Fructose Potentiates Bone Loss and Marrow Adipose Tissue Accumulation by Inhibiting Adenosine 5'-Monophosphate-Activated Protein Kinase in Mesenchymal Stem Cells.

Increased fructose consumption has been elucidated to contribute to metabolic diseases. Bone is a dynamic organ that undergoes constant remodeling. However, the effects of fructose on bone health are still in dispute. Here, we identified fructose deteriorated bone mineral density while promoting the abundance of bone marrow adipose tissue. Fructose remarkably promoted the bone marrow mesenchymal stem cells' (BMMSCs) adipogenic commitment at the expense of osteogenic commitment. Fructose boosted the glycolysis of BMMSCs and inhibited phosphorylation of adenosine 5'-monophosphate-activated protein kinase (AMPK), which played a crucial role in bone-fat alteration. Our results suggested that fructose potentiated bone loss and marrow adipose tissue accumulation by suppressing AMPK activation in BMMSCs. Understanding fructose which affected bone metabolism was thus of primary importance in order to establish preventative measures or treatments for this condition.

Comparative effects of calcitriol and calcimimetic on bone health in renal insufficiency.

Calcitriol and calcimimetics are used to treat hyperparathyroidism secondary to chronic kidney disease (CKD). Calcitriol administration and the subsequent increase in serum calcium concentration decrease parathyroid hormone (PTH) levels, which should reduce bone remodeling. We have previously reported that, when maintaining a given concentration of PTH, the addition of calcimimetics is associated with an increased bone cell activity. Whether calcitriol administration affects bone cell activity while PTH is maintained constant should be evaluated in an animal model of renal osteodystrophy. The aim of the present study was to compare in CKD PTH-clamped rats the bone effects of calcitriol and calcimimetic administration. The results show that the administration of calcitriol and calcimimetic at doses that induced a similar reduction in PTH secretion produced dissimilar effects on osteoblast activity in 5/6 nephrectomized (Nx) rats with secondary hyperparathyroidism and in Nx rats with clamped PTH. Remarkably, in both rat models, the administration of calcitriol decreased osteoblastic activity, whereas calcimimetic increased bone cell activity. In vitro, calcitriol supplementation inhibited nuclear translocation of ß-catenin and reduced proliferation, osteogenesis, and mineralization in mesenchymal stem cells differentiated into osteoblasts. In conclusion, besides the action of calcitriol and calcimimetics at parathyroid level, these treatments have specific effects on bone cells that are independent of the PTH level.

Histomorphometric analysis of patients with femoral neck fracture and 25-hydroxyvitamin D deficiency: a cross-sectional study.

INTRODUCTION: Vitamin D deficiency causes osteoporosis, bone mineralization disorders, and osteomalacia. Osteomalacia is diagnosed using blood biochemical tests, clinical symptoms, and imaging; however, accurate detection of mineralization disorders requires tissue observation. We investigated the prevalence of bone mineralization disorders and their relationship with serum 25-hydroxyvitamin D (25OHD) levels in patients with untreated osteoporosis with femoral neck fractures. MATERIALS AND METHODS: A non-demineralized specimen was prepared from the femoral head removed during surgery in 65 patients. Bone histomorphometry of cancerous bone in the femoral head center was conducted. Osteoid volume per bone volume (OV/BV) and osteoid thickness (O.Th) were measured as indicators of mineralization disorder. RESULTS: The mean serum 25OHD level (11.9 ± 5.7 ng/mL) was in the deficiency range (< 12 ng/mL). There were no clinically diagnosed cases of osteomalacia (OV/BV > 10% and O.Th > 12.5 µm); however, one case of mineralization disorder, considered histologically pre-osteomalacia (OV/BV > 5% and O.Th < 12.5 µm), was observed (OB/BV, 17.6%; O.Th, 12.3 µm). Excluding this case, those with severe (25OHD < 12 ng/mL, at risk of osteomalacia; n = 39) and non-severe deficiency (25OHD ≥ 12 ng/mL; n = 25) did not significantly differ in OV/BV (%; 0.77 ± 0.54 vs. 0.69 ± 0.38, p = 0.484) or O.Th (µm; 5.32 ± 1.04 vs. 5.13 ± 0.78, p = 0.410). Further, 25OHD and OV/BV were not significantly correlated (R = - 0.124, p = 0.327). CONCLUSION: This is the first study in the twenty-first century to examine serum 25OHD concentrations and bone mineralization disorders in Japanese patients with osteoporosis. The results indicate that vitamin D deficiency does not necessarily cause bone mineralization disorders and rarely leads to osteomalacia.

Pilot Study: Short Term Impact of Radiation Therapy on Bone Mineral Density and Bone Metabolism.

Despite the risk of complications, high dose radiation therapy is increasingly utilized in the management of selected bone malignancies. In this study, we investigate the impact of moderate to high dose radiation (over 50 Gy) on bone metabolism and structure. Between 2015 and 2018, patients with a primary malignant bone tumor of the sacrum that were either treated with high dose definitive radiation only or a combination of moderate to high dose radiation and surgery were prospectively enrolled at a single institution. Quantitative CTs were performed before and after radiation to determine changes in volumetric bone mineral density (BMD) of the irradiated and non-irradiated spine. Bone histomorphometry was performed on biopsies of the irradiated sacrum and the non-irradiated iliac crest of surgical patients using a quadruple tetracycline labeling protocol. In total, 9 patients were enrolled. Two patients received radiation only (median dose 78.3 Gy) and 7 patients received a combination of preoperative radiation (median dose 50.4 Gy), followed by surgery. Volumetric BMD of the non-irradiated lumbar spine did not change significantly after radiation, while the BMD of the irradiated sacrum did (pre-radiation median: 108.0 mg/cm3 (IQR 91.8-167.1); post-radiation median: 75.3 mg/cm3 (IQR 57.1-110.2); p = 0.010). The cancellous bone of the non-irradiated iliac crest had a stable bone formation rate, while the irradiated sacrum showed a significant decrease in bone formation rate [pre-radiation median: 0.005 mm3/mm2/year (IQR 0.003-0.009), post-radiation median: 0.001 mm3/mm2/year (IQR 0.001-0.001); p = 0.043]. Similar effects were seen in the cancellous and endocortical envelopes. This pilot study shows a decrease of volumetric BMD and bone formation rate after high-dose radiation therapy. Further studies with larger cohorts and other endpoints are needed to get more insight into the effect of radiation on bone. Level of evidence: IV.

Contemporary Advances in Computer-Assisted Bone Histomorphometry and Identification of Bone Cells in Culture.

Static and dynamic bone histomorphometry and identification of bone cells in culture are labor-intensive and highly repetitive tasks. Several computer-assisted methods have been proposed to ease these tasks and to take advantage of the increased computational power available today. The present review aimed to provide an overview of contemporary methods utilizing specialized computer software to perform bone histomorphometry or identification of bone cells in culture. In addition, a brief historical perspective on bone histomorphometry is included. We identified ten publications using five different computer-assisted approaches (1) ImageJ and BoneJ; (2) Histomorph: OsteoidHisto, CalceinHisto, and TrapHisto; (3) Fiji/ImageJ2 and Trainable Weka Segmentation (TWS); (4) Visiopharm and artificial intelligence (AI); and (5) Osteoclast identification using deep learning with Single Shot Detection (SSD) architecture, Darknet and You Only Look Once (YOLO), or watershed algorithm (OC_Finder). The review also highlighted a substantial need for more validation studies that evaluate the accuracy of the new computational methods to the manual and conventional analyses of histological bone specimens and cells in culture using microscopy. However, a substantial evolution has occurred during the last decade to identify and separate bone cells and structures of interest. Most early studies have used simple image segmentation to separate structures of interest, whereas the most recent studies have utilized AI and deep learning. AI has been proposed to substantially decrease the amount of time needed for analyses and enable unbiased assessments. Despite the clear advantages of highly sophisticated computational methods, the limited nature of existing validation studies, particularly those that assess the accuracy of the third-generation methods compared to the second-generation methods, appears to be an important reason that these techniques have failed to gain wide acceptance.

Bone Tissue Evaluation Indicates Abnormal Mineralization in Patients with Autoimmune Polyendocrine Syndrome Type I: Report on Three Cases.

Autoimmune polyendocrine syndrome type-1 (APS1) is characterized by autoimmune manifestations affecting different organs from early childhood on. Immunological abnormalities, the resulting endocrinopathies, and their treatments may compromise bone health. For the first time in APS1, we analyzed transiliac bone biopsy samples by bone histomorphometry and quantitative backscattered electron imaging in three adult patients (female P1, 38 years; male P2, 47 years; male P3, 25 years). All had biallelic mutations in the autoimmune regulator gene and in addition to endocrinopathies, also significant bone fragility. Histomorphometry showed bone volume in the lower normal range for P1 (BV/TV, - 0.98 SD) and P3 (- 1.34 SD), mainly due to reduced trabecular thickness (TbTh, - 3.63 and - 2.87 SD). In P1, osteoid surface was low (OS/BS, - 0.96 SD); active osteoblasts and double labeling were seen only on cortical bone. P3 showed a largely increased bone turnover rate (BFR/BV, + 4.53 SD) and increased mineralization lag time (Mlt, + 3.40 SD). Increased osteoid surface (OS/BS, + 2.03 and + 4.71 SD for P2 and P3) together with a large proportion of lowly mineralized bone area (Trab CaLow, + 2.22 and + 9.81 SD for P2 and P3) and focal mineralization defects were consistent with abnormal mineralization. In all patients, the density and area of osteocyte lacunae in cortical and trabecular bone were similar to healthy adults. The bone tissue characteristics were variable and included decreased trabecular thickness, increased amount of osteoid, and abnormal mineralization which are likely to contribute to bone fragility in patients with APS1.

Mild Chronic Kidney Disease Associated with Low Bone Formation and Decrease in Phosphate Transporters and Signaling Pathways Gene Expression.

The initial phases of molecular and cellular maladaptive bone responses in early chronic kidney disease (CKD) remain mostly unknown. We induced mild CKD in spontaneously hypertensive rats (SHR) by either causing arterial hypertension lasting six months (sham-operated rats, SO6) or in its' combination with 3/4 nephrectomy lasting two and six months (Nx2 and Nx6, respectively). Sham-operated SHRs (SO2) and Wistar Kyoto rats (WKY2) with a two-month follow-up served as controls. Animals were fed standard chow containing 0.6% phosphate. Upon follow-up completion in each animal, we measured creatinine clearance, urine albumin-to-creatinine ratio, renal interstitial fibrosis, inorganic phosphate (Pi) exchange, intact parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), Klotho, Dickkopf-1, sclerostin, and assessed bone response by static histomorphometry and gene expression profiles. The mild CKD groups had no increase in renal Pi excretion, FGF23, or PTH levels. Serum Pi, Dickkopf-1, and sclerostin were higher in Nx6. A decrease in trabecular bone area and osteocyte number was obvious in SO6. Nx2 and Nx6 had additionally lower osteoblast numbers. The decline in eroded perimeter, a resorption index, was only apparent in Nx6. Significant downregulation of genes related to Pi transport, MAPK, WNT, and BMP signaling accompanied histological alterations in Nx2 and Nx6. We found an association between mild CKD and histological and molecular features suggesting lower bone turnover, which occurred at normal levels of systemic Pi-regulating factors.

Can locally applied risedronate be an effective agent when combined with xenografts? An animal study.

BACKGROUND: To examine the effects of local risedronate application with xenografts on healing of rabbit skull defects using histological, histomorphometric, immunohistochemical, and three-dimensional radiological methods. METHODS: Two critical-sized defects with a diameter of 10 mm were created in 16 rabbits and filled with xenogenic bone graft and xenogenic bone graft + 5 mg risedronate in the control I and risedronate (RIS) groups, respectively. Residual graft, new bone, soft tissue areas, and bone volume were evaluated in the 4- and 8-week study groups. RESULTS: In both the 4- and 8-week samples, the RIS group samples had significantly higher mean new bone area values than the C group (p < 0.05). In both groups, the values for the new bone area were significantly higher in the 8-week-old samples than in the 4-week-old samples (p < 0.05). The h scores obtained for sialoprotein and osteopontin did not differ significantly between the groups at either time point (p > 0.05). The results of radiological evaluation showed that the bone density value was significantly higher in the C group than in the RIS group at either time point (p < 0.05). CONCLUSIONS: Although this study aimed to demonstrate the effect of risedronate on the osteoconductive properties of xenografts when applied locally, targeted results could not be achieved.

Diagnostic Accuracy of Noninvasive Bone Turnover Markers in Renal Osteodystrophy.

RATIONALE & OBJECTIVE: Bone biopsy remains the gold standard for diagnosing renal osteodystrophy as comparable noninvasive alternatives have yet to be established. This study investigated the diagnostic accuracy of biochemical markers of skeletal remodeling to predict bone turnover. STUDY DESIGN: Cross-sectional retrospective diagnostic test study. SETTING & PARTICIPANTS: Patients with chronic kidney disease glomerular filtration rate categories 4-5, including patients treated with dialysis (G4-G5D) and kidney transplant recipients with successful transiliac bone biopsies. TESTS COMPARED: Bone turnover as determined by bone histomorphometry was compared with the following biochemical markers: full-length (amino acids 1-84) "biointact" parathyroid hormone (PTH), bone-specific alkaline phosphatase (BsAP), intact procollagen type I N-terminal propeptide (PINP), and tartrate-resistant acid phosphatase isoform 5b (TRAP5b). OUTCOME: Diagnostic performance was evaluated by area under the receiver operator characteristics curve (AUC), sensitivity, specificity, and negative and positive predictive values. Optimal diagnostic cutoffs were determined in an exploration cohort (n = 100) and validated in a separate cohort (n = 99). RESULTS: All biomarkers differed across categories of low 33 (17%), normal 109 (55%), and high 57 (29%) bone turnover. AUC values were in the range of 0.75-0.85. High negative predictive values (≥90%) were found for both high and low bone turnover, indicating the ability to rule out both conditions using the suggested biomarker cutoffs. The highest diagnostic performances were seen with combinations of biomarkers, with overall diagnostic accuracies of 90% for high turnover, and 78% for low turnover. Results were comparable for kidney transplant candidates and recipients in a sensitivity analysis. LIMITATIONS: The single-center approach and heterogeneity of the study cohort are main limitations of this study. CONCLUSIONS: We conclude that the diagnostic performance of biochemical markers of bone turnover is acceptable, with clinical utility in ruling out both high and low turnover bone disease.

Bone Turnover, Mineralization, and Volume Estimated by 18F-Sodium Fluoride PET/CT and Biomarkers in Chronic Kidney Disease: Mineral and Bone Disorder Compared with Bone Biopsy.

INTRODUCTION: Invasive bone biopsy to assess bone metabolism in patients with chronic kidney disease-mineral and bone disorder may be replaced by the noninvasive 18F-NaF PET/CT and biomarkers of bone metabolism. We aimed to compare parameters of bone turnover, mineralization, and volume assessed by bone biopsies with results derived from 18F-NaF PET/CT and biomarkers (bone-specific alkaline phosphatase, osteocalcin, fibroblast growth factor 23, and osteoprotegerin). METHODS: A cross-sectional study included 17 dialysis patients, and results from 18F-NaF PET/CT scans and the biomarkers were directly compared with the results of histomorphometric analyses of tetracycline double-labeled trans-iliac bone biopsies. RESULTS: Bone biopsies showed 40% high, 20% normal, and 40% low bone turnover. No biopsies had generalized abnormal mineralization, and the bone volume/total tissue volume was low in 80% and high in 7%. The pelvic skeletal plasma clearance (Ki) from 18F-NaF PET/CT correlated with bone turnover parameters obtained by bone biopsy (activation frequency: r = 0.82, p < 0.01; bone formation rate/bone surface: r = 0.81, p < 0.01), and Ki defined low turnover with high sensitivity (83%) and specificity (100%). CT-derived radiodensity correlated with bone volume, r = 0.82, p < 0.01. Of the biomarkers, only osteocalcin showed a correlation with turnover assessed by histomorphometry. CONCLUSION: In conclusion, 18F-NaF PET/CT may be applicable for noninvasive assessment of bone turnover and volume in CKD-MBD.

Nothobranchius furzeri, the Turquoise Killifish: A Model of Age-Related Osteoporosis?

INTRODUCTION: Osteoporosis is a frequent age-related disease, which affects millions of people worldwide. Despite significant progress in the treatment of the disease, a high number of patients still are underdiagnosed and undertreated. Therefore, novel animal models for the investigation of the disease are necessary. Nothobranchius furzeri is the shortest-lived vertebrate (with a lifespan of 3-7 months) that can be kept in captivity. Although it is an established model for aging research, studies on bone are lacking. The aim of this study was therefore to characterize N. furzeri as a potential model for age-related osteoporosis. MATERIALS AND METHODS: Bone properties of aging N. furzeri were investigated in male and female fish of the Gona Re Zhou strain, which were between 8 and 20 weeks old. Micro-computed tomography (Scanco Medical µCT35) was performed to determine the bone properties of the vertebral bodies. Bone structure and remodeling were investigated by different histological staining techniques and histomorphometry. The chemical composition of fish vertebrae and intervertebral discs was analyzed by Raman microspectroscopy. RESULTS: Osteoblasts, mono- and multinucleated osteoclasts but no osteocytes could be observed in the vertebral area of N. furzeri. Histomorphometric evaluations revealed a significant decrease of the number of osteoblasts/bone perimeter and for osteoid volume/bone volume (BV) a trend toward a decrease in old male N. furzeri. Comparing male and female fish, males showed higher BV densities and cortical thickness. The relative values of the bone volume density of 20-week-old male N. furzeri were significantly lower than 10-week-old ones. The mineral to matrix ratio increased with age in male and female fish. In the intervertebral discs, proteoglycans in relation to the organic matrix were significantly lower in older female fish. CONCLUSION: Our finding of a lack of osteocytes is in agreement with the fact that N. furzeri belongs to the evolutionarily advanced teleost fish. Furthermore, not only age-specific but also sex-specific differences were visible in the bone properties of N. furzeri, which can be taken into consideration for the study of gender aspects of age-related musculoskeletal diseases.

Association between bone mineral metabolism and vascular calcification in end-stage renal disease.

BACKGROUND: Development of vascular calcification is accelerated in patients with end-stage renal disease. In addition to traditional risk factors of cardiovascular disease (CVD) abnormal bone and mineral metabolism together with many other factors contribute to the excess cardiovascular burden in patients on dialysis. Aortic calcification score and coronary calcification score are predictive of CVD and mortality. The aim of this study was to evaluate the possible relationship between arterial calcification and bone metabolism. METHODS: Thirty two patients on dialysis were included. All patients underwent a bone biopsy to assess bone histomorphometry and a 18F-NaF PET scan. Fluoride activity was measured in the lumbar spine (L1 - L4) and at the anterior iliac crest. Arterial calcification scores were assessed by computerized tomography for quantification of coronary artery calcification score and lateral lumbar radiography for aortic calcification score. RESULTS: This study group showed high prevalence of arterial calcification and 59% had verified CVD. Both CAC and AAC were significantly higher in patients with verified CVD. Only 22% had low turnover bone disease. There was a weak association between fluoride activity, which reflects bone turnover, measured in the lumbar spine, and CAC and between PTH and CAC. There was also a weak association between erosion surfaces and AAC. No significant association was found between calcification score and any other parameter measured. CONCLUSIONS: The results in this study highlight the complexity, when evaluating the link between bone remodeling and vascular calcification in patients with multiple comorbidities and extensive atherosclerosis. Several studies suggest an impact of bone turnover on development of arterial calcification and there is some evidence of reduced progression of vascular calcification with improvement in bone status. The present study indicates an association between vascular calcification and bone turnover, even though many parameters of bone turnover failed to show significance. In the presence of multiple other factors contributing to the development of calcification, the impact of bone remodeling might be diminished. TRIAL REGISTRATION: The study is registered in ClinicalTrials.gov protocol registration and result system, ID is NCT02967042 . Date of registration is 17/11/2016.

Non-oxidized parathyroid hormone (PTH) measured by current method is not superior to total PTH in assessing bone turnover in chronic kidney disease.

Parathyroid hormone (PTH) is a key regulator of bone turnover but can be oxidized in vivo, which impairs biological activity. Variable PTH oxidation may account for the rather poor correlation of PTH with indices of bone turnover in chronic kidney disease. Here, we tested whether non-oxidized PTH is superior to total PTH as a marker of bone turnover in 31 patients with kidney failure included from an ongoing prospective observational bone biopsy study and selected to cover the whole spectrum of bone turnover. Receiver Operating Characteristic (ROC) curves, Spearman correlation and regression analysis of non-oxidized PTH, total PTH and bone turnover markers (bone-specific alkaline phosphatase, procollagen N-terminal pro-peptide and tartrate-resistant acid phosphatase 5b) were used to assess the capability of non-oxidized PTH vs. total PTH to discriminate low from non-low and high from non-high bone turnover, as assessed quantitatively by bone histomorphometry. Serum levels of non-oxidized PTH and total PTH were strongly and significantly correlated. Histomorphometric parameters of bone turnover and the circulating bone turnover markers showed similar correlation coefficients with non-oxidized PTH and total PTH. The area under the ROC (AUROC) values for discriminating between low/non-low turnover for non-oxidized PTH and total PTH were significant and comparable (0.82 and 0.79, respectively). For high/non-high turnover the AUROCs were also significant and of the same magnitude (0.76 and 0.80, respectively). Thus, measuring non-oxidized PTH using the currently available method provides no added value compared to total PTH as an indicator of bone turnover in patients with kidney failure.

The Role of Bone Biopsy in the Management of CKD-MBD.

A bone biopsy is still considered the gold standard for diagnosis of renal osteodystrophy. It allows to measure both static and dynamic parameters of bone remodeling and is the only method able to evaluate mineralization and allows analysis of both cortical and trabecular bone. Although bone volume can be measured indirectly by dual-energy X-ray absorptiometry, mineralization defects, bone metal deposits, cellular number/activity, and even turnover abnormalities are difficult to determine by techniques other than qualitative bone histomorphometry. In this review, we evaluate the role of bone biopsy in the clinical practice.

Bone Histomorphometry and 18F-Sodium Fluoride Positron Emission Tomography Imaging: Comparison Between only Bone Turnover-based and Unified TMV-based Classification of Renal Osteodystrophy.

Bone biopsy is the gold standard for characterization of renal osteodystrophy (ROD). However, the classification of the subtypes of ROD based on histomorphometric parameters is not unambiguous and the range of normal values for turnover differ in different publications. 18F-Sodium Fluoride positron emission tomography (18F-NaF PET) is a dynamic imaging technique that measures turnover. 18F-NaF PET has previously been shown to correlate with histomorphometric parameters. In this cross-sectional study, 26 patients on dialysis underwent a 18F-NaF PET and a bone biopsy. Bone turnover-based classification was assessed using Malluche's historical reference values for normal bone turnover. In unified turnover-mineralization-volume (TMV)-based classification, the whole histopathological picture was evaluated and the range for normal turnover was set accordingly. Fluoride activity was measured in the lumbar spine (L1-L4) and at the anterior iliac crest. On the basis of turnover-based classification of ROD, 12% had high turnover and 61% had low turnover bone disease. On the basis of unified TMV-based classification of ROD, 42% had high turnover/hyperparathyroid bone disease and 23% had low turnover/adynamic bone disease. When using unified TMV-based classification of ROD, 18F-NaF PET had an AUC of 0.86 to discriminate hyperparathyroid bone disease from other types of ROD and an AUC of 0.87, for discriminating adynamic bone disease. There was a disproportion between turnover-based classification and unified TMV-based classification. More research is needed to establish normal range of bone turnover in patients with CKD and to establish the role of PET imaging in ROD.

Patterns of renal osteodystrophy 1 year after kidney transplantation.

BACKGROUND: Renal osteodystrophy is considered common, but is not well characterized in contemporary kidney transplant recipients. This study reports extensively on bone phenotype by bone histomorphometry, bone densitometry and novel bone biomarkers 1 year after kidney transplantation. METHODS: A transiliac bone biopsy and dual-energy X-ray absorptiometry scans were performed in 141 unselected kidney transplant recipients in this observational cohort study. Blood and 24-h urine samples were collected simultaneously. RESULTS: The median age was 57 ± 11 years, 71% were men and all were of Caucasian ethnicity. Bone turnover was normal in 71% of patients, low in 26% and high in just four cases (3%). Hyperparathyroidism with hypercalcaemia was present in 13% of patients, of which only one had high bone turnover. Delayed bone mineralization was detected in 16% of patients, who were characterized by hyperparathyroidism (137 versus 53 ρg/mL), a higher fractional excretion of phosphate (40 versus 32%) and lower levels of phosphate (2.68 versus 3.18 mg/dL) and calcidiol (29 versus 37 ng/mL) compared with patients with normal bone mineralization. Osteoporosis was present in 15-46% of patients, with the highest prevalence at the distal skeleton. The proportion of osteoporotic patients was comparable across categories of bone turnover and mineralization. CONCLUSIONS: The majority of kidney transplant recipients, including patients with osteoporosis, have normal bone turnover at 1-year post-transplant. Low bone turnover is seen in a substantial subset, while high bone turnover is rare. Vitamin D deficiency and hypophosphataemia represent potential interventional targets to improve bone health post-transplant.

Case report: Osteomalacia due to bisphosphonate treatment in a patient on hemodialysis.

BACKGROUND: No publications have reported on osteomalacia in patients receiving intermittent cyclical therapy with etidronate (a bisphosphonate) and undergoing long-term hemodialysis (HD). CASE PRESENTATION: We report on a 46-year-old Japanese man admitted to our hospital for further examination of left forearm pain. Maintenance HD was started at age 24 years, and the man had been on HD since then. At age 38 years, surgical parathyroidectomy was performed for secondary hyperparathyroidism; iliac crest bone biopsy performed at the same time showed osteitis fibrosa. The active vitamin D3 preparation calcitriol was started, and intermittent cyclical etidronate therapy was introduced 2 years later for osteoporosis. At age 45 years, the patient stopped taking calcitriol because of hypercalcemia but continued with etidronate. At age 46 years, a pseudofracture with a Looser zone occurred in the left ulna, and left femur bone biopsy revealed osteomalacia. Etidronate was discontinued, and calcitriol was restarted; open reduction and internal fixation with an angular stability plate were performed. Union of the bone was achieved 10 months after the operation. At age 49 years, a lumber bone biopsy confirmed improved bone morphometry. CONCLUSIONS: We believe that intermittent cyclical etidronate therapy without administration of active vitamin D3 during long-term HD might have induced osteomalacia, resulting in the ulna insufficiency fracture. Therefore, we propose that administration of active vitamin D3 is essential to prevent osteomalacia in patients on long-term HD who are receiving bisphosphonates and have potential vitamin D3 deficiency.

Vertebral bone marrow edema in magnetic resonance imaging correlates with bone healing histomorphometry in (sub)acute osteoporotic vertebral compression fracture.

BACKGROUND: BME on MRI has become the gold standard for the diagnosis of acute/subacute OVCF, but the correlation between the quantitative model of BME and histopathological manifestations of OVCF is rarely discussed in the literature. OBJECTIVES: This study aimed to retrospectively investigate the relationship between bone marrow edema (BME) in magnetic resonance imaging (MRI) and bone healing histomorphometry in (sub)acute osteoporotic vertebral compression fracture. METHODS: According to the period since fracture, 125 patients were divided into four stages: stage I (0 to 15 days), stage II (16 to 30 days), stage III (31 to 60 days) and stage IV (61 to 90 days). Bone marrow edema was evaluated by the signal changes and intensity patterns on MRI sagittal images. Decalcified biopsy specimens were obtained from the cancellous bone core in the fractured vertebral body. The histomorphometry study results were analyzed by light microscopy using grid analysis and defined using bone histomorphometry criteria. RESULTS: There were 70 (56%) patients in stage I, 29 (23.2%) in stage II, 12 (9.6%) in stage III and 14 (11.2%) in stage IV. BME and histomorphometry characteristics differentiated from each other stage: The BME percentage had a significantly negative correlation with the ratio of osteoid volume/bone volume (r = - 0.539, p = 0.001) and the ratio of woven bone volume/tissue volume (r = - 0.584, p = 0.001). There was also a positive correlation between the BME percentage and the ratio of fibrous tissue volume/tissue volume (r = 0.488, p = 0.001). CONCLUSIONS: Bone marrow edema significantly correlates with bone morphology parameters after vertebral fracture. The characteristics of histomorphological changes during fracture healing process can be preliminarily determined by observing the edema signal.

Bone Histomorphometry of Femoral Head Cancellous Bone in Patients Who Underwent Total Hip Arthroplasties due to Destructive Hip in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) affects the hip joints. The microarchitecture of the cancellous bone in RA-affected hip joints has been unclear. Here we investigated the bone metabolism changes in the subcapital cancellous bone of destructive hips of RA patients (n=26 patients; 28 hip joints) which were classified by Larsen grade on X-ray into the groups: destructive hip (Des) (Larsen grade IV, n=18) and neck fracture (Fx) (Larsen grade 0 or 1, n=10). The femoral heads of the Des-group showed significantly higher trabecular thickness versus those of the Fx-group (179±30.8 vs. 151±23.5 µm, p=0.02). The Des-group had significantly higher osteoid volume/tissue volume (OV/TV) and osteoid volume/bone volume (OV/BV) ratios than the Fx-group (OV/TV: 0.72±0.70% vs. 0.27±0.32%, p=0.028; OV/BV: 2.96±2.85% vs. 1.24±1.31%, p=0.039). The osteoblast and osteoclast surface areas of the Des-group were remarkably higher than those of the Fx-group (9.80±10.9 vs. 0.15±0.15%, p=0.0005; 0.34±0.48 vs. 0.06±0.06%, p=0.0285, respectively). The T-scores of hip (femoral neck) bone mineral density (BMD) of the Fx-group were significantly lower versus those of the Des-group (-3.1±0.76 vs. -1.6±1.17, p<0.01). Increased osteoid and resorption parameters and higher femoral neck BMD demonstrate a high bone-turnover state in response to destructive changes in the hips of RA patients.

Bone Turnover Markers and Bone Histomorphometry in Pubertal Rats with Intrauterine Growth Restriction.

OBJECTIVE: To investigate the effect of malnutrition during pregnancy on bone development in rat pups with intrauterine growth restriction (IUGR). Methods: IUGR offspring were induced with a 10% low protein diet, while the control group was given a 21% protein diet during pregnancy. Serum biomarkers including bone glutamyl protein (BGP), amino-terminal propeptide of type 1 procollagen (P1NP), cross linked N-telopeptide of type I collagen (NTX), and insulin like growth factor 1 (IGF-1) levels were measured at 7, 21 and 56 d. Left femurs taken at 56 d were used for bone histomorphometry analysis by micro-computed tomography (micro-CT). Results: Compared with the control group, the IUGR group had lower IGF-1 and BGP levels at 7 and 21 d, and higher P1NP and NTX levels at 7 d. The IUGR group had thinner trabecular thickness (Tb.Th), lower trabecular number (Tb.N), and increased trabecular separation (Tb.Sp) at 56 d. Conclusion: The effect of IUGR on bone development may persist after birth.