骨水泥填充治疗桡骨远端骨质疏松骨折

目的:探讨骨水泥填充治疗桡骨远端骨质疏松骨折的方法。方法:对本科2000以来对8例桡骨远端骨质疏松骨行有限切开、关节面撬拨复位后注入骨水泥填充关节软骨下缺损治疗。结果:全部病例获得随访10-68月,平均22月。所有患者术后1周内肿胀消失,3～4周功能恢复接近正常。X线检查显示骨折愈合良好,无延迟愈合或不愈合。患者自我感觉5例表示满意,2例表示基本满意,1例表示不满意,满意率87.5%。结论:有限切开、关节面撬拨复位后注入骨水泥填充关节软骨下缺损是治疗桡骨远端骨质疏松骨折的有效方法。     

Alendronate and Pamidronate calcium phosphate bone cements: setting properties and in vitro response of osteoblast and osteoclast cells

We have investigated the effect of Alendronate and Pamidronate, two bisphosphonates widely employed for the treatment of pathologies related to bone loss, on the setting properties and in vitro bioactivity of a calcium phosphate bone cement. The cement composition includes α-tricalcium phosphate (α-TCP) (90 wt%), nanocrystalline hydroxyapatite (5 wt%) and CaHPO₄ · 2H₂O (5 wt%). Disodium Alendronate and disodium Pamidronate were added to the liquid phase (bidistilled water) at two different concentrations: 0.4 and 1 mM (AL0.4, AL1.0, PAM0.4, PAM1.0). Both the initial and the final setting times of the bisphosphonate-containing cements increase with respect to the control cement. X-ray diffraction analysis, mechanical tests, and SEM investigations were carried out on the cements after different times of soaking in physiological solution. The rate of transformation of α-TCP into calcium deficient hydroxyapatite, as well as the microstructure of the cements, is not affected by the presence of Alendronate and Pamidronate. At variance, the bisphosphonates provoke a modest worsening of the mechanical properties. MG63 osteoblasts grown on the cements show a normal morphology and biological tests demonstrate very good rate of proliferation and viability in every experimental time. In particular, both Alendronate and Pamidronate promote osteoblast proliferation and differentiation, whereas they inhibit osteoclastogenesis and osteoclast function.     

BMPs in bone regeneration: Less is more effective,a paradigm-shift

Worldwide, the clinical application of BMP2 (bone morphogenetic protein 2) has helped an increasing number of patients achieve bone regeneration in a clinical area lacking simple solutions for difficult bone healing situations. In this review, the historical aspects and current critical clinical issues are summarized and positioned against new research findings on efficacy and function of BMP2. Knowledge concerning how the dose of this growth factor as well as its interaction with mechanical loading influences the efficacy of bone regeneration, might open possible future strategies in cases where bony bridging is unachievable so far. In conclusion, it is apparent that there is a substantial need for continued basic research to unravel the details of its function and the underlying signaling pathways involved, to make BMP2 even more relevant and safe in daily clinical use, even though this growth factor has been known for more than 125 years.     

Modulation of bone morphogenetic protein antagonists to stimulate clinical osteogenesis

Bone morphogenetic proteins (BMPs) are important for the development and functioning of a wide variety of tissues and organ systems. Their ability to induce bone formation has been harnessed for clinical application. Specifically, local application of BMPs into fractures and fusions has shown some efficacy in inducing bone formation. However, clinical success has not been as robust as might be expected from the results obtained using animal models. This difference may be due to a number of mechanisms regulating BMP activity in vivo. One class of major regulators is the extracellular antagonist (e.g. Noggin, Gremlin, DAN), the dysfunction of which has been shown to result in ectopic bone formation in animal models and human disease. We hypothesize that local application of BMPs at high concentrations induces increased production of BMP antagonists, thereby limiting BMP activity and clinical efficacy. Therapies blocking the function of BMP antagonists should therefore result in enhanced BMP activity and increased bone formation. Furthermore, titrated systemic regulation of BMP antagonist may potentially reverse osteoporosis. Our collective experience with the clinical use of BMP illustrates the importance of understanding mechanisms of endogenous antagonism and regulation in the exogenous application of a protein as a therapeutic.     

Micro-CT of rodents: State-of-the-art and future perspectives

Micron-scale computed tomography (micro-CT) is an essential tool for phenotyping and for elucidating diseases and their therapies. This work is focused on preclinical micro-CT imaging, reviewing relevant principles, technologies, and applications. Commonly, micro-CT provides high-resolution anatomic information, either on its own or in conjunction with lower-resolution functional imaging modalities such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT). More recently, however, advanced applications of micro-CT produce functional information by translating clinical applications to model systems (e.g. measuring cardiac functional metrics) and by pioneering new ones (e.g. measuring tumor vascular permeability with nanoparticle contrast agents). The primary limitations of micro-CT imaging are the associated radiation dose and relatively poor soft tissue contrast. We review several image reconstruction strategies based on iterative, statistical, and gradient sparsity regularization, demonstrating that high image quality is achievable with low radiation dose given ever more powerful computational resources. We also review two contrast mechanisms under intense development. The first is spectral contrast for quantitative material discrimination in combination with passive or actively targeted nanoparticle contrast agents. The second is phase contrast which measures refraction in biological tissues for improved contrast and potentially reduced radiation dose relative to standard absorption imaging. These technological advancements promise to develop micro-CT into a commonplace, functional and even molecular imaging modality.     

Effects of parathormone on osteocytes and their surrounding bone matrix

Summary Young chicks were treated with 25 U.S.P. units of Parathormone (PTH, Eli Lilly and Co.) each day for three days. Osteocytes in the tibial mid-diaphyses were studied. As early as two hours after the treatment, there was an evident increase in the amount of affected matrix. However, it was only partially broken down (modified). Based on the relative number of osteocytes in the formative, resorptive, and degenerative phase and of dead osteocytes (empty lacunae), the effects of PTH on the osteocyte population have been quantitatively evaluated. At two hours after the treatment, there was a decrease in the number of formative osteocytes and an increase in the number of resorptive osteocytes. The number of formative cells continued to decrease. The resorptive osteocytes were maximal (76±4.5% of the population) at one day after the treatment. Later this number decreased with a somewhat corresponding increase in the degenerative osteocytes. It seems that PTH treatment promotes the maturation of osteocytes and decreases the formative but enhances the resorptive phase of the osteocytes.This work was supported by Medical Research Council of Canada (Research Grant No. MA 3083).The guidance, encouragement and conceptual help of Dr. L. F. Bélanger, Professor and Chairman, is gratefully acknowledged. The author also sincerely appreciates pertinent suggestions by Dr. R. Narbaitz.     

Thyroid and bone

The hypothalamic-pituitary-thyroid axis plays a key role in skeletal development, acquisition of peak bone mass and regulation of adult bone turnover. Euthyroid status is essential for maintenance of optimal bone mineralization and strength. In population studies, hypothyroidism and hyperthyroidism have both been associated with an increased risk of fracture. Furthermore, recent studies in healthy euthyroid post-menopausal women indicate that thyroid status in the upper normal range is also associated with low bone mineral density and an increased risk of non-vertebral fracture. Studies in mutant mice have demonstrated that thyroid hormone receptor α is the major mediator of T3 action in bone and that thyroid hormones exert anabolic actions during growth but have catabolic effects on the adult skeleton. Nevertheless, TSH has also been proposed to be a direct negative regulator of bone turnover, although the relative importance of T3 and TSH actions in the skeleton has yet to be clarified.     

Phenolic phytochemicals and bone

Concerning the prevention of osteoporosis, recognized as a major public health problem, nutrition may appear as an alternative strategy for optimizing health skeleton. The importance of adequate calcium and vitamin D intakes for bone health is now well documented. But, in addition to essential macro- and micronutrients, human diet contains a complex array of non-nutrient natural bioactive molecules, namely the phytochemicals that may act and protect bone. Among phytochemicals, emphasis has been so far placed upon polyphenols. Indeed, subsequent epidemiological studies have suggested associations between long-term consumption of diets rich in polyphenols and protection against chronic diseases. With respect to human health, flavonoids are the most extensively studied polyphenols. These compounds may be partly responsible for some of the positive links found between fruit and vegetables intake and higher bone mineral density in adults and children. However, no long-term intervention studies in humans have investigated the effect of specific phenolic phytochemicals on the prevention of bone loss in postmenopausal women, except for phytoestrogens (soy isoflavones, lignans). Besides, in animal models of postmenopausal osteoporosis, consumption of some dietary flavonoids has been shown to prevent ovariectomy-induced bone loss. Finally, few in vitro experiments with bone cells have reported cellular and molecular mechanisms of phytochemicals involved in bone metabolism. To date, investigations providing some evidence of a positive impact of some phytochemicals on bone metabolism are accumulating but further studies, notably clinical trials, are needed to explore the various bioactivities offered by such compounds. Anyway, it can be postulated that increased consumption of plant-derived foods, especially fruit and vegetables, may be positive in the prevention of osteoporosis.     

Pros and cons of fatty acids in bone biology

Despite the growing interest in deciphering the causes and consequences of obesity-related disorders, the mechanisms linking fat intake to bone behaviour remain unclear. Since bone fractures are widely associated with increased morbidity and mortality, most notably in elderly and obese people, bone health has become a major social and economic issue. Consistently, public health system guidelines have encouraged low-fat diets in order to reduce associated complications. However, from a bone point of view, mechanisms linking fat intake to bone alteration remain quite controversial. Thus, after more than a decade of dedicated studies, this timely review offers a comprehensive overview of the relationships between bone and fatty acids. Using clinical evidences as a starting-point to more complex molecular elucidation, this work highlights the complexity of the system and reveals that bone alteration that cannot be solved simply by taking ω-3 pills. Fatty acid effects on bone metabolism can be both direct and indirect and require integrated investigations. Furthermore, even at the level of a single cell, one fatty acid is able to trigger several different independent pathways (receptors, metabolites…) which may all have a say in the final cellular metabolic response.     

A supra-cellular model for coupling of bone resorption to formation during remodeling: lessons from two bone resorption inhibitors affecting bone formation differently

The bone matrix is maintained functional through the combined action of bone resorbing osteoclasts and bone forming osteoblasts, in so-called bone remodeling units. The coupling of these two activities is critical for securing bone replenishment and involves osteogenic factors released by the osteoclasts. However, the osteoclasts are separated from the mature bone forming osteoblasts in time and space. Therefore the target cell of these osteoclastic factors has remained unknown. Recent explorations of the physical microenvironment of osteoclasts revealed a cell layer lining the bone marrow and forming a canopy over the whole remodeling surface, spanning from the osteoclasts to the bone forming osteoblasts. Several observations show that these canopy cells are a source of osteoblast progenitors, and we hypothesized therefore that they are the likely cells targeted by the osteogenic factors of the osteoclasts. Here we provide evidence supporting this hypothesis, by comparing the osteoclast-canopy interface in response to two types of bone resorption inhibitors in rabbit lumbar vertebrae. The bisphosphonate alendronate, an inhibitor leading to low bone formation levels, reduces the extent of canopy coverage above osteoclasts. This effect is in accordance with its toxic action on periosteoclastic cells. In contrast, odanacatib, an inhibitor preserving bone formation, increases the extent of the osteoclast-canopy interface. Interestingly, these distinct effects correlate with how fast bone formation follows resorption during these respective treatments. Furthermore, canopy cells exhibit uPARAP/Endo180, a receptor able to bind the collagen made available by osteoclasts, and reported to mediate osteoblast recruitment. Overall these observations support a mechanism where the recruitment of bone forming osteoblasts from the canopy is induced by osteoclastic factors, thereby favoring initiation of bone formation. They lead to a model where the osteoclast-canopy interface is the physical site where coupling of bone resorption to bone formation occurs.     

The roles of Orai and Stim in bone health and disease

Orai and Stim proteins are the mediators of calcium release-activated calcium signaling and are important in the regulation of bone homeostasis and disease. This includes separate regulatory systems controlling mesenchymal stem cell differentiation to form osteoblasts, which make bone, and differentiation and regulation of osteoclasts, which resorb bone. These systems will be described separately, and their integration and relation to other systems, including Orai and Stim in teeth, will be briefly discussed at the end of this review.     

Comparison between quantitative X-ray imaging,dual energy X-ray absorptiometry and microCT in the assessment of bone mineral density in disuse-induced bone loss

Objectives:

We recently introduced a new methodology called quantitative X-ray imaging (qXRI) to investigate bone mineral density in isolated rodent bones. The aims of the present study were to compare DXA and microCT with qXRI in a rat model of disuse osteoporosis.

Methods:

Fourteen Copenhagen rats were injected with a single dose of botulinum toxin (BTX - 2 UI) in the right Mus quadriceps femoris. The left hindlimb serves as control. Areal BMD and vBMD were determined with a Hologic Discovery-W device and a Skyscan 1172 microcomputed tomograph (microCT). Absorbing material density (AMD) was determined on digitized X-ray images obtained with a Faxitron M020 device.

Results:

All three methods highlighted significant lower values for aBMD, vBMD and AMD in trabecular and cortical bone in the BTX-injected side. In trabecular bone, aBMD, vBMD and AMD were significantly correlated with BV/TV. In cortical bone, only aBMD and vBMD were significantly correlated with cortical bone mass On the other hand, only AMD was significantly correlated with the mechanical parameters bending strength and bending modulus.

Conclusions:

qXRI is a rapid and cheap method to assess trabecular bone mass in isolated rodent bones and can be used as a surrogate for the densitometry of small animals.     

Female reproductive system and bone

The female reproductive system plays a major role in regulating the acquisition and loss of bone by the skeleton from menarche through senescence. Onset of gonadal sex steroid secretion at puberty is the major factor responsible for skeletal longitudinal and radial growth, as well as significant gain in bone density, until peak bone density is achieved in third decade of life. Gonadal sex steroids then help maintain peak bone density until menopause, including during the transient changes in skeletal mineral content associated with pregnancy and lactation. At menopause, decreased gonadal sex steroid production normally leads to rapid bone loss. The most rapid bone loss associated with decreased estrogen levels occurs in the first 8-10 years after menopause, with slower age-related bone loss occurring during later life. Age-related bone loss in women after the early menopausal phase of bone loss is caused by ongoing gonadal sex steroid deficiency, vitamin D deficiency, and secondary hyperparathyroidism. Other factors also contribute to age-related bone loss, including intrinsic defects in osteoblast function, impairment of the GH/IGF axis, reduced peak bone mass, age-associated sarcopenia, and various sporadic secondary causes. Further understanding of the relative contributions of the female reproductive system and each of the other factors to development and maintenance of the female skeleton, bone loss, and fracture risk will lead to improved approaches for prevention and treatment of osteoporosis.     

Ion channels in cancer: future perspectives and clinical potential

Ion transport across the cell membrane mediated by channels and carriers participate in the regulation of tumour cell survival, death and motility. Moreover, the altered regulation of channels and carriers is part of neoplastic transformation. Experimental modification of channel and transporter activity impacts tumour cell survival, proliferation, malignant progression, invasive behaviour or therapy resistance of tumour cells. A wide variety of distinct Ca²⁺ permeable channels, K⁺ channels, Na⁺ channels and anion channels have been implicated in tumour growth and metastasis. Further experimental information is, however, needed to define the specific role of individual channel isoforms critically important for malignancy. Compelling experimental evidence supports the assumption that the pharmacological inhibition of ion channels or their regulators may be attractive targets to counteract tumour growth, prevent metastasis and overcome therapy resistance of tumour cells. This short review discusses the role of Ca²⁺ permeable channels, K⁺ channels, Na⁺ channels and anion channels in tumour growth and metastasis and the therapeutic potential of respective inhibitors.     

Combination of bone tissue engineering and BMP-2 gene transfection promotes bone healing in osteoporotic rats

OBJECTIVE: The aim of this study was to develop a feasible approach to promote bone healing in osteoporotic rats using autogenous bone tissue-engineering and gene transfection of human bone morphogenetic protein 2 (hBMP-2). METHODS: Bone marrow stromal cells (BMSCs) from the left tibia of osteoporotic rats were transfected with the hBMP-2 gene in vitro which was confirmed by immunohistochemistry, in situ hybridization and Western blotting. Autogenous transfected or untransfected BMSCs were seeded on macroporous coral hydroxyapatite (CHA) scaffolds. Each cell-scaffold construct was implanted into a defect site which was created in the ramus of the mandible of osteoporotic rats. Four or eight weeks after implantation in situ hybridization was performed in BMSCs transfected with hBMP-2, X-ray examinations, histological and histomorphological analyses were used to evaluate the effect of tissue-engineered bone on osseous defect repair. RESULTS: Newly formed bone was observed at the margin of the defect 4 weeks after implantation with BMSCs transfected with BMP-2. Mature bone was observed 8 weeks after treatment. In the control group there was considerably less new bone and some adipose tissue was observed at the defect margins 8 weeks after implantation. CONCLUSIONS: Autogenous cells transfected with hBMP-2 promote bone formation in osteoporotic rats. BMSC-mediated BMP-2 gene therapy used in conjunction with bone tissue engineering may be used to successfully treat bone defects in osteoporotic rats. This method provides a powerful tool for bone regeneration and other tissue engineering.     

Aging bone and cartilage: cross-cutting issues

Aging is a major risk factor for osteoarthritis and osteoporosis. Yet, these are not necessary outcomes of aging, and the relationship between age-related changes in bone and cartilage and development of disease is not clear. There are some well-described cellular changes associated with aging in multiple tissues that appear to be fundamental to the decline in function of cartilage and bone. A better understanding of age-related changes in cells and tissues is necessary to mitigate or, hopefully, avoid loss of bone and cartilage with aging. In addition, a better understanding of the dynamics of tissue maintenance in vivo is critical to developing tissue replacement and repair therapies. The role of stem cells in this process, and why tissues are not well maintained with advancing age, are frontiers for future aging research.     

Optimization of a biomimetic bone cement: role of DCPD

We previously proposed a biomimetic α-tricalcium phosphate (α-TCP) bone cement where gelatin controls the transformation of α-TCP into calcium deficient hydroxyapatite (CDHA), leading to improved mechanical properties. In this study we investigated the setting and hardening processes of biomimetic cements containing increasing amounts of CaHPO₄·2H₂O (DCPD) (0, 2.5, 5, 10, 15 wt.%), with the aim to optimize composition. Both initial and final setting times increased significantly when DCPD content accounts for 10 wt.%, whereas cements containing 15 wt.% DCPD did not set at all. Differential scanning calorimetry (DSC), X-ray diffraction (XRD), thermogravimetry (TG) and scanning electron microscopy (SEM) investigations were performed on samples maintained in physiological solution for different times. DCPD dissolution starts soon after cement preparation, but the rate of transformation decreases on increasing DCPD initial content in the samples. The rate of α-TCP to CDHA conversion during hardening decreases on increasing DCPD initial content. Moreover, the presence of DCPD prevents gelatin release during hardening. The combined effects of gelatin and DCPD on the rate of CDHA formation and porosity lead to significantly improved mechanical properties, with the best composition displaying a compressive strength of 35 MPa and a Young modulus of 1600 MPa.     

The complex mutual connection between stroke and bone health

Both stroke and osteoporosis are prevalent conditions among the elderly. With increasing life expectancy across the world, despite better preventative measures, the incidence of both conditions is set to rise in the ageing populations. Alongside with sharing several common risk factors, the current evidence suggests that these conditions are risk factors for each other albeit more clear support for the effects of stroke on bone health. In this article, we present aetiopathophysiology of these two conditions and the current evidence of impact on each other particularly the impact of stroke on bone health. We also provide suggestions for improving bone health in people living with stroke based on the currently available evidence.     

Sex hormones and bone health in males

Sex steroids play a key role in maintaining skeletal integrity lifelong, through a complex variety of endocrine, but also paracrine and possibly autocrine actions. The current knowledge that androgens may act as pro-hormones for estrogens has seriously challenged many traditional views, so that, at least for their skeletal actions, these can no longer be considered exclusively “male” or “female” hormones.