RISEDRONATE IN CHILDREN WITH OSTEOGENESIS IMPERFECTA: A RANDOMISED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL

Nick Bishop, Silvano Adami, S Faisal Ahmed et al..

The Lancet Oct 2013;382:1424-32

Introduction
Osteogenesis imperfecta (OI) also known as brittle bone disease is the most common heritable bone disease with an osteoporotic phenotype.
Prevalence 1- 2 per 20000 population. Affected children sustain recurrent fractures, bony deformity and bone pain.

Bisphosphonates are an established treatment , they areal bone mineral density

Risedronate an 3rd generation orally administered bisphosphonate was well tolerated and significantly BMD and reduced long bone bowing deformities and fractures in mild to moderate disease state.

Objective
To investigate the safety and efficacy of risedronate in children with osteogenesis imperfecta ,most of whom had mild disease state.

Inclusion criteria
Children with osteogenesis imperfecta aged 4-15 years. With h/o at least one non traumatic fracture or a low impact fracture along with age adjusted or sex adjusted areal BMD Z score of -0.1 or less for either total body or lumbar spine sites, or An adjusted areal BMD Z score of -0.2 or less irrespective of history of fracture.

Exclusion criteria
Patients who weighed <10 kgs. Patients with h/o cancer within the previous 5 yrs. Those with untreated rickets during previous yrs. Serum 25-hydroxy vit D conc <20nmol/L. Had used treatments that could affect interpretation of study findings. Had disease that was severe enough that in their country of origin they would normally have been offered i.v bisphosphonates treatment.

Study design
Prospective, parallel, double-blind.

Randomized & placebo- controlled trail.

Multi centre study, 20 hospitals of 13 different countries Study period- 3 years Written Informed consent was obtained from the patients parents or their legal representatives.

Protocols were approved by the institutional ethics committee and review boards.

Methodology -Trial profile

231 pts were screened, of which 147 met study criteria and were assigned randomly 97 in risedronate group 50 in placebo group

15% withdrawals

Methodology
147 patients ,aged between 4-15 yrs with OI were included in the study

Telephone randomisation system was used to assign the patients under two groups in 2:1 ratio.
2 groups of 97 & 50 respectively (97-in risedronate group & 50- in placebo group) These groups received daily risedronate (2.5mg for those who weighed 10-30kgs and 5mg for those who weighed > 30 kgs) or placebo for 1 yr.

After 1st yr all the patients were given risedronate (open label phase).

Methodology
During 2nd and 3rd year of study patients received open label residronate daily depending on their wt at the end of 1st yr. Study treatment was given, along with 120ml water was asked to take at least 30 mins before 1st food /drink of the day and remained upright for 30 mins after dosing. All patients received daily calcium(500-1000mg) and vitamin D (200- 600 IU) appropriate to their weight.

Methodology
Patients visited study centers on screening, baseline, and months 3,6,12,15,18,24,30 and 36 for clinical review. Measurement of height and lateral lumbar spine radiographs were done for assessment of vertebral fracture status at screening and annually Dual energy xray absorptiometry scans of lumbar spine & total body were acquired at screening and months 6,12,24 and 36.

Methodology.
Serum & urine analysis for bone turn over markers were done at baseline & months 3,6,12,24 & 36. Urinary N-terminal crosslinking telopeptide of type 1 collagen was measured by ELISA Urinary creatinine was measured by std colorimetric assay. Serum bone specific alkaline phosphatase was measured by immuno chemiluminescence assay. Serum chemistry, heamatology, thyroid and parathyroid function tests, vit D analysis, urine analysis & radiograph of left hand and wrist were done periodically to assess bone age.

Statistical analysis
The primary efficacy analysis was done by ANCOVA and Z test with treatment, age group & pooled centre as fixed effects and baseline as covariate.

Results
Lumbar spine areal BMD Z score were similar in both the group at baseline. Mean total body areal BMD Z score risedronate group = -1.42 placebo group = -1.82 Mean BMD at the end of the placebo controlled phase was observed to be greater in risedronate group (14.4-18.2) than in placebo group(5.7- 11.7) with p<0.0001. (table-2)

Results
Table 2: changes from baseline in areal BMD Z score for lumbar spine & total body. Figure 2: shows mean % changes in areal bone mineral density.(A- areal BMD of lumbar spine; B- areal BMD for total body) Table 3: incidence of vertebral collapses Figure 4,5 : changes in urine NTx / creatinine & serum bone specific alkaline phosphatase conc.

Table 4: Adverse effects, > 90% patients developed adverse effects in both groups at both phases of study but none died.

discussion
The study shows significantly greater increase in lumbar spine areal BMD at 6 & 12months in children with osteogenesis imperfecta treated with oral risedronate than in those given placebo.

The study of alendronate in 139 children with moderate to severe osteogenesis imperfecta, did not show a reduction in fracture incidence despite an increase in lumbar spine areal BMD.

Discussion
Rise in lumbar spine areal BMD in children who received only vitamin D & calcium was steeper in first 6 months than in second 6months of placebo- controlled phase, this implies an effect of such supplementation on filling of the remodelling space. New morphometric vertebral collapses occurred in both groups during both placebo-controlled & open- label phases.

Conclusion
Oral risedronate increased areal BMD & reduced the risk of first & recurrent clinical fractures in children with osteogenesis imperfecta The drug was well tolerated. Less significant adverse effects with no deaths. Risedronate should be regarded as a treatment option for children with osteogenesis imperfecta.

merits
Prospective , parallel & double- blind

Randomized & placebo controlled

Multi centre study

Demerits
The study doesnt include asian population.

limitations
Confirmatory radiographs were not obtained and sent to central facility. No patient suffering from moderate to severe disease state were considered. No child with severe vitamin D deficiency were considered.

Critique of the paper

Is the title suitable for the study done? Is the study hypothesis presented clearly? Is the review of literature appropriate & adequate? Comment on the clarity & appropriateness of methodology. Comment on the statistical analysis done. Are the results described clearly and without bias? Does the discussion extend support to the hypothesis being tested? Does the study add to the current knowledge? Are limitations of the study discussed? Conflict of interest. Overall impression of the paper.