Bisphosphonate studies in connective tissue disease, including patients with JIA
| Study | Intervention group | Age (mean±SD) and sex | Bisphosphonate: dose and route | Control group | Age (mean ±SD) and sex | Follow up | Densitometry | Markers 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)20 | 11 patients: JIA (2), SLE (6), autoimmune haemolytic anaemia (1), inflammatory bowel disease (1), renal transplantation (1); 10 completed study | 9.9±2.8 years >6 F, 5 M | Alendronate oral, 1–2 mg/kg body weight once weekly | 11 patients: JIA (5), dermatomyositis (4), inflammatory bowel disease (1), cystic fibrosis (1); 8 completed study. Received placebo | 8.5±4.4 years >7 F 4 M | 1 year | DXA, 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 group | N-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)23 | 17 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 treatment | Matched for age and sex | Treated for 1 or 2 years, followed up to 3 years post treatment | DXA. 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±0.25 | Bone specific ALP and N-telopeptide/creatinine ratios did not significantly change during treatment |
| *Bianchi et al (2000)21 | 38 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 kg | 38 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 treatment | Matched for age (12.3±3.9 years) and sex (26 F 12 M) | 1 year | DXA, 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)22 | JCA (7) | Not reported | Clodronate, oral 1200 mg/day | JCA (6). Received standard treatment | 1 year | Computed 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)24 | 10 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 months | None | Not applicable | 4–12 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)19 | 45 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 kg | None | Not applicable | 1 year | DXA, 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)25 | 11 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) | None | Not applicable | 3–30 months | DXA, 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)26 | 25 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 course | None | Not applicable | 6–36 months | DXA. 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)29 | 12 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 | None | Not applicable | 11.7 years | DPA, 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 measured | ALP 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)30 | 5 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/kg | None | 1 year | DXA. 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)32 | 2 patients: JIA (1), SLE (1) | Patient 1: 10 years >Patient 2: 14 years >Both M | Alendronate oral 10 mg/day | None | Patient 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 reported | Not evaluated/reported | |