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      Efficacy and Safety of Denosumab Therapy for Osteogenesis Imperfecta Patients with Osteoporosis—Case Series

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          Abstract

          Osteogenesis imperfecta (OI) is a connective tissue disorder that is characterized by low bone density leading to recurrent fractures. The efficacy of the anti-resorption drug denosumab for OI with osteoporosis is still largely unknown. We herein describe the clinical outcomes of eight osteoporotic cases of OI to examine the effects and safety of denosumab. This retrospective, consecutive case series included eight patients respectively aged 42, 40, 14, 22, 3, 51, 37, and 9 years. We measured the bone mineral density (BMD) of the lumbar 1–4 spine (L-BMD) and bilateral hips (H-BMD), bone-specific alkaline phosphatase, urinary type I collagen amino-terminal telopeptide, and tartrate-resistant acid phosphatase 5b before and during denosumab therapy. Despite multiple pretreatment fractures in the cohort, no fractures or severe side effects, such as hypocalcemia, were observed during the observational period apart from a fracture in a young pediatric girl. Both L-BMD and H-BMD were increased by denosumab in seven of eight cases. Bone turnover markers were inhibited in most cases by denosumab therapy. Denosumab treatment could generally raise BMD without any adverse effects. The agent therefore represents a good therapeutic option for OI with osteoporosis.

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          Genetic heterogeneity in osteogenesis imperfecta.

          D Sillence, A Senn, D M Danks (1979)
          An epidemiological and genetical study of osteogenesis imperfecta (OI) in Victoria, Australia confirmed that there are at least four distinct syndromes at present called OI. The largest group of patients showed autosomal dominant inheritance of osteoporosis leading to fractures and distinctly blue sclerae. A large proportion of adults had presenile deafness or a family history of presenile conductive hearing loss. A second group, who comprised the majority of newborns with neonatal fractures, all died before or soon after birth. These had characteristic broad, crumpled femora and beaded ribs in skeletal x-rays. Autosomal recessive inheritance was likely for some, if not all, of these cases. A third group, two thirds of whom had fractures at birth, showed severe progressive deformity of limbs and spine. The density of scleral blueness appeared less than that seen in the first group of patients and approximated that seen in normal children and adults. Moreover, the blueness appeared to decrease with age. All patients in this group were sporadic cases. The mode of inheritance was not resolved by the study, but it is likely that the group is heterogeneous with both dominant and recessive genotypes responsible for the syndrome. The fourth group of patients showed dominant inheritance of osteoporosis leading to fractures, with variable deformity of long bones, but normal sclerae.
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            Cyclic administration of pamidronate in children with severe osteogenesis imperfecta.

            F Glorieux, N. Bishop, H Plotkin … (1998)
            Severe osteogenesis imperfecta is a disorder characterized by osteopenia, frequent fractures, progressive deformity, loss of mobility, and chronic bone pain. There is no effective therapy for the disorder. We assessed the effects of treatment with a bisphosphonate on bone resorption. In an uncontrolled observational study involving 30 children who were 3 to 16 years old and had severe osteogenesis imperfecta, we administered pamidronate intravenously (mean [+/-SD] dose, 6.8+/-1.1 mg per kilogram of body weight per year) at 4-to-6-month intervals for 1.3 to 5.0 years. Clinical status, biochemical characteristics reflecting bone turnover, the bone mineral density of the lumbar spine, and radiologic changes were assessed regularly during treatment. Administration of pamidronate resulted in sustained reductions in serum alkaline phosphatase concentrations and in the urinary excretion of calcium and type I collagen N-telopeptide. There was a mean annualized increase of 41.9+/-29.0 percent in bone mineral density, and the deviation of bone mineral density from normal, as indicated by the z score, improved from -5.3+/-1.2 to -3.4+/-1.5. The cortical width of the metacarpals increased by 27+/-20.2 percent per year. The increases in the size of the vertebral bodies suggested that new bone had formed. The mean incidence of radiologically confirmed fractures decreased by 1.7 per year (P<0.001). Treatment with pamidronate did not alter the rate of fracture healing, the growth rate, or the appearance of the growth plates. Mobility and ambulation improved in 16 children and remained unchanged in the other 14. All the children reported substantial relief of chronic pain and fatigue. In children with severe osteogenesis imperfecta, cyclic administration of intravenous pamidronate improved clinical outcomes, reduced bone resorption, and increased bone density.
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              Effects of denosumab on bone mineral density and bone turnover in postmenopausal women.

              Chui Kin Yuen, Nai-Chieh Liu, David L Kendler … (2008)
              Denosumab is an investigational fully human monoclonal antibody against receptor activator of nuclear factor-kappaB ligand, a mediator of osteoclastogenesis and osteoclast survival. This study evaluated the ability of denosumab to increase bone mineral density (BMD) and decrease bone turnover markers (BTMs) in early and later postmenopausal women with low BMD. This 2-yr randomized, double-blind, placebo-controlled study was conducted in North America. Subjects included 332 postmenopausal women with lumbar spine BMD T-scores between -1.0 and -2.5. SUBJECTS were randomly assigned to receive denosumab sc, 60 mg every 6 months, or placebo. Randomization was stratified by time since onset of menopause ( 5 yr). The primary end point was the percent change in lumbar spine BMD by dual-energy x-ray absorptiometry at 24 months. Additional end points were percent change in volumetric BMD of the distal radius by quantitative computed tomography; percent change in BMD by dual-energy x-ray absorptiometry for the total hip, one-third radius, and total body; hip structural analysis; percent change in BTMs; and safety. Denosumab significantly increased lumbar spine BMD, compared with placebo at 24 months (6.5 vs. -0.6%; P<0.0001) with similar results for both strata. Denosumab also produced significant increases in BMD at the total hip, one-third radius, and total body (P < 0.0001 vs. placebo); increased distal radius volumetric BMD (P < 0.01); improved hip structural analysis parameters; and significantly suppressed serum C-telopeptide, tartrate-resistant acid phosphatase-5b, and intact N-terminal propeptide of type 1 procollagen. The overall incidence of adverse events was similar between both study groups. Twice-yearly denosumab increased BMD and decreased BTMs in early and later postmenopausal women.
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Clin Med
                Journal ID (iso-abbrev): J Clin Med
                Journal ID (publisher-id): jcm
                Title: Journal of Clinical Medicine
                Publisher: MDPI
                ISSN (Electronic): 2077-0383
                Publication date (Electronic): 24 November 2018
                Publication date Collection: December 2018
                Volume: 7
                Issue: 12
                Electronic Location Identifier: 479
                Affiliations
                [1 ]Department of Orthopaedic Surgery, Shinshu University School of Medicine, Matsumoto, Nagano 390-8621, Japan; 16m0042e@ 123456shinshu-u.ac.jp (T.K.); takako1119@ 123456shinshu-u.ac.jp (T.S.); hirokato@ 123456shinshu-u.ac.jp (H.K.)
                [2 ]Center for Medical Genetics, Shinshu University Hospital, Matsumoto, Nagano 390-8621, Japan; t_yamaguchi@ 123456shinshu-u.ac.jp (T.Y.); ktomoki@ 123456shinshu-u.ac.jp (T.K.)
                [3 ]Division of Medical Genetics, Nagano Children’s Hospital, Azumino, Nagano 399-8288, Japan; ryojun_takeda@ 123456icloud.com
                [4 ]Department of Pediatrics, Keio University School of Medicine, Tokyo 160-8582, Japan; mtakagi1027@ 123456hotmail.com (M.T.); thaseg@ 123456keio.jp (T.H.)
                [5 ]Department of Medical Genetics, Shinshu University School of Medicine, Matsumoto, Nagano 390-8621, Japan
                Author notes
                [* ]Correspondence: yxn14@ 123456aol.jp ; Tel.: +81-263-37-2659
                Author information
                https://orcid.org/0000-0002-3911-7180
                Article
                Publisher ID: jcm-07-00479
                DOI: 10.3390/jcm7120479
                PMC ID: 6306860
                PubMed ID: 30477250
                SO-VID: 3cd60bb7-7763-4edb-9059-dde82f21b1e3
                Copyright © © 2018 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 21 October 2018
                Date accepted : 21 November 2018
                Categories
                Subject: Article

                Keywords: bone mineral density,denosumab,fractures,osteogenesis imperfecta,osteoporosis
                Data availability:
                Keywords: bone mineral density, denosumab, fractures, osteogenesis imperfecta, osteoporosis

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