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. Significant prevalence of rheumatoid arthritis (RA), an unceasing increase in morbidity, affliction of working age population, late diagnosis, not always effective treatment and large economic damage due to this disease and its complications, are the actual problems in medical field and should be further explored.

The aim of the studi. To make the review of the literature and the description of the clinical case devoted to finding out the features of pathogenesis, diagnosis and principles of differentiated treatment of calcium­phosphorus metabolism and bone state in patients with RA.

Materials and methods. The content analysis, the method of system and comparative analysis, the bibliosemantic method of studying the actual scientific research of the features of calcium­phosphorus metabolism and the state of bones in patients with RA, pathogenesis, diagnostic methods and principles of differentiated treatment were used. The search for the sources was carried out in the scientific­medical databases: PubMed­NCBI, Medline, CochraneLibrary, EMBASE, ResearchGate by keywords: RA, osteoporosis, RANK / RANKL / OPG, densitometry, P1NP, calcium, phosphorus, vitamin D, parthyroid hormone. In total, 75 sources in English and Ukrainian have been analyzed. The selected sources highlight the pathogenesis, diagnostic methods with proven high sensitivity and specificity, treatment principles. In addition, the clinical case is described.

Results. RA and its complications, which are mostly the result of calciumphosphorus exchange disorders, lead to early disability of people of working age, due to the occurrence of fractures. Clinical signs of osteoporosis in patients with RA are often nonspecific and diagnosed untimely. Therefore, the issue of early diagnosis and treatment principles is still relevant.

Conclusions. The overview of modern literature and the description of the clinical case suggest that patients with rheumatoid arthritis exhibit the significant disturbances in calcium­phosphorous metabolism with bone defeat, but the information on pathogenetic mechanisms, optimal methods for diagnosis of osteoporosis and its treatment are insufficient, and sometimes contradictory. That is why there is a need to continue the research in this direction.

References

  1. Abrahamovych UО, Abrahamovych OО, Tsyhanyk LV, Synenkyi OV, Guta SI. Сomparative evaluation of bone mineral density based upon the results of ultrasound osteodensitometry, X-ray osteodensitometry, and dual-energy X-ray absorptiometry tests in premenopausal women with systemic lupus erythematosus. Lviv Clinical Bulletin. 2017;1(17):32-37. (Ukrainian). https://doi.org/10.25040/lkv2017.01.032 
  2. Nogas AO. Rheumatoid arthritis – current state of the problem. Materials of the conference “Physical education, sports and health culture in modern society”: collection of scientific works of Lesya Ukrainka Eastern European National University. Lutsk, 2013;1(21):298-302. (Ukrainian).
  3. Povoroznyuk VV, Balacka NI. The role of markers of bone remodeling in diagnosing systemic osteoporosis. Art of Treatment. 2013;2-3(98-99):12-14. (Ukrainan)
  4. Synenkyi OV. The infuence of vitamin d defciency on the rheumatoid arthritis activity and the ways of its corrections. Lviv Clinical Bulletin. 2017;4(20):15-24. (Ukrainan). https://doi.org/10.25040/lkv2017.04.015
  5. Shimon VM, Stoyka VV, Sheremy AA, Lemko II, Kubash VI. Uzhgorod National University Biochemical markers of bone tissue in patients with subtrochanteric femoral fracture and thyrotoxicosis. Clinical and Experimental Pathology. 2017;16(2):179-185. (Ukrainan)
  6. Alam J, Jantan I, Bukhari SNA. Rheumatoid arthritis: Recent advances on its etiology, role of cytokines and pharmacotherapy. Biomed Pharmacother. 2017;92:615-633. https://doi.org/10.1016/j.biopha.2017.05.055
  7. Alves CH, Farrell E, Vis M, Colin EM, Lubberts E. Animal models of bone loss in inflammatory arthritis: from cytokines in the bench to novel treatments for bone loss in the bedside-a comprehensive review. Clin Rev Allergy Immunol.2016;51(1):27-47. https://doi.org/10.1007/s12016-015-8522-7
  8. Bolland MJ, Leung W, Tai V, Bastin S, Gamble GD, Grey A et al. Calcium intake and risk of fracture: systematic review. 2015;351:h4580. https://doi.org/10.1136/bmj.h4580
  9. Bone HG, Chapurlat R, Brandi ML, Brown JP, Czerwinski E, Krieg MA et al. The effect of three or six years of denosumab exposure in women with postmenopausal osteoporosis: results from the FREEDOM extension. J Clin Endocrinol Metab. 2013;98(11):4483-4492. https://doi.org/10.1210/jc.2013-1597
  10. Bragazzi N, Watad A, Neumann S, Simon M, Brown S, Abu Much A et al. Vitamin D and rheumatoid arthritis: an ongoing mystery. Curr Opin Rheumatol. 2017;29(4):378-388. https://doi.org/10.1097/BOR.0000000000000397
  11. Bellan M, Sainaghi P, Pirisi M. Role of Vitamin Din Rheumatoid Adv Exp Med Biol. 2017;996:155-168. https://doi.org/10.1007/978-3-319-56017-5_13
  12. Burch J, Rice S, Yang H, Neilson A, Stirk L, Francis R et al. Systematic review of the use of bone turnover markers for monitoring the response to osteoporosis treatment: the secondary prevention of fractures, and primary prevention of fractures in highrisk groups. Health Technol Assess. 2014;18(11):1-180. https://doi.org/10.3310/hta18110
  13. Calabresi E, Petrelli F, Bonifacio A, Puxeddu I, Alunno A. One year in review 2018: pathogenesis of rheumatoid arthritis. Clin Exp Rheumatol. 2018;36(2):175-184.
  14. Cavalier E, Bergmann P, Bruyere O, Delanaye P, Durnez A, Devogelaer JP et al. The role of biochemical of bone turnover markers in osteoporosis and metabolic bone disease: a consensus paper of the Belgian bone Osteoporos Int. 2016;27(7):2181-2195. https://doi.org/10.1007/s00198-016-3561-3
  15. Cesareo R, Iozzino M, D’Onofrio L, Terrinoni I, Maddaloni E, Casini A et al. Effectiveness and safety of calcium and vitamin D treatment for postmenopausal osteoporosis. Minerva Endocrinol. 2015;40(3):231-237.
  16. Cho SK, Kim D, Won S, Lee J, Choi CB, Choe JY et al. Factors associated with time to diagnosis from symptom onset in patients with early rheumatoid arthritis. Korean J Intern Med. 2017. Available from: http://kjim.org/journal/view.php?doi=10.3904/kjim.2017.113. https://doi.org/10.3904/kjim.2017.113
  17. Cross M, Smith E, Hoy D, Carmona L, Wolfe F, Vos T, Williams B et al. The global burden of rheumatoid arthritis: estimates from the global burden of disease 2010 study. Ann Rheum Dis. 2014;73(7):1316-1322. https://doi.org/10.1136/annrheumdis-2013-204627
  18. Di Munno О, Ferro F. The effect of biologic agents on bone homeostasis in chronic inflammatory rheumatic diseases. Clin Exp Rheumatol. 2019;37(3):502-507.
  19. Dougados M, Soubrier M, Antunez A, Balint P, Balsa A, Buch MH et al. Prevalence of comorbidities in rheumatoid arthritis and evaluation of their monitoring: results of an international, cross-sectional study (COMORA). Ann Rheum Dis. 2014;73:62-68. https://doi.org/10.1136/annrheumdis-2013-204223
  20. Dougados M, Soubrier M, Perrodeau E, Gossec L, Fayet F, Gilson M et al. Impact of a nurse-led programme on comorbidity management and impact of a patient self-assessment of disease activity on the management of rheumatoid arthritis: results of a prospective, multicentre, randomised, controlled trial (COMEDRA). Ann Rheum Dis. 2015;74(9):1725-1733. https://doi.org/10.1136/annrheumdis-2013-204733
  21. El-Henawy AA, Hafez EAR, Nabih N, Shalaby NM, Mashaly M. Anti-Toxoplasma antibodies in Egyptian rheumatoid arthritis patients. Rheumatol Int. 2017;37(5):785-790. https://doi.org/10.1007/s00296-017-3703-8
  22. Farooki A, Fornier M, Boland P. Atypical femur fractures associated with use of bisphosphonates and denosumab. Ann Oncol. 2015;26(4):819-820. https://doi.org/10.1093/annonc/mdv014
  23. Fautrel B, Verstappen SM, Boonen A. Economic consequences and potential benefits. Best Pract Res Clin Rheumatol. 2011;25:607-624. https://doi.org/10.1016/j.berh.2011.10.001
  24. Frisell T, Holmqvist M, Källberg H, Klareskog L, Alfredsson L, Askling J. Familial risks and heritability of rheumatoid arthritis: role of rheumatoid factor/anti-citrullinated protein antibody status, number and type of affected relatives, sex, and age. Arthritis Rheum. 2013;65:2773-2782. https://doi.org/10.1002/art.38097
  25. Gavan S, Harrison M, Iglesias C, Barton A, Manca A, Payne K. Economics of stratified medicine in rheumatoid arthritis. Curr Rheumatol Rep. 2014;16:468. https://doi.org/10.1007/s11926-014-0468-x
  26. Gullick NJ, Scott DL. Co-morbidities in established rheumatoid arthritis. Best Pract Res Clin Rheumatol. 2011;25:469-483. https://doi.org/10.1016/j.berh.2011.10.009
  27. Guo Q, Wang Y, Xu D, Nossent J, Pavlos NJ, Xu J. Rheumatoid arthritis: pathological mechanisms and modern pharmacologic therapies. Bone Res. 2018;6:15. https://doi.org/10.1038/s41413-018-0016-9
  28. Hamdi RA. Evaluation of Serum Osteocalcin level in Iraqi Postmenopausal women with primary osteoporosis. J Fac Med Baghdad. 2013;55(2):166-169.
  29. Harvey NC, Biver E, Kaufman JM, Bauer J, Branco J, Brandi ML et al. The role of calcium supplementation in healthy musculoskeletal ageing : an expert consensus meeting of the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) and the International Foundation for Osteoporosis (IOF). Osteoporosis international: a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. 2016. https://doi.org/10.1007/s00198-016-3773-6
  30. Hoes JN, Bultink IE, Lems WF. Management of osteoporosis in rheumatoid arthritis patients. Expert Opin Pharmacother. 2015;16(4):559-571. https://doi.org/10.1517/14656566.2015.997709
  31. Humphreys J, Verstappen S, Hyrich K, Chipping J, Marshall T, Symmons D. The incidence of rheumatoid arthritis in the UK: comparisons using the 2010 ACR/EULAR classification criteria and the 1987 ACR classification criteria. Results from the Norfolk Arthritis Register. Ann Rheum Dis. 2013; 72 (8):1315-1320. https://doi.org/10.1136/annrheumdis-2012-201960
  32. Hunter T, Boytsov N, Zhang X, Schroeder K, Michaud K, Araujo A. Prevalence of rheumatoid arthritis in the United States adult population in healthcare claims databases, 2004-2014. Rheumatol Int. 2017; 37(9):1551-1557. https://doi.org/10.1007/s00296-017-3726-1
  33. IngegnoliF, Castelli R, Gualtierotti R. Rheumatoid factors: clinical applications. Dis Markers. 2013;35(6):727-734. https://doi.org/10.1155/2013/726598
  34. Iseme RA, Mcevoy M, Kelly B, Agnew L, Walker FR, Attia Is osteoporosis an autoimmune mediated disorder? Bone Rep. 2017;7:121-131. https://doi.org/10.1016/j.bonr.2017.10.003
  35. Isogai Y, Takao-Kawabata R, Takakura A, Sugimoto E, Nakazono O, Ikegaki I et al. Early effects of single and low-frequency repeated administration of teriparatide, hPTH(1-34), on bone formation and resorption in ovariectomized rats. Calcif Tissue Int. 2015;97(4):412-420. https://doi.org/10.1007/s00223-015-0026-1
  36. Jagtap VR, Ganu JV, Nagane NS. BMD and serum intact osteocalcin in postmenopausal osteoporosis women. Ind J Clin Biochem. 2013;26(1):70-73. https://doi.org/10.1007/s12291-010-0074-2
  37. Kanis JA, McCloskey EV, Johansson H, Cooper C, Rizzoli R, Reginster JY.European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporos Int 2013;24:23-57. https://doi.org/10.1007/s00198-012-2074-y
  38. Katsarelis H, Shah NP, Dhariwal DK, Pazianas M. Infection and medication-related osteonecrosis of the jaw. J Dent Res. 2015;94(4):534-539. https://doi.org/10.1177/0022034515572021
  39. Kuo CF, Grainge MJ, Valdes AM, See LC, Yu KH, Shaw SWS et al. Familial aggregation of rheumatoid arthritis and co-aggregation of autoimmune diseases in affected families: a nationwide population-based study. 2017;56:928-933. https://doi.org/10.1093/rheumatology/kew500
  40. Li N, Li XM, Xu L, Sun WJ, Cheng XG, Tian W. Comparison of QCT and DXA: Osteoporosis Detection Rates in Postmenopausal Women. Int J Endocrinol. 2013;2013:895474. https://doi.org/10.1155/2013/895474
  41. Link TM, Lang T. Axial QCT: Clinical Applications and New Developments. J Clin Densitom. 2014;17:438-448. https://doi.org/10.1016/j.jocd.2014.04.119
  42. Luo Y, Hu Z, Hao J, Jiang W, Shen J, Zhao J. Significant associations between the A163G and G1181C polymorphisms of the osteoprotegerin gene and risk of osteoporosis, especially in postmenopausal women: a meta-analysis. Genetic testing and molecular biomarkers. 2014;18(3):211-219. https://doi.org/10.1089/gtmb.2013.0420
  43. Miller PD, Hattersley G, Riis BJ, Williams GC, Lau E, Russo LA et al. Effect of abaloparatide vs placebo on new vertebral fractures in postmenopausal women with osteoporosis: a randomized clinical trial. 2016;316(7):722-733. https://doi.org/10.1001/jama.2016.11136
  44. Miller PD, Pannacciulli N, Brown JP, Czerwinski E, Nedergaard BS, Bolognese MA et al. Denosumab or zoledronic acid in postmenopausal women with osteoporosis previously treated with oral bisphosphonates. J Clin Endocrinol Metab. 2016;101(8):3163-3170. https://doi.org/10.1210/jc.2016-1801
  45. Mori T, Miyamoto T, Yoshida H, Asakawa M, Kawasumi M. IL-1β and TNFα-initiated IL-6-STAT3 pathway is critical in mediating inflammatory cytokines and RANKL expression in inflammatory arthritis. Int Immunol. 2011;23(11):701-712. https://doi.org/10.1093/intimm/dxr077
  46. Moura CS, Abrahamowicz M, Beauchamp ME, Lacaille D, Wang Y, Boire G et al. Early medication use in new-onset rheumatoid arthritis may delay joint replacement: results of a large population-based study. Arthritis Res Ther. 2015;17:197. https://doi.org/10.1186/s13075-015-0713-3
  47. Naylor KE, Jacques RM, Paggiosi M, Gossiel F, Peel NF, McCloskey EV et al. Response of bone turnover markers to three oral bisphosphonate therapies in postmenopausal osteoporosis: the TRIO study. Osteoporos Int. 2016;27(1):21-31. https://doi.org/10.1007/s00198-015-3145-7
  48. Norton S, Koduri G, Nikiphorou E, Dixey J, Williams P, Young A. A study of baseline prevalence and cumulative incidence of comorbidity and extra-articular manifestations in RA and their impact on outcome. Rheumatology (Oxford). 2013;52(1):99-110. https://doi.org/10.1093/rheumatology/kes262
  49. Pietschmann P, Mechtcheriakova D, Meshcheryakova A, Föger-Samwald U, Ellinger I. Immunology of osteoporosis: a mini-review. 2016;62(2):128-137. https://doi.org/10.1159/000431091
  50. Project Europe 2030. http://espas.eu/orbis/sites/default/files/generated/ document/en/Project%20Europe%202030.pdf. Accessed 30 December 2015.
  51. Radner H. Multimorbidity in rheumatic conditions. Wien Klin Wochenschr. 2016;128(21-22):786-790. https://doi.org/10.1007/s00508-016-1090-x
  52. Ranganath VK, Maranian P, Elashoff DA, Woodworth T, Khanna D, Hahn T et al. Comorbidities are associated with poorer outcomes in community patients with rheumatoid arthritis. Rheumatology (Oxford). 2013;52(10):1809-1817. https://doi.org/10.1093/rheumatology/ket224
  53. Reid IR, Bristow SM, Bolland MJ. Calcium supplements: benefits and risks. J Intern Med. 2015;278(4):354-368. https://doi.org/10.1111/joim.12394
  54. Reid IR. Should we prescribe calcium supplements for osteoporosis prevention? J Bone Metabol. 2014;21(1):21-28. https://doi.org/10.11005/jbm.2014.21.1.21
  55. Ruyssen-Witrand A, Degboé Y, Cantagrel A, Nigon D, Lukas C, Scaramuzzino S et al. Association between RANK, RANKLand OPG polymorphisms with ACPA and erosions in rheumatoid arthritis: results from a meta-analysis involving three French cohorts. RMD Open.2016 Sep 8;2(2):e000226. https://doi.org/10.1136/rmdopen-2015-000226
  56. Schmickler J, Rupprecht A, Patschan S, Patschan D, Müller GA, Haak R et al. Cross-Sectional Evaluation of Periodontal Status and Microbiologic and Rheumatoid Parameters in a Large Cohort of Patients With Rheumatoid Arthritis. J Periodontol. 2017;88(4):368-379. https://doi.org/10.1902/jop.2016.160355
  57. Schweser KM, Crist BD. Osteoporosis: a discussion on the past 5 years. Curr Rev Musculoskelet Med. 2017;10(2):265-274. https://doi.org/10.1007/s12178-017-9410-y
  58. Shane E, Burr D, Abrahamsen B, Adler RA, Brown TD, Cheung AM et al. Atypical subtrochanteric and diaphyseal femoral fractures: second report of a task force of the American Society for Bone and Mineral Research. J Bone Minl Res. 2014;29(1):1-23. https://doi.org/10.1002/jbmr.1998
  59. Sheedy KC, Camara MI, Camacho PM. Comparison of the efficacy, adverse effects, and cost of zoledronic acid and denosumab in the treatment of osteoporosis. Endocr Pract. 2015;21(3):275-279. https://doi.org/10.4158/EP14106.OR
  60. Sherina N, Hreggvidsdottir HS, Bengtsson C, Hansson M, Israelsson L, Alfredsson L et al. Low levels of antibodies against common viruses associate with anti-citrullinated protein antibody-positive rheumatoid arthritis; implications for disease aetiology. Arthritis Res Ther. 2017;19(1):219. https://doi.org/10.1186/s13075-017-1423-9
  61. Sokolove J., Pisetsky D. Bone loss, pain and inflammation: three faces of ACPA in RA pathogenesis. Rheum Dis Published Online First. 2016. https://doi.org/10.1136/annrheumdis-2015-208308
  62. Svendsen AJ, Junker P, Houen G, Kyvik KO, Nielsen C, Skytthe A et al. Incidence of Chronic Persistent Rheumatoid Arthritis and the Impact of Smoking: A Historical Twin Cohort Study. Arthritis Care Res (Hoboken). 2017;69(5):616-624. https://doi.org/10.1002/acr.22987
  63. Tai V, Leung W, Grey A, Reid IR, Bolland MJ. Calcium intake and bone mineral density: systematic review and meta-analysis. 2015;351:h4183. https://doi.org/10.1136/bmj.h4183
  64. Tanaka Y, Ohira T. Mechanisms and therapeutic targets for bone damage in rheumatoid arthritis, in particular the RANK-RANKL system. Curr Opin Pharmacol. 2018;40:110-119. https://doi.org/10.1016/j.coph.2018.03.006
  65. Tanaka S, Tanaka Y, Ishiguro N, Yamanaka H, Takeuchi T. RANKL: A therapeutic target for bone destruction in rheumatoid arthritis. Mod Rheumatol. 2018;28(1):9-16. https://doi.org/10.1080/14397595.2017.1369491
  66. Taylor P, Keystone E, van der Heijde D, Weinblatt M, Del Carmen Morales L, Reyes Gonzaga J et al. Baricitinib versus Placebo or Adalimumab in Rheumatoid Arthritis. N Engl J Med. 2017;376(7):652-662. https://doi.org/10.1056/NEJMoa1608345
  67. Taylor P, Abdul Azeez M, Kiriakidis S. Filgotinib for the treatment of rheumatoid arthritis. Expert Opin Investig Drugs. 2017;26(10):1181-1187. https://doi.org/10.1080/13543784.2017.1372422
  68. Tenne M, McGuigan F, Besjakov J, Gerdhem P, Åkesson K. Degenerative changes at the lumbar spine-implications for bone mineral density measurement in elderly women. Osteoporos Int. 2013;24(4):1419-1428. https://doi.org/10.1007/s00198-012-2048-0
  69. Tsai JN, Uihlein AV, Burnett-Bowie SA, Neer RM, Zhu Y, Derrico N et al. Comparative effects of teriparatide, denosumab, and combination therapy on peripheral compartmental bone density, microarchitecture, and estimated strength: the DATA-HRpQCT study. J Bone Miner Res. 2015;30(1):39-45. https://doi.org/10.1002/jbmr.2315
  70. Tsai JN, Uihlein AV, Burnett-Bowie SM, Neer RM, Derrico NP, Lee H et al. Effects of two years of teriparatide, denosumab, or both on bone microarchitecture and strength (DATA-HRpQCT study). J Clin Endocrinol Metab. 2016;101(5):2023-2030. https://doi.org/10.1210/jc.2016-1160
  71. Tsai JN, Uihlein AV, Lee H, Kumbhani R, Siwila-Sackman E, McKay EA et al. Teriparatide and denosumab, alone or combined, in women with postmenopausal osteoporosis: the DATA study randomised trial. 2013;382(9886):50-56. https://doi.org/10.1016/S0140-6736(13)60856-9
  72. Węgierska M, Dura M, Blumfield E, Żuchowski P, Waszczak M, Jeka S. Osteoporosis diagnostics in patients with rheumatoid arthritis. 2016;54(1):29-34. https://doi.org/10.5114/reum.2016.58759
  73. Whittington M, McQueen R, Ollendorf D, Chapman R, Kumar V, Synnott P et al. Assessing the Value of Sarilumab Monotherapy for Adults with Moderately to Severely Active Rheumatoid Arthritis: A Cost-Effectiveness Analysis. J Manag Care Spec Pharm. 2019;25(1):80-87. https://doi.org/10.18553/jmcp.2019.25.1.080
  74. Zheng J, Mao X, Ling J, He Q, Quan J, Jiang H. Association between serum level of magnesium and postmenopausal osteoporosis: a meta-analysis. Biol Trace Elem Res. 2014;159(1-3):8-14. https://doi.org/10.1007/s12011-014-9961-3
  75. Zhou Z, Chen C, Zhang J, Ji X, Liu L, Zhang G et al. Safety of denosumab in postmenopausal women with osteoporosis or lw bone mineral density: a meta-analysis. Int J Clin Exp Pathol. 2014;7(5):2113-2122.