Osteoanabolic Agents Research Articles

Cardiovascular safety of osteoanabolic agents.

Several osteoanabolic agents have been developed to build new bone more efficiently than anti-resorptive drugs. Among them, romosozumab, an anti-sclerostin antibody, is a potent pharmacological tool to prevent fractures in osteoporosis patients. The efficacy of romosozumab in preventing osteoporotic fractures is robust. However, there remains a concern about increased cardiovascular (CV) adverse events related to romosozumab. Available data have been reviewed to address this concern. Published articles on romosozumab of which pivotal randomized controlled trials (RCTs), meta-analyses of RCTs, pharmacovigilance investigations, and retrospective observational clinical studies using real-world data were collected through PubMed and other available tools. Meta-analyses of RCTs of romosozumab compared to placebo and other anti-osteoporosis drugs have left room for controversy in the CV safety of romosozumab. Investigations of the real-world data also provide no conclusive evidence in this issue. We need more robust evidence to establish an appropriate and reasonable guide to prescribe romosozumab in our clinical practice.

Clinical effects of teriparatide, abaloparatide, and romosozumab in postmenopausal osteoporosis.

In the management of osteoporosis, anti-resorptive agents serve as a primary therapeutic approach. However, in cases where individuals exhibit an increased susceptibility to fractures, such as those characterized by severe low bone mass or a history of vertebral or hip fractures that markedly diminish life expectancy, the immediate reduction of fracture risk through the administration of osteoanabolic agents could be beneficial. Teriparatide, available in daily, once-weekly, or twice-weekly dosages, along with abaloparatide and romosozumab, constitutes a trio of such agents. Each of these medications is defined by unique characteristics, distinct efficacy profiles, and specific adverse effects. There is growing evidence to suggest that these agents have a superior effect on enhancing bone mineral density and reducing fracture incidence when compared to traditional bisphosphonate therapies. Nonetheless, their employment demands thorough consideration of clinical indications, which includes evaluating economic factors, the frequency of injections required, and the potential for adverse effects. The objective of this review is to consolidate the current evidence focusing primarily on the efficacy of these agents, with the goal of enhancing understanding and aiding in making more informed treatment decisions, particularly for those individuals who are at an elevated risk of fractures.

Romosozumab versus parathyroid hormone receptor agonists: which osteoanabolic to choose and when?

Osteoanabolic agents are used as a first line treatment in patients at high fracture risk. The PTH receptor 1 (PTH1R) agonists teriparatide (TPTD) and abaloparatide (ABL) increase bone formation, bone mineral density (BMD), and bone strength by activating PTH receptors on osteoblasts. Romosozumab (ROMO), a humanized monoclonal antibody against sclerostin, dramatically but transiently stimulates bone formation and persistently reduces bone resorption. Osteoanabolic agents increase BMD and bone strength while being more effective than antiresorptives in reducing fracture risk in postmenopausal women. However, direct comparisons of the antifracture benefits of osteoanabolic therapies are limited. In a direct comparison of TPTD and ABL, the latter resulted in greater BMD increases at the hip. While no differences in vertebral or non-vertebral fracture risk were observed between the two drugs, ABL led to a greater reduction of major osteoporotic fractures. Adverse event profiles were similar between the two agents except for hypercalcemia, which occurred more often with TPTD. No direct comparisons of fracture risk reduction between ROMO and the PTH1R agonists exist. Individual studies have shown greater increases in BMD and bone strength with ROMO compared with TPTD in treatment-naive women and in women previously treated with bisphosphonates. Some safety aspects, such as a history of tumor precluding the use of PTH1R agonists, and a history of major cardiovascular events precluding the use of ROMO, should also be considered when choosing between these agents. Finally, convenience of administration, reimbursement by national health systems and length of clinical experience may influence patient choice.

BIGH3 mediates apoptosis and gap junction failure in osteocytes during renal cell carcinoma bone metastasis progression

Renal cell carcinoma (RCC) bone metastatis progression is driven by crosstalk between tumor cells and the bone microenvironment, which includes osteoblasts, osteoclasts, and osteocytes. RCC bone metastases (RCCBM) are predominantly osteolytic and resistant to antiresorptive therapy. The molecular mechanisms underlying pathologic osteolysis and disruption of bone homeostasis remain incompletely understood. We previously reported that BIGH3/TGFBI (transforming growth factor-beta-induced protein ig-h3, shortened to BIGH3 henceforth) secreted by colonizing RCC cells drives osteolysis by inhibiting osteoblast differentiation, impairing healing of osteolytic lesions, which is reversible with osteoanabolic agents. Here, we report that BIGH3 induces osteocyte apoptosis in both human RCCBM tissue specimens and in a preclinical mouse model. We also demonstrate that BIGH3 reduces Cx43 expression, blocking gap junction (GJ) function and osteocyte network communication. BIGH3-mediated GJ inhibition is blocked by the lysosomal inhibitor hydroxychloroquine (HCQ), but not osteoanabolic agents. Our results broaden the understanding of pathologic osteolysis in RCCBM and indicate that targeting the BIGH3 mechanism could be a combinational strategy for the treatment of RCCBM-induced bone disease that overcomes the limited efficacy of antiresorptives that target osteoclasts.

Update of the S3-guideline on diagnostics, prophylaxis and treatment of osteoporosis

With the aid of anew fracture risk model, the great treatment gap for osteoporosis should be closed. All patients older than 70years should undergo a diagnostic procedure for osteoporosis. An additional risk threshold (≥ 10% per 3years for femoral and vertebral fractures) should enable patients with ahigh risk of fracture to be treated with osteoanabolic agents. The use of osteoanabolic agents makes it necessary to administer antiresorptive drugs afterwards. Due to the low event rate of osteonecrosis of the jaw, the initiation of aspecific osteoporosis treatment should not be delayed by prophylactic dental treatment. The adherence to the drug treatment should be improved by an individualized approach on the basis of acooperation between patients, caregivers, and physicians. Aregular assessment of falls, including the timed up and go test should be carried out in patients older than 70years.

Comparison of osteoanabolic agents (teriparatide and romosozumab) with bisphosphonates in prevention of subsequent vertebral fractures in patients treated for osteoporotic vertebral fracture for 12 months: An observational cohort study

IntroductionDomino osteoporotic vertebral fracture (OVF) is as a subsequent fracture that develops within 3 months before the initial OVF heals. There is limited evidence regarding the efficacy of osteoanabolic agents on its treatment. This study evaluated the effects of bisphosphonates and anabolic agents teriparatide and romosozumab on subsequent domino OVF. MethodsThis was post hoc analysis of a prospective, multicenter, observational study conducted across 8 hospitals, enrolling 144 patients with conservatively treated OVF, grouped into patients receiving bisphosphonate (BP, n = 55), teriparatide (TPTD, n = 62), and romosozumab (Romo, n = 27). The primary outcome was the incidence of subsequent OVF at 3 and 12 months, whereas the secondary outcomes included the incidence of pseudoarthrosis and progression of vertebral collapse (VC). Pseudoarthrosis was classified as stable or unstable based on vertebral instability. ResultsThe use of osteoanabolic agents did not reduce the incidence of subsequent OVF at 3 and 12 months. There were no significant differences in the background data or type of conservative treatment among the three groups. However, the TPTD and Romo groups had significantly lower rates of unstable pseudarthrosis (p = 0.03). Additionally, there were no significant differences in VC progression between groups, but it tended to be higher in the BP group than the TPTD and Romo group (p = 0.07). ConclusionOsteoanabolic agents were beneficial in reducing unstable pseudoarthrosis, but were not more effective than bisphosphonates in the development of subsequent domino OVF. A more comprehensive approach to the treatment of osteoporosis is needed to prevent domino OVFs.

Computer-guided design of novel nitrogen-based heterocyclic sphingosine-1-phosphate (S1P) activators as osteoanabolic agents.

Osteoanabolic agents, or drugs that promote bone formation, have gained considerable attention for osteoporosis management due to their curative and preventive potentials. Sphingosine-1-phosphate receptor 2 (S1PR2) is an attractive drug target, in which its activation leads to osteogenesis-promoting effect. Nitrogen-containing heterocyclic scaffolds (i.e., quinoxaline and indole) are promising pharmacophores possessing diverse bioactivities and were reported as S1PR2 activators. Quantitative structure-activity relationship (QSAR) modeling is a computational approach well-known as a fundamental tool for facilitating successful drug development. This study demonstrates the discovery of new S1PR2 activators using computational-driven rational design. Herein, an original dataset of nitrogen-containing S1PR2 activators was collected from ChEMBL database. The retrieved dataset was separated into two datasets according to their core scaffolds (i.e., quinoxaline and indole). QSAR modeling was performed using multiple linear regression (MLR) algorithm to successfully obtain two models with good predictive performance. The constructed models also revealed key properties playing essential roles for potent S1PR2 activation, such as Van der Waals volume (R2v+ and E3v), mass (MATS5m and Km), electronegativity (H3e), and number of 5-membered rings (nR05). Subsequently, the constructed models were further employed to guide rational design and predict S1PR2 activating effects of an additional set of 752 structurally modified compounds. Most of the modified compounds were predicted to have higher potency than their parents, and a set of promising potent newly designed compounds was highlighted. Additionally, drug-likeness prediction was performed to reveal that most of the newly designed compounds are druggable compounds with possibility for further development.

Update of the S3-guideline on diagnostics, prophylaxis and treatment of osteoporosis

With the aid of anew fracture risk model, the great treatment gap for osteoporosis should be closed. All patients older than 70years should undergo a diagnostic procedure for osteoporosis. An additional risk threshold (≥ 10% per 3years for femoral and vertebral fractures) should enable patients with ahigh risk of fracture to be treated with osteoanabolic agents. The use of osteoanabolic agents makes it necessary to administer antiresorptive drugs afterwards. Due to the low event rate of osteonecrosis of the jaw, the initiation of aspecific osteoporosis treatment should not be delayed by prophylactic dental treatment. The adherence to the drug treatment should be improved by an individualized approach on the basis of acooperation between patients, caregivers, and physicians. Aregular assessment of falls, including the timed up and go test should be carried out in patients older than 70years.

Skin and bones: systemic mastocytosis and bone.

We report the case of a 69-year-old female with systemic mastocytosis, diagnosed based on widespread pigmented papules and macules, elevated serum tryptase levels and confirmatory skin and bone marrow biopsy, on a background of osteoporosis. A CT demonstrated multiple sclerotic lesions within lumbar vertebral bodies, sacrum and ileum, with surrounding osteolysis but no obvious compression fractures. She was treated with the RANK-L inhibitor denosumab, resulting in significant bone mineral density gain over the following 5 years. However, her serum tryptase levels gradually increased during this period despite treatment with the multikinase inhibitor, midostaurin. It is thus conceivable that her rapid increase in bone mineral density may be partly contributed by a predominance of pro-osteoblastic mediators released by abnormal mast cells, suggestive of more advanced disease. This case highlights the complexities of systemic mastocytosis-related bone disease and the interplay of numerous mediators contributing to a phenotype of both increased bone resorption and formation. Systemic mastocytosis is a neoplastic disease of mast cells characterized by abnormal proliferation and accumulation in the skin and other organs. It is most frequently associated with the somatic gain-of-function KIT D816V mutation. Systemic mastocytosis should be suspected in patients presenting with not only cutaneous symptoms suggestive of mast cell degranulation such as anaphylaxis, flushing or urticaria but also unexplained osteoporosis and gastrointestinal and constitutional symptoms. The prevalence of osteoporosis in systemic mastocytosis is high. Mast cell activation leads to the secretion of numerous chemical mediators which either promote or inhibit osteoclastic and/or osteoblastic activity, with the balance usually in favour of increased bone resorption. However, in advanced diseases with high mast cell burden, mast-cell-derived cytokines and mediators may promote osteoblastic activity, leading to osteosclerosis and apparent increases in bone mineral density. Treatment of osteoporosis in systemic mastocytosis involves antiresorptive therapy with bisphosphonates and more recently, denosumab. There are limited data on the role of osteoanabolic agents.

Management of bone loss due to endocrine therapy during cancer treatment.

Bone modifying agents BMAs (oral and IV bisphosphonates, denosumab) are used to treat bone loss due to endocrine therapy in patients with hormone receptor positive (HR +) early breast cancer and non-metastatic prostate cancer (NMPC). Timely initiation of appropriate sequential therapy is imperative to reduce cancer treatment-induced bone loss (CTIBL). This narrative review summarizes current literature regarding management of CTIBL in HR + early breast cancer and NMPC patients. Risk factors for fragility fractures, screening strategies, optimal timing for the treatment, dosing/duration of therapy, and post treatment monitoring have not been clearly defined in HR + early breast and NMPC patients receiving endocrine therapy. This review aims to discuss the utility of fracture risk assessment (FRAX) tool for the prevention and management of CTIBL, osteoanabolic therapy for imminent fracture risk reduction, and sequential therapy options. Using predefined terms, PubMed, MEDLINE, and Google Scholar were searched for studies on CTIBL in HR + breast and NMPC patients. We included randomized clinical trials, meta-analysis, evidence-based reviews, observational studies, and clinical practice guidelines. Fracture risk assessment tools (FRAX) guide therapy for osteoporosis in patients with early HR + breast cancer and NMPC. BMAs to prevent bone loss should be initiated at higher T-score than recommended by FRAX in premenopausal HR + breast cancer patients with chemotherapy-induced ovarian failure, oophorectomy and gonadotropin releasing hormone (GnRH) therapy, post-menopausal women with HR + breast cancer receiving aromatase inhibitor therapy, and NMPC patients with androgen deprivation therapy. Sequential therapy with osteoanabolic agents as first line treatment offers a potential therapeutic strategy in patients with high imminent fracture risk. Due to limited data in cancer patients regarding management of osteoporosis, a dosing schedule similar to osteoporosis is considered appropriate. Risk stratification to identify vulnerable patient population, choosing the appropriate sequential therapy, and close monitoring of patients at the risk of bone loss can potentially reduce the mortality, morbidity, and health care cost related to CTIBL.

Recent Advances in Teriparatide Delivery by-virtue-of Novel Drug Delivery Approaches for the Management of Osteoporosis.

Osteoporosis is a bone incapacitating malady which globally accounts for over hundred million fractures annually. Therapeutic interventions for management of osteoporosis are divided as antiresorptive agents and osteoanabolic agents. Teriparatide is the only osteoana-bolic peptide which is available world-wide for the treatment of osteoporosis. It is administered as a daily subcutaneous injection for the treatment of osteoporosis which results in both poor patient compliance and increase in the cost of the therapy. Even after 20 years of clinical use of teriparatide, no formulation of teriparatide has yet been translated from lab to clinic which can be delivered by non-invasive route The present review critically discusses attempts made by the researchers for efficient delivery of teriparatide through various non-invasive routes such as oral, nasal, pulmonary, and transdermal route. It also discusses long-acting injectable formulations of teriparatide to improve patient compliance. Understanding on the pharmacology of teriparatide highlights the enhanced effectiveness of intermittent/pulsatile mode of teriparatide delivery which has also been elaborated. In addition, targeted delivery of teriparatide using different bone specific targeting moieties has been also discussed.

Clinical Utility of Romosozumab in the Management of Osteoporosis: Focus on Patient Selection and Perspectives.

As one of the most potent osteoanabolic agents with a unique mechanism of action, romosozumab has high efficacy for osteoporosis treatment. It is a monoclonal antibody against sclerostin, a natural inhibitor of the Wnt signaling pathway, and by inhibiting sclerostin, activation of Wnt signaling occurs with a cascade of changes ultimately leading to bone mineral density (BMD) gains. Romosozumab stimulates bone modeling and has a dual effect of activating bone formation while inhibiting bone resorption. With this unique mechanism of action, treatment with romosozumab leads to a rapid and significant gain in BMD; these gains are higher than seen with bisphosphonates, denosumab, or parathyroid hormone (PTH) analogs. The FRAME and ARCH studies represent two pivotal trials demonstrating the efficacy of romosozumab in treating osteoporosis. Treatment with romosozumab should be followed by an antiresorptive agent, as this approach has demonstrated maintenance of or greater increases in BMD and reduced fracture risk even after finishing romosozumab treatment. As an osteoanabolic agent, romosozumab has shown superiority to alendronate in reducing fracture risk, increasing bone density, and potentially more rapid fracture risk reduction. Recent data have suggested that romosozumab prior to antiresorptive therapy may be the ideal treatment sequence, especially in high-risk patients and patients at imminent risk of fracture. Carrying a black box warning, romosozumab should be avoided in patients who have had myocardial infarction or stroke in the past year. Further studies are needed to clarify the increased cardiovascular risk attributed to this drug. Romosozumab has expanded our osteoporosis armamentarium and has enabled novel approaches, including "treat to target." Future studies are needed to evaluate the optimal use sequence and to assess its safety, especially in patients with cardiovascular risk factors.

Osteoporosis treatment in Austria—assessment of FRAX-based intervention thresholds for high and very high fracture risk

SummaryThe adoption of the management pathway proposed by the National Osteoporosis Guideline Group (NOGG), UK applied using the Austrian FRAX® tool in a referral population of Austrian women categorises 22–29% of women age 40 years or more eligible for treatment of whom 28–34% are classified at very high risk.PurposeThe aim of this study is to provide a reference document for the further development of existing guidelines for the management of osteoporosis in Austria, considering FRAX-based intervention thresholds for high and very high fracture risk.MethodsThe model development was based on two Austrian hospital referral cohorts. Baseline information was collected to compute the 10-year probability (using the Austrian FRAX model) of a major osteoporotic fracture (MOF) and hip fracture both with and without the inclusion of femoral neck bone mineral density (BMD). Assessment thresholds for BMD testing were defined, as well as intervention thresholds. In addition, thresholds that characterise men and women at high and very high fracture risk were established. The management pathway followed that currently recommended by the UK National Osteoporosis Guideline Group (NOGG).ResultsThe two cohorts comprised a total of 1306 women and men with a mean age of 66.7 years. Slightly more than 50% were eligible for treatment by virtue of a prior fragility fracture. In those women without a prior fracture, 22% (n = 120) were eligible for treatment based on MOF probabilities. Of these, 28% (n = 33) were found to be at very high risk. When both MOF and hip fracture probabilities were used to characterise risk, 164 women without a prior fracture were eligible for treatment (29%). Of these, 34% (n = 56) were found to be at very high risk. Fewer men without prior fracture were eligible for treatment compared with women.ConclusionThe management pathway as currently outlined is expected to reduce inequalities in patient management. The characterisation of very high risk may aid in the identification of patients suitable for treatment with osteoanabolic agents.

Polypharmacy in Osteoporosis Treatment.

In older adults, polypharmacy and osteoporosis frequently occur contemporaneously. Polypharmacy is increasingly recognized as a risk factor for hip and fall-related fractures. Treatments for osteoporosis include antiresorptive (alendronate, risedronate, zoledronic acid, ibandronate, denosumab) and osteoanabolic (teriparatide, abaloparatide, romosozumab) agents. Polypharmacy is associated with worse adherence to pharmacologic therapy. Thus, the selection of osteoporosis treatment should be individualized and based on a variety of factors, including underlying fracture risk (high vs very high risk), medical comorbidities, medication burden, as well as fracture risk reduction profiles, modes of administration, and side effects of treatment options.

Disuse (post-mobilization) osteoporosis: literature review and clinical case series

Background. Disuse (рost-immobilization) osteoporosis is defined as secondary loss of bone mass in case of the absence or insufficient mechanical load on the skeleton. This disease can be associated with various risk factors, including long-time bed rest. The purpose of the research was to analyze modern literary data on the mechanisms of development, principles of diagnosis and treatment of disuse osteoporosis and to present own clinical data of disuse osteoporosis in the patients with multiple injuries of the skeleton in the conditions of war in Ukraine. Materials and methods. The review was based on the analysis of literature sources from the PubMed, WOS, Scopus, Google, Google Scholar, Cochrane Library databases for the years 2007–2022. The search was conducted using keywords: disuse osteoporosis, immobilization, bed rest, bone mineral density (BMD), bone remodeling, regeneration. Results. The data on the theory of the mechanostat are considered as links in the appearance of disuse osteoporosis. In conditions of immobilization, bone remodeling processes are slowing down. Histomorphometric studies confirm a decrease in trabecular bone density, thickness of the cortical layer, and an increase in its porosity. A change in bone architecture with a biphasic course is observed. Disruption of the synchronicity of remodeling processes with a decrease in the rate of osteoblastogenesis and an increase in osteoclastogenesis was noted, and the role of osteocytes as mechanosensors was emphasized. Disuse osteoporosis leads to a violation of biochemical marker of bone metabolism. Early laboratory manifestations of bed rest were recorded in the form of a violation of calcium level, an increase in bone resorption markers, while bone formation markers did not change significantly. Bone loss in disuse osteoporosis is manifested by a decrease in BMD indices. The greatest decrease was recorded in the lower extremities’ bones and the vertebrae of the lumbar spine. Modern methods of treatment of disuse osteoporosis involve the use of antiresorptive and osteoanabolic agents but clinical data are limited, which requires multicenter randomized studies. The article presents 3 clinical examples of disuse osteoporosis after gunshot fractures of the lower extremities’ bones.

Amino acid metabolism in skeletal cells

Amino acid metabolism regulates essential cellular functions, not only by fueling protein synthesis, but also by supporting the biogenesis of nucleotides, redox factors and lipids. Amino acids are also involved in tricarboxylic acid cycle anaplerosis, epigenetic modifications, next to synthesis of neurotransmitters and hormones. As such, amino acids contribute to a broad range of cellular processes such as proliferation, matrix synthesis and intercellular communication, which are all critical for skeletal cell functioning. Here we summarize recent work elucidating how amino acid metabolism supports and regulates skeletal cell function during bone growth and homeostasis, as well as during skeletal disease. The most extensively studied amino acid is glutamine, and osteoblasts and chondrocytes rely heavily on this non-essential amino acid during for their functioning and differentiation. Regulated by lineage-specific transcription factors such as SOX9 and osteoanabolic agents such as parathyroid hormone or WNT, glutamine metabolism has a wide range of metabolic roles, as it fuels anabolic processes by producing nucleotides and non-essential amino acids, maintains redox balance by generating the antioxidant glutathione and regulates cell-specific gene expression via epigenetic mechanisms. We also describe how other amino acids affect skeletal cell functions, although further work is needed to fully understand their effect. The increasing number of studies using stable isotope labelling in several skeletal cell types at various stages of differentiation, together with conditional inactivation of amino acid transporters or enzymes in mouse models, will allow us to obtain a more complete picture of amino acid metabolism in skeletal cells.

Concerns on Medications Used in Osteoporosis

Osteoporosis is a systemic skeletal disorder that affects bone microarchitecture resulting to fragility fractures. Randomized controlled trials have shown efficacy of antiresorptives and osteoanabolic agents in addressing concerns of osteoporosis especially in the older population. However, published guidance from several organizations started to focus as well on the perceived harms most especially of bisphosphonates considering their persistent effect on the bones. Similar to other chronic diseases, decision on whether or not to continue therapy depends on factors that might persistently provide signal on the individual’s further risk of unwanted but preventable outcomes.

Teriparatide in fracture healing: Case series and review of literature

Teriparatide (TPTD) (recombinant Parathyroid Hormone 1-34) is one of the pioneer osteo-anabolic agents approved for management of osteoporosis. Being an anabolic agent, it increases bone mineral density by inducing formation of new bone by the action on osteoblasts. As new bone formation is an important aspect of fracture healing as well, Teriparatide has long been a product of interest with respect to its effect on the process of fracture healing. Though fracture healing is not an approved indication for Teriparatide, there is quite a substantial amount of published data related to its effectiveness in fracture healing. With an intent to better understand the role of teriparatide in fracture, we share few case reports of successful fracture healing after giving Teriparatide and also review the published evidences of union taking place in difficult delayed union and non-union cases secondary to mechanical instability, inadequate fixation support or other reasons. This article thus, intended to summarize the accumulating preclinical and clinical evidence for role of TPTD in accelerating fracture healing in various conditions like conservative management of fractures, vertebral fractures, non-unions, delayed unions and atypical femoral fractures.

Romosozumab for the treatment of osteoporosis in women: Efficacy, safety, and cardiovascular risk.

Increased understanding of the Wnt signaling pathway has led to the development of romosozumab, one of the most potent osteoanabolic agents to date for osteoporosis treatment. Romosozumab is a monoclonal antibody that inhibits sclerostin, a natural inhibitor of the Wnt signaling pathway. Romosozumab, by inhibiting sclerostin activates the Wnt signaling pathway, leading to increased bone formation and decreased bone resorption. The pivotal ARCH and FRAME studies established romosozumab’s fracture reduction efficacy. Romosozumab was superior to alendronate in fracture reduction and bone mineral density gain in the ARCH study. Romosozumab treatment should be followed sequentially with a potent antiresorptive agent. The antifracture efficacy gained from romosozumab is maintained or improved after transitioning to an antiresorptive agent. As one of the most potent osteoanabolic agents, the introduction of romosozumab has significantly increased our ability to treat osteoporosis. Studies have provided important information on using romosozumab with other osteoporosis medications to optimize osteoporosis treatment. Romosozumab used before antiresorptive medications is associated with more significant bone mineral density increases than when an antiresorptive agent is used before romosozumab. Romosozumab is recommended for osteoporosis treatment in patients at very high risk for fracture with low cardiovascular risk. Romosozumab is generally well tolerated, with 4%–5% of patients having injection site reactions. The ARCH trial showed a higher risk of cardiovascular events in patients receiving romosozumab. Romosozumab carries a black box warning that romosozumab should not be initiated in patients with myocardial infarction or stroke in the preceding year. However, the information on romosozumab and increased cardiovascular risk is conflicting. The risk of cardiovascular disease with romosozumab is unclear. While romosozumab has demonstrated significant osteoanabolic effect and antifracture efficacy and will benefit high fracture risk patients, further studies are needed to investigate the cardiovascular safety of romosozumab.

Effects of Extracellular Osteoanabolic Agents on the Endogenous Response of Osteoblastic Cells.

The complex multidimensional skeletal organization can adapt its structure in accordance with external contexts, demonstrating excellent self-renewal capacity. Thus, optimal extracellular environmental properties are critical for bone regeneration and inextricably linked to the mechanical and biological states of bone. It is interesting to note that the microstructure of bone depends not only on genetic determinants (which control the bone remodeling loop through autocrine and paracrine signals) but also, more importantly, on the continuous response of cells to external mechanical cues. In particular, bone cells sense mechanical signals such as shear, tensile, loading and vibration, and once activated, they react by regulating bone anabolism. Although several specific surrounding conditions needed for osteoblast cells to specifically augment bone formation have been empirically discovered, most of the underlying biomechanical cellular processes underneath remain largely unknown. Nevertheless, exogenous stimuli of endogenous osteogenesis can be applied to promote the mineral apposition rate, bone formation, bone mass and bone strength, as well as expediting fracture repair and bone regeneration. The following review summarizes the latest studies related to the proliferation and differentiation of osteoblastic cells, enhanced by mechanical forces or supplemental signaling factors (such as trace metals, nutraceuticals, vitamins and exosomes), providing a thorough overview of the exogenous osteogenic agents which can be exploited to modulate and influence the mechanically induced anabolism of bone. Furthermore, this review aims to discuss the emerging role of extracellular stimuli in skeletal metabolism as well as their potential roles and provide new perspectives for the treatment of bone disorders.