Сhanges in bone metabolism during cerebral palsy

Introduction. Patients with cerebral palsy (CP) are especially vulnerable to the development of osteopenia. Skeletal deformities caused by immobility (prolonged bed rest, limited exercise, immobilization), antiepileptic drugs, hormonal and genetic factors can lead to significant bone loss. Diagnosis of osteoporosis includes densitometry and the study of biochemical markers to assess the state of bone mineralization at the time of the examination. However, densitometry in patients with cerebral palsy may present certain difficulties.

Purpose is to determine changes in the content of bone tissue metabolism markers in CP patients depending on the severity of movement disorders.

Materials and methods. We examined 32 CP patients aged 2 to 15 years for 3 months who were in rehabilitation in 2019–2021. The patients were divided into 2 groups: 18 children in the main group with motor dysfunctions of level IV–V and 14 children in the  comparisons group — with disorders of I–III levels. All children underwent an analysis of anthropometric parameters using the program “WHO AnthroPlus (2009)”, determination of the blood levels of biochemical markers of bone tissue metabolism: calcium, phosphorus, alkaline phosphatase, osteocalcin, vitamin D, parathyroid hormone, bone resorption marker β-CrossLaps.

Results. The indices of alkaline phosphatase, calcium and phosphorus in the majority of CP patients (88%) were within the reference values. The average concentrations of these compounds did not differ significantly in CP patients in the main group and the comparison group, including between children who received and did not receive antiepileptic drugs. There were no significant differences in 25(OH)D concentrations in patients of these groups. CP patients from the main group were found to be supplemented with vitamin D less frequently than children from the comparison group. Indicators of bone tissue resorption (β-CrossLaps) in patients with cerebral palsy increased significantly more than in patients of the comparison group, which indicates a pronounced loss of bone mass in severe impairment of motor functions. More than half of CP patients have high values of the bone resorption marker β-CrossLaps, which, together with an increase in the level of osteocalcin, indicates active osteoreparation, which is higher in children with severe motor disorders. At the same time, a close correlation (r = 0.596; p < 0.05) between the levels of osteocalcin and β-CrossLaps in patients may indicate activation of bone tissue repair in response to pronounced resorption. However, it should be noted that the determination of biomarkers of bone tissue metabolism in children with cerebral palsy is not indicative in the detection of osteopenia and osteoporosis due to the characteristics of these patients: reduced motor activity, growth retardation and psychophysical development.

Contribution:
Zvonkova N.G., Borovik T.E., Fisenko A.P., Kuzenkova L.M., Semikina E.L. — concept and design of the study;
Maslova N.А., Bushueva T.V., Mavrikidi E.F. — collecting the data;
Chernikov V.V. — statistical treatment;
Maslova N.A., Zvonkova N.G., Borovik T.E. — writing the text;
Maslova N.А. — editing the text.
All co-authors — Approval of the final version of the manu­script, responsibility for integrity.

Acknowledgment. The study had no sponsorship.

Conflict of interest. The authors declare no conflict of interest.

Received: March 31, 2022
Accepted: April 26, 2022
Published: May 07, 2022

1. Ward L.M., Weber D.R., Munns C.F., Högler W., Zemel B.S. A contemporary view of the definition and diagnosis of osteoporosis in children and adolescents. J. Clin. Endocrinol. Metab. 2020; 105(5): e2088-97. https://doi.org/10.1210/clinem/dgz294

2. Sakai T., Honzawa S., Kaga M., Iwasaki Y., Masuyama T. Osteoporosis pathology in people with severe motor and intellectual disability. Brain Dev. 2020; 42(3): 256–63. https://doi.org/10.1016/j.braindev.2019.12.010

3. Yaşar E., Adigüzel E., Arslan M., Matthews D.J. Basics of bone metabolism and osteoporosis in common pediatric neuromuscular disabilities. Eur. J. Paediatr. Neurol. 2018; 22(1): 17–26. https://doi.org/10.1016/j.ejpn.2017.08.001

4. Gulati S., Sondhi V. Cerebral palsy: an overview. Indian J. Pediatr. 2018; 85(11): 1006–16. https://doi.org/10.1007/s12098-017-2475-1

5. Henderson R.C., Lark R.K., Gurka M.J., Worley G., Fung E.B., Conaway M., et al. Bone density and metabolism in children and adolescents with moderate to severe cerebral palsy. Pediatrics. 2002; 110(1 Pt. 1): e5. https://doi.org/10.1542/peds.110.1.e5

6. Henderson R.C., Kairalla J.A., Barrington J.W. Longitudinal chan ges in bone density in children and adolescents with moderate to severe cerebral palsy. J. Pediatr. 2005; 146(6): 769–75. https://doi.org/10.1016/j.jpeds.2005.02.024

7. Galashevskaya A.A., Pochkaylo A.S. Modern approaches to prevention and treatment of osteoporosis in children with cerebral palsy. Pediatriya. Vostochnaya Evropa. 2021; 9(1): 94–106. https://doi.org/10.34883/PI.2021.9.1.008 (in Russian)

8. Krokhina K.N., Smirnov I.E., Kucherenko A.G., Belyaeva I.A. The dynamics of osteogenesis markers in newborns of various gestational age. Voprosy diagnostiki v pediatrii. 2011; 3(4): 25–31. (in Russian)

9. Krokhina K.N., Smirnov I.E., Belyaeva I.A. The specific features of bone formation in newborns. Rossiyskiy pediatricheskiy zhurnal. 2010; (5): 36–41. (in Russian)

10. Smirnov I.E., Krokhina K.N., Kucherenko A.G., Zayniddinova R.S., Belyaeva I.A. Markers of osteogenesis in healthy and sick neonates. Rossiyskiy pediatricheskiy zhurnal. 2011; (5): 13–8. (in Russian)

11. Leal-Martínez F., Franco D., Peña-Ruiz A., Castro-Silva F., Escudero-Espinosa A.A., Rolón Lacarrier O.G., et al. Effect of a nutritional support system (diet and supplements) for improving gross motor function in cerebral palsy: an exploratory randomized controlled clinical trial. Foods. 2020; 9(10): 1449. https://doi.org/10.3390/foods9101449

12. Sellier E., Uldall P., Calado E., Sigurdardottir S., Torrioli M., Platt M. Epilepsy and cerebral palsy: characteristics and trends in children born in 1976-1998. Eur. J. Paediatr. Neurol. 2012; 16(1): 48–55. https://doi.org/10.1016/j.ejpn.2011.10.003

13. Petty S., Wilding H., Wark J. Osteoporosis associated with epilepsy and the use of anti-epileptics – a review. Curr. Osteoporos. Rep. 2016; 14(2): 54–65. https://doi.org/10.1007/s11914-016-0302-7

14. Ko A., Kong J., Samadov F., Mukhamedov A., Kim Y., Lee Y., et al. Bone health in pediatric patients with neurological disorders. Ann. Pediatr. Endocrinol. Metab. 2020; 25(1): 15–23. https://doi.org/10.6065/apem.2020.25.1.15

15. Nurković J.S., Petković P., Tiosavljević D., Vojinović R. Measurement of bone mineral density in children with cerebral palsy from an ethical issue to a diagnostic necessity. Biomed. Res. Int. 2020; 2020: 7282946. https://doi.org/10.1155/2020/7282946

16. Moghadam N., Teimouri A., Khajeh A., Hoseini S. Bone metabolism disorder in epileptic children. Iran. J. Child Neurol. 2018; 12(2): 17–24.

17. Miziak B., Chrościńska-Krawczyk M., Czuczwar S. An update on the problem of osteoporosis in people with epilepsy taking antiepileptic drugs. Expert Opin. Drug Saf. 2019; 18(8): 679–89. https://doi.org/10.1080/14740338.2019.1625887

18. Finbråten A.K., Syversen U., Skranes J., Andersen G.L., Stevenson R.D., Vik T. Bone mineral density and vitamin D status in ambulatory and non-ambulatory children with cerebral palsy. Osteoporos. Int. 2015; 26(1): 141–50. https://doi.org/10.1007/s00198-014-2840-0

19. Iorgi N., Maruca K., Patti G., Mora S. Update on bone density measurements and their interpretation in children and adolescents. Best Pract. Res. Clin. Endocrinol. Metab. 2018; 32(4): 477–98. https://doi.org/10.1016/j.beem.2018.06.002

20. Albaghdadi O., Alhalabi M., Alourfi Z., Youssef L. Bone health and vitamin D status in young epilepsy patients on valproate monotherapy. Clin. Neurol. Neurosurg. 2016; 146: 52–6. https://doi.org/10.1016/j.clineuro.2016.04.019

21. Likasitthananon N., Nabangchang C., Simasathien T., Vichutavate S., Phatarakijnirund V., Suwanpakdee P. Hypovitaminosis D and risk factors in pediatric epilepsy children. BMC Pediatr. 2021; 21(1): 432. https://doi.org/10.1186/s12887-021-02906-7

22. Bell K.L., Benfer K.A., Ware R.S., Patrao T.A., Garvey J.J., Arvedson J.C., et al. Development and validation of a screening tool for feeding/swallowing difficulties and undernutrition in children with cerebral palsy. Dev. Med. Child Neurol. 2019; 61(10): 1175–81. https://doi.org/10.1111/dmcn.14220

23. Sees J., Sitoula P., Dabney K., Holmes L. Jr., Rogers K.J., Kecskemethy H.H., et al. Pamidronate treatment to prevent reoccurring fractures in children with cerebral palsy. J. Pediatr. Orthop. 2016; 36(2): 193–7. https://doi.org/10.1097/BPO.0000000000000421

24. Marrani E., Giani T., Simonini G., Cimaz R. Pediatric osteoporosis: diagnosis and treatment considerations. Drugs. 2017; 77(6): 679–95. https://doi.org/10.1007/s40265-017-0715-3

25. Song L. Calcium and bone metabolism indices. Adv. Clin. Chem. 2017; 82: 1–46. https://doi.org/10.1016/bs.acc.2017.06.005

26. Vasikaran S., Eastell R., Bruyere O., Foldes A., Garnero P., Griesmacher A. Markers of bone turnover for the prediction of fracture risk and monitoring of osteoporosis treatment: a need for international reference standards. Osteoporos. Int. 2011; 22(2): 391–420. https://doi.org/10.1007/s00198-010-1501-1

27. Wheater G., Elshahaly M., Tuck S., Datta H., Van Laar J. The clini cal utility of bone marker measurements in osteoporosis. J. Transl. Med. 2013; 11: 201. https://doi.org/10.1186/1479-5876-11-201

28. Kenis V., Bogdanova S., Prokopenko T., Sapogovskiy A., Kiseleva T. Bone metabolism biomarkers in walking children with cerebral palsy. Pediatric Traumatol. Orthop. Reconstr. Surg. 2019; 7(4): 79–86. https://doi.org/10.17816/PTOrS7479-86

29. Smirnov I.E., Roshal’ L.M., Kucherenko A.G., Karaseva O.V., Ponina I.V. Changes in the blood serum content of bone biomarkers and cytokines in children with combined trauma. Rossiyskiy pediatricheskiy zhurnal. 2017; 20(6): 371–8. https://doi.org/10.18821/1560-9561-2017-20-6-371-378 (in Russian)

30. Sakai T., Honzawa S., Kaga M., Iwasaki Y., Masuyama T. Osteoporosis pathology in people with severe motor and intellectual disability. Brain Dev. 2020; 42(3): 256–63. https://doi.org/10.1016/j.braindev.2019.12.010

31. Lewiecki E.M., Gordon C.M., Baim S., Binkley N., Bilezikian J.P., Kendler D.L., et al. Special report on the 2007 adult and pediatric Position Development Conferences of the International Society for Clinical Densitometry. Osteoporos. Int. 2008; 19(10): 1369–78. https://doi.org/10.1007/s00198-008-0689-9

32. Arsent’ev V.G., Aseev M.V., Baranov V.S. Study of bone mineral density in children and adolescents with connective tissue dysplasia. Pediatriya. Zhurnal im. G.N. Speranskogo. 2010; 89(5): 73–7. (in Russian)

33. Weber D.R., Boyce A., Gordon C., Högler W., Kecskemethy H.H., Misra M., et al. The utility of DXA assessment at the forearm, proximal femur, and lateral distal femur, and vertebral fracture assessment in the pediatric population: the 2019 official pediatric positions of the ISCD. J. Clin. Densitom. 2019; 22(4): 567–89. https://doi.org/10.1016/j.jocd.2019.07.002

34. Houlihan C.M., Stevenson R.D. Bone density in cerebral palsy. Phys. Med. Rehabil. Clin. N. Am. 2009; 20(3): 493–508. https://doi.org/10.1016/j.pmr.2009.04.004

35. Ozel S., Switzer L., Macintosh A., Fehlings D. Informing evidence-based clinical practice guidelines for children with cerebral palsy at risk of osteoporosis: an update. Dev. Med. Child Neurol. 2016; 58(9): 918–23. https://doi.org/10.1111/dmcn.13196

36. Akhter N., Khan A., Ayyub A. Motor impairment and skeletal mineralization in children with cerebral palsy. J. Pak. Med. Assoc. 2017; 67(2): 200–3.

37. Crofton P.M., Evans N., Taylor M.R., Holland C.V. Serum CrossLaps: Pediatric reference intervals from birth to 19 years of age. Clin. Chem. 2002; 48(4): 671–3.

38. Smirnova G.I., Rumyantsev R.E. Vitamin D and allergic diseases in children. Rossiyskiy pediatricheskiy zhurnal. 2017; 20(3): 166–72. https://doi.org/10.18821/1560-9561-2017-20-3-166-172 (in Russian)

39. Tatay Díaz A., Farrington D.M., Downey Carmona F.J., Macías Moreno M.E., Quintana del Olmo J.J. Bone mineral density in a population with severe infantile cerebral palsy. Rev. Esp. Cir. Ortop. Traumatol. 2012; 56(4): 306–12. https://doi.org/10.1016/j.recot.2012.03.001 (in Spanish)

40. Gissel T., Poulsen C.S., Vestergaard P. Adverse effects of antiepileptic drugs on bone mineral density in children. Expert Opin. Drug Saf. 2007; 6(3): 267–78. https://doi.org/10.1517/14740338.6.3.267

41. Petty S.J., O’Brien T.J., Wark J.D. Antiepileptic medication and bone health. Osteoporos. Int. 2007; 18(2): 129–42. https://doi.org/10.1007/s00198-006-0185-z

42. Suljic E.M., Mehicevic A., Mahmutbegovic N. Effect of long-term carbamazepine therapy on bone health. Med. Arch. 2018; 72(4): 262–6. https://doi.org/10.5455/medarh.2018.72.262-266

43. Min L., Chunyan W., Biaoxue R. Effects of valproic acid on skeletal metabolism in children with epilepsy: a systematic evaluation and meta-analysis based on 14 studies. BMC Pediatr. 2020; 20(1): 97. https://doi.org/10.1186/s12887-020-1984-7

44. Tosun A., Erisen Karaca S., Unuvar T., Yurekli Y., Yenisey C., Omurlu I.K. Bone mineral density and vitamin D status in children with epilepsy, cerebral palsy, and cerebral palsy with epilepsy. Childs Nerv. Syst. 2017; 33(1): 153–8. https://doi.org/10.1007/s00381-016-3258-0

45. Abdullah A.T., Mousheer Z.T. Vitamin D status in epileptic children on valproic acid; a case-control study. Arch. Acad. Emerg. Med. 2020; 8(1): e13.

46. Verrotti A., Greco R., Latini G., Morgese G., Chiarelli F. Increased bone turnover in prepubertal, pubertal, and postpubertal patients receiving carbamazepine. Epilepsia. 2002; 43(12): 1488–92. https://doi.org/10.1046/j.1528-1157.2002.13002.x

47. Vestergaard P. Effects of antiepileptic drugs on bone health and growth potential in children with epilepsy. Paediatr. Drugs. 2015; 17(2): 141–50. https://doi.org/10.1007/s40272-014-0115-z

48. Koo D., Hwang K., Han S., Kim J., Joo E., Shin W., et al. Effect of oxcarbazepine on bone mineral density and biochemical markers of bone metabolism in patients with epilepsy. Epilepsy Res. 2014; 108(3): 442–7. https://doi.org/10.1016/j.eplepsyres.2013.09.009

49. Romano C., Wynckel M., Hulst J., Broekaert I., Bronsky J., Dall’Oglio L., et al. European society for paediatric gastroenterology, hepatology and nutrition guidelines for the evaluation and treatment of gastrointestinal and nutritional complications in children with neurological impairment. J. Pediatr. Gastroenterol. Nutr. 2017; 65(2): 242–64. https://doi.org/10.1097/MPG.0000000000001646

50. Penagini F., Mameli C., Fabiano V., Brunetti D., Dilillo D., Zuccotti G.V. Dietary intakes and nutritional issues in neurologically impaired children. Nutrients. 2015; 7(11): 9400–15. https://doi.org/10.3390/nu7115469.59