In 1994, the World Health Organization defined osteoporosis as a systemic metabolic bone disease characterized by reduced bone mass and destruction of bone microarchitecture, leading to increased bone fragility and susceptibility to fracture. 2001 consensus on the prevention, diagnosis and treatment of osteoporosis, published by the NIH, concluded that the disease is characterized by impairment of bone strength and increased risk of fracture. Bone strength mainly reflects the sum of bone density and bone mass, which contains bone structure, bone transformation, accumulation of damage (e.g. microfractures), bone mineralization and the properties of bone material, i.e. collagen and mineral salts.
Statistics show that about one third of women between 60 and 70 years of age have osteoporosis, increasing to two thirds in those over 80 years of age. Even women in their 50’s are at serious risk of osteoporotic fractures.
(A) The purpose of osteoporosis treatment
1.To relieve bone pain.
2.Increase bone density.
3.Reduce the incidence of fracture. It is the most important and ultimate purpose of treatment.
(B) Classification of anti-osteoporosis drugs
The strength and integrity of bone depends on the balance between bone resorption by osteoclasts from hematopoietic tissue and bone reconstruction by osteoblasts from bone marrow stromal cells. With aging at menopause or due to disease, osteoclast bone resorption exceeds bone formation by osteoblasts, resulting in bone loss. Most of the osteoporosis drugs are bone resorption inhibitors, which inhibit bone resorption and prevent excessive bone loss by reducing osteoclast production or reducing osteoclast activity-based drugs. Bone resorption inhibitor drugs can be utilized in patients with severe osteoporosis with rapid loss. Currently, there is a lack of bone-forming drugs that stimulate osteoblast activity. The application of such drugs to people with slow bone loss is beneficial for maintaining the structural integrity of bone trabeculae.
Drugs that inhibit bone resorption and promote bone formation include bisphosphonates (sodium hydroxyethylphosphonate, pamidronate, alendronate, and risedronate), calcitonin (salmon calcitonin and eel calcitonin derivatives), estrogens, selective estrogen receptor modulators, active vitamin D, and calcium; drugs that stimulate osteoblast activity for bone formation include parathyroid hormone, fluoride, active vitamin D, and anabolic steroids (iii) Bisphosphonates
(C) Bisphosphonates
In the past 30 years (Bisphosphonates) drugs have developed into the strongest inhibitors of bone resorption. Because it can reduce bone resorption caused by various reasons, it is used to prevent and treat primary osteoporosis (ageing and postmenopausal), braking osteoporosis, bone tumors, osteogenesis imperfecta, bone fiber dysplasia, inflammatory bone disease and other treatments. It can be used for secondary osteoporosis caused by glucocorticoids, thyroxine and heparin. For malignant tumor and paget`s bone disease caused by hypercalcemia as the first-line treatment drugs.
The effect of bisphosphonates on bone is mainly to inhibit osteoclast-mediated bone resorption by.
(1) inhibition of osteoclast precursor differentiation and recruitment, and inhibition of osteoclast formation.
(2) Phagocytosis of bisphosphonates by osteoclasts, leading to apoptosis of osteoclasts.
(3) Attachment to the bone surface, affecting osteoclast activity.
(4) Interference with osteoclast reception of bone resorption signals from the matrix.
(5) Reducing osteoclast activity through osteoblast-mediated. The accessory groups of bisphosphonates regulate the above-mentioned effects.
Different bisphosphonate formulations differ significantly in their ability to inhibit bone resorption and affect bone mineralization due to different side chain structures attached to the carbon atom. the R1 side chain group (OH) enhances its binding to hydroxyphosphonite, while the R2 side chain group determines its ability to resist resorption. The first generation bisphosphonates of sodium hydroxyethylphosphonate cause mineralization impairment when applied in therapeutic amounts, so periodic intermittent treatment. A variety of third generation bisphosphonates have been successfully developed in recent years. It is a kind of R2 side chain on the amino group, and enhanced inhibition of bone resorption ability, compared with sodium hydroxyethylphosphonate enhanced 1000 times, when the application of therapeutic dose of 6000 times before affecting the mineralization, so the general therapeutic dose will not cause mineralization disorders.
(D) Calcitonin
1. Calcitonin and bone strength
Calcitonin inhibits bone resorption by directly binding to the receptors of osteoclasts and rapidly inhibiting the activity of osteoclasts. It can prevent bone trabecular fracture and perforation, increase bone mass in high-conversion osteoporosis and inhibit bone loss and maintain bone mass in low-conversion osteoporosis. However, long-term use of the drug in patients with low-conversion osteoporosis has the consequence of leading to a decrease in new bone, a relative increase in old bone, and deterioration of bone quality. In patients with high conversion rate, the bone mass increase peaks in 2-3 years and the same risk exists thereafter. Therefore, intermittent calcitonin can be administered to patients with high conversion rate osteoporosis to repeatedly suppress and release the treatment, and for normal or low conversion rate osteoporosis, the use of bone formation promotion agents should be considered.
2.Calcitonin has strong analgesic effect
For osteoporosis-induced low back pain (especially in acute fractures of vertebrae) in patients with high conversion rate osteoporosis, this type of preparation can be one of the drugs of choice. Calcitonin acts on nociceptor-specific receptors and elevates beta-endorphin levels. Calcitonin blocks the entry of calcium ions into nerve cells and inhibits the synthesis of the pain mediator prostaglandin. However, long-term application of calcitonin can lead to a decrease in calcitonin receptors, and care must be taken in the treatment.
(V) Sex hormone replacement therapy
Sex hormone replacement therapy for the prevention of osteoporosis in postmenopausal women. HRT has been used for more than 70 years. Previous population studies have focused on early menopausal women, with bone mineral density as the endpoint of effectiveness. Estrogen inhibits bone resorption, reduces bone loss, and increases crestal BMD by 2-4%. A preventive effect on osteoporosis has been recognized. However, the fracture-preventing effects of estrogen, as well as the cardiovascular effects of estrogen and progestin on many other tissues including breast, uterus, and cardiovascular, and the serious and less frequent side effects of deep vein embolism, have not been elucidated in long-term, prospective trials in the past.
Estrogen replacement therapy and sex hormone replacement therapy in the prevention of postmenopausal osteoporosis are being further explored as safe and effective options to prevent fractures and weigh the pros and cons of cardiovascular disease and breast cancer, with strict selection of indications and intensive follow-up in estrogen replacement therapy with a view to reducing risks. For example, sex hormones can be used for a short period of time in postmenopausal women without contraindications to estrogen and progestin, with menopausal symptoms or pain from urinary tract atrophy, and those who need to prevent osteoporosis (low bone mass and high risk factors for osteoporosis), and should be switched to other drugs when the symptoms disappear. Long-term application to prevent some chronic diseases including cardiovascular disease and osteoporosis is not recommended.
(vi) Selective estrogen receptor modulators
Selective estrogen receptor modulators (SERMs) are synthetic non-hormonal agents that can bind to estrogen receptors and selectively act on estrogen receptors in different tissues, producing estrogen-like or anti-estrogenic effects in different target tissues respectively. Due to the structural characteristics of different SERMs, different affinities for different receptors arise and different biological effects are exerted in the tissues.
Raloxifene is the first selective estrogen receptor modulator approved by the FDA for the prevention and treatment of postmenopausal osteoporosis. Raloxifene is a nonsteroidal benzothiophene SERM that has estrogen agonist activity in bone, adipose metabolism and brain tissue, and estrogen antagonist effects in the breast and uterus.
The drug development of SERM is just beginning. A new type of SERM is currently under development that is beneficial to bone and cardiovascular without stimulating the endometrium and mammary glands and without increasing hot flashes. none of the SERMs have the effect of estrogen to prevent inflammation after urinary tract atrophy and to relieve postmenopausal symptoms.
(vii) The role of vitamin D in the treatment of osteoporosis
As an essential nutrient and hormone, vitamin D plays an important role in maintaining the balance of calcium and phosphorus metabolism in the body. Vitamin D is the only hormone that promotes intestinal calcium absorption. When the level of vitamin D in the blood is reduced or the intestinal sensitivity to vitamin D is weakened, intestinal calcium absorption will decrease, and intestinal calcium malabsorption is one of the important causes of the development of osteoporosis.
The mechanism of vitamin D treatment for osteoporosis is mainly: (1) promote the absorption of Ca2+ and P2- in the small intestine: there are receptors for vitamin D in the whole segment of the small intestine, with the highest concentration in the duodenum, which actively transduces calcium. (2) Promote bone resorption: Vitamin D increases the activity and number of osteoclasts, and PTH promotes the coordinated effect of bone resorption to maintain blood calcium levels. (3) Promote the role of bone mineralization and bone growth, especially can promote epiphyseal cartilage plate, and thus has anti-rickets effect.
Active vitamin D3 plays a bidirectional role in the metabolic process of bone resorption and bone formation, and it is mainly used to promote bone formation and enhance muscle strength in the treatment of osteoporosis. Although it is not very obvious to improve bone mass, it has significant effects in improving bone quality, relieving neuromuscular pain and reducing the occurrence of crestal fractures. Active vitamin D3 can be applied not only alone, but also in combination with a variety of other anti-osteoporosis drugs with significant efficacy. It should be noted that the long-term use of large amounts of vitamin D (D3) can also cause vitamin D3 toxicity due to dosage transition.
(viii) Calcium
Calcium intake has a role in increasing bone mass and preventing bone loss or fracture. Estrogen in adult women promotes the absorption of calcium in the small intestine and promotes the reabsorption of calcium in the renal tubules. Postmenopausal estrogen reduction and old age both show reduced calcium absorption and increased urinary calcium excretion, and enhanced bone resorption, so more calcium should be supplemented in time than in adulthood to prevent or delay the loss of bone mass.
The results of a survey conducted by the Chinese Academy of Preventive Medicine in the 1990s on more than 90,000 people nationwide, the daily calcium intake was only 405mg, and the surveys conducted by Zhao and Hu on the calcium intake of middle-aged and elderly people in Beijing were 360mg and 320mg respectively, indicating that the calcium intake of our population is quite low, coupled with the fact that more than half of the population is lactose intolerant and cannot effectively absorb calcium and other nutrients from dairy products, therefore, when calcium intake from food is insufficient, calcium supplements should be taken. Calcium intake should be ≥1000 mg/day for elderly and osteoporotic patients. The elemental calcium content in calcium carbonate, calcium citrate, calcium chloride, calcium lactate and calcium gluconate is 40%, 27%, 21%, 13% and 9.3%, respectively. The time to take calcium, for those who lack stomach acid, it is recommended to take calcium immediately after meals, when the stomach acid secretion is more, calcium is easily absorbed. It is also advocated that calcium should be taken at night before going to bed to reduce the loss of bone calcium in the latter half of the night. The maximum tolerable intake is 2000mg/day, which is the upper limit of daily nutrient intake that will not cause health hazards to 97-98% of individuals in a certain population.
(ix) Parathyroid hormone
Parathyroid hormone (PTH) is one of the major peptide hormones that regulate calcium and bone metabolism, and it has the effect of increasing bone mass and improving bone microstructure and biomechanical properties. The absolute bioavailability of PTH by subcutaneous injection is 95%, and the blood PTH level increases linearly with increasing dose. 20ug of subcutaneous injection results in peak blood PTH at 30 minutes. The half-lives of intravenous and subcutaneous injections were 5 minutes and 1 hour, respectively.
Adverse effects, no serious adverse effects were seen after PTH application. Changes in blood calcium concentrations have been reported differently, with most reporting mild elevations that remain within the normal range, transient mild hypercalcemia, and decreases in blood calcium. There were nausea (5.3-8%), headache (5.3-8%), calf cramps (0.7-3%), dizziness (9%), and discontinuation due to adverse reactions in 6-9.3% of cases.
(X) Fluoride
Fluorine is a stimulant of bone formation, its mechanism of action: 1. fluorine can replace the hydroxyl group in hydroxyapatite, forming fluorapatite crystals, more resistant to bone resorption; 2. under the action of mechanical external force, fluorapatite crystals can generate a strong current, stimulating osteoblasts, along the direction of the line of action of mechanical external force; 3. fluoride can inhibit the synthesis of osteoblast-specific phosphate – tyrosine protease, so that Fluoride can inhibit the synthesis of osteoblast-specific phosphate-tyrosine protease and increase the content of phosphate-tyrosine protein in osteoblasts, which is a promoter to stimulate mitosis of osteoblasts.
Adverse effects.
1, mainly gastrointestinal symptoms: epigastric pain, nausea, vomiting.
2. Lower limb pain syndrome: most often involves the heel bone and is dose-related. The incidence is low when the drug is used periodically, and the symptoms disappear after dose reduction or discontinuation. The possible causes of pain are ① microfracture of bone trabeculae; ② local osteogenic reaction, which may be accompanied by local calcium deficiency.
3, mineralization disorders, high doses are prone to mineralization disorders, the dosage must be strictly controlled, and take calcium and vitamin D at the same time.