Bone最新文献

Objectives: Maintained bone health is critical for independent living when aging. Currently, multimodal exercise regimes including weight-bearing exercises with impact are prescribed as optimal for maintaining bone health, while there is less consensus on the effects of resistance training at different intensities upon bone. Here we examined whether bone health was positively influenced by 1 year of supervised resistance training at two different intensities.

Methods: Older adults at retirement age (mean age: 66 ± 3 years, n = 451) were randomized to either 1 year of heavy resistance training (HRT), moderate intensity training (MIT) or a non-exercising control group (CON) in the LISA (LIve active Successful Aging) study. Bone mineral density (BMD) was assessed at whole body level, femoral neck, and the lumbar region of the spine (L1-L4) using Dual-energy X-ray absorptiometry (DXA). Bone degradation and formation were evaluated with blood C-terminal telopeptide of type I collagen (CTX) and procollagen type I N-propeptide (PINP). Dephosphorylated uncarboxylated matrix Gla-protein (dp-ucMGP) was used as a biomarker of functional vitamin K status. Participants were assessed at baseline, immediately following the intervention (year 1), and at longitudinal follow-ups at years 2 and 4. Two-way mixed model ANOVAs were used to assess group differences at all time points.

Results: At the 4-year follow-up n = 329 participants (58 % women) remained in the study. BMD was not influenced by training and decreased across all groups over the 4 years for total body (F_3,977 = 4.617, p = 0.003, η² = 0.01) and femoral neck both in the dominant (F_3,893 = 45.135, p < 0.001, η² = 0.13) and non-dominant leg (F_3,896 = 33.821, p < 0.001, η² = 0.10). Independent of group, CTX increased (F_3,932 = 47.434, p < 0.001, η² = 0.13) over the 4 years. HRT resulted in an increased bone formation (PINP rise) only after the first year with systematic training (t(936) = 3.357, p = 0.04), and it was more pronounced than in CON (t(312) = 2.494, p = 0.04). Plasma dp-ucMGP remained unaltered over time in all groups. In general, women had significantly lower BMD and higher levels of CTX and PINP compared to men.

Conclusion: We demonstrated that 1 year of heavy resistance training positively influenced short-term bone formation in well-functioning older adults, although the effect was not maintained at long-term follow ups. These minor changes in bone biomarkers were not reflected in changes in BMD measured with DXA.

Trial registration: clinicaltrials.gov (NCT02123641).

Porphyromonas gingivalis (P. gingivalis), a major pathogenic bacterium of chronic periodontitis and central player in the onset and subsequent progression of periodontitis, can cause alveolar bone resorption. The osteoblast dysfunction induced by P. gingivalis infection is a crucial pathological process causing bone loss. However, the comprehensive responses of osteoblasts, especially metabolism processes involved in osteoblast dysfunction under P. gingivalis invasion are largely unknown. In the present study, to profile the molecules switched in osteoblast dysfunction caused by P. gingivalis infection, the effect of P. gingivalis invasion on osteoblast differentiation was assessed and investigated through transcriptomics and metabolomics approaches. We found that P. gingivalis infection dramatically impaired osteoblast function. P. gingivalis invasion disrupted homeostasis of phosphorus (Pi)/calcium (Ca²⁺) and induced robust oxidative stress, cell apoptosis and massive activation of inflammatory response in osteoblasts. Notably, the exposure to P. gingivalis induced the inactivation of endocrines pathways, involved in bone formation, which is characterized by downregulated genes and less accumulated metabolites in "Parathyroid hormone synthesis, secretion and action", its downstream "Wnt signaling pathway" and related Pi/Ca²⁺ transport. Furthermore, we found that disrupted purine metabolism produced less ATP in P. gingivalis-infected osteoblasts and the reduced ATP may directly inhibit phosphorus transport. Collectively, these results provide a new insight into the molecular changes in P. gingivalis-infected osteoblasts in a comprehensive way.

Romosozumab is an anti-sclerostin antibody that increases bone formation and decreases bone resorption, and it became available for patients at high risk of osteoporotic fractures in Japan in 2019. The aim of this study was to clarify the clinical effects, safety, and predictors of the effectiveness of 12 months of romosozumab therapy following daily or weekly administration of teriparatide. The study had an observational pre-post design and included 171 female patients. Romosozumab was administered at a dose of 210 mg subcutaneously every 4 weeks for 12 months following daily or weekly administration of teriparatide. The incidence of new fractures, safety, and changes in bone mineral density (BMD) and bone turnover markers were recorded. New fractures occurred in 3 cases (2.2 %). Four patients (2.3 %) with secondary osteoporosis experienced cardiovascular events, which were fatal in 1 patient (0.6 %). The percent changes in BMD at the spine and total hip at 12 months from baseline were + 7.9 % and + 2.4 %, respectively. The percent change in spine BMD did not significantly differ according to whether daily or weekly teriparatide was given as previous treatment. Romosozumab following teriparatide showed greater effectiveness in patients with primary osteoporosis, high P1NP level at 1 month, and low percent changes in TRACP-5b after 12 months of treatment. Romosozumab after treatment with daily or weekly teriparatide was relatively safe and more effective in patients with primary osteoporosis than in those with secondary osteoporosis.

Accurate 3D characterization of osteocyte lacunae is important when investigating the role of osteocytes under various physiological and pathological conditions but remains a challenge. With the continued development of laboratory X-ray micro-computed tomography, an increasing number of studies employ these techniques beyond traditional bone morphometry to quantify osteocyte lacunae. However, there is a lack of knowledge on the effect of measurement parameters on the image quality and resolution and in turn the osteocyte lacunar quantification. Herein, we have examined the interplay between scan parameters and the resultant lacunar quantification in terms of lacunar size, shape, and density by comparison with a synchrotron benchmark dataset. We summarize our conclusions in a guide for use of μ-CT for osteocyte lacunar quantification: (1) Identification of the measurement requirements to address the research questions. (2) Collection and preparation of suitable sample(s) that fulfills these requirements. (3) Experimental considerations including determination of the required voxel size, in turn dictating the maximum FOV and by extension the maximum size of the sample(s). The experimental parameters chosen should ensure optimal image contrast, sufficient signal to noise, angular sampling etc. Usually, it is advisable to measure as well as possible within the limits of time, budget, data storage and analysis capabilities. (4) Data analysis and reporting of the results, including visual examination of the data at multiple steps in the analysis, to ensure correct feature identification and suitable reporting approaches. (5) Cross study comparisons, which may be unsuitable if the experimental conditions and analysis strategies are not comparable.

This paper presents a review of the potential role of the endoplasmic reticulum/Golgi complex and intracellular vesicles in mediating events leading to or associated with vertebrate tissue mineralization. The possible importance of these organelles in this process is suggested by observations that calcium ions accumulate in the tubules and lacunae of the endoplasmic reticulum and Golgi. Similar levels of calcium ions (approaching millimolar) are present in vesicles derived from endosomes, lysosomes and autophagosomes. The cellular level of phosphate ions in these organelles is also high (millimolar). While the source of these ions for mineral formation has not been identified, there are sound reasons for considering that they may be liberated from mitochondria during the utilization of ATP for anabolic purposes, perhaps linked to matrix synthesis. Published studies indicate that calcium and phosphate ions or their clusters contained as cargo within the intracellular organelles noted above lead to formation of extracellular mineral. The mineral sequestered in mitochondria has been documented as an amorphous calcium phosphate. The ion-, ion cluster- or mineral- containing vesicles exit the cell in plasma membrane blebs, secretory lysosomes or possibly intraluminal vesicles. Such a cell-regulated process provides a means for the rapid transport of ions or mineral particles to the mineralization front of skeletal and dental tissues. Within the extracellular matrix, the ions or mineral may associate to form larger aggregates and potential mineral nuclei, and they may bind to collagen and other proteins. How cells of hard tissues perform their housekeeping and other biosynthetic functions while transporting the very large volumes of ions required for mineralization of the extracellular matrix is far from clear. Addressing this and related questions raised in this review suggests guidelines for further investigations of the intracellular processes promoting the mineralization of the skeletal and dental tissues.

Purpose: To evaluate the impact of prior teriparatide (TPTD) treatment on the effectiveness of romosozumab (ROMO) in postmenopausal osteoporosis.

Methods: In this retrospective, case-controlled, multicenter study, 323 postmenopausal patients were initiated ROMO. Of these, 275 were treatment-naïve, and 48 were switched from TPTD, with uninterrupted ROMO treatment for 12 months. Propensity score matching was applied to ensure clinical comparability, yielding 44 patients in each group. Baseline characteristics included a mean age of 78.0 years, lumbar spine (LS) T-score of -3.6, and total hip (TH) T-score of -2.8. Bone mineral density (BMD) and serum bone turnover markers were evaluated over the 12-month period.

Results: The increasing rate in the bone formation marker PINP was significantly greater in the treatment-naïve group compared to the TPTD-switched group throughout the 1-12 month period. Conversely, the reduction in the bone resorption marker TRACP-5b was similar between the groups, indicating a diminished anabolic window in the TPTD-switched group. After 12 months, the TPTD-switched group showed lower BMD gains in the LS (10.3 % vs. 17.3 %; P = 0.002) and TH (3.1 % vs. 7.8 %; P = 0.002) compared to the treatment-naïve group. Multiple regression analysis revealed positive associations between the 12-month percentage BMD increases (LS; β = 0.30; 95 % CI = 0.85-11.61; P = 0.024 / TH; β = 0.32; 95 % CI = 0.51-8.56; P = 0.028) and being treatment-naïve compared to prior TPTD treatment.

Conclusions: Prior TPTD treatment may attenuate the effectiveness of ROMO, potentially due to diminished bone formation activation.

Osteoarthritis (OA) is associated with sclerosis, a thickening of the subchondral bone plate, yet little is known about bone adaptations around full-thickness cartilage defects in severe knee OA, particularly beneath bone-on-bone wear grooves. This high-resolution micro-computed tomography (microCT) study aimed to quantify subchondral bone microstructure relative to cartilage defect location, distance from the joint space, and groove depth. Ten tibial plateaus with full-thickness cartilage defects were microCT-scanned to determine defect location and size. Wear groove depth was estimated as the thickness from its deepest point to a surface interpolated from the defect edges. Two 5 × 5 mm specimens were sampled from three regions (defect, edge, and cartilage-covered areas) and two from the contralateral condyle, then scanned at higher resolution. Bone density profiles were analyzed as a function of distance from the joint space to identify cortical and trabecular regions of interest and and compute their respective bone density and microstructure. Cortical bone beneath defects was four times thicker under wear grooves than beneath cartilage. Bone density profiles significantly differed between the three specimen types at depths up to 5 mm. Below defects, cortical porosity was 85 % higher, and trabecular density 14 % higher, than in cartilage-covered specimens. Some trabecular spaces were filled with woven bone-like tissue, forming a new cortical layer. These changes were confined to the defect region and ceased abruptly at the defect edge. No correlation was found between bone microstructural indices and the estimated groove depth. Our findings suggest an ongoing migration of the cortical layer during formation of the groove from its original position into the underlying trabecular bone, a process we termed "trabecular corticalization." Under deeper wear grooves, the new cortical layer exhibited large pores connecting bone marrow to the joint space, suggesting physiological limits to corticalization. These results highlight specific bone adaptations beneath cartilage defects in severe OA and provide insights into the progression of subchondral bone changes under bone-on-bone contact areas.

Bone tissue is a biological composite material with a complex hierarchical structure that could continuously adjust its internal structure to adapt to the alterations in the external load environment. The fluid flow within bone is the main route of osteocyte metabolism, and the pore pressure as well as the fluid shear stress generated by it are important mechanical stimuli perceived by osteocytes. Owing to the irregular multiscale structure of bone tissue, the fluid stimulation that lacunar-canalicular network (LCN) in different regions of the tissue underwent remained unclear. In this study, we constructed a multiscale conduction model of fluid flow stimulus signals in bone tissue based on the poroelasticity theory. We analyzed the fluid flow behaviors at the macro-scale (whole bone tissue), macro-meso scale (periosteum, interstitial bone, osteon and endosteum), and micro-scale (lacunar-osteocyte-canalicular) levels. We explored how fluid stimulation at the tissue level correlated with that at the cellular level in cortical bone and characterized the distributions of the pore pressure, fluid velocity and fluid shear stress that the osteocytes experienced across the entire tissue structure. The results showed that the initial conditions of intramedullary pressure had a significant impact on the pore pressure of Haversian systems, but had a relatively small influence on the fluid velocity. The osteocyte which were located at different positions in the bone tissue received very distinct fluid stimuli. Osteocytes in the vicinity of the Haversian Canals experienced higher fluid shear stress stimulation. When the permeability of the LCN was within the range from 10^-21 m² to 10^-18 m², the distribution of pressure, fluid velocity and fluid shear stress within the osteon near the periosteum and endosteum was significantly different from that in other parts of the bone. However, when the permeability was less than 10^-22 m², such a difference did not exist. Particularly, the flow velocity at the lacunae was markedly higher than that in the canaliculi. Meanwhile, the pore pressure and fluid shear stress were conspicuously lower than those in the canaliculi. In this study, we considered the interconnections of different biofunctional units at different scales of bone tissue, construct a more complete multiscale model of bone tissue, and propose that osteocytes at different locations receive different fluid stimuli, which provides a reference for a deeper understanding of bone mechanotransduction.

Obesity is a risk factor of developing type 2 diabetes (T2D) and metabolic complications, through systemic inflammation and insulin resistance. It has also been associated with increased bone marrow adipocytes along with increased bone fragility and fracture risk. However, the differential effects of obesity and T2D on bone fragility remain unclear. The cathelicidin-related antimicrobial peptide (CRAMP) is a multifunctional modulator of the innate immunity that has emerged as biomarker of cardiometabolic diseases. The aims of this study were i) to assess the differential impact between hyperinsulinemic obesity versus insulinopenic T2D, on bone phenotype and bone marrow adipose tissue (BMAT), and ii) to analyse the link with CRAMP expression and its circulating levels in the context of obesity and T2D. We used C57BL/6 J male mice models of obesity induced by high-fat diet (HFD), and of insulinopenic T2D induced by streptozotocin (STZ) treatment combined with HFD, reflecting the metabolic heterogeneity of the diseases. As compared to low-fat diet (LFD) control group after 16 weeks of feeding, the HFD mice exhibit a significant weight gain, moderate hyperglycaemia, impaired glucose tolerance and insulin sensitivity, and significant increase in serum insulin levels. This hyperinsulinemic obesity led to decreased trabecular (Tb.Th) and cortical thickness (Ct.Th) in the tibia, associated with significant BMAT expansion, in addition to increased subcutaneaous (SCAT) and visceral adipose tissue (VAT). No changes were observed in the circulating levels of CRAMP peptide neither in other bone parameters. While, STZ treatment in HFD/STZ group induced a more severe hyperglycaemia, glucose intolerance and insulin resistance, and hypoinsulinemia. We also observed a negative effect on the expansion of both SCAT and VAT, as well as lower increase in BMAT as compared to HFD group. However, these mice with insulinopenic T2D exhibit early decrease in trabecular number (Tb.N) in proximal tibia, progressively from 8 to 16 weeks of protocol, and impaired femoral biomechanical stiffness. These alterations are also accompanied with decreased circulating levels of the CRAMP peptide in the HFD/STZ mice. The CRAMP mRNA levels decreased in VAT of both HFD and HFD/STZ groups. Overall, these results provide novel insights into the differential negative impact of obesity versus T2D on bone microenvironment, and suggest a link between hyperglycaemia-induced bone quality alterations during insulinopenia, and impaired regulation of the cathelicidin peptide of the innate immunity. Further investigations are needed to elucidate this relationship.

Medium chained triglycerides (MCT) ketogenic diet is being extensively investigated for its neuroprotective effects against adverse effects associated with aging and neurodegenerative disorders. Aging is a common risk factor for the development of both osteoporosis and neurological disorders. Hence, suppression of aging and age-related neurodegeneration might contribute to delaying skeletal aging. The present study was designed to investigate the effects of the primary components of the MCT diet, against bone resorption associated with D-gal-induced accelerated aging and D-gal /AlCl₃-induced age-related toxicity. We report bone loss in accelerated aged mice and age-related neurotoxic mice through declined Sirtuin1 (SIRT1) expression, depleted bone turnover markers, (P1NP and β-CTX-1), low bone mineral density (BMD), and deterioration of trabecular bone microarchitecture in both the distal femur and proximal tibia bones. Administration of MCT dietary components decanoic acid and octanoic acid, led to a decrease in body weight and only octanoic acid increased serum levels of ketone body, β-hydroxybutyrate (β-HB), but both of them failed to reverse the diminishing effects on bone health associated with aging and age-related neurotoxicity. Surprisingly, decanoic acid, octanoic acid, and their combination also exhibited negative effects on trabecular bone microarchitecture and BMD in the distal femur and proximal tibia bones of healthy mice. The findings from this study provide supporting evidence on the deterioration of bone health associated with aging and age-related neurotoxicity, and the bone resorption potential of MCT dietary supplements that are being prescribed in healthy older populations and elderly persons diagnosed with neurological disorders.