1.1 Symptom-improving drugs Liu Weidi, Department of Pain, Hanzhong 3201 Hospital
1.1.1 Glucosamine
Glucosamine is a monosaccharide amino acid consisting of glucose bound to amino acids and is found in tissues such as cartilage. Glucosamine sulfate is often used in clinical experiments because it is easily absorbed by the gastrointestinal tract. And there has been a great controversy about the therapeutic effect of glucosamine.Lems et al [5] concluded that glucosamine did not significantly relieve pain symptoms in patients with knee OA, even though it relieved knee OA pain.
McAlindon et al [3] evaluated clinical trials related to oral glucosamine treatment from 1966 to 1999 using Meta-analysis and concluded that human factors and quality problems caused unreliable data from these trials and opposed the use of glucosamine as an “effective drug for OA”. The American College of Rheumatology lists glucosamine only as a nutritional agent and does not recommend its universal use [7]. Regardless of the comments on glucosamine, McAlindon et al [8] concluded that non-steroidal anti-inflammatory analgesics should be avoided as much as possible in elderly patients with OA who require long-term medication, and glucosamine should be considered as the drug of choice for OA treatment.
1.1.2 Glucosamine sulfate
Glucosamine sulfate is an intermediate in the synthesis of mucopolysaccharides. It can only improve the symptoms of OA, but also control the development of OA symptoms and facilitate the repair of cartilage. Hu Tongyu and Li Jianheng [9] applied a retrospective comparison method to observe the clinical efficacy of glucosamine sulfate on osteoarthritis of the knee in a controlled trial applying traditional nonsteroidal drugs and glucosamine sulfate, and concluded that it can stimulate osteoblast synthesis of proteoglycans to protect and repair cartilage matrix, and has a mild anti-inflammatory effect, and is a fundamental therapeutic drug for degenerative osteoarthritis with no It is a fundamental treatment for degenerative osteoarthritis without significant side effects.
Reginster et al [10] applied glucosamine sulfate to treat 212 patients with OA and observed in a clinical trial for up to 3 years. According to the combined efficacy assessment criteria of structural improvement and symptom improvement, patients in the treatment group showed significant improvement in symptoms and imaging performance.
1.1.3 Chondroitin sulfate
Aminoglucan and chondroitin sulfate are natural amino polysaccharide-containing compounds that are readily soluble in water, 90-98% of which are readily absorbed by the intestinal mucosa. The smaller molecular shape allows them to pass through the blood-a-synovial barrier, cover and disperse into the articular cartilage, and be able to be absorbed by chondrocytes. Both drugs, alone or in combination, have been shown to be clinically and experimentally effective, with few toxic side effects [11].
The results of the study suggest that aminoglucan and chondroitin sulfate, as important components of the articular cartilage matrix, have the property of protecting articular cartilage in in vitro and in vivo experiments, and can reduce the symptoms of osteoarthritis in clinical applications, providing a different approach to the pharmacological treatment of osteoarthritis, but the long-term effects still need to be further confirmed, and the improvement of the dosage form and the safety of the dosage need to be studied in depth.
1.1.4 Hydrolyzed collagen
Hydrolyzed collagen, an oral drug composed of hydrolyzed collagen, has received few clinical reports for the treatment of OA compared to aminoglucan and chondroitin sulfate. An experimental animal study found that continuous injection of hydrolyzed collagen into the joints of rabbits was effective in inhibiting the development of OA, which may be a promising and new conservative treatment for OA [13].
1.1.5 Sodium hyaluronate
Sodium hyaluronate is an important component of synovial fluid and cartilage matrix, and has various physiological functions such as lubricating joints, resisting infection, and participating in cartilage repair. Xu Peng [14] et al. in observing the clinical effects of intra-articular injection of sodium hyaluronate in OA and the changes in the levels of free radicals and inflammatory mediators in the joint fluid before and after treatment concluded that intra-articular injection of SH for knee OA could relieve clinical symptoms and improve joint function, and its effects may be achieved by reducing the levels of free radicals and inflammatory mediators such as IL-1 and TNF- in the joint fluid.
Electrophysiological and animal pain model studies have shown that joint cavity injection of SH can increase the elasticity and lubricity of synovial fluid and better improve OA. the physiological effects of SH are mainly shock absorption, cartilage protection, inhibition of chondrocyte loss, and reduction of inflammatory cell network such as phagocytes, lymphocytes, and mast cells in OA. Several experimental models of OA, such as anterior cruciate ligament cutting or partial meniscectomy, have demonstrated that joint cavity injection of SH can inhibit chondrocyte loss and promote meniscal regeneration.Pham et al [15] showed that joint cavity injection of SH can replenish exogenous SH, while stimulating the secretion of endogenous SH, restoring the lubricating effect of synovial fluid, improving the inflammatory response of synovial tissue, promoting articular cartilage repair and improve joint function.
1.1.6 Estrogen
Epidemiology shows that the incidence of OA in women after the age of 50 is significantly higher than that in men, and the development is rapid. The application of estrogen replacement therapy not only has an inhibitory effect on the decomposition of PG in OA, but also has the effect of maintaining the stability of the internal structure of the joint, inhibiting the occurrence of OA and reducing the incidence. Especially for postmenopausal women with persistently low estrogen levels, the clinical symptoms of OA can be relieved after HRT, delaying the development of OA and reducing the functional impairment caused by OA, which is perhaps where estrogen replacement therapy comes into play. The radiological presentation of estrogen replacement therapy and knee OA is negatively correlated, which is more pronounced in knee OA with the presence or grade of osteophytes, but not in patients with distal interphalangeal OA [16].
However, Maheu et al [17] concluded that the efficacy of patients with hand OA treated with estrogen replacement therapy was not significantly different from that of patients with hand OA not treated with estrogen replacement therapy, nor did it alleviate the symptoms of active hand OA. Ren, H. L. et al [18] concluded that estrogen has protective and therapeutic effects on OA, but the relationship between estrogen and osteoarthritis in women still needs further in-depth study because of the complex effects of estrogen on articular cartilage metabolism.
1.1.7 S-adenosyl-L-methionine (SAMe)
SAMe is a naturally occurring compound that undergoes sulfation and methylation reactions and is increasingly used as a therapeutic agent for OA. SAMe is gaining acceptance as a therapeutic agent for OA in some patients, but there are still few reports of clinical treatment and clinical trials of SAMe [19]. A randomized, double-blind controlled trial found that oral SAMe 1200/d compared with Celebrex 200/d for 16 weeks for the treatment of knee OA showed that Celebrex provided significantly more relief of knee OA pain than SAMe in the first month, while in the second month, both drugs provided similar relief of knee OA pain. Although SAMe was slow to take effect, it was equally effective as Celebrex in relieving knee OA symptoms [20].
1.1.8 Low molecular heparin
The application of LMWH in arthritis is mainly to prevent VTE in procedures such as arthroplasty, joint fracture, acute spinal cord injury and compound trauma, and to reduce the incidence of VTE in the lower limbs after artificial joint replacement [22] It has been proved through experiments that the use of LMWH to prevent VTE in patients with arthroplasty is simple, safe and effective, especially for the prevention of VTE in patients with fractures. Some studies have shown that VTE prevention with LMWH has a lower bleeding rate than when NSAID is used.
1.2 Condition-modifying drugs
1.2.1 Tetracyclines
They mainly refer to doxycycline and memantine. They significantly inhibit the activity and expression of most MMPs and inhibit the synthesis of NO synthase (NOS) in OA cartilage [23]. Experimentally, doxycycline was able to reduce the severity of OA in dogs. A study showed that doxycycline had a protective effect on the cartilage of the medial femoral condyle of OA animals. In in vitro experiments, it not only reduced cartilage collagenase and gelatinase activity, but also prevented proteoglycan loss, cell death and X-type collagen matrix deposition [24].
1.2.2 Aminoglucan
A liquid extract from calf cartilage and bone marrow, composed of aminoglucan and peptides, stimulates the synthesis of type II collagen and proteoglycans by chondrocytes, and it not only inhibits the synthesis of multiple MMPs by chondrocytes, but also significantly increases the amount of tissue-derived MMP inhibitors in OA cartilage [25]. Both intramuscular and intra-articular administration were used, and there was no difference in efficacy between the two modes of administration at the same dose [26].
1.2.3 Growth factors and cytokines
Xiang Chuan, Du Jingyuan et al [27] in observing the therapeutic effect of recombinant rat transforming growth factor and insulin-like growth gene transfected rabbit knee joint on OA concluded that intra-articular injection of transgenic chondrocytes has a certain therapeutic effect on OA, and the therapeutic effect of both genes is better than that of single gene, and the gene expression is diminished after 4 weeks of gene therapy, and gene therapy is time-sensitive.
1.2.4 Gene therapy
In recent years, with the rapid development of science and technology, the continuous application of new scientific research methods and means in the medical field, and the continuous deepening of the understanding of OA, gene therapy technology has become another new direction of OA treatment. Gene therapy technology is to transform a gene encoding a therapeutic protein into the synovial membrane or cartilage with an appropriate vector, so that the gene can be expressed in the joint in a stable and efficient manner over a long period of time, and continuously produce the protein and act on a single joint with a lesion. In OA and experimental animal models, IL-IRа, IL-10 and IL-13 are currently applied for experimental studies of gene transfection. IL-IRа gene therapy for osteoarthritis is currently a hot topic of research, mainly because this receptor antagonist inhibits cartilage degradation in vitro and slows down the OA experimental process [28].