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Avascular necrosis is a condition that results from disruption of the blood supply to bone. It can develop idiopathically or secondary to disease or corticosteroid use. To facilitate consistent clinical and research practice, this review aimed to identify methods used to assess, diagnose, and determine outcomes of non-femoral head (non-FH) lower limb avascular necrosis in children and adolescents. We conducted a scoping review up to January 2024, searching Ovid Medline, Embase, CINAHL, and Scopus databases. Studies were included if they had 10 or more individuals aged 0-17 yr with non-FH lower limb avascular necrosis, and included assessment, diagnostic criteria, or outcome measures. Measures identified were grouped according to the International Classification of Functioning, Disability, and Health framework of impairments of body function and structure, activity limitations, and participation restrictions. Following full-text screening, 31 studies met the inclusion criteria: 24 of these studies were retrospective (77%). Twenty-three studies involved secondary avascular necrosis (74%) and 8 studies involved primary avascular necrosis (26%). MRI and radiographs were most frequently used for diagnosis. Impairments were predominantly assessed via patient report, and use of validated measures was limited. There was also limited consideration of activity limitations and participation restrictions in both assessment and outcome measures. Where present, these were patient reported. The findings highlight a strong focus on impairments despite a need to consider the conditions impact on activity limitations and participation restrictions. Obtaining consensus on assessments and outcome measures, with increased use of validated measures to improve rigor, would facilitate collation of results in future research.

Pseudoarthroses (false joints) occur as a complication of fracture healing in the normotopic skeleton but have not been reported at ectopic sites. Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder characterized by progressive heterotopic ossification (HO) and congenital skeletal abnormalities including developmental arthropathy in the normotopic skeleton. Here, we report ectopic pseudojoint formation in 6 patients with FOP, all occurring after painful flare-ups and HO in soft connective tissues of the knee, hip, and forearm. To our knowledge, FOP is the only human condition in which ectopic pseudojoint formation occurs. These findings support that dysregulated BMP pathway signaling from mutant ACVR1 mediates not only HO, but also ectopic pseudojoint formation, and that ectopic pseudojoints can arise from de novo musculoskeletal elements.

Volumetric bone density, microarchitecture, and strength measures using HR-pQCT are valuable measures of bone health in pediatrics. Our cross-sectional study evaluated bone measure reproducibility in pediatric participants using repeat HR-pQCT (XtremeCT II, Scanco Medical) scans of non-dominant distal tibia and radius of 30 healthy children and adolescents (7-17 yr, 47% female) by 2 technicians. Additionally, we examined HR-pQCT and micro-CT of 26 cadaveric distal tibia specimens to evaluate agreement between the modalities. All HR-pQCT scans were analyzed using manufacturer-provided software (Image Processing Language, Scanco Medical) and a fully automated, previously validated, in-house algorithm, offering measures of bone microstructure (eg, trabecular plate-rod distribution, transverse trabeculae, trabecular bone strength) currently unavailable in the manufacturer-provided software. Root-mean-squared percent coefficient of variation (RMS-%CV) assessed precision and least significant change. Intraclass correlation coefficients (ICCs) using absolute-agreement, 2-way random-effects models assessed reliability. Pearson's correlation coefficients and ICC assessed linear relationships and agreements between HR-pQCT and micro-CT, respectively. In children and adolescents, RMS-%CV of HR-pQCT-derived trabecular bone measures at distal tibia and radius ranged from 0.8-4.4 to 0.8-6.0, respectively. Most cortical bone results were in a similar range. Both computational algorithms showed ICC > 0.90. RMS-%CV and least significant change values were lower for tibia than radius. ICCs were lower for cortical than trabecular outcomes. Most cadaveric results showed ICC > 0.83, other than trabecular bone thickness and modulus (ICC = 0.7). Pearson's r (>0.86) suggested strong correlations for almost all parameters. HR-pQCT and micro-CT results using in-house algorithm did not differ significantly, while manufacturer-provided algorithm results showed lower yet still moderate reliability (ICC > 0.55). Reliability of the second-generation HR-pQCT in pediatric participants is excellent-better in tibia vs radius. Our results support the high reproducibility of XtremeCT II scans and thus the use of this clinical imaging modality in studies of pediatric bone health.

Transforming growth factor-beta (TGF-β), a cytokine embedded in the bone matrix, is released during bone resorption, influencing osteoclast differentiation and coupling factor production, which affect osteoblasts and osteocytes. This study investigates the role of TGF-β in bone remodeling using an in vitro model with calcium phosphate-coated plates covalently bonded to latent TGF-β (LTGF-β(+)-CaP plates). This model replicates the natural release of TGF-β and its effects on RAW264 macrophage-like cells, which differentiate into osteoclasts upon stimulation of RANKL. Cells cultured on LTGF-β(+)-CaP plates formed resorption pits and released TGF-β, upregulating osteoclast differentiation- and resorption-related genes during early differentiation. During the resorption phase, TGF-β-enhanced osteoblast activation and coupling factor expression supporting bone formation in surrounding cells. In osteocytes, it differentially regulated gene expression by upregulating osteoprotegerin and downregulating sclerostin, suggesting a dual role in remodeling. Our findings demonstrate that TGF-β plays a critical role in bone homeostasis by directly promoting osteoclast differentiation and resorption while indirectly facilitating osteoblast differentiation through coupling factors. These results provide insights into the dynamic interactions between osteoclasts, osteoblasts, and osteocytes, emphasizing TGF-β's role in linking bone resorption and formation. This study establishes a novel in vitro platform to examine TGF-β-mediated bone remodeling and its underlying molecular mechanisms. Furthermore, our model can be used to explore how TGF-β signaling affects cellular communication in the bone and may contribute to identifying new therapeutic targets for osteoporosis and other bone-resorptive disorders.

The longitudinal impact of fractures associated with osteoporosis on costs and health-related quality of life is not well understood. The objective of this study was to characterize these outcomes over an 18-mo period following 4 common fracture types. Patients aged over 50 yr at 7 study sites with a diagnosis of incident hip, distal radius, proximal humerus, or vertebral fracture were enrolled in the International Costs and Utilities Related to Osteoporotic Fracture Study US. Data collection by questionnaire occurred at baseline (within 6 wk of fracture), 4-, 12-, and 18-mo post-fracture. Direct, indirect, and total costs were estimated over an 18-mo period and are reported in 2020 US Dollars. Health utilities were measured using EuroQol EQ-5D and the SF-6D. We performed longitudinal regression models of estimated costs adjusted for age and sex. We enrolled 284 patients with single fragility fractures (58 hip, 50 distal radius, 32 proximal humerus, 144 vertebral). Mean ages were 68.1 yr for distal radius and proximal humerus and 76 yr for hip patients. Most participants were women (76%-84% women). Over the 18-mo study period, direct costs (Including initial fracture and fracture related follow-up costs) were $18 495 for hip, $3451 for distal forearm, $6009 for humerus, and $9274 for vertebral fracture. Mean indirect costs were $9250 for hip, $1772 for distal radius, $4195 for humerus, and $4084 for vertebral fracture. Adjusted mean EQ-5D differences (95% CI) at 18-mo for those surviving/reporting compared with baseline were: hip -0.162 (95% CI, -0.22 to -0.103), distal radius -0.017 (95% CI, -0.056 to 0.022), proximal humerus -0.064 (95% CI, -0.103 to -0.0248), and vertebral -0.044 (95% CI, -0.083 to -0.0048). Substantial direct and indirect costs are observed in the 18-mo following 4 common osteoporotic fractures. Significant changes in health utility persisted for all fractures other than distal radius fractures regardless of the health utility measure used.

[This corrects the article DOI: 10.1093/jbmrpl/ziad002.].

Transferrin receptor 1 (Tfr1) plays a key role in mediating the cellular uptake of transferrin-bound iron. While Tfr1 is essential for iron uptake in erythroid cells and skeletal muscle, it is dispensable for iron acquisition in hepatocytes, intestinal epithelial, or endothelial cells. In this study, we investigated the significance of Tfr1 for iron uptake and cellular function in bone-forming osteoblasts. Therefore, we examined the bone characteristics of male and female Tfr1^fl/fl;Osx:cre^+/- (osteoprogenitors) conditional KO mice at 12 and 24 wk of age. Bone marrow-derived cells from Tfr1^fl/fl;Osx:cre^+/- mice were differentiated into osteoblasts in vitro to assess cellular iron status as well as cellular differentiation and function. Our findings indicate that Tfr1 deficiency in osteoprogenitors in male mice resulted in increased trabecular bone mass in the axial skeleton with decreased bone formation rate as well as decreased levels of serum bone turnover markers. Despite increased bone mass in the femur in females resulting from Tfr1 deficiency in osteoprogenitors, loss of bone mass following ovariectomy was not mitigated. Transferrin receptor 1-deficient osteoblasts showed mild changes in cytosolic iron levels and decreased mineralization. These results suggest a minor role of Tfr1 in osteoblasts differentiation and function but highlight distinct strategies for iron acquisition employed by bone cells to maintain cellular iron homeostasis.

Ionizing radiation (IR) exposure leads to mitochondrial alterations in osteoclasts and osteoblasts, contributing to musculoskeletal disintegration. Despite this, the mechanisms controlling mitochondrial activity in bone cells during IR exposure-associated bone disorders remain underexplored. Sirtuin-3 (SIRT3), a NAD-dependent mitochondrial deacetylase, is essential for the enhanced mitochondrial function in osteoclasts and the increased bone resorption observed in osteoporosis. However, it is still unclear whether and how SIRT3 drives IR exposure-induced bone disorders. Here, we show that deletion of Sirt3 greatly attenuated the IR exposure-induced loss of bone mass in young adult mice. This effect was associated with impaired osteoclast maturation and function, thus suppressing excessive bone resorption. IR exposure also increased mitochondrial activity and ROS production in osteoclasts. Deletion of Sirt3 abrogated these effects of IR exposure. The levels of mitochondrial superoxide dismutase 2 (SOD2), a major component of the metabolic machinery that handles ROS in the mitochondrial matrix, were significantly increased in osteoclasts by RANKL with an identical pattern as SIRT3. Deacetylation of lysine 68 of SOD2 enhanced the formation of giant osteoclasts and increased mitochondrial ROS production, mimicking the effects of IR exposure. Inhibition of mitochondrial ROS production via Mito-TEMPO recapitulated the effects of Sirt3 deletion on osteoclast maturation and mitochondrial activity during IR exposure. These findings demonstrate that SIRT3 plays an essential role in IR exposure-induced bone resorption by promoting deacetylation in osteoclast mitochondria. Understanding the mechanisms of mitochondrial quality control and protein acetylation in osteoclasts could pave the way for developing novel strategies to counteract IR exposure-associated bone disorders.

Denosumab is a potent antagonist of RANKL and is widely used to treat severe postmenopausal osteoporosis. Using high-resolution mass spectrometry (HRMS), we aimed to identify molecular mediators associated with the rapid reactivation of osteoclasts following discontinuation of denosumab. In a previously reported randomized controlled trial, 64 patients undergoing uncemented total hip arthroplasty were randomized to receive 2 doses of 60 mg denosumab or placebo, administered 1-3 d and 6 mo postoperatively. Serum samples were analyzed using untargeted HRMS coupled with liquid chromatography, and bone turnover markers were assessed. Data were evaluated using linear mixed-effects models and machine learning techniques. After surgery, 83 metabolite features showed significant concentration changes (p < .0001). Denosumab-treated patients exhibited increased levels of the dipeptides di-L-phenylalanine, phenylalanylleucine, and alpha-Asp-Phe, and decreased levels of fibrinopeptide A and related peptides 24 mo after surgery. The oxidized peptide AP(Ox)GDRGEP(Ox)GPP(Ox)GP, derived from the collagen type I alpha 1 chain (COL1A1) and referred to as COL1A1-OxP, showed a strong correlation with the bone formation marker procollagen type 1 amino-terminal propeptide (P1NP) (p = 4.4E^-83). Similarly, the tripeptide DL-alpha-aspartyl-DL-valyl-DL-proline (DVP) correlated highly with the bone resorption marker carboxy-terminal telopeptide of type 1 collagen (CTX) (p = 1.1E^-222). P1NP and CTX levels were suppressed at 3, 6, and 12 mo postoperatively but exceeded baseline levels by 24 mo. Global metabolic shifts were observed postoperatively, with distinct profiles between treatment groups. The observed increase in specific dipeptides may reflect mechanisms contributing to rebound bone loss following denosumab withdrawal. Fibrinopeptide A and its analogs may play a protective role, while COL1A1-OxP and DVP represent potential new markers of bone turnover. These findings suggest metabolomics-based biomarkers could aid clinical decision-making by allowing earlier detection of rebound effects and guiding individualized treatment strategies after denosumab therapy. Clinical trial registration number: ClinicalTrials.gov, NCT01630941 (URL: https://clinicaltrials.gov/); European Union Clinical Trials Register (EU CTR), EudraCT No. 2011-001481-18 (https://www.clinicaltrialsregister.eu/).

McCune-Albright syndrome (MAS) is a rare mosaic disorder characterized by the classic triad of fibrous dysplasia of bone (FD), café-au-lait skin macules, and hyperfunctioning endocrinopathies. MAS is caused by a postzygotic mutation in the G-protein alpha subunit (GNAS) gene resulting in G-protein α-subunit somatic activation. There is no approved treatment for MAS. We present the case of a 43-yr-old male carpenter with severe polyostotic FD and adult-onset growth hormone (GH) excess who was treated with denosumab and somatostatin analog, complicated with a diagnosis of chronic myeloid leukemia (CML). The patient had multiple skeletal lesions, resulting in pain on movement and neurovascular compromise of the left arm. A forequarter amputation was considered to treat a large clavicular lesion, however, involvement of his thoracic cage resulted in significant cardiopulmonary impairment, including restrictive lung disease, and the surgery was deemed too risky. Denosumab was commenced after failed intravenous bisphosphonate for pain management, resulting in alleviation of pain. Screening of endocrinopathy revealed GH excess with an elevated Insulin-like Growth Factor-1 (IGF-1) level and 7 mm pituitary adenoma. Lanreotide was commenced as a medical therapy, resulting in a reduction in IGF-1 levels. Over 9 mo into the denosumab treatment, the patient was diagnosed with CML in the context of routine full blood examination. The patient achieved a hematological remission with imatinib. Polyostotic FD can lead to serious complications from deformities of the skeleton, including cardiopulmonary complications. This case represents a patient with a severe spectrum of MAS/FD with a diagnosis of CML. We postulate that CML is unlikely due to the MAS, as the two have different pathogenic pathways. Denosumab is effective in pain management, however, it should be used with caution, and there are no large studies to guide long-term management. Evaluation and management of MAS should also include detailed endocrinopathy assessment and screening, even in adulthood.