Anti-sclerostin Monoclonal Antibody Research Articles

Influence of anti-sclerostin monoclonal antibody in the repair of post-extraction sockets of ovariectomized rats

ObjectiveThis study assessed the impact of an anti-sclerostin monoclonal antibody (Scl-Ab)-based osteoporosis drug on the post-extraction alveolar repair of ovariectomized rats. DesignFifteen female rats were randomly distributed into three groups: CTR (healthy animals), OST (osteoporosis induced by ovariectomy), and OST+Scl-Ab (osteoporosis induction followed by Scl-Ab treatment). Ovariectomy or sham surgery was performed 30 days before baseline, and Scl-Ab or a vehicle was administered accordingly in the groups. After seven days, all rats underwent the first lower molar extraction and were euthanized 15 days later. Computed microtomography, histological analysis, and collagen content measurement were performed on post-extraction sockets and intact mandibular and maxillary bone areas. ResultsMicrotomographic analyses of the sockets and mandibles did not reveal significant differences between groups on bone morphometric parameters (p > 0.05), while maxillary bone analyses resulted in better maintenance of bone architecture in OST+Scl-Ab, compared to OST (p < 0.05). Descriptive histological analysis and polarization microscopy indicated better post-extraction socket repair characteristics and collagen content in OST+Scl-Ab compared to OST (p < 0.05). ConclusionsScl-Ab-based medication did not accelerate alveolar bone formation but exhibited better post-extraction repair characteristics, and collagen content compared to ovariectomized animals only.

Glucocorticoid-Induced Osteoporosis: The Potential Role of Romosozumab

Glucocorticoid (GC)-induced osteoporosis (GIOP) is a major problem in patients with rheumatic diseases. The deleterious effect of GC on bone turnover is rapid and dose-dependent, with a predilection on the trabecular bone, resulting in vertebral fractures. Early recognition and prompt treatment of GIOP helps prevent bone loss and reduce fractures. There are pitfalls in current assessment tools for GIOP by dual-energy X-ray absorptiometry (DXA) and fracture risk assessment tool (FRAX) estimation formula. In this review, we evaluate different assessment methods for GIOP and summarize current therapies of GIOP, including the antiresorptive and anabolic agents. The potential role of newer anti-osteoporosis agent romosozumab, an anti-sclerostin monoclonal antibody, is also discussed.

Development of cyclic peptides with potent in vivo osteogenic activity through RaPID-based affinity maturation

Osteoporosis is caused by a disequilibrium between bone resorption and bone formation. Therapeutics for osteoporosis can be divided into antiresorptives that suppress bone resorption and anabolics which increase bone formation. Currently, the only anabolic treatment options are parathyroid hormone mimetics or an anti-sclerostin monoclonal antibody. With the current global increases in demographics at risk for osteoporosis, development of therapeutics that elicit anabolic activity through alternative mechanisms is imperative. Blockade of the PlexinB1 and Semaphorin4D interaction on osteoblasts has been shown to be a promising mechanism to increase bone formation. Here we report the discovery of cyclic peptides by a novel RaPID (Random nonstandard Peptides Integrated Discovery) system-based affinity maturation methodology that generated the peptide PB1m6A9 which binds with high affinity to both human and mouse PlexinB1. The chemically dimerized peptide, PB1d6A9, showed potent inhibition of PlexinB1 signaling in mouse primary osteoblast cultures, resulting in significant enhancement of bone formation even compared to non-Semaphorin4D-treated controls. This high anabolic activity was also observed in vivo when the lipidated PB1d6A9 (PB1d6A9-Pal) was intravenously administered once weekly to ovariectomized mice, leading to complete rescue of bone loss. The potent osteogenic properties of this peptide shows great promise as an addition to the current anabolic treatment options for bone diseases such as osteoporosis.

Liquid chromatography-mass spectrometry method for the quantification of an anti-sclerostin monoclonal antibody in cynomolgus monkey serum

Liquid chromatography tandem mass spectrometry (LC-MS/MS) has gradually become a promising alternative to ligand binding assay for the bioanalysis of biotherapeutic molecules, due to its rapid method development and high accuracy. In this study, we established a new LC-MS/MS method for the determination of the anti-sclerostin monoclonal antibody (SHR-1222) in cynomolgus monkey serum, and compared it to a previous electrochemiluminescence method. The antibody was quantified by detecting the surrogate peptide obtained by trypsin digestion. The surrogate peptide was carefully selected by investigating its uniqueness, stability and MS response. The quantitative range of the proposed method was 2.00–500 μg/mL, and this verified method was successfully applied to the toxicokinetic assessment of SHR-1222 in cynomolgus monkey serum. It was found that the concentrations of SHR-1222 in cynomolgus monkeys displayed an excellent agreement between the LC-MS/MS and electrochemiluminescence methods (ratios of drug exposure, 0.8–1.0). Notably, two monkeys in the 60 mg/kg dose group had abnormal profiles with a low detection value of SHR-1222 in their individual sample. Combining the high-level anti-drug antibodies (ADAs) in these samples and the consistent quantitative results of the two methods, we found that the decreased concentration of SHR-1222 was due to the accelerated clearance mediated by ADAs rather than the interference of ADAs to the detection platform. Taken together, we successfully developed an accurate, efficient and cost-effective LC-MS/MS method for the quantification of SHR-1222 in serum samples, which could serve as a powerful tool to improve the preclinical development of antibody drugs.

Laser irradiation decreases sclerostin expression in bone and osteogenic cells.

Anti-sclerostin monoclonal antibody romosozumab, a treatment for osteoporosis, reduced vertebral fracture risk and clinical fracture. Laser irradiation triggers various effects, including bio-stimulation, which can induce beneficial therapeutic effects and biological responses. Originally, we performed in vivo experiments to clarify the mechanism of better bone healing in laser-ablated bone. Here, we evaluated comprehensive and sequential gene expression in Er:YAG laser-ablated, bur-drilled, and nontreated control bones, and found laser irradiation suppressed Sost (coding protein: sclerostin) expression in the bone, possibly via stimulation of mechanotransducers. Surprisingly, bio-stimulation effect of laser suppressed Sost expression in the primary osteogenic cells. Decreased sclerostin expression after laser irradiation was also validated both in vivo and in vitro. In addition, sequential microarray analysis revealed that the gene expression pattern was clearly different at 24hours after bone ablation between bur-drilled and laser-ablated bones. The Hippo signaling pathway was significantly enriched, whereas inflammation-related pathways were not affected at 6hours after the laser ablation, indicating that laser irradiation caused mechanical stimulation. Only bur-drilled bone showed enriched inflammation-related gene sets and pathways at 24hours, not in the laser-ablated bone. Our study suggests that laser irradiation may become a new treatment modality for osteoporosis, by inhibiting sclerostin expression without inducing inflammation.

New Frontiers in Osteoporosis Therapy

Current osteoporosis medications reduce fractures significantly but have rare and serious adverse effects (osteonecrosis of the jaw, atypical femoral fractures) that may limit their safety for long-term use. Insights from basic bone biology and genetic disorders have led to recent advances in therapeutics for osteoporosis. New approaches now in clinical use include the antisclerostin monoclonal antibody romosozumab, as well as the parathyroid hormone-related peptide analog abaloparatide. Clinical trial data show significant antifracture benefits with recently approved romosozumab. Studies using abaloparatide build on our longstanding experience with teriparatide and the importance of consolidating the bone mineral density gains achieved from an anabolic agent by following it with an antiresorptive. Combination and sequential treatments using osteoporosis medications with different mechanisms of action have also been tested with promising results. On the horizon is the potential for cell-based therapies (e.g., mesenchymal stem cells) and drugs that target the elimination of senescent cells in the bone microenvironment.

Sequential treatment of osteoporosis with anti-sclerostin.

Romosozumab is a humanized anti-sclerostin monoclonal antibody that has just been approved for the treatment of osteoporosis in Japan. Romosozumab causes both transient stimulation of bone formation and continuous suppression of resorption, thereby increasing bone mineral density and decreasing fracture incidence. Because the effect of romosozumab is reversible, sequential therapy with anti-resorptives after romosozumab will be necessary. This overview summarizes the results of ARCH study demonstrating superior efficacy of romosozumab compared to alendronate and effect of sequential therapy with alendronate. Possible adverse effect of romosozumab on cardiovascular diseases will also be discussed.

Inhibitors of sclerostin: emerging concepts.

Recent data suggest that inhibitors of sclerostin, an osteocyte-produced Wnt signaling pathway antagonist, can stimulate bone formation. This review provides rationale and summarizes recent evidence supporting this novel approach to skeletal anabolism. Data from numerous preclinical models in rodents and monkeys consistently demonstrate that antisclerostin monoclonal antibody (Scl-Ab) treatment leads to improvements in bone mass and strength, as well as enhanced fracture repair. Delivery of Scl-Ab therapy either subcutaneously or intravenously in phase 1 and 2 human clinical trials demonstrates short-term anabolic responses in excess of those seen with teriparatide, the only currently available anabolic skeletal agent. Gains have been primarily at central (spine and hips) versus peripheral (wrist) sites. Strikingly, Scl-Ab treatment appears to both stimulate bone formation and inhibit bone resorption in humans. If proven, Scl-Ab would be the first pharmacologic agent with such dual properties. Data on fractures are not yet available. Scl-Ab therapy represents a novel pharmacologic approach to skeletal anabolism. Although many questions remain before Scl-Ab treatment can be introduced into clinical practice, phase 3 human clinical trials are currently underway and could provide the necessary data to bring this exciting class of skeletal anabolic agents to patient care.

Romosozumab. Humanized anti-sclerostin monoclonal antibody, Treatment of osteoporosis

Romosozumab. Humanized anti-sclerostin monoclonal antibody, Treatment of osteoporosis

Romosozumab. Humanized anti-sclerostin monoclonal antibody, Treatment of osteoporosis

Romosozumab. Humanized anti-sclerostin monoclonal antibody, Treatment of osteoporosis

Prophylaxe und Therapie beim multiplen Myelom und anderen tumorbedingten Knochenveränderungen

Multiple myeloma (MM) ranges second of all hematological malignancies and occurs most commonly in elderly patients. Almost all MM patients develop bone lesions in the course of their disease or have evidence of bone loss at initial diagnosis. Whole-body conventional radiography remains the gold standard in the diagnostic evaluation, albeit computed tomography (CT) and magnetic resonance imaging (MRI) are increasingly used as complementary techniques in the more sensitive detection of osteolytic processes. Bisphosphonates like zoledronate or pamidronate represent the cornerstone therapeutics in osteolytic disease, and are effective supportives to potent anti-myeloma therapies, including novel agents such as the proteasome inhibitor bortezomib or immunomodulatory drugs (IMIDs, e. g. thalidomide or lenalidomide). Several studies are ongoing to investigate the effects of alternative bone-seeking agents and their therapeutic potential for the management of myeloma bone disease, such as denosumab (RANKL-neutralizing antibody), anti-sclerostin (monoclonal antibody, generated against sclerostin) or sotatercept (potent activin-A inhibitor). This review summarizes the most prominent data on myeloma bone disease pathogenesis, the role of imaging techniques as well as therapy and prevention of lytic complications in myeloma which may similarly or equally be true for other bone metastases-inducing solid tumors.

New understanding and treatments for osteoporosis

To summarize promising areas of investigation in osteoporosis and to stimulate further research in this area, as discussed in a recent international conference. Over the recent years, there has been an improvement in the knowledge of molecular pathways involved in bone formation and resorption with the development of new drugs to treat osteoporosis. Intact parathyroid hormone, teriparatide, and anti-sclerostin monoclonal antibody are anabolic drugs, whereas denosumab and odanacatib are anti-resorptive drugs with more reversible effects as compared to bisphosphonates. Anabolic and anti-resorptive agents have different effects on bone, and research in this area includes the efficacy of combination and sequential therapies with them. New insights in the molecular pathways of bone remodeling have clarified the mechanisms responsible for skeletal fragility in several forms of secondary osteoporosis, such as that occurring in type 2 diabetes, following drug exposure and systemic inflammatory diseases. Future research is needed to address the efficacy of anti-osteoporotic drugs in these more recently recognized conditions of skeletal fragility. Osteoporosis continues to be an important field of biomedical research.

Alteration of bone remodeling in multiple myeloma bone disease : role of Sclerostin

Multiple myeloma (MM) is characterized by osteolytic bone lesions, adiacent to tumor foci within bone, that arise as a consequence of osteoblast inactivation and osteoclast activation. Canonical Wnt signaling is central to normal bone homeostasis, and secretion of Wnt signaling inhibitors by MM cells contributes to MM-related bone destruction and disease progression. In this study, we investigated the effects of MM cells on osteoblast differentiation and the potential role of Sclerostin, a Wnt signaling antagonist, in the inhibition of osteoblastogenesis in MM. In our study, we first showed that MM cells expressed Sclerostin at mRNA and protein levels. Moreover, using a co-culture system between human bone marrow stromal cells (BMSCs) and MM cells we demonstrated that MM cells induce an inhibitory effect on alkaline phosphatase, collagen I and AP-1 transcription factor expression in BMSCs. This inhibition was reverted by the addition of the anti-Sclerostin neutralizing monoclonal antibody. In the co-culture system, this antibody also partially rescued the inhibitory effect on BMSC mineralization. Moreover, knowing that the Wnt signaling activation affect the RANKL/OPG axis, we studied in our co-colture system the effect of the anti-Sclerostin monoclonal antibody on the expression of these two cytokines. In particular, we found that human MM cells upregulated RANKL expression, but strongly down-regulated OPG production by BMSCs at mRNA and protein levels. The presence in the co-culture of the neutralizing antibody reduced RANKL and increased OPG expression. Thus, our data indicate that Sclerostin could be one of the factors inducing the uncoupling between formation and resorption in MM patients by the direct inhibition of osteoblast differentiation and the indirect stimulation of osteoclast activity.