title: Abnormally High and Heterogeneous Bone Matrix Mineralization After Childhood Solid Organ Transplantation: A Complex Pathology of Low Bone Turnover and Local Defects in Mineralization.
abstract: Chronic renal, liver, and heart failure in children associates with multiple skeletal complications. Increased fracture incidence often persists after transplantation and could be related to alterations in bone material properties. In the present cohort study we evaluated bone mineralization density distribution (BMDD) by quantitative backscattered electron imaging (qBEI) in 23 pediatric solid organ allograft recipients with suspected osteoporosis. We measured BMDD in the entire cross-sectional area of transiliac bone biopsies obtained from kidney (n = 9), liver (n = 9), and heart (n = 5) transplant recipients (aged 7.6 to 19.7 years; 6.0 ± 5.6 years posttransplantation, patients with a history of clinical fractures: n = 14). The BMDD findings were compared with age-appropriate references and with a previously presented cohort of children with chronic kidney disease on dialysis (CKD5D, n = 18). Furthermore, we related the BMDD parameters with patients' clinical and bone histomorphometric outcomes. Compared to healthy children, qBEI results for cancellous and cortical bone in transplant recipients revealed an increase in the most frequently occurring calcium concentration (+2.9%, p = 0.001; +3.5%, p = 0.014), in the portion of fully mineralized bone (fivefold; 10-fold, both p < 0.0001) and in heterogeneity of mineralization (+26,5% and +27.8%, both p < 0.0001), respectively. Moreover, the BMDD parameters were nonsignificantly distinct from CKD5D cohort except that the heterogeneity in mineralization was higher posttransplantation. There was a strong inverse correlation between the average calcium content of the bone matrix and patients' biochemical ALP levels, histomorphometric indices of bone formation and resorption. The abnormally high bone matrix mineralization in transplant recipients, consistent with serum and histomorphometric outcomes, suggests a history of low bone turnover with accumulation of fully mineralized bone packets. Additionally, the increased heterogeneity of mineralization suggests local alterations in mineralization kinetics, which may be linked to dysfunctional osteocytes that were recently shown to accumulate within the bone matrix during organ failure and concomitant glucocorticoid and immunosuppressive medication. © 2017 American Society for Bone and Mineral Research.
authors.affiliation: Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of WGKK and AUVA Trauma Centre, Meidling, 1st Med. Dept. Hanusch Hospital, Vienna, Austria.
authors.forename: Nadja
authors.initials: N
authors.lastname: Fratzl-Zelman
authors.affiliation: Children's Hospital, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland.
authors.forename: Helena
authors.initials: H
authors.lastname: Valta
authors.affiliation: Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
authors.forename: Renata C
authors.initials: RC
authors.lastname: Pereira
authors.affiliation: Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of WGKK and AUVA Trauma Centre, Meidling, 1st Med. Dept. Hanusch Hospital, Vienna, Austria.
authors.forename: Barbara M
authors.initials: BM
authors.lastname: Misof
authors.affiliation: Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of WGKK and AUVA Trauma Centre, Meidling, 1st Med. Dept. Hanusch Hospital, Vienna, Austria.
authors.forename: Paul
authors.initials: P
authors.lastname: Roschger
authors.affiliation: Children's Hospital, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland.
authors.forename: Hannu
authors.initials: H
authors.lastname: Jalanko
authors.affiliation: Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
authors.forename: Katherine
authors.initials: K
authors.lastname: Wesseling-Perry
authors.affiliation: Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of WGKK and AUVA Trauma Centre, Meidling, 1st Med. Dept. Hanusch Hospital, Vienna, Austria.
authors.forename: Klaus
authors.initials: K
authors.lastname: Klaushofer
authors.affiliation: Children's Hospital, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland.|Folkhälsan Research Center, Helsinki, Finland.|Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden.|Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Outi
authors.initials: O
authors.lastname: Mäkitie
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D015519:Bone Density / Q000187:drug effects*; D016723:Bone Remodeling / Q000187:drug effects*; D002648:Child; D002675:Child, Preschool; D005260:Female; D005387:Finland; D005938:Glucocorticoids / Q000008:administration & dosage / Q000009:adverse effects*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects*; D007223:Infant; D008297:Male; D016377:Organ Transplantation
chemical_list: D005938:Glucocorticoids; D007166:Immunosuppressive Agents
keywords: BMDD; BONE MINERALIZATION DENSITY DISTRIBUTION; CHILDREN; QBEI; QUANTITATIVE BACKSCATTERED ELECTRON IMAGING; SOLID ORGAN TRANSPLANTATION; TRANSILIAC BONE BIOPSIES