Th17 cell frequency is associated with low bone mass in primary sclerosing cholangitis.

BACKGROUND & AIMS: Osteoporotic fractures are a major cause of morbidity and reduced quality of life in patients with primary sclerosing cholangitis (PSC), a progressive bile duct disease of unknown origin. Although it is generally assumed that this pathology is a consequence of impaired calcium homeostasis and malabsorption, the cellular and molecular causes of PSC-associated osteoporosis are unknown. METHODS: We determined bone mineral density by dual-X-ray absorptiometry and assessed bone microstructure by high-resolution peripheral quantitative computed tomography in patients with PSC. Laboratory markers of liver and bone metabolism were measured, and liver stiffness was assessed by FibroScan. We determined the frequency of Th17 cells by the ex vivo stimulation of peripheral blood mononuclear cells in a subgroup of 40 patients with PSC. To investigate the potential involvement of IL-17 in PSC-associated bone loss, we analyzed the skeletal phenotype of mice lacking Abcb4 and/or Il-17. RESULTS: Unlike in patients with primary biliary cholangitis, bone loss in patients with PSC was not associated with disease duration or liver fibrosis. However, we observed a significant negative correlation between the bone resorption biomarker deoxypyridinoline and bone mineral density in the PSC cohort, indicating increased bone resorption. Importantly, the frequency of Th17 cells in peripheral blood was positively correlated with the urinary deoxypyridinoline level and negatively correlated with bone mass. We observed that Abcb4-deficient mice displayed a low-bone-mass phenotype, which was corrected by an additional Il-17 deficiency or anti-IL-17 treatment, whereas the liver pathology was unaffected. CONCLUSIONS: Our findings demonstrate that an increased frequency of Th17 cells is associated with bone resorption in PSC. Whether antibody-based IL-17 blockade is beneficial against bone loss in patients with PSC should be addressed in future studies. LAY SUMMARY: Primary sclerosing cholangitis (PSC) is a cholestatic liver disease characterized by progressive bile duct destruction. One serious complication of PSC is reduced bone mass resulting in increased fracture risk. Herein, we demonstrate that Th17 cells mediate bone loss in PSC by inducing bone resorption, which suggests that antibody-based IL-17 blockade might be beneficial for the treatment of bone loss in affected patients.

Bone microstructure is significantly altered in CRPS-affected distal tibiae as detected by HR-pQCT: a retrospective cross-sectional study.

In the course of complex regional pain syndrome (CRPS), local osteopenia in the subchondral/subcortical areas of the affected limb represents a central manifestation. Mechanistic aspects of CRPS-associated pathologies remain unclear, and knowledge about bone morphology in CRPS-affected areas is rare. The aim of this study was to assess trabecular and cortical bone microstructure in patients with CRPS of the distal tibiae. We retrospectively analysed 14 women diagnosed with unilateral CRPS type I of the lower limb whose affected and unaffected distal tibiae were examined by high-resolution peripheral quantitative computed tomography (HR-pQCT). Laboratory tests included serum levels of calcium, phosphate, 25-hydroxyvitamin D, bone alkaline phosphatase, parathyroid hormone, osteocalcin and urinary levels of deoxypyridinoline (DPD). Bone mineral density was measured by dual-energy X-ray absorptiometry (DXA) at the lumbar spine and both proximal femurs. Average urinary DPD levels, a biochemical marker of bone resorption, were elevated in the examined patient cohort (7.1 ± 1.9 nmol/mmol, reference 3.0-7.0 nmol/mmol). According to HR-pQCT, CRPS-affected distal tibiae showed significantly lower values of cortical BMD and cortical thickness compared to the unaffected contralateral side. Also, bone volume relative to total volume was significantly lower. Trabecular number and trabecular thickness tended to be lower in the affected tibiae. CRPS is associated with significant alterations in bone microstructure of the affected tibiae. Increased bone resorption seems to play a crucial role within a multifactorial process of CRPS-mediated bone atrophy. HR-pQCT could possibly serve as a diagnostic tool in specific CRPS therapy.

Clinical Significance of DXA and HR-pQCT in Autosomal Dominant Osteopetrosis (ADO II).

The main hallmark of high bone mass (HBM) disorders is increased bone mineral density, potentially visible in conventional radiographs and quantifiable by other radiographic methods. While one of the most common forms of HBM is CLCN7-related autosomal dominant osteopetrosis type II (ADO II), there is no consensus on diagnostic thresholds. We therefore wanted to assess whether CLCN7-osteopetrosis patients differ from benign HBM cases in terms of (1) bone mineral density, (2) bone structure, and (3) microarchitectural abnormalities. 16 patients meeting the criteria of HBM (DXA T/Z-score ≥ 2.5 at all sites) were included in this retrospective study. Osteologic assessment using dual-energy X-ray absorptiometry (DXA), high-resolution peripheral quantitative computed tomography (HR-pQCT), and serum analyses was performed. The presence of CLCN7 and/or other HBM gene mutations affecting bone mass were tested using a custom designed bone panel. While a DXA threshold for ADO II could be implemented (DXA Z-score ≥ + 6.0), the differences in bone microarchitecture were of lesser extent compared to the benign HBM group. All adult patients with ADO II suffered from elevated fracture rates independent from Z-score. In HR-pQCT, structural alterations, such as bone islets were found only inconsistently. In cases of HBM, a DXA Z-score ≥ 6 may be indicative for an inheritable HBM disorder, such as ADO II. Microarchitectural bone alterations might represent local microfracture repair or accumulation of cartilage remnants due to impaired osteoclast function, but seem not to be correlated with fracture risk.

Comparison of Bone Microarchitecture Between Adult Osteogenesis Imperfecta and Early-Onset Osteoporosis.

Diagnosis and management of adult individuals with low bone mass and increased bone fragility before the age of 50 can be challenging. A number of these patients are diagnosed with mild osteogenesis imperfecta (OI) through detection of COL1A1 or COL1A2 mutations; however, a clinical differentiation from early-onset osteoporosis (EOOP) may be difficult. The purpose of this study was to determine the bone microstructural differences between mild OI and EOOP patients. 29 patients showed mutations in COL1A1 or COL1A2 and were classified as OI. Skeletal assessment included dual-energy X-ray absorptiometry (DXA), high-resolution peripheral quantitative computed tomography (HR-pQCT), and bone turnover serum analyses. Bone microstructure of 21/29 OI patients was assessed and compared to 23 age- and sex-matched patients clinically classified EOOP but without mutations in the known disease genes as well as to 20 healthy controls. In the OI patients, we did not observe an age-dependent decrease in DXA Z-scores. HR-pQCT revealed a significant reduction in volumetric BMD and microstructural parameters in the distal radius and tibia in both the OI and EOOP cohorts compared to the healthy controls. When comparing the bone microstructure of OI patients with the EOOP cohort, significant differences were found in terms of bone geometry in the radius, while no significant changes were detected in all other HR-pQCT parameters at the radius and tibia. Taken together, adult mild OI patients demonstrate a predominantly high bone turnover trabecular bone loss syndrome that shows minor microstructural differences compared to EOOP without mutation detection.

Skeletal dissemination in Paget's disease of the spine.

PURPOSE: Paget's disease of bone (PDB) is a common skeletal disorder that is associated with locally increased bone turnover, skeletal deformity and pain. We report a case of skeletal dissemination in PDB of the spine. METHODS: Case report. RESULTS: A 46-year-old former professional athlete suffered from disseminated PDB throughout the spine and hips after various surgical interventions including spondylodesis, bone grafting and bone morphogenetic protein (rhBMP-2) administration. Only intravenous zoledronic acid prevented the further progression of skeletal dissemination, which was expressed by a normalization of (bone-specific) alkaline phosphatase levels. The biopsy obtained from the lumbar spine confirmed the diagnosis of PDB in the absence of malignant transformation. CONCLUSIONS: We outline skeletal dissemination as a possibly surgery-related complication in a patient with PDB in the lumbar spine. Bisphosphonates remain the treatment of first choice in PDB and surgical interventions should be considered very carefully.

Pulmonary cement embolism is not associated with the cause of death in a post-mortem cohort of cement-augmented interventions in the spine.

PURPOSE: Complications of cement-augmented interventions (e.g., kyphoplasty) in the spine include local cement leakage and pulmonary cement embolisms (PCE). This study was conducted to determine their extent in a unique post-mortem cohort. METHODS: Retrospective analysis of post-mortem whole-body CT scans and review of autopsy results in 29 consecutive cases with cement-augmented interventions in the spine. PCE findings were graded based on cement deposits: grade 0 (no PCE), grade 1 (1-3 PCE), grade 2 (4-6 PCE), and grade 3 (> 6 or branch-shaped PCE). Bone and lung tissue specimens were obtained in representative cases to confirm the findings histologically. RESULTS: Local cement leakage was detected in 69%: intravenous (34%), intervertebral (31%), intraspinal (14%), and retrograde (17%). Lung sections showed PCE in 52%: grade 0 (48%), grade 1 (31%), grade 2 (10%), and grade 3 (10%). Matching with autopsy findings revealed that none of the cases died due to the impact of PCE. CONCLUSIONS: The presented data reveal a high frequency of PCE making it a notable finding-especially since not only single but also branch-like embolisms were detected. Thus, it is of great importance that none of the causes of death were related to the impact of PCE. Nevertheless, it is crucial to consider the underlying diseases for increased PCE risk and to apply latest surgical techniques and preventive measures. These slides can be retrieved under Electronic Supplementary material.

Cartilage calcification of the ankle joint is associated with osteoarthritis in the general population.

BACKGROUND: Cartilage calcification (CC) is associated with osteoarthritis (OA) in weight-bearing joints, such as the hip and the knee. However, little is known about the impact of CC and degeneration on other weight-bearing joints, especially as it relates to the occurrence of OA in the ankles. The goal of this study is to analyse the prevalence of ankle joint cartilage calcification (AJ CC) and to determine its correlation with factors such as histological OA grade, age and BMI in the general population. METHODS: CC of the distal tibia and talus in 160 ankle joints obtained from 80 donors (mean age 62.4 years, 34 females, 46 males) was qualitatively and quantitatively analysed using high-resolution digital contact radiography (DCR). Correlations with factors, such as the joint's histological OA grade (OARSI score), donor's age and BMI, were investigated. RESULTS: The prevalence of AJ CC was 51.3% (95% CI [0.40, 0.63]), independent of gender (p = 0.18) and/or the joint's side (p = 0.82). CC of the distal tibia was detected in 35.0% (28/80) (95% CI [0.25, 0.47]) and talar CC in 47.5% (38/80) (95% CI [0.36, 0.59]) of all cases. Significant correlations were noted between the mean amount of tibial and talar CC (r = 0.59, p = 0.002), as well as between the mean amount of CC observed in one ankle joint with that of the contralateral side (r = 0.52, p = 0.02). Furthermore, although the amount of AJ CC observed in the distal tibia and talus correlated with the histological OA-grade of the joint (r = 0.70, p < 0.001 and r = 0.72, p < 0.001, respectively), no such correlation was seen in the general population with relation to age (p = 0.32 and p = 0.49) or BMI (p = 0.51 and p = 0.87). CONCLUSION: The prevalence of AJ CC in the general population is much higher than expected. The relationship between the amount of AJ CC and OA, independent of the donors' age and BMI, indicates that CC may play a causative role in the development of OA in ankles.

Dynamics of Skeletal Status under Optimized Management during Subsequent Pregnancy in Three Women with a History of Pregnancy- and Lactation-Associated Osteoporosis Carrying pathogenic Variants in WNT1 and LRP5.

Pregnancy- and lactation-associated osteoporosis (PLO) is a rare but clinically highly relevant condition, characterized by reduced bone mineral density (BMD) and acute onset of severe pain due to symptomatic bone marrow edema of the hip or vertebral and/or insufficiency fractures, among others. Previous reports showed a high frequency of hereditary bone disorders unmasked by PLO, predisposing for more severe forms. To date, no data on the risk for additional fractures during subsequent pregnancy in women with PLO and genetic bone disorder have been available. To address this question, we retrospectively analyzed the clinical, biochemical, and densitometric course of three women with a history of PLO and detected variants in WNT1 or LRP5 and subsequent pregnancies. Calcium homeostasis and bone turnover were optimized by basic treatment, and timely initiation of weaning was recommended. Teriparatide treatment for 12 months under strict contraception was initiated in one woman after the diagnosis of PLO. In none of the women did additional fractures or symptomatic bone marrow edemas occur, and BMD by dual-energy X-ray absorptiometry as bone microarchitecture by high-resolution peripheral quantitative computed tomography remained stable. In conclusion, this report expands the understanding of this rare but severe condition and helps to improve clinical counseling and management. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Increased local bone turnover in patients with chronic periprosthetic joint infection.

Aims: The management of periprosthetic joint infection (PJI) remains a major challenge in orthopaedic surgery. In this study, we aimed to characterize the local bone microstructure and metabolism in a clinical cohort of patients with chronic PJI. Methods: Periprosthetic femoral trabecular bone specimens were obtained from patients suffering from chronic PJI of the hip and knee (n = 20). Microbiological analysis was performed on preoperative joint aspirates and tissue specimens obtained during revision surgery. Microstructural and cellular bone parameters were analyzed in bone specimens by histomorphometry on undecalcified sections complemented by tartrate-resistant acid phosphatase immunohistochemistry. Data were compared with control specimens obtained during primary arthroplasty (n = 20) and aseptic revision (n = 20). Results: PJI specimens exhibited a higher bone volume, thickened trabeculae, and increased osteoid parameters compared to both control groups, suggesting an accelerated bone turnover with sclerotic microstructure. On the cellular level, osteoblast and osteoclast parameters were markedly increased in the PJI cohort. Furthermore, a positive association between serum (CRP) but not synovial (white blood cell (WBC) count) inflammatory markers and osteoclast indices could be detected. Comparison between different pathogens revealed increased osteoclastic bone resorption parameters without a concomitant increase in osteoblasts in bone specimens from patients with Staphylococcus aureus infection, compared to those with detection of Staphylococcus epidermidis and Cutibacterium spp. Conclusion: This study provides insights into the local bone metabolism in chronic PJI, demonstrating osteosclerosis with high bone turnover. The fact that Staphylococcus aureus was associated with distinctly increased osteoclast indices strongly suggests early surgical treatment to prevent periprosthetic bone alterations.

Does Juvenile Idiopathic Arthritis Affect the Course of Legg-Calvé-Perthes Disease? A Case-Control Study with a Mean Follow-Up of 8 Years.

BACKGROUND: This study aimed to determine the clinical and radiological course in children who had Legg-Calvé-Perthes disease (LCPD) associated with juvenile idiopathic arthritis (JIA). METHODS: In a retrospective chart review between 2007 and 2019, eight consecutive JIA patients diagnosed with concomitant LCPD were identified and compared with a case-control group of 10 children with LCPD only. RESULTS: LCPD was diagnosed at a mean age of 8.1 years (3.0-14.7) in children with JIA as compared to 6.1 years (2.9-10.0) in controls. According to the modified Harris Hip Score (mHHS), four children with JIA and all controls had an excellent result. Regarding the fragmentation severity and the duration of each stage, we found no differences using the lateral pillar and modified Elizabethtown classification. Five hips were classified as Stulberg I/II, two hips as Stulberg III, and one hip as Stulberg V with no evidence of hip dysplasia or severe overcoverage in either group. CONCLUSIONS: The radiological outcome of LCPD did not differ between both groups, while the clinical outcome was slightly better in controls. Physicians should be aware that children with LCPD may have JIA too. In suspicious cases, further investigations are recommended, and patients should be referred to pediatric rheumatologists.