Bone最新文献

Both trabecular and cortical bone undergo changes at multiple scales. We previously demonstrated the multi-scale changes in trabecular bone quality that contribute to bone fragility in type 2 diabetes (T2D). The link between increased fragility in T2D and multi-scale changes in cortical bone and their interaction with glycation remains unclear. This study presents, first-ever, multi-scale cortical bone quality parameters in T2D patients after their first hip fracture. The study objective was to determine the association between cortical porosity (Ct.Po.), mechanical, material, and bone compositional properties in T2D. Inferomedial femoral neck (FN) bone tissue specimens were collected from patients (n = 10 with T2D, n = 25 age- and sex-matched non-diabetes controls) who underwent hip replacement surgery following the first hip fragility fracture. Bone mineral density at FN was found to be similar between groups. In T2D, Ct.Po was higher (p = 0.038), while ultimate stress (p = 0.021), ultimate strain (p = 0.040), post-yield strain (p = 0.011), toughness (p = 0.005), yield energy (p = 0.003), and post-yield energy (p = 0.004) were notably lower. Tissue compositional differences included lower gravimetric mineral/matrix (p = 0.017), higher non-enzymatic collagen cross-link ratio (NE-xLR) (p = 0.049) and higher sugar/matrix ratio (p = 0.042) in T2D. Fluorescent advanced glycation end-products (fAGEs) content was higher in T2D bone (p = 0.043). At the mesoscale, the fAGEs in the bone matrix are inversely related to the yield- and ultimate strain of T2D bone, and NE-xLR is negatively correlated with yield- and ultimate- stress in the T2D group. In conclusion, study findings demonstrate that elevated glycation weakens the mechanical integrity of cortical bone by reducing its ability to absorb energy and resist deformation, thereby contributing to bone fragility in T2D. The strong association of fAGEs with lower yield strain, along with the association of NE-xLR with lower yield- and ultimate stress, establishes a causal link between AGEs and the deterioration of cortical bone mechanical properties. These findings underscore the need for strategies targeting glycation and collagen quality to mitigate fracture risk in T2D patients.

Introduction: Fibrous dysplasia (FD) is a rare genetic disease, in which normal bone is replaced by fibro-osseus tissue. Disease severity varies greatly from single monostotic lesions to widespread polyostotic disease. Craniofacial lesions are common and, due to the complex anatomy, can cause several disabling symptoms and local extra-skeletal complications. Since relatively rare, reported cases of craniofacial FD (CFD), specifically, are few and the appropriate management remains incompletely defined.

Methodology: We performed a systematic literature review following the PRISMA guidelines for articles considering CFD in the years 2010-2023. The search was conducted in the PubMed and OVID Medline libraries. Altogether 193 articles were retrieved and reviewed.

Results: Overall, the clinical presentation of CFD is highly variable depending on site and extent of lesion, with pain, deformity or impairment of function being most common. Diagnoses are often incidental and primarily based on CT imaging, while more extensive imaging, genetic studies and lesion biopsies are reserved for unclear cases. Asymptomatic patients are suitable for observation, while symptomatic or widespread disease may require more active approach with medical or surgical treatment. Follow-up is encouraged in all patients to observe possible lesion reactivation, late-stage complications and, though rarely, malignant transformation. Management should be individually tailored with a multidisciplinary team and wholesome consideration of individual needs.

Conclusions: This review provides an updated discussion on craniofacial FD with focus on improved understanding of disease pathophysiology, appropriate line of surgical management, and new potential means of medical treatment.

Introduction: Managing osteoporotic patients at immediate fracture risk is challenging, in part due to the slow and localized effects of anti-osteoporotic drugs. Combining systemic anti-osteoporotic therapies with local bone augmentation techniques offers a promising strategy, but little is known about potential interactions. We hypothesized that integrating systemic treatments with local bone-strengthening biomaterials would have an additive effect on bone density and structure. This study investigated interactions and synergies between systemic therapies and injectable biomaterials, HA2 and HA2-ZOL, designed for local bone strengthening. HA2-ZOL incorporates Zoledronate, a bisphosphonate, to enhance anti-resorptive effects. These materials were tested in an in vivo rat model of osteoporosis using microCT and histology.

Methods: Thirty-six ovariectomized Wistar rats were treated systemically with vehicle (VEH), alendronate (ALN), or parathyroid hormone (PTH). One week later, their tibiae were randomly assigned to local treatment groups: HA2, HA2-ZOL, or NaCl control. Bilateral injections targeted metaphyseal trabecular bone, with microCT scans tracking changes over 8 weeks. Regions of interest (ROIs) were identified and analyzed for bone volume fraction (BV/TV), tissue mineral density (TMD), and trabecular morphology. Histological analyses were performed at week 8 to assess bone structure and mineral inclusions.

Results: VEH animals with NaCl injections experienced marked bone loss, partially mitigated by ALN and PTH. HA2 injections increased BV/TV by factors of 2.5 to 3.4 across treatments compared to baseline, with effects confined to the injected material. HA2-ZOL amplified this response, with BV/TV increases up to 4.8-fold, particularly in VEH and PTH animals. The effects peaked at 2-4 weeks post-injection, followed by remodeling and restoration. Both local treatments increased trabecular thickness, with HA2-ZOL showing slower post-peak resorption.

Discussion: HA2 injections significantly densified bone, independent of systemic therapy. Zoledronate in HA2-ZOL enhanced bone formation and delayed resorption in control and PTH animals, but offered no additional benefit when combined with systemic bisphosphonate. These findings support the hypothesis of an additive effect, suggesting that injectable hydrogels with localized drug delivery can complement systemic therapies by rapidly increasing local bone density, thereby potentially preventing fractures in high-risk osteoporotic patients.

Trisomy of human chromosome 21 (Ts21) individuals present with a spectrum of low bone mineral density (BMD) that predisposes this vulnerable group to skeletal injuries. To determine the bone regenerative capacity of Down syndrome (DS) mice, male and female Dp16 and Ts65Dn DS mice underwent amputation of the digit tip (the terminal phalanx (P3)). This is a well-established mammalian model of bone regeneration that restores the amputated skeletal segment and all associated soft tissues. P3 amputation was performed in 8-week-old male and female DS mice and WT controls and followed by in vivo μCT, histology and immunofluorescence. Following P3 amputation, the bone degradation phase was attenuated in both Dp16 and Ts65Dn males. In Dp16 males, P3 regeneration was delayed but complete by 63 days post amputation (DPA); however, male Ts65Dn exhibited attenuated regeneration by 63 DPA. In both Dp16 and Ts65Dn female DS mice, P3 regenerates were indistinguishable from WT by 42 DPA. In Ts65Dn males, osteoclasts and eroded bone surface were significantly reduced, and osteoblast number significantly decreased in the regenerating digit. In Ts65Dn females, no significant differences were observed in any osteoclast or osteoblast parameter. Like Ts21 individuals and DS mice with sex differences in bone mass, these data expand the characteristic sexually dimorphism to include bone resorption and regeneration in response to skeletal injury in Ts65Dn mice. These observations suggest that sex differences contribute to the poor bone healing of DS and compound the increased risk of bone injury in the Ts21 population.

Objective: This study aims to investigate the roles of the EXT1 and FGFR3 genes in the development of osteochondromas, focusing specifically on their potential interactions in chondrocyte proliferation, differentiation, and tumor formation.

Methods: In vitro, the ATDC5 chondroprogenitor cell line was used to examine the effects of inactivation of both EXT1 and FGFR3. In vivo, a mouse model with dual gene knockout of Ext1 and Fgfr3 was constructed to further explore these genes' roles in tumor formation by observing the incidence and distribution patterns of osteochondromas.

Results: The in vitro experiments demonstrated that ATDC5 cells with reduced expression of EXT1 and FGFR3 genes exhibited enhanced chondrogenic differentiation. In vivo, Fgfr3^+/-;Ext1^+/- mice showed a significant incidence of osteochondromas (72.7 %), primarily located in the humerus, fibula, and tibia, while mice with a single heterozygous deletion did not display notable lesions.

Conclusion: The EXT1 and FGFR3 genes play crucial regulatory roles in the development of osteochondromas. Deficiencies in Ext1 and Fgfr3 can induce the formation of osteochondromas.

Treatments for metabolic acidosis are not well studied; however, one treatment that is commonly used is sodium bicarbonate administration. Sodium bicarbonate has been shown to help reduce symptoms of metabolic acidosis, but its benefits for bone health remain uncertain. Potassium bicarbonate has become a potential new treatment due to its reduction in bone resorption markers, unlike sodium bicarbonate. However, very few studies have looked at the connection between bone functionality and potassium bicarbonate supplementation, especially under the influence of an acidic challenge. To determine the impact of potassium bicarbonate and sodium bicarbonate on the mechanical, structural, compositional, and cellular properties of bone, acidotic mice were given either potassium bicarbonate or sodium bicarbonate for seven days. Blood gas analysis was conducted to evaluate their acidotic states throughout the study. After experimentation, the mice were euthanized, and their femurs excised for further analysis. Before bicarbonate supplementation, the acidotic mice given sodium bicarbonate were in acidosis while the acidotic mice given potassium bicarbonate were in acidemia. The bicarbonate treatment somewhat rescued the blood gas parameters in both acidosis groups, but acidemia and bone dissolution continued occurring in the acidotic mice given potassium bicarbonate, as made evident by the continuous elevation in blood sodium levels compared to the control. The acidosis group given potassium bicarbonate group also had worsened composition and structure, while the acidosis group given sodium bicarbonate had no changes in bone metrics. In this study, potassium bicarbonate was not effective at reducing bone dissolution under acidotic conditions.

Bone fractures due to osteoporosis are a significant problem. Limited accuracy of standard bone mineral density (BMD) for fracture risk assessment, combined with low adherence to bone health screening precludes identification of those at risk of fracture. Because of the wide availability of digital breast tomosynthesis (DBT) imaging, bone screening using a DBT scanner at the time of breast screening has been proposed. Earlier studies have shown that BMD, microstructure, and stiffness of the distal radius can be calculated using digital tomosynthesis imaging of the wrist (DWT). However, strength and stress/strain parameters, which are more relevant to structural failure, and have the potential to enhance the utility of DWT, were not examined previously. Therefore, this study aimed to examine the ability of DWT to discriminate patients with and without fragility fracture using DWT based finite element (DWT-FE) derived strength and stress/strain distribution properties, and to determine in vivo repeatability of these biomechanical properties. Twenty-two postmenopausal women with any fragility fracture (included spine, hip, distal radius, humerus and tibia fractures) and 68 without were recruited. Each participant's nondominant arm (dominant arm if history of fracture in the nondominant arm) was scanned with DWT and compressive loading was simulated using FE modeling. Six additional patients were DWT-scanned thrice, with repositioning, to determine the repeatability of the study variables. Age and T-score were not different between fracture and nonfracture groups (p > 0.1), but strength and stress/strain parameters were significant predictors of fracture status (AUC = 0.64-0.74). Standard deviation of tensile strain was the most discriminatory variable for fracture status (AUC = 0.74) and was independent from stiffness. Repeatability error of DWT biomechanical properties was 0.7 % to 5.8 %. This study demonstrated that DWT-FE based strength and standard deviation of tensile strain were reproducible and predict fracture status independent from BMD and stiffness. The results suggest that the accuracy of fracture risk screening can be improved in the highly accessible environment of mammographic imaging.

Purpose: This study evaluated the efficacy, safety, pharmacodynamics (PD), pharmacokinetics (PK), and immunogenicity of SB16 versus reference denosumab (DEN) up to 18 months in postmenopausal osteoporosis (PMO) patients, and assessed outcomes after switching from DEN to SB16 compared to those who continued with DEN or SB16.

Methods: 457 PMO patients were initially randomized, with 407 re-randomized at Month 12 to either continue DEN (DEN+DEN), switch to SB16 (DEN+SB16), or continue SB16 (SB16 + SB16) through Month 18. Efficacy was assessed by the percent change from baseline in bone mineral density (BMD) at the lumbar spine, total hip, and femoral neck. Safety, PD, PK, and immunogenicity were evaluated throughout the study period.

Results: Mean percent changes from baseline in lumbar spine, total hip, and femoral neck BMD at Month 18 were comparable across treatment groups, indicating comparable efficacy between SB16 and DEN. The mean percent change in lumbar spine BMD was 6.8 % (SB16 + SB16), 6.2 % (DEN+SB16), and 6.8 % (DEN+DEN). Total hip BMD increased by 4.4 %, 3.5 %, and 4.0 %, and femoral neck BMD by 3.4 %, 3.1 %, and 2.7 % for SB16 + SB16, DEN+SB16, and DEN+DEN, respectively. Safety profiles were similar among groups, with no new safety concerns identified after switching. Only one patient in the DEN+SB16 group developed non-neutralizing anti-drug antibodies by Month 18, indicating a low immunogenicity risk for SB16.

Conclusion: Switching from DEN to SB16 demonstrated comparable efficacy, safety, PD, PK, and immunogenicity in PMO patients relative to those who continued DEN. SB16 was well tolerated over 18 months, demonstrating comparable outcomes to DEN.

RANKL and its receptor RANK play a vital role in osteoclastogenesis. RANK primarily recruits TRAFs to promote osteoclastogenesis but also contains an TRAF-independent motif (IVVY^535-538), which mediates osteoclast lineage commitment in vitro. Here, we have developed knockin mice in which inactivating mutations are introduced in the IVVY motif (IVVY to IVAF). Homozygous knockin (RANK^AF/AF) mice are viable and born at the expected Mendelian ratio. Micro-computed tomography (μCT) and histomorphometric analyses of femurs of wild type (RANK^+/+) and RANK^AF/AF mice reveal significant increases in trabecular bone mass in RANK^AF/AF compared to age and sex matched RANK^+/+ mice due to impaired osteoclastogenesis in vivo. Bone marrow macrophages (BMMs) from RANK^AF/AF mice do not form osteoclasts in vitro upon M-CSF and RANKL treatment. RANKL-induced activation of NF-ĸB, ERK, p38 and JNK pathways in RANK^AF/AF BMMs remains intact, but RANKL-induced expression of c-Fos and NFATc1 is impaired in RANK^AF/AF BMMs. Consistent with the crucial role of the IVVY motif in priming BMMs into the osteoclast lineage, RANKL-primed RANK^AF/AF BMMs do not form osteoclasts in response to subsequent Porphyromonas gingivalis (Pg)-stimulation, indicating that the IVVY Motif plays a role in Pg-induced osteoclastogenesis. Mechanistically, RANK IVVY motif mediates Pg-induced osteoclast gene expression by rendering NFATc1 and c-Fos genes responsive to Pg stimulation. Consistently, cell penetrating peptides fused to RANK segments containing the IVVY motif impair Pg-induced osteoclastogenesis by impairing RANKL-activated c-Fos and NFATc1 expression. In conclusion, the RANK IVVY motif plays crucial roles in osteoclastogenesis in vivo and modulates Pg-mediated osteoclast formation in vitro.

Objective: Bone anabolic treatment has been shown to be superior to oral bisphosphonates, especially in osteoporosis patients with a very high fracture-risk. The current German osteoporosis guideline classifies the very high 3-year fracture-risk based upon a novel fracture-risk model. As age is a severe risk-factor, we examined the distribution and associations to geriatric assessment parameters of the very high-risk group in a well-characterized cohort of community-dwelling geriatric patients.

Methods: Analyses were based on 166 patients (mean age 82 ± 6 years) taken from MUSAR (MUnich SArcopenia Registry). Fracture-risk was calculated as described in the current German guideline. Thereupon, patients were allocated to the low-/moderate (<5 %), high- (5-10 %) or very high-risk group (>10 %). Associations of geriatric assessment parameters with the group allocation to the fracture-risk group were evaluated by covariate-adjusted linear regression analysis.

Results: >80 % of the study population were at an increased fracture-risk. Besides, >50 % were allocated to the very high-risk group. Patients in the very high-risk group showed limitations in all physical performance tests (short physical performance battery (SPPB), gaitspeed, handgrip strength and chair rise test). Also, polypharmacy and a risk for malnutrition (from mini nutritional assessment short form (MNA-SF)), were present. All parameters showed significant associations with group allocation to very high-risk group.

Conclusion: Most of the geriatric patients are at a very high-risk for osteoporotic fractures. Also, this group presented several limitations in the comprehensive geriatric assessment highlighting the vulnerability of this group. Clinicians need to reinforce fracture-risk assessment and familiarize with treatment options.