骨质疏松症治疗新药-甲状旁腺激素的研究进展

骨质疏松症已成为严重影响老年人生活质量的慢性疾病，其发病过程复杂，危害严重，近年来的研究表明，甲状旁腺激素(PTH)是治疗骨质疏松症的理想药物。文章就PTH的基因结构、蛋白表达、生理功能及治疗骨质疏松症的进展进行了综述。     

骨质疏松症药物治疗概述

回顾分析近年来国内外对骨质疏松症药物治疗的研究概况，从钙和维生素D。、性激素补充治疗、选择性雌激素受体调节剂、二膦酸盐、降钙素、氟化物、甲状旁腺激素、中药等方面加以阐述，提示对骨质疏松症合理用药的方法。     

甲状旁腺激素构效关系的研究进展

甲状旁腺激素(PTH)是生物体内调节钙、磷代谢最为重要的肽类激素之一,其氨基端1-34片段具有全分子PTH与受体结合的能力及生物活性,被广泛用于研究PTH的结构与功能。PTH二级结构中富含α-螺旋,该螺旋结构在PTH与受体相互作用中起重要作用,其中羧基端负责与受体结合,氨基端负责生理活性。现从甲状旁腺激素的结构、与受体的相互作用和构效关系等角度出发,综述了甲状旁腺激素近年来的研究状况,为开发新型骨质疏松症治疗药物提供理论依据。     

骨质疏松症的药物治疗现状

目的;介绍骨质疏松症的药物治疗现状。方法：参考国内外文献,从药理作用、临床疗效和不良反应及发展前景等方面综述VD、降钙素、雌激素、双膦酸盐盐、氟化物、甲状旁腺激素、VK2、伊普拉芬、钙剂和骨生长因子制剂等骨质疏松症治疗药物。结果与结论：上述十类药物对骨质疏松症治疗都有效,其作用机制及疗程长短尚待深入研究。     

甲状旁腺素研究进展

甲状旁腺素是治疗骨质疏松症的重要药物,具有刺激骨骼生长,加强骨组织微结构,降低骨脆性的作用。但是,甲状旁腺素属于肽类药物需注射给药且价格昂贵,发展新型非肽类骨质疏松症治疗药物成为当前研究热点。文章综述了甲状旁腺素的生物学活性、结构特征及其构效关系,并对甲状旁腺素与受体的结合机制进行了总结,为开发新型非肽类抗骨质疏松症药物提供了理论依据。     

骨质疏松症的药物治疗现状

目的:介绍骨质疏松症的药物治疗现状。方法:参考国内外文献,从药理作用、临床疗效和不良反应及发展前景等方面综述V_D、降钙素、雌激素、双膦酸盐、氟化物、甲状旁腺激素、V_K2、伊普拉芬、钙剂和骨生长因子制剂等骨质疏松症治疗药物。结果与结论:上述十类药物对骨质疏松症治疗都有效,其作用机制及疗程长短尚待深入研究。     

治疗骨质疏松症的新药米诺膦酸

骨质疏松症是一种以低骨量和骨组织结构性退化为特征的骨疾病。目前临床上使用的骨质疏松症治疗药物,如雌激素类、选择性雌激素调节剂、降钙素和双膦酸盐类主要有利于减少骨吸收;还有一些治疗药物,如氟化物和甲状旁腺激素可增加骨的形成。抗骨吸收疗法在治疗骨质疏松症中非常有效,即便其通常并不能诱导新骨的形成。     

骨质疏松症治疗市场最新动态

1．市场近况 骨质疏松症治疗市场在过去十余年间发生了实质性的变化，后者以二膦酸盐类药物逐渐替代激素替代疗法成为市场优势药物类别为重要特征。然至今日，因Lilly公司于2002年底上市的重组甲状旁腺激素特瑞帕肽（teriparatide／Forteo）业已获得显著成长。故生物技术产品亦已开始影响骨质疏松症治疗市场格局。     

甲状旁腺激素激动剂特立帕肽

骨质疏松症是一种以低骨量和骨组织退化为特征的最常见的代谢性骨病。这种疾病将导致大量骨质丢失，骨骼脆性增加，容易发生骨折。常见骨折部位是髋骨、脊椎骨和腕骨。市场上多数治疗骨质疏松症的药物，如雌激素、双磷酸盐类和降血钙素均属骨吸收抑制剂。而其他一些药物如氟化物、甲状旁腺激素(PTH)是骨形成促进剂。     

甲状旁腺激素治疗骨质疏松症的研究进展

甲状旁腺激素(PTH)在骨代谢中具有促进骨骼重建、增加骨密度的作用,因此有效的应用新型的骨形成促进剂PTH,将为骨质疏松症等代谢性骨病提供新的药物选择。     

Design and applications of parathyroid hormone analogues.

The endocrine parathyroid hormone (PTH) is the major regulator of serum calcium levels. In contrast, the autocrine/paracrine parathyroid hormone-related peptide (PTHrP) has been associated with organism development. Both are secreted as much larger molecules but have their major functions associated with their N-terminal 34 residues. They share a common receptor expressed in organs critical to PTH function - bone, kidney, and intestine. PTH and PTHrP receptor activation stimulates adenylyl cyclase (AC), phospholipase C (PLC), and phospholipase D (PLD) in target cells. It has been possible to separate the AC-stimulation from that of PLC. AC-stimulation requires at least the N-terminal 28 residues of PTH and PLC-stimulation requires a minimum of residues 29-32-NH2. Intermittent administration of PTH stimulates bone growth and requires AC-stimulation. The shortest linear sequence of hPTH with essentially full anabolic activity for bone growth-stimulation is hPTH(1-31)NH2. Two applications are postulated for PTH and PTHrP-based pharmaceuticals - treatment of bone loss due to osteoporosis and reversal of the hypercalcemic effect of malignancy. PTHrP analogues which strongly inhibit PTHrP AC-stimulation showed promise for the treatment of malignancy-associated hypercalcemia in animal trials but failed in human ones. However, both animal and human trials of hPTH have shown significant bone growth-stimulating effects. New deletion, substitution and cyclized analogues of PTH show great promise both for greater in vitro activity and possibly for improved delivery and greater specificity as agents for restoration of bone loss in osteoporosis.     

Effects of parathyroid hormone on cancellous bone mass and structure in osteoporosis

Parathyroid hormone (PTH) is the major hormonal regulator of calcium homeostasis. PTH is a potent stimulator of bone formation and can restore bone to an osteopenic skeleton, when administered intermittently. Osteoblasts are the primary target cells for the anabolic effects of PTH in bone tissue. Anabolic effects of PTH on bone have been demonstrated in animals and humans, by numerous measurement techniques including bone mineral density and bone histomorphometry. Clinically, the most important aspect of treatment for osteoporosis is prevention of fractures. Microstructural alterations, such as loss of trabecular connectivity, have been implicated in increased propensity for fracture. Recent two-dimensional (2D) and three-dimensional (3D) assessments of cancellous bone structure have shown that PTH can re-establish lost trabecular connectivity in animals and humans. These results provide new insight into the positive clinical effects of PTH in osteoporosis. In recent randomized controlled clinical trials of intermittent PTH treatment, PTH decreased incidence of vertebral and non-vertebral fractures in postmenopausal women. Thus, PTH shows strong potential as therapy for osteoporosis. However, 2D and 3D structural analysis of advanced osteopenia in animals has shown that there is a critical limit of trabecular connectivity and bone strength below which PTH cannot completely reverse the condition. Given that PTH treatment fails to completely restore trabecular connectivity and bone strength in animals with advanced osteopenia, early treatment of osteoporosis appears important and efficacious for preventing fractures caused by decreased bone strength resulting from decreased trabecular connectivity.     

Efficacy and safety of alendronate and risedronate for postmenopausal osteoporosis

INTRODUCTION: This paper discusses the efficacy and safety of alendronate and risedronate in the treatment of postmenopausal osteoporosis. METHODS: The literature was searched with the PubMed from 1996 to the present, with respect to strictly conducted systematic reviews with homogeneity, meta-analyses with homogeneity, and randomized controlled trials (RCTs) with narrow Confidence Interval. RESULTS: According to the results of large randomized controlled trials (RCTs), bisphosphonates (alendronate, risedronate, and ibandronate), raloxifene, calcitonin, parathyroid hormone (PTH), and strontium ranelate effectively prevent vertebral fractures in postmenopausal women with osteoporosis. Because raloxifene has been shown to be effective in preventing the initial vertebral fracture in postmenopausal osteoporotic women without prevalent vertebral fractures, it is considered in the treatment of postmenopausal women with mild osteoporosis or osteopenia with some risk factors for fractures. RCTs have also demonstrated that alendronate, risedronate, PTH, and strontium are useful to prevent non-vertebral fractures and that alendronate and risedronate prevent hip fractures, thus alendronate or risedronate are primarily considered as the first-line drugs in the treatment of elderly women with osteoporosis having some risk factors for falls. While it has been suggested that PTH may be considered in patients with severe osteoporosis, the use of PTH in the treatment for osteoporosis is limited to 2 years or less, and it may be appropriate to use other anti-resorptive drugs after the completion of PTH treatment to maintain the skeletal effects gained during the treatment. RCTs have demonstrated that the incidence of gastrointestinal tract adverse events in postmenopausal osteoporotic women treated with bisphosphonates and placebo are similar, and also the long-term efficacy and safety of alendronate and risedronate. CONCLUSION: The evidence derived from the literature, based on strict evidence-based medicine guidelines, suggests that there is long-term efficacy and safety with alendronate and risedronate in the treatment of osteoporosis in postmenopausal women.     

Oral delivery of biologically active parathyroid hormone

Purpose. Parathyroid hormone (PTH), the only drug known to stimulate bone formation, is a peptide therapeutic indicated in the treatment of osteoporosis. Unfortunately, PTH is only effective when dosed by injection because it has no oral bioavailability. Herein we report the oral absorption of PTH in rats and monkeys facilitated by the novel delivery agent, N-[8-(2-hydroxy-4-methoxy)bensoyl]amino caprylic acid (4-MOAC). Methods. 4-MOAC was selected from a group of 100 delivery agents based on in vitro chromotography studies and in vivo screening studies in rats. The PTH/4-MOAC combination was then tested in monkeys. The interaction of 4-MOAC and PTH was evaluated by nuclear magnetic resonance (NMR) spectroscopy. Results. Monkeys were administered an aqueous solution containing 4-MOAC and PTH and mean peak serum PTH concentrations of about 3000 pg/mL were obtained. The relative bioavailability of oral PTH was 2.1% relative to subcutaneous administration. The biological activity of the orally-delivered PTH was further evaluated in a rat model of osteoporosis. These studies showed that the bone formed following oral PTH/4-MOAC administration was comparable to that formed following PTH injections. The 4-MOAC mediated absorption of PTH is hypothesized to be the result of a noncovalent interaction between 4-MOAC and PTH. The preliminary evaluation of this interaction by NMR is described. Conclusions. 4-MOAC facilitates the absorption of PTH following oral administration to both rats and monkeys. The orally-absorbed PTH is biologically active as demonstrated in a rat model of osteoporosis.     

Novel calcium sensing receptor ligands: a patent survey

INTRODUCTION: In the parathyroid gland, the calcium sensing receptor responds to small changes in circulating levels of Ca(2+), and consequently stimulates or inhibits the secretion of parathyroid hormone (PTH). Thus, ligands potentiating the action of calcium (calcimimetics) lead to decreased PTH secretion and can thus be useful for the treatment of hyperparathyroidism. On the other hand, ligands which antagonize the action of calcium (calcilytics) stimulate PTH secretion, favoring bone tissue regeneration. AREAS COVERED: This review first discusses the rapid development of calcimimetics (only one of which has been approved for the treatment of hyperparathyroidism) followed by that of calcilytics (none of which has as yet been approved for the treatment of osteoporosis). Peer-reviewed articles generated by these patents are also surveyed. EXPERT OPINION: The rapid progress in developing a clinically approved calcimimetic has not been matched by an identical success in finding an orally available calcilytic useful for the treatment of osteoporosis. However, the growing importance of osteoporosis as a debilitating disease is a stimulating factor in discovering such compounds.     

Efficacy and safety of alendronate and risedronate for postmenopausal osteoporosis

ABSTRACT

Introduction: This paper discusses the efficacy and safety of alendronate and risedronate in the treatment of postmenopausal osteoporosis.

Methods: The literature was searched with the PubMed from 1996 to the present, with respect to strictly conducted systematic reviews with homogeneity, meta-analyses with homogeneity, and randomized controlled trials (RCTs) with narrow Confidence Interval.

Results: According to the results of large randomized controlled trials (RCTs), bisphosphonates (alendronate, risedronate, and ibandronate), raloxifene, calcitonin, parathyroid hormone (PTH), and strontium ranelate effectively prevent vertebral fractures in postmenopausal women with osteoporosis. Because raloxifene has been shown to be effective in preventing the initial vertebral fracture in postmenopausal osteoporotic women without prevalent vertebral fractures, it is considered in the treatment of postmenopausal women with mild osteoporosis or osteopenia with some risk factors for fractures. RCTs have also demonstrated that alendronate, risedronate, PTH, and strontium are useful to prevent non-vertebral fractures and that alendronate and risedronate prevent hip fractures, thus alendronate or risedronate are primarily considered as the first-line drugs in the treatment of elderly women with osteoporosis having some risk factors for falls. While it has been suggested that PTH may be considered in patients with severe osteoporosis, the use of PTH in the treatment for osteoporosis is limited to 2 years or less, and it may be appropriate to use other anti-resorptive drugs after the completion of PTH treatment to maintain the skeletal effects gained during the treatment. RCTs have demonstrated that the incidence of gastrointestinal tract adverse events in postmenopausal osteoporotic women treated with bisphosphonates and placebo are similar, and also the long-term efficacy and safety of alendronate and risedronate.

Conclusion: The evidence derived from the literature, based on strict evidence-based medicine guidelines, suggests that there is long-term efficacy and safety with alendronate and risedronate in the treatment of osteoporosis in postmenopausal women.     

Parathyroid hormone as an anabolic skeletal therapy

The quest for effective treatment for osteoporosis merits great attention because of the widespread prevalence of this disease, which is not only associated with fragility fractures, but also with significant morbidity and mortality. The efficacy of the antiresorptive drugs in this disease is achieved by reducing bone turnover, increasing bone density and improving other aspects of bone quality. This article concentrates on another approach to the treatment of osteoporosis, namely the use of anabolic therapy, which has even greater prospects for improving bone quality.Parathyroid hormone (PTH) is currently available only as the recombinant amino-terminal fragment, PTH(1-34), known as teriparatide. The full-length molecule, human PTH(1-84), is currently being investigated, as are other PTH molecules. Teriparatide improves bone quality through actions on bone turnover, bone density, bone size and bone microarchitecture. In postmenopausal women with osteoporosis, teriparatide reduces the incidence of vertebral and nonvertebral fractures. In individuals who have previously been treated with an antiresorptive agent, the subsequent actions of teriparatide on bone density are transiently delayed if bone turnover has been markedly suppressed. Combination therapy with teriparatide or PTH(1-84) and an antiresorptive agent does not appear, at this time, to offer advantages over the use of PTH or an antiresorptive agent alone. However, in order to maintain the densitometric gains in bone density obtained with PTH, it is important to follow its use with that of an antiresorptive agent.