Parathyroid hormone (PTH) is the main hormone that regulates calcium and phosphorus metabolism and maintains calcium homeostasis in the body. Its peripheral metabolism is mainly carried out in the kidney, bone and liver, and acts directly on bone and kidney, and the target cells are osteoblasts and renal tubular cells. Osteoblasts have PTH receptors on their membranes that bind PTH1-84 and PTH1-34 fragments, and it is believed that bone preferentially takes up PTH1-34 and responds to it in a timely manner. The renal tubular cell membrane also has receptors for both peptide fragments that bind PTH1-84 and PTH1-34 and can be reabsorbed, where PTH1-84 can be mediated. The liver is not the main target tissue of PTH, but only takes up PTH1-34 and is the main site of its degradation into the amino and carboxy termini. The effects of PTH on bone are, on the one hand, to increase the number and viability of osteoclasts, promote bone resorption, and release Ca2+ and P3+ into the blood; on the other hand, to increase the number of osteoblasts and promote the release of bone growth factor from osteoblasts, thus promoting bone formation, which is the basis of the much talked about effect of PTH on osteoporosis treatment. the effect of PTH on the kidney is in the proximal tubule for Ca2+ reabsorption, promoting 1a hydroxylase activity and the conversion of 25(OH)VitD3 to active 1,25(OH)2VitD3, thereby increasing the absorption of Ca2+ in the duodenum and small intestine and increasing blood calcium concentrations. Recently, the relationship between PTH and osteoporosis has received increasing attention, and there are some reports of PTH treatment of osteoporosis in the literature, which are briefly described below. 1. The rationale for PTH treatment of osteoporosis Osteoporosis is a common bone metabolic disease. With the development of the economy and the extension of human life expectancy, osteoporosis has become an increasingly serious global health problem, and osteoporotic fracture is a disease with high morbidity and mortality among the elderly population in many countries in the world, seriously endangering people’s health and known as a silent epidemic. The prevention and treatment of this disease is a common concern in the medical community, but due to its multiple causes and complex pathogenesis, the search for a reasonable and effective treatment pathway has increasingly attracted the attention of endocrinologists. Prank et al. observed that the secretion of PTH in normal subjects is temporal in nature. One is the variability of the kinetic state of PTH secretion from minute to minute, and the main role of this phase is to regulate blood calcium homeostasis. The other is the high stability of PTH secretion state, i.e., the regularity of the number of secretions per day and the amount of each secretion, and the main role of this phase is to maintain normal bone mass and bone metabolic balance. In normal subjects, the variability of PTH plasma concentration during bone reconstruction prevents the down-regulation of PTH affinity by PTH receptors; and the shift from variability of PTH secretion to high regularity of PTH secretion maintains the physiological balance of bone resorption and bone formation, while in osteoporotic patients PTH is secreted in a haphazard form, causing imbalance of bone formation and bone resorption and causing bone loss with bone structural changes. This indicates that the alteration of PTH secretion pattern may be one of the main reasons for the formation of osteoporosis. In general, the treatment of osteoporosis should start from two aspects, one is the use of osteoclast inhibitors, such as the well-known diphosphonates, estrogen, calcitonin, etc. can slow down or inhibit osteoclast activity too much to prevent the development of osteoporosis, but these agents can not stimulate osteoclasts to produce strong new bone, that is, they can not make the bone that has suffered damage to rebuild, but only slow down the rate of bone resorption. Another aspect is the use of bone formation stimulating agents, such as fluoride agents, PTH, but PTH differs from fluoride agents in that:the bone formed by PTH stimulation is normal. Therefore, PTH is considered to be the most effective of such drugs, in fact, as early as the 1930s of this century, PTH has now been discovered, is but failed to attract attention. In the last decade, a large number of animal and clinical studies have revealed that PTH alone or in combination is a new way to increase bone mass, improve bone quality, and treat osteoporosis. ejersted et al. reported that PTH has a pro-bone proliferative effect. toromanoff et al. showed experimentally that:after PTH was administered to osteoporotic female rats, the total calcium amount in the rats returned to normal levels, and daily injections of human(h) PTH1-34 dose-dependently increased the amount and dry weight of bone calcium in de-ovalized and vitamin D-deficient rats, corrected bone loss, and promoted bone formation. Moreover, its effects were superior to those of estrogen, diphosphonates and fluoride preparations. In China, Bai Xiuying et al. also found that PTH does contribute to the proliferation of bone-like cells through multilevel and multilevel laboratory studies. The intracellular messaging pathway through which PTH contributes to the proliferation and differentiation of osteoid cells is not well understood, with some suggesting that the proliferation signal is transmitted through adenylate cyclase/protein kinase A and others suggesting that it is transmitted through phospholipase C/protein kinase C. Rixon et al. suggested that the cellular mechanism by which PTH stimulates bone growth is that PTH binds to the low-affinity region of the PTH receptor in osteoblasts, thereby activating protein kinase. PTH stimulates osteoblasts containing PTH receptors, which in turn secrete autocrine and paracrine pro-osteogenic biochemical factors, such as insulin-like growth factor I (IGF-I), and PTH stimulates the proliferation of osteoblast precursors in the bone marrow and promotes the differentiation of these precursors into osteoblasts with an active osteogenic role, while enhancing osteoblast activity to stimulate bone formation. 2. Specific use of PTH in the treatment of osteoporosis 2.1 Combination of PTH in the treatment of osteoporosis The adult skeleton is constantly being reshaped to repair minor fractures caused by daily life and to maintain an optimal weight-bearing structure, and it has been studied that the adult skeleton is renewed once every 8-10a, depending on the osteoclast’s pro-bone resorption and the osteoblast’s pro-bone formation. Therefore, an effective treatment for osteoporosis is the administration of PTH to promote new bone formation and, of course, the administration of osteoclast inhibitors to prevent resorption of the new bone formed. The importance of the combination of the bone formation stimulant PTH and bone resorption inhibition is evident. 2.2 Dosage of PTH for osteoporosis It is generally believed that high doses of long-term PTH inhibit osteoblasts and convert large monocytes into osteoclasts, thereby promoting bone resorption, whereas low doses of PTH have an anabolic effect on bone, stimulating osteoblasts to form new bone and increasing bone mechanical strength. Osteoblast stimulation by periodic injections of small doses of PTH produces a range of autocrine and paracrine osteogenic factors, but sustained high-dose PTH stimulation causes osteoblasts to express a number of different factors, such as collagenase, granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-6 (IL-6), and the fibrinogen activator prostaglandin E2 (PGE2), which together complement and activate osteoclasts. Together they complement and activate osteoblasts. The binding of PTH to specific receptors on target cell membranes is the trigger for altered target cell function; PTH binding to receptors activates a variety of intracellular messaging pathways, transducing or amplifying extracellular messages and regulating target cell function. formation than bone resorption; while high doses of PTH activate the phospholipase C system through PTH-R2, enhancing osteoporosis-breaking bone resorption. 2.3 Mode of administration of PTH for osteoporosis PTH has both osteogenic and osteolytic effects, and different modes of administration can have different consequences, with continuous infusion of PTH causing bone loss, while intermittent administration is effective in increasing bone mass. As previously mentioned, Prank et al. found that PTH secretion in osteoporotic patients lacked the temporal phase of normal subjects, so intermittent subcutaneous injections of PTH can artificially cause PTH secretion in osteoporotic patients to resemble that of normal subjects, thus achieving the goal of treating osteoporosis. Bone formation is enhanced in rats following either daily subcutaneous injections or continuous intravenous infusions of PTH, but only rats receiving continuous infusions show a concomitant increase in bone resorption, with the end result that daily injections of PTH increase bone mass, which was replicated in experimental dogs. Inhibition of bone resorption with the drug followed by continuous or intermittent administration of PTH was found to increase bone calcium and dry weight in rats by both modes of administration, suggesting that the failure of continuous infusion of PTH to increase bone mass is due to the fact that the bone formation it produces is offset by the concomitant increase in bone resorption. 3. Problems Currently, hPTH1-3440-100ug is commonly used for the treatment of osteoporosis by subcutaneous injection three to five times a week. The necessity to use the subcutaneous route of administration is the main drawback of the treatment, which may be difficult to obtain long-term cooperation from patients, and the development of an orally active or nasal mucosal spray active PTH preparation is an urgent problem to be solved. The most functionally homogeneous fragment of stimulated adenylate cyclase, hPTH1-31, has the same osteogenic effect as the larger dual-signaling fragments hPTH1-84 and hPTH1-34, but without their initial Ca2+ and protein kinase C induction, and therefore does not affect blood Ca2+ concentrations. Thus the fragment of PTH that activates adenylate cyclase ~hPTH1-31 is an agent to improve the efficacy of osteoporosis, which can effectively stimulate osteoblasts to form strong bone with safety, efficiency and few side effects. With the development of molecular biology technology, the study of gene expression, molecular structure and signaling system of PTH and its receptor will help the development of small fragments of PTH by non-injection route. The manufacture of inexpensive, single-functional PTH fragments with few side effects for administration via the non-injection route is the trend in the use of PTH for the treatment of osteoporosis.