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BACKGROUND To evaluate the efficacy of different pharmacological interventions, with emphasis on monoclonal antibodies (McAbs) for the treatment of postmenopausal osteoporotic women. METHODS A search of PubMed, Google Scholar, Embase, and the Cochrane Library, as well as China National Knowledge Infrastructure (CNKI) was performed. Data were collected and pooled using Bayesian network meta-analysis (NMA), which conducts both direct and indirect comparisons. The primary outcome was the percentage change in bone mineral density (BMD) in the lumbar spine from baseline to 1 year of treatment. All drugs were ranked based on the surface under the cumulative ranking area (SUCRA). Furthermore, the heterogeneity, consistency, and publication bias of the enrolled literature were assessed. RESULTS There were 14 randomized controlled trials (RCTs) consisting of 4,881 participants included to compare 11 interventions. Compared with that of a placebo, all the 10 selected therapies showed significant efficacy through changes in BMD ranging from 6.0% to 19.0% (all P

SummaryResearch into the drug romosozumab began with the investigation of patients with excess bone formation. The understanding of the wingless-type mouse mammary tumor virus integration site (Wnt) signaling pathway in bone metabolism identified the negative regulator of bone mass sclerostin as a potential target for the treatment of osteoporosis. Preclinical studies confirmed this idea because they showed that sclerostin antibodies have the potential to increase bone formation. Biochemical analyses of clinical studies showed a significant increase in bone formation markers, which then slowly decreased within a year. This was accompanied by a particularly initially pronounced decrease in bone resorption. This dual mechanism of action led to an increase in bone mineral density and a significant reduction in fracture risk. Clinical vertebral fractures decreased by between 28 and 36%, nonvertebral fractures shown in a post hoc analysis by 42%. Romosozumab is administered once a month in the form of two injections. At the puncture site, reactions occur in about 5%. The most significant side effects are cardiovascular. In phase III studies, the number of serious cardiovascular complications was not significantly, albeit numerically, higher than in the control group. In Japan, South Korea, Canada, Australia, and the USA, osteoporosis patients at a high risk of fracture may already be treated with romosozumab (Evenity). Approval in the European Union was granted by 2019-12-12.

Sclerostin is a cysteine-knot glycoprotein product of the SOST gene, predominately expressed by osteocytes, that is a regulator of osteoblastic bone formation. When sclerostin binds to its low-density lipoprotein receptor-related proteins 5 and 6 on the cell membrane of osteoblasts, it inhibits canonical Wnt/β-catenin signaling and reduces osteoblastic bone formation. Sclerostin was first identified in the study of two rare autosomal recessive disorders, sclerosteosis and van Buchem disease, which are associated with absent or reduced levels of sclerostin. Although homozygote patients with these disorders have serious adverse clinical consequences due to excessive bone growth, heterozygote patients have a normal phenotype, high bone mass, and very low risk of fractures. This has led to the concept that downregulation of sclerostin might be effective in the treatment of osteoporosis. Several humanized monoclonal antibodies to sclerostin, including romosozumab and blosozumab, are now in clinical development. Preliminary data show that these agents result in a transient increase in bone formation markers, a sustained decrease in bone resorption markers, and a robust increase in bone mineral density. If any of these agents are found to reduce fracture risk with a favorable safety profile, it will expand the options for osteoanabolic therapy for patients at high risk for fractures.

Sclerostin, a SOST protein secreted by osteocytes, negatively regulates formation of mineralized bone matrix and bone mass. We report the results of a randomized, double-blind, placebo-controlled multicenter phase 2 clinical trial of blosozumab, a humanized monoclonal antibody targeted against sclerostin, in postmenopausal women with low bone mineral density (BMD). Postmenopausal women with a lumbar spine T-score -2.0 to -3.5, inclusive, were randomized to subcutaneous blosozumab 180 mg every 4 weeks (Q4W), 180 mg every 2 weeks (Q2W), 270 mg Q2W, or matching placebo for 1 year, with calcium and vitamin D. Serial measurements of spine and hip BMD and biochemical markers of bone turnover were performed. Overall, 120 women were enrolled in the study (mean age 65.8 years, mean lumbar spine T-score -2.8). Blosozumab treatment resulted in statistically significant dose-related increases in spine, femoral neck, and total hip BMD as compared with placebo. In the highest dose group, BMD increases from baseline reached 17.7% at the spine, and 6.2% at the total hip. Biochemical markers of bone formation increased rapidly during blosozumab treatment, and trended toward pretreatment levels by study end. However, bone specific alkaline phosphatase remained higher than placebo at study end in the highest-dose group. CTx, a biochemical marker of bone resorption, decreased early in blosozumab treatment to a concentration less than that of the placebo group by 2 weeks, and remained reduced throughout blosozumab treatment. Mild injection site reactions were reported more frequently with blosozumab than placebo. In conclusion, treatment of postmenopausal women with an antibody targeted against sclerostin resulted in substantial increases in spine and hip BMD. These results support further study of blosozumab as a potential anabolic therapy for osteoporosis.

Sclerostin is an osteocyte-derived glycoprotein that inhibits Wnt/β-catenin signaling and activation of osteoblast function, thereby inhibiting bone formation. It plays a vital role in the regulation of skeletal growth. In adults, sclerostin secretion is modulated by skeletal loading (increased secretion with immobilization; less with weight bearing) and by hormonal/cytokine actions on the osteocyte. Sclerostin deficiency syndromes in humans and animals are characterized by high bone mass of normal quality. In animal models of osteoporosis, inhibition of sclerostin by monoclonal antibodies induces osteoblast activity and new bone formation, normalizing bone mass and improving bone architecture and strength. In recently completed clinical trials, anti-sclerostin antibody therapy results in marked increases in bone mineral density and rapid and substantial reduction in fracture risk. This review will focus on these recent studies and anticipate the role of anti-sclerostin therapy in the management of patients with osteoporosis.

The Wnt/β signaling pathway (Wnt-SP) is a phylogenetically ancient mechanism that regulates development and maintains tissue homeostasis through the control of cell proliferation, differentiation, migration, and apoptosis. The accurate regulation of the canonical Wnt/β-catenin signaling pathway (Wnt-SP) is critical for embryogenesis and postnatal development; and impaired signal transduction at one of its stages leads to various diseases, including organ malformations, cancers, metabolic and neurodegenerative disorders. The literature review discusses the biological role of the canonical Wnt-SP in the development of the skeleton and in the remodeling of bone tissue. The Wnt signal transmission changes observed during genetic mutations cause various human skeletal diseases. Understanding the functional mechanism involved in the development of bone abnormality could open new horizons in the treatment of osteoporosis, by affecting the Wnt-SP. The design of antibodies to sclerostin, a Wnt-SP inhibitor, is most promising now. The paper summarizes the studies that have investigated the canonical Wnt-SP and designed drugs to treat osteoporosis.Сигнальный путь Wnt (СП-Wnt) - филогенетически древний механизм регуляции развития и поддержания гомеостаза тканей за счет контроля пролиферации, дифференциации, миграции и апоптоза клеток. Точность регуляции канонического сигнального пути Wnt/β-катенин (далее в тексте сигнальный путь Wnt - СП-Wnt) имеет решающее значение в эмбриогенезе и постнатальном развитии, а нарушение проведения сигналов на одном из его этапов приводит к различным заболеваниям, включая пороки развития органов, раковые заболевания, метаболические и нейродегенеративные расстройства. Обзор литературы посвящен обсуждению биологической роли канонического СП-Wnt в развитии скелета и ремоделировании костной ткани. Изменения в передаче сигнала Wnt, наблюдаемые при генетических мутациях, вызывают различные заболевания скелета человека. Понимание функциональных механизмов развития патологии костной ткани позволило открыть новые горизонты в лечении остеопороза за счет влияния на СП-Wnt. Наиболее перспективным в настоящее время является разработка антител к склеростину - ингибитору СП-Wnt. Статья обобщает исследования, посвященные каноническому СП-Wnt и разработке лекарственных препаратов для лечения остеопороза.

Based on a platform of strong preclinical data, several studies in humans have demonstrated that inhibiting sclerostin with specific antibodies results in a brisk albeit transient anabolic response in the skeleton without an accompanying increase in bone resorption. Impressive increases in bone mineral density and bone strength have been demonstrated. Other than mild injection site reactions, therapy for up to 2 years has been well tolerated. The restriction of sclerostin expression almost exclusively to skeletal tissues, coupled with the absence of recognized medical problems in patients with heterozygous sclerostin deficiency, provides promise that the drug can be used safely. Recent results from a Phase 3 fracture trial suggest that anti-sclerostin therapy will be a useful and welcomed new treatment for patients with severe osteoporosis in need of skeletal reconstruction.

The recognition of the importance of the Wnt-signaling pathway in bone metabolism and studies of patients with rare skeletal disorders characterized by high bone mass identified sclerostin as target for the development of new therapeutics for osteoporosis. Findings in animals and humans with sclerostin deficiency as well as results of preclinical and early clinical studies with sclerostin inhibitors demonstrated a new treatment paradigm with a bone building agent for the management of patients with osteoporosis, the antifracture efficacy, and long-term tolerability of which remain to be established in on-going phase III clinical studies. In this article we review the currently available preclinical and clinical evidence supporting the use of sclerostin inhibitors in osteoporosis.

The development of bone-rebuilding anabolic agents for treating bone-related conditions has been a long-standing goal. Genetic studies in humans and mice have shown that the secreted protein sclerostin is a key negative regulator of bone formation. More recently, administration of sclerostin-neutralizing monoclonal antibodies in rodent studies has shown that pharmacologic inhibition of sclerostin results in increased bone formation, bone mass, and bone strength. To explore the effects of sclerostin inhibition in primates, we administered a humanized sclerostin-neutralizing monoclonal antibody (Scl-AbIV) to gonad-intact female cynomolgus monkeys. Two once-monthly subcutaneous injections of Scl-AbIV were administered at three dose levels (3, 10, and 30 mg/kg), with study termination at 2 months. Scl-AbIV treatment had clear anabolic effects, with marked dose-dependent increases in bone formation on trabecular, periosteal, endocortical, and intracortical surfaces. Bone densitometry showed that the increases in bone formation with Scl-AbIV treatment resulted in significant increases in bone mineral content (BMC) and/or bone mineral density (BMD) at several skeletal sites (ie, femoral neck, radial metaphysis, and tibial metaphysis). These increases, expressed as percent changes from baseline were 11 to 29 percentage points higher than those found in the vehicle-treated group. Additionally, significant increases in trabecular thickness and bone strength were found at the lumbar vertebrae in the highest-dose group. Taken together, the marked bone-building effects achieved in this short-term monkey study suggest that sclerostin inhibition represents a promising new therapeutic approach for medical conditions where increases in bone formation might be desirable, such as in fracture healing and osteoporosis.

Osteoporosis and osteoporosis-related fractures are growing problems with the aging population and are associated with significant morbidity and mortality. At this time, other than parathyroid hormone analogs, all therapies for osteoporosis are antiresorptive. Therefore, researchers have focused efforts on development of more anabolic therapies. Understanding of the Wnt signaling pathway, which is critical for skeletal development, and the role of sclerostin in inhibition of Wnt signaling has led to the discovery of a novel therapeutic approach in the treatment of osteoporosis - sclerostin inhibition. In this review, we discuss the biology of Wnt signaling and sclerostin inhibition. We then discuss human disorders of decreased sclerostin function and animal models of sclerostin inhibition. Both have served to elucidate the effects of decreased sclerostin levels and function - increased bone mass and strength and fewer fractures. In addition, we review data from Phase I and II studies of the two humanized sclerostin monoclonal antibodies, romosozumab and blosozumab, both of which have had positive effects on bone mineral density. We conclude with a discussion of the ongoing Phase III studies of romosozumab. The available data support the potential for neutralizing sclerostin monoclonal antibodies to serve as anabolic agents in the treatment of osteoporosis.

In addition to other chronic diseases such as hypertension, hypercholesterolemia, and diabetes, a treat-to-target strategy was recently applied in rheumatoid arthritis and has now been discussed in osteoporosis. An important goal of osteoporosis therapy is normal risk of hip fracture associated with significant morbidity and mortality, but the anti-fracture efficacies of currently approved drugs are limited (1, 2). Although fundamental methods to effectively prevent osteoporotic fracture include pharmacological treatment of sarcopenia that results in improving bone fragility as well as reducing fall risk, the present article focuses on anti-sclerostin antibodies such as romosozumab and blosozumab, the investigational agents for osteoporosis, and provides new insights into their effects from natural homeostatic system in the skeleton.

Sclerosteosis and Van Buchem disease are two rare bone sclerosing disorders characterized by increased bone mineral density, tall stature and entrapment of cranial nerves due to overgrowth of a highly dense bone. Recent advances in human genetics have revealed the genetic background of these disorders by cloning the SOST gene, which is localized on chromosome region 17q12-q21 and codes for sclerostin. Sclerostin is a protein produced almost exclusively from osteocytes inhibiting bone formation by both osteoblasts and osteocytes. At the molecular level, sclerostin inhibits the Wnt signaling pathway, which plays a critical role in osteoblast development and function. Induced sclerostin deficiency in mice reproduces the bone sclerosing human diseases, while sclerostin excess leads to bone loss and reduced bone strength. The extracellular nature of sclerostin has rendered it a promising target for the development of novel anti-osteoporotic treatment. Otherwise healthy carriers of the SOST mutation present with increased bone mass and low levels of sclerostin in serum in contrast to patients with sclerosteosis, who exhibit undetectable levels, thus pointing to the possibility of titration of sclerostin levels in the circulation. Based on these unique characteristics, human anti-sclerostin antibodies have been developed and tested in ovariectomized rats and monkeys, demonstrating very promising results in bone formation. Clinical phase II and III trials are currently underway thereby translating human genetics to drug development.

Osteoporotic fracture is a cause of pain, loss of autonomy and excess mortality. Current drugs however, do not allow for a satisfactory non vertebral fracture risk reduction and the compliance is suboptimal.Current treatments consist of mainly bisphosphonates, denosumabs, selective estrogen receptor modulators and teriparatides. All drugs currently in development will target some aspect of bone remodeling by using the recent advances in our knowledge of bone biology: cathepsin-K inhibitors (odanacatib) are antiresorptive, antisclerostin monoclonal antibodies (romosozumab and blosozumab) are anabolic agents and PTHrp 1-34 (abaloparatide) is an anabolic agent.New drugs with better tolerance and ideally with intermittent administration may improve their compliance. New drugs will have to provide higher efficiency levels with regards to reducing the risk of fractures. They may be second-line options, targeted at patients who are poor responders, or those who display contraindications to the older drugs, as a result of cost issues. In addition, some of these new drugs with potent anabolic effect may be confined to niches, for those patients at high risk of refracture after an initial severe fracture such as a hip fracture or a clinical vertebral fracture.

Monoclonal antibodies to molecular targets important for bone formation and bone resorption are being investigated for treatment of postmenopausal osteoporosis. Postmenopausal osteoporosis is characterized by increased bone turnover, with bone resorption typically exceeding bone formation. These pathophysiological changes cause decreased bone mineral density and disruption of bone microarchitecture which lead to low-trauma fractures. Sclerostin is a glycoprotein inhibitor of osteoblast Wnt signaling produced by osteocytes that has been recognized as a new target for therapeutic intervention in patients with osteoporosis. Sclerostin was first recognized when disorders with inactivating mutations of the sclerostin gene SOST were found to be associated with high bone mass. These observations suggested that inhibitors of sclerostin might be used to increase bone mineral density. Romosozumab (AMG 785) is the first humanized anti-sclerostin monoclonal antibody that has been demonstrated to increase bone formation. This investigational monoclonal antibody, and blosozumab, another investigational anti-sclerostin antibody, have osteoanabolic properties with the potential to improve clinical outcomes in patients with osteoporosis. Similar to preclinical animal studies with sclerostin antibodies, initial clinical studies have shown that romosozumab increases bone formation and BMD. Further evaluation of the efficacy and safety of this agent in a large phase III controlled study is awaited. Phase I clinical trial data have recently been published with blosozumab. These novel interventions appear to be promising agents for the treatment of osteoporosis.

Sclerostin is a small protein expressed by the SOST gene in osteocytes, bone cells that respond to mechanical stress applied to the skeleton and appear to play an important role in the regulation of bone remodeling. When sclerostin binds to its receptors on the cell surface of osteoblasts, a downstream cascade of intracellular signaling is initiated, with the ultimate effect of inhibiting osteoblastic bone formation. Recent studies have shown that the SOST gene is also expressed by articular chondrocytes and that modulation of its activity may have effects on articular cartilage and subchondral bone. The role of sclerostin in the pathogenesis of osteoarthritis in humans has not yet been defined, and the potential utility of treating osteoarthritis with interventions that alter sclerostin is not known. Rare genetic skeletal disorders in humans with low sclerostin levels, such as sclerosteosis and van Buchem disease, have been associated with a high bone mineral density (BMD) phenotype and low risk of fractures. This has led to the concept that antisclerostin interventions might be useful in the treatment of patients with osteoporosis and skeletal disorders associated with low bone mass. Compounds that inhibit sclerostin have been shown to stimulate bone formation and reduce bone resorption, with a robust increase in BMD. Investigational monoclonal antibodies to sclerostin, including romosozumab, blosozumab, and BPS804, have advanced to phase II clinical trials or beyond. If antisclerostin therapy is found to have beneficial effects on clinical endpoints, such as reduction of fracture risk or improvement in quality of life in patients with osteoarthritis, with a favorable balance of benefit and risk, then this class of compounds may become a prominent addition to the options for therapy of osteoporosis and other skeletal disorders.

The development of bone-rebuilding anabolic agents for potential use in the treatment of bone loss conditions, such as osteoporosis, has been a long-standing goal. Genetic studies in humans and mice have shown that the secreted protein sclerostin is a key negative regulator of bone formation, although the magnitude and extent of sclerostin's role in the control of bone formation in the aging skeleton is still unclear. To study this unexplored area of sclerostin biology and to assess the pharmacologic effects of sclerostin inhibition, we used a cell culture model of bone formation to identify a sclerostin neutralizing monoclonal antibody (Scl-AbII) for testing in an aged ovariectomized rat model of postmenopausal osteoporosis. Six-month-old female rats were ovariectomized and left untreated for 1 yr to allow for significant estrogen deficiency-induced bone loss, at which point Scl-AbII was administered for 5 wk. Scl-AbII treatment in these animals had robust anabolic effects, with marked increases in bone formation on trabecular, periosteal, endocortical, and intracortical surfaces. This not only resulted in complete reversal, at several skeletal sites, of the 1 yr of estrogen deficiency-induced bone loss, but also further increased bone mass and bone strength to levels greater than those found in non-ovariectomized control rats. Taken together, these preclinical results establish sclerostin's role as a pivotal negative regulator of bone formation in the aging skeleton and, furthermore, suggest that antibody-mediated inhibition of sclerostin represents a promising new therapeutic approach for the anabolic treatment of bone-related disorders, such as postmenopausal osteoporosis.