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PubMed2005

Variation in genes involved in the RANKL/RANK/OPG bone remodeling pathway are associated with bone mineral density at different skeletal sites in men.

In order to assess the contribution of polymorphisms in the RANKL (TNFSF11), RANK (TNFRSF11A) and OPG (TNFRSF11B) genes to variations in bone mineral density (BMD), a population-based cohort with 1,120 extreme low hip BMD cases or extreme high hip BMD controls was genotyped on five SNPs. We further explored the associations between these genetic variations and forearm BMDs by genotyping 266 offspring and 309 available parents from 160 nuclear families. A family-based association test was used. Significantly positive associations were found for A163G polymorphisms in the promoter regions of the OPG gene, a missense substitution in exon 7 (Ala192Val) of the RANK gene and rs9594782 SNP in the 5' UTR of the RANKL gene with BMD in men only. Men with TC/CC genotypes of the rs9594782 SNP had a 2.1 times higher risk of extremely low hip BMD (P = 0.004), and lower whole body BMD (P < 0.001). Subjects with the TC genotype of the Ala192Val polymorphism had a 40% reduced risk of having extremely low hip BMD (P < 0.01), and higher whole body BMD (P < 0.01). Subjects with the GG genotype of the A163G polymorphism had a 70% reduced risk of having extremely low hip BMD (P < 0.05), and higher whole body BMD (P < 0.01). Significant gene-gene interactions were also observed among the OPG, RANK and RANKL genes. Our findings suggest that genetic variation in genes involved in the RANKL/RANK/OPG bone remodeling pathway are strongly associated with BMD at different skeletal sites in adult men, but not in women.

Adult↗
PubMed1989

Indomethacin and bone remodeling. Effect on cortical bone after osteotomy in rabbits.

Remodeling in cortical bone close to a plated tibial midshaft osteotomy was histomorphometrically evaluated in 32 rabbits. The animals were divided into two groups, one being treated with indomethacin (10 mg/kg per day) and the other receiving placebo. In the placebo-treated group, the remodeling activity was higher in the osteotomized leg compared with the intact leg. Two and 6 weeks after osteotomy, the number of resorptive and formative foci was reduced in the indomethacin-treated group compared with the placebo group. Porosity did not differ between the groups after 2 weeks; but after 6 weeks, it was reduced in the indomethacin-treated animals. Throughout the study, the bone formation rate did not differ between the two groups. This study demonstrates that indomethacin inhibits the remodeling of traumatized bone.

Animals↗
PubMed2001

The bone remodeling transient: interpreting interventions involving bone-related nutrients.

The bone remodeling transient is a temporary alteration in the balance between bone formation and bone resorption, brought about by any agency that affects bone remodeling. Ascertaining the steady state effect of an intervention requires factoring the component of the change due to the transient out of the total bony response. Since parathyroid hormone (PTH) is the principal regulator of the quantity of remodeling activity, and since calcium intake influences PTH secretion, it follows that altering calcium intake will always induce a remodeling transient. Worked examples from three published calcium intervention studies are presented, and the errors that can be made by ignoring the transient and simply measuring change in bone mass across treatment are described.

Bone Development↗
PubMedDate not supplied

Opposite bone remodeling effects of teriparatide and alendronate in increasing bone mass.

BACKGROUND: Antiresorptive agents for the treatment of osteoporosis suppress bone remodeling and reestablish bone turnover at a lower rate to reduce bone loss. Recombinant teriparatide (human parathyroid hormone 1-34) stimulates bone formation, increases bone mass, and improves bone microarchitecture. We contrasted the effects of once-daily doses of 20 mug of teriparatide and 10 mg of alendronate sodium on bone mineral density (BMD) and markers of bone turnover. METHODS: Markers of bone turnover and areal BMD were assessed in 203 postmenopausal women with osteoporosis in an 18-month randomized parallel double-blind study; volumetric BMD was measured in a subset of women. RESULTS: Teriparatide significantly increased markers of bone turnover that peaked at 6 months (serum procollagen type I N-terminal propeptide, 218%, and urinary N-telopeptide corrected for creatinine, 58%; P<.001); alendronate significantly decreased the markers at 6 months (-67% and -72%, respectively; P<.001). At 18 months, areal and volumetric spine BMDs were significantly higher with teriparatide than with alendronate (10.3% vs 5.5% [P<.001] and 19.0% vs 3.8% [P<.01], respectively). Areal femoral neck BMD was significantly higher than baseline in the teriparatide and alendronate groups (3.9% and 3.5%, respectively). There were no significant differences in trabecular femoral neck BMD between the teriparatide and alendronate groups (4.9% and 2.2%, respectively). Cortical volumetric femoral neck BMD was significantly different between the teriparatide and alendronate groups (-1.2% and 7.7%, respectively; P = .05). CONCLUSION: Two distinct options for the management of osteoporosis lead to increases in BMD by opposite mechanisms of action on bone remodeling.

Aged↗
PubMed1999

Comparison of biochemical markers of bone remodelling in the assessment of the effects of alendronate on bone in postmenopausal osteoporosis.

The effects of alendronate treatment on biochemical markers of bone remodelling and bone mineral density (BMD) were studied in 30 Caucasian women (postmenopausal for at least 3 years, age 42-76 years, with BMD of the lumbar spine at least 2 S.D. below the mean for mature, premenopausal women). The patients were randomly assigned to receive alendronate (10 mg/day) or placebo for 12 months (double blind). The study was subsequently extended to a second year of open alendronate treatment. The treatment with alendronate resulted in a significant and progressive increase in BMD of the lumbar spine and femoral neck. Under the treatment, the maximal decrease of biochemical markers of bone remodelling (osteocalcin in plasma, bone-specific alkaline phosphatase, N-terminal propeptide of type I procollagen and C-terminal telopeptide of type I collagen in serum, and cross-linked amino-terminal N-telopeptide and total hydroxyproline in urine) was observed at 6 months with no further change during the 2-year period. There were no significant differences in discriminating between patients treated for 1 year with alendronate or placebo using either the percentage change in spine BMD at month 12, or a single measurement of the marker at month 6, or log (percent of baseline at month 6 of value of the marker). In this respect, the power of all the biochemical markers were comparable. The markers are a valuable adjunct to the measurements of BMD, especially in the patients not showing an increase of 3% or more at the lumbar spine BMD after 1 year of treatment.

Adult↗
PubMed2002

Bone remodelling and tumour grade modifications induced by interactions between bone and swarm rat chondrosarcoma.

Chondrosarcoma is currently defined as a malignant cartilage tumour arising de novo or within a pre-existing benign cartilage tumour. Chondrosarcoma can be surgically resected, but all grades have significant rates of local recurrence. The purpose of the present study was to develop an animal intraosseous chondrosarcoma model simulating the progression of human chondrosarcoma and elucidating its behaviour and biology. An intraosseous Swarm rat model was designed to assess interactions between bone and chondrosarcoma. A comparison of tumour grading was carried out according to transplantation site. The effects of chondrosarcoma cells (SRC cells) on the mineralisation capacities of osteoblasts and on osteoclast differentiation were studied in relation to modifications observed in vivo at the cellular level. Transplantation of Swarm rat chondrosarcoma within bone marrow or contiguous to induced periosteal lesions led to extensive bone remodelling with trabecular bone rarefaction and periosteal apposition. Transplantation in close contact to bone but without any periosteal lesion had no effect on bone, suggesting that bone healing factors interact with tumour development. With the intramedullary model, the development of tumours of different grade confirms that bone environment is an important factor in malignancy. A decrease of bone nodule formation was noted after cocultures of SRC cells with rat bone marrow, but there was no modification of osteoclast differentiation after cultures of total rabbit bone cells with SRC cells. These data reveal the importance of interactions between bone environment and tumour in inducing bone remodelling and variations in tumour malignancy.

Animals↗
PubMedDate not supplied

The significance of transient changes in trabecular bone remodeling activation.

After menopause, bone turnover is increased due to an increase in the activation of bone remodeling basic multicellular units (BMUs). The importance of changes in BMU activation to bone histomorphometry data and bone volume has not received adequate attention by many skeletal researchers. Therefore, the influence of BMU activation on the above parameters was modeled by way of computer simulation, and the results were compared to data from published post-menopausal bone loss studies. Using control theory concepts, the increase in BMU activation after menopause was modeled as a zero-, first-, or underdamped (oscillatory) second-order transient BMU activation response to the step input: the decline in estrogen. A computer simulation was developed to model the influence of these three transient BMU activation responses on quantitative histological surface parameters and bone volume. The transient BMU activation responses doubled the number of active BMUs. All three types of transient BMU activation responses produced a rapid 5% decline in bone volume due to increased remodeling space. Oscillations in bone volume and histologic surface parameters over time, similar in nature to those seen in studies of ovariectomized animals, were predicted by the simulation for the oscillatory activation response examined, underdamped second order. An oscillatory BMU activation response may explain some of the transient events during menopause. The increased coherence of BMUs created by such a response may increase the likelihood of trabecular perforations. the inherent nature of an oscillatory activation response may cause its detection to be overlooked and bone remodeling data to be misinterpreted.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Relationships between tooth eruption, occlusion and alveolar bone resorption: histochemical and cytological studies of bone remodeling on rat incisor alveolar bone facing the enamel after root resection.

The labial side of rat incisor alveolar bone facing the enamel is continuously resorbed as the result of compressive force produced by the occlusion and eruption of incisors. In order to clarify the relationship between this mechanical compressive force and the bone cells involved in bone remodeling, we examined morphological changes occurring in the alveolar bone once the compressive force was eliminated by the removal of the proliferative odontogenic base (root resection according to Berkovitz and Thomas, 1969). After root resection, the incisor migrated halfway along the socket. On the crestal part where incisor still existed, active osteoclasts were prominent on the bone surface, and flattened mononuclear cells lay close upon active osteoclasts. Sinusoidal blood vessels or capillaries were observed at short distances from the bone surface. On the basal part where socket was vacant, osteoblasts lined up on the newly formed bone, and the osteogenic cell layer lay on the osteoblasts. Between the two parts, which correspond to the reversal phase proposed by Baron (1977), osteoblastic cells with developed cell organelles increased in number and the distance between blood vessels and bone surface increased. Osteoclasts reduced their activities, and osteoblastic cells often wedged themselves between the osteoclasts and bone surface. These findings indicate that the elimination of compressive force mediated by incisors leads to the activation of osteoblastic cells and inactivation of osteoclasts, which results in a conversion from bone resorption to bone formation. Thus, osteoblastic cells may play an important role in controlling osteoclastic activity in conversion from bone resorption to bone formation, partly by a direct effect and partly by controlling the access of blood vessels to the bone surface.

Acid Phosphatase↗
PubMed1989

Increased cancellous bone remodeling during lactation in beagles.

Changes in bone mass and cancellous bone remodeling parameters were determined during lactation in adult beagles. Bone mineral content was determined by photon absorptiometry, fraction of mineralized cancellous bone area and perimeter to area ratios by image analysis of microradiographs, and bone remodeling parameters by fluorochrome-based histomorphometry. Bone mineral content of the intact proximal humerus and fraction of mineralized tissue areas of lumbar vertebral cancellous bone were decreased during lactation when compared with controls. There were significant increases during lactation in osteoid volumes and osteoid surface, although osteoid seam thickness was not changed. There were significant increases in the fraction of fluorochrome-labeled cancellous bone surfaces in the lactating dogs when compared with controls. The mineralizing surface, bone formation rate and activation frequency were significantly increased in the lactating dogs when compared with controls. There were also significant increases in resorption parameters during lactation. These data indicate that during lactation, bone remodeling and bone turnover is increased. Increased bone remodeling during lactation in a longer-lived mammal may represent an example of a "reversible mineral deficit" which may be an important physiological mechanism in nursing mothers to ensure adequate calcium for milk production. Increased bone remodeling may also provide a physiological mechanism to enhance the capacity of the skeleton to better accommodate the greatly increased and episodic changes in mineral homeostasis during lactation.

Animals↗
PubMed1984

Oophorectomy and cortical bone remodeling in the beagle.

Cortical bone remodeling measurements were carried out on the ribs of 6 spayed and five control Beagle dams which had been subjected to a period of observation equal to more than one sigma of cortical bone remodeling activity. The results of the measurements of static and dynamic parameters indicate that the lack of ovarian hormones does not produce a major alteration in the rates of cortical bone remodeling, but does result in an increase in the number of resorption spaces per mm2 of cortical bone without altering the parameters of bone function. This latter fact supports the hypothesis that decreased levels of circulatory ovarian hormones may influence the duration of the resorption activity as well as possibly uncoupling the resorption/formation (R/F) mechanism of the bone remodeling unit.

Animals↗
PubMed1996

Seasonal differences in biochemical parameters of bone remodelling.

AIMS: To compare bone remodelling parameters in late autumn and early spring in 20 post-menopausal women. METHODS: The parameters measured were serum osteocalcin and its apparent degree of carboxylation (measured by hydroxyapatite binding), total and bone specific alkaline phosphatase and urinary bone resorption markers, (pyridinoline and deoxypyridinoline). RESULTS: Serum osteocalcin concentrations were lower in autumn than in spring but the degree of carboxylation was similar. Total and bone specific alkaline phosphatase activities in serum were higher in autumn than in spring. These results support previous observations. However, notable and previously unreported changes in urinary bone resorption markers were observed. Pyridinoline concentrations were lower and deoxypyridinoline higher in autumn compared with spring. The ratio of pyridinoline:deoxypyridinoline was therefore very different between the seasons. CONCLUSIONS: The results clearly demonstrate that seasonal changes in these variables of bone remodelling must be taken into consideration when designing, reporting or analysing studies of bone metabolism in vivo.

Aged↗
PubMed2006

Multinucleate osteoclasts in medaka as evidence of active bone remodeling.

Putative sites of bone resorption in the acellular bony skeleton of the medaka fish (Oryzias latipes) were investigated primarily by RNA in situ hybridization and histological analysis. Numerous cells that displayed intense enzymatic activity of tartrate-resistant acid phosphatase (TRAP), the main marker of osteoclasts, were distributed in the pharyngeal region of this fish. Moreover, these cells expressed cathepsin K, an osteoclast-specific gene, as well as the genes for TRAP and vacuolar-type proton ATPase (V-ATPase). Some of the TRAP-positive cells displayed all of the morphological characteristics equivalent to those of mammalian- and bird-type osteoclasts. These cells were associated primarily with the shedding teeth and their supporting bones (pedicles), where alkaline phosphatase (ALPase)-positive osteoblasts were also located, implying progressive bone remodeling associated with tooth replacement in these regions. In contrast, the inner aspects of the neural and hemal arches of the vertebral column, which were the only sites of bone resorption other than the tooth-bearing bones, showed sporadically aligned flat mononuclear TRAP-positive cells without a ruffled border, indicating a different mode of bone remodeling in these regions. These results suggest the feasibility of medaka as a model animal for the investigation of bone-related abnormalities and their genetic backgrounds.

Acid Phosphatase↗
PubMed2000

[Effect of low calcitonin doses on bone remodeling in postmenopausal women with high bone turnover rate].

BACKGROUND: Calcitonin is specially indicated for the treatment of osteoporosis in women that cannot receive estrogen replacement therapy or that have a high bone turnover rate. AIM: To study the effects of low intranasal calcitonin doses on bone remodeling in postmenopausal women with a high bone turnover. PATIENTS AND METHODS: Forty one healthy women aged 56 +/- 6 years old, with a mean lapse after menopause of 7.6 +/- 6.5 years and with a high bone turnover rate, evidenced by an urinary hydroxyproline (mg/dl)/creatinine (g/dl) ratio of 52.4 +/- 7.2, were studied. They were randomly assigned to receive 100 or 50 U/calcitonin thrice a week during 3 months or to a control group that received placebo. All received 500 mg/day calcium carbonate. Urinary hydroxyproline/creatinine ratio was measured a 0, 15, 30, 60 and 90 days. Plasma bone fraction of alkanine phosphatases was measured at 0, 30 and 90 days. RESULTS: Initial urinary hydroxyproline/creatinine ratio and plasma bone fraction of alkanine phosphatases were similar in all study groups and there was no change in these parameters during the study period. CONCLUSIONS: Intranasal calcitonin in doses of 100 U thrice a week or less, does not modify accelerated bone turnover in postmenopausal women.

Alkaline Phosphatase↗
PubMed1996

Bone remodeling around cementless hip implants.

Bone remodeling results from the adaptation of bone to the stresses that act upon it. The insertion of an endoprosthesis into a femur changes the stress distribution within the femur, causing the bone to remodel. In this paper, we show how radiographic bone remodeling changes can be used to determine implant fixation and how bone remodeling changes can be quantitated by using dual-energy x-ray absorptiometry analysis as well as computer-assisted videodensitometry.

Absorptiometry, Photon↗
PubMed1991

Osteopenia and osteomalacia after gastrectomy: interrelations between biochemical markers of bone remodelling, vitamin D metabolites, and bone histomorphometry.

The prevalence of metabolic disease in a population of 68 postgastrectomy patients was assessed using histomorphometric evaluation of transiliac bone biopsy specimens after tetracycline double labelling. Trabecular bone volume was significantly lower in the postgastrectomy group (p less than 0.01): 62% of the patients had increased osteoid surface, 56% increased osteoid thickness, and 24% increased mineralisation lag time. Only 18%, however, fulfilled the diagnostic criteria for osteomalacia--increased osteoid thickness and increased mineralisation lag time. Postgastrectomy patients had reduced serum concentrations of calcium (p less than 0.01), phosphate (p less than 0.01), and 25-hydroxyvitamin D, while levels of alkaline phosphatase and 1,25 dihydroxyvitamin D were high (p less than 0.01). The severity of the mineralisation defect as reflected by mineralisation lag time was positively correlated to serum 25-hydroxyvitamin D, but unrelated to serum 1,25-dihydroxyvitamin D. Multiple linear regression analysis showed that serum 25-hydroxyvitamin D, age, and the duration of postoperative follow up were significant determinants of the mineralisation defect in a given patient. The limited value of serum markers in the diagnosis of osteomalacia was emphasised by the fact that six of the eight patients with osteomalacia had normal serum levels of calcium and alkaline phosphatase, and five of the eight had values for 25-hydroxyvitamin D in the normal range for healthy control subjects. The results clearly show the need for vitamin D supplementation and regular control after gastric resection.

Adult↗
PubMed2004

Endogenous levels of serum estradiol and sex hormone binding globulin determine bone mineral density, bone remodeling, the rate of bone loss, and response to treatment with estrogen in elderly women.

A total of 489 elderly women aged 65-75 yr who participated in a 3-yr, randomized, blinded osteoporosis trial underwent measurements of serum estradiol, bioavailable estradiol, and SHBG. At baseline, bone mineral density (BMD) was lower at the femoral sites (7-19%, P < 0.05), total body (6-8%, P < 0.05), and spine (5-9%, P = 0.2) in women in the lowest tertile for serum total estradiol [<9 pg/ml (33 pmol/liter)], serum bioavailable estradiol [<2.4 pg/ml (8.8 pmol/liter)], or highest tertile for serum SHBG (>165 nmol/liter), compared with women in the highest tertiles of total estradiol [>13.3 pg/ml (49 pmol/liter)] and bioavailable estradiol [>4 pg/ml (14 pmol/liter)] or lowest tertile for SHBG (<113 nmol/liter). Bone markers were increased in women in the lowest tertile for serum total estradiol (not significant) and bioavailable estradiol (P < 0.05) and highest tertile for SHBG (P < 0.05). In the longitudinal study, the rate of bone loss in the placebo group was significantly higher in total body (P < 0.05) and spine (P < 0.05) in women in the lowest tertile, compared with the highest tertile of serum bioavailable estradiol. After treatment with conjugated equine estrogens 0.625 mg/d, the increase in BMD was 4-6% higher at the femoral sites (P < 0.05), total body (P < 0.05), and spine (not significant), in the lowest tertile, compared with the highest tertile of serum bioavailable estradiol or highest tertile, compared with the lowest tertile of serum SHBG. In summary, small variations in endogenous serum estradiol and high serum SHBG determine differences in BMD and rate of bone loss in elderly women and also affect the response to treatment with estrogen. Women with a serum estradiol level of less than 9 pg/ml (33 pmol/liter) are optimal candidates for estrogen therapy for osteoporosis prevention.

Aged↗
PubMed2005

Diagnostic value of bone remodeling markers in the diagnosis of bone metastases in patients with breast cancer.

Metastatic spread to bone is common in patients with breast cancer and its early detection is required for the better management of these patients. Several biochemical markers of bone remodeling have been recently developed, in order to assess metastatic bone disease with non radiologic methods. The pyridinolin cross-linked amino-terminal telopeptide of type I collagen (NTx) has been measured in serum and urine as a specific marker of bone collagen breakdown, while the bone-isoform of alkaline phosphatase (BAP) has been used to determine bone formation activity. Thirty-three consecutive ambulatory patients with metastatic breast cancer and bone metastases and 31 with extraskeletal metastases only, matched for age and menopausal status, were studied. Serum levels of NTx and BAP were measured by enzyme-linked immunosorbent assays. The diagnostic accuracy of both markers was evaluated by receiver operating characteristic (ROC) analysis. Patients with bone metastases had significantly higher levels of NTx (37.0+/-36.9 nM BCE versus 23.5+/-21.0 nM BCE, P<0.05) and BAP (57.8+/-31.7 U/L versus 36.5+/-28.5 U/L, P<0.01) compared to those without bone metastases. NTx was positively correlated with BAP (R=0.340, P<0.01). The area under the ROC curve was 0.671 for NTx and 0.755 for BAP. Using a cut-off value of 29.7 nM BCE for NTx, specificity and sensitivity were 87.1% and 45.5%, respectively; in the case of BAP, using a cut-off value of 50.6 U/L, the specificity and sensitivity were 90.3% and 54.5%, respectively. In patients not receiving concomitant hormonal treatment, the area under the ROC curve was 0.724 for NTx and 0.822 for BAP; in this subgroup of patients, using a cut-off value of 30.0 nM BCE for NTx, the specificity and sensitivity were 96.2% and 47.1%, respectively, while using a cut-off value of 50.0 U/L for BAP, the corresponding percentages were 92.3% and 70.6%. Although serum NTx and BAP are quite specific, they are not sensitive enough to diagnose bone metastases in patients with advanced breast cancer. Their diagnostic accuracy, however, is considerably enhanced in patients not receiving hormonal therapy.

Aged↗