氟化物在骨质疏松症治疗中的应用

氟化物是一种有明显疗效的骨形成刺激剂，是目前临床应用的作用最强的骨同化药物。氟化物通过刺激细胞增生促进骨形成。同时它可减少骨吸收。氟化物可有效增加椎骨小梁骨的骨矿密度，对皮质骨无明显作用，甚至使其减少。另外，氟化物有明显的抗脊椎骨折效应，从而用于治疗Ⅰ型骨质疏松症及其某些继发性骨质疏松症。在使用氟化物用于治疗时应补充足量的钙剂、适量的维生素Ｄ，并为避免其毒副作用应选择合理的剂量与剂型。     

氟化物在骨质疏松症治疗中的应用

氟化物是一种有明显疗效的骨形成刺激剂，是目前临床应用的作用最强的骨同化药物。氟化物通过刺激成骨细胞增生促进骨形成，同时它可减少骨吸收。氟化物可有效增加椎骨小梁骨的骨矿密度，对皮质骨无明显作用，甚至使其减少。另外，氟化物有明显的抗脊椎骨折效应，从而用于治疗Ｉ型骨质疏松症及某些继发性骨质疏松症。在使用氟化物用于治疗时应补充足量的钙剂、适量的维生素Ｄ，并为避免其毒副作用应选择合理的剂量与剂型     

甲状旁腺激素调控人成骨样细胞膜型基质金属蛋白酶-1表达

目的 探讨甲状旁腺激素(PTH)对人成骨样MG-63细胞膜型基质金属蛋白酶-1(MT1-MMP)表达的影响及调节骨代谢作用的机制。方法 用PTH(1-34)干预MG-63细胞培养，Northern杂交及Western杂交检测MT1-MMP mRNA与蛋白质表达水平。结果 PTH(1-34)10^-9mmol／L～10^-7mmol／L浓度对MG-63细胞MT1-MMP mRNA及蛋白质表达有抑制作用，并呈剂量依赖性。10^-8mmol／L干预在2～48h内对抑制MT1-MMP mRNA及蛋白质表达抑制有时间依赖性。蛋白激酶A(PKA)抑制剂H-89阻断PTH(1-34)抑制MT1-MMP表达的效应，而蛋白激酶A(PKA)激动剂Forskolin抑制MT1-MMP表达。结论 PTH具有抑制成骨样细胞MT1-MMP表达的作用，其作用途径可能有PKA信号转导途径参与。     

氟化物对骨形成中成骨细胞的影响及机制

氟化物作为促骨形成药物之一 ,最早被推荐应用于骨质疏松症的临床治疗 ,目前仍是唯一可供临床使用的有效的促骨形成的药物。近年来由于成骨细胞 (osteoblast OB)培养技术及基因工程技术的发展 ,对氟化物刺激骨形成作用有了更进一步的认识 ,有助于我们对氟中毒时氟骨症机制的探讨。1　氟化物对成骨细胞的直接作用　　氟是一种已知可影响骨形成的非激素因子。具有双相调节作用。长期小剂量氟可促进骨形成 ;大剂量可引起骨质疏松或骨硬化。在人体和动物实验研究中 ,较多学者报道氟中毒时骨量增多是由于 OB数增多 ,活性增加 ,生命周期延长 [1 …     

结核分枝杆菌对乙硫异烟胺/丙硫异烟胺耐药的机制及其增敏剂研究进展

乙硫异烟胺(ethionamide,ETH)/丙硫异烟胺(prothionamide,PTH)是异烟肼(isoniazid,INH)的类似物,属于二线抗结核药品,目前主要用于耐多药结核病(multidrug resistant tuberculosis,MDR-TB)的治疗。ETH/PTH的临床应用受到与INH交叉耐药,以及临床治疗剂量ETH、PTH杀菌作用弱和产生消化道不良反应的影响。最近几年来,基于ETH/PTH的分子作用机制的ETH增敏剂的研究也取得了明显进展。作者复习文献,主要从ETH/PTH耐药及INH交叉耐药机制、增敏剂研究等方面进行了总结。     

糖皮质激素诱导骨质疏松的细胞及分子学机制

长期大剂量使用糖皮搏击激素会诱导骨质疏松,其机制为糖皮质激素抑制成骨细胞的增殖及分化,促进成骨细胞的凋亡,并降低其功能,使骨形成延迟并减少。它可抑制破骨细胞的产生,但是否影响破骨细胞的活性则尚不清楚;此外,它也可促进破骨细胞凋亡。     

糖皮质激素诱导骨质疏松的细胞及分子学机制

长期大剂量使用糖皮质激素会诱发骨质疏松 ,其机制为糖皮质激素抑制成骨细胞的增殖及分化 ,促进成骨细胞的凋亡 ,并降低其功能 ,使骨形成延迟并减少。它可抑制破骨细胞的产生 ,但是否影响破骨细胞的活性则尚不清楚 ;此外 ,它也可促进破骨细胞凋亡。     

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)及重组人甲状旁腺激素(rhPTH)作为骨形成促进剂可以有效促进骨骼重建,增加骨密度,预防骨折发生,越来越受到人们的关注。本文对PTH及rhPTH的基础研究、动物实验以及临床观察进行综述。     

骨质疏松症的联合治疗与序贯治疗

联合和序贯治疗骨质疏松症是为了追求更大疗效的一种选择,本文检索分析近45年来发表的此类临床研究结果。目前尚无证据表明两种抗骨吸收联合治疗有降低骨折发生率的叠加作用（如双膦酸盐加ERT或雷洛昔芬,雌激素加降钙素）,仅观察到联合治疗可以降低骨转换和增加骨密度的结果。联合甲状腺激素（PTH）同抗骨吸收药物,随着药物的不同对骨密度的效果各异。在停止使用促进骨形成剂PTH后序贯使用双膦酸盐、雷洛昔芬或锶盐,可以防止因停用PTH后的骨丢失,可能成为未来治疗严重的绝经后骨质疏松症的重要选择。     

骨定量超声测量的临床应用

骨定量超声测量(QUS)是一种诊断骨质疏松症和预测骨折风险的新技术,不但可反映骨密度,还可反映骨的微结构、弹性和脆性等骨结构特性。QUS使用的临床有效性主要体现在其对骨质疏松诊断、骨折风险预测及抗骨质疏松治疗疗效评估3个方面,具有广阔的应用前景。目前认为它更适合于大规模人群的筛查,但是在使用过程中必须充分估计误差对QUS准确性及精确性的影响。     

PTH

Injectable forms of parathyroid hormone (PTH) and its N-terminal fragments are bone anabolic agents proven by randomized clinical trials. Alternate delivery forms of parathyroid hormone are under clinical or preclinical studies, including nasal, transdermal, and pulmonary formulations of PTH (1-34). Oral forms of PTH (1-34) and its analogs or orally active calcium sensing receptor antagonist, which induces PTH secretion from parathyroid gland, are also under development. PTH will be the one of the major therapeutic agents for osteoporosis treatment.     

Cells of the osteoclast lineage as mediators of the anabolic actions of parathyroid hormone in bone

PTH is an anabolic agent used to treat osteoporosis, but its mechanisms of action are unclear. This study elucidated target cells and mechanisms for anabolic actions of PTH in mice during bone growth. Mice with c-fos ablation are osteopetrotic and lack an anabolic response to PTH. In this study, there were no alterations in PTH-regulated osteoblast differentiation or proliferation in vitro in cells from c-fos -/- mice compared with +/+; hence, the impact of osteoclastic cells was further investigated. A novel transplant model was used to rescue the osteopetrotic defect of c-fos ablation. Vertebral bodies (vossicles) from c-fos -/- and +/+ mice were implanted into athymic hosts, and the c-fos -/- osteoclast defect was rescued. PTH treatment to vossicle-bearing mice increased 5-bromo-2'-deoxyuridine (BrdU) positivity in the bone marrow and increased bone area regardless of the vossicle genotype. To inhibit recruitment of osteoclast precursors to wild-type vossicles, stromal derived factor-1 signaling was blocked, which blunted the PTH anabolic response. Treating mice with osteoprotegerin to inhibit osteoclast differentiation also blocked the anabolic action of PTH. In contrast, using c-src mutant mice with a late osteoclast differentiation defect did not hinder the anabolic action, suggesting key target cells reside in the intermediately differentiated osteoclast population in the bone marrow. These results indicate that c-fos in osteoblasts is not critical for PTH action but that cells of the osteoclast lineage are intermediate targets for the anabolic action of PTH.     

Anabolic therapy for osteoporosis: Parathyroid hormone

Recombinant human parathyroid hormone (PTH 1–34) is the only anabolic agent currently approved for the treatment of osteoporosis. The term anabolic is based on mechanism of action. PTH stimulates bone formation, in contrast to antiresorptive agents, which reduce bone resorption and formation. Recent investigations involving the PTH(1-34) and PTH(1-84) peptides, alone and in combination or sequential regimens with antiresorptive agents, have provided a greater understanding of the place of PTH in the armamentarium against osteoporosis. These studies indicate that adding a bisphosphonate to PTH in previously untreated individuals does not produce additional bone benefit; however, sequential use of PTH followed-up by an antiresorptive agent is highly effective at increasing bone mineral density. Adding PTH after an antiresorptive agent also produces substantial bone density increments, though the magnitude of bone density increase may differ for different antiresorptive agents. PTH can repair underlying micro-architectural defects in bone, improve bone mass substantially, and perhaps change macro-architecture and geometry of bone. There are still many unanswered questions regarding PTH treatment of osteoporosis, including the optimal duration of treatment, optimal dosing regimen, mechanism of resistance to its effect after 18–24 months, and the effect of subsequent rechallenge.     

Enhancement of fracture healing with parathyroid hormone

Since the approval of parathyroid hormone (PTH) as an anabolic treatment for osteoporosis, there has been an increasing interest in other potential clinical uses for this compound in musculoskeletal conditions. Fracture healing is one area of particular interest. It is now widely recognized that daily PTH administration is an effective therapy for increasing bone mineral density and preventing fractures in both male and female osteoporosis patients. More recently, a growing body of evidence supports the conclusion that PTH will also be an effective anabolic therapy for the enhancement of bone repair following fracture. Several animal studies have demonstrated that PTH therapy consisting of daily subcutaneous injections during repair leads to increased callus volumes and a more rapid return of bone strength. Additionally PTH, these reports demonstrated that PTH treatment enhanced repair in older animals, models of osteoporosis, and healthy sexually mature animals. These results underscore the potential of PTH as an anabolic therapy for enhancing the rate of bone repair and regain of mechanical strength in a broad spectrum of fracture patients.     

Mathematical model of paracrine interactions between osteoclasts and osteoblasts predicts anabolic action of parathyroid hormone on bone

To restore falling plasma calcium levels, PTH promotes calcium liberation from bone. PTH targets bone-forming cells, osteoblasts, to increase expression of the cytokine receptor activator of nuclear factor kappaB ligand (RANKL), which then stimulates osteoclastic bone resorption. Intriguingly, whereas continuous administration of PTH decreases bone mass, intermittent PTH has an anabolic effect on bone, which was proposed to arise from direct effects of PTH on osteoblastic bone formation. However, antiresorptive therapies impair the ability of PTH to increase bone mass, indicating a complex role for osteoclasts in the process. We developed a mathematical model that describes the actions of PTH at a single site of bone remodeling, where osteoclasts and osteoblasts are regulated by local autocrine and paracrine factors. It was assumed that PTH acts only to increase the production of RANKL by osteoblasts. As a result, PTH stimulated osteoclasts upon application, followed by compensatory osteoblast activation due to the coupling of osteoblasts to osteoclasts through local paracrine factors. Continuous PTH administration resulted in net bone loss, because bone resorption preceded bone formation at all times. In contrast, over a wide range of model parameters, short application of PTH resulted in a net increase in bone mass, because osteoclasts were rapidly removed upon PTH withdrawal, enabling osteoblasts to rebuild the bone. In excellent agreement with experimental findings, increase in the rate of osteoclast death abolished the anabolic effect of PTH on bone. This study presents an original concept for the regulation of bone remodeling by PTH, currently the only approved anabolic treatment for osteoporosis.     

The use of parathyroid hormone in the treatment of osteoporosis

Anabolic skeletal agents have recently broadened our therapeutic options for osteoporosis. By directly stimulating bone formation, they reduce fracture incidence by improving bone qualities in addition to increasing bone mass. Teriparatide [recombinant human parathyroid hormone(1–34)], the only anabolic agent currently approved in the United States for osteoporosis, has emerged as a major therapeutic approach to selected patients with osteoporosis. Teriparatide is approved for both postmenopausal women and men with osteoporosis who are at high risk for fracture. With the use of this anabolic agent, bone density and bone turnover increase, microarchitecture improves, and bone size is beneficially altered. The incidence of vertebral and nonvertebral fractures is reduced with teriparatide use. Combination therapy with parathyroid hormone and an antiresorptive does not appear to offer definitive advantages over the use of PTH or an antiresorptive alone, although recent ideas about combining these agents may offer new insights. In order to maintain increases in bone density acquired during PTH therapy, it is important to follow its use with an antiresorptive agent.     

PTH and stem cells

At least 2 different types of cells, hematopoietic and mesenchymal, are present in the adult bone marrow, in addition to endothelial cells. Hematopoietic and mesenchymal cells are believed to originate from hematopoietic stem cells (HSC) and mesenchymal stem cells (MSC), respectively. The bone marrow stroma, a cellular microenvironment that supports HSC, is composed of non-hematopoietic cells and contains MSC. A unique expansion of the bone marrow stroma, also known as marrow fibrosis, is the hallmark of a variety of disorders including hyperparathyroidism and fibrous dysplasia. PTH is the first bone anabolic agent approved by US Food and Drug Administration for the treatment of osteoporosis. Recent studies have suggested that PTH treatment may affect the number of hematopoietic stem cells in the bone marrow and their mobilization into the bloodstream. In addition, cells with classical features of mesenchymal stem cells/progenitors have been shown to express receptors for PTH, and to increase in number and undergo redistribution in the adult bone marrow upon PTH treatment. In this review, we will summarize the up-to-date knowledge on PTH and its relation to stem cells. We will also discuss the contribution of different cell types to the development of marrow fibrosis and the involvement of PTH signaling in this pathology.     

Parathyroid hormone activates adhesion in bone marrow stromal precursor cells

The ability of parathyroid hormone (PTH) to enhance bone formation has recently been exploited in the treatment of osteoporosis. However, the underlying mechanisms are unknown. Osteoblasts, the bone-forming cells, derive from multipotential bone marrow stromal precursors called colony-forming units-fibroblastic (CFU-F) upon culture ex vivo. Adhesion of such stromal precursors to bone is likely to be an early event in the anabolic response of bone to PTH. To test this, we measured the number of CFU-F that could be extracted from murine bone marrow after administration of an anabolic dose of PTH. We found that a very early response is a dramatic reduction, starting within 2 h, in the number of CFU-F that could be extracted from their bone marrow. We then tested whether PTH has the ability to activate adhesion of CFU-F in vitro. For this, bone marrow cells were incubated in PTH for varying times. Non-adherent cells were then removed, and the adherent cells were incubated in PTH-free medium for 14 days to assess, as colony formation, the number of CFU-F that had adhered in the preceding period. We found that incubation in PTH caused a substantial increase in the number of CFU-F that adhered within 24 h. This increase was abrogated by peptidic inhibitors of integrins. The increase did not seem to be mediated through a PTH-induced increase in interleukin-6, since interleukin-6 had no effect on CFU-F numbers when substituted for PTH. Similarly, adhesion was unaffected by incubation of bone marrow cells in dibutyryl cyclic AMP, nor by inhibitors or donors of nitric oxide. However, activation of CFU-F in vitro by PTH was strongly inhibited by indomethacin and mimicked by prostaglandin E(2), and indomethacin reversed the PTH-mediated reduction of CFU-F that could be extracted from mouse bone marrow. These results suggested that PTH rapidly activates adhesion of CFU-F to plastic or bone surfaces. This activation may represent an early event in the anabolic response of bone cells to PTH.     

Catabolic and anabolic actions of parathyroid hormone on the skeleton

PTH, an 84-amino acid peptide hormone synthesized by the parathyroid glands, is essential for the maintenance of calcium homeostasis.While in its traditional metabolic role, PTH helps to maintain the serum calcium concentration within narrow, normal limits and participates as a determinant of bone remodeling, more specific actions, described as catabolic and anabolic are also well known. Clinically, the catabolic effect of PTH is best represented by primary hyperparathyroidism (PHPT), while the osteoanabolic effect of PTH is best seen when PTH or its biological amino-terminal fragment [PTH(1-34)] is used as a therapy for osteoporosis. These dual functions of PTH are unmasked under very specific pathological (PHPT) or therapeutic conditions. At the cellular level, PTH favors bone resorption, mostly by affecting the receptor activator of nuclear factor κ-B (RANK) ligand (RANKL)-osteoprotegerin- RANK system, leading to an increase in osteoclast formation and activity. Increased bone formation due to PTH therapy is explained best by its ability to enhance osteoblastogenesis and/or osteoblast survival. The PTH-induced bone formation is mediated, in part, by a decrease in SOST/sclerostin expression in osteocytes. This review focuses on the dual anabolic and catabolic actions of PTH on bone, situations where one is enhanced over the other, and the cellular and molecular mechanisms by which these actions are mediated.