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Actual investigational trends at bone remodelation activity level aim to reveal function of local produced bone factors, influencing phases of tissue remodelation and consequently bone mass. In this article author gives surveillance of local produced bone formation stimulating factors.
UNLABELLED: Bone microstructural and biomechanical properties were analyzed in mice genetically lacking cathepsin K (CatK). CatK deficiency (CatK(-/-)) produced mild osteopetrosis, elevated numbers of osteoclasts, regions of disorganized bone microstructure, and increased bone fragility, showing how chronic alteration of enzyme activity during skeletal development dramatically affects bone organization and function. INTRODUCTION: Mouse models of CatK deficiency recapitulate the osteopetrosis of human pyknodysostosis and allow study of clinically relevant issues: how inhibition of this enzyme activity affects bone integrity structurally and biomechanically. To address these questions, we generated CatK-deficient mice by targeted disruption of the Ctsk gene and compared their bone structural and mechanical properties with wildtype (WT) controls. MATERIALS AND METHODS: Standard histomorphometric and biomechanical analyses were performed on femora from C57BL/6J male and female CatK(-/-), CatK(+/-), and WT mice. RESULTS: CatK(-/-) femora exhibited the mild metaphyseal osteopetrosis, a greater cortical bone area and thickness, normal bone strength, but a high degree of brittleness (nearly 50-70% decrease in postyield displacement versus WT) and a 30-40% reduction in the work-to-failure. In cancellous bone, osteoclast numbers and resorption surface were increased markedly (approximately 150% and 50%, respectively), despite the overall decrease in net bone resorption for CatK-deficient mice. Bone formation indices were altered in CatK(-/-) mice as well, with significant increases in mineral appositional rate, but not in bone formation surface; these data suggest difference in osteoblast work but not in their recruitment in CatK deficiency. CatK-deficient cortical bones had large areas of woven bone and intracortical resorption spaces within the disorganized tissue. Bone phenotype in CatK(-/-) was similar in males and females. CONCLUSIONS: Genetic CatK deficiency in mice results not only in the impairment of osteoclast function and osteopetrosis, but also altered osteoblast function, defective tissue organization, and very brittle bones. Whether this bone fragility in CatK deficiency results entirely from indirect effects of suppressed bone turnover because of impaired osteoclast function or perhaps represents a previously unappreciated more direct role for CatK in bone formation remains to be established.
Biochemical markers of bone turnover have been developed over the past 20 years that are more specific for bone tissue than conventional ones such as total alkaline phosphatase and urinary hydroxyproline. They have been widely used in clinical research and in clinical trials of new therapies as secondary end points of treatment efficacy. Most of the interest has been devoted to their use in postmenopausal osteoporosis, a condition characterized by subtle modifications of bone metabolism that cannot be detected readily by conventional markers of bone turnover. Although several recent studies have suggested that biochemical markers may be used for the management of the individual patient in routine clinical practice, this has not been clearly defined and is a matter of debate. Because of the crucial importance to clarify this issue, the Société Francaise de Biologie Clinique prompted an expert committee to summarize the available data and to make recommendations. The following paper includes a review on the biochemical and analytical aspects of the markers of bone formation and resorption and on the sources of variability such as sex, age, menstrual cycle, pregnancy and lactation, physical activity, seasonal variation and effects of diseases and treatments. We will also describe the effects of pre-analytical factors on the measurements of the different markers. Finally based on that review, we will make practical recommendations for the use of these markers in order to minimize the variability of the measurements and improve the clinical interpretation of the data.
OBJECTIVES: To elucidate factors that may be responsible for the inhibition of remodeling of bone within the otic capsule. METHODS: Expression of osteoprotegerin (OPG), receptor activator of nuclear factor kappa B (RANK), and RANK ligand (RANKL) were assayed in samples of bone obtained from the otic capsule, calvarium, and femur, and from the soft tissue within the cochlea using semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR) in mice. Immunostaining was used for histologic localization of the gene products. An enzyme-linked immunosorbent assay (ELISA) was used to quantify the amount of OPG within perilymph, serum, and cerebrospinal fluid. The micro-anatomy of the interface between the otic capsule and the fluid spaces of the cochlea was investigated by brightfield and phase-contrast microscopy and by three-dimensional reconstruction in the mouse and human. RESULTS: OPG, a powerful inhibitor of bone remodeling, was expressed at extremely high levels within the soft tissue of the cochlea and was present in the perilymph at very high concentrations. The OPG produced within the inner ear may diffuse into the surrounding otic capsule, where it may be responsible for inhibition of bone turnover. Our anatomic studies revealed an extensive system of interconnected canaliculi within the otic capsule that had direct openings into the fluid spaces of the inner ear, thus providing a possible anatomic route for the diffusion of OPG from the inner ear into the surrounding bone. CONCLUSION: OPG, a potent inhibitor of osteoclast formation and function, is expressed at high levels within the inner ear and is secreted into the perilymph and the surrounding bone and may serve to inhibit active bone remodeling within the otic capsule, especially immediately adjacent to the cochlea. By this means, the cochlear soft tissue may control the nature of the surrounding petrous bone.
Bone remodelling in cementless hip stem replacement occurs as interface and periprosthetic bone remodelling. Results of radiological, histological and bone mineral density (BMD) findings are discussed. Atrophic, hypertrophic and normotrophic bone reactions are described. Osteodensitometry measurements have shown a bone density decrease of 20% within the first 6 months in the region of the proximal femur. Measurements up to 4 years revealed no further loss of BMD.
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The spectrum of bone disease in uremic patients on hemodialysis has changed in the last years. Undecalcified bone biopsy with histomorphometric measurements and tetracycline labelling remains the gold standard for diagnosis of the different forms of renal osteodystrophy. But because of its invasive nature and complicated laboratory processing a number of non-invasive biochemical parameters have been proposed. The aim of our study was to determine the prevalence of the different forms of renal osteodystrophy in our patients in hemodialysis. Moreover we analyse the correlation between several biochemical parameters and the histological findings and evaluate their diagnostic and predictive value. Transiliac bone biopsies were performed in seventy three uremic patients (31 males) on chronic hemodialysis and static and dynamic parameters were measured. Serum levels of intact parathyroid hormone (iPTH), osteocalcin (OC), total alkaline phosphatase (FAT) and bone alkaline phosphatase (FAO) were determined. High-bone remodelling (50 pts, 68.5%) predominates over low-bone remodelling (23 pts, 31.5%). The distribution of the different types of bone disease was: Mild hyperparathyroidism 8 pts, Osteitis fibrosa 37 pts, Mixed lesions 5 pts, Adynamic bone disease 21 pts and Osteomalacia 2 pts. Six of our 73 patients were diabetics and they had adynamic bone disease (4 pts), osteomalacia (1 pt) and osteitis fibrosa (1 pt). Patients older than 50 years presented lower cellular activity (osteoblast surface, ObS/BS) and lower bone formation rate (BFR/BS). iPTH showed different correlation with these parameters of bone formation in patients above and below 50 years old suggesting that older patients need higher levels of PTH to obtain a determined level of bone formation. iPTH, OC, FAT and FAO correlated with the majority of histomorphometric indices of bone formation and resorption, though the best correlations were those with iPTH. The diagnostic and predictive value of these bone markers is better with high-bone remodelling. Serum levels of FAT > 300 U/l, OC > 150 ng/ml, FAO > 40 ng/ml and iPTH > 200 pg/ml showed a positive predictive value of 1 (with a specificity of 1, but sensibility below 0.78 except for iPTH that is 0.95) in the diagnosis of high-bone remodelling. After an analysis with ROC curves the cut-off value to differentiate high from low-bone remodelling was obtained. iPTH level > 200 pg/ml combined with one of the other markers (FAT > 150 U/l, FAO > 30 ng/ml or OC > 100 ng/ml) are predictive of high-bone remodelling, while values below those figures are predictive of low-bone remodelling.
Bone tissue undergoes continual renewal in order to keep the mechanical competence of the bone matrix. This is performed by two cells: osteoclasts which resorb the calcified matrix and osteoblast which synthetize a new bone matrix. Biochemical markers of bone remodelling allow the evaluation of the activity of each type of bone cells. An unbalance in this process induces modifications of the amount of calcified tissue and of the bone microarchitecture. Several technics based on X-ray and ultrasound allow a non invasive evaluation of these modifications.
BACKGROUND: Bisphosphonates have an established role in the treatment of bone metastases from a variety of solid tumours. The objective response to anti-resorptive treatment cannot be evaluated by imaging techniques. A number of bone remodelling markers have been associated with bone metastases status; among them, urine and serum levels of N-terminal telopeptide of collagen type I (NTx) seem to have the best diagnostic accuracy. However, serum NTx has not yet been properly evaluated. PATIENTS AND METHODS: Seventy-one consecutive patients with newly diagnosed skeletal metastases were enrolled in this prospective study. All of them were treated with zoledronic acid at 4 mg, every 3 or 4 weeks. Serum NTx and bone-isoform of alkaline phosphatase (BAP) were measured by enzyme-linked immunosorbent assays at baseline and every 2 months thereafter. RESULTS: At baseline, serum NTx and BAP levels were significantly higher in patients with blastic than lytic bone lesions and in those with multiple rather than few bone site involvement. Forty-seven patients were followed for a median period of 139 days. Zoledronic acid resulted in a significant NTx reduction at first and second post-treatment evaluations (mean reduction of 43% at first evaluation); thereafter, mean NTx levels remained suppressed. In contrast, BAP levels did not show any significant changes. Bone disease progression resulted in a significant NTx elevation by an average of 69%. The initial response of NTx to zoledronic acid was correlated with the long-term clinical outcome of bone disease: patients with an initial NTx elevation had a significantly higher rate of bone disease progression compared to those with an initial NTx decline (66.7% versus 18.8%, p=0.001). Extraskeletal disease or bone irradiation did not influence NTx response. CONCLUSION: Serum NTx appears to be a useful marker in monitoring patients with skeletal metastases, as it is correlated with the type and bulk of bone disease and reflects bone disease progression. It is also useful in monitoring bisphosphonate therapy, while the initial response to this therapy seems to bear a prognostic significance for bone disease outcome.
For bone to remodel adaptively, the cells responsible should follow some algorithm. Nine different loading situations and structures are discussed. It seems that either algorithm must be extremely complex, or cells in different structures must follow different algorithms.
Bone remodelling, a highly regulated succession of events, is the temporal sequence of osteoclastic bone resorption and osteoblastic bone formation. Bone loss with age and in osteoporotic patients is due to a disequilibrium between both processus. Bone histomorphometry was the method used to measure these events. Its shows clearly that, with age, the quantity of bone formed in one remodelling unit (so called mean wall thickness) decreases. In osteoporotic women, compared to control women of the same age the amount of bone formed is also decreased. Concordant data on this point have been obtained in different laboratories. By contrast, the cellular mechanism underlying this decreased amount of bone formed is largely controversial: a decreased osteoblast recruitment or life span or capacity to synthesize collagen have been suggested. Bone loss with age is associated with an increase in the amount of bone resorbed. This observation is the result of an indirect measurement founded on the distance between trabeculae. As the decreased bone formation, this processus is exaggerated in postmenopausal osteoporosis. The respective importance of decreased bone formation and increased bone resorption is however difficult to assess. Some osteoporotic patients have increased bone resorption surfaces compared to control women on their bone biopsy; however, it does not seem that these patients form a definite subgroup of osteoporotic patients as the extent of resorption surfaces changes with time in an untreated osteoporotic. In conclusion, the observed changes in bone remodelling in osteoporotic post-menopausal women are an exaggeration of those observed during ageing. These changes should be a basis for a coherent therapy of bone loss in osteoporotic patients.
Periprosthetic adaptive bone remodelling after total hip arthroplasty (THA) has been frequently simulated in computer models, combining bone remodelling theory with finite element analysis. Unfortunately, there still subsist a lack of clinical data, which are necessary for validation of these simulation results. Therefore, the objective of the current project is to collect prospective volumetric bone density data with a clinical computerized tomography study in seven patients after THA. A retrospective study 12 years after implantation in 11 patients was added. A data set of about 100000 bone voxels for each femur was collected. In all prospective cases, the predominant change is seen during the first year. The average density reduction in the horizontal slices was between 50 and 150 Hounsfield units (HU) (approx. 10%; p<0.001) after 2 years. Loss of density is particularly strong distal of the minor trochanter and decreases from proximal to distal. For the 12 years retrospective study, the contralateral femur provided the control. Similar trends comparable to the prospective 2-year follow-up CT density values were seen in most cases with density reductions of up to 400 HU (30%). However, in one of these cases there was no difference between the operated and the control density. As far as we are aware, this is the first collection of fully prospective 3D validation data in vivo for periprosthetic adaptive bone remodelling theories. The data are also unique as they are suitable for direct patient-specific 3D finite element meshing and individual weight-related loading.
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It appears that at present, serum BGP is the one bone protein that has the most promise for assisting in the diagnosis and management of high turnover metabolic bone disease states. If further studies confirm its usefulness in osteoporosis as a predictor of rapid bone loss without the need for bone biopsy, this serum marker will then not only allow early detection but also an appropriate choice of therapy in osteoporosis, i.e. the use of specific inhibitors of high turnover states such as estrogen, calcitonin, or bisphosphonates. In addition, it may also permit more accurate follow-up of patients suffering from diseases such as primary hyperparathyroidism after surgery. In low turnover osteoporosis, it may also serve a useful function to observe whether the osteoblast can be stimulated to enhance bone formation with therapies such as fluoride, anabolic steroids, PTH, etc. As yet, additional measurements, such as bone histomorphometry and other bone mineral markers, are required for definitive diagnosis. Hopefully, the availability of specific well-characterized antibodies against BGP may define its role more accurately. Recently, several other new bone proteins have been identified but at present they have very limited clinical application. Future studies into the structure-function relationship of these bone proteins may identify those markers which will be most relevant to the diagnosis and treatment of metabolic bone disease.
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The mechanism by which aluminum chloride stimulates de novo bone formation is unknown. To evaluate the role of bone remodeling and mature osteoblastic function in aluminum-induced neoosteogenesis, we compared the osteogenic effects of aluminum in normal beagles to those in animals with low turnover osteomalacia induced by treatment with etidronate [1-hydroxyethane-1,1-diphosphoric acid (HEBP)]. As assessed by quantitative bone histomorphology, beagles treated with HEBP developed low turnover osteomalacia characterized by a 78% reduction in osteoblast number, a 5.5-fold increase in osteoid volume, complete absence of active mineralization, and diminished resorption surfaces compared to untreated controls. The iv administration of aluminum chloride to normal dogs generated new trabecular structures in the marrow cavity consistent with induction of de novo bone formation. This response consisted of increased trabecular bone volume and number, accumulation of woven osteoid, and increased number of bone-forming cells. The concomitant administration of HEBP failed to prevent induction of de novo bone formation by aluminum. Instead, the neoosteogenic process was superimposed on low turnover osteomalacia in HEBP-treated dogs. Serum aluminum concentrations were increased 2-fold, whereas bone aluminum accumulation was reduced by 58% in HEBP- and aluminum-treated dogs compared to that in aluminum-treated controls. These findings indicate that aluminum stimulation of neoosteogenesis in beagles is independent of mature osteoblast function, normal bone remodeling, and total bone aluminum accumulation. Rather, aluminum-induced de novo bone formation appears to result from stimulation of mesenchymal precursors to form a primitive type of bone which is distinct from coupled bone formation.
Bone as most of living tissues is able, during its entire lifetime, to adapt its internal microstructure and subsequently its associated mechanical properties to its specific mechanical and physiological environment in a process commonly known as bone remodelling. Bone is therefore continuously renewed and micro-damage, accumulated by fatigue or creep, is removed minimizing the risk of fracture. Nevertheless, bone is not always able to repair itself completely. Actually, if bone repairing function is slower than micro-damage accumulation, a type of bone fracture, usually known as "stress fracture", can finally evolve. In this paper, we propose a bone remodelling continuous model able to simulate micro-damage growth and repair in a coupled way and able therefore to predict the occurrence of "stress fractures". The biological bone remodelling process is modelled in terms of equations that describe the activity of basic multicellular units. The predicted results show a good correspondence with experimental and clinical data. For example, in disuse, bone porosity increases until an equilibrium situation is achieved. In overloading, bone porosity decreases unless the damage rate is so high that causes resorption or "stress fracture".
Bone remodeling has been viewed both as a process which adapts bone tissue to the mechanical environment at each point in the structure, and as a process which optimally adjusts the tissue distribution within bones to bear the loads placed on them. We have developed a connection between these two views of bone remodeling, in a restricted sense. We start with a remodeling rate equation based on strain energy density. We then define an indicator function which is a weighted sum of total strain energy and a measure of bone mass, and we show that finding bone density distributions in which the remodeling rate equation predicts no changes with time is the same as finding density distributions in which the indicator function is insensitive to small changes in density. The set point in the remodeling rate equation corresponds to a parameter in the indicator function which determines the relative importance of bone mass and strain energy in the optimization indicator function. We have not assessed whether the density distributions which make the density rate of change zero are actually local or global minima for the indicator function in this study, but a related study shows that there is a single unique minimum for the indicator function developed here, implying that a unique solution exists for the bone remodeling rate equations considered in this study.