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PubMed2004

[Genistein inhibits the promotive effect of IL-1beta on osteoclastic bone resorption].

OBJECTIVE: To investigate the effect of genistein, a soybean-derived isoflavone, on the stimulating effect on bone resorption of IL-1beta. METHODS: The osteoclasts (OCs) were isolated with the methods of Yu Shifeng. The rat calvaria were cultured as an organ. The cells in the experiment were grown in four respectively: Control (without genistein or IL-1beta), 10(-6) mol/L genistein,10 microg/L IL-1beta and 10(-6)mol/L genisteine + 10 microg/L IL-1beta. The area of bone resorption, the concentration of Ca(2+) in the supernatant liquid of OCs cultures and mice calvaria were tested. The contents of acid phosphatase(ACP) were also examined by biochemistry method. The index of bone resorption was counted as the ratio of the experiment average and control ones, which indicated the increase in bone resorption when it was above 1.0. RESULTS: The area of bone resorption of 10(-6) mol/L genisteine + 10 microg//L IL-1beta increased compared with that of 10(-6) mol/L genistein, while the concentration of Ca(2+) in the supernatant liquid of OCs cultures decreased significantly. The index of bone resorption of 10(-6) mol/L genisteine + 10 microg//L IL-1beta lied between 10(-6) mol/L genistein and 10 mug/L IL-1beta. In the organ culture, there was no difference in the content of ACP among all the groups. The index of bone resorption of 10(-6) mol/L genisteine + 10 microg//L IL-1beta was below that of 10 mug/L IL-1beta, but both were above 1.0. The index of bone resorption was below 1.0 in the group of 10(-6) mol/L genistein. CONCLUSION: Genistein can suppress obviously the bone resorption simulated by single IL-1beta.

Animals↗

PubMed1997

Regulation of osteoclastic bone resorption by glucose.

Osteoclasts degrade bone by pumping molar quantities of HCl to dissolve the calcium salts of bone, an energy intensive process evidently supported by abundant mitochondria. This is the first study to directly examine the ability of various metabolites to serve as potential energy sources for osteoclastic bone resorption. Glucose, and to a lesser extent lactate, supported osteoclastic bone degradation. However, fatty acids (palmitate, myristate and stearate), essential amino acids plus 20 mM alanine, or ketone bodies (acetoacetate, beta-hydroxybutyrate and alpha-ketoglutarate) did not support bone degradation. Resorption declined to 10-30% of glucose controls when fatty acids or ketoacids were substituted for glucose. Resorption was glucose concentration dependent, with maximal activity at approximately 7 mM (K(M) approximately 3 mM). Glucose transport was linear for approximately 15 minutes, specific for D-glucose, and inhibited by cytochalasin B. Osteoclasts cultured on bone transported glucose at almost twice the rate of those off bone (Vmax 23 versus 13 nmols/mg/min, respectively) and medium acid accumulation paralleled glucose uptake, while the K(M) was unchanged. We conclude that glucose is the principal energy source required for bone degradation. Further, characteristics of glucose transport are consistent with the hypothesis that fluctuations in serum glucose concentration are an important component in regulation of osteoclastic bone degradation.

Alanine↗

PubMed1995

The diurnal rhythm of bone resorption in the rat. Effect of feeding habits and pharmacological inhibitors.

Prevention of low bone mass is important to reducing the incidence of osteoporotic fractures. This paper shows that, in rats, bone mass can be increased by feeding habits per se. Using six-hourly urinary excretion of [3H]tetracycline from prelabeled rats to monitor bone resorption, we previously found a peak of bone resorption following food administration. We now demonstrate that dividing the solid and liquid intake into portions blunts this peak and leads to a decrease in 24-h bone resorption to the level observed in thyroparathyroidectomized animals. Calcium balance increases and, when such feeding schedules are imposed for 30 d, bone mass increases. Dividing the intake is not effective in thyroparathyroidectomized animals, indicating the importance of PTH and/or calcitonin. Administration of calcitonin inhibits practically only the peak of bone resorption, suggesting that it is osteoclast mediated. In contrast, treatment with a bisphosphonate reduces basal bone resorption without a specific effect on the peak, indicating a fundamentally different mechanism of action. This is also supported by the finding that their combined effects are additive. Whether bone mass in humans is also under the control of dietary habits is not known. If so, an increased meal frequency may be used to prevent osteoporosis.

Animals↗

PubMed1986

The effects of hydrocortisone, parathyroid hormone and the bisphosphonate, APD, on bone resorption in neonatal mouse calvaria.

The effects of hydrocortisone and parathyroid hormone (PTH) upon bone resorption rates in neonatal mouse calvaria have been studied. Bone resorption (measured as 45Ca release) was significantly increased by hydrocortisone (10(-7) M and 10(-6) M) and there was a dose-dependent rise with PTH (0.3-0.9 micrograms/liter). When both PTH 0.3 micrograms/liter and hydrocortisone 10(-8) M were present in the incubating medium, bone resorption did not differ from control, but increasing the hydrocortisone concentration to 10(-7) M augmented 45Ca release by 25% (P less than 0.02) and doubling of the PTH level was associated with a 10% increase (nonsignificant). When both PTH and hydrocortisone were present in the higher concentrations (0.6 micrograms/liter and 10(-7) M, respectively) 45Ca release increased by 39% (P less than 0.005) above that resulting from the lower levels of both hormones (0.3 micrograms/l and 10(-8) M, respectively). (3-Amino-1-hydroxypropylidene)-1,1-bisphosphonate (APD) in concentrations of 3 X 10(-5) M and 10(-4) M, produced inhibition of basal and hydrocortisone/PTH-stimulated bone resorption without evidence of toxicity. These results indicate that hydrocortisone stimulates bone resorption in neonatal mouse calvaria in vitro, in contrast to the results found in fetal rat bone culture systems. PTH has a similar effect, which is additive to that of hydrocortisone and the combined stimulation can be overcome by APD. The possible relevance of these results to the development and prevention of glucocorticoid-induced osteoporosis is discussed.

Animals↗

PubMed1999

Thiazolidinediones inhibit osteoclast-like cell formation and bone resorption in vitro.

Osteoblasts and adipocytes are derived from common bone marrow stromal cells that play crucial roles in the generation of osteoclasts. Activation of peroxisome proliferator-activated receptor-gamma (PPARgamma) induces adipogenic differentiation of stromal cells; however, whether this would affect osteoblast/osteoclast differentiation is unknown. Thus, we examined the effects of the thiazolidinedione (TZD) class of antidiabetic agents that activate PPARgamma on osteoblast/osteoclast differentiation using mouse whole bone marrow cell culture. As reported, all TZDs we tested (troglitazone, pioglitazone, and BRL 49653) markedly increased the number of Oil Red O-positive adipocytes and the expression of adipsin and PPARgamma 2. 1alpha,25-Dihydroxyvitamin D3 [1,25-(OH)2D3] did not affect adipogenic differentiation induced by TZDs. TZDs did not affect alkaline phosphatase activity, an early marker of osteoblastic differentiation, despite their marked adipogenic effects. TZDs decreased the number of tartrate-resistant acid phosphatase-positive multinucleated osteoclast-like cells induced by 1,25-(OH)2D3 or PTH. Troglitazone dose dependently inhibited basal and 1,25-(OH)2D3- and PTH-induced bone resorption as assessed by pit formation assay. Interleukin-11 blocked the induction by troglitazone of adipogenesis, but had no effect on the inhibition of osteoclast-like cell formation. These results indicate that TZDs are potent inhibitors of bone resorption in vitro. Inhibitory effects of TZDs on osteoclastic bone resorption was not osteotropic factor specific and did not appear to be related to their adipogenic effects. Thus, TZDs may suppress bone resorption in diabetic patients and prevent bone loss.

Acid Phosphatase↗

PubMed1980

Influence of diphenylhydantoin on lysosomal enzyme release during bone resorption in vitro.

The effect of diphenylhydantoin (DPH) on the release of lysosomal enzymes during resorption of cultured mouse calvarial bone was studied. The enzyme activities of beta-glucuronidase and beta-galactosidase in the culture medium was taken as indicators for lysosomal enzyme release. In concentrations 50 micrograms/ml or higher, DPH inhibited the release of beta-glucuronidase and beta-galactosidase in parallel with bone resorption as indicated by reduced release of 45Ca, Ca2+, Pi and hydroxyproline. The release of the cytosolic enzyme lactate dehydrogenase was not influenced by concentrations of DPH up to 50 micrograms/ml but higher concentrations caused an increased release indicating cell injury. When bone resorption was stimulated by prostaglandin E2, DPH (50 micrograms/ml) also reduced the mobilization of bone mineral and the release of beta-glucuronidase without influencing the release of lactate dehydrogenase. It is suggested that DPH by interfering with cellular release processes reduces the resorption of bone.

Animals↗

PubMed1997

Functional role of endogenous CD14 in lipopolysaccharide-stimulated bone resorption.

Lipopolysaccharide (LPS) is a bacterial cell component that plays multifunctional roles in inflammatory reactions, and one of these roles is that of a powerful stimulator of bone resorption. However, the mechanism by which LPS stimulates bone resorption is not yet understood. In the present study, we show, by using mouse embryonic calvarial cells, that endogenous CD14 and interleukin-1 beta (IL-1 beta) play an important role in the LPS-mediated bone resorption and that interferon-gamma (IFN-gamma) functions as a strong inhibitor of this resorption by suppressing LPS-stimulated expression of CD14 and IL-1 beta genes in the calvarial cells. We observed that LPS-stimulated differentiation of osteoclastic cells and bone resorption were markedly neutralized by anti-mouse CD14 antibody and were clearly inhibited by anti-sense CD14 oligonucleotide treatment. In addition, because LPS stimulated CD14 gene expression in the calvarial cells, these observations demonstrate the precise role of endogenous CD14 in LPS-stimulated differentiation of osteoclastic cells and bone resorption. However, the stimulation of the differentiation of osteoclastic cells and bone resorption was also inhibited by anti-mouse IL-1 beta antibody. Interestingly, anti-sense CD14 oligonucleotide inhibited LPS-stimulated expression of the IL-1 beta gene in the calvarial cells. These observations suggest a functional role of endogenous CD14 in LPS-stimulated expression of the IL-1 beta gene in the cells. Because IFN-gamma is a potent inhibitor of bone resorption stimulated by IL-1, in additional experiments, we examined whether IFN-gamma is able to inhibit LPS-stimulated differentiation of osteoclastic cells and bone resorption. We found that IFN-gamma inhibited these stimulations by suppressing CD14 and IL-1 beta genes in the calvarial cells. The present study thus clearly demonstrates a functional role of endogenous CD14 in LPS-stimulated bone resorption.

Acid Phosphatase↗

PubMed1993

[Influence of epiphyseal cartilages on bone resorption of fetal rat femora].

We developed a facile method for studying bone resorption using fetal rat femur by labelling the bone with 45Ca in vitro. We found that cartilages stimulated the bone resorption of a shaft which was obtained by cutting off both distal and proximal cartilages from the femur. When the shaft was co-cultured with the cartilages isolated by a 0.4-microns microporous membrane in the same Transwell, the bone resorption of the shaft was increased. This finding suggests that the stimulation of bone resorption by the cartilages is not a result of recruitment of osteoclasts or the precursor cells from the cartilages. Indomethacin (10(-6) M) failed to influence the bone resorbing activity of the cartilages. The bone resorbing activity in the supernatant obtained from the cartilage-culture was decreased by heating. The bone resorbing activity of the supernatant did not remain in the lipid-extract or the pronase-digested supernatant, but was present in a fraction whose molecular weight was greater than 50,000. These results collectively suggest that the cartilages produce a bone resorption-stimulating factor(s) which is water-soluble, is a non-prostanoid material, contains protein and has a molecular weight greater than 50,000.

Animals↗

PubMed2003

Lipopolysaccharide concentration and bone resorption in cholesteatoma.

HYPOTHESIS: There is a relationship between the local lipopolysaccharide (LPS) concentration in cholesteatoma and local bone resorption in chronic otitis media (COM) with cholesteatoma. BACKGROUND: During the past decade, it has become known that the recruitment of osteoclasts is the main causative factor that induces bone destruction in COM with cholesteatoma. Cellular inflammation factors like cytokines may trigger the osteoclast. Sequel to this, LPS is able to up-regulate cytokines. This makes it of interest to study whether the local LPS concentration is related to bone resorption in cholesteatoma. MATERIALS AND METHODS: Twenty-four cholesteatoma samples and control tissue from COM patients without cholesteatoma were collected. During surgery, the degree of bone resorption was established and classified. Retrospectively, the authors checked whether patients had chronic purulent otorrhea. LPS concentration of the tissue samples was measured by the limulus amebocyte lysate test. The one-way analysis of variance test was used to determine the relation between LPS concentration, otorrhea, and local bone resorption. RESULTS: A significantly higher concentration of LPS was measured in samples from patients with cholesteatoma with bone resorption and otorrhea compared with cholesteatoma without bone resorption and control tissue. There were no significant differences between the LPS levels of the different groups of patients with bone resorption. CONCLUSION: It is suggested that LPS is one of the first factors in the cascade of bone resorption in COM with cholesteatoma.

Bone Resorption↗

PubMed1985

Flurbiprofen: a potent inhibitor of alveolar bone resorption in beagles.

The nonsteroidal anti-inflammatory drug, flurbiprofen, a potent cyclooxygenase inhibitor, significantly decreases the resorption of alveolar bone in naturally occurring chronic destructive periodontal disease in beagles. This observation indicates that arachidonic acid metabolites are important in the alveolar bone loss of periodontitis and suggests a use for flurbiprofen in the management of bone resorption disease.

Alveolar Process↗

PubMed1992

Effect of macrophage colony-stimulating factor on in vitro osteoclast generation and bone resorption.

To investigate the role of recombinant human macrophage colony-stimulating factor (rhM-CSF) on in vitro bone resorption, two bone explants, each at a different developmental stage, were adopted, namely 1) radii and 2) metatarsals of 17-day-old embryonic mice. At this stage of gestation, bone resorption in the radii is exclusively dependent upon fusion of osteoclast precursors and activation of mature osteoclasts, whereas in metatarsals it is dependent upon the generation of new osteoclasts. rhM-CSF showed no effect in radii, but stimulated 45Ca release in metatarsals, when they were either intact or periosteum stripped in coculture with embryonal liver as a source of hemopoietic progenitors. The rhM-CSF-induced increase in 45Ca release was paralleled by a higher number of osteoclasts. The stimulating effect was found to be in a concentration range between 250-500 U/ml M-CSF. The action of rhM-CSF was blocked by irradiation, indicating that it is dependent upon cell proliferation. These results, thus, show that M-CSF stimulates bone resorption only when it is dependent on generation of new osteoclasts. M-CSF does not appear to have any effect on the activity of mature osteoclasts. The mechanism of action might be direct on osteoclast precursors or indirect on accessory cells influencing osteoclast generation.

Animals↗

PubMed1996

Role of tumor necrosis factor alpha in particulate-induced bone resorption.

The purpose of this study was to determine the role of tumor necrosis factor alpha in bone resorption secondary to mediator release from macrophages exposed to cement particles. The J774 mouse macrophage cell line was exposed to polymethylmethacrylate particles for 24 hours and the resulting conditioned medium was analyzed for prostaglandin E2, tumor necrosis factor alpha, interleukin-1 alpha and beta, and the ability to stimulate release of prostaglandin E2 and 45Ca from radiolabeled mouse calvaria. Macrophage exposure to polymethylmethacrylate particles led to a 9-fold increase in release of tumor necrosis factor alpha (p < 0.01), but did not lead to a significant increase in release of prostaglandin E2, interleukin-1 alpha, or interleukin-1 beta when compared to unexposed cells. Exposure of the macrophages to polymethylmethacrylate particles over a time course from 30 minutes to 96 hours led to an increase in the release of tumor necrosis factor alpha that was initially detected at 30 minutes and was maximum at 48 hours. Incubation of the macrophage-polymethylmethacrylate conditioned medium with rat calvaria significantly increased the release of 45Ca and prostaglandin E2 from the bone. To study the role of release of tumor necrosis factor alpha in bone resorption, the macrophage-polymethylmethacrylate conditioned medium was then preincubated with anti-tumor necrosis factor alpha antibody prior to exposure of the conditioned medium to the calvaria. This preincubation was successful in significantly inhibiting 45Ca release by calvaria (p <0.01) to levels that were not significantly different from the levels of release by unexposed calvaria. Tumor necrosis factor alpha appears to play a critical role in initiating particulate-induced bone resorption. Exposure of macrophages to polymethylmethacrylate particles leads to a significant release of tumor necrosis factor alpha in a time-dependent fashion. This macrophage-polymethylmethacrylate conditioned medium stimulated release of prostaglandin E2 and bone resorption in bone organ culture. The addition of anti-tumor necrosis factor alpha antibody to this in vitro system inhibited the bone resorption stimulated by the macrophage-polymethylmethacrylate conditioned medium and partially suppressed the production of prostaglandin E2. The sequence of events in this model for particulate-induced bone resorption appears to be initiated by the production of tumor necrosis factor alpha by the macrophage, followed by production of prostaglandin E2 by cells in bone, and then by bone resorption.

Analysis of Variance↗

PubMed1999

Tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) stimulate osteoclastic bone resorption.

As both tissue inhibitor of metalloproteinases-1 (TIMP-1) and TIMP-2 have been reported to inhibit bone resorption, we examined whether TIMP-1 or TIMP-2 in fetal calf serum (FCS), with which culture media were supplemented, affected osteoclastic bone resorption in vitro. Contrary to our expectation, almost complete suppression of osteoclastic bone resorption was observed when both TIMP-1 and TIMP-2 were removed from the FCS. Bone resorption was, however, almost fully restored by the addition of recombinant TIMPs. TIMPs stimulate bone resorption at significantly lower concentrations (approximately ng/ml) than those (approximately micrograms/ml) required to inhibit bone resorption. To understand the mechanism of TIMP-dependent bone resorption, we counted and compared the number of tartrate-resistant acid phosphatase-(TRAP-) positive and multinuclear cells in cultures containing either 10% FCS or TIMP-1-free and/or TIMP-2-free FCS. There was essentially no difference in number among these, suggesting that the TIMP role seems to be related to the functional expression of osteoclasts. Metalloproteinase inhibitors, either BE16627B[L-N-(N-hydroxy-2-isobutylsuccinynamoyl)-seryl-L-val ine] or R94138 ¿N-methyl-(3S)-2-[(2R)-2-hydroxycarbamoylmethylundecanoyl] hexahydropyridazine-3-carboxamide¿, could not replace TIMPs, suggesting that the osteoclast-stimulating activity of TIMPs cannot be ascribed to merely their inhibitory effect on matrix metalloproteinases.

Acetamides↗

PubMed1997

Inhibition of bone resorption by pamidronate cannot restore normal gain in cortical bone mass and strength in tail-suspended rapidly growing rats.

To clarify how the changes in bone formation and resorption affect bone volume and strength after mechanical unloading, the effect of inhibition of bone resorption by a potent bisphosphonate, pamidronate, on bone mineral density (BMD), histology, and strength of hind limb bones was examined using tail-suspended growing rats. Tail suspension for 14 days reduced the gain in the BMD of the femur at both the metaphysis rich in trabecular bone and the diaphysis rich in cortical bone. Treatment with pamidronate increased the total BMD as well as that of the metaphysis of the femur but had almost no effect on the BMD of the diaphysis in both control and tail-suspended rats. Histological examinations revealed that 14-day tail suspension caused a loss of secondary cancellous bone with a reduction in the trabecular number and thickness in comparison with control rats. In the femoral diaphysis, the diameter and cortical bone thickness increased to a lesser degree in tail-suspended rats when compared with rats without tail suspension, and a marked reduction in bone formation and the layers of alkaline phosphatase-positive cells was observed at the periosteal side. Pamidronate treatment increased secondary cancellous bone but could not restore normal growth-induced periosteal bone apposition and bone strength. Because the material strength of the femoral diaphysis at the tissue level was not affected by pamidronate treatment, the inability of pamidronate to prevent the reduction in physical strength of the femoral diaphysis does not appear to be due to a change in the quality of newly formed bone. These results demonstrate that tail suspension reduces the growth-induced periosteal modelling drift and that the antiresorptive agent pamidronate is unable to restore normal periosteal bone apposition.

Amino Acids↗

PubMed2003

Xanthine oxidase mediates cytokine-induced, but not hormone-induced bone resorption.

Reactive oxygen species (ROS) such as hydrogen peroxide (H2O2) have been implicated as mediators of osteoclastic bone resorption. Xanthine oxidase (XO) a ubiquitous enzyme is widely known for its production of these ROS. We therefore evaluated the potential of XO as a source of ROS in cytokine-and hormone-induced bone resorption. XO activity in rat calvarial osteoblasts was found to be significantly elevated upon stimulation by the cytokines, TNFalpha and IL-1beta. These cytokines also caused a dose related increase in bone resorption of mouse calvariae, which was significantly inhibited by catalase (10 IU/ml). Allopurinol, the competitive inhibitor of XO, also caused a dose related (1-50 microM) inhibition of TNFalpha (20 ng/ml) and (0.01-10 microM) IL-1beta (50 IU/ml)-induced bone resorption, respectively. PTH- and 1,25-(OH)2 Vitamin D3-induced bone resorption could also be inhibited by catalase (100 IU/ml) but was unaffected by allopurinol, indicating that another mediator, other than XO, is required for hormone-induced bone resorption. These results demonstrate, that modulation of the redox balance in the bone microenvironment, which contains XO, can affect the bone resorbing process. Therefore, XO may play a pivotal role in cytokine-induced bone resorption and, if manipulated appropriately, could show a therapeutic benefit in inflammatory bone disorders such as RA.

Allopurinol↗

PubMed2004

The effects of binge alcohol exposure on bone resorption and biomechanical and structural properties are offset by concurrent bisphosphonate treatment.

BACKGROUND: Chronic alcohol consumption reduces bone mass and strength, increasing fracture risk for alcohol abusers. Mechanisms underlying this vulnerability involve modulation of bone remodeling. Direct effects of alcohol on bone formation have been documented; those on bone resorption are less well studied. Skeletal effects of exposure to high blood alcohol concentrations (BAC's) attained during binge drinking have not been studied. We examined the effects of repeated binge-like alcohol treatment on bone resorption, bone mineral density and vertebral compressive strength in adult male rats treated with the aminobisphosphonate, risedronate. METHODS: A binge alcohol exposure model was developed using intraperitoneal (IP) injection to administer a 20% (vol/vol) alcohol/saline solution (3 g/kg, 1X/day) on four consecutive days for 1, 2 or 3 weeks in 400 g rats, with and without weekly risedronate treatment (0.5 mg/kg, 1X/week). Total serum deoxypyridinoline (Dpd) a crosslink of bone type collagen released during resorption was measured by ELISA. Bone mineral density (BMD) was measured using peripheral quantitative computed tomography (pQCT). Vertebral compressive strength was determined using an Instron materials testing machine. Trabecular integrity was analyzed by computer-aided trabecular analysis system (TAS). RESULTS: Peak BAC's averaged 308.5 +/- 12 mg/dL; average BAC was 258.6 +/- 28.7 mg/dL at time of euthanasia. No significant effects of treatment were observed after 1 or 2 weeks of binge alcohol exposure. At 3 weeks of alcohol treatment serum Dpd was significantly increased (205%, p < 0.05) over controls. Bone mineral density (BMD) in cancellous bone of distal femur and lumbar spine were significantly decreased (34% and 21% respectively, p < 0.01) after 3 weeks of binge treatment. Vertebral (L4) compressive strength (maximum load sustained before failure) also decreased (27%, p < 0.05) after 3 binge alcohol cycles. Risedronate maintained the Dpd level (p < 0.01), BMD (p < 0.001) and vertebral structural biomechanical properties (p < 0.01) of binge-treated rats at control levels (E vs ER). Indices of trabecular architectural integrity [Trabecular bone volume/tissue volume (BV/TV), bone area (BAR) and trabecular separation (Tb.Sp)] analyzed at week 3 showed (BV/TV) and (BAR) were significantly reduced in alcohol-binged rats (p < 0.01), while (Tb.Sp) was significantly increased (p < 0.01). Risedronate also maintained the trabecular architectural indices of binge-treated rats at control levels (E versus ER, p < 0.01). CONCLUSIONS: In adult male rats, BAC's reflective of those attained during alcoholic binge drinking may affect the skeleton in part by stimulating bone resorption, an effect mitigated by risedronate.

Amino Acids↗

PubMed2005

Predictive value of bone resorption and formation markers in cancer patients with bone metastases receiving the bisphosphonate zoledronic acid.

PURPOSE: Three large, randomized trials of patients with bone metastases recently demonstrated that zoledronic acid reduces the risk of skeletal-related events. These trials provide an opportunity for investigating the correlation between bone metabolism and clinical outcome during bisphosphonate therapy. PATIENTS AND METHODS: Urinary measurements of N-telopeptide (Ntx) and serum bone alkaline phosphatase (BAP) were obtained in 1,824 bisphosphonate-treated patients-1,462 with zoledronic acid (breast, 490; prostate, 411; myeloma, 210; non-small-cell lung, 183; other, 168) and 362 with pamidronate (breast, 254; myeloma, 108). This exploratory cohort analysis grouped patients by baseline and most recent levels of Ntx as low (< 50 nmol/mmol creatinine), moderate (50 to 99 nmol/mmol creatinine), or high (> or = 100 nmol/mmol creatinine), and BAP as low (< 146 U/L) or high (> or = 146 U/L). The relative risks for negative clinical outcomes were estimated for each group using multiple-event and Cox regression models with time-varying covariates. RESULTS: Patients with high and moderate Ntx levels had 2-fold increases in their risk of skeletal complications and disease progression compared with patients with low Ntx levels (P < .001 for all). High Ntx levels in each solid tumor category were associated with a 4- to 6-fold increased risk of death on study, and moderate Ntx levels a 2- to 4-fold increased risk compared with low Ntx levels (P < .001 for all). Bone alkaline phosphatase also showed some correlation with risk of negative clinical outcomes. CONCLUSION: The bone resorption marker Ntx provides valuable prognostic information in patients with bone metastases receiving bisphosphonates.

Adult↗

PubMed1979

Collagenase, procollagenase and bone resorption. Effects of heparin, parathyroid hormone and calcitonin.

1. The addition of heparin to the culture fluid of mouse tibiae or calvaria did not cause any significant resorption of bone collagen or mineral. However, heparin (or analogue sulfated polyanions), enhanced greatly the amount of latent, trypsin-activatable collagenase (i.e. procollagenase) released by the bones in the medium without influencing that of directly active collagenase which was always very low. Heparin appeared to act by increasing the production of the enzyme which is immediately excreted. Procollagenase and collagenase are not stored in bone tissue, even under conditions where it is in active resorption. 2. Parathyroid hormone induced in the explants a resorption of both mineral and collagen that was inhibited by calcitonin. These hormones, however, had no influence on the release of procollagenase or collagenase either in the presence or in the absence of heparin. 3. Once activated, bone collagenase digested the collagen of the bone explants, and more extensively after their demineralization. Thus the latent collagenase that accumulates around non-resorbing bones has to be considered as a precursor, (and not as a residue), of active enzyme. 4. Active collagenase added to incipient cultures of bones disappeared with a half-life of 24 h. The lost enzyme could, however, not be reactivated by trypsin and thus was not transformed into latent procollagenase.

Animals↗