Table 1

 Bisphosphonate studies in connective tissue disease, including patients with JIA

StudyIntervention groupAge (mean±SD) and sexBisphosphonate: dose and routeControl groupAge (mean ±SD) and sexFollow upDensitometryMarkers of bone turnover
*The case series reported by Cimaz et al,19 included children from the cohort study conducted by Bianchi et al, as well as some additional children.
†Conference abstract.
JIA, juvenile idiopathic arthritis, International League against Rheumatism criteria; JRA, juvenile rheumatoid arthritis, American Rheumatism Association criteria; JCA, juvenile chronic arthritis, European League Against Rheumatism (EULAR) criteria; SLE, systemic lupus erythematosus; OI, osteogenesis imperfecta; DPA, dual photon absorptiometry; ALP, alkaline phosphatase.
Randomised controlled trial
Rudge et al (2005)2011 patients: JIA (2), SLE (6), autoimmune haemolytic anaemia (1), inflammatory bowel disease (1), renal transplantation (1); 10 completed study9.9±2.8 years
>6 F, 5 M
Alendronate oral, 1–2 mg/kg body weight once weekly11 patients: JIA (5), dermatomyositis (4), inflammatory bowel disease (1), cystic fibrosis (1); 8 completed study. Received placebo8.5±4.4 years
>7 F 4 M
1 yearDXA, BMAD estimated. Mean lumbar spine BMAD increased from 0.266 to 0.307 g/cm3 (p = 0.013) in the alendronate and from 0.255 to 0.276 in the placebo group. Mean femoral shaft BMAD increased from 1.06 to 1.09 g/cm3 in the alendronate group and from 1.03 to 1.04 in the placebo groupN-telopeptide/creatinine ratio decreased significantly in the alendronate group after 12 months (299 to 148, p = 0.007) but not in the placebo group (303 to 301)
Prospective cohort, controlled
Acott et al (2005)2317 patients with fractures while on corticosteroid therapy: JRA (1), dermatomyositis (1), polychondritis (1), post renal transplant (2), rapidly progressive glomerulonephritis (5), nephrotic syndrome (2)Age not reported
>8 F, 9 M
Pamidronate iv, 1 mg/kg/dose (max 90 mg) once every 2 months for 1 (n = 15) or 2 years (n = 2)17 patients. Matched for disease and corticosteroid exposure. Received standard treatmentMatched for age and sexTreated for 1 or 2 years, followed up to 3 years post treatmentDXA. Control group had higher baseline lumbar spine aBMD than pamidronate group. With pamidronate, Z-scores increased (F = 11.27 p = 0.0057): by 30 or 36 months, 0.77±0.71 v controls, −0.68±0.25Bone specific ALP and N-telopeptide/creatinine ratios did not significantly change during treatment
*Bianchi et al (2000)2138 patients: systemic JIA (7), polyarticular JIA (9), SLE (11), dermatomyositis (6), Bechet’s syndrome (2), Wegener’s granulomatosis (1), undefined connective tissue disease (2)12.8±3.6 years
>26 F, 12 M
Alendronate oral, 5 mg daily for body weight ⩽20 kg, 10 mg daily for >20 kg38 patients: 19 JIA, 13 SLE, 6 dermatomyositis. Less severe disease not requiring corticosteroid therapy, no fractures. Tanner stage 1 (11), 2 (6), 3 (5), 4 (5), 5 (11), (11 menarche). Received standard treatmentMatched for age (12.3±3.9 years) and sex (26 F 12 M)1 yearDXA, adjusted for body size. Patients: mean increase BMD = 14.9±9.8% (p<0.002) compared with baseline. Controls: mean BMD increase = 2.6±5%In the alendronate group, serum bone specific ALP decreased by mean of 16.5±10.8%, urinary excretion N-terminal cross-linked telopeptides of type I collagen (NTX) decreased by 27±16.5%. In the control group, ALP increased from 223±180 to 299±157 units/L, NTX was not evaluated
Lepore et al (1991)22JCA (7)Not reportedClodronate, oral 1200 mg/dayJCA (6). Received standard treatment1 yearComputed tomography. Patients: lumbar spine mean vBMD increased from 129 mg/cm3 to 134 mg/cm3 (8% increase)
>Controls: from 123 mg/cm3 to 115 mg/cm3 (7% decrease)
Not evaluated/reported
Case series
Noguera et al (2003)2410 patients with rheumatic diseases and glucocorticoid-induced osteoporosis: JIA (8), SLE (1), dermatomyositis (1)11.1±4.7 years
>8 F, 2 M
Pamidronate iv, 2–4 mg/kg body weight, cycle repeated every 6 monthsNoneNot applicable4–12 cycles (2–6 years)DXA. Before treatment lumbar spine aBMD Z-scores −1.87 to −4.73. After treatment mean Z-score for 7 patients improved from −3.76 to −1.91 (p<0.02) (2–131% improvement)Levels of serum ALP and osteocalcin were normal before treatment, no significant changes during the study
*Cimaz et al (2002)1945 patients: systemic JIA (8), polyarticular JIA (10), SLE (14) dermatomyositis (7), other (6)12.9±3.8 years
>31 F, 14 M
Alendronate oral, 5 mg/kg daily for body weight <20 kg and 10 mg/kg for body weight ⩾20 kgNoneNot applicable1 yearDXA, adjusted for body size. Lumbar spine BMD Z-score: median % change 34.08, mean absolute change 0.87±0.57 (p<0.001)Statistically significant decrease in bone markers after 6 months of treatment which continued throughout 12 months: median % change N-terminal cross-linked telopeptides of type I collagen −40.27% (p = 0.001), pyridinoline −29% (p<0.001), bone-specific ALP −40.77% (p = 0.011), osteocalcin −38.51% (p = 0.006)
Gandrud et al (2003)2511 patients: JIA (1), corticosteroid-induced osteoporosis (4), OI (6)9.9±3.7 years
>7 F, 4 M
Pamidronate iv, 1 mg/kg once every 3 months (maximum 30 mg)NoneNot applicable3–30 monthsDXA, BMAD estimated.
>Mean annualised increase in lumbar spine aBMD 20.1±16.9%. Mean increase in BMD Z-scores 1.260±0.943. Mean annualised increase in BMAD 15.1±18.1%. Mean increase in BMAD Z-score 1.403±1.209. BMD at other sites also improved
Serum ALP levels fluctuated in several children without a noticeable trend
†Gattinara et al (2000)2625 patients on corticosteroid treatment: systemic JCA (7), polyarticular JCA (11), pauciarticular JCA (4), SLE (3)15.6 years, (range 7.8–25.0)
>6 M, 19 F
Etidronate oral, 150–300 mg/day for 15 days followed by calcium citrate 0.5–1.0 g/day for 75 days on a cyclic courseNoneNot applicable6–36 monthsDXA. Mean % change in lumbar spine aBMD in the year before start of treatment was −6.5%±5.0, 6 months: 3.4%±4.7 (p<0.0001), 12 months: 3.5%±6.1 (p = 0.005), 24 months: 13.8%±11.8 (p = 0.004), 36 months: 4.5%±11.8 (p = 0.05)Not evaluated/reported
Brumsen et al (1997)2912 patients: JRA (1), idiopathic juvenile osteoporosis (1), idiopathic osteoporosis (5), OI (4), mitochondrial myopathy (1)JIA: 10.7 years.
>All patients: 14.1±2.2 years
JIA: pamidronate iv, 7.5 mg daily for 18 days, then oral pamidronate 300 mg/day
>All patients: oral and/or iv pamidronate, range of doses. Oral olpadronate
NoneNot applicable11.7 yearsDPA, DXA. JIA (1 patient): lumbar spine aBMD at baseline Z-score = −3.7, increased with treatment to −1.1 (2.6%). All patients: aBMD increased at all sites measuredALP and urinary hydroxyproline secretion decreased progressively in all children; final values were at the upper part of the normal adult range
Shaw et al (2000)305 patients: JIA (1), Cushing’s syndrome (1), OI (1), liver transplant (1), idiopathic juvenile osteoporosis (1)JIA: 10 years
>F
>All patients: 10–15 y
>4 F, 1 M
Pamidronate iv, every 3 months Total dose over 1 year range 0.5–12 mg/kgNone1 yearDXA. JIA: baseline lumbar spine aBMD = 0.444 g/cm2. After 1 year, aBMD = 0.556 g/cm2, % change 26%.
>All patients: aBMD and Z-scores increased
Not evaluated/reported
Fernandes et al (2004)322 patients: JIA (1), SLE (1)Patient 1: 10 years
>Patient 2: 14 years
>Both M
Alendronate oral 10 mg/dayNonePatient 1: 25 months
>Patient 2: 21 months
DXA, not clear whether BMC or BMD reported. Patient 1 SLE: No change in Z-score at 7, 13 and 25 months but effect size not reported. Patient 2 JIA: A substantial improvement in Z-score at 9 months but effect size not reportedNot evaluated/reported