双膦酸盐的发展及临床应用

骨质疏松是一种全身性骨骼疾病,以骨组织丢失,微结构破坏,以及骨脆性增加为特征,导致骨折风险增加,骨折发生前的骨丢失及低骨量通常是无症状的。绝经后雌激素缺乏是骨质疏松最常见的原因。双膦酸盐是治疗骨质疏松的经典药物。     

微重力状态下骨量丢失对抗措施的研究进展

微重力状态下骨量丢失不同于老年性骨质疏松,是一种局部力学信号转导起主导作用、并受多层次调节的复杂变化过程,是一种特殊的废用性骨质疏松和继发性骨质疏松。长期的微重力环境,骨矿盐的持续丢失是航天飞行中人类所面临的严重生理反应之一,也是妨碍人类长期太空停留和探索外星球的主要障碍之一。目前微重力环境下骨量丢失的对抗措施主要有:物理对抗、营养、药物、细胞因子与基因治疗。航天飞行中,阻力锻炼、振动、人工重力等物理对抗措施的研究较为成熟;营养措施中着重阐述维生素、矿物质、蛋白质、Ω-3脂肪酸对骨代谢的作用,各种营养物质的具体摄入量仍有待规范;药物措施中双膦酸盐的使用基本得到广泛认可,其他药物的应用仍需要继续人体探索;细胞因子与基因的研究目前仍限于应用细胞进行研究。高级阻力训练系统(ARED)联合营养(部分联合双膦酸盐)是目前公认有效的对抗航天飞行中骨量丢失的措施。本文将详细阐述以上各个方面国内外的进展及争议,以及探讨未来微重力状态下骨量丢失的对抗措施的发展方向。     

失重骨丢失与防治措施研究进展

笔者综述了部分干预措施在稳定钙平衡和骨代谢以及防治骨量丢失方面的作用。空间飞行中提高钙的摄入量和补充维生素D,通过增加骨化三醇水平,能防止血清钙水平升高,维生素K能抵抗骨形成的减少。然而,目前还没有防止空间飞行航天员发生骨质疏松的有效药剂。在尾吊成年大鼠模拟失重动物模型中,应用双膦酸盐能够防护胫骨的松质骨量丢失,睾酮和维生素K2通过防止骨吸收增加和骨形成减少,能够对抗后肢的BMD下降。然而,这些药剂是否能够防止尾吊模拟失重大鼠引起的皮质骨骨量丢失尚不清楚。因此,除了补充钙、维生素D、维生素K,有待寻找有效的兼具抑制吸收和促合成代谢的药物来维持空间飞行中航天员的钙平衡和骨代谢,从而防护骨量丢失。     

儿童骨代谢标志物

儿童骨骼处于生长发育阶段,不同年龄阶段骨骼的生长存在不均衡性,且容易受疾病、外界环境、药物等诸多因素的影响,所以建立儿童特异的骨代谢标志物十分重要。骨代谢的检测方法很多,传统的双能X线吸收测定法辐射剂量低,精度及准确度高,且为无创性而被广泛应用于儿童骨骼系统疾病的检测,但其测定的骨密度反映的是一段时间内骨骼的静态状况,不能反映骨组织的动态本质,不能早期反映骨量的丢失,易导致骨质疏松的漏诊及误诊。而骨代谢标志物能反映骨代谢转换的动态情况,能反映骨代谢的早期灵敏变化,其测量可以早期评估骨代谢性疾病及监测治疗效果,联合骨密度检测能更准确地评估骨量的丢失,减少骨质疏松的漏诊及误诊。本文综述儿童骨代谢标志物特点及其意义,儿童参考范围、临床应用及影响因素等。以期早期发现儿童骨量的变化,对儿童骨骼系统疾病做到早发现、早诊断、早治疗,提高患儿骨骼系统疾病的近期及远期预后,进而提高儿童的生活质量。     

未产妇与骨质疏松性骨折

骨质疏松是一种常见的老年性疾病，绝经后雌激素缺乏和与年龄相关的骨量丢失是造成这一健康问题的主要原因。骨骼的生长和发育始自胚胎时期，并持续到出生后20多年。成年人骨量不再发生变化，但骨的代谢却持续不休，即骨生成和骨吸收这两个过程同时进行。年龄超过40岁后骨生成保持不变，骨吸收却增加，数十年后骨量是30岁时的一半。     

失重与骨代谢调节失衡

在失重飞行引起的所有人体生理系统变化中，其骨代谢的调节失衡为最严重的危害。其他生理系统的变化在航天飞行中会达到一种新的平衡状态，返回地面后，经过一段时间可以很快得到恢复。但骨钙的丢失却持续发展，且在返回地面后需要很长时间恢复。今后载人航天的重点在于长期飞行，太空失重导致航天员骨质疏松引起的危害就更大，因此失重状态下骨质丢失的研究已成为目前航天医学研究的重点。     

骨质疏松性骨折临床干预的管控

骨质疏松性骨折是骨骼在骨质疏松病变的基础上发生的病理性骨折,临床干预强调全程规范管理。管控要点包括：骨骼病变评估和与相关骨病的鉴别诊断;疼痛与急性骨丢失干预;骨折处理;骨折愈合促进;植入物松动预防;再骨折预防及抗骨质疏松治疗等关键点的管控。     

肌肉与骨质疏松症

老年性常见病骨质疏松症的发病原因主要是绝经后雌激素缺乏及与年龄相关的骨量丢失.肌肉作为骨骼最为邻近的组织之一,收缩时产生的机械负荷作用于骨骼,使骨产生应变;这种应变再作用于骨组织中的力学-生物力学调控系统,刺激成骨细胞和破骨细胞,调节骨形成和骨吸收,使骨密度和骨矿物含量发生改变.此外,肌肉收缩可增加身体协调和稳定性,减少跌倒的发生,与骨质疏松性骨折关系密切.该文就肌肉在骨代谢中的作用、肌肉与骨密度和骨矿物含量、肌肉与骨质疏松性骨折的相关研究作一综述.     

糖代谢对骨骼细胞的影响

骨骼细胞之间的相互平衡是维持骨骼健康的重要因素之一,骨骼细胞之间失衡容易造成骨质疏松等骨骼疾病。很多研究表明,糖代谢异常会打破骨形成和骨吸收的平衡,从而引起骨量减少和骨质疏松性骨折等疾病。笔者对成骨细胞、破骨细胞以及骨细胞相关的糖代谢的最新研究进展进行总结,系统剖析糖代谢对成骨细胞、破骨细胞以及骨细胞分化和功能的关键调控作用,为骨质疏松等骨疾病的治疗提供理论指导。     

失重性骨质疏松的发生机制及中药对其防治作用的研究进展

太空中由于重力消失,体液分布紊乱,会导致承重骨的肌肉发生进行性萎缩,骨骼所受到的应力刺激减少或消失,成骨细胞增殖障碍,从而导致了失重骨质疏松的发生。与其他骨质疏松不同的是该类型的骨质疏松的发生和发展具有一定的部位选择性,且返回地面后恢复比较困难。常规干预措施如药物、体育锻炼、机械刺激等虽然对缓解骨丢失起到一定的疗效,但也存在着一定弊端。中医认为"肾主骨生髓",主张从肾论治,收到了满意的疗效。在地面实验中,研究人员也发现采用补肾中药可以有效促进成骨细胞增殖,从而对抗模拟失重所造成的骨量丢失。因此本文拟对失重骨质疏松的发生机制及中医药在对抗失重骨质疏中的应用进行概述。     

Spaceflight-induced Bone Loss: Is there an Osteoporosis Risk?

Currently, the measurement of areal bone mineral density (aBMD) is used at NASA to evaluate the effects of spaceflight on the skeletal health of astronauts. Notably, there are precipitous declines in aBMD with losses >10 % detected in the hip and spine in some astronauts following a typical 6-month mission in space. How those percentage changes in aBMD relate to fracture risk in the younger-aged astronaut is unknown. Given the unique set of risk factors that could be contributing to this bone loss (eg, adaptation to weightlessness, suboptimal diet, reduced physical activity, perturbed mineral metabolism), one might not expect skeletal changes due to spaceflight to be similar to skeletal changes due to aging. Consequently, dual-energy X-ray absorptiometry (DXA) measurement of aBMD may be too limiting to understand fracture probability in the astronaut during a long-duration mission and the risk for premature osteoporosis after return to Earth. Following a brief review of the current knowledge-base, this paper will discuss some innovative research projects being pursued at NASA to help understand skeletal health in astronauts.     

Use of Quantitative Computed Tomography to Assess for Clinically-relevant Skeletal Effects of Prolonged Spaceflight on Astronaut Hips

Introduction: In 2010, experts in osteoporosis and bone densitometry were convened by the Space Life Sciences Directorate at NASA Johnson Space Center to identify a skeletal outcome in astronauts after spaceflight that would require a clinical response to address fracture risk. After reviewing astronaut data, experts expressed concern over discordant patterns in loss and recovery of bone mineral density (BMD) after spaceflight as monitored by dual-energy X-ray absorptiometry (DXA) and quantitative computed tomography (QCT). The pilot study described herein demonstrates the use of QCT to evaluate absence of recovery in hip trabecular BMD by QCT as an indicator of a clinically actionable response. Methodology: QCT and DXA scans of both hips were performed on 10 astronauts: once preflight and twice postflight about 1 wk and 1 yr after return. If trabecular BMD had not returned to baseline (i.e., within QCT measurement error) in 1 or both hips 1 yr after flight, then another QCT hip scan was obtained at 2 yr after flight. Results: Areal BMD by DXA recovered in 9 of 10 astronauts at 1 yr postflight while incomplete recovery of trabecular BMD by QCT was evident in 5 of 10 astronauts and persisted in 4 of the 5 astronauts 2 yr postflight. Conclusion: As an adjunct to DXA, QCT is needed to detect changes to hip trabecular BMD after spaceflight and to confirm complete recovery. Incomplete recovery at 2 yr should trigger the need for further evaluation and possible intervention to mitigate premature fragility and fractures in astronauts following long-duration spaceflight.     

女性内分泌与骨质疏松

骨质疏松症是目前全球发病率、致残率及医疗费用较高的疾患之一,是以骨强度下降、骨折风险性增加为特征的骨骼系统疾病.因其严重影响人们健康及生活质量,受到医学界广泛关注.骨质疏松症与机体内分泌息息相关,甲状腺功能异常、绝经后女性激素水平下降、补充激素医学干预等,均在不同程度上改变了骨分泌代谢.绝经后骨质疏松症是原发性骨质疏松症中最常见类型,雌、孕激素水平降低是其主要因素.补充女性激素对改善骨质疏松症状具有一定作用,但长期服用将导致激素依赖性肿瘤患病率增加.探索安全而有效的针对女性绝经后骨质疏松的个体化方案成为学术界研究的焦点.     

From earth to Mars: sex differences and their implications for musculoskeletal health

Historically, most diagnostic and treatment modalities have been based on a male model. Osteoporosis is one of the few diseases in which there has been sex-based research and treatment bias in favor of women. As such, it is not known whether treatments developed for women will be efficacious for men. Similarly, scientists are just beginning to research whether sex-based differences in musculoskeletal health exist with extended space travel. Both women and men lose muscle and bone with extended space travel, but the low numbers of female astronauts combined with a lack of discrete data make it challenging to accurately pinpoint sex-based differences. More data collection is needed to ensure that the musculoskeletal health of astronauts is better managed both on earth and in space.     

Bone metabolism and renal stone risk during International Space Station missions

Bone loss and renal stone risk are longstanding concerns for astronauts. Bone resorption brought on by spaceflight elevates urinary calcium and the risk of renal stone formation. Loss of bone calcium leads to concerns about fracture risk and increased long-term risk of osteoporosis. Bone metabolism involves many factors and is interconnected with muscle metabolism and diet. We report here bone biochemistry and renal stone risk data from astronauts on 4- to 6-month International Space Station missions. All had access to a type of resistive exercise countermeasure hardware, either the Advanced Resistance Exercise Device (ARED) or the Interim Resistance Exercise Device (iRED). A subset of the ARED group also tested the bisphosphonate alendronate as a potential anti-resorptive countermeasure (Bis + ARED). While some of the basic bone marker data have been published, we provide here a more comprehensive evaluation of bone biochemistry with a larger group of astronauts. Regardless of exercise, the risk of renal stone formation increased during spaceflight. A key factor in this increase was urine volume, which was lower during flight in all groups at all time points. Thus, the easiest way to mitigate renal stone risk is to increase fluid consumption. ARED use increased bone formation without changing bone resorption, and mitigated a drop in parathyroid hormone in iRED astronauts. Sclerostin, an osteocyte-derived negative regulator of bone formation, increased 10–15% in both groups of astronauts who used the ARED (p < 0.06). IGF-1, which regulates bone growth and formation, increased during flight in all 3 groups (p < 0.001). Our results are consistent with the growing body of literature showing that the hyper-resorptive state of bone that is brought on by spaceflight can be countered pharmacologically or mitigated through an exercise-induced increase in bone formation, with nutritional support. Key questions remain about the effect of exercise-induced alterations in bone metabolism on bone strength and fracture risk.     

Standards for performing DXA in individuals with secondary causes of osteoporosis.

This document addresses skeletal health assessment in individuals with secondary causes of osteoporosis. Recommendations are based on consensus of the Canadian Panel of the International Society for Clinical Densitometry and invited international experts. Bone mineral density (BMD) testing in these populations is performed in conjunction with careful evaluation of the disease state contributing to bone loss and increased fragility fracture risk, as well as assessment of other contributing risk factors for fracture. The presence of secondary causes of bone loss may further increase the risk of fracture independently of BMD and may necessitate earlier pharmacologic intervention. Dual-energy X-ray absorptiometry is indicated in the initial workup of secondary causes of osteoporosis. The BMD fracture risk relationship is not known for individuals with chronic renal failure (CRF). The BMD testing in this population may be normal in the presence of skeletal fragility, and quantitative bone histomorphometry is better at evaluating skeletal status than BMD in CRF. Dual-energy X-ray absorptiometry is a valuable tool in assessing skeletal health in individuals with secondary causes of osteoporosis.     

Effects of orbital spaceflight on human osteoblastic cell physiology and gene expression

During long-term spaceflight, astronauts lose bone, in part due to a reduction in bone formation. It is not clear, however, whether the force imparted by gravity has direct effects on bone cells. To examine the response of bone forming cells to weightlessness, human fetal osteoblastic (hFOB) cells were cultured during the 17 day STS-80 space shuttle mission. Fractions of conditioned media were collected during flight and shortly after landing for analyses of glucose utilization and accumulation of type I collagen and prostaglandin E(2) (PGE(2)). Total cellular RNA was isolated from flight and ground control cultures after landing. Measurement of glucose levels in conditioned media indicated that glucose utilization occurred at a similar rate in flight and ground control cultures. Furthermore, the levels of type I collagen and PGE(2) accumulation in the flight and control conditioned media were indistinguishable. The steady-state levels of osteonectin, alkaline phosphatase, and osteocalcin messenger RNA (mRNA) were not significantly changed following spaceflight. Gene-specific reductions in mRNA levels for cytokines and skeletal growth factors were detected in the flight cultures using RNase protection assays. Steady-state mRNA levels for interleukin (IL)-1alpha and IL-6 were decreased 8 h following the flight and returned to control levels at 24 h postflight. Also, transforming growth factor (TGF)-beta(2) and TGF-beta(1) message levels were modestly reduced at 8 h and 24 h postflight, although the change was not statistically significant at 8 h. These data suggest that spaceflight did not significantly affect hFOB cell proliferation, expression of type I collagen, or PGE(2) production, further suggesting that the removal of osteoblastic cells from the context of the bone tissue results in a reduced ability to respond to weightlessness. However, spaceflight followed by return to earth significantly impacted the expression of cytokines and skeletal growth factors, which have been implicated as mediators of the bone remodeling cycle. It is not yet clear whether these latter changes were due to weightlessness or to the transient increase in loading resulting from reentry.     

Bone markers, calcium metabolism, and calcium kinetics during extended-duration space flight on the mir space station.

Bone loss is a current limitation for long-term space exploration. Bone markers, calcitropic hormones, and calcium kinetics of crew members on space missions of 4-6 months were evaluated. Spaceflight-induced bone loss was associated with increased bone resorption and decreased calcium absorption. INTRODUCTION: Bone loss is a significant concern for the health of astronauts on long-duration missions. Defining the time course and mechanism of these changes will aid in developing means to counteract these losses during space flight and will have relevance for other clinical situations that impair weight-bearing activity. MATERIALS AND METHODS: We report here results from two studies conducted during the Shuttle-Mir Science Program. Study 1 was an evaluation of bone and calcium biochemical markers of 13 subjects before and after long-duration (4-6 months) space missions. In study 2, stable calcium isotopes were used to evaluate calcium metabolism in six subjects before, during, and after flight. Relationships between measures of bone turnover, biochemical markers, and calcium kinetics were examined. RESULTS: Pre- and postflight study results confirmed that, after landing, bone resorption was increased, as indicated by increases in urinary calcium (p < 0.05) and collagen cross-links (N-telopeptide, pyridinoline, and deoxypyridinoline were all increased >55% above preflight levels, p < 0.001). Parathyroid hormone and vitamin D metabolites were unchanged at landing. Biochemical markers of bone formation were unchanged at landing, but 2-3 weeks later, both bone-specific alkaline phosphatase and osteocalcin were significantly (p < 0.01) increased above preflight levels. In studies conducted during flight, bone resorption markers were also significantly higher than before flight. The calcium kinetic data also validated that bone resorption was increased during flight compared with preflight values (668 +/- 130 versus 427 +/- 153 mg/day; p < 0.001) and clearly documented that true intestinal calcium absorption was significantly lower during flight compared with preflight values (233 +/- 87 versus 460 +/- 47 mg/day; p < 0.01). Weightlessness had a detrimental effect on the balance in bone turnover such that the daily difference in calcium retention during flight compared with preflight values approached 300 mg/day (-234 +/- 102 versus 63 +/- 75 mg/day; p < 0.01). CONCLUSIONS: These bone marker and calcium kinetic studies indicated that the bone loss that occurs during space flight is a consequence of increased bone resorption and decreased intestinal calcium absorption.     

Men and Women in Space: Bone Loss and Kidney Stone Risk After Long‐Duration Spaceflight

Bone loss, a key concern for long‐duration space travelers, is typically considered a female issue. The number of women who have flown long‐duration space missions is now great enough to allow a quantitative comparison of changes in bone and renal stone risk by sex. Participants were 42 astronauts (33 men and 9 women) on long‐duration missions to the International Space Station. Bone mineral density (by dual‐energy X‐ray absorptiometry) and biochemical markers of bone metabolism (from blood and urine samples) were evaluated before and after flight. Data were analyzed in two groups, based on available resistance exercise equipment. Missions were 49 to 215 days in duration, flown between 2000 and 2012. The bone density response to spaceflight was the same for men and women in both exercise groups. The bone mineral density response to flight was the same for men and women, and the typical decrease in bone mineral density (whole body and/or regional) after flight was not observed for either sex for those using an advanced resistive exercise device. Biochemical markers of bone formation and resorption responded similarly in male and female astronauts. The response of urinary supersaturation risk to spaceflight was not significantly different between men and women, although risks were typically increased after flight in both groups, and risks were greater in men than in women before and after flight. The responses of men and women to spaceflight with respect to these measures of bone health were not different. © 2014 American Society for Bone and Mineral Research.