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Objectives: Little is known about bone mineralization and osteocyte lacunae properties in chronic kidney disease mineral bone disorder (CKD-MBD)., Methods: In this retrospective study, we measured the bone mineralization density distribution (BMDD) and osteocyte lacunar section (OLS) 2D-characteristics by quantitative backscatter electron imaging in Straumann drill biopsy samples from n=58 patients with CKD-MBD. Outcomes were studied in relation to serum parathyroid hormone (PTH), alkaline phosphatase (APH), histomorphometric bone turnover and treatment with cinacalcet or phosphate binders., Results: Lower calcium concentrations in bone from high turnover (average degree of bone mineralization -6.2%, p<0.001) versus low turnover patients were observed. OLS-characteristics were distinctly different (p<0.01 to p<0.05) in patients with highest compared to those with lowest turnover. Patients with cinacalcet had different OLS-characteristics (p<0.05) compared to those without cinacalcet. Furthermore, patients with phosphate binders had differences in BMDD and OLS-characteristics (p<0.05) compared to patients without phosphate binders., Conclusions: Our findings suggest that in patients with CKD-MBD secondary hyperparathyroidism and increased bone turnover decrease the average degree of bone matrix mineralization. Conversely, density and lacunar size of the osteocytes are increased compared to adynamic bone disease pointing at distinct patterns of bone mineralization and osteocyte lacunar properties in these two disease entities.

Inflammatory bowel disease (IBD) affects many organ systems including the skeleton. In children with IBD, bone mineral density (BMD) and bone turnover are frequently low. Disturbances in bone mineralization density distribution (BMDD) are linked to alterations in bone material strength; however, BMDD has not previously been reported in children with chronic inflammatory disorders. The aim of this study was to characterize BMDD based on quantitative backscatter electron imaging in cancellous (Cn.) and cortical (Ct.) compartments from trans-iliac biopsy samples from a cohort of 20 treatment-naïve children at the time of their IBD diagnosis (12 males, mean age 14.5±2.3years). The outcomes were compared to pediatric reference BMDD data and correlation with revisited biochemical and histomorphometric outcomes was analyzed. BMDD in treatment-naïve children with IBD was shifted toward higher calcium concentrations compared to reference: (i) In cancellous bone, the most frequent calcium concentration (Cn.CaPeak+2.8%, p=0.004) and the portion of highly mineralized bone (Cn.CaHigh+52%, p=0.009) were increased. (ii) In cortical bone, the mineralization heterogeneity (Ct.CaWidth+17.0%, p=0.001) and Ct.CaHigh (+30.4%, p=0.006) were increased. (iii) Furthermore, significant correlations with serum alkaline phosphatase (ALP), bone-specific alkaline phosphatase (bsALP), and urinary crosslinked N-telopeptide of type I collagen (uNTX) were observed: the higher CaMean (the average calcium concentration), CaPeak and CaHigh, the lower were ALP, bsALP, and uNTX (p-value from <0.001 to 0.05). Children with treatment-naïve IBD have decreased bone turnover leading to a higher bone matrix mineralization density, findings which may contribute to compromised bone strength., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Unlabelled: Bone matrix mineralization based on quantitative backscatter electron imaging remained unchanged during the first year of menopause in paired transiliac biopsy samples from healthy women. This suggests that the reported early perimenopausal reductions in bone mineral density are caused by factors other than decreases in the degree of mineralization., Introduction: It is unknown whether perimenopausal loss of bone mass is associated with a drop in bone matrix mineralization., Methods: For this purpose, we measured the bone mineralization density distribution (BMDD) by quantitative backscatter electron imaging (qBEI) in n = 17 paired transiliac bone biopsy samples at premenopausal baseline and 12 months after last menses (obtained at average ages of 49 ± 2 and 55 ± 2 years, respectively) in healthy women. For interpretation of BMDD outcomes, previously measured bone mineral density (BMD) and biochemical and histomorphometric markers of bone turnover were revisited for the present biopsy cohort., Results: Menopause significantly decreased BMD at the lumbar spine (-4.5 %) and femoral neck (-3.8 %), increased the fasting urinary hydroxyproline/creatinine ratio (+60 %, all p < 0.01) and histomorphometric bone formation rate (+25 %, p < 0.05), but affected neither cancellous nor cortical BMDD variables (paired comparison p > 0.05). Mean calcium concentrations of cancellous (Cn.CaMean) and cortical bone (Ct.CaMean) were within normal range (p > 0.05 compared to established reference data). Ct.CaMean was significantly correlated with Cn.CaMean before (R = 0.81, p < 0.001) and after menopause (R = 0.80, p < 0.001) and to cortical porosity of mineralized tissue (Ct.Po.) after menopause (R = -0.57, p = 0.02)., Conclusions: Surprisingly, the BMDD was found not affected by the changes in bone turnover rates in this cohort. This suggests that the substantial increase in bone formation rates took place shortly before the second biopsy, and the bone mineralization changes lag behind. We conclude that during the first year after the last menses, the degree of bone matrix mineralization is preserved and does not contribute to the observed reductions in BMD.

Background: Patients with chronic kidney disease (CKD) develop renal osteodystrophy with alterations in bone turnover, mineralization, and volume (TMV). A specific skeletal complication in children is growth impairment, which currently is treated by recombinant human growth hormone (rhGH). The effects on bone material properties are poorly understood. This study assesses the effects of rhGH treatment on bone matrix mineralization., Study Design: Observational study., Setting & Participants: 18 short children and adolescents (aged 3.6-16 years) with CKD on dialysis therapy., Predictor: rhGH treatment for 1 year., Outcomes: Tetracycline-labeled bone biopsy classified according to the TMV system., Measurements: Bone mineralization density distribution (BMDD) was evaluated by quantitative backscattered electron imaging in trabecular and cortical compartments. Additional data for patients' height and biochemical bone serum parameters were obtained., Results: Prior to rhGH treatment, our cohort showed low bone turnover and high mineralization densities versus reference data: Ca(mean) (weighted mean calcium content) in cancellous bone, +3.3% (P = 0.04); Ca(mean) in cortical bone, +6.7% (P < 0.001); Ca(peak) (mode of the BMDD) in cancellous bone, +5.0% (P < 0.001); Ca(peak) in cortical bone, +8.2% (P < 0.001); Ca(width) (heterogeneity in mineralization), no significant difference for cancellous (P = 0.2) and cortical (P = 0.1) bone; Ca(high) (portion of fully mineralized bone) in cancellous bone, 5-fold greater (P < 0.001); Ca(high) in cortical bone, 14-fold greater (P < 0.001); Ca(low) (portion of low mineralized bone) in cancellous bone, +23.9% (P = 0.02); Ca(low) in cortical bone, -22.2% (P = 0.05). After rhGH treatment, height increased by 9.1 cm (P < 0.001) and bone turnover indices to normal values or beyond. Matrix mineralization was lesser and more heterogeneous compared to baseline: Ca(width) for cancellous bone, +15.3% (P < 0.001); Ca(width) for cortical bone, +34.1% (P < 0.001). Ca(mean), Ca(peak), and Ca(high) for cancellous bone and Ca(mean) and Ca(peak) for cortical bone were no longer significantly different from reference data. Ca(high) for cortical bone dramatically decreased after treatment but was still substantially greater than reference data., Limitations: Low case number per TMV subgroup, no measurements of fibroblast growth factor 23., Conclusions: Children and adolescents with CKD and growth deficiency are at risk of having low bone turnover. rhGH treatment improves height and concomitantly bone modeling/remodeling, which appears beneficial for bone matrix mineralization., (Copyright © 2013 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

The pathogenesis of primary osteoporosis in younger individuals is still elusive. An important determinant of the biomechanical competence of bone is its material quality. In this retrospective study we evaluated bone material quality based on quantitative backscattered electron imaging to assess bone mineralization density distribution (BMDD) in bone biopsies of 25 male patients (aged 18-61 years) who sustained fragility fractures but were otherwise healthy. BMDD of cancellous bone was compared with previously established adult reference data. Complementary information was obtained by bone histomorphometry. The histomorphometric results showed a paucity of osteoblasts and osteoclasts on the bone surface in the majority of patients. BMDD revealed a significant shift to lower mineralization densities for cancellous bone values: CaMean (weighted mean Ca content, -5.9%), CaPeak (mode of the BMDD, -5.6%), and CaHigh (portion of fully mineralized bone, -76.8%) were decreased compared to normative reference; CaWidth (heterogeneity in mineralization, +18.5%) and CaLow (portion of low mineralized bone, +68.8; all P < 0.001) were significantly increased. The shift toward lower mineral content in the bone matrix in combination with reduced indices of bone formation and bone resorption suggests an inherent mineralization defect leading to undermineralized bone matrix, which might contribute to the susceptibility to fragility fractures of the patients. The alteration in bone material might be related to osteoblastic dysfunction and seems fundamentally different from that in high bone turnover osteoporosis with a negative bone balance.

Cartilage-associated protein (CRTAP) is an essential cofactor for the proper post-translational chain modification and collagen folding. CRTAP mutations lead mice (Crtap-/- mice) and humans (OI type VII) to a severe/lethal osteochondrodystrophy; patients have fractures at birth, deformities of the lower extremities and impaired growth. The consequences of CRTAP deficiency on intrinsic bone material properties are still unknown. In the present study we evaluated bone quality based on quantitative backscattered electron imaging (qBEI) to assess bone mineralization density distribution (BMDD) in femurs from 12 weeks old Crtap-/- mice and transiliac bone biopsies from 4 children with hypomorphic mutations and having residual CRTAP expression. The analyses revealed in the bone matrix of Crtap-/- animals and OI type VII patients a significant increase in mean (CaMean) and most frequent mineral concentration (CaPeak) compared to wild-type littermates and control children, respectively. The heterogeneity of mineralization (CaWidth) was reduced in Crtap-/- mice but normal in OI type VII patients. The fraction of highly mineralized bone matrix (CaHigh) was remarkably increased in the patients: cancellous bone from 2.1 to 3.7 times and cortical bone from 7.6 to 25.5 times, associated with an increased persistence of primary bone. In conclusion, the BMDD data show that CRTAP deficiency results in a shift towards higher mineral content of the bone matrix similar to classical OI with collagen gene mutations. Our data further suggest altered mineralization kinetics resulting ultimately in an overall elevated tissue mineralization density. Finally, in OI type VII patients the increased portion of primary bone is most likely reflecting a disturbed bone development.