Multicenter,Single-arm Study to Evaluate Efficacy, Safety, & Pharmacokinetics of Denosumab in Children w/ OI

To Evaluate the Effect of Denosumab in Lumbar Spine Bone Mineral Density (BMD) Z-score at 12 Months, as Assessed by Dual-energy X-ray Absorptiometry (DXA), in Children 2 to 17 Years of Age (at the Time of Screening) on a 3-Month Dosing Regimen With OI

This is a prospective, multicenter, single-arm study in children 2 to 17 years of age with OI to evaluate efficacy and safety of denosumab.

To evaluate the effect of denosumab in lumbar spine bone mineral density (BMD) Z-score at 12 months, as assessed by dual-energy X-ray absorptiometry (DXA), in children 2 to 17 years of age (at the time of screening) on a 3-Month Dosing Regimen with osteogenesis imperfecta (OI)

• Eligibility criteria relates to initial enrollment into this study (6-Month Dosing Regimen). Subjects reconsenting to a 3-Month Dosing Regimen will not repeat eligibility assessments

Inclusion Criteria:

• Clinical diagnosis of OI defined as a clinical history consistent with type I-IV OI Clinical severity of OI as defined by 2 or more prevalent vertebral compression fractures; OR1 prevalent vertebral compression fracture and 1 or more nonvertebral fractures within the previous 2 years; OR 3 or more fractures within the previous 2 years.

Exclusion Criteria:

• Inability or unwillingness to comply with the requirements for frequent calcium and phosphorus monitoring for 14 days after the first dose of denosumab (only applies to the first 5 subjects age 11 to17 enrolled in the study and the first 5 subjects of any age meeting the criteria for increased bone turnover

• Currently unhealed fracture or osteotomy as defined by orthopedic opinion

• Osteotomy within 5 months of screening

• Evidence of untreated oral cavities or oral infections

• Recent or planned invasive dental procedure

• Surgical tooth extraction which has not healed by screening

• History of an electrophoresis pattern inconsistent with type I to IV OI

• History of genetic testing results inconsistent with type I to IV OI

• Abnormalities of the following per central laboratory reference ranges at screening: Serum albumin corrected calcium < lower limit of normal (LLN) Serum vitamin D < 20 ng/mL; re-screening for Vitamin D level < 20 ng/mL will be allowed, after adequate supplementation

• Aspartate aminotransferase (AST), alanine aminotransferase (ALT) > 1.5 x upper limit of normal (ULN)

• Total bilirubin (TBL) > 1.5 x ULN (subjects with Gilbert syndrome are eligible)

• Serum phosphorus < LLN

• Serum alkaline phosphatase > 20% above the ULN or > 20% below the LLN

• Estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 (calculated bythe Schwartz equation at screening) Evidence of any of the following: Current hyperthyroidism (unless well-controlled on stable antithyroid therapy)

• Current clinical hypothyroidism (unless well-controlled on stable thyroid replacement therapy)

• History of hyperparathyroidism

• Current hypoparathyroidism

• Current, uncontrolled hypercalcemia (albumin-corrected serum Ca >10% ULN)

• History of osteomalacia or rickets (chart review)

• Other bone diseases that affect bone metabolism (eg, osteoporosis pseudoglioma syndrome, idiopathic juvenile osteoporosis, osteopetrosis, hypophosphatasia)

• History of autoimmune disease

• History of rare hereditary problems of fructose intolerance

• Positive blood screen for human immunodeficiency virus -1 or -2 antibody

• Positive blood screen for hepatitis B surface antigen or hepatitis C antibody

• Received other osteoporosis treatment or bone active treatment with the following guidelines:

• Prior treatment with

  • denosumab
  • fluoride or strontium for bone disease (fluoride taken for routine dental care is permitted)
  • parathyroid hormone (PTH) or PTH derivatives within 12 months prior to screening
  • zoledronic acid within 6 months prior to screening
  • oral bisphosphonates or intravenous bisphosphonates other than zoledronic acid if the first dose of denosumab would be before their next scheduled bisphosphonate dose would have been given

• Administration of systemic glucocorticoids (≥ 5.0 mg prednisone equivalents/day for more than 10 days) within 3 months of screening.

• Topical and inhaled glucocorticoids will be allowed

• Administration of any of the following treatment within 3 months of screening:

  • Growth hormone (subjects on stable dose of growth hormone for at least 3 months prior to screening will be allowed)

• Currently receiving treatment in another investigational drug study, or less than 30 days since ending treatment on another investigational drugstudy(s), or current or planned participation in a clinical trial that would preclude compliance with study requirements Other inclusion/exclusion criteria may apply.