Two years' experience with denosumab for children with osteogenesis imperfecta type VI.

Heike Hoyer-Kuhn,Eckhard Schoenau,Christian Netzer,Oliver Semler,Friederike Koerber

doi:10.1186/s13023-014-0145-1

Heike Hoyer-Kuhn, Eckhard Schoenau + Show 3 more

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https://doi.org/10.1186/s13023-014-0145-1

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Abstract

BackgroundOsteogenesis imperfecta (OI) is a hereditary disease causing reduced bone mass, increased fracture rate, long bone deformities and vertebral compressions. Additional non skeletal findings are caused by impaired collagen function and include hyperlaxity of joints and blue sclera. Most OI cases are caused by dominant mutations in COL1A1/2 affecting bone formation. During the last years, recessive forms of OI have been identified, mostly affecting posttranslational modification of collagen. In 2011, mutations in SERPINF1 were identified as the molecular cause of OI type VI, and thereby a novel pathophysiology of the disease was elucidated. The subgroup of patients with OI type VI are affected by an increased bone resorption, leading to the same symptoms as observed in patients with an impaired bone formation. Severely affected children are currently treated with intravenous bisphosphonates regardless of the underlying mutation and pathophysiology. Patients with OI type VI are known to have a poor response to such a bisphosphonate treatment.MethodDeciphering the genetic cause of OI type VI in our 4 patients (three children and one adolescent) led to an immediate translational approach in the form of a treatment with the monoclonal RANKL antibody Denosumab (1 mg/kg body weight every 12 weeks).ResultsShort-term biochemical response to this treatment was reported previously. We now present the results after 2 years of treatment and demonstrate a long term benefit as well as an increase of bone mineral density, a normalization of vertebral shape, an increase of mobility, and a reduced fracture rate.ConclusionThis report presents the first two-year data of denosumab treatment in patients with Osteogenesis imperfecta type VI and in Osteogenesis imperfecta in general as an effective and apparently safe treatment option.

Highlights

We present the results after 2 years of treatment and demonstrate a long term benefit as well as an increase of bone mineral density, a normalization of vertebral shape, an increase of mobility, and a reduced fracture rate
Osteogenesis imperfecta (OI) is a genetically heterogeneous hereditary disease characterized by reduced bone mass, increased fracture rate, vertebral collapses and deformities of long bones
Osteogenesis imperfecta type VI (OI VI) is caused by mutations in SERPINF1, a gene which is coding for the pigment epithelium-derived factor (PEDF) [6,7]

Summary

Results

After two years of treatment all 4 patients were in a stable clinical condition. There was no treatment interruption based on unexpected side effects. Results of mobility and data of one year follow up were presented in detail only for patient 1 and 2. A continuous increase of aBMD was seen after one and two years of denosumab treatment. In patient 3 and 4 aBMD (total body less head) changed from 0.373 g/cm (z-score −2.9) to 0.407 g/cm (z-score −2.9) and from 0.59 g/cm (z-score −2.8) to 0.633 g/cm (z-score −2.6), respectively at the only follow up visit after two years. BAMF was assessed every year and showed a slight increase after two years of denosumab treatment in all patients (Table 1). Serum calcium concentrations decreased repeatedly, and serum parathyroid hormone levels increased slightly (Table 3).

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