Pathogenesis, prevention and therapy of steroid osteoporosis

The pathogenesis of glucocorticoid osteoporosis is complex. Numerous, controversial mechanisms have been postulated. However, there is certainly both a reduction in bone formation as well as an increase in resorption. The increase in resorption probably occurs before the reduction in formation. As of a threshold dose of approx. 7.5% prednisone equivalents per day, administered for approx. 1 year, a loss of cancellous bone occurs; the reduction in compact bone is far less pronounced. Histologically, bone matrix synthesis appears to be uniformly reduced, while resorption varies considerably. The cancellous bone structure has a filigree appearance which is also recognizable by the glass-like appearance on radiographs. The development of new glucocorticoid preparations such as Deflazacort, which promotes osteoporosis less than, e.g., prednisone, is very promising. For the prevention and treatment of glucocorticoid-induced osteoporosis, frequently used drugs today are fluorides, ossein-hydroxy-apatite complexes and, especially in acute glucocorticoid osteoporosis, calcitonin.     

The influence of age and sex on bone resorption of secondary hyperparathyroidism in renal osteodystrophy

Summary The severity and incidence of subperiosteal and intracortical bone resorption were evaluated from fine-detail hand radiographs at × 8 magnification in relation to age and sex in 239 chronically dialyzed adult renal failure patients. The severity of subperiosteal resorption decreased significantly with advancing age in both sexes and the incidence decreased somewhat more in males than in females; no such trends were apparent for intracortical resorption. Although the mean values for the grades of subperiosteal and intracortical resorption were significantly higher in females than in males, when the effect of age and duration of follow-up were taken into consideration, this sex difference remained significant only for intracortical resorption. It is concluded that when studying certain aspects of renal osteodystrophy, differences due to age, sex, and duration of follow-up should be considered in the final interpretation of data.     

Longitudinal microradioscopic comparisons on endosteal and juxtaendosteal bone loss in premenopausal and postmenopausal women, and in those with end-stage renal disease

Endosteal bone resorption is the principal mechanism of bone loss in involutional osteoporosis and in renal osteodystrophy. In the cortical bone it is often accompanied by juxtaendostal bone resorption. Using finedetail radiographs and × 6 magnified viewing, longitudinal radiographie observations and measurements were made on these two forms of bone resorption in the metacarpals II, III, and IV in three groups of women: (1) premenopausal, (2) postmenopausal, and (3) patients with end-stage renal disease. Bone loss was found to be negligible in the premenopausal women, but in postmenopausal and renal patients both endosteal and Juxtaendosteal bone resorption were frequently demonstrable. It is suggested that when a base-line fine-detail hand radiograph is obtained at the time of the menopause, follow-up radiographs may permit detection of relatively early endosteal and Juxtaendosteal bone loss by comparing the respective areas in metacarpals with those of the original radiograph. Since the methodology does not require expensive equipment, has a low intraobserver error and is simple to perform, it may deserve to be further evaluated in studies aimed at developing a simple and inexpensive approach as a screening method for early detection of postmenopausal osteoporosis.     

Comparative study of axial and femoral bone mineral density and parameters of mandibular bone quality in patients receiving dental implants

Introduction In view of the increase in the life expectancy of humans and in edentulism of the population above 50 years of age, in which the prevalence of osteoporosis is also higher, it is fundamental to better understand the effects of systemic bone mass loss on the healing process of dental implants and to determine the quality of the bone that surrounds them. The objective of the present study was to compare systemic osteoporosis (axial and femoral) and parameters of mandibular bone quality, and to evaluate osseointegration in postmenopausal women receiving dental implants. Methods The sample consisted of 39 women aged 48–70 years, 19 with a densitometric diagnosis of osteoporosis in the lumbar spine and femoral neck and 20 controls with a normal densitometric diagnosis. Bone mineral density was measured in the patients and controls by dual-energy X-ray absorptiometry. Eighty-two osseointegrated dental implants were placed in the mandible, 39 of them in the osteoporosis group and 43 in the control group. Mandibular bone quality was evaluated by classifying mandibular inferior cortical and trabecular bone on panoramic radiographs and by histomorphometric analysis of a mandibular bone biopsy. Osseointegration was analyzed after 9 months. Results No significant difference was observed between patients with osteoporosis and controls when comparing individuals with a normal cortex and those with a severely or moderately eroded cortex determined on panoramic radiographs. Histomorphometric analysis also revealed no difference in the parameters of bone formation or resorption between the two groups. Implant failure was observed in only one case. Conclusion We conclude that there is no association between systemic osteoporosis (axial and femur) and parameters of poor mandibular bone quality. The loss of one implant (1.2%) is compatible with the literature and cannot be attributed to systemic osteoporosis. An erratum to this article can be found at     

Hedgehog-Gli信号通路在骨质疏松发生中作用的研究进展

国内外骨质疏松患病率逐年增高,因此对骨质疏松的研究也一直是医学热点。骨质疏松的发生发展是由多种细胞和信号通路共同作用的结果,其中成骨细胞和破骨细胞的正常偶联是维持骨稳态防止骨质疏松发生的重要因素。Hedgehog-Gli信号通路可以通过调控成骨细胞的增殖、分化及活性,进而调控骨组织的形成,另一方面它还可以通过刺激破骨细胞RANKL表达进而促进破骨细胞增殖分化,从而调控骨吸收的过程,因此对维持骨稳态亦发挥重要作用。本文主要归纳总结了近年来中外学者对Hedgehog-Gli信号通路在骨质疏松发生中作用机制的研究结果,以期进一步明确在骨质疏松发生中Hedgehog-Gli信号通路的作用,从而为骨质疏松的防治开拓新的思路和方向。     

Comparative study of axial and femoral bone mineral density and parameters of mandibular bone quality in patients receiving dental implants

INTRODUCTION: In view of the increase in the life expectancy of humans and in edentulism of the population above 50 years of age, in which the prevalence of osteoporosis is also higher, it is fundamental to better understand the effects of systemic bone mass loss on the healing process of dental implants and to determine the quality of the bone that surrounds them. The objective of the present study was to compare systemic osteoporosis (axial and femoral) and parameters of mandibular bone quality, and to evaluate osseointegration in postmenopausal women receiving dental implants. METHODS: The sample consisted of 39 women aged 48-70 years, 19 with a densitometric diagnosis of osteoporosis in the lumbar spine and femoral neck and 20 controls with a normal densitometric diagnosis. Bone mineral density was measured in the patients and controls by dual-energy X-ray absorptiometry. Eighty-two osseointegrated dental implants were placed in the mandible, 39 of them in the osteoporosis group and 43 in the control group. Mandibular bone quality was evaluated by classifying mandibular inferior cortical and trabecular bone on panoramic radiographs and by histomorphometric analysis of a mandibular bone biopsy. Osseointegration was analyzed after 9 months. RESULTS: No significant difference was observed between patients with osteoporosis and controls when comparing individuals with a normal cortex and those with a severely or moderately eroded cortex determined on panoramic radiographs, although patients with MEC/SEC had lower femoral neck BMD than those with NC (0.688 +/- 0.17 vs. 0.814+/- 0.144 g/cm2, P<0.012). Histomorphometric analysis also revealed no difference in the parameters of bone formation or resorption between the two groups. Implant failure was observed in only one case. CONCLUSION: We conclude that there is an association between low femoral neck BMD and poor mandibular bone quality as assessed by panoramic radiography. The loss of one implant (1.2%) is compatible with the literature and cannot be attributed to systemic osteoporosis.     

New targets for intervention in the treatment of postmenopausal osteoporosis

Postmenopausal osteoporosis is a disease of high bone remodeling, with an imbalance of bone resorption over bone formation, resulting in decreased bone mineral density and disruption of bone microarchitecture. With our improved understanding of the molecular and cellular regulators and mediators of bone remodeling, new targets for therapeutic intervention have been identified. Receptor activator of nuclear factor κB ligand (RANKL) is the principal regulator of osteoclast differentiation, activity, and survival; denosumab, a fully human monoclonal antibody to RANKL, inhibits bone resorption and is approved for the treatment of women with postmenopausal osteoporosis at high risk of fractures. Cathepsin K is a protease produced by activated osteoclasts that degrades the protein matrix of bone. An inhibitor of cathepsin K, odanacatib, is in phase III clinical trials for the treatment of postmenopausal osteoporosis; it decreases bone resorption while seeming to suppress bone formation less than other antiresorptive agents. Sclerostin is a cytokine produced by osteocytes that inhibits osteoblastic bone formation; investigational monoclonal antibodies to sclerostin, such as AMG 785, have osteoanabolic properties with the potential to improve clinical outcomes in patients with osteoporosis. These and other novel interventions that target newly recognized regulators of bone remodeling are promising agents for the treatment of osteoporosis.     

Assessment of the effects of breast cancer on bone and the response to therapy

The skeleton is the most frequent site of metastatic disease in breast cancer and also the site of greatest morbidity. In addition, there is now recognition that accelerated bone loss associated with chemotherapy or hormonal therapy leads to an increased risk of osteoporosis in long-term breast cancer survivors. An improved range of treatment options is available and assessment of skeletal response both to the disease and to therapy is therefore of growing importance. Plain radiographs remain widely used to assess response, but are of limited sensitivity. The isotope bone scan is more sensitive, but lacks specificity. Computerised tomography, magnetic resonance imaging and positron emission tomography all have an increasing role. In treatment-induced osteoporosis, bone mineral density is now readily measured by DEXA scanning. Tumour markers such as CEA, CA 15-3, CA 549 and TPA may have a role in assessing response, but probably in combination rather than individually, using an appropriate quantitative model. Several trials have shown that bone markers, especially markers of bone resorption such as Ntx, Ctx, PYD and DPD, appear to have strong potential as rapid, convenient and inexpensive measures of response. There is also evidence that they may be used as predictive or prognostic indicators. Evidence is accumulating that the reduction of bone resorption markers into the normal range results in substantially reduced morbidity in metastatic breast cancer and that this should be a major target of therapy.     

Palangeal Quantitative Ultrasound,Phalangeal Morphometric Variables,and Vertebral Fracture Discrimination

The aim of this study was to evaluate the association among phalangeal morphometric parameters, amplitude-dependent speed of sound (AD-SOS), ultrasound bone profile index (UBPI), and spinal bone mineral density (BMD) and fracture status. One hundred women (controls, mean age 53 +/- 12 years) and 40 osteoporotic women (mean age 59 +/- 7 years) with atraumatic fractures, diagnosed by spinal radiographs, were investigated. Quantitative ultrasound (QUS) assessment was performed using the DBM Sonic 1200. Morphological properties of the phalanges were measured from a digitized X-ray image of the hand acquired using industrial film. Spinal BMD was assessed by dual X-ray absorptiometry (DXA) and quantitative computed tomography (QCT). An increase in medullary canal width and a decrease in cortical thickness with aging were observed from the morphometric analysis of the hand radiographs. This phenomenon can be attributed mainly to endosteal resorption. QUS measurements at the phalanges were not significantly related to finger thickness (r <0.20, n.s.). They were significantly correlated to medullary canal ratio (r = -0.57, P <0.0001, for AD-SOS and r = -0.64, P <0.0001, for UBPI) and to cortical thickness (r = +0.52, P <0.0001 for AD-SOS and r = +0.59, P <0.0001 for UBPI). In the discrimination analysis between nonfractured and atraumatic vertebral fracture subjects we found that cortical thickness at the level of the phalanges were similar to lumbar spine BMD. The age and BMI-adjusted odds ratio ranged from 2.0 to 3.1 for QUS, 4.28 for BMD by QCT, 4.1 for BMD by DXA, and 4.1 for cortical thickness. We conclude from these data that phalangeal QUS is related to cortical thickness, which in turn is influenced by endosteal bone resorption occurring in association with spinal osteoporosis.     

Urinary excretion of pyridinoline crosslinks correlates with bone turnover measured on iliac crest biopsy in patients with vertebral osteoporosis

Vertebral osteoporosis, a common disorder in elderly women, is characterized by a wide spectrum of bone turnover abnormalities on iliac crest biopsy. The level of bone formation can be assessed noninvasively by measuring serum osteocalcin, whereas conventional biochemical markers of bone resorption lack specificity and do not reflect bone resorption assessed from histology. We measured the urinary excretion of pyridinoline crosslinks Pyr and D-Pyr, a specific marker of bone and cartilage collagen degradation, along with serum osteocalcin and urinary hydroxyproline, in 36 elderly women with vertebral osteoporosis who had a simultaneous iliac crest biopsy. Urinary pyridinoline crosslinks, but not hydroxyproline, correlated significantly with histologic resorption, assessed by the osteoclast surface (r = 0.35, p less than 0.05 for Pyr; r = 0.46, p less than 0.01 for D-Pyr). In addition, Pyr and D-Pyr were correlated with the bone formation rate as well as serum osteocalcin, with correlation coefficients ranging from 0.69 to 0.80, p less than 0.0001. These data indicate that Pyr and D-Pyr are sensitive markers of bone turnover in elderly women with vertebral osteoporosis. The poor correlation between the level of urinary collagen crosslinks and histological assessment of bone resorption indicates the low sensitivity of iliac crest histomorphometry in the measurement of resorption rate of the skeleton.     

原发性胆汁性胆管炎继发骨质疏松的研究进展

原发性胆汁性胆管炎(primary biliary cholangitis,PBC)又称原发性胆汁性肝硬化,是一种以进行性、非化脓性肝内胆管炎为病理特征,最终发展为肝硬化的慢性自身免疫性肝病。骨质疏松症(osteoporosis,OP)是一种以骨密度下降、骨结构损伤和骨折风险增加为特征的全身性疾病。骨质疏松是PBC的常见并发症,随病情进展发病率逐渐增加,发病率和骨折风险均高于普通人群,正日益受到关注。骨质疏松的危险因素包括老年、女性、吸烟、过量饮酒、低体重、早绝经、类固醇激素治疗、低体力活动、维生素D和钙摄入减少等。PBC继发骨质疏松是由多种病理机制导致的,其中严重的骨吸收和缓慢的骨形成发挥了主要作用,遗传、性腺机能减退、脂溶性维生素缺乏、高脂血症等也参与骨质疏松发病。确诊PBC后应早期开始骨质疏松的预防和治疗。目前尚无治疗PBC并发骨质疏松患者的统一方案,可按照老年性骨质疏松和绝经后骨质疏松方案治疗,包括双膦酸盐、激素替代治疗、甲状旁腺激素、调脂药物、降钙素等。本文就PBC并发骨质疏松的临床表现、危险因素、病理机制及治疗方面的研究进展进行综述。     

骨质疏松症治疗药物研究进展

骨质疏松症是一种与增龄相关的代谢性骨病,主要是由成骨细胞介导的骨形成与破骨细胞介导的骨吸收之间的失衡所致.随着骨质疏松症患病率的逐年递增,如何防治骨质疏松已经成为我国重要公共健康问题.目前骨质疏松症治疗药物主要可分为促进骨形成剂和抑制骨吸收剂.本文主要就骨质疏松症治疗药物的研究进展作一综述,为临床治疗骨质疏松症提供理论...     

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。     

Altered bone mineral metabolism in patients with osteoarthritis

OBJECTIVE: Investigation of the relationship between osteoarthritis (OA) and mineral density, and determination of any alteration in bone mineral, metabolism as assessed by biochemical markers of bone resorption and formation. METHODS: Forty females and 20 males were included in the study. Spinal OA as well as knee OA were defined from radiographs and graded according to Lane et al.'s and Spector et al.'s scoring systems. Bone mineral density (BMD) of the lumbar spine was measured by osteo CT. Bone turnover rates were estimated by measuring biochemical markers of bone resorption (urinary deoxypyridinoline) and bone formation (bone-specific alkaline phosphatase). Forty females and 20 males of the same age were studied as a control group. RESULTS: BMD was greater in women with spinal OA as compared to controls (P < 0.05). Also, males with OA had a non-significantly higher BMD than controls. The bone resorption markers were higher than normal values. However, they were lower than the control group. Similarly, the bone formation markers were lower as compared to the control group. CONCLUSION: Spinal OA is associated with higher BMD. This protective effect of spinal OA against osteoporosis may be mediated through decreased rate of bone turnover.     

Basic principles and clinical applications of biochemical markers of bone metabolism: biochemical and technical aspects.

The interest in and the need for effective measures to be used in the screening, diagnosis, and follow-up of disorders of connective tissue, bone, and mineral metabolism has markedly grown. Next to clinical and imaging techniques, indices of bone turnover have come to play an important role in the assessment of metabolic bone disease. In osteoporosis, recent research has shown that bone markers may also be used to predict future bone loss and hip fractures (in larger cohorts of older patients), identify individuals at risk for osteoporosis, select therapy, and predict and monitor the therapeutic response in individual patients. The development of new markers of bone metabolism has greatly enriched the spectrum of serum and urine analytes used in the assessment of skeletal pathologies. Besides total alkaline phosphatase, other markers such as bone-specific alkaline phosphatase, osteocalcin, or the collagen propeptides are being used to measure bone formation. Bone resorption, previously assessed only by the measurement of urinary calcium and hydroxyproline, may now be detected more precisely by a number of new serum and urine markers. Among these, the pyridinium crosslinks and the telopeptides of collagen type I are presently considered the most specific markers of bone resorption. More recently, bone sialoprotein has also been suggested as a marker of bone resorption in serum. Tartrate-resistant acid phosphatase is now measurable by immunoassay. This article surveys the biochemistry and relevant technical aspects of the currently available markers of bone metabolism.     

Diagnosis of osteoporosis: visual assessment on conventional versus digital radiographs

In many radiological departments conventional radiography has been replaced by digital radiography. Therefore, the purpose of this study was to analyze the visual detection of osteopenia/osteoporosis with both digital and conventional radiographs. In 286 patients we retrospectively evaluated radiographs of the lumbar spine in two planes. One hundred twenty-eight patients had conventional and 158 patients had digital radiographs. Patients with pre-existing vertebral fractures were excluded. Four experienced musculoskeletal radiologists blinded to the values of DXA and to the patients ages assessed independently from each other whether the bone density of the lumbar spines was normal or decreased. The results of dual X-ray absorptiometry served as the standard of reference. The threshold value for the diagnosis of osteopenia was a T-score less than –1 SD according to the WHO classification of osteoporosis. Sensitivity/specificity was 86%/36% for conventional and 72%/47% for digital radiographs. The overall diagnostic accuracy was 68% for conventional and 64% for digital radiographs. Eighty percent of the patients with osteopenia and 96% of the patients with osteoporosis were correctly assessed as true positive on conventional radiographs and 65% (osteopenia) and 82% (osteoporosis) on digital radiographs. Interobserver agreement was markedly lower for digital (35%) than for conventional radiographs (73%). However, the differences were not statistically significant. There is no major difference in diagnostic accuracy in the assessment of osteopenia/osteoporosis using digital and conventional radiographs, respectively. However, the high interobserver variance on digital radiographs indicates that visual assessment of osteoporosis/osteopenia is problematic, which may be due to image processing and postprocessing algorithms that manipulate the visual aspect of bone density.     

Insufficiency fracture of the femoral neck during osteoporosis treatment: a case report

 A case of insufficiency fracture of the femoral neck that occurred during treatment for osteoporosis is reported. A 77-year-old woman (height 150 cm, body weight 43 kg) with osteoporosis associated with high bone turnover was treated with oral cyclical etidronate (400 mg/day for 2 weeks every 3 months). Three months after the treatment was started the patient experienced pain in the right hip joint while walking despite no evidence of trauma. Although radiographs were normal, weight-bearing was not possible because of pain. T2-weighted magnetic resonance (MR) imaging was used to detect a fracture line localized on the inferior aspect of the femoral neck. Because on bone marker measurement bone resorption was increased and bone formation was decreased from baseline, treatment was switched to oral alendronate (5 mg/day, daily). Pain resolved 3 weeks after the fracture was evident, and free gait was possible during the following 3 weeks. Follow-up radiographs, obtained 3 and 6 months after the fracture was evident, showed bony sclerosis on the aspect in which the fracture line was observed on the T2-weighted MR image. The dissociation (imbalance) of bone formation and resorption was also alleviated. A possibility of increased bone fragility should be kept in mind when oral cyclical etidronate is applied to elderly Japanese, small-physique women with osteoporosis at a daily dose of 400 mg (higher dose). Received: March 22, 2002 / Accepted: June 19, 2002 Offprint requests to: J. Iwamoto     

Posttraumatic necrosis of the talus: the Hawkins sign versus magnetic resonance imaging

Magnetic resonance imaging (MRI) is reported to be more sensitive than plain radiographs, computed tomography, or radionuclide bone scanning in detecting osteonecrosis. Few cases of MRI scans falsely negative for osteonecrosis have been reported. A 36-year-old man with posttraumatic necrosis of the body of the talus proven by biopsy had three serial MRI scans that were interpreted as showing the talus to be viable. Eight weeks after injury, the plain radiographs did not show subchondral resorption of bone in the talus (Hawkins sign) and, thus, did correctly indicate necrosis. Most likely a non-union of the talus neck fracture resulted in the false-negative MRI scans.     

Reactive oxygen species and oxidative stress in osteoclastogenesis,skeletal aging and bone diseases

Osteoclasts are cells derived from bone marrow macrophages and are important in regulating bone resorption during bone homeostasis. Understanding what drives osteoclast differentiation and activity is important when studying diseases characterized by heightened bone resorption relative to formation, such as osteoporosis. In the last decade, studies have indicated that reactive oxygen species (ROS), including superoxide and hydrogen peroxide, are crucial components that regulate the differentiation process of osteoclasts. However, there are still many unanswered questions that remain. This review will examine the mechanisms by which ROS can be produced in osteoclasts as well as how it may affect osteoclast differentiation and activity through its actions on osteoclastogenesis signaling pathways. In addition, the contribution of ROS to the aging-associated disease of osteoporosis will be addressed and how targeting ROS may lead to the development of novel therapeutic treatment options.     

ED-71, a vitamin D analog, is a more potent inhibitor of bone resorption than alfacalcidol in an estrogen-deficient rat model of osteoporosis

Although active vitamin D is used in certain countries for the treatment of osteoporosis, the risk of causing hypercalcemia/hypercalciuria means that there is only a narrow therapeutic window, and this has precluded worldwide approval. The results of our previous animal studies have suggested that the therapeutic effect of active vitamin D on bone loss after estrogen deficiency can be dissociated at least partly from its effect of enhancing intestinal calcium absorption and suppressing parathyroid hormone (PTH) secretion. To test this, we compared the effects of ED-71, a hydroxypropoxy derivative of 1alpha,25-dihydroxyvitamin D3, with orally administered alfacalcidol, on bone mineral density (BMD) and the bone remodeling process as a function of their effects on calcium metabolism and PTH, in a rat ovariectomy (ovx) model of osteoporosis. ED-71 increased bone mass at the lumbar vertebra to a greater extent than alfacalcidol, while enhancing calcium absorption (indicated by urinary calcium excretion) and decreasing serum PTH levels to the same degree as alfacalcidol. ED-71 lowered the biochemical and histological parameters of bone resorption more potently than alfacalcidol, while maintaining bone formation markers. These results suggest that active vitamin D exerts an antiosteoporotic effect by inhibiting osteoclastic bone resorption while maintaining osteoblastic function, and that these anticatabolic/anabolic effects of active vitamin D take place independently of its effects on calcium absorption and PTH. The demonstration that ED-71 is more potent in these properties than alfacalcidol makes it an attractive candidate as an antiosteoporotic drug.