Do Bisphosphonates Alter the Skeletal Response to Mechanical Stimulation in Children With Osteogenesis Imperfecta?
Condition: Osteogenesis Imperfecta
MeSH terms: Osteogenesis Imperfecta
Study type: Interventional
Phase: Phase 2

Summary: 
      Osteogenesis Imperfecta(OI) is an inherited disorder characterised by extreme fragility of
      the bones. Bones often break from little or no apparent cause.

      Current available medicine can increase bone strength by making bones wider and "filling in"
      the holes in the bone walls that weaken it. These medicines are bisphosphonates, given either
      by a drip intravenously (eg pamidronate), or taken by mouth (eg risedronate). Their major
      action is to prevent bone breakdown by stopping the normal process of removing and then
      replacing old bone tissue, so in some parts of the bone, new bone formation is actually
      reduced. Most studies of bisphosphonates in children with OI have shown increased bone
      mineral density and improved exercise tolerance that could positively affect new bone
      formation; some have shown reduced fracture rate. Bone is highly responsive to mechanical
      stimulation. Whole body vibration (WBV) is a form of mechanical stimulation that has been
      shown to improve bone mineral density in some individuals with narrow bones.

      Little is known whether bisphosphonates affect the response of the skeleton to mechanical
      stimulation. We will determine the response to mechanical stimulation in children with OI by
      looking at bone turnover markers following WBV in those who are and are not treated with
      bisphosphonates.

      The results from this study will help us to understand whether skeleton in children with OI
      is normally responsive to mechanical stimulation, and whether bisphosphonates alter that
      responsiveness in a way that is either beneficial or not for increasing bone strength.
    

Detailed description: 
      Essentially, subjects will have a baseline assessment (WBV1) of their bone turnover marker
      response to a week-long period of whole body vibration (10 minutes/day), followed by a
      "washout period" of 5 weeks during which bone turnover is expected to return to normal.
      Following this, there will be a period of 6 weeks of treatment with risedronate (1
      mg/kg/week). Immediately following this will come a second assessment (WBV2) of the bone
      turnover marker response to a week-long period of whole body vibration (10 minutes/day) as
      previously.

      The subjects stand on the vibration platform for 10 minutes for 7 days on 2 occasions. The
      vibration is delivered as 4 "blocks" of 2.5 minutes each, with 30 seconds rest in between
      each block. The initial Whole Body Vibration (WBV) on day 1 will be undertaken in the
      Sheffield Children's Hospital Clinical Research Facility (SCHCRF) under supervision.
      Subsequent WBVs D2-D7 and D85-91 will be done in the participants' homes. Participants will
      be asked to record the administration and timing of WBV in a diary.

      Blood samples will be taken after an overnight fast according to the following schedule:

      Pre-WBV1 D1; D8 (postWBV); D15; D43 (immediate pre-risedronate); D85 (post-risedronate and
      pre-WBV2); D92 (post-WBV2) and D99 (final). 7 samples are taken altogether.

      The blood tests are bone turnover markers (Alkaline phosphatase[ALP], Procollagen Type 1
      N-Terminal Propeptide[P1NP] and C-Terminal Telopeptide of Type 1 Collagen[CTX]). The first
      blood test will be done by the researcher (Dr Sithambaram) in the SCHCRF and the subsequent 6
      blood tests can be done by the research nurse/researcher at the participant's home. Blood
      samples taken will be allowed to clot for ½ an hour. Samples will be spun at 2500 rpm for 10
      minutes at 4°C. The centrifuged sample will be stored in SCHCRF at -80°C. Blood tests will be
      analysed in the Mellanby Centre for Bone Research, University of Sheffield.

      Participants will be taking risedronate (oral bisphosphonate, once weekly), rounded to the
      nearest 5 mg) together with Vitamin D and calcium for 6 weeks. Vitamin D and Calcium will be
      given as Calcichew 500mg/200 IU tablets, 1 tablet for participants weighing less than 30 kg
      and 2 tablets for participants weighing 30 kg or more. Risedronate Sodium belongs to
      Bisphosphonates group of medicine. As per BNF, it is not licensed for use in children. The
      trade name is Actonel® Warner Chilcott). This study will use 5mg and 35mg film-coated
      tablets.
    

Intervention name(s): Risedronate Sodium; Calcichew tablets
Intervention type(s): Drug; Dietary Supplement
Intervention description(s): Participants will be initially tested on the response to mechanical stimulation as a baseline and then tested again after 6 weeks treatment with Risedronate; Participants will take calcichew tablets during the 6 week period of risedronate treatment
Other intervention name(s): Bisphosphonate
Intervention MeSH terms: Risedronic Acid; Diphosphonates
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Basic Science