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