CRA Forum: Review

A randomized controlled trial of calcium supplementation to increase bone mineral density in children with juvenile rheumatoid arthritis.
Lovell DJ, Glass D, Ranz J, Kramer S, Huang B, Sierra R, Henderson C, Passo M, Graham B, Bowyer S, Higgins G, Rennebohm R, Schikler K, Giannini G. Arthritis Rheum 2006; 54:2235-2242.

Dr. CIARÁN DUFFY
MB BCh MSc FRCPC

Editorial by Dr. CIARÁN DUFFY

A number of studies have shown that children and adolescents with juvenile rheumatoid arthritis (JRA) (now encompassed within the term juvenile idiopathic arthritis) have reduced bone mass, irrespective of preceding medication, and that such loss persists into adulthood. Since peak bone mass is achieved towards the end of the second decade of life, intervention strategies to prevent bone loss must be initiated early, a fact confirmed by a number of intervention trials which demonstrated that calcium supplementation increases bone mineralization in healthy children, especially in pre-adolescent children. Since the role of bisphosphonates has yet to be clearly established in children with growing bone, the administration of calcium supplementation to young children with JRA to prevent osteopenia has become an accepted strategy although it had never been studied in a well-conducted interventional trial.

Lovell and colleagues addressed this issue in a well-conducted large multi-centre trial that included a total of 198 children and adolescents with JRA, present for a mean of 5.6 years, who were randomized to one of two groups who received 1,000 mg of elemental calcium daily, together with 400 IU of Vitamin D, or placebo, together with 400 IU of Vitamin D. Patients underwent total body bone mineral density (TBBMD) measurement by dual X-ray absorptiometry (DEXA) at baseline and every 6 months for 24 months. Data were carefully controlled for potential confounding effects (outcome effect modifiers) by the conduct of a longitudinal random-effects mixed model. The latter strategy proved to be important as it assisted in demonstrating a small, but statistically significant difference, in favour of the active treatment group. Of note is that TBBMD also increased in the placebo group, partly due to growth, but possibly also contributed to by the administration of Vitamin D to this group.

This trial which took over 6 years to complete, and involved many of the larger centres in the US, highlights some of the difficulties in conducting large trials in children with JRA – acquiring an adequate sample size, the need for many centres, long period of time from initiation to publication of the results (here it took 10 years). While it shows a treatment effect in favour of the active treatment group, this small effect would not have been noted without a carefully constructed analytic model. Moreover, the demonstrated small treatment effect suggests that calcium and Vitamin D alone are insufficient in treating this problem and other interventions need to be studied.

LEARNING OBJECTIVES

Intervention trials in healthy children and adolescents suggest that calcium supplementation increases bone mineralization.
In children with juvenile rheumatoid arthritis, calcium supplementation increases total body bone mineral density (TBBMD) even in the absence of pre-existing osteopenia, although the effect is small.
Intervention trials in children with juvenile rheumatoid arthritis need to control carefully for potential outcome effect modifiers lest small but statistically significant effects might be missed.

ABSTRACT

Objective: To examine the effects of daily supplementation with calcium (Ca) in combination with vitamin D on total body and lumbar spine bone mineral density (BMD) in patients with juvenile rheumatoid arthritis (JRA) who had not taken corticosteroids for at least 3 months prior to the beginning of the study.

Methods: One hundred ninety-eight children and adolescents (141 girls and 57 boys) with JRA, ages 6 to 18 years, with a mean +/- SD age of 11.7 +/- 3.3 years and a mean +/- SD disease duration of 5.6 +/- 3.8 years at the beginning of the study, were enrolled in this randomized double-blind, placebo-controlled trial to receive either daily oral supplements of 1,000 mg of Ca and 400 IU of vitamin D (n = 103) or matched placebo tablets and 400 IU of vitamin D (n = 95) for 24 months. Total body BMD (TBBMD) was measured by dual x-ray absorptiometry at baseline and every 6 months for 24 months.

Results: At baseline, the mean +/- SD TBBMD was 0.89 +/- 0.14 gm/cm2 among patients randomized to the Ca group and 0.87 +/- 0.14 gm/cm2 among those randomized to placebo (P = 0.445). At 24 months, the mean +/- SD TBBMD among those receiving Ca was 0.95 +/- 0.13 gm/cm2, compared with 0.92 +/- 0.14 gm/cm2 among those receiving placebo. A longitudinal random-effects mixed model analysis that controlled for differences in the subject's initial BMD, sex, Tanner stage, adherence to the study medication regimen, and body composition revealed significantly higher TBBMD among patients who received Ca compared with patients who received placebo during the study period (P = 0.03).

Conclusion: Ca supplementation resulted in a small, but statistically significant, increase in TBBMD compared with placebo in children with JRA.

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Review by Dr. CIARAN DUFFY
CRA Forum : Review by Dr. CIARAN DUFFY