Bone modeling involves the addition of bone material through osteoblast-mediated deposition or the removal of bone material via osteoclast-mediated resorption in response to perceived changes in loads by osteocytes. This process is characterized by the independent occurrence of deposition and resorption, which can take place simultaneously at different locations within the bone due to variations in stress levels across its different regions. The principle of bone functional adaptation states that cortical and trabecular bone tissues will respond to mechanical stimuli by adjusting (i.e., bone modeling) their morphology and architecture to mechanically improve their mechanical function in line with the habitual in vivo loading direction. This principle is relevant to various research areas, such as the development of improved orthopedic implants, preventative medicine for osteopenic elderly patients, and the investigation of locomotion behavior in extinct species. In the present review, the mammalian tibia is used as an example to explore cortical and trabecular bone modeling and to examine its implications for the functional adaptation of bones. Following a short introduction and an exposition on characteristics of mechanical stimuli that influence bone modeling, a detailed critical appraisal of the literature on cortical and trabecular bone modeling and bone functional adaptation is given. By synthesizing key findings from studies involving small mammals (rodents), large mammals, and humans, it is shown that examining both cortical and trabecular bone structures is essential for understanding bone functional adaptation. A combined approach can provide a more comprehensive understanding of this significant physiological phenomenon, as each structure contributes uniquely to the phenomenon.

Gradual elevation of the periosteum from the original bone surface, based on the principle of distraction osteogenesis, induces endogenous hard and soft tissue formation. This study aimed to assess the impact of alternating protocols of activation with relaxation (periosteal pumping) on bone modeling and remodeling. One hundred and sixty-two adult male Wistar rats were used in this study. Four test groups with different pumping protocols were created based on the relaxation applied. Two control groups underwent an activation period without relaxation or only a single activation. One group was sham-operated. Periosteal pumping without period of activation induced gene expression in bone and bone remodeling, and following activation period enhanced bone modeling. Four test groups and control group with activation period equaled the values of bone modeling at the end-consolidation period, showing significant downregulation of Sost in the bone and periosteum compared to that in the sham group (p < 0.001 and p < 0.001, respectively). When all test groups were pooled together, plate elevation from the bony surface increased bone remodeling on day 45 of the observation period (p = 0.003). Furthermore, bone modeling was significantly affected by plate elevation on days 17 and 45 (p = 0.047 and p = 0.005, respectively) and by pumping protocol on day 31 (p = 0.042). Periosteal pumping was beneficial for increasing bone repair when the periosteum remained in contact with the underlaying bony surface during the manipulation period. Following periosteal elevation, periosteal pumping accelerated bone formation from the bony surface by the modeling process.

Modeling and remodeling are essential processes in the development and refinement of maxillofacial bones. Dysregulated bone modeling during the developmental stage may lead to maxillofacial bone malformations and malocclusion. Bone remodeling under mechanical loading serves as the biological basis for orthodontic treatment. Although previous reviews have indicated the significance of microRNAs (miRNAs) in bone metabolism, their roles in orchestrating maxillofacial bone modeling and remodeling remain unclear. This review aims to discuss the mechanisms by which miRNAs regulate the morphogenesis and development of maxillofacial bones, as well as their implications for maxillofacial malformations and malocclusion. Moreover, miRNAs participating in maxillofacial bone remodeling and their impacts on cell mechanosensing are also summarized. Given the intricate interplay of cells and signaling pathways, exosomal miRNAs emerge as the orchestrators of the modeling and remodeling processes. The diagnostic and therapeutic potentials of miRNAs are also highlighted in this review for future clinical applications.

Recent studies in mice have indicated that the gut microbiome can regulate bone tissue strength. However, prior work involved modifications to the gut microbiome in growing animals and it is unclear if the same changes in the microbiome, applied later in life, would change matrix strength. Here we changed the composition of the gut microbiome before and/or after skeletal maturity (16 weeks of age) using oral antibiotics (ampicillin + neomycin). Male and female mice (n=143 total, n=12-17/group/sex) were allocated into five study groups:1) Unaltered, 2) Continuous (dosing 4-24 weeks of age), 3) Delayed (dosing only 16-24 weeks of age), 4) Initial (dosing 4-16 weeks of age, suspended at 16 weeks), and 5) Reconstituted (dosing from 4-16 weeks following by fecal microbiota transplant from Unaltered donors). Animals were euthanized at 24 weeks of age. In males, bone matrix strength in the femur was 25-35% less than expected from geometry in mice from the Continuous (p= 0.001), Delayed (p= 0.005), and Initial (p=0.040) groups as compared to Unaltered. Reconstitution of the gut microbiota, however, led to a bone matrix strength similar to Unaltered animals (p=0.929). In females, microbiome-induced changes in bone matrix strength followed the same trend as males but were not significantly different, demonstrating sex-related differences in the response of bone matrix to the gut microbiota. Minor differences in chemical composition of bone matrix were observed (Raman spectroscopy). Our findings indicate that microbiome-induced impairment of bone matrix in males can be initiated and/or reversed after skeletal maturity. The portion of the femoral cortical bone formed after skeletal maturity (16 weeks) is small; however, this suggests that microbiome-induced changes in bone matrix occur without osteoblast/osteoclast turnover using an, as of yet unidentified mechanism. These findings add to evidence that the mechanical properties of bone matrix can be altered in the adult skeleton.

The importance of finite element analysis (FEA) is growing in orthopedic research, especially in implant design. However, Young\'s modulus (E) values, one of the most fundamental parameters, can range across a wide scale. Therefore, our study aimed to identify factors influencing E values in human bone specimens. We report our systematic review and meta-analysis based on the recommendation of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guideline. We conducted the analysis on November 21, 2021. We included studies investigating healthy human bone specimens and reported on E values regarding demographic data, specimen characteristics, and measurement specifics. In addition, we included study types reporting individual specimen measurements. From the acquired data, we created a cohort in which we performed an exploratory data analysis that included the explanatory variables selected by random forest and regression trees methods, and the comparison of groups using independent samples Welch\'s t test. A total of 756 entries were included from 48 articles. Eleven different bones of the human body were included in these articles. The range of E values is between 0.008 and 33.7 GPa. The E values were most heavily influenced by the cortical or cancellous type of bone tested. Measuring method (compression, tension, bending, and nanoindentation), the anatomical region within a bone, the position of the bone within the skeleton, and the bone specimen size had a decreasing impact on the E values. Bone anisotropy, specimen condition, patient age, and sex were selected as important variables considering the value of E. On the basis of our results, E values of a bone change with bone characteristics, measurement techniques, and demographic variables. Therefore, the evaluation of FEA should be performed after the standardization of in vitro measurement protocol. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Objective.Virtual imaging trials enable efficient assessment and optimization of medical image devices and techniques via simulation rather than physical studies. These studies require realistic, detailed ground-truth models or phantoms of the relevant anatomy or physiology. Anatomical structures within computational phantoms are typically based on medical imaging data; however, for small and intricate structures (e.g. trabecular bone), it is not reasonable to use existing clinical data as the spatial resolution of the scans is insufficient. In this study, we develop a mathematical method to generate arbitrary-resolution bone structures within virtual patient models (XCAT phantoms) to model the appearance of CT-imaged trabecular bone.Approach. Given surface definitions of a bone, an algorithm was implemented to generate stochastic bicontinuous microstructures to form a network to define the trabecular bone structure with geometric and topological properties indicative of the bone. For an example adult male XCAT phantom (50th percentile in height and weight), the method was used to generate the trabecular structure of 46 chest bones. The produced models were validated in comparison with published properties of bones. The utility of the method was demonstrated with pilot CT and photon-counting CT simulations performed using the accurate DukeSim CT simulator on the XCAT phantom containing the detailed bone models.Main results. The method successfully generated the inner trabecular structure for the different bones of the chest, having quantiative measures similar to published values. The pilot simulations showed the ability of photon-counting CT to better resolve the trabecular detail emphasizing the necessity for high-resolution bone models.Significance.As demonstrated, the developed tools have great potential to provide ground truth simulations to access the ability of existing and emerging CT imaging technology to provide quantitative information about bone structures.

The alteration in the shape of the femoral neck is an important radiographic sign for scoring canine hip dysplasia (CHD). Previous studies have reported that the femoral neck thickness (FNT) is greater in dogs with hip joint dysplasia, becoming progressively thicker with disease severity. The main objective of this work was to describe a femoral neck thickness index (FNTi) to quantify FNT and to study its association with the degree of CHD using the Fédération Cynologique Internationale (FCI) scheme. A total of 53 dogs (106 hips) were randomly selected for this study. Two examiners performed FNTi estimation to study intra- and inter-examiner reliability and agreement. The paired t-test, the Bland-Altman plots, and the intraclass correlation coefficient showed excellent agreement and reliability between the measurements of the two examiners and the examiners\' sessions. All joints were scored in five categories by an experienced examiner according to FCI criteria. The results from examiner 1 were compared between FCI categories. Hips that were assigned an FCI grade of A (n = 19), B (n = 23), C (n = 24), D (n = 24), and E (n = 16) had a mean ± standard deviation FNTi of 0.809 ± 0.024, 0.835 ± 0.044, 0.868 ± 0.022, 0.903 ± 0.033, and 0.923 ± 0.068, respectively (ANOVA, p < 0.05). Therefore, these results show that FNTi is a parameter capable of evaluating proximal femur bone modeling and that it has the potential to enrich conventional CHD scoring criteria if incorporated into a computer-aided diagnosis capable of detecting CHD.

Osteoblast Wnt/β-catenin signaling conditions skeletal development and health. Bone formation is stimulated when on the osteoblast surface a Wnt binds to low-density lipoprotein receptor-related protein 5 (LRP5) or 6 (LRP6), in turn coupled to a frizzled receptor. Sclerostin and dickkopf1 inhibit osteogenesis if either links selectively to the first β-propeller of LRP5 or LRP6, thereby disassociating these cognate co-receptors from the frizzled receptor. Sixteen heterozygous mutations identified since 2002 within LRP5 and three heterozygous mutations identified since 2019 within LRP6 prevent this binding of sclerostin or dickkopf1 and account for the exceptionally rare, but highly instructive, autosomal dominant disorders called LRP5 and LRP6 high bone mass (HBM). Herein, we characterize LRP6 HBM in the first large affected family. Their novel heterozygous LRP6 missense mutation (c.719C>T, p.Thr240Ile) was present in two middle-aged sisters and three of their sons. They considered themselves healthy. Their broad jaw and torus palatinus developed during childhood and, contrary to the two previous reports of LRP6 HBM, the appearance of their adult dentition was unremarkable. Skeletal modeling, defined radiographically, supported classification as an endosteal hyperostosis. Areal bone mineral density (g/cm2) of the lumbar spine and total hip featured accelerated increases reaching Z-scores of ~ +8 and +6, respectively, although biochemical markers of bone formation were normal. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Multiple endocrine neoplasia type 1 (MEN1) is a rare, inherited cancer syndrome characterized by the development of multiple endocrine and non-endocrine tumors. MEN1 patients show a reduction of bone mass and a higher prevalence of early onset osteoporosis, compared to healthy population of the same age, gender, and ethnicity. During the monitoring and follow-up of MEN1 patients, the attention of clinicians is primarily focused on the diagnosis and therapy of tumors, while the assessment of bone health and mineral metabolism is, in many cases, marginally considered. In this study, we retrospectively analyzed bone and mineral metabolism features in a series of MEN1 patients from the MEN1 Florentine database. Biochemical markers of bone and mineral metabolism and densitometric parameters of bone mass were retrieved from the database and were analyzed based on age ranges and genders of patients and presence/absence of the three main MEN1-related endocrine tumor types. Our evaluation confirmed that patients with a MEN1 diagnosis have a high prevalence of earlyonset osteopenia and osteoporosis, in association with levels of serum and urinary markers of bone turnover higher than the normal reference values, regardless of their different MEN1 tumors. Fifty percent of patients younger than 26 years manifested osteopenia and 8.3% had osteoporosis, in at least one of the measured bone sites. These data suggest the importance of including biochemical and instrumental monitoring of bone metabolism and bone mass in the routine medical evaluation and follow-up of MEN1 patients and MEN1 carriers as important clinical aspects in the management of the syndrome.

Intermittent injections of parathyroid hormone (PTH) and mechanical loading are both known to effect a net increase in bone mass. Fundamentally, bone metabolism can be divided into modeling (uncoupled formation or resorption) and remodeling (subsequent formation biologically coupled to resorption in space and time). Methods to delineate the bone response between these regimes are scant but have garnered recent attention and acceptance, and will be critical tools to properly assess short- and long-term efficacy of osteoporosis treatments. To this end, we employ a time-lapse micro-computed tomography strategy to quantify and localize modeling and remodeling volumes over 4 weeks of concurrent PTH treatment and mechanical loading. Modeled and remodeled volumes are probed for differences with respect to treatment, loading, and interactions thereof in trabecular and cortical bone compartments, which were further separated by plate/rod microarchitecture and periosteal/endosteal surfaces, respectively. Loading effects are further considered independently with regard to localized strain environments. Our findings indicate that in trabecular bone, PTH and loading stimulate anabolic modeling additively, and remodeling synergistically. PTH tends to lead to bone accumulation indiscriminate of trabecular microarchitecture, whereas loading tends to more strongly affect plates than rods. The cortical surfaces responded uniquely to PTH and loading, with synergistic effects on the periosteal surface for anabolic modeling, and on the endosteal surface for catabolic modeling. The increase in catabolic modeling due to loading, which is enhanced by PTH, is concentrated to areas of the endosteal surface under low strain and to our knowledge has not previously been reported. Taken together, the effects of PTH, loading, and their interactions, are shown to be dependent on the specific bone compartment and metabolic regime; this may explain some discrepancies in previously-reported findings.