At present, China’s aging population has reached 130 million, and osteoporosis has become a serious public health and social problem in an aging society. Prevention of osteoporosis is firstly to improve peak bone mass, enhance muscle strength and bone quality; secondly, to develop good dietary and living habits to maintain the relative stability of bone mass and bone quality.
I. Drugs to reduce bone resorption
(A) Estrogen and selective estrogen receptor modulators (SERM)
Ovarian dysfunction and endocrine disorders in pre- and post-menopausal women eventually lead to insufficient secretion of estrogen, which is an important cause of osteoporosis and psychological and organ dysfunctions. Hormone replacement therapy (HRT) was once the method of choice to alleviate the condition, both by inhibiting bone turnover and by reducing the number and inhibiting the activity of osteoclasts. Estrogen promotes calcitonin secretion and inhibits bone resorption; enhances hepatic 25-(OH)D3 and renal 1α-(OH)D3 activity, increases 1,25-(OH)2D3 levels, and promotes intestinal calcium absorption; decreases parathyroid hormone (PTH) response to blood calcium, inhibits PTH secretion, and reduces bone resorption. Estrogen also decreases PGE2 and inhibits the release of IL-1, IL-6 and TNF.
Estrogen has long been regarded as the gold standard agent for the protection of postmenopausal women. The most commonly used natural estrogen is estradiol (E2), which is the most active. Bound estrogen is a biological agent isolated from the urine of pregnant horses that has both progestational and androgenic activity. Postmenopausal women usually require long-term estrogen supplementation, but may experience side effects such as abnormal endometrial hyperplasia and breast cancer. Periodic addition of progestin was once thought to counteract the pro-proliferative effects of estrogen on the endometrium, but its recent effects on quality of life and on Alzheimer’s disease have called its use into question. Also the combination of the two does not reduce the incidence of breast cancer. Although HRT is beneficial against osteoporosis, postmenopausal women’s syndrome, bone, cardiovascular, colon diseases and Alzheimer’s disease; it can increase the incidence of breast cancer and venous thrombosis. It is currently believed that HRT can be used consistently to relieve patients with significant cardiovascular symptoms, but the duration of use should be short, the dose should be low, and regular testing is required; for asymptomatic women with osteoporosis, HRT can be used as an anti-bone resorption agent, but it is not recommended for the prevention of chronic disease.
In the last decade, selective estrogen receptor modulators (SERMs) have been developed. These compounds behave as agonists in some tissues and antagonists in others by binding to estrogen receptors. SERMs prevent vertebral fractures and increase bone mineral density (BMD) in the spine and hip. SERMs significantly reduce the incidence of cardiovascular disease or breast cancer, but can increase venous thrombosis. Commonly used SERMs are tamoxifen of the triptans and raloxifene of the benzothiophenes.
(ii) Calcitonin (CT)
It is secreted by parafollicular C cells of thyroid gland in mammals and is a peptide consisting of 32 amino acids. At present, four types of CT can be synthesized, namely salmon calcitonin (sCT), eel calcitonin (eCT), human calcitonin (hCT) and porcine calcitonin (pCT), the first two being more commonly used.CT injections and nasal sprays are the four anti-bone resorption drugs approved by the FDA for the treatment of osteoporosis so far, together with alendronate, risedronate and raloxifene.
CT acts on the ruffled edges of osteoclasts, increasing the membrane potential of osteoclasts and isolating them, inhibiting their activity and reducing their number. sCT (mikegaixin) has been widely used in primary and secondary osteoporosis characterized by increased bone resorption and bone loss. sCT prevents bone loss and increases BMD. sCT is administered intramuscularly as 50 IU daily or every other day
or 100 IU daily, or 200 IU/day given as a nasal spray (sCNS), can significantly reduce pain, improve activity and function, and enhance health-related quality of life. However, long-term use of CT can lead to drug resistance, known as “escape”, and a small number of patients may experience facial or trunk skin flushing and gastrointestinal discomfort such as nausea and vomiting. Nasal sprays have fewer adverse effects than injections. Although nasal spray sCNS has limited increase in BMD, trials have demonstrated its significant efficacy in preventing vertebral compression fractures, and sCNS has been shown to be effective in improving bone quality.
Once-daily CT injections inhibited bone turnover for 24 hours, and its changes in BMD or biochemical indices of bone resorption were less pronounced than those of diphosphonate, but there was no difference in fracture hazard rates or 95% confidence intervals. When applied, anti-bone resorption agents are effective in preventing fractures as long as BMD does not decline. Although bone mineral content generally correlates linearly with bone strength and has a greater effect on fracture occurrence, this is not always the case. CT has long been used in clinical practice, has a high safety profile, and can significantly increase bone biomechanical properties. Oral dosage forms are being developed to make administration more convenient in the future, especially for elderly people with low BMD who have difficulty tolerating bisphosphonates.
(iii) Bisphosphonates (BP)
After BP treatment in postmenopausal women, the frequency of activation of bone units decreases significantly, which greatly reduces the space for bone reconstruction and consequently increases bone mass. BP has been used in clinical practice for many years and is extremely safe with no obvious toxicity, but can cause some side effects such as gastrointestinal inflammation, muscle pain, increased body temperature, headache and iritis. Since this drug can specifically bind to the site of activated bone reconstruction, it does not cause abnormalities in the liver, kidney, heart, lung and central nervous system.
Alendronate
Alendronate is the most commonly used and powerful inhibitor of bone resorption, promoting calcium homeostasis and increasing bone mineral content. Anti-bone resorption therapy aims to reduce the amount of bone resorption per cycle, and its increased BMD can greatly reduce the risk of fracture. Alendronate should generally be taken orally in the early morning on an empty stomach and maintained in an upright position for at least half an hour, during which time milk, coffee, or other medications may interfere with the effectiveness of the drug. Alendronate can produce esophageal and gastrointestinal symptoms, but is well tolerated by most patients when administered in the standard manner. Since the half-life of alendronate on the bone surface is several weeks, once-weekly administration is as effective as daily administration in inhibiting bone resorption, i.e., the same amount and strength of bone is achieved.
The safety of long-term BP application is better. Iliac bone biopsies taken for 3 years on alendronate showed normal bone mineralization, bone histology, activation frequency, bone mass and new bone formation, but bone turnover was reduced by 88%-95%. There is no clear opinion whether BP needs to be given continuously or intermittently for a long time. In conclusion, depending on BMD and biochemical tests, oral BP can be given in a take-stop-take manner. What is the effect of combination therapy with different anti-bone resorption agents? The combined administration of alendronate and estrogen or raloxifene has been prospectively reported to improve both spinal and hip BMD compared to single agents.
Bone formation-promoting drugs
The treatment of osteoporosis lies in the selection of drugs that favorably inhibit bone resorption and stimulate bone formation. The use of anti-bone resorption agents, after a phase of causing uncoupling and reducing bone formation. Newer therapeutic perspectives require the use of bone formation stimulating agents alone or simultaneously, with the aim of correcting the erosion surface left by osteoclastic resorption, while restoring trabecular bone thickness and mineral salt density. In addition, such agents should be able to repair the defective inter-trabecular junctions in order to restore their microarchitecture. Only the combination of all corrective actions will restore the trabecular network to its normal mechanical properties.
(i) Parathyroid hormone (PTH) 1-34 fragment
PTH is one of the important peptide hormones that regulate calcium and phosphorus metabolism and bone conversion, and can precisely regulate the anabolic and catabolic processes of bone. PTH fragments have now become important bone formation promoters, and the increase in bone strength induced by PTH has been demonstrated through large samples of RCTs. Bone formation agents can be used in combination with bone resorption inhibitors. Combined application of hPTH 1-34 and HRT in postmenopausal women with osteoporosis restored bone mass to above the level of bone loss in both the lumbar spine and the femoral neck. hPTH has promising applications, but its mechanism of action, reasonable and effective timing of administration, dose, dosage form and the effect of the drug on cortical bone biomechanics, especially the minimum effective dose for elderly patients, safety of long-term application, bone tissue resistance to However, the mechanism of action, the reasonable and effective administration time, dose, dosage form and the effect of the drug on cortical bone biomechanics, especially the minimum effective dose, the safety of long-term application, the resistance of bone tissue to PTH, the combined application with other drugs, the comparison of the effect of continuous and cyclic injection, the comparison of the effect of hPTH 1-34 and hPTH 1-84, and the effect on endogenous PTH secretion, etc. still need to be further studied.
(ii) Statins
Statins are used to stimulate bone formation by inhibiting the cholesterol synthesis reaction, reducing the production of mevalonate and inhibiting HMGCoA reductase; while BP is used to inhibit bone resorption mainly by blocking the synthesis of yakinyl pyrophosphate and farnesyl pyrophosphate and inhibiting the activity of glutamyl transpeptidase, leading to the death of osteoclasts. The effects of statins in clinical applications are still divergent. Statins are first metabolized in the liver, so that only a very small amount enters the bone cells in vivo. Their effective dose is 10-20 times higher than that of animals, which may bring about serious adverse effects in liver and muscle tissue. Although statins promote osteoblast differentiation, increase powerful active regulatory factors, and also increase bone mass and decrease bone turnover, no reduction in fracture rates, especially in the hip, has been reported. Several clinical case-control studies have shown that administration of lipid-lowering agents can reduce the incidence of fracture, but have failed to provide sufficient evidence.
(iii) Strontium ranelate (SR)
Strontium is a trace element that is closely related to calcium in terms of chemical properties. Preclinical studies have shown that SR may increase lumbar spine BMD in postmenopausal women. clinical phase III trials are ongoing.
(iv) Fluorine preparation
Fluoride is an osteophilic element that can replace OH- in hydroxyapatite (HAP) and form fluorapatite crystals, which are more resistant to bone resorption than HAP. Fluoride can promote microfracture healing, form new bone trabeculae, and strengthen bone structure, and the efficacy is somewhat dose-dependent. The combination of fluorapatite and osteocalcin enhances bone mineralization and resists bone resorption, which is one of the mechanisms of fluoride treatment for osteoporosis. Sodium fluoride can cause secondary hyperparathyroidism and increase bone resorption, which must be accompanied by calcium and vitamin D. Gastrointestinal irritation can occur during fluoride treatment, with patients experiencing anorexia, nausea, vomiting, and in some cases pain around the joints of the lower extremities or incomplete stress fractures. Switching to a slow-release dosage form accompanied by calcium phosphate or switching to monofluorophosphates may reduce the occurrence of side effects, but it has not been proven to be more effective against fractures. The application of fluoride for the treatment of osteoporosis remains controversial. The incidence of spinal fractures is not reduced despite an increase in mesial bone mass. With long-term application of relatively high doses, fluoride gradually accumulates in the bone, resulting in a decrease in bone quality and mineralization defects. Biopsy of the iliac crest showed chondromalacia with increased fluoride content in the bone.