JBMR Plus最新文献

Fibrous dysplasia (FD) is a rare disorder caused by somatic activating mutations in GNAS, encoding the alpha subunit of the Gs protein. Activating GNAS mutations result in focal expansile bone lesions, which cause pain, deformity, and increased risk of fracture. Somatic mosaicism in FD leads to both GNAS mutant and genetically WT osteoprogenitor cells, which jointly contribute to the formation of fibrotic lesions within the bone. Additionally, these lesions contain numerous osteoclasts formed in response to robust lesional expression of RANKL. Neutralizing antibody to RANKL is effective in reducing lesion growth in patients with FD and in preclinical models. To determine the effect of RANKL neutralization specifically on mutant cells early after onset of FD, we used a murine model of C57BL/6 Sox9^CreERT;Gnas^(R201H)fl/+;Rosa26^LSL-tdTomato mice, which recapitulates the somatic mosaicism of FD bone lesions and in which mutant cells are lineage traced. Analysis of Gnas^(R201H)fl/+ mice showed a diffuse accumulation of SMA⁺ early osteoblastic cells, with contribution from both tdTomato⁺ mutant and tdTomato^- WT populations. Anti-RANKL treatment of Gnas^(R201H)fl/+ mice inhibited osteoclast formation and substantially reduced fibrosis, detected by Masson's trichrome staining within the proximal metaphysis of the femur and the femoral head. Treatment with anti-RANKL decreased the accumulation of both mutant and WT SMA⁺ cells, accompanied by an increased number of mutant cells expressing the mature osteoblast marker osteocalcin, and an increase in overall osteoblast density. To elucidate the role of RANKL expression by mutant cells in the formation of FD lesions, we generated Sox9^CreERT;Gnas^(R201H)fl/+;Rosa26^LSL-tdTomato;Rankl^fl/fl mice. Deletion of Rankl in Gnas^(R201H)fl/+ mutant cells did not prevent fibrosis in this model. The results suggest that while anti-RANKL treatment promotes osteoprogenitor differentiation to reduce fibrosis, the loss of RANKL expression from GNAS mutant cells alone is not sufficient to reverse the pathology of FD bone lesions.

Hereditary hypophosphatemia (HH) is a rare diseases characterized by excessive renal phosphate wasting. Hereditary hypophosphatemia presents as rickets and osteomalacia in children, and osteomalacia in adults. Previous studies have suggested an increased burden of comorbidities and higher risk of early death in individuals with HH compared with controls. This study investigates the comorbidities in HH throughout life and their association with survival compared with controls. Possible HH cases were initially identified from the Danish National Patient Register (DNPR) using diagnostic codes for rickets or hypophosphatemia between 1971 and 2019, and the diagnosis was verified by the review of medical files. A total of 120 individuals with verified HH (case population) were matched by gender, birth year, and month with 50 controls per individual with HH, totaling 6000 controls randomly selected from the Danish Civil Registration System. Comorbidity data related to HH were retrieved from the DNPR. The burden of investigated comorbidities was significantly higher in individuals with HH than controls, with multiple conditions diagnosed and at an earlier age. The lifelong risk of arthrosis was significantly higher and diagnosed earlier in individuals with HH (p < .001). By age 50, 31.9% of individuals with HH received their first diagnosis of arthrosis, compared with 4.4% of controls. The lifelong risk of hearing loss was elevated (p < .001), often diagnosed by school age, with a rapid increase by age 60. Additionally, risks of hyperparathyroidism and renal failure were higher (both p < .001), along with increased rates of hypertensive disease (p < .001) and obesity (p = .021), with diagnoses increasing from the third decade of life. However, there was no significant increase in ischemic heart disease risk or overall mortality in HH. Further analysis revealed that comorbidities in HH were not associated with a higher risk of death compared with controls with the same conditions.

X-linked hypophosphatemia (XLH) is a phosphate-wasting disorder caused by increased fibroblast growth factor 23 (FGF23); it leads to skeletal deformities, muscle weakness, and pain. In a pediatric phase 3 trial, the FGF23 inhibitor burosumab improved rickets severity and bone biochemistry. The current study characterizes health-related quality of life (HRQL) in children with XLH using real-world data collected at centers in France for the International XLH Registry from April 2017 to January 2024. Age-appropriate versions of the Pediatric Quality of Life Inventory were completed. Data from the first completion after registry entry were analyzed. Variation in scores by demographic, medical history, and treatment history variables was assessed using bivariate analysis. The data were collected from 96 children (59% female; mean age 8.1 [SD 4.4] yr); 82% were taking burosumab. Mean total, summary, and domain scores were similar in different age groups. Mean total score (74.2 [SD 14.1]), Psychosocial Health Summary (72.0 [16.8]), and Physical Health Summary (78.3 [12.3]) scores were lowest in patients aged 5-7 yr and highest in patients aged 13-17 yr (81.0 [13.3], 79.8 [14.1], and 83.1 [15.2]). The mean Psychosocial Health Summary score was lower than the Physical Health Summary score for all patients combined (77.8 [13.9] vs 81.7 [14.3]). Better total scores were associated with not currently taking phosphate/vitamin D analogs, better Psychosocial Health Summary scores with higher serum phosphate and not taking phosphate/vitamin D analogs, and better Physical Health Summary scores with lower serum PTH and currently taking burosumab. Patients with XLH who were taking burosumab at the time of PedsQL completion had better total and summary scores than children with other chronic musculoskeletal disorders. Children aged 5-7 yr had worse HRQL than a healthy Dutch sample. Overall, better HRQL was associated with higher serum phosphate levels and burosumab treatment.

X-linked hypophosphatemia (XLH) is a rare genetic disorder, for which burosumab treatment may be beneficial. This study evaluated the efficacy, pharmacokinetics, and safety of burosumab in Chinese adults with XLH. In this open-label, multicenter, postmarketing phase 4 study, 18 Chinese adult outpatients with XLH received conventional oral phosphate (30 mg/kg/d in 5 doses) and calcitriol (0.50 μg/d in 2 doses) during a 14-wk run-in period. Patients then received subcutaneous burosumab 1.0 mg/kg every 4 wk for 48 wk (12 doses). The main outcome measures were changes from baseline in mean serum phosphate level at the end of burosumab treatment, along with patient-reported outcomes. Sixteen (88.9%) and four (22.2%) patients achieved mean serum phosphate levels >2.5 mg/dL at the mid-point and the end of the dose cycle, respectively. The mean (SD) serum phosphate level increased from 1.6 (0.25) mg/dL at baseline to 2.4 (0.28) mg/dL at the end of the dose cycle. The mean (SD) change from baseline in serum phosphate level was 50.1% (14.11%) following burosumab treatment. The tubular maximum reabsorption rate of phosphate to glomerular filtration rate (TmP/GFR) increased from 1.3 (0.32) mg/dL at week 0 to 2.0 (0.42) mg/dL at week 48. Over 48 wk, patients reported that their worst pain, severity, interference, and stiffness were relieved and Measurement Information System quality of life assessment scores increased. Motor function assessed by the 6-min walking test improved significantly (72.7% increase from baseline to week 48). All treatment-emergent adverse events were mild or moderate; none were serious or serious treatment-related. Burosumab treatment led to sustained correction of serum phosphate levels, enhanced renal phosphate reabsorption (ie, TmP/GFR improvements), and improved stiffness, pain, and functional exercise capacity. Treatment was well-tolerated without any new safety signals in Chinese patients with XLH.

Opportunistic screening for osteoporosis using images acquired for other purposes is a burgeoning area that may be of particular utility for the identification of surgical candidates with poor bone health. Texture analysis of clinical MRIs can be used to evaluate the heterogeneity of trabecular bone as a potential metric of bone quality. This cohort study investigated relationships between MRI-based vertebral trabecular bone texture and material properties by Fourier-transform infrared (FTIR) spectroscopy. We hypothesized that texture features from preoperative MRI images would reflect vertebral bone mineralization and collagen properties. In a cohort of 30 postmenopausal women (mean age 65) undergoing spine fusion surgery, T1-weighted MRI images were obtained using standard clinical sequences. A gray-level co-occurrence matrix was used to characterize the distribution and spatial organization of voxel intensities and derive texture features, including inverse difference moment, feature correlation, and contrast. Lumbar vertebral bone biopsies were obtained intraoperatively and analyzed with FTIR spectroscopy to assess composition, including metrics of mineral maturity (acid phosphate and carbonate:phosphate ratio). We found that vertebral trabecular bone texture by MRI was related to directly measured bone material properties: more heterogeneous texture was associated with less mature bone. Women with lower inverse difference moment had higher acid phosphate (r = -0.43, p < .02). Similarly, women with lower feature correlation had higher acid phosphate (r = -0.39, p < .04) and higher carbonate: phosphate (r = -0.47, p < .01). Women with higher contrast had higher acid phosphate (r = 0.381, p < .04). Our results suggest that preoperative MRI texture may predict intraoperative bone properties, specifically FTIR metrics of tissue age that may reflect local remodeling or microdamage repair processes. This finding supports the potential of MRI as a screening tool to identify individuals with abnormal bone quality.

McCune-Albright syndrome (MAS) is a rare mosaic genetic disorder caused by a mutation in the GNAS gene and typically presents with a triad of symptoms: fibrous dysplasia of bones, café-au-lait macules, and precocious puberty. The GNAS mutation leads to overproduction of fibroblast growth factor-23 (FGF23), which may result in hypophosphatemia. Burosumab, a monoclonal antibody against FGF23, is approved for the treatment X-linked hypophosphatemia and tumor-induced osteomalacia. There are currently no data on its efficacy and safety in fibrous dysplasia/MAS patients. A 27-yr-old male with MAS was under the care of the Endocrinology Department for persistent hypophosphatemia and skeletal complications despite treatment with oral phosphate supplements and calcitriol. He started treatment with burosumab (1 mg/kg s.c. every 4 wk) and achieved normalization of calcium-phosphate metabolism (phosphate 0.83 mmol/L vs 0.38 mmol/L; PTH 70.4 pg/mL vs 177 pg/mL) and significant reduction in alkaline phosphatase activity (ALP 620 IU/L vs 1182 IU/L) and bone fraction of alkaline phosphatase activity (BALP 327 IU/L vs 603 IU/L). No further fractures were observed during 24 mo of treatment. The patient reported a reduction in bone pain and improved well-being. No adverse effects were reported during treatment. This is the first reported case of burosumab treatment in an adult patient with fibrous dysplasia/MAS. The therapy had positive effects on the patient's well-being, calcium-phosphate balance, and bone markers. However, longer follow-up and further safety studies are needed before routine use in adult fibrous dysplasia/MAS patients.

Osteoporotic vertebral fractures represent a significant yet underdiagnosed manifestation of osteoporosis, particularly affecting older White women. While vertebral fractures are among the most common osteoporotic fractures, their contribution to mortality has received less attention compared to hip fractures, creating a critical knowledge gap. This study analyzed temporal trends in age-adjusted mortality rates from osteoporotic vertebral fractures among White women aged 65 and older in the United States from 1999 to 2020. We conducted a retrospective analysis using Centers for Disease Control and Prevention's Multiple Cause of Death files, identifying cases where both vertebral fractures and osteoporosis were listed as causes of death using specific ICD-10 codes. Age-adjusted mortality rates per 100 000 population were calculated using the 2000 US standard population, and joinpoint regression analysis identified significant changes in mortality trends over the 22-yr study period. Our findings revealed a concerning 87.5% increase in age-adjusted mortality rates, rising from 0.24 per 100 000 in 1999 to 0.45 per 100 000 in 2020. Joinpoint regression identified three distinct trend segments: a non-significant decline from 1999 to 2004, followed by a statistically significant increase from 2004 to 2009 with an annual percent change (APC) of 13.93%, and a more modest upward trend from 2009 to 2020. The overall average APC was 4.21%, indicating a highly significant upward trend in mortality rates. The pronounced increase during 2004-2009 coincides with important developments in osteoporosis management, including declining hormone replacement therapy use following Women's Health Initiative findings and emerging bisphosphonate safety concerns. These findings underscore vertebral fractures as potentially life-threatening complications requiring aggressive prevention and management strategies. As the population ages, our results highlight the urgent need for improved osteoporosis screening, enhanced fracture risk assessment, and optimized treatment approaches to reduce the growing burden of vertebral fracture-related mortality in this vulnerable population.

Current methods of diagnosing osteoporosis, such as DXA, have limitations in predicting fracture risk. Cortical bone mechanics technology (CBMT) offers a novel approach by using a three-point bend test with multifrequency vibration analysis to directly measure ulnar bending stiffness and calculate flexural rigidity, a mechanical property highly predictive of whole-bone strength under bending conditions. Cortical bone mechanics technology targets the diaphyseal ulna, a site composed primarily of cortical bone, enhancing its specificity for cortical bone quality. In this study of 388 postmenopausal women, we developed and validated a 20-point signal quality indicator (SQI) scoring system to quantify CBMT signal quality and evaluated its relationship to biometric characteristics. The SQI was developed through expert assessment of representative frequency response function (vibration data) trials and refined over 17 iterations. The final system achieved excellent classification performance (AUC = 0.974; sensitivity, specificity, and accuracy all >97%). A total of 22 740 trials were collected across 758 total arm tests, sampling 10 ulnar sites per arm under three vibration amplitudes. Two expert analysts evaluated signal features associated with high signal quality. The resulting SQI is fully automated and provides real-time feedback. All correlations between SQI scores and biometric attributes were weak or very weak (|ρ| < 0.30). The correlations with body weight (ρ = -0.11), BMI (ρ = -0.12), ulnar BMD (ρ = -0.17), CBMT-derived flexural rigidity (ρ = -0.28), and grip strength (ρ = 0.17) were statistically significant (p < .05) but remained small in magnitude. SQI scores were modestly lower in individuals with higher BMI or flexural rigidity (~2 to 3 points), but values remained in the acceptable-to-good range. This study introduces a robust, automated CBMT signal quality metric and demonstrates that its performance remains stable across a broad range of biometric profiles, supporting its application in both clinical and research settings.

Disruptions of the composition of the gut microbiome are linked to impaired bone tissue strength. Fecal microbiota transplantation (FMT) is an established clinical therapy that can restore a healthy gut microbiome and reduce systemic inflammation. However, whether FMT from a healthy donor could rescue bone fragility is unknown. As induced inflammation causes mineralization defects, we hypothesize that manipulations of the gut microbiota alter bone fracture resilience through changes in mineral quality. Here, we altered the compositions of the gut microbiome in mice via antibiotics (ampicillin and neomycin) and FMT. Mice were allocated to 5 groups (M/F, N = 13-18/group): Unaltered, Continuous (dosed 4-24 wk), Initial (dosed 4-16 wk), Reconstituted (dosed 4-16 wk with subsequent FMT from age- and sex-matched mice with unaltered gut microbiota), and Delayed (dosed 16-24 wk). Fracture toughness testing and Raman spectroscopy were conducted on the femora. The maximum toughness was greater in the Reconstituted group (for females, p < .05 compared to Continuous, Unaltered, and Delayed groups; for males, p < .05 compared to groups with antibiotic dosing). The Reconstituted group showed lower type-B carbonate substitution in the bone mineral (all p < .01 for both sexes), and lower mineral-to-matrix ratio (all p < .01 for males, for females, p < .01 compared to Unaltered, Initial, and Delayed groups). In females, mineral crystallinity was higher in the Reconstituted group than those dosed with antibiotics (all p < .05). Serum inflammation marker TNF-α was positively correlated with type-B carbonate substitutions (ρ = 0.66), mineral-to-matrix ratio (ρ = 0.71), and carboxymethyl-lysine (CML) in bone matrix (ρ = 0.43). Enhanced bone maximum fracture toughness was associated with reduced type-B carbonate substitution (r = -0.45), decreased mineral-to-matrix ratio (r = -0.40), increased mineral crystallinity (r = 0.33), and lower levels of bone CML (r = -0.49, all p < .01). These results suggest that the introduction of more beneficial gut microbiota can increase fracture resistance by modifying mineral composition and quality, likely through the reduction of systemic inflammation.

Osteogenesis imperfecta (OI) is a family of heritable collagen I-related skeletal disorders for which, to date, no definitive cure is available. Individuals with OI are mainly treated with bisphosphonates that enhance bone mass by inhibiting bone resorption. However, new strategies combining antiresorptive molecules with bone anabolic drugs are likely to provide valid alternatives for skeletal health, protecting physiological bone turnover. Recently, cellular stress has been identified as a therapeutic target in both dominant and recessive forms of OI characterized by overmodified collagen I. The chemical chaperone 4-phenylbutyrate (4PBA) successfully ameliorated cell homeostasis in both in vitro and in vivo OI models. In this study, dominant Chihuahua (Chi/+) and recessive p3h1^-/- zebrafish OI models were treated for 2 mo either with the bisphosphonate alendronate (ALN) or with 4PBA or with a combination of the two. The treatment effect at the tissue level was evaluated by microCT analysis of the vertebral body, while histology and gene expression analyses allowed to dissect the consequences at a cellular level. Only ALN administration improved the vertebral thickness in the dominant Chi/+ model. The combined therapy synergistically improved osteoblast homeostasis and promoted the formation of mature extracellular collagen fibers in both models. All treatment conditions reduced osteoclast TRAP activity in Chi/+, whereas 4PBA and 4PBA + ALN had the opposite effect on p3h1^-/- . Finally, 4PBA and the combination of ALN and 4PBA reduced osteocyte apoptosis only in p3h1^-/- . Our data demonstrated for the first time in vivo a differential effect of the combination of an antiresorptive and a new anabolic compound in dominant and recessive OI zebrafish models, stressing the importance of identifying the specific causative molecular defect to define the best treatment option.