Biochemical markers of bone turnover associated with calcium supplementation in children with juvenile rheumatoid arthritis: Results of a double-blind, placebo-controlled intervention trial†
Corresponding Author
Ruy Carrasco
Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
Specially for Children, Pediatric Rheumatology, 1301 Barbara Jordan Boulevard, Austin, TX 78723Search for more papers by this authorDaniel J. Lovell
Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
Search for more papers by this authorEdward H. Giannini
Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
Search for more papers by this authorCarol J. Henderson
TriHealth, Hatton Institute for Research and Education, Cincinnati, Ohio
Search for more papers by this authorBin Huang
Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
Search for more papers by this authorSandy Kramer
Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
Search for more papers by this authorJulie Ranz
Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
Search for more papers by this authorJames Heubi
Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
Search for more papers by this authorDavid Glass
Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
Search for more papers by this authorCorresponding Author
Ruy Carrasco
Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
Specially for Children, Pediatric Rheumatology, 1301 Barbara Jordan Boulevard, Austin, TX 78723Search for more papers by this authorDaniel J. Lovell
Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
Search for more papers by this authorEdward H. Giannini
Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
Search for more papers by this authorCarol J. Henderson
TriHealth, Hatton Institute for Research and Education, Cincinnati, Ohio
Search for more papers by this authorBin Huang
Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
Search for more papers by this authorSandy Kramer
Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
Search for more papers by this authorJulie Ranz
Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
Search for more papers by this authorJames Heubi
Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
Search for more papers by this authorDavid Glass
Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
Search for more papers by this authorClinicalTrials.gov identifier: NCT00000429.
Abstract
Objective
To determine the effects of calcium supplementation on bone physiology in corticosteroid-free children with juvenile rheumatoid arthritis (JRA) by measuring serum and urinary bone-related hormones, minerals, and markers of bone formation and resorption.
Methods
In this double-blind trial, patients were randomized to receive daily oral supplementation with 1,000 mg of calcium and 400 IU of vitamin D or with placebo and 400 IU of vitamin D for 24 months. The effect of calcium supplementation on bone physiology was determined periodically using markers of bone turnover.
Results
One hundred ninety-eight patients met the inclusion criteria and were followed up in the study. At baseline, there were no differences in markers of bone turnover between the groups. Patients with ≤4 joints with active disease had higher serum levels of calcium and parathyroid hormone (PTH). Calcium-treated patients with ≤4 joints with active disease had lower levels of osteocalcin (OC). At followup, levels of 1,25-dihydroxyvitamin D3, PTH, OC, and urine phosphorus were lower in the group receiving calcium supplementation. Hypercalciuria, as determined by the urinary calcium-to-creatinine ratio, was not noted in 24-hour urine studies.
Conclusion
Levels of markers of bone physiology were significantly decreased in children with JRA receiving calcium supplementation. The physiologic changes were noted as early as 12 months into calcium supplementation. The hypercalciuria noted on spot testing of the urinary calcium-to-creatinine ratio was not demonstrated on further evaluation, nor did it lead to renal pathology. These findings suggest that the calcium supplementation met physiologic needs and caused an increased calcium loss in urine.
REFERENCES
- 1 JT Cassidy, RE Petty, editors. Textbook of pediatric rheumatology. 4th ed. Philadelphia: WB Saunders; 2001.
- 2 Elsasser U, Wilkins B, Hesp R, Thurnham DI, Reeve J, Ansell BM. Bone rarefaction and crush fractures in juvenile chronic arthritis. Arch Dis Child 1982; 57: 377–80.
- 3 Martel W, Holt JF, Cassidy JT. Roentgenologic manifestations of juvenile rheumatoid arthritis. Am J Roentgenol Radium Ther Nucl Med 1962; 88: 400–23.
- 4 Maenpaa H, Savolainen A, Lehto MU, Belt EA. Multiple stress fractures in a young girl with chronic idiopathic arthritis: extended case report. Joint Bone Spine 2001; 68: 438–42.
- 5 Zak M, Hassager C, Lovell DJ, Nielsen S, Henderson CJ, Pedersen FK. Assessment of bone mineral density in adults with a history of juvenile chronic arthritis: a cross-sectional long-term followup study. Arthritis Rheum 1999; 42: 790–8.
- 6 French AR, Mason T, Nelson AM, Crowson CS, O'Fallon WM, Khosla S, et al. Osteopenia in adults with a history of juvenile rheumatoid arthritis: a population based study. J Rheumatol 2002; 29: 1065–70.
- 7 Roth J, Palm C, Scheunemann I, Ranke MB, Schweizer R, Dannecker GE. Musculoskeletal abnormalities of the forearm in patients with juvenile idiopathic arthritis relate mainly to bone geometry. Arthritis Rheum 2004; 50: 1277–85.
- 8 Vestergaard P, Rejnmark L, Mosekilde L. Fracture risk associated with systemic and topical corticosteroids. J Intern Med 2005; 257: 374–84.
- 9 Verstraeten A, Dequeker J. Vertebral and peripheral bone mineral content and fracture incidence in postmenopausal patients with rheumatoid arthritis: effect of low dose corticosteroids. Ann Rheum Dis 1986; 45: 852–7.
- 10 Curtiss PH Jr, Clark WS, Herndon CH. Vertebral fractures resulting from prolonged cortisone and corticotropin therapy. J Am Med Assoc 1954; 156: 467–9.
- 11 Van Staa TP, Leufkens HG, Abenhaim L, Zhang B, Cooper C. Use of oral corticosteroids and risk of fractures. J Bone Miner Res 2000; 15: 993–1000.
- 12 Van Staa TP, Cooper C, Leufkens HG, Bishop N. Children and the risk of fractures caused by oral corticosteroids. J Bone Miner Res 2003; 18: 913–8.
- 13 Henderson CJ, Cawkwell GD, Specker BL, Sierra RI, Wilmott RW, Campaigne BN, et al. Predictors of total body bone mineral density in non–corticosteroid-treated prepubertal children with juvenile rheumatoid arthritis. Arthritis Rheum 1997; 40: 1967–75.
- 14 Levinson JE, Wallace CA. Dismantling the pyramid. J Rheumatol Suppl 1992; 33: 6–10.
- 15 Rabinovich CE. Osteoporosis: a pediatric perspective [editorial]. Arthritis Rheum 2004; 50: 1023–5.
- 16 Cameron MA, Paton LM, Nowson CA, Margerison C, Frame M, Wark JD. The effect of calcium supplementation on bone density in premenarcheal females: a co-twin approach. J Clin Endocrinol Metab 2004; 89: 4916–22.
- 17 Johnston CC Jr, Miller JZ, Slemenda CW, Reister TK, Hui S, Christian JC, et al. Calcium supplementation and increases in bone mineral density in children. N Engl J Med 1992; 327: 82–7.
- 18 Lloyd T, Martel JK, Rollings N, Andon MB, Kulin H, Demers LM, et al. The effect of calcium supplementation and Tanner stage on bone density, content and area in teenage women. Osteoporos Int 1996; 6: 276–83.
- 19 Chan GM, Hoffman K, McMurry M. Effects of dairy products on bone and body composition in pubertal girls. J Pediatr 1995; 126: 551–6.
- 20 Slemenda CW, Miller JZ, Hui SL, Reister TK, Johnston CC Jr. Role of physical activity in the development of skeletal mass in children. J Bone Miner Res 1991; 6: 1227–33.
- 21 Chinn DJ, Fordham JN, Kibirige MS, Crabtree NJ, Venables J, Bates J, et al. Bone density at the os calcis: reference values, reproducibility, and effects of fracture history and physical activity. Arch Dis Child 2005; 90: 30–5.
- 22 Reed A, Haugen M, Pachman LM, Langman CB. 25-Hydroxyvitamin D therapy in children with active juvenile rheumatoid arthritis: short-term effects on serum osteocalcin levels and bone mineral density. J Pediatr 1991; 119: 657–60.
- 23 Warady BD, Lindsley CB, Robinson FG, Lukert BP. Effects of nutritional supplementation on bone mineral status of children with rheumatic diseases receiving corticosteroid therapy. J Rheumatol 1994; 21: 530–5.
- 24 Lovell DJ, Glass D, Ranz J, Kramer S, Huang B, Sierra RI, et al. A randomized controlled trial of calcium supplementation to increase bone mineral density in children with juvenile rheumatoid arthritis. Arthritis Rheum 2006; 54: 2235–42.
- 25 Stark LJ, Davis AM, Janicke DM, Mackner LM, Hommel KA, Bean JA, et al. A randomized clinical trial of dietary calcium to improve bone accretion in children with juvenile rheumatoid arthritis. J Pediatr 2006; 148: 501–7.
- 26 Stapleton FB, Hanissian AS, Miller LA. Hypercalciuria in children with juvenile rheumatoid arthritis: association with hematuria. J Pediatr 1985; 107: 235–9.
- 27 Reed A, Haugen M, Pachman LM, Langman CB. Abnormalities in serum osteocalcin values in children with chronic rheumatic diseases. J Pediatr 1990; 116: 574–80.
- 28 Reeve J, Loftus J, Hesp R, Ansell BM, Wright DJ, Woo PM. Biochemical prediction of changes in spinal bone mass in juvenile chronic (or rheumatoid) arthritis treated with glucocorticoids. J Rheumatol 1993; 20: 1189–95.
- 29 Nemcova D, Kutilek S, Bayer M, Stepan JJ, Hoza J. Calciuria in children with juvenile chronic arthritis. Acta Univ Carol [Med] (Praha) 1994; 40: 43–5.
- 30 Polito C, Strano CG, Rea L, Alessio M, Iammarrone CS, Todisco N, et al. Reduced bone mineral content and normal serum osteocalcin in non-steroid-treated patients with juvenile rheumatoid arthritis. Ann Rheum Dis 1995; 54: 193–6.
- 31 Bardare M, Bianchi ML, Furia M, Gandolini GG, Cohen E, Montesano A. Bone mineral metabolism in juvenile chronic arthritis: the influence of steroids. Clin Exp Rheumatol 1991; 9 Suppl 6: 29–31.
- 32 Falcini F, Ermini M, Bagnoli F. Bone turnover is reduced in children with juvenile rheumatoid arthritis. J Endocrinol Invest 1998; 21: 31–6.
- 33 Kasapcopur O, Sever L, Tasdan Y, Caliskan S, Arisoy N. Hypercalciuria and hematuria in juvenile rheumatoid arthritis. J Rheumatol 1998; 25: 993–6.
- 34 Cassidy JT, Levinson JE, Bass JC, Baum J, Brewer EJ Jr, Fink CW, et al. A study of classification criteria for a diagnosis of juvenile rheumatoid arthritis. Arthritis Rheum 1986; 29: 274–81.
- 35 Rockett HR, Wolf AM, Colditz GA. Development and reproducibility of a food frequency questionnaire to assess diets of older children and adolescents. J Am Diet Assoc 1995; 95: 336–40.
- 36 Blair SN, Haskell WL, Ho P, Paffenbarger RS Jr, Vranizan KM, Farquhar JW, et al. Assessment of habitual physical activity by a seven-day recall in a community survey and controlled experiments. Am J Epidemiol 1985; 122: 794–804.
- 37 Henderson CJ, Lovell DJ, Specker BL, Campaigne BN. Physical activity in children with juvenile rheumatoid arthritis: quantification and evaluation. Arthritis Care Res 1995; 8: 114–8.
- 38 Howe S, Levinson J, Shear E, Hartner S, McGirr G, Schulte M, et al. Development of a disability measurement tool for juvenile rheumatoid arthritis: the Juvenile Arthritis Functional Assessment Report for children and their parents. Arthritis Rheum 1991; 34: 873–80.
- 39 Ravelli A, Viola S, Ruperto N, Corsi B, Ballardini G, Martini A. Correlation between conventional disease activity measures in juvenile chronic arthritis. Ann Rheum Dis 1997; 56: 197–200.
- 40 Steinbrocker O, Traeger CH, Batterman RC. Therapeutic criteria in rheumatoid arthritis. JAMA 1949; 140: 659–62.
- 41 Dunbar-Jacob J. Contributions to patient adherence: is it time to share the blame? Health Psychol 1993; 12: 91–2.
- 42 Olivieri NF, Matsui D, Hermann C, Koren G. Compliance assessed by the Medication Event Monitoring System. Arch Dis Child 1991; 66: 1399–402.
- 43 Cramer J, Rosenheck R, Kirk G, Krol W, Krystal J. Medication compliance feedback and monitoring in a clinical trial: predictors and outcomes. Value Health 2003; 6: 566–73.
- 44 Yang L, Grey V. Pediatric reference intervals for bone markers. Clin Biochem 2006; 39: 561–8.
- 45 Osterberg L, Blaschke T. Adherence to medication. N Engl J Med 2005; 353: 487–97.
