SO07118F-SODIUM FLUORIDE POSITRON EMISSION TOMOGRAPHY AND BONE HISTOMORPHOMETRY - COMPARISON BETWEEN ONLY BONE TURNOVER -BASED AND EXPERT EVALUATION -BASED CLASSIFICATION OF RENAL OSTEODYSTROPHY

Abstract Background and Aims The diagnosis and the differentiation of renal osteodystrophy (ROD) are challenging. Bone biopsy is the golden standard, but it is invasive and not available in every center. Bone turnover rate is defined by bone formation rate and/or activation frequency. Adynamic bone disease is defined as low turnover bone with reduced osteoblast- and osteoclast activities. Hyperparahyreoid bone disease or osteitis fibrosa is defined as high turnover bone with osteoclast- and osteoblast activities and fibrosis. 18F- Sodium Fluoride positron emission tomography (18F-NaF PET) is a noninvasive imaging technique that allows assessment of regional bone turnover. The aim was to assess how well bone turnover –based classification of ROD correlates with the classification determined by an expert histomorphometrist (HK), and how these correlate with 18F-NaF PET analysis Method A total of 24 dialysis patients underwent a 18F-NaF PET scan. Fluoride activity was measured at the anterior iliac crest and in the lumbar region. An iliac crest bone biopsy was obtained within 4 weeks from the PET-scan. The diagnosis of bone histomorphometry was determined based on turnover-mineralization-volume (TMV) classification. Firstly, bone turnover was assessed using bone formation rate and activation frequency. Secondly, also other histomorphometric parameters (eg. osteoid volume, osteoid surface, resorption surface, mineralized surface, osteoblast and osteoclast surfaces and peritrabecular fibrosis) were also taking into account for classification of ROD by a histomorphometrist. Results Based on bone turnover parameters only, 12% of the patients had high turnover and 64% low turnover. When the diagnosis of renal osteodystrophy was made by a histomorphometrist, 40% had hyperparathyreoid bone/osteitis fibrosa and 24% adynamic bone disease or ostemalasia. 18F-NaF PET´s sensitivity to recognize hyperparathyreoid bone disease was 80% end specificity 100% (cut-of value 0.055).18F-NaF PET´s sensitivity to recognize adynamic bone disease was 100% and specificity 61% (cut-of value of fluoride-activity 0.038) Conclusion 18F-NaF PET works well as a diagnostic tool, when the diagnosis of ROD is based on the histopathological evaluation. It remains unknown how variations in normal bone turnover rate can be detected in CKD patients by 18F-NaF PET and if treatment decisions of ROD can be made only based on bone turnover.

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

Calcified Tissue International ◽

10.1007/s00223-021-00874-9 ◽

2021 ◽

Author(s):

Louise Aaltonen ◽

Niina Koivuviita ◽

Marko Seppänen ◽

Inari S. Burton ◽

Heikki Kröger ◽

...

Keyword(s):

Positron Emission Tomography ◽

Bone Turnover ◽

Bone Disease ◽

Bone Biopsy ◽

Emission Tomography ◽

Adynamic Bone Disease ◽

High Turnover ◽

Positron Emission ◽

Adynamic Bone

AbstractBone 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.

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P0885THE RELATIONSHIP BETWEEN BONE REGULATORY MARKERS AND BONE TURNOVER IN RENAL OSTEODYSTROPHY

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa142.p0885 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Syazrah Salam ◽

Orla Gallagher ◽

Fatma Gossiel ◽

Arif Khwaja ◽

Richard Eastell

Keyword(s):

Bone Formation ◽

Bone Turnover ◽

Renal Osteodystrophy ◽

Bone Biopsy ◽

Formation Rate ◽

Tartrate Resistant Acid Phosphatase ◽

Bone Resorption Marker ◽

Bone Formation Rate ◽

Bone Formation Markers ◽

The Relationship

Abstract Background and Aims Renal osteodystrophy is common in advanced chronic kidney disease (CKD) patients and is characterized by abnormal bone turnover and mineralization. Parathyroid hormone (PTH) increases bone turnover through osteoblast and osteoclast activation. Osteoprotegerin (OPG) is a decoy receptor of receptor activator of nuclear factor kappa-β ligand and thus, inhibits osteoclast maturation. Meanwhile, sclerostin is an inhibitor of the Wnt signalling pathway and thus, inhibits osteoblast maturation. We aimed to assess the relationship between these bone regulatory markers and bone turnover as assessed by bone histomorphometry and bone turnover markers (BTMs). Method We recruited 43 CKD patients with eGFR<30ml/min/1.73m2 or on dialysis. Fasting serum samples were analysed using Immunodiagnostic Systems automated assays (Boldon, UK) for intact PTH (iPTH) and BTMs such as bone alkaline phosphatase (bALP) and intact procollagen type 1 N-terminal propeptide (intact PINP) which are bone formation markers, and tartrate-resistant acid phosphatase 5b (TRAP5b) which is a bone resorption marker. OPG and sclerostin were analysed using manual ELISA by Biomedica (Vienna, Austria). Trans-iliac bone biopsy was performed after tetracycline labelling. Bone samples were analysed using quantitative histomorphometry. Normal bone turnover was defined as bone formation rate/bone surface (BFR/BS) of 18 - 38µm3/µm2/year. Spearman rank correlation was used to test the relationship between the variables. Results Median BFR/BS was 32.12 (IQR 17.76 – 48.25) um3/um2/year. 26% of patients had low and 40% had high bone turnover. iPTH and OPG were positively correlated with BFR/BS (rho = 0.42, p<0.01 and rho = 0.36, p<0.05 respectively). Sclerostin was not correlated with BFR/BS. Furthermore, sclerostin did not correlate with bALP and intact PINP whereas OPG correlated with TRAP5b (rho = 0.43, p<0.01). iPTH correlated with bALP (rho = 0.62, p<0.001), intact PINP (rho = 0.62, p<0.001) and TRAP5b (rho = 0.50, p = 0.001). Conclusion Circulating levels of iPTH and OPG were modestly associated with bone turnover but sclerostin was not. There are likely to be bone regulators other than iPTH, OPG and sclerostin which regulate bone turnover in renal osteodystrophy.

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Plasma total versus bone alkaline phosphatase as markers of bone turnover in hemodialysis patients.

Journal of the American Society of Nephrology ◽

10.1681/asn.v73506 ◽

1996 ◽

Vol 7 (3) ◽

pp. 506-512

Author(s):

P Ureña ◽

M Hruby ◽

A Ferreira ◽

K S Ang ◽

M C de Vernejoul

Keyword(s):

Alkaline Phosphatase ◽

Bone Formation ◽

Bone Turnover ◽

Bone Disease ◽

Formation Rate ◽

Bone Alkaline Phosphatase ◽

Hemodialysis Patients ◽

High Turnover ◽

Bone Formation Rate ◽

Markers Of Bone Turnover

Plasma total versus bone alkaline phosphatase as markers of bone turnover in hemodialysis patients. Plasma bone-specific alkaline phosphatase (bAP) has been demonstrated to be more reliable than total alkaline phosphatases (tAP) in providing information about bone turnover in patients with metabolic bone diseases. This study surveyed 42 hemodialysis patients who underwent a systematic transiliac bone biopsy for histomorphometry study. Plasma bAP was determined by using a new immunoassay (Tandem-R Ostase, Hybritech, Liège, Belgium). Plasma bAP values were compared with those of two other plasma markers of bone metabolism, namely tAP and intact parathyroid hormone (iPTH), for the correlations with bone histomorphometric parameters. Patients with high-turnover bone disease (HTBD) (N = 32) had significantly higher plasma bAP levels than patients with normal or low bone turnover (N/LTBD) (N = 10) (66.9 +/- 63.5 ng/mL versus 10.8 +/- 4.2 ng/mL, respectively). Bone formation and resorption were highly correlated in these patients, and plasma bAP levels were positively correlated with bone resorption parameters, including osteoclast surface (r = 0.39, P < 0.0001) and osteoclast number/mm2 (r = 0.36, P < 0.001), and with bone formation parameters, osteoblast surface (r = 0.50, P < 0.005), and bone formation rate (r = 0.91, P < 0.0001). The bone formation rate was better correlated with plasma bAP levels than with either plasma tAP or iPTH concentrations. Plasma bAP level equal or higher than 20 ng/mL, either alone or combined with plasma iPTH of 200 pg/mL, had the highest sensitivity, specificity, and predictability values for the diagnosis of high-turnover bone disease, and formally excluded patients with normal or LTBD. In conclusion, plasma bAP can be measured with a reliable immunoassay in hemodialysis patients. It represents a highly sensitive and specific biochemical marker of skeletal remodeling in these patients. Therefore, both serum iPTH and bAP are complementary in diagnoses of the type of renal osteodystrophy.

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Spectrum of bone pathologies in chronic kidney disease

10.1093/med/9780199592548.003.0122 ◽

2015 ◽

Author(s):

Stuart M. Sprague ◽

James M. Pullman

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Bone Formation ◽

Bone Disease ◽

Bone Biopsy ◽

Fibroblast Growth Factor 23 ◽

Osteitis Fibrosa ◽

Adynamic Bone Disease ◽

Osteoblast Activity ◽

Adynamic Bone

Histologic bone abnormalities begin very early in the course of chronic kidney disease. The KDIGO guidelines recommend that bone disease in patients with chronic kidney disease should be diagnosed on the basis of bone biopsy examination, with bone histomorphometry. They have also proposed a new classification system (TMV), using three key features of bone histology—turnover, mineralization, and volume—to describe bone disease in these patients. However, bone biopsy is still rarely performed today, as it involves an invasive procedure and highly specialized laboratory techniques. High-turnover bone disease (osteitis fibrosa cystica) is mainly related to secondary hyperparathyroidism and is characterized by increased rates of both bone formation and resorption, with extensive osteoclast and osteoblast activity, and a progressive increase in peritrabecular marrow space fibrosis. On the other hand, low-turnover (adynamic) bone disease involves a decline in osteoblast and osteoclast activities, reduced new bone formation and mineralization, and endosteal fibrosis. The pathophysiological mechanisms of adynamic bone include vitamin D deficiency, hyperphosphataemia, metabolic acidosis, inflammation, low oestrogen and testosterone levels, bone resistance to parathyroid hormone, and high serum fibroblast growth factor 23. Mixed uraemic osteodystrophy describes a combination of osteitis fibrosa and mineralization defect. In the past few decades, an increase in the prevalence of mixed uraemic osteodystrophy and adynamic bone disease has been observed.

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Radial Bone Mineral Density in Hemodialysis Patients with Adynamic Bone Disease

The International Journal of Artificial Organs ◽

10.1177/039139880302600304 ◽

2003 ◽

Vol 26 (3) ◽

pp. 200-204 ◽

Cited By ~ 7

Author(s):

A. Nakashima ◽

N. Yorioka ◽

S. Doi ◽

C. Ueda ◽

K. Usui ◽

...

Keyword(s):

Bone Mineral Density ◽

Bone Turnover ◽

Bone Disease ◽

Hemodialysis Patients ◽

Mineral Density ◽

Intact Pth ◽

Adynamic Bone Disease ◽

Normal Bone ◽

Phosphate Product ◽

Adynamic Bone

Adynamic bone disease (ABD) has attracted attention as the most frequent type of renal osteodystrophy, but there are few reports about the bone mineral density (BMD) in ABD patients. This study investigated the BMD in hemodialysis patients with ABD and with relatively normal bone turnover. We measured the BMD of the distal one-third of the radius by dual-energy X-ray adsorptiometry. In the ABD group (intact PTH<65pg/ml, intact osteocalcin<30ng/ml), there were 19 men and 17 women with a mean age of 56.4±12.0 years. In the relatively normal bone turnover group (intact PTH: 120-250pg/ml), there were 24 men and 16 women with a mean age of 57.1±14.7 years. Although there were no significant differences between the two groups with respect to age, gender, and duration of hemodialysis, a significant increase of the BMD and the calcium x phosphate product was observed in the ABD group (radial BMD: 0.648±0.137 g/cm2 versus 0.572±0.132 g/cm2, calcium x phosphate product: 57.53±14.92 mg2/dl2 versus 49.76±12.13 mg2/dl2). These findings suggest that an increase in radial BMD may not be a useful marker of the improvement in bone lesions in ABD patients.

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MO568STATIC PARAMETERS OF HISTOMORPHOMETRY FOR THE EVALUATION OF BONE TURNOVER IN RENAL OSTEODYSTROPHY

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfab086.006 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

Hanne Skou Jørgensen ◽

Geert Behets ◽

Patrick D'Haese ◽

Pieter Evenepoel

Keyword(s):

Bone Turnover ◽

Diagnostic Accuracy ◽

Renal Osteodystrophy ◽

Bone Biopsy ◽

Bone Formation Rate ◽

Suitable Alternative ◽

Predictive Values ◽

Bone Biopsies ◽

Low Bone Turnover ◽

Tetracycline Labeling

Abstract Background and Aims A full histomorphometric analysis of a transiliac bone biopsy with prior tetracycline labeling remains the gold standard to diagnose renal osteodystrophy. Bone turnover is primarly evaluated by the dynamic parameter bone formation rate, calculated from the incorporation of tetracycline in bone. In cases of failed tetracycline labels, however, an evaluation of bone turnover based on static parameters is warranted. This study investigates the diagnostic accuracy of static histomorphometric parameters for the diagnosis of high and low bone turnover. Method Bone biopsies with prior tetracycline labeling of sufficient quality for a full histomorpometric analysis were included (n = 205). Mean age of participants was 56±13 years, 67% were men, and 22% had diabetes mellitus. Diagnostic accuracy of static histomorphometric parameters for bone turnover was evaluated by area under the receiver operator characteristics curve (AUC) statistics, against the full set of static and dynamic histomorphometric parameters. The cohort was randomly split to allow calculation of optimal diagnostic cutoffs in an exploration cohort (n=105), with subsequent validation in a separate subset of patients (n=100). Results All histomorphometric parameters were significantly different across categories of low (24%), normal (60%), and high (16%) bone turnover (p < 0.01), and all were significant predictors of both high and low bone turnover (Figure 1). Calculated optimal cutoffs and their sensitivities and specificities in the validation cohort are shown in Table 1. Diagnostic accuracy was very good for high turnover, as the combination of presence of fibrosis with ObPm>5.4%, OcPm>1.5%, and OAr>2.4% provided a correct diagnosis in 94% of patients, with positive (PPV) and negative (NPV) predictive values of 80% and 96%, respectively. Using the same predefined combination, an accuracy of 80% was achieved for low turnover (no fibrosis, ObPm≤1.9% OcPm≤0.9% and OAr≤1.6%), with a PPV of 71% and a NPV of 82%. Conclusion Static histomorphometric parameters provide an acceptable alternative for the diagnosis of high and low bone turnover. In the absence of successful tetracycline labeling, the proposed cutoffs may provide a suitable alternative for the evaluation of bone turnover in renal osteodystrophy.

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