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PubMed1994

Effects of lithium on bone resorption in cultured foetal rat long-bones.

Increased serum calcium has been observed in manic depressive patients treated with lithium (Li), and one of the mechanisms increasing serum calcium could be a sensitizing effect of Li on bone resorption. In a previous study, however, Li has been found slightly to inhibit PTH-stimulated resorption in cultured foetal rat long-bones. In this work, we extended the study of the effects of Li on bone resorption in culture when resorption of foetal rat long-bones was stimulated by factors other than PTH. Li 3 mM had no effect on basal resorption, a slight and inconsistent inhibitory effect on PTH stimulated bone resorption, a moderate and inconstant inhibitory effect on prostaglandin E2 (PGE2) stimulated resorption, and did not significantly affect the enhancement of resorption by interleukin 1 (IL1). The more constant effect of Li was a nearly complete inhibition of the resorption response to 1,25-dihydroxycholecalciferol (1,25(OH)2D3). This study confirms that Li has no stimulatory effect on bone resorption by itself, nor a sensitizing action on the stimulation of resorption by several activators. Conversely, Li has a striking inhibitory effect on bone resorption stimulated by 1,25(OH)2D3.

Animals↗
PubMed1992

Abnormal bone remodelling in patients with myelomatosis and normal biochemical indices of bone resorption.

We studied bone biopsies from 26 patients with myelomatosis with apparently normal skeletal metabolism. Quantitative histomorphometric measurements suggested that skeletal disease was progressive despite normocalcaemia and normal urinary excretion rates of calcium and hydroxyproline. When biopsies were divided according to the involvement of marrow by plasma cells, bone resorption--as judged by the eroded surface--increased significantly the greater plasma cell burden. Osteoclasts were frequent with moderate tumour burdens, but there was no further increase in the number of osteoclasts when plasma cell infiltration increased by more than 50% of bone marrow. Contrary to expectation, the numbers of osteoblasts and bone formation rates were increased with bone biopsies with moderate tumour burden, but were markedly lower when plasma cell infiltration occupied more than 50% of bone marrow, due to a decreased functional capacity of osteoblasts. We conclude that skeletal bone disease in myeloma is commonly progressive despite apparently stable bone disease as judged by biochemical measurements. The major mechanism of bone loss in myelomatosis is increased osteoclastic resorption but decreased bone formation contributes to bone loss with heavy plasma cell burdens. Urinary excretion of calcium and hydroxyproline provide insensitive indices of bone resorption in myelomatosis.

Alkaline Phosphatase↗
PubMed1988

Blood coagulation and bone metabolism: some characteristics of the bone resorptive effect of thrombin in mouse calvarial bones in vitro.

Chronic inflammatory processes are often associated with bone resorption. Stimulated by the current great interest in the role of coagulation factors in inflammation and immune injury, we have studied the effect of thrombin on mouse calvarial bones in vitro. Thrombin caused a dose-dependent (0.1-7 U/ml) stimulation of 45Ca release from neonatal mouse calvarial bones. Thrombin also stimulated the mobilization of stable calcium and inorganic phosphate, the release of 3H from [3H]proline-labelled calvaria, the production of lactate and the release of the lysosomal enzymes, beta-glucuronidase and beta-N-acetylglucosaminidase. Thrombin also enhanced 45Ca release from fetal rat long bones, although this bone resorption assay was less sensitive to thrombin than the mouse calvarial system. The bone resorption stimulatory activity of thrombin in mouse calvaria could be inhibited by calcitonin and an increased concentration of phosphate in the culture medium. Thrombin-induced 45Ca release in mouse calvaria was sensitive to inhibition by hydrocortisone and dexamethasone. By contrast, 45Ca release response to parathyroid hormone was insensitive to corticosteroids. The prostaglandin synthetase inhibitors indomethacin, meclofenamic acid and naproxen and 5,8,11,14-eicosatetraynoic acid reduced 45Ca release from thrombin-stimulated calvaria. However, significant stimulation by thrombin could be achieved also in bones treated with inhibitors of arachidonate metabolism. The results obtained suggest that thrombin can stimulate cell-mediated bone resorption by an osteoclast-dependent mechanism. The mechanism of action may involve both prostaglandin-dependent and prostaglandin-independent pathways. Our findings indicate that thrombin may contribute to the bone resorptive processes seen in periodontal disease and rheumatoid arthritis.

Adrenal Cortex Hormones↗
PubMed2005

Skeletal retention of bisphosphonate (pamidronate) and its relation to the rate of bone resorption in patients with breast cancer and bone metastases.

UNLABELLED: Bisphosphonate pharmacokinetics may affect individual responses. Skeletal retention of pamidronate infused monthly to patients with bone metastases was highly variable (12-98%) and did not diminish with time, showing the capacity of the skeleton to retain large amounts of bisphosphonate. Relationships between skeletal retention of pamidronate and rate of bone resorption are complex and depend on previous treatment and the total amount of retained bisphosphonate. INTRODUCTION: Bisphosphonates (BPs) given intravenously every 3-4 weeks are effective in the management of metastatic bone disease from breast cancer, but responses among patients vary, and it is not known whether current dose and dose intervals are appropriate for an individual patient. An influence of pharmacokinetics of BPs on antiresorptive action may contribute to this variation in response. To test this hypothesis, we determined the skeletal retention of intravenous pamidronate and its association to the rate of bone resorption in patients with bone metastases from breast cancer. MATERIALS AND METHODS: In a cross-sectional study, 24-h urinary excretion of pamidronate and the biochemical marker of bone resorption N-terminal telopeptide of type 1 collagen and serum alkaline phosphatase were measured in 40 patients with bone metastases from breast cancer at the beginning, after 3-6 months, and after 1 year of treatment with intravenous pamidronate 90 mg every 3-4 weeks. RESULTS AND CONCLUSIONS: Skeletal retention (dose--amount excreted into urine) 2 days after infusion varied between 12% and 98% (mean, 62%) of the administered dose, but there were no differences in retention between patients receiving pamidronate for the first time or after 3-6 months or after 1 year of treatment. Retention of pamidronate was related to the prevalent rate of bone turnover in previously untreated patients, whereas no such relationship was found in previously treated patients. Rate of bone resorption after treatment seemed to be related to the amount of pamidronate retained. During 1 year of treatment, retention of pamidronate remained constant, indicating no saturation of skeletal binding sites with treatment. The variability in retention among individual patients can be attributed to the number of available binding sites. This is related, however, to bone turnover only before the start of treatment. The apparent relationships between skeletal retention and antiresorptive effect could have implications for the design of optimal therapeutic regimens with BPs in patients with bone metastases from breast cancer.

Aged↗
PubMed1990

Leukemia inhibitory factor (LIF) inhibits basal bone resorption in fetal rat long bone cultures.

Leukemia inhibitory factor (LIF) has a wide variety of biologic actions. In vivo, its net effect on bone is to increase new bone formation. Recently, the sequence of human LIF was found to differ by only a single amino acid from that of human differentiation-inducing factor (D-factor). The effects of LIF on bone appear to be complex since purified murine D-factor and recombinant LIF stimulate bone resorption in cultured newborn mouse calvaria. To examine further the responses of bone to LIF, we studied the effects of recombinant human LIF (glycosylated and nonglycosylated) and recombinant human D-factor (non-glycosylated) on resorption in another in vitro organ culture model, fetal rat long bones. Both LIF preparations and D-factor inhibited basal bone resorption rates by 25% to 44% in these cultures. Resorption rates in maximally inhibited LIF-treated cultures were similar to those in devitalized bones. Inhibitory effects typically occurred at concentrations of greater than or equal to 10 ng/mL (0.5 nM) for the non-glycosylated LIF and D-factor and 1000 U/mL for glycosylated LIF. Neither LIF nor D-factor blocked the resorptive response to interleukin 1 (IL 1) or parathyroid hormone (PTH) nor did they alter total DNA synthesis. Hence, their inhibitory effects appeared to be specific for the mechanisms regulating basal resorptive activity. These results demonstrate that LIF has potent inhibitory actions on basal resorption rates in these cultures. These effects may be important for the anabolic responses that LIF has on bone in vivo. In addition, they may also be involved in the interactions between inflammatory or tumor cells and bone.

Animals↗
PubMed2004

Osteoblast-like cells complete osteoclastic bone resorption and form new mineralized bone matrix in vitro.

Bone remodeling involves old bone resorption by osteoclasts and new bone formation by osteoblasts. However, the precise cellular mechanisms underlying these consecutive events remain obscure. To address this question in vitro, we have established a cell culture model in which the resorption lacunae are first created by osteoclasts and osteoblast-like cells accomplish the subsequent bone formation. We isolated osteoclasts from rat bone marrow and cultured them on bovine bone slices for 48 hours to create resorption lacunae. After removing osteoclasts, confluent differentiated primary osteoblast cultures were trypsinized and the cells were replaced on the resorbed bone slices for up to 14 days. The cultures were then examined by confocal microscopy, field emission scanning electron microscopy (FESEM), and transmission electron microscopy (TEM). Our data suggest that after osteoclastic bone resorption, osteoblast-like cells, not macrophages, remove the remaining organic matrix in the lacuna. After cleaning the lacuna, osteoblast-like cells deposit new collagen fibrils at the bottom of the lacuna and calcify the newly formed matrix only, as visualized by labeled tetracycline accumulation merely in the lacuna during the osteoblast culture. Furthermore, an electron-dense layer rich in osteopontin separates the old and new matrices suggesting formation of the cement line. Since the morphology of the newly formed matrix is similar to the natural bone with respect to the cement line and osteoid formation as well as matrix mineralization, the present method provides for the first time a powerful in vitro method to study the cellular mechanisms leading to bone remodeling also in vivo.

Animals↗
PubMed1999

The role of geranylgeranylation in bone resorption and its suppression by bisphosphonates in fetal bone explants in vitro: A clue to the mechanism of action of nitrogen-containing bisphosphonates.

Bisphosphonates, synthetic compounds used in the treatment of skeletal disorders, suppress osteoclast-mediated bone resorption by a yet unidentified mechanism. Previous studies showed that some bisphosphonates can inhibit enzymes of the mevalonate pathway, and nitrogen-containing bisphosphonates inhibit protein prenylation in mouse macrophages. In the present study, we examined the involvement of the mevalonate pathway in basal and bisphosphonate-inhibited osteoclastic resorption in fetal mouse long bone explants, an experimental model representative of the in vivo action of bisphosphonates. Mevastatin inhibited bone resorption at concentrations similar to those of the potent bisphosphonate ibandronate. This effect could be totally reversed by the addition of mevalnate and geranylgeraniol but not farnesol. The first two intermediates but not the latter could also stimulate basal bone resorption. The inhibitory effect of ibandronate on bone resorption could be totally reversed by the addition of geranylgeraniol and to a small extent only by mevalonate and farnesol, indicating that the bisphosphonate acts at a level of the mevalonate pathway different from that of mevastatin. Histologic sections of ibandronate-treated bone explants showed further rescue of functioning osteoclasts during concomitant treatment with geranylgeraniol. Finally, the reversibility of bisphosphonate inhibited osteoclastic resorption by geranylgeraniol was also demonstrated for the potent nitrogen-containing bisphosphonates alendronate, olpadronate, and risedronate but not for the non-nitrogen-containing bisphosphonates clodronate and etidronate. These studies demonstrate that protein geranylgeranylation but not farnesylation is important for osteoclast-mediated bone resorption and that nitrogen-containing bisphosphonates exert their antiresorptive action probably by affecting enzymes of the mevalonate pathway involved in the generation of geranylgeranyl pyrophosphate.

Animals↗
PubMed1996

Comparison of biochemical markers of bone resorption in patients with metabolic and malignant bone diseases.

The clinical usefulness of the urinary excretion of three bone resorption markers is compared in patients after renal transplantation and in tumour patients with and without bone metastases. The markers were the 3-hydroxypyridinium derivatives pyridinoline and deoxypyridinoline (pyridinium cross-links; measured by a polyclonal enzyme immunoassay), the cross-linked N-telopeptid-to-helix domain of type I collagen and the destruction products of type I collagen metabolism cross-reacting with a peptide sequence of the alpha 1-chain of the C-terminal telopeptide region of type I collagen (CrossLapsTM). In patients receiving renal transplantation the discriminating power of N-telopeptides was superior to that of pyridinium cross-links and CrossLapsTM, with Z scores (number of SDs from apparently healthy controls) of 6.61, 2.17 and 1.35, respectively. However, the pyridinium cross-links were the only markers for bone resorption which showed a significant increase with time (P < 0.001). Receiver operating-characteristic analysis for discriminating patients with bone metastases from those without revealed that the accuracy was 0.81 for pyridinium cross-links, 0.76 for the N-telopeptides and 0.61 for CrossLapsTM. The discriminating power for patients with bone metastases was higher for pyridinium cross-links and N-telopeptides than for CrossLapsTM, with Z scores (number of SDs from patients without bone metastases) of 4.38, 3.00 and 1.24, respectively. Linear correlation coefficients for the different markers were between +0.35 and +0.65 in patients receiving renal transplants, and between +0.58 and +0.84 in patients with bone metastases. In conclusion, in patients with metabolic and malignant bone diseases there are marked differences in the diagnostic performance of different biochemical markers of bone resorption. It is suggested that this may reflect the different facets of bone resorption or the different metabolic fates of the marker substances examined.

Biomarkers↗
PubMed2000

Regulation of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) by bone resorptive factors in osteoblastic cells.

In addition to their stimulating function on osteoclastic bone resorption, bone resorptive factors may regulate proteinases and related factors in osteoblastic cells to degrade bone matrix proteins. This study investigated the regulation of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) by bone resorptive factors in the cultures of mouse osteoblastic MC3T3-E1 cells, mouse primary osteoblastic (POB) cells, and neonatal mouse calvariae. Expression of either MMP-2, -3, -9, -11, -13, and -14 or TIMP-1, -2, and -3 was detected in MC3T3-E1 cells and POB cells. When the bone resorptive factors parathyroid hormone, 1,25-dihydroxyvitamin D(3), prostaglandin E(2), interleukin-1beta (IL-1beta), and tumor necrosis factor-alpha (TNF-alpha) were added to the cell cultures, MMP-13 mRNA levels were found predominantly to increase by all resorptive factors in the three cultures. mRNA levels of either MMP-3 and -9 or TIMP-1 and -3 were found to increase mainly by the cytokines IL-1beta and TNF-alpha. BB94, a nonselective MMP inhibitor, neutralized the (45)Ca release stimulated by these resorptive factors to an extent similar to that of calcitonin, strongly suggesting that bone resorptive factors function at least partly through MMP formation. We propose that MMP-13 mRNA expression in osteoblastic cells may play an important role in stimulating matrix degradation by both systemic and local resorptive factors, whereas either MMP-3 and -9 or TIMP-1 and -3 might modulate matrix degradation by local cytokines only.

Animals↗
PubMed1986

Forskolin has both stimulatory and inhibitory effects on bone resorption in fetal rat long bone cultures.

The diterpene forskolin which increases 3',5'-cyclic adenosine monophosphate concentrations (cAMP) in intact cells by directly activating the enzyme adenyl cyclase, was examined for its ability to alter bone resorption in fetal rat long bone cultures. After 48 h, forskolin inhibited resorption at 1.0 and 10 microM. However, after 120 h, it had a small stimulatory effect at 1.0 microM and no net effect on resorption at 10 microM. Isobutyl-methylxanthine (IBMX), which elevates cAMP levels in cells by inhibiting the enzyme 3',5'-cyclic adenosine monophosphate phosphodiesterase, produced a resorptive response which was slightly different from that of forskolin. After both 48 and 120 h, IBMX at 0.1 mM stimulated resorption while at 1.0 mM, it had only inhibitory effects. In bones which were stimulated to resorb with either parathyroid hormone or 1,25(OH)2 vitamin D, forskolin inhibited resorption. The inhibitory effects of forskolin on hormonally stimulated resorption were transient in cultures treated with 1.0 microM but were sustained with 10 microM. Inhibitory responses to forskolin did not appear to result from toxicity since they were completely reversed when forskolin was removed from the media. These results imply that agents which increases 3',5'-cyclic adenosine monophosphate concentrations in bone activate two resorptive pathways: one which is inhibitory and another which is stimulatory.

1-Methyl-3-isobutylxanthine↗
PubMed1993

Urinary collagen crosslink excretion: a better index of bone resorption than hydroxyproline in Paget's disease of bone?

The 24 h urinary excretion of the collagen degradation products pyridinoline (Pyr) and deoxypyridinoline (Dpyr) have been proposed as specific and quantitative indices of bone resorption. We compared the value of the urinary excretion of Pyr and Dpyr to that of hydroxyproline (OHP) in 11 patients with Paget's disease of bone before and during treatment with inhibitors of bone resorption, during admission to a metabolic ward and maintenance on a gelatin-free diet. Pyr and Dpyr excretion rates were significantly correlated with those of OHP (r = 0.81 and 0.77, respectively, P < 0.001; n = 106). The rate and degree of suppression of bone resorption were monitored in 6 of the patients similarly treated with intravenous dimethyl-APD at a dose of 4 mg/day for 10 days, by daily measurements of the 24 h urinary excretion of Pyr, Dpyr and OHP. Treatment with dimethyl-APD resulted in a decrease in the three indices of bone resorption. The percentage change from baseline values was similar for the three indices, although changes in Dpyr appeared to follow more closely those of OHP. Our findings suggest that Pyr and Dpyr are useful and specific indices of bone resorption in Paget's disease of bone. They appear to confer no advantage, however, over the traditional determination of the urinary excretion of OHP, in the monitoring of response to treatment of such patients with inhibitors of bone resorption. Further studies are required to establish the value of these new biochemical indices of bone resorption, possibly in more subtle disorders of bone metabolism such as osteoporosis.

Amino Acids↗
PubMed2001

Influence of bone resorption on the mobilization of lead from bone among middle-aged and elderly men: the Normative Aging Study.

Bone stores of lead accrued from environmental exposures and found in most of the general population have recently been linked to the development of hypertension, cognitive decrements, and adverse reproductive outcomes. The skeleton is the major endogenous source of lead in circulating blood, particularly under conditions of accelerated bone turnover and mineral loss, such as during pregnancy and in postmenopausal osteoporosis. We studied the influence of bone resorption rate on the release of lead from bone in 333 men, predominantly white, middle-aged and elderly (mostly retired) from the Boston area. We evaluated bone resorption by measuring cross-linked N-telopeptides of type I collagen (NTx) in 24-hr urine samples with an enzyme-linked immunosorbent assay. We used K-X-ray fluorescence to measure lead content in cortical (tibia) and trabecular (patella) bone; we used graphite furnace atomic absorption spectroscopy and inductively coupled plasma mass spectroscopy to measure lead in blood and urine, respectively. After adjustment for age and creatinine clearance, the positive relation of patella lead to urinary lead was stronger among subjects in the upper two NTx tertiles (beta for patella lead > or =0.015) than in the lowest NTx tertile (beta for patella lead = 0.008; overall p-value for interactions = 0.06). In contrast, we found no statistically significant influence of NTx tertile on the relationship of blood lead to urinary lead. As expected, the magnitude of the relationship of bone lead to urinary lead diminished after adjustment for blood lead. Nevertheless, the pattern of the relationships of bone lead to urinary lead across NTx tertiles remained unchanged. Furthermore, after adjustment for age, the relation of patella lead to blood lead was significantly stronger in the upper two NTx tertiles (beta for patella lead > or =0.125) than in the lowest NTx tertile (beta for patella lead = 0.072). The results provide evidence that bone resorption influences the release of bone lead stores (particularly patella lead) into the circulation.

Adult↗
PubMed1991

Inhibition of bone resorption by bisphosphonates: interactions between bisphosphonates, osteoclasts, and bone.

Bisphosphonates are nonbiodegradable pyrophosphate analogues that are being used increasingly to inhibit bone resorption in disorders characterized by excessive bone loss. We have previously found that dichloromethylene bisphosphonate (Cl2MBP) inhibits bone resorption through injury to the cells that resorb Cl2MBP-contaminated surfaces. 3-amino-1-hydroxypropylidene-1,1-bisphosphonate (AHPrBP) is a more potent inhibitor of bone resorption in vivo, and we have attempted to identify a step in the resorptive pathway that accounts for this increased potency. We found that when osteoclasts, isolated from neonatal rat long bones, were incubated on bone slices in the presence of bisphosphonates, AHPrBP was less, rather than more potent as a resorption-inhibitor than Cl2MBP. The greater sensitivity of resorption to AHPrBP in vivo could neither be attributed to an effect of AHPrBP on the ability of osteoblastic cells to stimulate resorption in response to calcium-regulating hormones in vitro nor to an effect on osteoclast generation: osteoclast formation was unaffected by concentrations of AHPrBP 10-fold higher than those of Cl2MBP which inhibit bone resorption in the bone slice assay. We also found no evidence for impaired osteoclast generation in vivo in AHPrBP-treated rats. These results suggest that the comparisons of potency in vitro do not include all the factors responsible for determining bisphosphonate potency in vivo. Because bisphosphonates owe the specificity of their actions to their ability to bind to bone surfaces, we performed experiments using bone slices that had been immersed in bisphosphonates before use. Bone resorption was virtually abolished on bone slices preincubated in 10(-3) M AHPrBP.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1980

Indomethacin inhibits bone resorption and lysosomal enzyme release from bone in organ culture.

The effect of indomethacin on bone resorption was studied in an organ culture system, using calvarial bones from 6--7-day-old mice. It was found that indomethacin inhibited spontaneous bone resorption, as estimated by decreased release of 45Ca, Ca2+ and Pi. Indomethacin reduced the release of beta-glucuronidase, beta-galactosidase and beta-N-acetylglucosaminidase, diminished glucose consumption and lactate production, but showed no effect on the release of lactate dehydrogenase. No inhibitory effect of indomethacin on the release of 45Ca stimulated by parathyroid hormone, prostaglandin E2 or 1 alpha(OH)D3 could be registered. 5,8,11,14-eicosatetraynoic acid, an inhibitor of both cyclo- and lipoxygenase pathway of arachidonate metabolism, reduced the spontaneous release of 45Ca, whereas the selective lipoxygenase inhibitor 5,8,11-eicosatriynoic acid was without effect. The results presented indicate that indomethacin may have an inhibitory effect upon the osteoclasts, probably by decreased metabolism of arachidonic acid via the cyclo-oxygenase pathway. A possible relationship between this finding and the pathogenesis of rapid destruction of articular bone in osteoarthritic patients treated with indomethacin is discussed.

Animals↗
PubMed1995

[Effects of bisphosphonates on vitamin A-induced bone resorption in thyroparathyroidectomized rat].

A bone resorption model in which osteoclasts were selectively activated was made by administering vitamin A--a bone resorption agent--to juvenile thyroparathyroidectomized rat. Inhibition of bone resorption by YM-175--a third generation bisphosphonate--was studied using this model based on bone histomorphometry of the proximal part of the tibia and on biochemical data. Six-week-old male SD rats were thyroparathyroidectomized (TPTX). On the 11th day following TPTX they were treated with vitamin A (etretinate). In the calcitonin group, salmon calcitonin or its vehicle was added, and in the bisphosphonate group, YM-175 or its vehicle was added. They were sacrificed on the 21st day following TPTX. Calcitonin was used to confirm its inhibitory activity of bone resorption in this model. Cancellous bone in the epiphysis was subjected to histomorphometry using tetracycline labeling or TRAP staining, and the number of primary trabeculae at the metaphysis was counted to evaluate bone resorption activity. Serum calcium, phosphorus, urinary calcium, phosphorus, pyridinoline and deoxypyridinoline were measured for biochemical analysis. YM-175 did not change any bone formation parameters in the histomorphometry of the epiphysis, while it significantly decreased resorption parameters both histomorphometrically and biochemically. Primary trabeculae at the metaphysis were found to be longer and denser after administration of YM-175. The effect of YM-175 as a bone resorption inhibitor was observed even in a short duration experiment. There was no damage to mineralization, and no inhibiting effect was observed on bone formation. Similar results were observed by calcitonin. YM-175 was concluded to be an inhibitor of bone resorption caused by vitamin A administration.

Animals↗
PubMed2002

Mechanism of circadian variation in bone resorption.

The diurnal variation in bone resorption markers is poorly understood and may contain essential information about regulation of bone resorption. To explore the acute regulation of bone resorption we studied bone turnover in 14 postmenopausal women during a randomized, crossover, 24 h study of oral glucose tolerance test (OGTT), normal diet, or fasting. Whereas fasting counteracted variation in bone resorption, as measured by serum C-telopeptide fragments of collagen type 1 degradation (s-CTx), OGTT and normal diet induced a 50% reduction (p < 0.001) over 2 h. For OGTT, s-CTx reverted to baseline levels after 6 h, and for normal diet s-CTx remained suppressed during the afternoon and returned to baseline overnight. Repeated OGTT at 8:00 A.M. and 8:00 P.M. in nine postmenopausal women demonstrated that identical reductions in s-CTx could be obtained at both timepoints with an intermediate return to baseline between tests. A 2 h randomized, crossover study of OGTT and fasting in 23 men and premenopausal women similarly revealed a 50% decrease in s-CTx. A randomized, crossover 2 h study of insulin tolerance test compared with fasting in six men and premenopausal women demonstrated a 20%-30% decrease in s-CTx (p < 0.01-0.05). Nine hour follow-up of ten healthy individuals during a crossover experiment of OGTT, protein, and fat intake revealed a comparable 50% reduction in s-CTx, but distinct profiles of serum glucose and serum insulin. Bone resorption was reduced by intake of food, glucose, fat, and protein and counteracted by fasting, and this seems to have been be independent of age and gender. Both exogenous and endogenous insulin stimulation tests induced a reduction in bone resorption, but this was only partial when compared with the reduction observed during food intake.

Biomarkers↗