Calcified Tissue International最新文献

Larsen syndrome is a rare genetic condition characterized by facial dysmorphism and skeletal deformities. It is caused by heterozygous pathogenic variants in the Filamin B encoding gene (FLNB). FLNB is a cytoskeletal protein that plays a key role in bone morphogenesis; however, the skeletal phenotype of Larsen syndrome has not been described in detail. Here, we studied the skeletal presentation in two subjects with Larsen syndrome. A case-study including a 63-year-old women and her 33-year-old daughter with Larsen syndrome, both carrying a novel FLNB c.688G > T, p.(Val230Phe) variant. The bone morphologic evaluation included, radiographs, bone mineral density assessment, and high-resolution peripheral quantitative tomography (HR-pQCT). In addition, a transiliac crest bone biopsy from the mother was evaluated by µCT, histomorphometry, and in situ examination of FLNB expression within physiological human bone remodeling sites of controls. Both women were diagnosed with severe osteoporosis (T-score < -5). The HR-pQCT analysis showed a low trabecular bone volume, as well as a low cortical thickness compared to a healthy cohort. Histomorphometry and µCT analysis of the iliac bone biopsy confirmed low cortical thickness, and revealed a high density of small eroded and quiescent intracortical pores. The trabecular bone remodeling was not affected, while cortical remodeling events accumulated as small eroded pores and quiescent pores with an improved infilling. The FLNB variant is associated with low bone mineral density reflecting severe osteoporosis and an altered trabecular and cortical bone structure, while bone turnover was less affected at the time of analysis.

It is well documented that the activation frequency of basic multicellular units (BMUs) is increased following menopause, but it is unclear if a negative BMU balance also contributes to osteoporosis-related bone loss or how remodeling dynamics are altered to maintain or disrupt BMU balance. Time-lapsed imaging was used to track individual BMUs in cortical bone and investigate their spatio-temporal balance in a rabbit model of osteoporosis. The distal tibiae of female New Zealand White rabbits that received ovariohysterectomy (OVH) or SHAM surgery were scanned in vivo using synchrotron radiation micro-CT and two weeks later ex vivo using desktop micro-CT. Remodeling spaces were partitioned into resorption and formation zones based on their 3D morphology. BMU balance was assessed by the maximum radius, canal radius, wall thickness, and relative resorption and formation volumes. The longitudinal erosion rate and zone lengths were used to calculate the radial rate and duration of resorption and formation. Remodeling spaces were larger in OVH vs. SHAM rabbits; however, this augmented resorption was accompanied by increased formation such that OVH and SHAM BMUs were similarly balanced. Maintaining this balance was achieved by a 50% longer formation period in OVH vs. SHAM (21.0 vs 13.2days) as the radial infill rate was equivalent (OVH = 2.1 vs SHAM = 2.0μm/day). Radial erosion rate was faster in OVH (10.3 vs 8.6 μm/day), but resorption duration (OVH = 4.2 vs SHAM = 3.5days) and longitudinal erosion rate (OVH=41.3 vs SHAM = 40.1μm/day) were not different. This novel imaging pipeline demonstrated that the spatio-temporal dynamics of cortical BMUs are altered in this rabbit model of osteoporosis, but the collective changes in resorption and formation activity work in concert to maintain BMU balance. In contrast to the common perspective in the literature, this suggests that the elevated cortical porosity in osteoporosis is predominately due to increased activation of remodeling events rather than negative BMU balance.

X-linked hypophosphataemia (XLH) is a genetic phosphate-wasting disorder caused by excess fibroblast growth factor 23 (FGF23), which leads to skeletal morbidities, pain, stiffness, and impairments in physical function and health-related quality of life. Burosumab inhibits excess circulating FGF23, restoring bone biochemistry. Here we report real-world data from adults with debilitating XLH symptoms who started treatment with burosumab through a UK early access programme. Change from baseline was assessed for bone biochemistry and patient-reported outcomes (PROs) collected from patients' medical records from September 2019 to December 2022. The proportion of patients (n = 136; 66% female, median age 44.0 years [range 18-83]) with normal serum phosphate increased from 5% (6/126) at baseline to 63% (52/82) after 6 months' burosumab treatment; mean serum phosphate increased significantly from baseline. Significant improvements from baseline were observed in Brief Pain Inventory short-form Worst Pain, Pain Severity and Pain Interference scores (mean [SD] improvement at 6 months: 1.8 [2.3], 1.6 [2.1] and 1.9 [2.2] points, respectively). Western Ontario and McMaster Universities Arthritis Index Stiffness, Pain, Physical Function and total scores improved significantly at 6 months (15.9 [29.7], 11.4 [24.3], 15.7 [19.7] and 15.4 [18.3], respectively), as did EuroQol five-dimension five-level (EQ-5D-5L) utility and visual analogue scale (VAS) scores (0.16 [0.22] and 17.0 [21.6]). Most improvements were clinically meaningful (where benchmarks exist). This study demonstrates the effectiveness of burosumab in real-world practice, supporting findings from clinical trials, and provides new evidence that burosumab treatment substantially improves EQ-5D-5L utility and VAS scores in adults with XLH.

Hypoparathyroidism (HypoPT) results from deficient parathyroid hormone (PTH) secretion or action, leading to hypocalcemia, hyperphosphatemia, and hypercalciuria. Traditionally, treatment involves oral calcium and active vitamin D supplementation. Recombinant PTH therapies, such as rh-PTH (1-84) and PTH (1-34), offer a more physiological alternative, improving calcium homeostasis and reducing associated complications. Recently, palopegteriparatide, a long-acting prodrug of PTH (1-34), was approved as PTH replacement therapy for chronic HypoPT, offering improved biochemical control. However, there is limited information regarding the effects of discontinuing palopegteriparatide. We present the case of a 62-year-old male with postsurgical HypoPT who discontinued palopegteriparatide therapy after three years of treatment, and restarted calcium and calcitriol therapy at different regimens (25% reduction in calcium and double dose of calcitriol compared to the respective doses before starting palopegteriparatide). One week post-discontinuation, his calcium and phosphorus remained stable. However, one month later, he developed symptomatic hypocalcemia (albumin-adjusted serum calcium 7.4 mg/dL and phosphorus 5.1 mg/dL), requiring increased oral calcium doses to restore calcium levels to target ranges. After dose adjustments, calcium and phosphorus levels returned to therapeutic ranges, with the patient reporting symptom improvement. Six months later, his calcium and phosphorus levels remained stable, and the dose of calcium and calcitriol therapy was lower than pre-treatment with palopegteriparatide. This case highlights a potential rebound effect following the discontinuation of palopegteriparatide. While the hypocalcemia was mild and managed at the outpatient setting, this case emphasizes the need for close monitoring and possible adjustments in therapy upon discontinuation of palopegteriparatide.

X-linked hypophosphatemia (XLH) is a rare and progressive disease, due to inactivating mutations in the phosphate-regulating endopeptidase homolog X-linked (PHEX) gene. These pathogenic variants result in elevated circulating levels of fibroblast growth factor 23 (FGF23), responsible for the main clinical manifestations of XLH, such as hypophosphatemia, skeletal deformities, and mineralization defects. However, XLH also involves muscular disorders (muscle weakness, pain, reduced muscle density, peak strength, and power). Although XLH is characterized by muscle disorders, to date there are few studies on the action of FGF23 on muscle. Therefore, this study aims to evaluate the effects of FGF23 in an in vitro model of skeletal muscle satellite cells derived from human biopsies (hSMCs). After isolating and characterizing three lines of hSMCs from three volunteers, we evaluated the effect of FGF23 on the proliferative and myogenic differentiation process. We observed that none of the three concentrations of FGF23 tested (1, 10, 100 ng/mL) affected the proliferative process after 48 h of treatment. On the contrary, after 24 and 48 h of treatment, FGF23 resulted in a significant reduction in the gene expression of the myogenic regulatory factors family (Myf-5, MyoD-1, Myogenin, and MRF4), irisin, myosin heavy chain, myostatin, desmin, FGF23 receptors (FGRF1-4) and KLOTHO coreceptor. We, therefore, hypothesized that FGF23 is directly involved in the muscular disorders that characterize XLH, and clarifying these effects at the molecular and cellular level is essential to elucidate XLH pathogenesis and, consequently, its management.

Rare diseases, defined by the 2002 Rare Disease Act, affect fewer than 5 in 10,000 individuals. Rare metabolic bone diseases (MBDs), such as osteogenesis imperfecta, hypophosphatasia, osteopetrosis, and other unclassified disorders, can disrupt bone development and remodeling, posing diagnostic and management challenges. This study analyzed data from the rarembd.in registry (2010-2024), a 15-year database documenting only rare MBDs. Clinical presentation and demographic data of patients with rare MBDs were collated. Common MBDs (osteoporosis, primary hyperparathyroidism) were excluded. Genetic testing was performed in a subset of patients. There was a total of 218 patients with an almost equal gender distribution (male-to-female ratio of 1:1.07) and a mean age of 29.1 ± 18.9 years. The registry identified 29 rare MBDs with three main disease categories: demineralization disorders (50.4%), disorders of bone matrix and cartilage formation (32.5%), and sclerotic disorders (13.7%); with a smaller proportion categorized as unclassified bone disorders (2.7%). Rickets/osteomalacia (27.1%) was the most common, followed by osteogenesis imperfecta (23.4%) and fibrous dysplasia/McCune-Albright syndrome (18.8%). Fractures affected 57.7% of patients, with 24.5% experiencing multiple fractures, while 31.1% exhibited skeletal deformities. Mutation analysis in our registry identified pathogenic variants in the SOST, TGFβ1, SLC34A3, ALPL, and VCP genes, confirming the genetic basis of sclerosteosis, Camurati-Engelmann disease, hypophosphatemic rickets, hypophosphatasia, and IBMPFD, respectively. Different management strategies were used that included teriparatide, bisphosphonates (zoledronate or alendronate) with total contact casting, intralesional zoledronate, denosumab, calcium, active vitamin D, and recombinant human growth hormone. Total parathyroidectomy was performed in specific cases. The registry classified RMBDs into four categories, with demineralization disorders being the most common, followed by bone matrix/cartilage formation disorders, sclerotic diseases, and unclassified cases. There were 29 RMBDs, and rickets/osteomalacia was the most prevalent subtype, tumor-induced osteomalacia followed by familial hypophosphatemic osteomalacia. Among the unclassified bone disorders, fragility fractures emerged as the most common presentation.

This study investigated the association between energy and macronutrient intake and bone health in 63 adolescents of both sexes who participated in volleyball, track and field, or swimming. Bone mineral content (BMC) and density (BMD) of the total body less head (TBLH), lumbar spine (L1-L4), and femoral neck were assessed using DXA. Bone geometry parameters, including cross-sectional area (CSA), cross-sectional moment of inertia (CSMI), and section modulus, were estimated. Nutritional intake was evaluated through 24-h dietary recalls. Multiple linear regression was performed adjusting for sex, maturity, body mass index, sports discipline, and total moderate-to-vigorous physical activity (Model 1), with further adjustments for calcium intake (Model 2) and total energy intake (Model 3). Energy, protein, and total as well as fractional lipid intake (particularly monounsaturated and polyunsaturated fatty acids) were predictors of BMD at TBLH, L1-L4, and femoral neck. These associations persisted in Model 2 but were attenuated in Model 3. Total lipid intake remained a predictor of BMC at TBLH and L1-L4 across all models, whereas energy and protein intakes were associated with BMC at L1-L4 in Models 1 and 2. Femoral neck BMC was associated with energy, protein, and total lipid only in Model 2. Both CSA and CSMI showed positive associations with total lipid intake, and CSA was associated with energy and protein intakes. No significant associations were found between carbohydrate or fiber and bone parameters. This study highlights energy, protein, and lipid intake as important factors in bone health among adolescent athletes.

Previous studies have shown that the gut microbiota regulates bone mass and that certain strains of Bifidobacterium longum prevent bone loss in ovariectomized (ovx) mice. A novel strain of Bifidobacterium longum (B. longum subsp. longum DSM 32947; BL) with a broad carbohydrate degradation capacity and the ability to stimulate certain lactobacilli was recently identified. In the present study, we tested if BL improves bone health in gonadal intact and ovx female mice.Ten-week-old C57BL/6 J female mice were subjected to ovx or sham surgery. One week after surgery, mice were treated with arabinoxylan oligosaccharides (AXOS; veh) or a combination of AXOS and BL for five weeks. BL treatment increased BL abundance in the cecal content.Dual-energy X-ray absorptiometry showed that BL increased total body bone mineral density in both sham and ovx mice compared with veh-treated mice (p < 0.01). Computed tomography analyses showed that BL increased trabecular bone volume fraction of the L4 vertebra, mainly due to increased trabecular thickness in both sham and ovx mice (p < 0.05). In addition, BL increased the mid-diaphyseal cortical bone area of the femur (p < 0.05) and improved its strength (p = 0.05).In conclusion, treatment with BL increases parameters for bone health in female mice.

Pachydermoperiostosis (PDP) is a rare genetic disorder manifesting with periostosis, clubbing, and thickened skin. The impact of PDP on bone density and microarchitecture is underexplored despite the potential derangement in bone health due to systemic inflammation. This cross-sectional case-control study was conducted in a tertiary care center in north India from July 2022 to July 2023. We compared treatment naïve PDP patients (n = 8) with age and BMI-matched apparently healthy controls. All participants underwent clinical examination and estimation of biochemical parameters including calcium, phosphorus, alkaline phosphatase, 25(OH)D, and iPTH. Bone turnover markers C-terminal telopeptide of type I collagen (CTX) and procollagen type I N-propeptide (P1NP) were also assessed. All patients underwent areal and volumetric bone density measurements using dual-energy X-ray absorptiometry (DXA) and high-resolution peripheral quantitative computed tomography (HR-pQCT). HR-pQCT analysis revealed diminished cortical volumetric bone mineral density and altered microarchitecture in PDP patients at the radius and tibia, characterized by increased cortical porosity. Bone geometry assessment demonstrated increased cross-sectional bone area both in the cortical and trabecular compartments. Finite element analysis (FEA) indicated a substantial reduction in failure load, cortical and trabecular von Mises stress (VMS) at the tibia and stiffness at the radius in PDP patients compared to controls. PDP patients had similar biochemical and bone turnover parameters to controls. Individuals with PDP show reduced cortical vBMD with disrupted bone microarchitecture. These changes may reflect PGE2-mediated inflammation and bone resorption, suggesting increased fracture risk and the need for ongoing monitoring.

Severe, treatment-refractory or early-onset osteoporosis should prompt evaluation for secondary causes. Hyper-IgE syndrome (HIES) is a rare primary immunodeficiency disorder characterised by markedly elevated serum IgE, recurrent infections and skeletal anomalies, including osteoporosis and increased fracture burden. We present two cases of severe osteoporosis in early postmenopausal women. Both women exhibited markedly elevated IgE levels, raising the possibility of underlying HIES. Case 1, despite anabolic and anti-resorptive treatment, experienced multiple fragility fractures, with fracture burden out of keeping with bone mineral density. Case 2 did not respond to bisphosphonate therapy and developed a severe erythematous skin reaction following romosozumab therapy. Both cases highlight the importance of evaluating for secondary causes of osteoporosis. The novel reaction to romosozumab in Case 2 raises questions about its use in patients with immune dysregulation.