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.

Bone Matrix Mineralization and Response to Burosumab in Adult Patients With X-Linked Hypophosphatemia: Results From the Phase 3, Single-Arm International Trial

“…( 26 ) Hence, within the post‐burosumab group, CnCaLow was positively associated with the number (surface extent) of osteoblasts, as expected in situations of normal bone formation. ( 40,62 )…”

“…(26) Hence, within the postburosumab group, CnCaLow was positively associated with the number (surface extent) of osteoblasts, as expected in situations of normal bone formation. (40,62) This temporal uncoupling between matrix formation and matrix mineralization in XLH, strongly suggests that the cells within the osteoid are responsible for the mineralization process. Such an assumption is in accordance with the growing body of evidence that mineralization starts around young osteocytes, the osteoid-osteocytes, a distinct cell population descendent from osteoblasts, which become embedded within the unmineralized matrix and are differentiating into mature osteocytes.…”

A 3‐year longitudinal study of skeletal effects and growth in children after kidney transplantation

“…Circulating levels of bone markers represent an overall assessment of the modeling and remodeling processes in the entire skeleton, which can differ between different skeletal sites and different bone compartments such as trabecular and cortical bone . Fratzl‐Zelman et al demonstrated recently a broad heterogeneity in bone matrix mineralization in pediatric solid‐organ recipients by bone histomorphometry, which further explains some of the observed alterations in bone material properties that impact skeletal fragility.…”

Quantitative Backscattered Electron Imaging of Bone Using a Thermionic or a Field Emission Electron Source

“…A quantitative assessment of bone mineralization is important as many metabolic diseases, and medication may affect mineralization. Examples include (high and low bone turnover) osteoporosis [9][10][11][12], osteogenesis imperfecta [13][14][15], melorheostosis [16,17], hypophosphatemia [18], hypophosphatasia [19,20] as well as bisphosphonate [21][22][23] or teriparatide [24] treatment.…”