Bisphosphonate Action on the Appendicular Skeleton: Evidence for Differential Effects
Condition: Post-menopausal Osteoporosis
MeSH terms: Osteoporosis; Osteoporosis, Postmenopausal
Study type: Interventional
Phase: Phase 2

Summary: 
      A study to determine if the three licensed bisphosphonates (alendronate, ibandronate and
      risedronate):a) affect the peripheral skeleton differently, as assessed by quantitative
      ultrasound of bone (QUS), peripheral quantitative computed tomography (pQCT) and dual-energy
      x-ray absorptiometry (DXA)? b) have different effects on bone cells and their activity as
      assessed by flow cytometry and biochemical markers of bone cell activity? The aim of the
      study is to compare the effects of three licensed bisphosphonates on bone quantity and
      quality. There has been no such study before. Most of the measures of bone quantity and
      quality used in this protocol have not been studied with any of these three agents. The
      novelty of the study necessitates the establishment of reference ranges and this explains the
      need for the inclusion of a group of young women.
    

Detailed description: 
      There have been a number of randomised controlled trials examining the effect of
      bisphosphonates on fracture risk. The results of these trials have not been uniform,
      especially in relation to non-vertebral fractures. We have proposed that much of the fracture
      risk reduction with risedronate can be explained by the reduction in bone resorption markers
      (Eastell et al, 2003). Each of these three bisphosphonates reduces bone resorption markers,
      and alendronate and ibandronate are at least as effective as risedronate in this regard.
      However, there have been few direct comparisons of the different bisphosphonates on surrogate
      endpoints such as bone mineral density and bone turnover markers. This raises the question of
      whether the bisphosphonates might affect some other aspect of bone strength, such as 'bone
      quality'.

      The purpose the study is to determine whether three licensed bisphosphonates affect the
      skeleton differently using a variety of methods (various bone densitometry devices and
      ultrasound measurements of the bone) at a variety of bone sites (spine, hip, fingers, heel,
      forearm and leg). These changes will be compared to changes in other markers of bone health
      such as biochemical markers of bone turnover to help us determine the possible mechanism of
      action for the different treatments. The study will last for 48 weeks which should be long
      enough to detect signfiicant changes on bone strength as measured by DXA at the spine/hip. As
      we are interested in how these changes occur there are more visits in the first three months
      of the study than the last 9 months of the study. This is expected to help us detect the
      difference between the onset of the effects of the three treatments more clearly.

      Study vists will be: screening, baseline 1, baseline 2, 1 week, 2 weeks, 4 weeks, 12 weeks,
      13 weeks (phone calls to participants at 24 and 36 weeks), 48 weeks and 49 weeks. The two
      baseline visits will allow duplicate measurements of bone stregth/quality on different
      occasions at the start of the study to minimise variability. Treatment will begin at baseline
      2 (0 days) and last for 48 weeks. The visits at 13 weeks and 49 weeks are to perform bone
      density/quality tests in duplicate to minimise variability as at baseline visit.

      Bone mineral density of various bones (hip/spine/whole body and forearm) will be measured by
      DXA on various devices, quantitative ultrasound will be performed at the heel and fingers,
      and bone quality will be measured by pQCT at the forearm and tibia/3D analysis of the hip
      scans at the baseline visits, at 12 and 13 weeks and at 48 and 49 week visits Surrogate
      markers of bone health (biochemical markers of bone turnover) will be measured at baseline,
      1, 2 4, 12, 13, 48 and 49 weeks. Exploratory methods included in the protocol include:
      Assessing the number of bone breaking down cell numbers (osteoclasts) at baseline, 1 week and
      48 weeks Assessing nail brittleness at baseline 12 and 48 weeks.

      Subjects will be randomised using a stratification method to ensure all groups have an equal
      range of bone strength at study entry. Randomisation will be performed by the hospital
      pharmacy. The study is not blinded and subjects will know which treatment they are on.
      Subjects will be asked not to discuss their assigned treatment with staff performing bone
      measurements. There is no placebo group in this trial as all subjects will taking one of the
      three treatments. We have chosen the active comparator design as many of the measurements
      (especially the biochemical and cellular ones) do not change unless treatment is given; also,
      these treatments are indicated and effective in this patients group.

      To generate control data we will recruit a group of 200 healthy young women aged 35-40 years.
      The control group will undertake all the measurements of bone strength/quality that the
      treatment group will have as well as the biochemical maerkers of bone turnover. There will be
      only 2 study visits for the control group,baseline and 48 weeks. This data will serve as
      internal controls and as reference ranges for each of the devices used in the study. Ethical
      considerations for this study include the use of ionising radiation, blood sampling at each
      study visit and the number of study visits. This may be balanced by the close monitoring of
      the subject whilst on the study and a thorough assessment of bone health for 49 weeks.
      Research participants, patient groups or communities were not involved in the design of this
      research study.

      The hypothesis of the study is that bisphosphonates have varying magnitude of effect on
      non-vertebral fractures and this is reflected in different changes in measures of bone
      quality (QUS), bone density in the appendicular skeleton (DXA and pQCT) and novel biochemical
      markers of bone resorption and osteoclast precursors.
    

Intervention name(s): Ibandronate; Risedronate; Alendronate
Intervention type(s): Drug; Drug; Drug
Intervention description(s): once monthly; Risedronate 35mg once weekly; Alendronate 70mg once weekly
Other intervention name(s): Bonviva; Actonel; Fosamax
Intervention MeSH terms: Alendronate; Risedronic Acid; Ibandronic Acid
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Osteoporosis; Post-menopausal osteoporosis; Bisphosphonates; Alendronate; Ibandronate; Risedronate