Deteriorated bone microarchitecture caused by sympathetic overstimulation in pheochromocytoma and paraganglioma.

PURPOSE: Despite the potentially destructive effect of sympathetic activity on bone metabolism, its impact on bone microarchitecture, a key determinant of bone quality, has not been thoroughly investigated. This study aims to evaluate the impact of sympathetic activity on bone microarchitecture and bone strength in patients with pheochromocytoma and paraganglioma (PPGL). METHODS: A cross-sectional study was conducted in 38 PPGL patients (15 males and 23 females). Bone turnover markers serum procollagen type 1 N-terminal propeptide (P1NP) and ß-carboxy-terminal crosslinked telopeptide of type 1 collagen (ß-CTX) were measured. 24-h urinary adrenaline (24hUE) and 24-h urinary norepinephrine levels (24hUNE) were measured to indicate sympathetic activity. High-resolution peripheral quantitative computed tomography (HR-pQCT) was conducted to evaluate bone microarchitecture in PPGL patients and 76 age-, sex-matched healthy controls (30 males and 46 females). Areal bone mineral density (aBMD) was measured by dual-energy X-ray absorptiometry (DXA) simultaneously. RESULTS: PPGL patients had a higher level of ß-CTX. HR-pQCT assessment revealed that PPGL patients had notably thinner and more sparse trabecular bone (decreased trabecular number and thickness with increased trabecular separation), significantly decreased volume BMD (vBMD), and bone strength at both the radius and tibia compared with healthy controls. The deterioration of Tt.vBMD, Tb.Sp, and Tb.1/N.SD was more pronounced in postmenopausal patients compared with the premenopausal subjects. Moreover, subjects in the highest 24hUNE quartile (Q4) showed markedly lower Tb.N and higher Tb.Sp and Tb.1/N.SD at the tibia than those in the lowest quartile (Q1). Age-related bone loss was also exacerbated in PPGL patients to a certain extent. CONCLUSIONS: PPGL patients had significantly deteriorated bone microarchitecture and strength, especially in the trabecular bone, with an increased bone resorption rate. Our findings provide clinical evidence that sympathetic overstimulation may serve as a secondary cause of osteoporosis, especially in subjects with increased sympathetic activity.

Na-Cl Co-transporter (NCC) gene inactivation is associated with improved bone microstructure.

Gitelman syndrome (GS) is the disease model of the inactivation of thiazide-sensitive sodium chloride cotransporter (NCC), which is believed to benefit bone mass and reduce fracture risk. In this study, we found that GS patients have superior bone microarchitecture, which is associated with the disease status. Several decreased bone parameters with aging in healthy controls were reversed in GS patients to a certain extent. PURPOSE: To evaluate the impact of the inactivation of NCC on bone turnover and microarchitecture in Gitelman syndrome patients. METHODS: A cross-sectional study was conducted in 45 GS patients (25 males and 20 females). Serum procollagen type 1 N-terminal propeptide (P1NP), ß-carboxy-terminal crosslinked telopeptide of type 1 collagen (ß-CTX), and osteocalcin were measured. High-resolution peripheral quantitative computed tomography (HR-pQCT) was conducted to evaluate bone microarchitecture in GS patients and age- and sex-matched healthy controls. Areal bone mineral density (aBMD) was measured by dual-energy X-ray absorptiometry (DXA) simultaneously. RESULTS: GS patients had a relatively lower level of ß-CTX. aBMD at several skeletal sites was improved in GS patients. HR-pQCT assessment revealed that GS patients had slightly thinner but significantly more compact trabecular bone (increased trabecular number and decreased thickness), notably decreased cortical porosity, and increased volume BMD (vBMD) at both the radius and tibia compared with controls. The disease severity, represented as the relationship with the minimum level of magnesium during the course and standard base excess, was associated with bone microarchitecture parameters after adjusting for age, sex, and BMI. The decreased vBMD and Tb.BV/TV, and increased Tb.Sp and Ct.Po with aging, were reversed in GS patients to a certain extent. CONCLUSION: GS patients have superior bone microarchitecture, which suggests that the inactivation of NCC might be beneficial for avoiding osteoporosis.

Relationships between QUS and HR-pQCT, DXA, and bone turnover markers.

INTRODUCTION: Relationship of quantitative ultrasound (QUS) with high-resolution peripheral quantitative computed tomography (HR-pQCT), dual-energy X-ray absorptiometry (DXA), and bone-related biochemical markers was analyzed. MATERIALS AND METHODS: The subjects were 480 individuals. Speed of sound (SOS) was measured by calcaneal QUS. Volumetric bone mineral density (vBMD) and microarchitecture of trabecular and cortical bone in the distal radius and tibia were assessed by HR-pQCT. Areal bone mineral density (aBMD) in the lumbar spine and proximal femur were measured by DXA. TRACP-5b, P1NP, 25 (OH) vitamin D, and pentosidine were evaluated by biochemical tests. The correlation of each parameter was analyzed for all subjects and by sex and age group. RESULTS: QUS was moderately correlated with Tb.vBMD and Tb.BV/TV in the radius and tibia. No correlation was seen with Ct.vBMD or cortical porosity (Ct.Po). Although a correlation was seen with cortical thickness (Ct.Th) in the tibia in all subjects, no correlation was seen in women aged ≥ 60 years. QUS showed moderate correlations with aBMD in the proximal femur. Although moderate correlation was seen with aBMD in the lumbar spine in all subjects, no correlation was seen in subjects aged ≥ 60 years. No significant correlations were seen between QUS and biochemical markers. CONCLUSIONS: Moderate correlations were seen between QUS and Tb.vBMD and microarchitecture in the radius and tibia and aBMD of the proximal femur. On the other hand, practically no correlations were seen with Ct.vBMD or Ct.Po and the bone-related biochemical markers. Only in middle age, moderate correlations were seen with Ct.Th in the tibia and with aBMD of the lumbar spine.

Development of a QUS Device to Evaluate Deterioration of Cortical Bone: Verification by HR-pQCT and Measurements in Healthy Individuals and Dialysis Patients.

INTRODUCTION: The objectives of this study were to identify what is reflected in cortical speed of sound (cSOS) measured by a cortical quantitative ultrasound (cortical QUS) device we have developed, and to investigate cSOS measurements in healthy individuals and dialysis patients. METHODS: The cSOS and the SOS were measured by cortical QUS and conventional QUS in 20 volunteers, and the correlations between these measurements and areal bone mineral density measured by dual-energy X-ray absorptiometry and bone microstructural parameters on high-resolution peripheral quantitative computed tomography were analyzed. The cSOS and the SOS were measured in 91 young adults (47 men, 44 women), 64 elderly people (30 men, 33 women), and 64 dialysis patients (33 men, 31 women). The period of hemodialysis and intact parathyroid hormoneevels were also investigated in the dialysis patients. RESULTS: cSOS was correlated with cortical tissue mineral density (tibia: r = 0.74, radius: r = 0.72) on high-resolution peripheral quantitative computed tomography, reflecting the degree of minaralization and microporosity of cortical bone. There was no correlation with the thickness of cortical bone, suggesting that it measured the bone quality rather than bone mass. Elderly women had lower cSOS than young adults (3865 ± 74 vs 3971 ± 63 m/s, p < 0.01). Many of dialysis patients showed very low cSOS and it was related to higher intact parathyroid hormone levels (male: ß = -0.67, female: ß = -0.60). CONCLUSIONS: Our cortical QUS device is capable of evaluating the qualitative degradation of cortical bone, which cannot be assessed by conventional QUS, and its use in combination with conventional QUS may provide a better understanding of fracture risk.

Association of secondary displacement of distal radius fractures with cortical bone quality at the distal radius.

INTRODUCTION: The aim of this study was to investigate the associations of patient characteristics, bone mineral density (BMD), bone microarchitecture and calculated bone strength with secondary displacement of a DRF based on radiographic alignment parameters. MATERIALS AND METHODS: Dorsal angulation, radial inclination and ulnar variance were assessed on conventional radiographs of a cohort of 251 patients, 38 men and 213 women, to determine the anatomic position of the DRF at presentation (primary position) and during follow-up. Secondary fracture displacement was assessed in the non-operatively treated patients (N = 154) with an acceptable position, preceded (N = 97) or not preceded (N = 57) by primary reduction (baseline position). Additionally, bone microarchitecture and calculated bone strength at the contralateral distal radius and tibia were assessed by HR-pQCT in a subset of, respectively, 63 and 71 patients. OUTCOME: Characteristics of patients with and without secondary fracture displacement did not differ. In the model with adjustment for primary reduction [OR 22.00 (2.27-212.86), p = 0.008], total [OR 0.16 (95% CI 0.04-0.68), p = 0.013] and cortical [OR 0.19 (95% CI 0.05-0.80], p = 0.024] volumetric BMD (vBMD) and cortical thickness [OR 0.13 (95% CI 0.02-0.74), p = 0.021] at the distal radius were associated with secondary DRF displacement. No associations were found for other patient characteristics, such as age gender, BMD or prevalent vertebral fractures. CONCLUSIONS: In conclusion, our study indicates that besides primary reduction, cortical bone quality may be important for the risk of secondary displacement of DRFs.

Impaired geometry, volumetric density, and microstructure of cortical and trabecular bone assessed by HR-pQCT in both sporadic and MEN1-related primary hyperparathyroidism.

This study evaluated bone features of PHPT using HR-pQCT. The results showed both cortical and trabecular bones were significantly impaired in PHPT patients. Male and female PHPT patients suffered similar damages in bone. HR-pQCT indices were not observed to differ in MEN1 and sporadic PHPT patients. INTRODUCTION: High-resolution peripheral quantitative CT is a novel imaging technique used to separately assess trabecular and cortical bone status of the radius and tibia in vivo. Using HR-pQCT, we aimed to evaluate bone features of primary hyperparathyroidism patients in a Chinese population and reveal similarities and differences in bone features in multiple endocrine neoplasia type 1-related PHPT and sporadic PHPT patients in the Chinese population. METHODS: A case-control study was designed. In 58 PHPT patients and 58 sex- and age-matched healthy controls, the distal radius and tibia were scanned using HR-pQCT. Areal bone mineral density (aBMD) was also determined in PHPT patients using dual-energy X-ray absorptiometry (DXA). RESULTS: In comparison with controls, PHPT patients were observed to exhibit reduced volumetric BMD at the cortical and trabecular compartments, thinner cortices, and more widely spaced trabeculae. Significant differences were still observed when comparing data of female and male patients with age-matched controls separately. MHPT patients (n = 11) were found to have lower aBMD Z-scores in the lumbar spine, trochanteric region, and total hip compared with sporadic PHPT patients (n = 47), while no differences were observed in HR-pQCT indices between the two groups. In multiple linear regression models, no significant correlations were identified between PTH and HR-pQCT indices. However, height was found to positively correlate with HR-pQCT-derived trabecular indices at both the radius and tibia. CONCLUSIONS: PHPT affects geometry, volumetric density, and microstructure in both the cortical and trabecular bones in both male and female Chinese patients. MHPT patients were observed to have reduced aBMD as determined by DXA in the lumbar spine and hip in comparison with sporadic PHPT patients. However, HR-pQCT indices were not observed to differ.

Deterioration of bone microstructure by aging and menopause in Japanese healthy women: analysis by HR-pQCT.

INTRODUCTION: Second-generation high-resolution peripheral quantitative computed tomography (HR-pQCT) has provide higher quality of bone images with a voxel size of 61 µm, enabling direct measurements of trabecular thickness. In addition to the standard parameters, the non-metric trabecular parameters such as trabecular morphology (plate to rod-like structures), connectivity, and anisotropy can also be analyzed. The purpose of this study is to investigate deterioration of bone microstructure in healthy Japanese women by measuring standard and non-metric parameters using HR-pQCT. MATERIALS AND METHODS: Study participants were 61 healthy Japanese women (31-70 years). The distal radius and tibia were scanned using second-generation HR-pQCT, and microstructures of trabecular and cortical bone were measured. Non-metric trabecular parameters included structure model index (SMI), trabecular bone pattern factor (TBPf), connectivity density (Conn.D), number of nodes (N.Nd/TV), degree of anisotropy (DA), and star volume of marrow space (V*ms). Estimated bone strength was evaluated by micro finite element analysis. Associations between bone microstructure, estimated bone strength, age, and menopause were analyzed. RESULTS: Trabecular number declined with age, and trabecular separation increased. SMI and TBPf increased, Conn.D and N.Nd/TV declined, and V*ms increased. Cortical BMD and thickness declined with age, and porosity increased. Stiffness and failure load decreased with age. Cortical thickness and estimated bone strength were affected by menopause. Cortical thickness was most associated with estimated bone strength. CONCLUSIONS: Trabecular and cortical bone microstructure were deteriorated markedly with age. Cortical thickness decreased after menopause and was most related to bone strength. Non-metric parameters give additional information about osteoporotic changes of trabecular bone.

Assessing bone mineralisation in children with chronic kidney disease: what clinical and research tools are available?

Mineral and bone disorder in chronic kidney disease (CKD-MBD) is a triad of biochemical imbalances of calcium, phosphate, parathyroid hormone and vitamin D, bone abnormalities and soft tissue calcification. Maintaining optimal bone health in children with CKD is important to prevent long-term complications, such as fractures, to optimise growth and possibly also to prevent extra-osseous calcification, especially vascular calcification. In this review, we discuss normal bone mineralisation, the pathophysiology of dysregulated homeostasis leading to mineralisation defects in CKD and its clinical consequences. Bone mineralisation is best assessed on bone histology and histomorphometry, but given the rarity with which this is performed, we present an overview of the tools available to clinicians to assess bone mineral density, including serum biomarkers and imaging such as dual-energy X-ray absorptiometry and peripheral quantitative computed tomography. We discuss key studies that have used these techniques, their advantages and disadvantages in childhood CKD and their relationship to biomarkers and bone histomorphometry. Finally, we present recommendations from relevant guidelines-Kidney Disease Improving Global Outcomes and the International Society of Clinical Densitometry-on the use of imaging, biomarkers and bone biopsy in assessing bone mineral density. Given low-level evidence from most paediatric studies, bone imaging and histology remain largely research tools, and current clinical management is guided by serum calcium, phosphate, PTH, vitamin D and alkaline phosphatase levels only.

Early characteristics of bone deficits in children with Fontan palliation.

BACKGROUND: This is a cross-sectional study aiming to understand the early characteristics and background of bone health impairment in clinically well children with Fontan circulation. METHODS: We enrolled 10 clinically well children with Fontan palliation (operated >5 years before study entrance, Tanner stage ≤3, age 12.1 ± 1.77 years, 7 males) and 11 healthy controls (age 12.0 ± 1.45 years, 9 males) at two children's hospitals. All patients underwent peripheral quantitative CT. For the Fontan group, we obtained clinical characteristics, NYHA class, cardiac index by MRI, dual x-ray absorptiometry, and biochemical studies. Linear regression was used to compare radius and tibia peripheral quantitative CT measures between Fontan patients and controls. RESULTS: All Fontan patients were clinically well (NYHA class 1 or 2, cardiac index 4.85 ± 1.51 L/min/m2) and without significant comorbidities. Adjusted trabecular bone mineral density, cortical thickness, and bone strength index at the radius were significantly decreased in Fontan patients compared to controls with mean differences -30.13 mg/cm3 (p = 0.041), -0.31 mm (p = 0.043), and -6.65 mg2/mm4 (p = 0.036), respectively. No differences were found for tibial measures. In Fontan patients, the mean height-adjusted lumbar bone mineral density and total body less head z scores were -0.46 ± 1.1 and -0.63 ± 1.1, respectively, which are below the average, but within normal range for age and sex. CONCLUSIONS: In a clinically well Fontan cohort, we found significant bone deficits by peripheral quantitative CT in the radius but not the tibia, suggesting non-weight-bearing bones may be more vulnerable to the unique haemodynamics of the Fontan circulation.

Characterization of trabecular bone microstructure in premenopausal women with distal radius fractures.

Individual trabecular segmentation was utilized to identify differences in trabecular bone structure in premenopausal women with wrist fractures and non-fracture controls. Fracture subjects had reduced trabecular plate volume, number, thickness, and connectivity. Identifying altered trabecular microarchitecture in young women offers opportunities for counseling and lifestyle modifications to reduce fracture risk. INTRODUCTION: Premenopausal women with distal radius fractures (DRF) have worse trabecular bone microarchitecture than non-fracture controls (CONT), yet the characteristics of their trabecular bone structure are unknown. METHODS: Premenopausal women with DRF (n = 40) and CONT (n = 80) were recruited. Primary outcome variables included trabecular structure at the distal radius and tibia, assessed by volumetric decomposition of individual trabecular plates and rods from high-resolution peripheral quantitative CT images. Trabecular morphology included plate and rod number, volume, thickness, and connectivity. Areal bone mineral density (aBMD) of the femoral neck (FN aBMD), and ultradistal radius (UDR aBMD) were measured by DXA. RESULTS: Trabecular morphology differed between DRF and CONT at the radius and tibia (OR per SD decline 1.58-2.7). At the radius, associations remained significant when adjusting for age and FN aBMD (ORs = 1.76-3.26) and age and UDR aBMD (ORs = 1.72-3.97). Plate volume fraction, number and axially aligned trabeculae remained associated with DRF after adjustment for trabecular density (ORs = 2.55-2.85). Area under the curve (AUC) for discriminating DRF was 0.74 for the proportion of axially aligned trabeculae, compared with 0.60 for FN aBMD, 0.65 for UDR aBMD, and 0.69 for trabecular density. Plate number, plate-plate junction, and axial bone volume fraction remained associated with DRF at the tibia (ORs = 2.14-2.77) after adjusting for age, FN aBMD, or UDR aBMD. AUCP.P.Junc.D was 0.72 versus 0.61 for FNaBMD, 0.66 for UDRaBMD, and 0.70 for trabecular density. CONCLUSION: Premenopausal women with DRF have lower trabecular plate volume, number, thickness, and connectivity than CONT. Identification of young women with altered microarchitecture offers opportunities for lifestyle modifications to reduce fracture risk.

The Quantification of Bone Mineral Density Using Photon Counting Computed Tomography and its Implications for Detecting Bone Remodelling.

High-Resolution peripheral quantitative CT (HR-pQCT) has become standard practice when quantifying volumetric bone mineral density (vBMD) in vivo. Yet, it is only accessible to peripheral sites, with small fields of view and lengthy scanning times. This limits general applicability in clinical workflows. The goal of this study was to assess the potential of Photon Counting CT (PCCT) in quantitative bone imaging. Using the European Forearm Phantom, PCCT was calibrated to hydroxy-apatite (HA) density. Eight cadaveric forearms were scanned twice with PCCT, and once with HR-pQCT. The dominant forearm of two volunteers was scanned twice with PCCT. In each scan the carpals were delineated. At bone-level, accuracy was assessed with a paired measurement of total vBMD (Tt.vBMD) calculated with PCCT and HR-pQCT. At voxel-level, repeatability was assessed by image registration and voxel-wise subtraction of the ex vivo PCCT scans. In an ideal scenario, this difference would be zero; any deviation was interpreted as falsely detected remodelling. For clinical usage, the least detectable remodelling was determined by finding a threshold in the PCCT difference image that resulted in a classification of bone formation and resorption below acceptable noise levels (<0.5%). The paired measurement of Tt.vBMD had a Pearson correlation of 0.986. Compared to HR-pQCT, PCCT showed a bias of 7.46 mgHA/cm3. At voxel-level, the repeated PCCT scans showed a bias of 17.66 mgHA/cm3 and standard error of 96.23 mgHA/cm3. Least detectable remodelling was found to be 250 mgHA/cm3, for which 0.37% of the voxels was incorrectly classified as newly added or resorbed bone. In vivo, this volume increased to 0.97%. Based on the cadaver data we conclude that PCCT can be used to quantify vBMD and bone turnover. We provided proof of principle that this technique is also accurate in vivo, hence, that it has high potential for clinical applications.

In quantitative computed tomography (QCT) , bone images have grey values that reflect the local bone mineral content within each voxel. Aggregated over large bone regions, a total bone mineral density can be calculated, which helps in identifying weak bones and fracture risk. At small scales, QCT can detect where bone is being formed, and thus the bone mineral content increases, and where bone is being removed, and thus the bone mineral content decreases. These measurements are typically done with high-resolution peripheral QCT (HR-pQCT). However, HR-pQCT can only scan small regions of the arms and legs, for which a long scanning time is needed. This makes it challenging to use HR-pQCT in a clinical context. Photon Counting CT (PCCT) is a new CT device that can scan bone with an image quality similar to HR-pQCT, yet it can scan faster and cover a larger area. Used at the large scale, our results indicate that PCCT and HR-pQCT can be used interchangeably for the quantification of bone mineral density in large bone regions. Used at small scales, our results indicate that both technologies can detect changes in bone mineral content with similar sensitivity. These results demonstrate that PCCT enables the use of these QCT analyses in a clinical context.

Bone Mineral Density and Vascular Calcification in Children and Young Adults With CKD 4 to 5 or on Dialysis.

Introduction: Older adults with chronic kidney disease (CKD) can have low bone mineral density (BMD) with concurrent vascular calcification. Mineral accrual by the growing skeleton may protect young people with CKD from extraosseous calcification. Our hypothesis was that children and young adults with increasing BMD do not develop vascular calcification. Methods: This was a multicenter longitudinal study in children and young people (5-30 years) with CKD stages 4 to 5 or on dialysis. BMD was assessed by tibial peripheral quantitative computed tomography (pQCT) and lumbar spine dual-energy X-ray absorptiometry (DXA). The following cardiovascular imaging tests were undertaken: cardiac computed tomography for coronary artery calcification (CAC), ultrasound for carotid intima media thickness z-score (cIMTz), pulse wave velocity z-score (PWVz), and carotid distensibility for arterial stiffness. All measures are presented as age-adjusted and sex-adjusted z-scores. Results: One hundred participants (median age 13.82 years) were assessed at baseline and 57 followed up after a median of 1.45 years. Trabecular BMD z-score (TrabBMDz) decreased (P = 0.01), and there was a nonsignificant decrease in cortical BMD z-score (CortBMDz) (P = 0.09). Median cIMTz and PWVz showed nonsignificant increase (P = 0.23 and P = 0.19, respectively). The annualized increase in TrabBMDz (ΔTrabBMDz) was an independent predictor of cIMTz increase (R 2 = 0.48, ß = 0.40, P = 0.03). Young people who demonstrated statural growth (n = 33) had lower ΔTrabBMDz and also attenuated vascular changes compared with those with static growth (n = 24). Conclusion: This hypothesis-generating study suggests that children and young adults with CKD or on dialysis may develop vascular calcification even as their BMD increases. A presumed buffering capacity of the growing skeleton may offer some protection against extraosseous calcification.

Studying bone mineral density in young people: The complexity of choosing a pQCT reference database.

BACKGROUND: Many chronic illnesses affect bone health, and commonly lead to mineralization abnormalities in young people. As cortical and trabecular bone may be differentially affected in certain diseases, an imaging technique that allows for detailed study of the bone structure is required. Peripheral quantitative computed tomography (pQCT) overcomes the limitations of dual energy X-ray absorptiometry (DXA) and is perhaps more widely available for use in research than bone biopsy. However, in contrast to DXA, where there are large reference datasets, this is not the case for pQCT. METHODS: Fifty-five children and young adults aged 7 to 30 years had the non-dominant tibia scanned at the 3% & 4% sites for trabecular bone mineral density and the 38% site for cortical bone mineral density and bone mineral content. Image acquisition and analysis was undertaken according to the protocols of two of the largest reference datasets for tibial pQCT. The Z-scores generated were compared to examine the differences between protocols and the differences from the expected median of zero in a healthy population. RESULTS: The trabecular bone mineral density Z-scores generated by the two protocols were similar. The same was true for cortical mineral content Z-scores at the 38% site. Cortical bone mineral density was significantly different between protocols and likely affected by differences in the ethnicity of our cohort compared to the reference datasets. Only one reference dataset extended from childhood to young adulthood. Only trabecular bone mineral density, periosteal and endosteal circumference Z-scores from one methodology were not significantly biased when tested for deviation of the median from zero. CONCLUSIONS: pQCT is a useful tool for studying trabecular and cortical compartments separately but, there are variations in pQCT scanning protocols, analysis methodology, and a paucity of reference data. Reference datasets may not be generalizable to local study populations, even when analysed using identical analysis protocols.

Naturally Occurring Stable Calcium Isotope Ratios in Body Compartments Provide a Novel Biomarker of Bone Mineral Balance in Children and Young Adults.

Serum calcium (Ca), bone biomarkers, and radiological imaging do not allow accurate evaluation of bone mineral balance (BMB), a key determinant of bone mineral density (BMD) and fracture risk. We studied naturally occurring stable (non-radioactive) Ca isotopes in different body pools as a potential biomarker of BMB. 42 Ca and 44 Ca are absorbed from our diet and sequestered into different body compartments following kinetic principles of isotope fractionation; isotopically light 42 Ca is preferentially incorporated into bone, whereas heavier 44 Ca preferentially remains in blood and is excreted in urine and feces. Their ratio (δ44/42 Ca) in serum and urine increases during bone formation and decreases with bone resorption. In 117 healthy participants, we measured Ca isotopes, biomarkers, and BMD by dual-energy X-ray absorptiometry (DXA) and tibial peripheral quantitative CT (pQCT). 44 Ca and 42 Ca were measured by multi-collector ionization-coupled plasma mass-spectrometry in serum, urine, and feces. The relationship between bone Ca gain and loss was calculated using a compartment model. δ44/42 Caserum and δ44/42 Caurine were higher in children (n = 66, median age 13 years) compared with adults (n = 51, median age 28 years; p < 0.0001 and p = 0.008, respectively). δ44/42 Caserum increased with height in boys (p < 0.001, R2 = 0.65) and was greatest at Tanner stage 4. δ44/42 Caserum correlated positively with biomarkers of bone formation (25-hydroxyvitaminD [p < 0.0001, R2 = 0.37] and alkaline phosphatase [p = 0.009, R2 = 0.18]) and negatively with bone resorption marker parathyroid hormone (PTH; p = 0.03, R2 = 0.13). δ44/42 Caserum strongly positively correlated with tibial cortical BMD Z-score (n = 62; p < 0.001, R2 = 0.39) but not DXA. Independent predictors of tibial cortical BMD Z-score were δ44/42 Caserum (p = 0.004, ß = 0.37), 25-hydroxyvitaminD (p = 0.04, ß = 0.19) and PTH (p = 0.03, ß = -0.13), together predicting 76% of variability. In conclusion, naturally occurring Ca isotope ratios in different body compartments may provide a novel, non-invasive method of assessing bone mineralization. Defining an accurate biomarker of BMB could form the basis of future studies investigating Ca dynamics in disease states and the impact of treatments that affect bone homeostasis. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Effects of monthly intravenous ibandronate on bone mineral density and microstructure in patients with primary osteoporosis after teriparatide treatment: The MONUMENT study.

PURPOSE: To investigate the effects of sequential therapy with monthly intravenous ibandronate on bone mineral density (BMD) and microstructure in patients with primary osteoporosis who received teriparatide treatment. METHODS: Sixty-six patients with primary osteoporosis who had undergone teriparatide treatment for more than 12 months (mean 18.6 months) received sequential therapy with 1 mg/month intravenous ibandronate for 12 months. The patients were evaluated using dual-energy X-ray absorptiometry (DXA), quantitative ultrasound, bone turnover markers, and high-resolution peripheral quantitative computed tomography (HR-pQCT) at baseline and 6 and 12 months after beginning administration. RESULTS: At 12 months after beginning sequential therapy, the bone resorption marker, tartrate-resistant acid phosphatase-5b, decreased by 39.5%, with 82.3% of the patients exhibiting levels within the normal limit. DXA revealed that the BMD of the lumbar spine increased by 3.2%, with 79.0% of the patients exhibiting a response, and 40.3% experiencing an increase in BMD over 5%. HR-pQCT revealed that the cortical thickness of the distal tibia was increased by 2.6%. The cortical area increased by 2.5%, and the buckling ratio (an index of cortical instability) decreased by 2.5%. Most parameters of the trabecular bone showed no significant changes. These changes in the cortical bone were observed in both the distal radius and tibia and appeared beginning 6 months after treatment initiation. CONCLUSIONS: Sequential therapy with monthly intravenous ibandronate increased the BMD and improved the cortical bone microstructure of osteoporotic patients who had undergone teriparatide treatment.

Bone health in adolescents with idiopathic scoliosis.

AIMS: Idiopathic scoliosis is the most common spinal deformity in adolescents and children. The aetiology of the disease remains unknown. Previous studies have shown a lower bone mineral density in individuals with idiopathic scoliosis, which may contribute to the causation. The aim of the present study was to compare bone health in adolescents with idiopathic scoliosis with controls. METHODS: We included 78 adolescents with idiopathic scoliosis (57 female patients) at a mean age of 13.7 years (8.5 to 19.6) and 52 age- and sex-matched healthy controls (39 female patients) at a mean age of 13.8 years (9.1 to 17.6). Mean skeletal age, estimated according to the Tanner-Whitehouse 3 system (TW3), was 13.4 years (7.4 to 17.8) for those with idiopathic scoliosis, and 13.1 years (7.4 to 16.5) for the controls. Mean Cobb angle for those with idiopathic scoliosis was 29° (SD 11°). All individuals were scanned with dual energy x-ray absorptiometry (DXA) and peripheral quantitative CT (pQCT) of the left radius and tibia to assess bone density. Statistical analyses were performed with independent-samples t-test, the Mann-Whitney U test, and the chi-squared test. RESULTS: Compared with controls, adolescents with idiopathic scoliosis had mean lower DXA values in the left femoral neck (0.94 g/cm2 (SD 0.14) vs 1.00 g/cm2 (SD 0.15)), left total hip (0.94 g/cm2 (SD 0.14) vs 1.01 g/cm2 (SD 0.17)), L1 to L4 (0.99 g/cm2 (SD 0.15) vs 1.06 g/cm2 (SD 0.17)) and distal radius (0.35 g/cm2 (SD 0.07) vs 0.39 g/cm2 (SD 0.08; all p ≤ 0.024), but not in the mid-radius (0.72 g/cm2 vs 0.74 g/cm2; p = 0.198, independent t-test) and total body less head (1,559 g (SD 380) vs 1,649 g (SD 492; p = 0.0.247, independent t-test). Compared with controls, adolescents with idiopathic scoliosis had lower trabecular volume bone mineral density (BMD) on pQCT in the distal radius (184.7 mg/cm3 (SD 40.0) vs 201.7 mg/cm3 (SD 46.8); p = 0.029), but not in other parts of the radius or the tibia (p ≥ 0.062, Mann-Whitney U test). CONCLUSION: In the present study, idiopathic scoliosis patients seemed to have lower BMD at central skeletal sites and less evident differences at peripheral skeletal sites when compared with controls. Cite this article: Bone Joint J 2020;102-B(2):268-272.

The interobserver reliability of the diagnosis and classification of scaphoid fractures using high-resolution peripheral quantitative CT.

AIMS: Besides conventional radiographs, the use of MRI, CT, and bone scintigraphy is frequent in the diagnosis of a fracture of the scaphoid. However, which techniques give the best results remain unknown. The investigation of a new imaging technique initially requires an analysis of its precision. The primary aim of this study was to investigate the interobserver agreement of high-resolution peripheral quantitative CT (HR-pQCT) in the diagnosis of a scaphoid fracture. A secondary aim was to investigate the interobserver agreement for the presence of other fractures and for the classification of scaphoid fracture. METHODS: Two radiologists and two orthopaedic trauma surgeons evaluated HR-pQCT scans of 31 patients with a clinically-suspected scaphoid fracture. The observers were asked to determine the presence of a scaphoid or other fracture and to classify the scaphoid fracture based on the Herbert classification system. Fleiss kappa statistics were used to calculate the interobserver agreement for the diagnosis of a fracture. Intraclass correlation coefficients (ICCs) were used to assess the agreement for the classification of scaphoid fracture. RESULTS: A total of nine (29%) scaphoid fractures and 12 (39%) other fractures were diagnosed in 20 patients (65%) using HR-pQCT across the four observers. The interobserver agreement was 91% for the identification of a scaphoid fracture (95% confidence interval (CI) 0.76 to 1.00) and 80% for other fractures (95% CI 0.72 to 0.87). The mean ICC for the classification of a scaphoid fracture in the seven patients diagnosed with scaphoid fracture by all four observers was 73% (95% CI 0.42 to 0.94). CONCLUSION: We conclude that the diagnosis of scaphoid and other fractures is reliable when using HR-pQCT in patients with a clinically-suspected fracture. Cite this article: Bone Joint J 2020;102-B(4):478-484.

Consensus approach for 3D joint space width of metacarpophalangeal joints of rheumatoid arthritis patients using high-resolution peripheral quantitative computed tomography.

BACKGROUND: Joint space assessment for rheumatoid arthritis (RA) by ordinal conventional radiographic scales is susceptible to floor and ceiling effects. High-resolution peripheral quantitative computed tomography (HR-pQCT) provides superior resolution, and may detect earlier changes. The goal of this work was to compare existing 3D methods to calculate joint space width (JSW) metrics in human metacarpophalangeal (MCP) joints with HR-pQCT and reach consensus for future studies. Using the consensus method, we established reproducibility with repositioning as well as feasibility for use in second-generation HR-pQCT scanners. METHODS: Three published JSW methods were compared using datasets from individuals with RA from three research centers. A SPECTRA consensus method was developed to take advantage of strengths of the individual methods. Using the SPECTRA method, reproducibility after repositioning was tested and agreement between scanner generations was also established. RESULTS: When comparing existing JSW methods, excellent agreement was shown for JSW minimum and mean (ICC 0.987-0.996) but not maximum and volume (ICC 0.000-0.897). Differences were identified as variations in volume definitions and algorithmic differences that generated high sensitivity to boundary conditions. The SPECTRA consensus method reduced this sensitivity, demonstrating good scan-rescan reliability (ICC >0.911) except for minimum JSW (ICC 0.656). There was strong agreement between results from first- and second-generation HR-pQCT (ICC >0.833). CONCLUSIONS: The SPECTRA consensus method combines unique strengths of three independently-developed algorithms and leverages underlying software updates to provide a mature analysis to measure 3D JSW. This method is robust with respect to repositioning and scanner generations, suggesting its suitability for detecting change.

Bone Microarchitecture and Distal Radius Fracture Pattern Complexity.

Distal radius fractures (DRFs) occur in various complexity patterns among patients differing in age, gender, and bone mineral density (BMD). Our aim was to investigate the association of patient characteristics, BMD, bone microarchitecture, and bone strength with the pattern complexity of DRFs. In this study, 251 patients aged 50-90 years with a radiologically confirmed DRF who attended the Fracture Liaison Service of VieCuri Medical Centre, the Netherlands, between November 2013 and June 2016 were included. In all patients fracture risk factors and underling metabolic disorders were evaluated and BMD measurement with vertebral fractures assessment by dual-energy X-ray absorptiometry was performed. Radiographs of all DRFs were reviewed by two independent investigators to assess fracture pattern complexity according to the AO/OTA classification in extra-articular (A), partially articular (B), and complete articular (C) fractures. For this study, patients with A and C fractures were compared. Seventy-one patients were additionally assessed by high-resolution peripheral quantitative computed tomography. Compared to group A, mean age, the proportion of males, and current smokers were higher in group C, but BMD and prevalent vertebral fractures were not different. In univariate analyses, age, male gender, trabecular area, volumetric BMD (vBMD), and stiffness were associated with type C fractures. In multivariate analyses, only male gender (odds ratio (OR) 8.48 95% confidence interval (CI) 1.75-41.18, p = 0.008]) and age (OR 1.11 [95% CI 1.03-1.19, p = 0.007]) were significantly associated with DRF pattern complexity. In conclusion, our data demonstrate that age and gender, but not body mass index, BMD, bone microarchitecture, or strength were associated with pattern complexity of DRFs.© 2019 The Authors. Journal of Orthopaedic Research® Published by Wiley Periodicals, Inc. J Orthop Res 37:1690-1697, 2019.