The 2022 World Congress on Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (WCO-IOF-ESCEO2022) will be held in the cloud from March 24 to 27. Dr. Michael R. McClung of the Oregon Osteoporosis Center in the United States launched a wonderful report on “the drug treatment of osteoporosis”. Is there a need to further explore new drugs or therapies for osteoporosis based on existing treatment options? Professor Xu Yong from the Affiliated Hospital of Southwest Medical University also shared his unique insights on this topic. Now organize its essence for readers.
Osteoporosis is a disease characterized by decreased bone mass and Systemic bone disease leading to increased bone fragility and susceptibility to fractures. This is a global disease that seriously affects the health of people, especially the elderly, and imposes a huge economic burden on society. There is no cure for osteoporosis, and the goal of treatment is to prevent or avoid further bone loss and prevent fractures.
What are the medications for osteoporosis?
Currently, drugs for the treatment of osteoporosis are roughly divided into two categories: bone resorption inhibitors and bone formation promoters.
Bone resorption inhibitors
- Estrogen: For female patients only, by inhibiting bone turnover, preventing Bone loss.
- Estrogen agonist-antagonist: It has estrogen-like and estrogen-like antagonistic effects, represented by raloxifene. Potential benefits and risks should be weighed during use.
- Bisphosphonates: The mainstream drug for the prevention and treatment of osteoporosis, by inhibiting the function of osteoclasts, promoting the apoptosis of osteoclasts, reducing the rate of bone turnover, inhibiting the Absorption, reduce bone loss and preserve bone mass. It can be used alone or in combination, orally or intravenously. Attention should be paid to adverse reactions such as esophagitis and mandibular osteonecrosis.
- Denosumab: It specifically targets nuclear factor kappa B receptor activator activator ligand (RANK) and its ligand (RANKL) to inhibit osteoclast Cell activation and development, reducing bone resorption and increasing bone density. It can be used for the treatment of postmenopausal osteoporosis in women and osteoporosis in men.
Bone formation promoters
- Parathyroid hormone/parathyroid hormone-related protein analogs:Special Riparatide and abalotide are its representative drugs, which can promote bone formation. These drugs need to be used in combination with anti-resorptive agents to prevent bone loss after drug discontinuation.
- Sclerostin inhibitor: Romosozumab is a humanized IgG2 monoclonal antibody targeting sclerostin and can bind to sclerostin , antagonize its activity, block the sclerostin-LRP-5/6 pathway, promote bone formation and reduce bone resorption, thereby relieving the symptoms of osteoporosis.
All in all, these drugs for osteoporosis have different mechanisms of action, The indications and contraindications are different, the efficacy is different, and the side effects are also different. Among them, the bone resorption inhibitor denosumab and the bone formation promoter lomoxolizumab have significant curative effects and are suitable for almost all osteoporosis patients.
Need more medicine for osteoporosis?
Therapeutic effect of osteoporosis
Existing osteoporosis drugs can increase bone density—about 20% in lumbar spine and about 10% in hip joint after 3 years of treatment; reduce fracture risk—about 60% in vertebral fracture risk ~70%, the risk of multiple vertebral fractures is reduced by about 75% to 96%, the risk of hip fractures is reduced by about 40% to 50%, and the risk of nonvertebral fractures is reduced by about 20% to 35%. These drugs have shown good tolerability and safety in clinical studies.
Limitations of Osteoporosis Treatment
Large Most nonvertebral fractures cannot be prevented with treatment, and there is no drug “cure” for osteoporosis. On the one hand, long-term drug treatment can increase the risk of rare side effects, especially bone resorption inhibitors; on the other hand, long-term drug treatment can lead to a bottleneck or even failure of efficacy, such as bisphosphonates after 5 years of treatment, there is no further benefit. With the exception of bisphosphonates, the efficacy of other anti-osteoporosis drugs declines rapidly once discontinued. Most patients have low acceptance of existing treatments, low long-term treatment compliance, and unaffordable treatment costs.
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Combination therapy: Different anti-osteoporosis drugs have different mechanisms of action. Combining drugs that inhibit bone resorption and promote bone formation is used for anti-osteoporosis drugs. Treatment for osteoporosis appears to be more effective, but does not appear to significantly reduce fracture risk.
Sequential therapy: due to bone formation promoters There are limited courses of treatment, and bone resorption inhibitors should be used sequentially after drug withdrawal to avoid the interruption effect caused by drug withdrawal.
New drug development: development to inhibit bone resorption with long-lasting effects Drugs such as salt-inducible kinase (SIK), oleoylserine derivatives, proteasome inhibitors, cannabinoid receptor ligands. However, there are no drugs in clinical phase II or III studies.
Although the current treatments for osteoporosis have certain effects, they are not ideal. The ideal treatment for osteoporosis should not only rebuild the disordered bone microstructure, but also normalize and maintain bone mass for a long time; it has no serious side effects, and is simple and convenient, which is widely accepted by clinicians and patients. To sum up, it is the focus of all countries in the world to seek new therapeutic methods that can promote bone regeneration in patients with osteoporosis, which are safe, effective and risk-free.
What new treatments for osteoporosis are being explored?
Intestinal flora:Intestinal flora caused by diet, drugs, inflammation and other factors The imbalance of gut microbiota may affect bone health by changing mineral absorption, releasing bone active molecules, changing the efficacy of osteoporosis drugs in various ways. Ongoing Phase II studies are designed to evaluate the efficacy of probiotics, prebiotics or microbial secreted products in the treatment of osteoporosis. This is a very interesting area, not only because of the potential effectiveness, but also because the therapy might be understood as a “natural” remedy.
MicroRNAs (miRNAs) and exosomes:miRNAs are small non-coding RNAs Molecules that can regulate the expression of post-transcriptional genes in eukaryotic cells. miRNAs are the regulators of various proteins and participate in bone metabolism, and the dysregulation of some miRNAs is closely related to osteoporosis. In addition to intracellular effects, miRNAs can also be transported to neighboring cells via exosomes, affecting related functions. Studies have shown that miRNAs have the potential to be biomarkers and therapeutic targets for osteoporosis.
Mesenchymal stem cells (MSCs):MSCs are derived from mesoderm, present in bone marrow and A type of stem cells with multi-directional differentiation in various tissues, which can differentiate into osteoblasts, adipocytes, chondrocytes and nerve cells. Animal studies have shown that transplanted MSCs regulate the differentiation and proliferation of osteoblasts through signaling pathways such as the mitogen-activated protein kinase (MAPK) pathway, and promote bone regeneration, thereby improving osteoporosis. MSCs transplantation therapy can effectively improve osteoporosis, but direct use still faces huge costs and challenges.
Anti-cell aging:In the process of accumulation in the body, senescent cells will continuously secrete a series of The pro-inflammatory factor SASP, these pro-inflammatory factors can cause chronic inflammation, damage surrounding healthy cells, and induce various diseases. Mouse studies show that increased senescent cells, SASP, are associated with decreased osteoblastic differentiation, increased levels of RANK ligands, and age-dependent cortical bone loss—an osteoporotic phenotype that is age-related but not associated with estrogen deficiency . Bone mass, bone strength, and microarchitecture were significantly improved in mice after anti-cellular aging treatment. Two ongoing phase II clinical studies are investigating the efficacy of antiaging drugs to improve bone health in the elderly.
Increase muscle mass and function to reduce risk of falls:Most nonvertebral fractures occur during falls Afterwards, frequent falls are important risk factors for fractures, whereas muscle weakness and impaired sensory function are risk factors for falls and fractures. Myostatin-inhibiting drugs improve muscle mass, but not function. And animal studies have confirmed that stem cell transplantation therapy with muscle regeneration function can promote muscle regeneration and repair.
Epilogue
With the deepening of osteoporosis research, more and more signaling pathways and targets have been discovered, and new anti-osteoporosis drugs are gradually being developed. diversification. However, concerns about the side effects and long-term efficacy of novel drugs have led to inadequate treatment of a large number of osteoporosis patients in the clinic. While waiting for safe and effective new treatments to come out, clinicians should fully understand the mechanism of action of existing drugs, related side effects, the optimal treatment time for fracture prevention, and the sequential order of different drug treatments to provide osteoporosis patients. individualizedPrecise treatment.
Expert Reviews
Professor Xu Yong
< span class="data-color--tt-darkmode-a180f5">Affiliated Hospital of Southwest Medical University
The status quo is urgentIn recent years, the global prevalence of osteoporosis has risen sharply, and it has become a global epidemic disease, seriously threatening human health and causing a huge social and economic burden. Nonetheless, current means of control and treatment are limited.
Traditional treatment has reached a bottleneckCurrently, the drugs for the treatment of osteoporosis are divided into bone nutritional supplements (Calcium + Vit D), bone resorption inhibitors (estrogen, bisphosphonates, denosumab), bone-promoting agents (denosumab, lomoxolizumab), dual-function drugs (ranelide) strontium acid, ipriflavone). For many people, drug therapy + lifestyle intervention is difficult to adhere to, and it is accompanied by different degrees of side effects, and long-term drug therapy will make the efficacy bottleneck or even fail. Therefore, most patients have low acceptance of existing treatments, poor long-term treatment compliance, and cannot afford treatment costs. Combination therapy and sequential therapy have been tried, but the effect is unsatisfactory. It does not significantly reduce the risk of fractures, and may increase adverse drug reactions. Drugs that inhibit bone resorption and have long-lasting effects are still in the research and development stage.
New treatments are urgently needed to be explored to seek safe, effective, safe, and effective treatments that can promote bone regeneration in patients with osteoporosis. Novel treatments with low risk are the focus of common concern around the world. At present, the establishment of a balance in the intestinal flora (probiotics, prebiotics or microbial secretion products) is the new “natural” treatment. miRNAs and exosomes are expected to be biomarkers and therapeutic targets for osteoporosis. Mesenchymal stem cells can effectively promote bone formation by regulating osteoblast differentiation and proliferation. Anticellular senescence ameliorates age-related but not estrogen-deficiency osteoporotic phenotypes. Stem cell transplant therapy increases muscle mass and function to reduce the risk of falls and osteoporotic fractures.
In short, until the cloud is clear, effective and safe new treatments are urgently needed.
May you have a strong heart and strong bones.