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May 12-13, 2016, PPMD convened a workshop of 48 opinion leaders, research experts and clinicians from the US and Canada, on the subject of Duchenne and bone biology. Bone health has long been a confusing and often neglected aspect of Duchenne care. There is very little knowledge of underlying bone health in Duchenne, which is further complicated by the possible effects of glucocorticoids on both bone development and bone density/strength.

The members of our esteemed group of experts include:

  • Jonathan D Adachi, St Joseph’s Healthcare, McMaster, University, Hamilton, Ontario, Canada
  • Laura Bachrach, Stanford University, Stanford, California,, USA
  • Teresita Bellido, Indiana University School of Medicine, Indiana, USA
  • Marco Brotto, University of Texas, Arlington, Texas, USA
  • Lynda Bonewald, University Missouri, Kansas City, Missouri, USA (Co-Chair)
  • Joanne Donovan, Catabasis Pharmaceuticals, Cambridge, Massachusetts, USA
  • Eric Hoffman, Reveragen, Rockville, Maryland, USA
  • Kathi Kinnett, Parent Project Muscular Dystrophy, Middletown, Ohio, USA
  • Mary Leonard, Stanford University, Stanford, California, USA
  • Hugh J McMillan, Children’s Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada
  • Susan Novotny, Gillette Children’s Specialty Healthcare, St. Paul, Minnesota, USA
  • Jill Rafael-Fortney, Ohio State University, Columbus, Ohio, USA
  • Frank Rauch, Shriners Hospital for Children and McGill University, Montreal, Quebec, Canada
  • Leanne Ward, Children’s Hospital of Eastern Ontario, University of Ottawa, Ontario, Canada (Co-Chair)
  • Stuart Warden, Indiana University, Indianapolis, Indiana, USA

We applaud the incredible work of this group, and hope that, with increased awareness, further work to prevent osteoporosis and enhance bone health in people living with Duchenne will continue. 

Below are some of the questions that led to the development of this workshop. Here are the answers provided by this amazing group of experts:

  • What is the underlying effect of Duchenne on bone?
    • Muscles and bones secrete chemicals that directly influence each other, so weakness in the muscles will affect the strength of the bones
    • Weak skeletal muscles exert less skeletal muscle force which results in inadequate bone gain in a growing skeleton (rather than bone loss, which happens in an adult skeleton)
    • Decreased skeletal muscle force prevents the bones from growing in width (which makes them look thinner in x-ray)
    • High impact exercise (jumping, hopping) “loads” the skeletal and helps with bone formation; these exercises are contraindicated, or are not possible, in Duchenne.
    • Exercise programs need to target the fracture prone regions of bone in Duchenne and need more investigation
  • What impact does glucocorticoid (steroid) use have on bone development and density/strength?
    • Glucocorticoids cause minerals to be reabsorbed from the bone (“reabsorption”) making bones weaker), decrease bone formation and decrease the bone forming cells (osteoblasts and osteocytes)
    • 20-60% of patients with Duchenne have low trauma extremity fractures (usually of the femur or tibia/fibula), while up to 30% have painful vertebral compression fractures; fat emboli syndrome is a huge risk with long bone breaks
  • How should bone health/density/strength be monitored?
    • DEXA scans – to evaluate bone mineral density
    • Spine x-ray – to evaluate the spine and assess for vertebral body compression fractures/risk by looking at the Genant Score (the Genant score measure the height of the vertebral bodies in the spine); this is different than an x-ray for scoliosis
  • How often should these scans be done?
    • The Care Considerations recommended baseline DEXA at start of glucocorticoids then repeated regularly there after if normal or stable
    • Spine x-rays should be done in at the start of glucocorticoids and repeated every 1-2 years in the absence of pain and a normal/stable DEXA score
    • If only 1 test can be done, the spine x-ray should take priority, as it will give more information about spinal health and the development of osteoporosis
  • When should bone health medications (bisphosphonates) be started?
    • The goal of therapy is to identify and treat early signs of vertebral collapse in order to preserve the height of the vertebral bodies and preserve spinal health
    • The Genant score is graded as 1 (mild), 2 (moderate) or 3 (severe); bisphosphonates are recommended for a score of 2 or 3, regardless of the presence of pain; grade 1 should be closely monitored and treated if it becomes more severe
    • Bisphosphonates should be started also in the presence of low trauma vertebral compression or long bone fractures
  • Bisphosphonate therapy
    • There have been no studies evaluating the safety and efficacy of medical therapy to prevent first ever fractures; studies have shown a positive impact of bisphosphonates on bone health after osteoporosis is present
    • IV bisphosphonates seem to offer better protection against vertebral compression fractures than oral bisphosphonates, but studies are limited
    • Important: it is important to use the lowest effective dose of bisphosphonates to reduce the risk of over-suppression of bone turn over
    • Adverse effects of bisphosphonates include
      • Common adverse effects include
        • Adverse effects are most common after the first infusion
        • Bone pain, myalgia, nausea and vomiting 
      • Severe adverse effects
        • Avascular necrosis of the jaw - has NOT been reported in pediatrics
        • Atypical fractures may occur
    • Oral bisphosphonates: alendronate
      • Fosomax: take weekly
      • Risedronate:
        • Actonel – take weekly
        • Atlevia and Atelevia extended release (ER) – take weekly
        • Ibandronate: Boniva – take monthly
      • IV bisphosphonates:
        • Pamidronate: infusion every 3-4 months
        •  zolendronic acid:
          • Reclast - infusion once per year  
          • Zometa - infusion every 6 mos (pediatrics), annually (adults)
      • Both oral and IV increase bone density. Data about VCF and low trauma long bone fracture is inconclusive.  IV bisphosphonates may help more with vertebral body height and re-shaping. Very little is known in Duchenne.
    • Non-bisphosphonate therapy for adults
      • Forteo/Teriparatide: “anabolic therapy” (increase bone mass and strength); black box warning against use in pediatrics
      • Denosumab: synthetic parathyroid hormone (PTH); “reabsorptive therapy” targets RANKL, subcutaneous injection every 6 months, preventing bone reabsorption and increases bone strength; has been used in pediatric patients with osteogenesis imperfect (OI); may cause severe “rebound hypercalcemia” when discontinued
      • Anti-sclerostin antibodies: may improve bone mass and reduce long bone fractures; has not been studied in animals or humans with Duchenne         
      • Others
      • Odanactib: suppresses CatK, oral, decreasing bone reabsorption and allows for continued new bone formation
      • Anti-TGF-antibodies: decreases bone turnover in osteoporosis       
    • How long should bisphosphonates be used?
      • Most clinicians agree that bisphosphonates should be discontinued when adult height has been reached (this will help to prevent fractures at the junction of the “treated” older bone and the “new” added bone added in the long bones).  This may be difficult to assess in Duchenne, due to growth and pubertal delays with glucocorticoids.
      • Some adult clinicians recommend “drug holidays” off bisphosphonates for patients who are stable and have a lower risk of fracture. Adults who are on glucocorticoids continue to be at high risk of fracture. There are no studies around bisphosphonate drug holidays in Duchenne.
    • How do we know if the bisphosphonates are working?
      • By assessing that there are no new VCF or low trauma long bone fractures, vertebral body height increases/stabilizes, and/or DEXA scores improve.
      • Other labs may need to be obtained (Ca, 25-OH Vitamin D); bone turnover markers are not well described in Duchenne and may need further study.
    • What is the potential impact on bone of novel agents?
      • Edasalonexent (CAT-1004): NF kappa-B inhibitor; hypothesized to have positive effects on muscle function and inhibit inflammatory bone loss      
      • Vamorolone (VBP15): first in class steroid compound; decreased concerns with adrenal suppression, bone turn over and insulin resistance in animal models.
    • Are there other agents, other than bisphosphonates, that might be better for bone health in Duchenne?
      • Odanactib: suppresses CatK, oral, decreasing bone reabsorption and allows for continued new bone formation
      • Anti-TGF-antibodies: decreases bone turnover in osteoporosis

 

 

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