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High-turnover periprosthetic bone remodeling and immature bone formation around loose cemented total hip joints.

Aseptic loosening and periprosthetic osteolysis are the major problems awaiting solution in total hip surgery. The clinical investigation focused on the analysis of periprosthetic bone remodeling to clarify one important key event in the cascade of periprosthetic connective tissue weakening and osteolysis around loose artificial hip joints. Twelve acetabular bone samples adjacent to granulomatous synovial-like membrane of loose hip prosthesis were retrieved at revision surgery and processed for Villanueva bone staining for morphological observation and bone histomorphometric analysis. Eight well-fixed bony samples were used as control. Although osteoclastic surface and eroded surface by osteoclasts were evident in the periprosthetic bone from loose hip joints (p = 0.003 and p = 0.027), increased osteoid/low-mineralized bone matrix (p < 0.001) and osteoid width (p < 0.001) also were significant findings in structural analysis. In addition, not only elevated mineral apposition rate (MAR; p = 0.044) but also increased mineralizing surface (p = 0.044) and bone formation rate (BFR; p = 0.002) in loose periprosthetic bones were shown in dynamic data analysis. These results were confirmed by precise morphological observation by confocal laser scanning microscopy. Active coupling of bone formation and resorption and increased osteocytes with abundant bone canalicular projections were found in combined with the presence of immature bone matrices (osteoid and low-mineralized bone areas) in periprosthetic bones from loose hip joints. These results indicated that active osteoclastic bone resorption and/or defective bone formation are coupled with monocyte/macrophage-mediated foreign body-type granuloma in the synovial-like interface membrane of loose hip joints. Thus, this unique high-turnover periprosthetic bone remodeling with bad bone quality probably is caused by the result of cellular host response combined with inappropriate cyclic mechanical loading. The fragile periprosthetic bone may contribute to hip prosthesis loosening.

Aged↗

Clinical review 165: Markers of bone remodeling in metastatic bone disease.

Many cancers have a strong propensity to spread to bone. The processes involved in cancer dissemination to bone are complex and variable, and the changes in bone metabolism, once bony metastases have occurred, are usually profound. This review surveys the usefulness of bone markers in the diagnosis and follow-up of patients with malignant bone disease. In patients with established bone metastases, most markers of bone remodeling are abnormal compared with healthy controls or cancer patients without bone lesions. Although bone markers may have a potential as diagnostic tools in cancer patients, the available data do not allow final conclusions regarding the accuracy and validity of any of the presently used markers in the diagnosis of bone metastases. As regards monitoring of anticancer therapy, most markers of bone remodeling respond to active treatments. These indices therefore may have the potential to be used in the monitoring of antitumor therapies. However, most if not all of the available evidence on the use of bone markers in monitoring anticancer therapy is observational, and it remains unclear whether they have any beneficial effects on overall outcome. The same is true for their prognostic value, although evidence suggests that suppressed levels of bone formation or high rates of bone resorption are independent predictors of poor survival.

Biomarkers↗

Trabecular bone remodeling and bone balance in hyperthyroidism.

In vivo tetracycline double-labeled iliac crest bone biopsies from 15 hyperthyroid patients were used for the reconstruction of curves describing the variation of resorption depth and formation thickness with time. The curves emerging were compared to curves reconstructed from 13 age- and sex-matched normal individuals (mean age 44 years). The median function period for resorptive cells in hyperthyroid patients (16 days) was about one-third the resorptive period in normals (51 days). No significant difference between the osteoclast-, mononuclear-, or preosteoblast-like cell resorption depths could be demonstrated between the two groups. Consequently, the median resorption rate in hyperthyroid patients (3.8 microns/day) was more than 3 times higher than the value in the control group (1.1 micron/day). Median Sigma, was shorter in the hyperthyroid group (109 days) than in the control group (151 days, P less than 0.05), as was the median initial mineralization lag time (5 and 16 days, respectively, P less than 0.01). No significant difference between the measured mean completed wall thickness (mcwT) values in the hyperthyroid groups and the control group could be demonstrated (58.1 and 60.5 micron respectively). Median initial mineralization rate in the hyperthyroid group (1.2 micron3/micron2 per day) was not significantly higher than the value calculated in the control group (0.9 micron3/micron2 per day), but median initial matrix appositional rate in hyperthyroid (4.8 microns3/micron2 per day) was 3 times higher than the value calculated for normals (1.6 micron3/micron2 per day) (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Markers of bone remodelling in metabolic bone disease.

New specific markers of bone remodelling have been developed that allow the evaluation of bone formation (plasma levels of osteocalcin and bone alkaline phosphatases) or bone resorption (collagen crosslink levels in urine). These markers can be used to evaluate bone disease. Their best application is currently in renal osteodystrophy, where there is a broad spectrum of bone abnormalities. In patients with this disease, bone markers can obviate the need for bone biopsy. So far, bone alkaline phosphatase is the most sensitive and specific marker for predicting the type of bone disease and therefore for deciding treatment in dialysed patients, although it is not ideal. Bone markers have also allowed a dramatic improvement in the comprehensive approach to bone loss with aging in women. Monitoring of the marked increase in bone turnover, and its persistence, in older women after menopause may help in the design of treatment strategies for osteoporosis. There is some hope that the measurement of urinary levels of collagen crosslinks will help to predict the clinical outcome of osteoporosis with respect to fractures in postmenopausal women. Bone markers could, besides being a measurement of bone density, help to determine the optimal treatment of postmenopausal women. Bone markers could also be used to predict or ascertain the response to treatment of osteoporosis, but few data are currently available to judge the routine usefulness of these new applications.

Biomarkers↗

Monocyte recruitment and expression of monocyte chemoattractant protein-1 are developmentally regulated in remodeling bone in the mouse.

Tooth eruption is defined as the movement of a tooth from its site of development within the alveolar bone to its position of function in the oral cavity. It represents an excellent model to examine osseous metabolism as bone resorption and bone formation occur simultaneously and are spatially separated. Bone resorption occurs in the coronal (occlusal) area, whereas bone formation occurs in the basal area. Monocytes are thought to have a significant role in the regulation of osseous metabolism. The goal of this study was to examine the recruitment of monocytes to bone in C57BL/6J mice that are undergoing developmentally regulated bone remodeling. Monocytes were detected by immunohistochemistry and osteoclasts were counted as bone-associated multi-nucleated, tartrate-resistant acid phosphatase (TRAP)-positive cells. Cell numbers were obtained from histological sections of animals sacrificed daily for 14 days after birth; an image analysis system was used for quantification. The results demonstrated that, immediately after birth, there were relatively few monocytic cells. In the area of bone resorption, the number of monocytes increased with time, reaching peaks at 5 and 9 days, and decreased thereafter. A similar pattern was observed for osteoclasts. In the area of bone formation, there was a time-dependent increase in the number of monocytes. In contrast, the number of osteoclasts in this area was highest at the earliest time points and decreased after day 3. To investigate potential mechanisms for the recruitment of monocytes, expression of monocyte chemoattractant protein (MCP)-1 was assessed. The number of MCP-1-positive cells increased with time and was generally proportional to the recruitment of mononuclear phagocytes. Osteoblasts were the principal bone cell type expressing MCP-1. The results demonstrate that the recruitment of mononuclear cells in the occlusal area is associated with bone resorption. In contrast, recruitment of monocytes in the basal area is associated with bone formation and a decrease in the number of osteoclasts. These results suggest that monocytes have different functional roles in areas of bone formation compared with bone resorption. Furthermore, the expression of MCP-1 is developmentally regulated and may provide a mechanistic basis to explain the recruitment of monocytic cells.

Animals↗

Attenuated bone aluminum deposition in nonuremic beagles with reduced bone remodeling.

Excess bone aluminum accumulates in uremic subjects after parathyroidectomy. To evaluate whether decreased bone remodeling caused by parathyroidectomy augments bone aluminum deposition, we administered aluminum chloride (0.75 mg/kg iv 3 times/wk) or vehicle to thyroparathyroidectomized (TPTX) and sham-operated (Sham) nonuremic beagles for 8 wk. TPTX alone effectively lowered plasma parathyroid hormone concentrations (8.2 +/- 2.8 vs. 27 +/- 2.2 pg/ml) and consequently suppressed bone remodeling, as evidenced by the diminished resorptive surface (0.8 +/- 0.3 vs. 4.0 +/- 0.5%), osteoid surface (0.5 +/- 0.2 vs. 13.3 +/- 2.3%), and bone formation rate (1.8 +/- 0.6 vs. 15.5 +/- 2.2%/yr) compared with untreated Shams. Aluminum treatment resulted in no further suppression of bone remodeling in TPTX dogs and did not cause osteomalacia. Aluminum-treated TPTX dogs, however, accumulated much less total bone (28.1 +/- 4.5 micrograms/g) and surface aluminum (3.8 +2- 1.4%) than similarly treated Shams (61.4 +/- 5.6 micrograms/g; 12.2 +/- 2.7%, respectively) despite displaying higher plasma aluminum concentrations (1,209 +/- 330 vs. 181 +/- 18 micrograms/l). These observations illustrate that diminished bone turnover retards rather than augments bone aluminum accumulation. Thus bone aluminum deposition after parathyroidectomy in uremic subjects is not likely to be the result of passive aluminum accumulation on inactive bone surfaces. Further studies are needed to determine whether factors, such as prior bone aluminum accumulation and/or the degree of preexistent hyperosteoidosis, modulate aluminum accumulation after parathyroidectomy.

Alkaline Phosphatase↗

Stability analysis and finite element simulation of bone remodeling model.

Bone remodeling is widely viewed as a dynamic process--maintaining bone structure through a balance between the opposed activities of osteoblast and osteoclast cells--in which the stability problem is often pointed out. By an analytical approach, we present a bone remodeling model applied to n unit-elements in order to analyze the stationary states and the condition of their stability. In addition, this theory has been simulated in a computer model using the Finite Element Method (FEM) to show a relationship between the bone remodeling process and the stability analysis.

Bone Remodeling↗

Clinical utility of biochemical marker of bone remodelling in patients with bone metastases of solid tumors.

Bone turnover is characterized both by the formation of new bone by the osteoblasts and the resorption of old tissue by the osteoclast. This process takes place only on the surface of bone and can be described in terms of spatio-temporal events that are the bone metabolic unit and the bone remodelling cycle. The former consists of a discrete group of cells (osteoblasts and osteoclasts) involved in a particular remodelling event while the latter represents the succession of resorption and formation. In a typical remodelling cycle, resorption takes 7-10 days, whereas formation requires 2-3 months. Remodelling is regulated either by local or systemic factors, including electrical and mechanical forces, hormones (e.g. parathyroid hormone, sexual steroids, calcitriol, cortisol, thyroid hormones, calcitonin), growth factors and cytokines. Recently different circulating biochemical markers have been proposed for the investigation of bone turnover. In addition to classical parameters such as serum alkaline phosphatase and urinary calcium and hydroxyproline, new markers have gained clinical attention because of their accuracy in assessing the dynamic changes in bone remodelling (bone alkaline phosphatase, osteocalcin, propeptides PICP and PINP, tartrate-resistant acid phosphatase, deoxypyridinoline, pyridinoline, telopeptide CTx and NTx). The aim of this review is to present the recent advances in this field and the clinical application of markers of bone turnover in patients with bone metastases from solid tumors. Also the cellular and molecular bases of bone remodelling are reported with details.

Acid Phosphatase↗

Peri-implant bone response to orthodontic loading: Part 2. Implant surface geometry and its effect on regional bone remodeling.

INTRODUCTION: Bone response to orthodontic loading was compared around 2 different types of osseointegrated implants (porous surfaced and machined threaded) to determine the effect of implant surface geometry on regional bone remodeling. METHODS: Five beagles each received 3 implants of each design in contralateral mandibular extraction sites. After a 6-week initial healing period, abutments were placed, and, 1 week later, the 2 mesial implants on each side were orthodontically loaded for 22 weeks. All implants remained osseointegrated throughout orthodontic loading except for 1 threaded implant that loosened. Back-scattered scanning electron microscopy and fluorochrome bone labeling techniques were used to compare responses around the 2 types of implants. RESULTS: The loaded, porous-surfaced implants had significantly higher marginal bone levels and greater bone-to-implant contact than did the machined-threaded implants. CONCLUSIONS: Significant differences in peri-implant bone remodeling and bone formation in response to controlled orthodontic loading were observed for the 2 implant designs. Short, porous-surfaced implants might be more effective for orthodontic applications than machine-threaded implants.

Alveolar Process↗

Markers of bone remodeling predict rate of bone loss in multiple sclerosis patients treated with low dose glucocorticoids.

BACKGROUND: The aim of this study was to evaluate the clinical value of markers of bone remodeling in assessment of rate of bone loss in patients with multiple sclerosis (MS) long term treated with low dose glucocorticoids. METHODS: The study involved 70 patients with MS. Motor function of the patients was evaluated using the Kurtzke Expanded Disability Status Scale (KEDSS). Bone mineral density (BMD) was determined at the lumbar spine and proximal femur at baseline and after 1.8 +/- 0.8 years. Bone remodeling was assessed using circulating concentrations of type 1 collagen cross-linked C-telopeptide (beta CTX), aminoterminal propeptide of type I procollagen, and N-MID osteocalcin (OC). A control group of 140 age-matched healthy subjects was used to compare bone-turnover markers. RESULTS: The plasma CTX concentration was the most significant parameter of bone remodeling which correlated with the rate of bone loss and with the KEDSS. The rate of bone loss at the proximal femur was not significantly different between tertiles of plasma OC concentrations. CONCLUSION: In physically active patients with MS treated with low-dose GC, the bone-turnover markers were not different from controls. Patients having plasma CTX but markers of bone formation higher as compared to controls were confirmed 2 years later as bone losers.

Adult↗

Inhibition of TGF-beta receptor signaling in osteoblasts leads to decreased bone remodeling and increased trabecular bone mass.

Transforming growth factor-beta (TGF-beta) is abundant in bone matrix and has been shown to regulate the activity of osteoblasts and osteoclasts in vitro. To explore the role of endogenous TGF-(beta) in osteoblast function in vivo, we have inhibited osteoblastic responsiveness to TGF-beta in transgenic mice by expressing a cytoplasmically truncated type II TGF-beta receptor from the osteocalcin promoter. These transgenic mice develop an age-dependent increase in trabecular bone mass, which progresses up to the age of 6 months, due to an imbalance between bone formation and resorption during bone remodeling. Since the rate of osteoblastic bone formation was not altered, their increased trabecular bone mass is likely due to decreased bone resorption by osteoclasts. Accordingly, direct evidence of reduced osteoclast activity was found in transgenic mouse skulls, which had less cavitation and fewer mature osteoclasts relative to skulls of wild-type mice. These bone remodeling defects resulted in altered biomechanical properties. The femurs of transgenic mice were tougher, and their vertebral bodies were stiffer and stronger than those of wild-type mice. Lastly, osteocyte density was decreased in transgenic mice, suggesting that TGF-beta signaling in osteoblasts is required for normal osteoblast differentiation in vivo. Our results demonstrate that endogenous TGF-beta acts directly on osteoblasts to regulate bone remodeling, structure and biomechanical properties.

Age Factors↗

Sympathectomy, which induces membranous bone remodeling, has no effect on endochondral long bone remodeling in vivo.

Sympathectomy has been shown to induce resorption within the membranous middle ear bone of gerbils. It is unknown whether sympathectomy exerts a similar effect on endochondral long bone. In the present study, guanethidine sulfate (GS) and 6-hydroxydopamine (HDA) were administered to gerbils to induce sympathectomy. One week later, samples of middle ear bulla bone and radial long bone were harvested and assessed for osteoclastic activity. Histomorphometric analysis showed both pharmacologic sympathectomy with GS and chemical sympathectomy with HDA significantly increased the osteoclast counts and osteoclast surfaces of bulla bone samples but not radial long bone samples, respectively. In contrast, HDA but not GS increased the osteoclast profile area of both long bone and membranous bone samples when compared with vehicle-treated controls. Sympathectomy, induced both chemically and pharmacologically, thus has been shown to increase resorption in membranous bone but not endochondral long bone in the gerbilline model.

Animals↗

Effects of exercise training on bone remodeling, insulin-like growth factors, and bone mineral density in postmenopausal women with and without hormone replacement therapy.

The purpose of this study was to determine the effects of 12 months of weight bearing and resistance exercise on bone mineral density (BMD) and bone remodeling (bone formation and bone resorption) in 2 groups of postmenopausal women either with or without hormone replacement therapy (HRT). Secondary aims were to characterize the changes in insulin-like growth factors-1 and -2 (IGF-1 and -2) and IGF binding protein 3 (IGFBP3) in response to exercise training. Women who were 3-10 years postmenopausal (aged 40-65 years) were included in the study. Women in the HRT and no HRT groups were randomized into the exercise intervention, resulting in four groups: (1) women not taking HRT, not exercising; (2) those taking HRT, not exercising; (3) those exercising, not taking HRT; and (4) women exercising, taking HRT. The number of subjects per group after 1 year was 27, 21, 25, and 17, respectively. HRT increased BMD at most sites whereas the combination of exercise and HRT produced increases in BMD greater than either treatment alone. Exercise training alone resulted in modest site-specific increases in BMD. Bone remodeling was suppressed in the groups taking HRT regardless of exercise status. The bone remodeling response to exercise training in women not taking HRT was not significantly different from those not exercising. However, the direction of change suggests an elevation in bone remodeling in response to exercise training, a phenomenon usually associated with bone loss. No training-induced differences in IGF-1, IGF-2, IGF-l:IGF-2 (IGF-1 : IGF-2), and IGFBP3 were detected.

Adult↗

Recombinant human transforming growth factor beta 1 modulates bone remodeling in a mineralizing bone organ culture.

TGF-beta 1 increases cell proliferation and collagen synthesis in osteoblast-like cells and bone organ cultures. However, the effects of TGF-beta 1 on bone resorption remain contradictory. Therefore, the exact role that this growth factor plays in the process of bone remodeling is still not clear. We studied the effects of recombinant human TGF-beta 1 (rhTGF-beta 1) on bone formation and resorption in a mineralizing bone organ culture system. Parietal bones from 20-day-old fetal rat calvariae were cultured up to 7 days in serum-free BGJb medium. They responded to a 1 day pulse or continuous treatment of rhTGF-beta 1 with dose-dependent increases in dry weight, [3H]thymidine ([3H]TdR) incorporation, and collagen synthesis. In contrast, rhTGF-beta 1 reduced the calcium content of the bones. This is not due to increased bone resorption but rather to failure of calcium deposition. The following responses occurred at 1 nM rhTGF-beta 1. Dry weight was increased 25-50% after 6 days in culture. DNA synthesis was increased to a maximum at day 1, reaching twofold of the control level. Adding hydroxyurea at day 0 reduced [3H]TdR incorporation in rhTGF-beta 1 treated bones to 20% of the control and indomethacin abrogated the increase in [3H]TdR stimulated by rhTGF-beta 1 to the control level. Both treatments completely blocked the increase in dry weight induced by rhTGF-beta 1 at day 6. rhTGF-beta 1 stimulated collagen synthesis to reach its maximum at day 2, with a twofold increase in [3H]proline incorporation. Basal alkaline phosphatase activity fell continuously in culture, reaching 35% of day 0 level at day 6. Enzyme activity was not altered by rhTGF-beta 1. Morphologic observations by light and electron microscopy confirmed these findings. In summary, rhTGF-beta 1 altered bone remodeling by increasing organic components and decreasing calcification in a mineralizing bone organ culture system.

Alkaline Phosphatase↗