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Dysregulation of Kirsten rat sarcoma virus (KRAS) plays crucial roles in many tumors. It is reported that KRAS could promote proliferation of osteosarcoma (OS) cells. Nonetheless, the contribution of KRAS to the invasion and spread of OS is still not well understood. This study aimed to investigate KRAS-driven metastasis and the mechanisms behind it in human OS. Tissue microarrays were utilized to assess KRAS expression and its relationship with clinicopathological characteristics. The migratory and invasive abilities of OS cells were evaluated through wound-healing assays and transwell analysis. Furthermore, the regulatory mechanisms of KRAS in human OS were analyzed using RNA sequencing, tandem mass tags assays, multiple immunofluorescence assays, micro-CT, and bioluminescence imaging. In vivo experiments were conducted using established lung metastatic models. Our data showed that downregulation of KRAS in human OS cells could inhibit cell migration and invasion in vitro and in vivo (tumor metastasis model by tail vein injection in BALB/c nude mice). We identify IL-17A, a crucial marker of IL-17 signal pathway, as a downstream target of KRAS. The reduction of KRAS may suppress matrix metalloproteinase (MMP1), MMP3, and MMP9, which are recognized as proteins associated with tumor metastasis, through a mechanism dependent on IL-17 signaling. In summary, these findings indicate that KRAS could serve as a potential biomarker for therapeutic strategies in human OS. Mechanistically, our data revealed that KRAS knockdown affects tumor metastasis by inactivating IL-17 signal pathway via IL-17A-dependent manner.

In this study, QCT was used to analyze the AGN1 Local Osteo-Enhancement Procedure (LOEP) as a treatment to form bone in the proximal femurs of patients with osteoporosis. Using this minimally invasive procedure, a resorbable triphasic AGN1 implant material was injected into the left femurs of 12 women with post-menopausal osteoporosis. Computed tomography scans were taken before treatment (baseline) and at 12 wk, 24 wk, and 5-7 yr after treatment. Quantitative computed tomography was used to investigate the resorption of AGN1 within the treated proximal femurs and to analyze the treatment's impact on integral, trabecular, and cortical bone. The untreated right femurs were used as controls. Data illustrated an increase in trabecular volumetric BMD (trab vBMD) of treated hips at all timepoints (baseline: 22 ± 21 mg/cm³ vs 217 ± 56 mg/cm³, 161 ± 18 mg/cm³, and 121 ± 37 mg/cm³ at 12-wk, 24-wk, and 5- to 7-yr timepoints, respectively), and an increase in integral vBMD of 65% at the 12-wk timepoint and 34% at the 5- to 7-yr timepoint. The increase in trab vBMD was observed in the location where the AGN1 implant material bolus was injected, and at the 5- to 7-yr timepoint, no significant BMD change was observed in the trabecular regions surrounding the original implantation zone (treated: 32 ± 16 mg/cm³, control: 31 ± 16 mg/cm³). This QCT study provides a more detailed understanding of the resorption and transformation of the AGN1 implant material into bone and supports, with some limitations, that the AGN1 LOEP treatment can locally increase trabecular bone density in weakened areas of the proximal femur where strength increase is most needed to reduce the risk of hip fragility fracture.

Pompe disease is a lysosomal storage disorder defined by a mutation in the GAA gene encoding alpha-1,4-glucosidase alpha (acid maltase). Pompe disease encompasses a range of clinical presentations that are broadly characterized as either classic infantile Pompe disease or late-onset Pompe disease (LOPD). LOPD is a milder manifestation of the disease that presents after the first year of life and is typically characterized by mild proximal muscle weakness and lack of cardiac involvement compared to the classic infantile form. The mainstay of treatment is enzyme replacement therapy (EnRT). Decreased bone mineral density (BMD) is frequently encountered in LOPD. While bone loss is thought to be due to mechanical unloading secondary to the progressive muscle weakness associated with the disease, there is a lack of tissue-level data in support of this mechanism. We describe a 60-yr-old female with LOPD managed with EnRT who presented with proximal muscle weakness and decreased BMD on dual-energy X-ray absorptiometry. Undecalcified bone histology showed low turnover osteoporosis, and treatment was initiated with romosozumab. Romosozumab specifically may provide a promising osteoporosis therapy for LOPD-associated osteoporosis. As a sclerostin inhibitor, it both inhibits bone resorption and promotes new bone formation. We additionally emphasize that bone biopsy should be considered as a useful diagnostic tool in the evaluation of osteoporosis associated with uncommon pathologies, since bone histology provides more specific tissue-level information over clinical and laboratory evaluation as well as substantive guidance for treatment.

The influence of obesity and type 2 diabetes (T2D) on the skeleton is complex, with affected individuals having higher fracture risk despite having higher BMD. To evaluate how obesity and T2D affect skeletal health, we studied mice with disruption of a gene that regulates energy intake and expenditure, Ksr2, which results in reduced metabolic rate and severe insulin resistance in both mice and a subpopulation of humans. Relative to 28-wk-old littermate sibling controls, Ksr2 mutants weighed more than double the body and fat weight. Moreover, leptin and insulin were elevated by 20- and 10-fold in Ksr2 mutant serum, consistent with prior reports of a T2D state. Micro-computed tomography analysis revealed increased trabecular bone volume (BV) per total volume (TV) in the mutant's distal femur, proximal tibia, and vertebrae. While the bone size (cortical (Ct) cross-sectional bone area) was increased by 7%-11% at the mid-diaphysis of femurs and tibiae, Ct BV adjusted for TV was unaffected. Three-point bending tests revealed increased ultimate force to failure and ultimate bending stress at the mid-diaphysis of femurs by 13% and 8%, respectively in Ksr2 mutants. However, bone toughness, a measure of bone quality that assesses how well Ct bone resists fracture, was reduced by 25%. To determine the cause of reduced bone quality in Ksr2 mutants, we evaluated femurs for bone hydration by nuclear magnetic resonance relaxometry and found reduced pore water (20%) in Ksr2 mutant femurs relative to controls. Moreover, analysis of hydrolysates from femurs for advanced glycation end products revealed a 14% increase in Ksr2 mutants. Based on our data, we conclude that while bone density and strength are increased in mice with obesity-induced insulin resistance, bone toughness is compromised due to reduced bone tissue quality, thus suggesting therapeutics focused on improving bone tissue are needed to reduce fracture risk in obese patients.

Stable calcium isotope fractions have long been related to the calcium metabolism in living organisms. The blood and urine proportions of calcium isotopes ⁴⁴Ca and ⁴²Ca (δ^44/42Ca) have recently again attracted attention as a potential diagnostic tool in metabolic bone diseases, in particular osteoporosis. The hypothesis is that the lighter isotopes (Ca⁴²) get incorporated into bone more quickly; hence, δ^44/42Ca ratios in urine and serum are higher for bone formation and lower for resorption phases. Therefore, δ^44/42Ca in blood and urine may serve as an indicator of bone metabolism, potentially reflecting bone density in general. We have conducted clinical characterization by means of laboratory assessment, bone densitometry, HRpQCT, and isotope analysis to test for the hypothesis in patients with monogenic bone diseases. We included 40 adult subjects with hereditary bone diseases, such as early-onset osteoporosis (n = 7), osteogenesis imperfecta (n = 12), hypophosphatasia (n = 12), and X-linked hypophosphatemia (XLH, n = 9), and controls (n = 17). Regression analyses revealed significant correlations of δ^44/42Ca with Ca/creatinine_urine (R ² = 0.6200, p < .0001), and bone densitometric parameters were significantly correlated with δ^44/42Ca (BMD: δ^44/42Ca_serum  R ² = 0.2685, p ≤ .001; δ^44/42Ca_urine  R ² = 0.3554; p < .0002). XLH differed significantly from the other diseases and controls by means of higher δ^44/42Ca_urine. Our results suggest that δ^44/42Ca is strongly coupled to urinary calcium excretion in patients with hereditary bone diseases. Significant correlations with BMD suggest an interaction of δ^44/42Ca and bone mass though it lacks discriminative power. Further studies are needed to evaluate the utility of δ^44/42Ca in clinical practice.

Adrenal incidentalomas (AIs) may secrete excess cortisol, representing an elevated endogenous exposure to glucocorticoids, which could decrease bone mineral density and increase fracture risk. However, measurement of cortisol excess is not routinely done in patients with AI; thus, those with hormonally active AI at increased risk for fracture are under-identified. We sought to examine the association between excess cortisol levels and the incidence of fragility fracture in people with AI. This retrospective cohort study, conducted within two Kaiser Permanente regions (Southern California and Georgia), comprised women and men aged ≥50 yr with identified AI in the study period January 1, 2015-August 31, 2022. Patients' cortisol excess status was categorized by the type of test conducted (if any) and the test result. Fractures and relevant covariates were ascertained via International Classification of Diseases (ICD)-9/10 codes. Hazard ratios (HR) were estimated using Cox proportional hazard models with mortality as a competing risk. Among the cohort of 14 886 patients with AI, 273 (1.8%) had autonomous cortisol secretion (ACS) confirmed by dexamethasone suppression test (DST) results >1.8 μg/dL (>50 nmol/L), and another 201 (1.4%), tested with urine free or random cortisol tests, had results suggestive of excess cortisol production. Most of the cohort (n = 9353, 62.8%) were untested around AI diagnosis or during follow-up. Compared to patients with normal DST results (and adjusted for age, sex, race/ethnicity, and several other clinical characteristics), the estimated HR of fracture risk for patients with ACS (HR 1.42, CI 0.86-2.32), evidence of cortisol excess (1.41, 0.85-2.32), and untested patients (1.28, 0.88-1.87) were suggestive of elevated risk. However, none of the elevated hazard rates were statistically significant at the 95% significance level. The apparent elevated risk in the untested patients suggests that many untested patients may have hormonally active AI that puts them at risk for fracture from secondary osteoporosis.

Fibrous dysplasia/McCune-Albright syndrome (FD/MAS) is a rare condition caused by a mutation in the GNAS locus. Apart from endocrinopathies, some cases are characterized by excessive fibroblast growth factor 23 (FGF23) production from abnormal fibro-osseous tissue in FD lesions, resulting in increased renal phosphate excretion. We present a girl with FD/MAS and severe skeletal burden, evidenced by the presence of polyostotic fibrous dysplasia, which was complicated with bone fractures. She also had hyperthyroidism and GnRH-independent precocious puberty. She received zoledronic acid infusions in preparation for hip surgery. Despite optimal conventional management with oral phosphate and alphacalcidol, which was poorly tolerated, she presented persistent hypophosphatemia. To control hypophosphatemia and its deleterious effects on bone health, treatment with burosumab off-label at a dose of 0.66 mg/kg (20 mg) every 2 wk was initiated. Serum phosphate levels normalized within 2 wk of treatment. Laboratory results showed improvement in serum alkaline phosphatase (ALP) and PTH levels. After the second injection of burosumab, phosphate and PTH rose above the normal range with normal vitamin D levels; therefore, the interval between doses was increased to 3 wk, and calcium 500 mg daily was added. However, phosphate levels dropped again below normal range, so she had to return to 2-weekly injections of 20 mg. After 11 mo on burosumab, she remains with high normal phosphate levels and normal PTH and ALP values. Burosumab is well tolerated, with no adverse events to date. Burosumab is a human monoclonal antibody against FGF23 that reduces the risk of developing FGF23-mediated hypophosphatemia and its associated complications. Burosumab should be considered as an effective and safe alternative strategy for FGF23-mediated hypophosphatemia in FD/MAS for those who either cannot tolerate or do not respond to conventional therapy. To our knowledge, this is the fourth published case worldwide describing successful treatment with burosumab in FD/MAS.

Gallium-68-DOTA-Tyr3-Octreotate (Ga-68-DOTATATE) positron emission tomography/computed tomography (PET/CT) has recently been shown to have utility for the localization of phosphaturic mesenchymal tumors (PMT) that cause tumor-induced osteomalacia (TIO), a rare renal phosphate-wasting disorder. The aim of this study was to evaluate the accuracy of Ga-68-DOTATATE PET/CT in localizing PMTs causing TIO and to compare its performance with other functional imaging modalities. Prospective recruitment and retrospective chart review of 30 patients with suspected TIO and evaluation with Ga-68-DOTATATE PET/CT between 2017 and 2023 were conducted at a tertiary medical center. True positive (TP) lesions were defined by histological confirmation of PMT. There were 22 TP lesions identified among 18 patients, with a mean SUV_max of 16.8 (±10.9). Sensitivity, specificity, and accuracy of Ga-68-DOTATATE PET/CT were 85.7%, 77.8%, and 83.3% on patient-based analysis, and 84.6%, 56.3%, and 73.8% on lesion-based analysis. Lesions such as subacute fractures, parathyroid adenomas, thymus uptake, vertebral hemangiomas, bone enchondromas, liver hemangiomas, and avascular necrosis were some of the pitfalls in interpretation. Ga-68-DOTATATE PET/CT led to a significant impact on clinical management in 24 (80%) of patients. The presence of DOTATATE-avid fractures was significantly associated with a localizing scan on univariable (OR 15.0, 95% CI 2.80-110, p = .001) and multivariable analysis (OR 9.45, 95% CI 1.33-98.4, p = .003). Ga-68-DOTATATE PET/CT has good accuracy for the localization of TIO, with superior sensitivity compared to F-18-FDG PET/CT. This significantly impacted clinical treatment decisions. Although DOTATATE-avid fractures may be a source of false positives, they may also indicate a higher probability of a localizing study.