity is constitutionally inherent in such individuals. Traditional pathogenetic therapy and prevention of osteoporosis in UCTD are less effective. The triad: calcitriol disorders, OC<2 ng/ml, moderate osteopenia at BMD -10-14% can be treated as the marker of UCTD, and, under training-competitive stress, determine an increased risk of yearly osteoporosis and related complications.

References

1. Abdualimov, T.P. Displaziya soedinitel’noy tkani, shchitovidnaya zheleza i sport (Connective tissue dysplasia, thyroid and sport) / T.P. Abdualimov, O.E. Grigor'eva, O.V. Danilenko et al. // Ştiinţa culturii fizice (Cişinău). – 2011. – Nr 8(2). – P. 161–166.
2. Belyaeva, I.V. Katelitsidiny, vitamin D i tuberkulez (Cathelicidins, vitamin D and TB) / I.V. Belyaeva, A.V. Nikolaev, L.P. Churilov, P.K. Yablonsky // Vestnik Sankt Peterburgskogo un-ta. Ser. 11: Meditsina. – 2013. – № 3. – P. 3–18.
3. Viktorova, I.A. Displaziya soedinitel’noy tkani: variant normy ili patologiya? (Connective tissue dysplasia: a kind of norm or pathology?) / I.A. Viktorova // Book of abstracts of the I session of therapists of Siberia and the Far East. - Novosibirsk: Avangard, 2005. – P. 119–122.
4. Viktorova, I.A. Gipermobilnost’ sustavov: vliyanie izbytochnykh fizicheskikh nagruzok na formirovanie bolevogo sindroma (Hypermobility of joints: the impact of excessive physical load on pain syndrome formation) / I.A. Viktorova, D.S. Kiseleva, I.G. Kalitskaya et al. // Med. vestn. Sev. Kavkaza. – 2008. № 2(10). – P. 105–108.
5. Danilenko, O.V. Vozmozhnosti primeneniya peptidoterapii pri NDST-assotsiirovannom osteoporoze (Applications peptidotherapy at NCTD-associated osteoporosis) / O.V. Danilenko // Proceedings of the XIX Internat. theor.-pract. conf on biotherapy (19 April 2014). – Moscow: RegBioMed, 2014. – P. 56.
6. Zaychik, A.S. Patokhimiya. Endokrinno-metabolicheskie narusheniya (Pathochemistry. Endocrine and metabolic disorders) / A.S. Zaychik, L.P. Churilov. – St. Petersburg: ELBI-SPB, 2007. – 756 P.
7. Kadurina, T.I. Displaziya soedinitel’noy tkani Connective tissue dysplasia / T.I. Kadurina, V.N. Gorbunova. – St. Petersburg: ELBI-SPB, 2009. – 704 P.
8. Kenis, V.M. Sindrom dobrokachestvennoy gipermobil’nosti  (Benign hypermobility syndrome) / V.M. Kenis // Mater. Ros. kongr. s mezhdunar. uchast. «Molek. Osnovy klin. med. – vozmozhnoe i real’noe» pamyati prof. E.I. Shvartsa (6-9 iyunya 2010 g.) (Proceedings of Rus. congress with internat. participation "Molec. grounds of clin. med. - potentials and real" in memory of prof. E.I. Schwartz (6-9 June 2010). – St. Petersburg: Chelovek i ego zdorov'e, 2010.
9. Marushko, J.V. Klinicheskoe znachenie sindroma displazii soedinitel’noy tkani dlya vrachebnoy i sportivnoy praktiki (Clinical significance of connective tissue dysplasia syndrome for medical and sports practice) / J.V. Marushko, T.V. Marushko, I.N. Gordienko // Sportivnaya meditsina. – 2007. – № 2. – P. 24–31.
10. Pochkaylo, A.S. Sovremennye podkhody k lecheniyu osteoporoza u detey (Modern approaches to treatment of osteoporosis in children) / A.S. Pochkaylo // Med. novosti. – 2013. – № 7. – P. 42–48.
11. Sposob kompleksnoy diagnostiki nizkoy kostnoy massy i osteoporoza u detey i molodykh vzroslykh: instruktsiya po primeneniyu № 154-1208: utv. MZ RB 13.02.2009 (The method of complex diagnostics of low bone mass and osteoporosis in children and young adults: application instructions № 154-1208: decl. MH BR13.02.2009) / V.F. Zhernosek [et al.]. - Minsk: BelMAPO, 2009. – 34 P.
12. Stroev, Yu.I. Klinicheskaya patofiziologiya yuvenil’nogo metabolicheskogo sindroma: rol’ yunosheskogo dispituitarizma, displazii soedinitel’noy tkani i autoimmunnogo tiroidita (Clinical pathophysiology of juvenile metabolic syndrome: the role of youth dispituitarism, connective tissue dysplasia and autoimmune thyroiditis) / Yu.I. Stroev, L.P. Churilov, J.I. Kononova et al // Patol. fiziol. eksperim. terap. – 2011. – № 3. – P. 3–15.

Corresponding author: olgadanil@mail.ru