Anti sclerostin antibodies

BACKGROUND: Fracture repair involves the reactivation of developmental signaling cascades, including Wnt signaling that stimulates bone formation and bone regeneration. Rodent data indicate that dual inhibition of the Wnt signaling antagonists sclerostin and Dickkopf-1 (DKK1) increases callus bone volume and strength while increasing bone mass systemically. METHODS: We evaluated the effects of 16 weeks of subcutaneously administered carrier solution (vehicle, VEH), anti-sclerostin antibody (Scl-Ab), anti-DKK1 antibody (DKK1-Ab), or Scl-Ab plus DKK1-Ab combination therapy (COMBO) on ulnar osteotomy healing in nonhuman primates (cynomolgus monkeys; 20 to 22 per group)...

SHR-1222, a novel humanized monoclonal antibody targeting sclerostin, has been shown to induce bone formation and decrease bone resorption at a single dose ranging 50-400 mg in our previous phase 1 trial. This study was a randomized, double-blind, placebo-controlled, dose-escalation phase 1 trial, which further investigated the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of multiple ascending doses of SHR-1222 in women with postmenopausal osteoporosis (POP). A total of 105 women with POP were enrolled and randomly assigned...

The mechanisms underlying the bone disease induced by diabetes are complex and not fully understood; and antiresorptive agents, the current standard of care, do not restore the weakened bone architecture. Herein, we reveal the diabetic bone signature in mice at the tissue, cell, and transcriptome levels and demonstrate that three FDA-approved bone-anabolic agents correct it. Diabetes decreased bone mineral density (BMD) and bone formation, damaged microarchitecture, increased porosity of cortical bone, and compromised bone strength...

Romosozumab (Evenity®) is a humanized monoclonal anti-sclerostin antibody. It represents a major breakthrough in the treatment of osteoporosis: while most treatments inhibit bone resorption, romosozumab has a dual effect, by increasing bone formation and reducing bone resorption. It is reimbursed in postmenopausal osteoporosis in patients with very high fracture risk (i.e. after a recent major fracture, occurring within two years). Its ideal use, in the therapeutic sequence for post-menopausal women, is as first line treatment in case of a recent major fracture...

An imbalance between bone resorption and bone formation underlies the devastating osteolytic lesions and subsequent fractures seen in more than 90% of multiple myeloma (MM) patients. Currently, Wnt-targeted therapeutic agents that prevent soluble antagonists of the Wnt signaling pathway, sclerostin (SOST) and dickkopf-1 (DKK1), have been shown to prevent bone loss and improve bone strength in pre-clinical models of MM. In this study, we show increasing Wnt signaling via a novel anti-LRP6 antibody, which potentiates Wnt1-class ligand signaling through binding the Wnt receptor LRP6, prevented the development of myeloma-induced bone loss primarily through preventing bone resorption...

Osteogenesis imperfecta (OI) is a rare bone disease that is associated with fractures and low bone mass. Sclerostin inhibition is being evaluated as a potential approach to increase bone mass in OI. We had previously found that in Col1a1Jrt/+ mice, a model of severe OI, treatment with an anti-sclerostin antibody had a minor effect on the skeletal phenotype. In the present study, we assessed the effect of genetic sclerostin inactivation in the Col1a1Jrt/+ mouse. We crossed Col1a1Jrt/+ mice with Sost knockout mice to generate Sost-deficient Col1a1Jrt/+ mice and assessed differences between Col1a1Jrt/+ mice with homozygous Sost deficiency and Col1a1Jrt/+ mice with heterozygous Sost deficiency...

The secreted protein sclerostin is primarily produced by osteocytes and suppresses osteoblast differentiation and function by inhibiting the canonical Wnt signaling pathway. Genetic and pharmacological inhibition of sclerostin has been shown to increase bone formation and an anti-sclerostin antibody has been clinically approved for the treatment of osteoporosis. Canonical Wnt signaling is also involved in the progression of several types of cancers including breast cancer. Here, we studied the effects of sclerostin inhibition on the development of bone metastases of breast cancer using mouse models...

As a key regulator of bone homeostasis, sclerostin has garnered a lot of interest over the last two decades. Although sclerostin is primarily expressed by osteocytes and is well known for its role in bone formation and remodelling, it is also expressed by a number of other cells and potentially plays a role in other organs. Herein, we aim to bring together recent sclerostin research and discuss the effect of sclerostin on bone, cartilage, muscle, liver, kidney and the cardiovascular and immune systems. Particular focus is placed on its role in diseases, such as osteoporosis and myeloma bone disease, and the novel development of sclerostin as a therapeutic target...

Vertical sleeve gastrectomy (VSG), the most utilized bariatric procedure in clinical practice, greatly reduces body weight and improves a variety of metabolic disorders. However, one of its long-term complications is bone loss and increased risk of fracture. Elevated circulating sclerostin (SOST) and granulocyte-colony stimulating factor (G-CSF) concentrations have been considered as potential contributors to VSG-associated bone loss. To test these possibilities, we administrated antibodies to SOST or G-CSF receptor and investigated alterations to bone and marrow niche following VSG...

Age-associated low bone mass disease is a growing problem in the US. Development of osteoanabolic therapies for treating skeletal fragility has lagged behind anti-catabolic therapies, but several bone-building molecules are clinically available. We reported previously that antibody-based neutralization of the Lrp5/Lrp6 inhibitor Dkk1 has minimal effects on bone gain, but can potentiate the already potent osteoanabolic effects of sclerostin inhibition (another Lrp5/Lrp6 inhibitor highly expressed by osteocytes)...

Bone disease is the most common complication in patients with multiple myeloma (MM), and it may lead to skeletal-related events (SREs) such as bone pain, pathological fractures, and spinal cord compression, which impair a patients' quality of life and survival. The pathogenesis of myeloma bone disease (MBD) involves disruption of bone reconstitution balance including excessive activation of osteoclasts, inhibition of osteoblasts, and participation of osteocytes and bone marrow stromal cells. Various factors, such as the receptor activator of nuclear factor-κB ligand (RANKL)/osteoprotegerin (OPG), dickkopf-1 (DKK-1), sclerostin, and activin-A, are involved in the development of MBD...

Adults with β- thalassemia major (β-TM) develop low BMD and fragility fractures at a higher incidence and at a younger age compared to the general population. The disease itself, including direct effects of anemia and iron overload toxicity on bone turnover, genetic susceptibility, thalassemia-related endocrinopathies and acquittance of suboptimal peak bone mass contribute to low bone mass and increased bone fragility frequently encountered among these patients. Current management of osteoporosis requires long-term treatment that can be provided by agents that reduce the risk of all osteoporotic fractures by modulating bone metabolism with different mechanisms of action...

Permanently anchored metal implants are frequently used in dental, craniomaxillofacial, and orthopaedic rehabilitation. The success of such therapies is owed to the phenomenon of osseointegration-the direct connection between the living bone and the implant. The extent of biomechanical anchorage (i.e., physical interlocking between the implant and bone) can be assessed with removal torque (RTQ) measurement. Implant anchorage is strongly influenced by underlying bone quality, involving physicochemical and biological properties such as composition and structural organisation of extracellular matrix, extent of micro-damage, and bone turnover...

Postmenopausal bone loss often leads to osteoporosis and fragility fractures. Bone mass can be increased by the first 34 amino acids of human parathyroid hormone (PTH), parathyroid hormone-related protein (PTHrP), or by a monoclonal antibody against sclerostin (Scl-Ab). Here, we show that PTH and Scl-Ab reduce the expression of microRNA-19a and microRNA-19b (miR-19a/b) in bone. In bones from patients with lower bone mass and from osteoporotic mice, miR-19a/b expression is elevated, suggesting an inhibitory function in bone remodeling...

Wnt signaling and its bone tissue-specific inhibitor sclerostin are key regulators of bone homeostasis. The therapeutic potential of anti-sclerostin antibodies (Scl-Abs), for bone mass recovery and fragility fracture prevention in low bone mass phenotypes, has been supported by animal studies. The Scl-Ab romosozumab is currently used for osteoporosis treatment. INTRODUCTION: Wnt signaling is a key regulator of skeletal development and homeostasis; germinal mutations affecting genes encoding components, inhibitors, and enhancers of the Wnt pathways were shown to be responsible for the development of rare congenital metabolic bone disorders...

Reactivation of bone lining cells (BLCs) is a crucial mechanism governing the anabolic action of anti-sclerostin antibody (Scl-Ab) via modeling-based bone formation; however, it remains unclear whether this reactivation can be attenuated after persistent administration of Scl-Ab. Here, we aimed to investigate the reproducibility of persistent Scl-Ab administration for the reactivation of BLCs, and to elucidate the relationship between the activity of BLCs and serum levels of N-terminal procollagen type I (P1NP) during chronic Scl-Ab administration...

Bone disease is a known complication of cystic fibrosis (CF). To date, there have been no reports on the effectiveness of romosozumab, monoclonal antibody to sclerostin, to treat CF-related bone disease. We report a case of a 46-year-old premenopausal female with CF-related bone disease and multiple fractures who was treated with romosozumab. After one year of therapy with romosozumab, the patient tolerated therapy and bone mineral density (BMD) significantly improved. Of the currently available anti-resorptive or anabolic osteoporosis medications, only bisphosphonates have been studied in individuals with CF...

Prolonged disuse and substantial mechanical unloading are particularly damaging to skeletal integrity. Preclinical studies in rodents and clinical studies have highlighted the need for potent bone anabolic drugs to counteract disuse-induced osteopenia. The aim of present study was to compare the efficacy of romosozumab (Scl-Ab) and abaloparatide (ABL), alone or in combination, to prevent botulinum toxin (BTX) induced bone loss in a rat model. Eighty female Wistar rats were divided into the following six groups: 1...

Bone formation by osteoblasts is achieved through remodeling-based bone formation (RBBF) and modeling-based bone formation (MBBF). The former is when bone formation occurs after osteoclastic bone resorption to maintain bone mass and calcium homeostasis. The latter is when new bone matrices are added on the quiescent bone surfaces. Administration of anti-sclerostin neutralizing antibody promotes MBBF in ovariectomized rats and postmenopausal women. However, it remains to be elucidated which mode of bone formation mainly occurs in Sost-deficient mice under physiological conditions...

Osteocytes sense the microenvironmental stimuli, including mechanical stress, and regulate bone resorption by osteoclasts and bone formation by osteoblasts. Diabetes and cancer metastasis to bone raise l-lactic acid in the bone tissue, causing acidification. Here, we investigated the effects of l-lactic acid and extracellular acidification on the function of mouse Ocy454 osteocytes. L- and d-lactic acid with low chiral selectivity and acidification of the medium raised the production of sclerostin and osteoprotegerin by Ocy454 cells...