Bisphosphonate treatment of children and adolescents with osteogenesis imperfecta : Effects on clinical symptoms and bone turnover

Sammanfattning: Background: Osteogenesis imperfecta (OI) is a group of genetic diseases with a wide spectrum of severity, ranging from very mild bone fragility to lethal forms. Without treatment the more severe forms have multiple fractures leading to progressive bone deformities with extreme shortness, frequent skeletal pain and immobilisation. Before Study I there was no effective symptomatic treatment of these patients. Aims: The overall aim of these studies were initially to find and later to optimise a symptomatic treatment of children and adolescents with osteogenesis imperfecta including assessments of untreated children of different ages and types of OI to find criteria for and to monitor treatment. Patients and Methods: Studies I-V involve 130 children and adolescents with different types OI of which 69 were treated with bisphosphonates. Treatment was given as monthly infusions of disodium pamidronate (APD). Assessments were done according to a prospective observational study protocol every six month for 1-2 years then annually. In Study I three adolescents with severe OI were treated during 2-5 years. In Study II we treated 28 children aged 0.6-18 years during 2-9 years. They had severe or milder forms of OI with vertebral compression fractures. In Study III eleven infants aged 3-13 months were treated during 3-6 years and were at the latest recording at median age of 4.8 years compared to our own historic control group of untreated age and type-matched children with OI. In the retrospective Study IV all 64 patients treated with APD over 0.5 years were assessed due to alarm reports of osteonecrosis of the jaw (ONJ) after dental surgery in patients treated with second- and third-generation bisphosphonates. APD infusions were administered for 0.5-12.5 years. Ten patients continued treatment with oral alendronate and two with infusions of zoledronate. In Study V we assessed bone turnover markers in 130 untreated children and in 69 of those also during treatment for 1.0-12.5 years. Results: Patient diaries showed less pain and improved well-being during treatment. Bone mineral density (BMD) measured by DXA increased gradually. Mobility and vertebral height improved more in younger children. Treated infants achieved the motor milestones earlier and more complete than controls. Mobility, vertebral height and BMD improved greatly during treatment and differed much compared to controls where some even had deteriorated. Bone turnover markers in serum and urine decreased gradually. Significant differences in bone markers, however, not sufficient for clinical sub typing, were found in the larger untreated group. Comparison with 14 untreated immobilised controls indicated that the immobilisation per se was not the cause of these differences. No ONJ was seen after 38 dental surgical procedures in 22 of the APD treated patients or in any other of the treated patients. Conclusions: APD is an effective symptomatic treatment of children and adolescents with severe OI and milder forms with vertebral compression fractures. Bone turnover markers cannot predict vertebral compressions or therapy response on BMD, mobility or pain. Serum ALP and urine deoxypyridinoline are sensitive in monitoring treatment. The risk of ONJ after dental surgery in this patient group must be considered so low that the patients with indications for treatment should be treated and get the chance to experience the well-documented beneficial effect.