RISEDRONATE IN CHILDREN WITH OSTEOGENESIS IMPERFECTA: A RANDOMISED, DOUBLE-BLIND, PLACEBOCONTROLLED 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 .

Bisp osp onates are an established treatment , they areal bone mineral density
!isedronate an 3rd generation orally administered bisphosphonate was well tolerated and significantly B"# and reduced lon bone bowin deformities and fractures in mild to moderate disease state.

Objective
!o investi ate the safety and efficacy of risedronate in children with osteo enesis imperfecta ,most of whom had mild disease state.

Inclusion criteria
"hildren with osteo enesis imperfecta a ed 4-1$ years% #ith h$o at least one non traumatic fracture or a low impact fracture alon with age ad&usted or se' ad&usted areal B"# ( score of -0%1 or less for either total body or lumbar spine sites, or An ad&usted areal B"# ( score of -0%2 or less irrespective of history of fracture.

Exclusion criteria
Patients who )eig ed *10 +gs. Patients with ,o cancer within the previous % yrs.

!hose with untreated ric+ets durin previous yrs.

-erum 2$- ydro'y .it # conc *20nmol,/%

&ad used treatments that could affect interpretation of study findings%

&ad disease that was se.ere enou h that in their country of ori in they would normally have been offered i%. bisp osp onates treatment%

Study design
Prospective, parallel, double'blind. (andomi)ed * placebo' controlled trail.

+ulti centre study, ,- hospitals of ./ different countries

0tudy period' / years

#ritten Informed consent was obtained from the patients1 parents or their le al representatives.

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

Methodology -Trial profile

,/. pts were screened, of which .23 met study criteria and were assi ned randomly 43 in risedronate roup %- in placebo roup
1$0 )it dra)als

Methodology
.23 patients ,a ed between 2'.% yrs with OI were included in the study

1elep one randomisation system was used to assi n the patients under two roups in ,5. ratio.

, roups of 43 * %- respectively (43'in risedronate roup * %-' in placebo roup)

!hese roups received daily risedronate (,.%m for those who wei hed .-'/-k s and %m for those who wei hed 6 /- k s) or placebo for . yr.

2fter 1st yr all the patients were iven risedronate (open label p ase).

Methodology
7urin ,nd and /rd year of study patients received open label residronate daily dependin on their wt at the end of .st yr.

0tudy treatment was iven, alon with 120ml )ater was asked to take at least /- mins before .st food $drink of the day and remained upri ht for /- mins after dosin .

All patients received daily calcium(%--'.---m ) and .itamin # (,--' 8-- I9) appropriate to their wei ht.

Methodology
Patients visited study centers on screenin , baseline, and months /,8,.,,.%,.:,,2,/- and /8 for clinical review.

+easurement of hei ht and lateral lumbar spine radio raphs were done for assessment of vertebral fracture status at screenin and annually

7ual ener y ;ray absorptiometry scans of lumbar spine * total body were ac<uired at screenin and months 8,.,,,2 and /8.

Methodology.
0erum * urine analysis for bone turn o.er mar+ers were done at baseline * months /,8,.,,,2 * /8.

9rinary ='terminal crosslinkin telopeptide of type 1 collagen was measured by 3/4-2

5rinary creatinine was measured by std colorimetric assay.

0erum bone specific al+aline p osp atase was measured by immuno chemiluminescence assay.

0erum chemistry, eamatology, t yroid and parat yroid function tests, .it # analysis, urine analysis * radiograp of left and and )rist were done periodically to assess bone a e.

Statistical analysis
!he primary efficacy analysis was done by 267O82 and ( test with treatment, a e roup * pooled centre as fi;ed effects and baseline as covariate.

Results
>umbar spine areal B"# ( score were similar in bot baseline. the roup at

"ean total body areal B"# ( score risedronate roup ? '..2, placebo roup ? '..:,

"ean B"# at the end of t e placebo controlled p ase was observed to be greater in risedronate group (.2.2'.:.,) than in placebo roup(%.3' ...3) with p*0%0001. (table',)

Results
1able 2: chan es from baseline in areal B"# ( score for lumbar spine * total body.

9igure 2: shows mean 0 c anges in areal bone mineral density .(2' areal @+7 of lumbar spineA B' areal @+7 for total body)

1able 35 incidence of vertebral collapses

9igure 4,$ : c anges in urine 61' , creatinine : serum bone specific al+aline p osp atase conc%

1able 45 Adverse effects, ; <00 patients developed adverse effects in both roups at both phases of study but none died.

discussion
!he study shows si nificantly reater increase in lumbar spine areal @+7 at 8 * .,months in children with osteo enesis imperfecta treated with oral risedronate than in those iven placebo.

!he study of alendronate in ./4 children with moderate to severe osteo enesis imperfecta, did not show a reduction in fracture incidence despite an increase in lumbar spine areal @+7.

Discussion
!ise in lumbar spine areal B"# in children who recei.ed only .itamin # : calcium was steeper in first = mont s t an in second 8months of placebo' controlled phase, this implies an effect of such supplementation on fillin of the remodellin space.

=ew morp ometric .ertebral collapses occurred in bot groups durin both placebo'controlled * open' label phases.

Conclusion
Oral risedronate increased areal B"# * reduced t e ris+ of first * recurrent clinical fractures in children with osteo enesis imperfecta

!he dru was )ell tolerated.

>ess si nificant adverse effects with no deat s%

(isedronate should be regarded as a treatment option for children with osteo enesis imperfecta.

merits
Prospective , parallel * double' blind

(andomi)ed * placebo controlled

+ulti centre study

Demerits
!he study doesn1t include asian population.

limitations
7onfirmatory radiograp s )ere not obtained and sent to central facility.

=o patient sufferin from moderate to se.ere disease state were considered.

=o child with se.ere .itamin # deficiency were considered.

Criti ue of the paper

Is the title suitable for the study doneB Is the study hypothesis presented clearlyB Is the review of literature appropriate * ade<uateB "omment on the clarity * appropriateness of methodolo y. "omment on the statistical analysis done. Are the results described clearly and without biasB 7oes the discussion e;tend support to the hypothesis bein testedB 7oes the study add to the current knowled eB Are limitations of the study discussedB "onflict of interest. Overall impression of the paper.