Histochemical characteristics on minimodeling-based bone formation induced by anabolic drugs for osteoporotic treatment
Tomomaya YamamotoTomoka HasegawaPaulo Henrique Luiz de FraitasHiromi HongoShen ZhaoTsuneyuki YamamotoAlireza NasooriMiki AbeHaruhi MaruokaKeisuke KubotaYasuhito MORIMOTOMai HaraguchiTomohiro ShimizuMasahiko TakahataNorimasa IwasakiMinqi LiNorio Amizuka
6
Citation
40
Reference
10
Related Paper
Citation Trend
Abstract:
Modeling, the changes of bone size and shape, often takes place at the developmental stages, whereas bone remodeling-replacing old bone with new bone-predominantly occurs in adults. Unlike bone remodeling, bone formation induced by modeling i.e., minimodeling (microscopic modeling in cancellous bone) is independent of osteoclastic bone resorption. Although recently-developed drugs for osteoporotic treatment could induce minimodeling-based bone formation in addition to remodeling-based bone formation, few reports have demonstrated the histological aspects of minimodeling-based bone formation. After administration of eldecalcitol or romosozumab, unlike teriparatide treatment, mature osteoblasts formed new bone by minimodeling, without developing thick preosteoblastic layers. The histological characteristics of minimodeling-based bone formation is quite different from remodeling, as it is not related to osteoclastic bone resorption, resulting in convex-shaped new bone and smooth cement lines called arrest lines. In this review, we will show histological properties of minimodeling-based bone formation by osteoporotic drugs.Keywords:
Bone remodeling
Bone remodeling period
Bone Formation
Cancellous bone
Teriparatide
Bone cell
Osteon
Bone remodeling
Bone cell
Bone Formation
Bone remodeling period
Apposition
Cite
Citations (2)
Teriparatide (TPTD) is the only currently available therapeutic agent that increases the formation of new bone tissue and can provide some remediation of the architectural defects in the osteoporotic skeleton. The use of teriparatide clinically is limited to 24 months. We review clinical findings during daily teriparatide treatment over time. Teriparatide appears to increase bone formation more than bone resorption as determined biochemically and histologically. Teriparatide exerts its positive effects on bone formation in two distinct fashions. The first is direct stimulation of bone formation that occurs within active remodeling sites (remodeling-based bone formation) and on surfaces of bone previously inactive (modeling-based bone formation). The second is an increase in the initiation of new remodeling sites. Both processes contribute to the final increase in bone density observed by non-invasive tools such as DXA. Remodeling is the repair process by which skeletal tissue is maintained in a young healthy state, and when stimulated by TPTD is associated with a positive bone balance within each remodeling cavity. It seems likely therefore that this component will contribute to the anti-fracture efficacy of TPTD. Teriparatide reduces the risk of fracture, and this effect appears to increase with longer duration of therapy. The use of novel treatment regimens, including shorter courses, should be held in abeyance until controlled clinical trials are completed to define the relative fracture benefits of such approaches in comparison to the 24-month daily use of the agent. Summary In patients with osteoporosis at high risk for fracture, the full continuous 24-month course with teriparatide results in improved skeletal health and outcomes than shorter time periods.
Teriparatide
Bone remodeling
Bone Formation
Bone tissue
Cite
Citations (170)
Calcium intake shows a small impact on bone mineral density and fracture risk. Denosumab is a more potent inhibitor of bone resorption than zoledronate. Abaloparatide, PTHrP analog, increases bone mineral density and decreases fracture incidence. Teriparatide could be delivered via a transdermic device. Romosozumab and odanacatib improve calculated bone strength. Sequential or combined treatments with denosumab and teriparatide could be of interest, but not denosumab followed by teriparatide. Fibrous dysplasia, Paget disease and hypophosphatasia are updated, as well as atypical femoral fracture and osteonecrosis of the jaw.
Teriparatide
Denosumab
Sclerostin
Cite
Citations (0)
Bone tissue is continuously remodeled through the concerted actions of bone cells, which include bone resorption by osteoclasts and bone formation by osteoblasts, whereas osteocytes act as mechanosensors and orchestrators of the bone remodeling process. This process is under the control of local (e.g., growth factors and cytokines) and systemic (e.g., calcitonin and estrogens) factors that all together contribute for bone homeostasis. An imbalance between bone resorption and formation can result in bone diseases including osteoporosis. Recently, it has been recognized that, during bone remodeling, there are an intricate communication among bone cells. For instance, the coupling from bone resorption to bone formation is achieved by interaction between osteoclasts and osteoblasts. Moreover, osteocytes produce factors that influence osteoblast and osteoclast activities, whereas osteocyte apoptosis is followed by osteoclastic bone resorption. The increasing knowledge about the structure and functions of bone cells contributed to a better understanding of bone biology. It has been suggested that there is a complex communication between bone cells and other organs, indicating the dynamic nature of bone tissue. In this review, we discuss the current data about the structure and functions of bone cells and the factors that influence bone remodeling.
Bone remodeling period
Osteocyte
Bone remodeling
Bone cell
Bone tissue
Cite
Citations (1,637)
Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
Teriparatide
Zoledronic Acid
Cite
Citations (0)
PTH (1-34) daily subcutaneous injection is a bone anabolic agent. It has already been approved in more than 80 countries over the world (including Europe and United States) and in Japan on Jul 2010. The number of patients treated with this agent is more than 20 thousand in Japan and about one million over the world. In nonclinical studies, teriparatide was shown to have a unique bone formation-stimulating effect not seen in existing drugs. In domestic and overseas clinical studies, teriparatide was shown to have strong effects in increasing BMD, promoting remodeling of bone microstructure and suppressing the onset of fracture. Furthermore, it can increase BMD through stimulation of bone formation regardless of the nature of prior treatment or the presence/absence of responses to prior treatment. With these features, teriparatide is expected to serve as a first-line drug for management of patients with osteoporosis at high risk for fracture.
Teriparatide
Bone Formation
Subcutaneous injection
Cite
Citations (1)
Bone remodeling
Bone remodeling period
Bone cell
Bone Formation
Cite
Citations (299)
Bone is remodelled by the coordinated actions of osteoclasts and osteoblasts. Cellular remodelling occurs in discrete packets of bone, and is regulated by local cytokines produced in the environment of the remodelling cells. These cytokines are secreted by immune cells and by bone cells. In addition, some growth regulatory factors are incorporated into the noncollagenous bone matrix and are released in an active form when bone is stimulated to resorb. Complex interactions between these cytokines and their target cells are responsible for the normal delicate balance between bone resorption and bone formation, and disorders of bone loss are due to imbalances between the rates of resorption and formation.
Bone remodeling
Bone remodeling period
Bone cell
Bone matrix
Osteoimmunology
Bone Formation
Proinflammatory cytokine
Cite
Citations (114)
Our concepts of the cellular events in bone remodeling began in the 1960s with Harold Frost, who described remodeling as a destructive process, wrought by osteoclasts that resorb bone, followed by a productive process ascribed to osteoblasts that form bone.1 To replace old or damaged bone, bone remodeling takes place asynchronously throughout the skeleton in bone multicellular units (BMUs). An essential feature of the process is that at each BMU, equal volumes of bone are removed by osteoclasts and replaced by osteoblasts.2-4 Just as osteoblastic lineage cells control osteoclast formation, so too it seemed likely that either the products of bone resorption or products of the osteoclasts themselves promote osteoblast differentiation from precursors in the BMU and, hence, bone formation. It is the latter communication mechanism that is referred to as "coupling." This term is confined to events taking place within individual BMUs throughout the skeleton; at each BMU the volume of bone removed by resorption is approximately equaled by that replaced by formation. On the other hand, the overall "balance" of bone resorption and formation—the close matching of the whole body rates of these two5—represents the summation of the contributions from BMUs throughout the body, where many BMUs are at different stages of maturation. Thus, "coupling" should not be applied as a descriptive term to that overall bone balance. The focus of interest on this topic has led to experiments giving rise to a number of "candidate" coupling factors, a further one provided in this issue of JBMR by Matsuoka and colleagues,6 who propose that complement factor 3a, the active cleavage product of complement component 3 (C3), is released from active osteoclasts and promotes osteoblast differentiation and bone formation. Treatment of mouse calvarial osteoblasts in culture with concentrated conditioned medium from osteoclast cultures resulted in dose-dependent increase in alkaline phosphatase (ALP) activity and increased mineralization when the cells were grown under appropriate conditions. Because the activity appeared to be protein in nature, purification was approached using three successive ion exchange chromatography steps. In monitoring purification, they used stimulation of ALP activity in calvarial osteoblasts, the highest activity fraction after purification containing a number of peptide sequences. Among these, the authors identified complement component 3 and used an ELISA with conditioned medium to identify its bioactive cleavage product, C3a. C3a was not detected in conditioned medium from bone marrow macrophages but increased with differentiation to osteoclasts, and its Gi-coupled G-protein receptor, C3aR, was expressed in stromal cell lines and mouse calvarial osteoblasts. The failure to find C3a in bone marrow-derived macrophage (BMM) conditioned medium in the present experiments is surprising, given the substantial production of complement by other macrophage populations. A C3aR antagonist inhibited the promotion of ALP in calvarial osteoblasts by conditioned medium, and knockdown of C3 in osteoclasts by lentiviral shRNA expression ablated the activity in conditioned medium, whereas a C3aR agonist drug promoted ALP activity in calvarial osteoblast cultures. In in vivo experiments, bone and bone marrow C3 mRNA were significantly increased 4 days after ovariectomy (OVX) in mice, and in marrow after receptor activator of NF-κB ligand (RANKL) treatment in vivo. In mice examined 14 days after OVX, the bone formation and mineral apposition rates were significantly greater than those in sham-operated mice or in those treated from day 6 with the C3aR antagonist, SB290157. The latter treatment also significantly enhanced the post-OVX bone loss, as determined by micro-CT. The interpretation of these data was that osteoclast C3a production increased after OVX, acting through the C3aR to promote bone formation. The in vivo data rely on a small albeit statistically significant difference in the two bone formation parameters. The data would have benefited from a more thorough analysis, including the provision of quantitative osteoclast data. Because there is much more to osteoblast differentiation than a change in ALP at a particular stage, it would be important also to consider other differentiation parameters, rather than relying solely upon promotion of ALP activity in purification and even in assessing the importance of C3a. For the latter, among the many outstanding questions are: What other osteoblast lineage genes are affected by actions through the C3aR in osteoblasts and at what stage of osteoblast differentiation does C3aR optimally act? Because the macrophage is such a prominent target of C3a action, is C3aR mRNA so evident in calvarial osteoblasts because of the macrophage content of mouse calvarial cultures?7 Macrophage-mediated actions of C3a need to be considered in both the in vitro and in vivo experiments of the present work, in view of the known activation through Ca3R in monocytes and macrophages of mediators such as IL-1β through participation of Toll-like receptor and ATP-mediated P2X purinoreceptor (P2 × 7) signals in monocytes and macrophages.8, 9 Further, the fact that C3a circulates in such substantial amounts (approximately 50 ng/mL in human serum)10 might call into question a role for C3a only at selected sites in the skeleton as they undergo remodeling. The same research group suggested in a recent report that collagen triple helix repeat containing 1 (CTHRC1) is a coupling factor by virtue of its production by actively resorbing osteoclasts and the fact that it stimulated bone formation in vitro and in vivo.11 The conclusion from that work, based on in situ hybridization, was that CTHRC1 was not produced by osteoblasts, but by chondrocytes in the embryo, as well as at the growth plate until 3 months of age. In contrast, Kimura and colleagues12 found CTHRC1 to be a product of the osteoblast lineage, including mesenchymal precursors, that markedly stimulates bone formation. Reconciliation of these discrepant findings will require careful cellular localization studies to establish whether CTHRC acts as an osteoclast product or a signal within the osteoblast lineage. Either way, it could be a participant in local events that contribute to the overall bone remodeling process, whether strictly as one of a number of coupling factors or not. The proposal some decades ago of TGFβ and IGF-1 as coupling agents13, 14 has gained recent support from mouse genetic experiments,15, 16 but there is much emphasis now on the search for osteoclast-derived control of coupling.17 When osteoclast conditioned medium stimulated mesenchymal stem cell migration and osteoblastic differentiation, Pedersen and colleagues18 undertook a microarray study that led them to identify sphingosine-1-phosphate (S1P), Wnt 10b, and BMP6 as osteoclast products that might be coupling factors. Whether important as an osteoclast product or not, Wnt10b has been invoked in another context as a T-cell–derived mediator of the anabolic effect of parathyroid hormone (PTH).19 The roles of the sphingosine kinase product, S1P, in bone are complex. It can have inhibitory or stimulatory effects on osteoblasts depending on the stage of cell differentiation and on the source of precursors,18, 20, 21 can limit bone resorption by increasing recirculation of osteoclast precursors from bone to blood,22 and can promote osteoprotegerin production by osteoblasts.23 Data more encouraging of S1P as a coupling agent showed that catK null osteoclasts, with impaired resorption, were nevertheless able to promote aspects of osteoblast differentiation in co-culture, an effect inhibited by S1P receptor antagonist.24 In addition to osteoblast stimulators from osteoclasts, semaphorin 4D was found as an osteoclast product that inhibits osteoblast differentiation and bone formation.25 In addition to such secreted positive and negative regulators of coupling, membrane activities have been invoked, including ephrinB2, membrane-bound in the mature osteoclast, and suggested to act on its receptor, EphB4, in the osteoblast lineage to promote differentiation, a process that would require cell contact.26 Such contact would also be required to support the hypothesized role of RANK driving reverse signaling through RANKL in the osteoblast lineage.27 These and other "candidates" are considered in more detail in recent reviews that highlight the complexity of coupling in the BMU, including the likely contribution of products of cells other than osteoclasts.28, 29 How many candidates can there be? It seems likely that there are many factors derived from matrix and cells in the BMU—not only osteoclasts, but T cells, macrophages, and osteoblasts themselves—that contribute to some extent to the process of coupling. The likelihood of finding a dominant, single factor analogous to RANKL in promotion of osteoclasts seems remote. The precision in time and space required to program osteoblast lineage cells in the BMU likely requires a number of local factors acting at different stages of osteoblast differentiation. No studies so far address this question: At what stages of osteoblast differentiation do "candidate" coupling factors exert their actions, and what are those actions? Most of the candidate coupling factors have been arrived at through in vitro studies of osteoblast cells at particular stages of differentiation or occasionally ex vivo studies on cells from genetically manipulated mice. As can be said of most—or even all—of the other candidate coupling factors so far, there are aspects of interest in the present work,6 but more would be required to be convincing of a critical role for C3a in remodeling within the BMU and how it might operate. The work provides another link with the immune system and even with inflammation, something that might not necessarily be so surprising. In describing bone remodeling, Frost likened it to the healing of a soft tissue wound, an event associated with the release of inflammatory mediators,1 and certain similarities have been pointed out between bone remodeling and inflammation.30 The biological effects of activated complement result from the release of cytokine signals from macrophages, T cells, and dendritic cells. C3a leads to inflammation by amplifying the immune response31 in asthma, sepsis, liver regeneration, and autoimmune encephalomyelitis.31, 32 Mice null for the C3aR gene had a marked reduction in macrophage content of adipose tissue, reduced adiposity, and enhanced insulin sensitivity.33 Any possible contribution of activated complement to enhanced osteoblast differentiation in the cellular events in remodeling in the BMU should take into account the participation of other cells. The author states that he has no conflicts of interest. The author acknowledges support from the National Health and Medical Research Council, Australia, and the Victorian Government OIS Program to St. Vincent's Institute of Medical Research.
Bone remodeling period
Bone remodeling
Bone cell
Bone Formation
Skeleton (computer programming)
Cite
Citations (16)
Osteogenesis imperfecta (OI) is a generalised connective tissue disorder associated with low bone mass, bone fragility and increased susceptibility to fractures. First-line treatment to improve bone mineral density (BMD) is usually with bisphosphonates but long-term usage has been associated with uncommon complications such as atypical femoral fractures (AFF). Treatment with teriparatide in this situation has been reported with positive outcomes. However, choice of treatment after 2 years of teriparatide has not been well studied or reported. We describe a patient with OI treated with bisphosphonates for 9 years, who then suffered a spontaneous AFF, was subsequently started on teriparatide for 2 years followed by 6 monthly Denosumab. 1 year post-treatment with Denosumab, there was significant improvement in BMD, good fracture healing and no new fractures. This case highlights the potential use of denosumab following 2 years of teriparatide treatment in patients with OI with AFF.
Teriparatide
Denosumab
Cite
Citations (5)