Osteocyte-Driven Bone Remodeling

Osteocytes, the most abundant cells in bone, have been long postulated to detect and respond to mechanical and hormonal stimuli and to coordinate the function of osteoblasts and osteoclasts. The discovery that the inhibitor of bone formation sclerostin is primarily expressed in osteocytes in bone and downregulated by anabolic stimuli provided a mechanism by which osteocytes influence the activity of osteoblasts. Advances of the last few years provided experimental evidence demonstrating that osteocytes also participate in the recruitment of osteoclasts and the initiation of bone remodeling. Apoptotic osteocytes trigger yet-to-be-identified signals that attract osteoclast precursors to specific areas of bone, which in turn differentiate to mature, bone-resorbing osteoclasts. Osteocytes are also the source of molecules that regulate the generation and activity of osteoclasts, such as OPG and RANKL; and genetic manipulations of the mouse genome leading to loss or gain of function or to altered expression of either molecule in osteocytes markedly affect bone resorption. This review highlights these investigations and discusses how the novel concept of osteocyte-driven bone resorption and formation impacts our understanding of the mechanisms by which current therapies control bone remodeling.     

Influence of Factors Regulating Bone Formation and Remodeling on Bone Quality in Osteonecrosis of the Femoral Head

Osteonecrosis of the femoral head (ONFH) usually affects young individuals and has a major impact on lifestyle. Notably, the pathogenetic mechanisms of osteonecrosis are unresolved and no effective treatment exists. The objective of this study was to assess the gene expression levels of factors regulating bone formation and remodeling (bone morphogenetic protein [BMP]-2, BMP-7, Runx2, osteocalcin, osteoprotegerin [OPG]) in patients with ONFH and to compare them to those of patients with primary osteoarthritis (OA). The cellular and macromolecular composition of the bone matrix was assessed by osteocalcin immunohistochemistry, and the three-dimensional organization of trabecular bone was characterized by micro-computed tomographic analysis. Our results demonstrate that gene expression of BMP-2, BMP-7, and Runx2 is elevated in patients with ONFH. We observed increased extracellular osteocalcin deposition, presumably caused by a higher number of osteoblasts in concordance with increased activity of Runx2. Constant gene expression level of OPG implies an unchanged osteoclast differentiation rate in ONFH bone. We found no significant change in bone volume, connectivity, and structural model index; further, no significant differences were detected for trabecular properties in ONFH bone. In conclusion, we have shown increased gene expression of factors regulating bone formation and remodeling in the femoral head and/or neck of patients with ONFH. Further, we observed an increase in osteocalcin immunoreactivity and osteoblast/osteocyte cell number, while no significant changes in trabecular microarchitecture were detected. This study increases our understanding of the pathophysiology and repair process following ONFH and might help in the development of new treatment strategies in the future.     

Notch Signaling and Bone Remodeling

Notch signaling plays context-dependent roles in the development and maintenance of many cell types and tissues in mammals. In the skeleton, both osteoblasts and osteoclasts require Notch signaling for proper differentiation and function, and the specific roles of Notch are dependent on the differentiation status of the cell. The recent discovery of activating NOTCH2 mutations as the cause of Hajdu-Cheney syndrome has highlighted the significance of Notch signaling in human bone physiology.     

Surgical Revascularization in Structural Orthotopic Bone Allograft Increases Bone Remodeling

Background

Osseous defects reconstructed with cryopreserved structural allografts are poorly revascularized and therefore are prone to nonunion, infection, deterioration of mechanical properties, and fracture. Whether this can be mitigated by specific interventions such as intramedullary surgical revascularization has been incompletely evaluated.

Questions/purposes

We aimed to study surgical revascularization as a means to improve bone remodeling in cryopreserved allograft. Second, we questioned whether spatial histomorphometric differences occur in cortical bone areas after intramedullary surgical revascularization. Third, biomechanical properties of the graft-recipient construct in surgically revascularized allograft were compared with those of conventional allografts.

Methods

Allografts were harvested from 10 Brown Norway rats, cryopreserved, and transplanted orthotopically in a 10-mm defect in two groups of 10 Lewis rats each (major histocompatibility mismatch). In the control group, no surgical revascularization was performed, whereas in the experimental group, a saphenous arteriovenous bundle was transposed in the bone marrow cavity. Bone remodeling was measured with histomorphometry, histology, and microcomputed tomography at 16 weeks. Spatial differences were analyzed with histomorphometry. To determine biomechanical properties, load at failure and structural stiffness in bending were evaluated by the three-point bend testing. In both groups, normal values of the contralateral femur also were analyzed.

Results

Surgically revascularized allografts had increased bone remodeling (bone formation rate to bone surface ratio: 130 ± 47 µm³/µm²/year versus 44 ± 43 µm³/µm²/year, p = 0.006) and higher cortical osteocyte counts (18.6% ± 12.7% versus 3.1% ± 2.8%, p = 0.002) than nonrevascularized grafts. In nonrevascularized grafts, the bone formation rate to bone surface ratio was 35% of the contralateral normal values, whereas in surgically revascularized grafts, the bone formation rate to bone surface ratio in the grafts exceeded the contralateral values (110%). Microcomputed tomography did not show differences in bone volume between groups, however in both groups, bone volume was less in grafts compared with the contralateral femurs. Inner cortical bone formation rate to bone surface ratio was greater in surgically revascularized grafts (65 ± 30 µm³/µm²/year versus 13 ± 16 µm³/µm²/year in the control group, p = 0.012). Outer cortical bone formation rate to bone surface ratio also increased in surgically revascularized grafts (49 ± 31 µm³/µm²/year versus 19 ± 21 µm³/µm²/year, p = 0.032). No differences were found in load at failure and structural stiffness between both groups. In the control group, load at failure and structural stiffness were lower in grafts than in the contralateral femurs (p = 0.004 and p = 0.02, respectively). In the experimental group, surgically revascularized grafts also had lower load at failure and structural stiffness than the contralateral femurs (p = 0.008 and p = 0.02, respectively).

Conclusions

Surgical revascularization of large segmental allografts improved bone remodeling and viability without an adverse effect on total bone volume or bending strength and stiffness in this short-term analysis.

Clinical Relevance

Cryopreserved allografts remain largely necrotic and are associated with a high rate of complications. Surgical revascularization increases graft healing which could contribute to graft survival with time.     

Inflammatory Mediators as Essential Elements in Bone Remodeling

Inflammatory disorders such as rheumatoid arthritis (RA), may have profound effects on skeletal homeostasis. In contrast to physiologic remodeling in which mechanical influences and/or systemic endocrine hormones initiate the remodeling process, in disorders such as RA the recruitment of macrophage lineage cells to sites of inflammation and the action of local osteoclastogenic cytokines associated with the inflammatory process initiate the remodeling process. In both physiologic and pathologic remodeling, osteoclasts appear to be the principal cell type responsible for the bone resorption. In addition, many of the same cytokines and mediators are involved in physiologic and pathologic bone remodeling. These observations have important implications with respect to the development of therapeutic strategies to prevent bone loss in inflammatory conditions. Abbreviations: rheumatoid arthritis (RA), interleukin-1 and (IL-1 and ), interleukin-6 (IL-6), interleukin-11 (IL-11), interleukin-15 (IL-15), interleukin-17 (IL-17), macrophage-colony stimulating factor (M-CSF), tumor necrosis factor- (TNF-), parathyroid hormone related peptide (PTHrP), receptor activator of NF- (RANK), RANK ligand (RANKL), and osteoprotegerin (OPG)     

Direct Actions of Leptin on Bone Remodeling

Calcified Tissue International -     

Role of Wnt Signaling in Bone Remodeling and Repair

The Wnt genes encode a highly conserved class of signaling factors required for the development of several types of tissues including musculoskeletal and neural structures. There is increasing evidence that Wnt signaling is critical for bone mass accrual, bone remodeling, and fracture repair. Wnt proteins bind to cell-surface receptors and activate signaling pathways which control nuclear gene expression; this Wnt-regulated gene expression controls cell growth and differentiation. Many of the components of the Wnt pathway have recently been characterized, and specific loss-of-function or gain-of-function mutations in this pathway in mice and in humans have resulted in disorders of deficient or excess bone formation, respectively. Pharmacologically targeting components of the Wnt signaling pathway will allow for the manipulation of bone formation and remodeling and will have several orthopedic applications including enhancing bone formation in nonunion and osteoporosis and restricting pathologic bone formation in osteogenic tumors and heterotopic ossification.     

BMP9 Reduces Bone Loss in Ovariectomized Mice by Dual Regulation of Bone Remodeling

Bone remodeling is dynamic and is tightly regulated through bone resorption dominated by osteoclasts and bone formation dominated by osteoblasts. Imbalances in this process can cause various pathological conditions, such as osteoporosis. Bone morphogenetic protein 9 (BMP9), a biomolecule produced and secreted by the liver, has many pharmacological effects, including anti-liver fibrosis, antitumor, anti-heart failure, and antidiabetic activities. However, the effects of BMP9 on the regulation of osteoblast and osteoclast functions and the underlying molecular mechanism(s) have not yet been investigated. In this study, BMP9 increased the expression of osteoblastogenic gene markers, such as ALP, Cola1, OCN, RUNX2, and OSX, and ALP activity in MC3T3-E1 cells by upregulating LGR6 and activating the Wnt/β-catenin pathway. BMP9 also suppressed receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL)-induced osteoclast differentiation of bone marrow macrophages (BMMs) by inhibiting the Akt-NF-κB-NFATc1 pathway. More importantly, in an ovariectomy (OVX) mouse model, BMP9 attenuated bone loss and improved bone biomechanical properties in vivo by increasing bone-forming activity and suppressing bone resorption activity. Accordingly, our current work highlights the dual regulatory effects that BMP9 exerts on bone remodeling by promoting bone anabolic activity and inhibiting osteoclast differentiation in OVX mice. © 2020 American Society for Bone and Mineral Research.     

Mechanical Loading: Bone Remodeling and Cartilage Maintenance

Bone remodeling and cartilage maintenance are strongly influenced by biomechanical signals generated by mechanical loading. Although moderate loading is required to maintain bone mass and cartilage homeostasis, loading can cause deleterious effects such as bone fracture and cartilage degradation. Because a tight coupling exists between cartilage and bone, alterations in one tissue can affect the other. Bone marrow lesions are often associated with an increased risk of developing cartilage defects, and changes in the articular cartilage integrity are linked to remodeling responses in the underlying bone. Although mechanisms regulating the maintenance of these two tissues are different, compelling evidence indicates that the signal pathways crosstalk, particularly with the Wnt pathway. A better understanding of the complex tempero-spatial interplay between bone remodeling and cartilage degeneration will help develop a therapeutic loading strategy that prevents bone loss and cartilage degeneration.     

Tubular Remodeling of Massive Cancellous Bone Graft in the Treatment of Long Bone Defects

Abstract Background: This case report describes the clinical and radiological result at the 4.5-year follow-up after an extensive reconstruction of the femoral diaphysis using autologous cancellous bone graft. The radiological study including axial tomography demonstrates secondary remodelling to form tubular diaphyseal bone. Methods: A patient with an existing hip fusion, who sustained a fracture of the proximal femur 12 years later, was treated by open internal fixation using a plate and screws. Infection followed which became chronic, causing bone resorption and necrosis and producing a septic non-union. Reconstruction in two stages was performed: open radical debridement which ended with a 14.5 cm diaphyseal defect of the femur, temporary alloplastic spacer interposition and secondary de-arthrodesis of the hip with massive autologous cancellous grafts into the induced foreign body membrane left by the spacer. Fixation was provided by a plate and screws. Results: The femur was free of infectious recurrence at 4.5 years. The patient walks without crutches with a shortened lower limb using a leg length compensation shoe and a painfree sine-sine hip arthroplasty. The former bone defect is fully remodelled into new cortical bone. X-ray and CT-scan demonstrate the tubular form of the reconstructed bone. Conclusion: This clinical case demonstrates the restoration of a medullar cavity after massive cancellous bone grafting of a diaphyseal defect of the femur. The question remains open as to whether the foreign body membrane has only a simple passive protective function against extraosseous bone resorbing factors or whether it functions actively by producing growth factors or other beneficial bone inducing factors.     

Intracortical Bone Remodeling Variation Shows Strong Genetic Effects

Intracortical microstructure influences crack propagation and arrest within bone cortex. Genetic variation in intracortical remodeling may contribute to mechanical integrity and, therefore, fracture risk. Our aim was to determine the degree to which normal population-level variation in intracortical microstructure is due to genetic variation. We examined right femurs from 101 baboons (74 females, 27 males; aged 7–33 years) from a single, extended pedigree to determine osteon number, osteon area (On.Ar), haversian canal area, osteon population density, percent osteonal bone (%On.B), wall thickness (W.Th), and cortical porosity (Ct.Po). Through evaluation of the covariance in intracortical properties between pairs of relatives, we quantified the contribution of additive genetic effects (heritability [h ²]) to variation in these traits using a variance decomposition approach. Significant age and sex effects account for 9 % (Ct.Po) to 21 % (W.Th) of intracortical microstructural variation. After accounting for age and sex, significant genetic effects are evident for On.Ar (h ² = 0.79, p = 0.002), %On.B (h ² = 0.82, p = 0.003), and W.Th (h ² = 0.61, p = 0.013), indicating that 61–82 % of the residual variation (after accounting for age and sex effects) is due to additive genetic effects. This corresponds to 48–75 % of the total phenotypic variance. Our results demonstrate that normal, population-level variation in cortical microstructure is significantly influenced by genes. As a critical mediator of crack behavior in bone cortex, intracortical microstructural variation provides another mechanism through which genetic variation may affect fracture risk.     

Bone Remodeling Around Porous Metal Cementless Acetabular Components

Bone remodeling around cementless acetabular components after total hip arthroplasty has not been well characterized. A randomized, prospective study of total hip arthroplasty was performed comparing 2 cementless acetabular implants: a solid titanium and a more elastic porous tantalum design. Seventeen hips (9 porous tantalum, 8 titanium) underwent quantitative computed tomography at mean of 7.7 years, and adjacent bone mineral density (BMD) was calculated. The absolute and relative decrease in BMD from preoperative level was less in zones 9 to 15 mm adjacent to the porous tantalum compared to the titanium component (P ≤ .02) and predominated posterosuperiorly. The relative BMD increased in all regions adjacent to the porous tantalum component from 5% to 40% over the control. This data demonstrates stress-shielding likely occurs less around a highly porous metal implant of material with an elastic modulus similar to bone.     

Bone Remodeling and Hydroxyapatite Resorption in Coated Primary Hip Prostheses

Hydroxyapatite coatings for THA promote bone ongrowth, but bone and coating are exposed to stress shielding-driven osteoclastic resorption. We asked: (1) if the resorption of hydroxyapatite coating and bone ongrowth correlated with demographics; (2) if the resorption related to the stem level; and (3) what happens to the implant-bone interface when all hydroxyapatite coating is resorbed? We recovered 13 femoral components from cadaveric specimens 3.3 to 11.2 years after uneventful primary THA. Three cross sections (proximal, medial, distal) of the hydroxyapatite-coated proximal implant sleeve were analyzed by measuring the percentage of residual hydroxyapatite and bone ongrowth on the implant perimeter. Hydroxyapatite resorption was independent of patient age but increased with time in vivo and mostly was gone after 8 years. Bone ongrowth was independent of time in vivo but decreased with aging patients. Only in the most proximal section did less residual hydroxyapatite correlate with less bone ongrowth. Hydroxyapatite resorption, which was more proximal than distal, showed no adverse effects on the implant-bone interface.     

Low-Magnitude Forces for Bone Modeling and Remodeling in Dentofacial Orthopedics

Purpose of Review

To examine the evidence in support of light continuous forces for enhancing bone adaptation (modeling and remodeling) in orthodontics and dentofacial orthopedics.

Recent Findings

Clinical evidence suggests that light continuous orthodontic force can achieve physiologic expansion of the maxillary arch, but the long-term stability and the biological effects of the procedure are unclear. Compared to conventional orthodontic appliances that deliver heavy interrupted forces for tooth movement, the application of low-magnitude forces in animal models leads to anabolic modeling and remodeling of the alveolar bone in the path of orthodontic tooth movement. This results in dental translation and expansion of the alveolar process.

Summary

Light continuous forces are preferable to heavy forces for more physiologic dentofacial orthopedics. The interaction of low-magnitude loads with soft tissue posture achieves therapeutic adaptation of the craniofacial skeleton. The increasing emphasis on genomic medicine and personalized treatment planning should focus on low-magnitude loads in orthodontics and dentofacial orthopedics.

     

Effects of Exercise Training on Bone Remodeling,Insulin-Like Growth Factors,and Bone Mineral Density in Postmenopausal Women With and Without Hormone Replacement Therapy

The purpose of this study was to determine the effects of 12 months of weight bearing and resistance exercise on bone mineral density (BMD) and bone remodeling (bone formation and bone resorption) in 2 groups of postmenopausal women either with or without hormone replacement therapy (HRT). Secondary aims were to characterize the changes in insulin-like growth factors-1 and -2 (IGF-1 and -2) and IGF binding protein 3 (IGFBP3) in response to exercise training. Women who were 3-10 years postmenopausal (aged 40-65 years) were included in the study. Women in the HRT and no HRT groups were randomized into the exercise intervention, resulting in four groups: (1) women not taking HRT, not exercising; (2) those taking HRT, not exercising; (3) those exercising, not taking HRT; and (4) women exercising, taking HRT. The number of subjects per group after 1 year was 27, 21, 25, and 17, respectively. HRT increased BMD at most sites whereas the combination of exercise and HRT produced increases in BMD greater than either treatment alone. Exercise training alone resulted in modest site-specific increases in BMD. Bone remodeling was suppressed in the groups taking HRT regardless of exercise status. The bone remodeling response to exercise training in women not taking HRT was not significantly different from those not exercising. However, the direction of change suggests an elevation in bone remodeling in response to exercise training, a phenomenon usually associated with bone loss. No training-induced differences in IGF-1, IGF-2, IGF-l:IGF-2 (IGF-1 : IGF-2), and IGFBP3 were detected.     

The Effect of Fluvastatin on Parameters of Bone Remodeling

Statins decrease the hepatic biosynthesis of cholesterol, and reduce the incidence of myocardial infarction in women who have already experienced a myocardial infarction. Statins also reduce the risk of atherosclerosis in diabetic patients, but it is unknown whether they influence the glucose tolerance. It has further been suggested that they may influence bone metabolism. Vitamin C is an antioxidant and it decreases serum cholesterol moderately. Antioxidants may also have other metabolic effects, but these are insufficiently studied. The aim of the present study was to investigate the metabolic effects of the cholesterol-lowering agent fluvastatin and the antioxidant vitamin C. Sixty-eight elderly, postmenopausal women with osteoporosis and mild hypercholesterolemia were randomly assigned to 12 weeks open treatment with either fluvastatin (40 mg daily) + 500 mg vitamin C (n = 45) or vitamin C only (n = 23). We measured biochemical markers of bone formation (serum osteocalcin and total alkaline phosphatase) and bone resorption (serum and urinary CTX), parameters related to diabetes and serum lipids and lipoproteins. Fluvastatin in combination with vitamin C had no effect on bone formation markers. We found a weak decrease in parameters of bone resorption, which was significant from baseline, but not different between the two groups. There were no significant effects on any of the other markers of either fluvastatin or vitamin C. The lipid-lowering effect of fluvastatin was confirmed with a decrease of 20% and 30% in serum total cholesterol and LDL-cholesterol, respectively. We conclude that fluvastatin given in clinically relevant doses has no influence on parameters of bone remodeling. Other statins remain to be investigated. Received: 6 June 2000 / Accepted: 4 December 2000     

New Suggestions for the Mechanical Control of Bone Remodeling

Bone is constantly renewed over our lifetime through the process of bone (re)modeling. This process is important for bone to allow it to adapt to its mechanical environment and to repair damage from everyday life. Adaptation is thought to occur through the mechanosensitive response controlling the bone-forming and -resorbing cells. This report shows a way to extract quantitative information about the way remodeling is controlled using computer simulations. Bone resorption and deposition are described as two separate stochastic processes, during which a discrete bone packet is removed or deposited from the bone surface. The responses of the bone-forming and -resorbing cells to local mechanical stimuli are described by phenomenological remodeling rules. Our strategy was to test different remodeling rules and to evaluate the time evolution of the trabecular architecture in comparison to what is known from μ-CT measurements of real bone. In particular, we tested the reaction of virtual bone to standard therapeutic strategies for the prevention of bone deterioration, i.e., physical activity and medications to reduce bone resorption. Insensitivity of the bone volume fraction to reductions in bone resorption was observed in the simulations only for a remodeling rule including an activation barrier for the mechanical stimulus above which bone deposition is switched on. This is in disagreement with the commonly used rules having a so-called lazy zone. J. W. C. Dunlop and M. A. Hartmann contributed equally to this research.     

Periosteal PTHrP Regulates Cortical Bone Remodeling During Fracture Healing

Parathyroid hormone-related protein (PTHrP) is widely expressed in the fibrous outer layer of the periosteum (PO), and the PTH/PTHrP type I receptor (PTHR1) is expressed in the inner PO cambial layer. The cambial layer gives rise to the PO osteoblasts (OBs) and osteoclasts (OCs) that model/remodel the cortical bone surface during development as well as during fracture healing. PTHrP has been implicated in the regulation of PO modeling during development, but nothing is known as regards a role of PTHrP in this location during fracture healing.We propose that PTHrP in the fibrous layer of the PO may be a key regulatory factor in remodeling bone formation during fracture repair. We first assessed whether PTHrP expression in the fibrous PO is associated with PO osteoblast induction in the subjacent cambial PO using a tibial fracture model in PTHrP-lacZ mice. Our results revealed that both PTHrP expression and osteoblast induction in PO were induced 3 days post-fracture. We then investigated a potential functional role of PO PTHrP during fracture repair by performing tibial fracture surgery in 10-week-old CD1 control and PTHrP conditional knockout (PTHrP cKO) mice that lack PO PTHrP. We found that callus size and formation as well as woven bone mineralization in PTHrP cKO mice were impaired compared to that in CD1 mice. Concordant with these findings, functional enzyme staining revealed impaired OB formation and OC activity in the cKO mice.We conclude that deleting PO PTHrP impairs cartilaginous callus formation, maturation and ossification as well as remodeling during fracture healing. These data are the initial genetic evidence suggesting that PO PTHrP may induce osteoblastic activity and regulate fracture healing on the cortical bone surface.     

Effects of Uremic Toxins on Vascular and Bone Remodeling

Chronic kidney disease (CKD) is associated with both extensive vascular calcification and abnormal bone remodeling, namely renal osteodystrophy. Moreover, there is increasing evidence for a close relationship between bone and vessel function. Pathological vascular calcification has been recently recognized as an active, cell-mediated process with similarities to physiological skeletal mineralization. Accordingly, we described the concept of vascular remodeling, in analogy to bone remodeling. In this review, we discuss the role of uremic toxins in the cross-talk between bone and vessel, and emphasize their potential contribution to the development of both vascular and bone remodeling disorders in patients with CKD.