The treatment of osteoporosis in modern medicine is based on the understanding of its etiology and pathogenesis, and the current drugs for the treatment of osteoporosis can be divided into 3 main categories.
① drugs that inhibit osteoclast activity, mainly estrogen, calcitonin, bisphosphonates, isoproterenol, selective estrogen receptor modulators, etc.
(ii) drugs that promote osteoclastogenesis, mainly fluoride, parathyroid hormone, and protein-synthesizing hormone.
③ drugs that promote ossification, mainly calcium and vitamin D and its derivatives, etc.
1.Drugs that inhibit osteoclast activity
Hormone replacement therapy (HRT): HRT is the treatment of choice for postmenopausal osteoporosis. Estrogen can directly inhibit osteoclastic bone resorption; at effective inhibitory concentrations, estrogen can directly cause osteoclastic apoptosis, significantly reducing the total incidence of fracture. In addition, estrogen also exerts a regulatory effect on bone metabolism through calcium-regulating hormones, such as parathyroid hormone, calcitonin, and vitamin D. However, estrogen, when used in elderly women with osteoporosis, may increase the risk of endometrial cancer in addition to the risk of breast cancer, and its adverse effects may be avoided by the combined application of progestin. At present, the commonly used preparations include Bemelia, Venetian, Leviare, estradiol patch, etc.
Calcitonin (CT): CT can inhibit osteoclast activity and reduce the number of osteoclasts, thus inhibiting bone resorption; it has the effects of central analgesia, enhancing activity function, improving calcium balance and slowing down bone loss; clinically, two preparations of salmon calcitonin (calcitonin) and eel calcitonin (calcitonin) are commonly used for subcutaneous or intramuscular injection. Calcitonin nasal spray is now also widely used in clinical practice and is considered the initial treatment for symptomatic osteoporotic fractures. The side effects of CT are loss of appetite, nausea and vomiting in some patients, and the “escape phenomenon”, i.e., reduced efficacy or even ineffectiveness, may be related to the decrease in the number of CT receptors and the opposite effect of parathyroid hormone (PTH). This may be due to the reduction in the number of CT receptors and the opposite effect of parathyroid hormone (PTH).
Bisphosphonates: For patients with HRT, especially osteoporosis due to increased bone resorption, such as postmenopausal, disuse, or hormone-induced osteoporosis, this type of inhibitor of bone resorption may be considered. This drug acts on osteoclasts or their precursors to increase cell death and decrease the rate of bone resorption. There are 3 generations of clinical application so far: 1 generation: sodium hydroxyethylphosphonate (etidron), which has the adverse effect of inhibiting bone mineralization and advocates intermittent treatment; 2 generation: disodium pamidronate (Bonin), which is suitable for all kinds of osteoporosis, especially for patients with gastrointestinal diseases, does not affect bone mineralization and has a stronger effect; 3 generation: alendronate, which is suitable for the treatment of postmenopausal osteoporosis and is the strongest bone resorption inhibitors.
Isoproterenol (IP): IP is a new non-hormonal drug for the prevention and treatment of osteoporosis, which can both inhibit bone resorption and promote bone formation. Experimental studies have shown that IP has the effect of directly inhibiting osteoclasts and indirectly promoting calcitonin secretion in synergy with estrogen, resulting in an increase in bone density. IP has estrogen-like effects on bone, but does not have other properties inherent to estrogen, so it can reduce the risk of breast cancer and endometrial cancer. This drug is mainly used for postmenopausal women and elderly patients with osteoporosis. Clinical and experimental studies have confirmed that this drug is well tolerated and has a small incidence of side effects, mostly digestive symptoms such as gastric distention, nausea, vomiting and abdominal pain; no serious adverse effects have been observed, making it a promising and ideal drug for the treatment of osteoporosis.
Selective estrogen receptor modulators (SERM): These drugs have both estrogen receptor activating and antagonizing effects, with estrogen activator effects on bone and cardiovascular system, and antagonizing effects on breast and endometrium, reducing their side effects on breast and endometrium compared with estrogen, and can be used to prevent and treat postmenopausal osteoporosis in women; especially, they have no irritating effects on endometrium and reduce This makes it an alternative drug to estrogen for the treatment of postmenopausal osteoporosis. A clinical trial (raloxifene 30mg, 60mg and 150mg daily in 601 postmenopausal women followed for 2 years) showed that all dose groups increased bone mineral density, and the higher the dose the greater the increase, with no change in endometrial thickness. It has also been shown that raloxifene 60 mg/d or 120 mg/d significantly reduced the risk of invasive breast cancer by 76% in a 40-month follow-up of postmenopausal patients with osteoporosis; and the drug also had a favorable effect on lipid metabolism, with 60 mg/d significantly reducing serum LDL levels in postmenopausal women; however, HDL and triglycerides were not affected. The study also showed that raloxifene significantly increased bone density in postmenopausal women, and 60mg/ or 120mg/d reduced the risk of vertebral fracture by 30% to 50% compared to the placebo group. SERM representative drugs include tamoxifen, raloxifene, droloxifene, etc. The side effects can be seen as facial flushing, painful leg cramps, and severe venous thromboembolism.
2.Drugs that promote osteoblastogenesis
Fluoride: It has been confirmed that it has the effect of stimulating bone formation and increasing the bone density of the vertebrae and hip, but the mechanism is still unknown. Some studies have shown that fluoride can increase the BMD (bone mineral density) of the lumbar spine, but not to reduce vertebral fractures, with its dose increases the risk of increased bone fragility, and increased gastrointestinal side effects. However, the incidence of vertebral fractures has also been reported to be reduced in recent years.
Parathyroid hormone (PTH): PTH has been proven to have a role in promoting bone formation in a large number of animal tests. Small doses of PTH can increase the number of osteoblasts, promote bone formation and reduce the loss of cancellous bone, but it is ineffective in increasing osteoclasts; large doses of PTH enhance osteoclast activity and promote bone resorption. Further studies on the dose-related effects of PTH and its clinical application are needed.
Protein synthesis hormone: these hormones can produce androgen-like effects and promote protein synthesis, promote the production of osteoblasts and thus increase bone mass; they can be used clinically in the elderly with progressive disease, with masculinization as a side effect, and should not be widely used; the main preparations are nandrolone phenylpropionate, Conilon, etc.
3.Drugs to promote ossification
Calcium: Calcium and vitamin D are the basic drugs for the prevention and treatment of osteoporosis, and are often used in combination. Calcium supplementation in appropriate amounts can inhibit the overproduction of parathyroid hormone, thus reducing bone resorption and fracture incidence. Calcium supplements can be divided into inorganic calcium and organic calcium according to their structures. Organic calcium does not require calcium-binding protein transfer during active absorption and is not irritating to the gastrointestinal tract, so it is more commonly used clinically, such as calcium L-threonate and calcium Leroy amino acid chelate. However, as age increases, the absorption rate of calcium in human body also decreases significantly; the intestinal calcium absorption rate for children aged 1-6 years is 36%-40%; for adults, it is 15%-20%, and about half of the elderly have an absorption rate of 15%. In order to obtain the synergistic effect of enhancing calcium absorption and inhibiting the overproduction of parathyroid hormone, the combination of calcium and vitamin D is commonly used clinically, such as Calcium D, Cathlip, Strep, etc.
Active vitamin D: the current first-line drug for the prevention and treatment of osteoporosis, physiological doses can promote calcium absorption and mineralization of bone in the small intestine, greatly reducing the incidence of fractures. According to research, this may be related to the action of vitamin D on the collagen matrix in bone and enhancement of bone density; however, high doses can cause a significant increase in bone resorption, which increases the bone conversion rate and predisposes to high blood calcium and high urine calcium. Currently, the commonly used preparations are Alpha D3, osteopontin, and 1.25(OH)2D3.
4.Sequential therapy
Also known as ADFR therapy, that is, activation (activation), inhibition (depress), discontinuation (free), and repetition (repeat), including the sequence of the 2 processes of bone resorption and bone formation. In 1979, Frost first proposed to use PTH or active vitamin D and neutral phosphorus as activators to temporarily activate osteoclasts, and then switch to CT or bisphosphonates to inhibit osteoclast function before osteoclasts undergo bone resorption. The osteoclast function is inhibited, followed by a period of discontinuation, and then repeated after one cycle, resulting in a significant increase in bone mass after several cycles of treatment. This method is a new therapy. It is not yet commonly used, and there are not many clinical reports yet, but it provides another new way for the treatment of osteoporosis.
5.The choice of drug treatment for senile osteoporosis
Age-related osteoporosis is a degenerative lesion of the systemic skeletal system that can occur in both men and women due to aging. The main physiopathological changes in the elderly include.
(i) Decrease in organic material synthesis in bone, more notably 1.25(OH)2D3 production, due to a decrease in the function of the ovaries and testes, resulting in a decrease in estrogen and thus a decrease in the absorption of calcium in the elderly.
(ii) Significant decline in renal function in the elderly, elevated blood phosphorus, secondary to rising parathyroid hormone (PTH) and further decline in bone calcium; decline in thyroid C-cell function in the elderly, reduced calcitonin (CT) secretion and decreased bone formation.
(iii) Decline in digestive system function in the elderly, with reduced intake of nutritional elements, especially calcium.
(iv) Decreased outdoor exercise in the elderly, reduced vitamin D synthesis in the body, decreased intestinal calcium and phosphorus absorption; decreased weight-bearing activities in the elderly, decreased bone formation and bone mineralization, resulting in increased bone loss. This eventually leads to decreased bone production and increased bone release.
The pathology of senile osteoporosis is characterized by decreased bone mass, degradation of bone microarchitecture, increased brittleness and increased susceptibility to fracture, decreased bone mineral content in proportion to the matrix, resulting in bone loss, while bone reconstruction is in negative equilibrium. Osteoclasts enhance bone resorption, while osteoblasts decline in function, resulting in insufficient bone formation and low conversion bone loss. In contrast, geriatric spine and proximal femur fractures are one of the major complications of geriatric osteoporosis. If the fractures are not treated with relevant anti-osteoporosis medications, further deterioration of bone quality with age may lead to fractures in other areas or re-fracture of healed areas.
Age-related osteoporosis is essentially a degenerative process of bone tissue structure. None of the current treatments can reverse this process. The goals of treatment for osteoporosis in the elderly include reducing bone loss, increasing bone mass, relieving bone pain, improving function, and preventing fractures. The ultimate goal of interventions for osteoporosis is to reduce the incidence of fractures. The role of drug therapy is mainly to prevent bone loss by regulating the function of osteoblasts, inhibiting bone resorption; stimulating osteoblasts to multiply and increase bone density, leading to increased bone formation and then establishing a balanced bone metabolism; and increasing alkaline phosphatase activity to stimulate mineralized material deposition in the matrix, thus maintaining bone mass. The treatment plan should be formulated with a comprehensive evaluation of the patient’s medical history, clinical manifestations and laboratory findings. The treatment is based on the application of bone formation promoters and ADFR therapy, and active vitamin D, fluoride, and protein-synthesizing hormones can be used during the activation phase; calcitonin, bisphosphonates, and estrogen are used during the inhibition phase.
Drugs that inhibit bone resorption, such as calcitonin, can be used in the early stage of senile osteoporotic fractures. The current popular method of intermittent medication can be used, mircalcitol 50IU intramuscular injection, 1 time/d. After 14d, it is changed to 2 times/week, 50IU each time, and maintained for 3 months. Add or switch to active VITD3 preparations such as osteopontin triol in the middle of treatment when bone resorption slows down. Rohypnol, 0.25 μg per day. drugs to improve bone quality, such as alendronate, can be used in the later stages. The mechanism of action is to inhibit the activity of osteoclasts and reduce bone pain. Fosamax 70mg, orally, once/week. As the base line treatment of the drug, it is necessary to supplement 600-1000mg of elemental calcium daily for patients with senile osteoporosis.