Treatment options for glucocorticoid-induced osteoporosis

ABSTRACT

Introduction

Glucocorticoid (GC) induced osteoporosis (GIOP) is the most common form of secondary osteoporosis. It develops in a dose and time dependent manner, due to a rapid and transient increase in bone resorption, followed by the inhibition of bone formation.     

Biomechanics

Therapeutic agents used to treat osteoporosis reduce the incidence of vertebral and nonvertebral fractures in osteoporotic women. The antiremodeling agents, such as the bisphosphonates, prevent bone loss by suppressing the remodeling rate, perhaps increasing bone volume slightly, and increasing mineralization of the tissue. The anabolic agents, of which rhPTH(1–34) is the only one approved, accomplish this in a manner that is almost completely the opposite in terms of biological process. rhPTH(1–34) causes net bone gain by stimulating both modeling and remodeling, by increasing bone volume significantly through direct bone apposition to trabecular and endocortical surfaces, and by reducing the mean degree of tissue mineralization (a natural consequence of enhanced remodeling). Each of these treatments maintains or increases bone strength and is similarly effective at preventing fractures. However, because of their different mode of action, each has different consequences for bone matrix quality (defined here by microdamage accumulation and by the properties of mineral and collagen) and the mechanical properties of the tissue. Although bone's composite nature makes it a relatively tough material—more like fiberglass than glass—the accumulation of damage will nevertheless reduce its residual mechanical properties until the damage is repaired through remodeling. Agents that suppress remodeling are associated with both microdamage accumulation and increased mineralization. The biological importance of damage and mineralization to bone's mechanical properties is still a source of debate.     

Teriparatide in the management of osteoporosis

Fracture of the hip is frequently a catastrophic event in the elderly, often resulting in death within a year and of the survivors, few regain pre-fracture quality of life. Although less appreciated, fractures of the spine result in significant morbidity and are also associated with increased mortality compared with individuals without a fracture. In recent years there has been an explosion in the development of new drugs for the treatment of osteoporosis. Recombinant human parathyroid hormone (1–34) (20 μg/day) is a recent addition to this armamentarium with a novel mechanism of action, which was approved by the US FDA for the treatment of post-menopausal osteoporosis and male osteoporosis secondary to hypogonadism in November 2002. It is the first osteoporosis treatment that leads to the formation of new bone with architecture similar to normal bone. Intense efforts have been made to understand the effect of teriparatide on antiresorptive therapy and vice versa. Although these relationships are not completely understood, the results of recent studies allow clinicians to begin to optimize therapeutic gains in bone mineral density and improve anti-fracture efficacy.     

Combination therapy with anabolic and antiresorptive agents

Combination therapy, the use of an anabolic agent with an antiresorptive agent in some sequence, has been evaluated in a number of clinical trials. There is no fracture data on combination therapy except for a small trial using PTH and estrogen. It appears that simultaneous use of a bisphosphonate (alendronate 10 mg per day) with PTH offers no advantage (and appears to blunt PTH's effect) compared with the use of PTH alone based on bone density gains. Previous therapy with alendronate also blunts gains in bone density with PTH therapy. Estrogen and raloxifene, whether given before or with PTH, do not blunt its anabolic effect. Sequential therapy with PTH followed by an antiresorptive agent (alendronate) offers the greatest gains in bone mass. It is possible that alendronate or other bisphosphonates given in a different dosing regimes may have different effects on PTH's anabolic effect. More trial data on combination therapy is needed.     

The differential effects of bisphosphonates,SERMS (selective estrogen receptor modulators), and parathyroid hormone on bone remodeling in osteoporosis

Osteoporosis is a skeletal metabolic disease characterized by a compromised bone fragility, leading to an increased risk of developing spontaneous and traumatic fractures. Osteoporosis is considered a multifactorial disease and fractures are the results of several different risk factors both extra- and intraskeletal. Thus bone fragility can be the end point of several different causes: a) failure to reach an optimal peak bone mass during growth; b) excessive bone resorption resulting in decreased bone mass and microarchitectural deterioration; c) inadequate formation upon an increased resorption during the process of bone remodeling. The pharmacological therapeutical options, available to date, are directed on prevention of fractures. The aim of this paper is to describe the activities and the mechanisms of action, as known at present, of the most used therapies for osteoporosis and their clinical implications. Improvement of knowledge in this field will allow us to further improve therapeutical choices and pharmacological interventions.     

Management of bisphosphonate‐related osteonecrosis of the jaw: a literature review

Osteonecrosis of the jaw (ONJ) is a serious side effect of bisphosphonate use in patients with osteoporosis, Paget's disease, hypercalcemia of malignancy, metastatic bone disease and multiple myeloma, although recently this complication has also been reported in patients under non‐bisphosphonate medication, such as denosumab and bevacizumab. The occurrence of ONJ is higher in oncology patients treated with high‐dose iv bisphosphonates than in osteoporosis patients treated with oral bisphosphonates. Although multiple hypotheses have been proposed, the exact pathogenic mechanism of ONJ still remains unclear. As treatment protocols based on randomized controlled trials (RCTs) do not exist, we critically reviewed the existing data concerning the management of bisphosphonate‐related osteonecrosis of the jaw, including the most recent data for the use of teriparatide and hyperbaric oxygen.     

重组人甲状旁腺激素(1-34)促成骨作用及在口腔领域的应用

文题释义： 特立帕肽(teriparatide)：即重组人甲状旁腺激素(1-34)(rhPTH 1-34),2002年经美国食品药品监督管理局(FDA)批准应用于骨质疏松症的治疗,是第一代骨合成代谢药。它可以直接刺激新骨的成骨细胞形成,实现有效的合成代谢,在口腔领域的研究也表现出良好的促进种植体-骨结合及牙周再生等效果。 甲状旁腺激素：由甲状旁腺主细胞合成与分泌,是含84个氨基酸残基的单链多肽,位于人类甲状旁腺激素分子氨基端(N-端)的1-34位氨基酸序列是其生物活性部位。甲状旁腺激素是调节人体钙磷内环境稳态及骨代谢的重要激素,间歇低剂量给予甲状旁腺激素对骨骼发挥合成代谢作用。 背景：重组人甲状旁腺激素(1-34)(recombinant human parathyroid hormone 1-34,rhPTH 1-34),即特立帕肽,为甲状旁腺激素氨基端片段,作为骨合成代谢药,因可以直接刺激新骨形成、增加骨量而成为研究热点,也因其强大的成骨效应引起口腔领域的关注与应用。 目的：对特立帕肽的成骨机制、有效性和安全性及其在口腔领域的研究进展进行综述。 方法：第一作者检索近20年PubMed数据库、万方数据库收录的相关文章。英文检索词为“rhPTH(1-34),teriparatide,osteoporosis,stomatology,Jaw,implant-osseointegration,periodontal”,中文检索词为“重组人甲状旁腺激素(1-34),特立帕肽,骨质疏松,口腔医学,颌骨,种植体-骨结合,牙周”。共选取56篇文献进行综述。 结果与结论：特立帕肽可以直接刺激新骨的成骨细胞形成,实现有效的合成代谢,其在口腔领域的研究表现出良好的促进种植体-骨结合、牙周再生、骨缺损愈合及提高正畸稳定性的效果,在口腔领域有良好的应用前景,但仍需要更多更高质量的动物实验及临床研究证实。未来甲状旁腺激素类药物及其类似物可与骨组织工程技术有机结合,更好地促进骨修复,同时也更好地服务于口腔颌面部的修复治疗。 ORCID: 0000-0002-2333-4260(董西玲) 中国组织工程研究杂志出版内容重点：组织构建;骨细胞;软骨细胞;细胞培养;成纤维细胞;血管内皮细胞;骨质疏松;组织工程