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PubMed1993

The cyclic-AMP antagonist adenosine-3',5'-cyclic monophosphosphorothioate, RP-isomer inhibits parathyroid hormone induced bone resorption, in vitro.

Stimulation of osteoclastic bone resorption is mediated via the osteoblasts. In order to investigate the second messenger events that cause the osteoblasts to initiate bone resorption we have evaluated the effect of the cyclic AMP antagonist adenosine-3'5'-cyclic monophosphosphorothioate, Rp-isomer (Rp-cAMPS) on bone resorption in vitro, by measuring the release of prelabelled 45Ca from cultured neonatal mouse calvarial bones. Forskolin (FSK, at and above 10 nM), an agent that enhances cyclic AMP-formation, stimulated bone resorption in 96 h cultures. Addition of Rp-cAMPS to the incubation media dose-dependently inhibited bone resorption induced by FSK (0.5 microM), with total inhibition obtained at 30 microM Rp-cAMPS. Bone resorption stimulated by parathyroid hormone (PTH, 0.1-10 nM, 72 h) was also inhibited by Rp-cAMPS (30 microM), while bone resorption induced by 1.25(OH)2D3 (1-10 nM, 72 h) was unaffected by Rp-cAMPS. These data demonstrate that PTH and 1,25(OH)2D3 cause bone resorption via different mechanisms and that cyclic AMP is the major second messenger in PTH-induced bone resorption.

Animals↗

PubMed2003

Bone resorption predicts for skeletal complications in metastatic bone disease.

Relationships between the rate of bone resorption (measured by urinary N-telopeptide (Ntx) excretion) and a range of skeletal complications have been evaluated in patients with metastatic bone disease. A total of 121 patients had monthly measurements of Ntx during treatment with bisphosphonates. All skeletal-related events, plus hospital admissions for bone pain and death during the period of observation, were recorded. Data were available for 121 patients over the first 3-month period of monitoring (0-3 months) and 95 patients over the second 3-month period (4-6 months). N-telopeptide levels were correlated with the number of skeletal-related events and/or death (r=0.62, P<0.001 for 0-3 months and r=0.46, P<0.001 for 4-6 months, respectively). Patients with baseline Ntx values > or =100 nmol mmol(-1) creatinine (representing clearly accelerated bone resorption) were 19.48 times (95% CI 7.55, 50.22) more likely to experience a skeletal-related event/death during the first 3 months than those with Ntx <100 (P<0.001). In a multivariate logistic regression model, Ntx was highly predictive for events/death. This study is the first to indicate a strong correlation between the rate of bone resorption and the frequency of skeletal complications in metastatic bone disease. N-telopeptide appears useful in the prediction of patients most likely to experience skeletal complications and thus benefit from bisphosphonate treatment.

Aged↗

PubMed1988

Effect of strontium chloride on bone resorption induced by prostaglandin E2 in cultured bone.

We examined whether the bone resorption induced by PGE2 was inhibited by SrCl2 using 45Ca-labelled calvaria of CD-strain mice in tissue culture. It was found that Sr salts inhibited physiological bone resorption in a dose-dependent manner (0.1-5.0 mM) and did not act via PGE2. Accordingly, it was suggested that Sr salts did not inhibit bone resorption induced by exogenous PGE2.

Animals↗

PubMed1985

Prostaglandin E2 and 2-chloroadenosine act in concert to stimulate bone resorption in cultured murine calvarial bones.

2-Chloroadenosine-induced calcium release from cultured mouse calvarial bones is reduced by inhibitors of prostaglandin production, whereas PTH stimulated calcium release is not. When calvaria were treated with 2-chloroadenosine (10 microM) for 48 hr the production of PGE was significantly increased. The stimulation of PGE synthesis was totally inhibited by indomethacin (1 microM) and partially by hydrocortisone (0.1 microM). When PGE2 and 2-chloroadenosine, at submaximal concentrations, were simultaneously added to cultures of calvarial bones, in which the endogenous production of prostaglandins was reduced by indomethacin, a supraaditive effect on calcium mobilization by the two agents was seen. No such synergism could be observed between PGE2 and PTH or between 2-chloroadenosine and PTH. The degree of stimulation in indomethacin-treated bones by 2-chloroadenosine (i.e. when compared to indomethacin-treated controls) was almost the same as that seen in bones stimulated by 2-chloroadenosine in the absence of indomethacin. These data suggest that 2-chloroadenosine can induce bone resorption by a mechanism independent of stimulation of prostaglandin synthesis but that the amount of 2-chloroadenosine stimulated resorption is enhanced by endogenous and exogenous PGE2.

2-Chloroadenosine↗

PubMed1986

Osteoblasts mediate interleukin 1 stimulation of bone resorption by rat osteoclasts.

A monocyte-derived factor with IL-1-like properties has recently been shown to cause resorption of bone in organ culture. We have investigated the action of IL-1 on disaggregated populations of osteoclasts, incubated alone or in the presence of osteoblastic cells, in an attempt to identify the target cell for IL-1 in bone, and to elucidate the mechanism by which IL-1 induces osteoclastic resorption. Osteoclasts were disaggregated from neonatal rat long bones and incubated on slices of human femoral cortical bone. Under these conditions, the majority of osteoclasts form distinctive excavations in the bone surface within 24 h, the volume of which can be quantified by computer-assisted morphometric and stereophotogrammetic techniques. IL-1 had no effect on bone resorption by osteoclasts alone, but when incubated in the presence of calvarial cells or cloned osteosarcoma cells, it induced a 3.8 (+/- 0.38)-fold increase in osteoclastic bone resorption, with significant enhancement at concentrations of greater than or equal to 30 pg/ml. The osteoblastic populations themselves did not resorb bone. The mechanism by which osteoblastic cells stimulate osteoclasts did not appear to depend upon PG synthesis; nor could we detect a diffusible substance in the medium of stimulated cocultures. These results indicate that IL-1 stimulates bone resorption through a primary action on osteoblasts, which are induced by IL-1 to transmit a short-range signal that stimulates osteoclastic bone resorption.

Animals↗

PubMed1998

Macrophage colony-stimulating factor increases bone resorption by osteoclasts disaggregated from human fetal long bones.

Macrophage colony-stimulating factor (M-CSF) is known to play an important role in human and murine osteoclast formation. Although M-CSF has been shown to inhibit isolated neonatal rat osteoclasts from resorbing bone, its action on the mature human osteoclast has not been described. We now report that M-CSF increases osteoclastic bone resorption in a dose-responsive manner. Bone resorption by mature human fetal osteoclasts, including pit area, depth, and volume, was increased in the presence of M-CSF compared with vehicle. The number of osteoclasts in the cultures was similar after 2 and 18 h in the presence of M-CSF, whereas there was a significant reduction in osteoclast number, whether assessed as the number of tartrate-resistant acid phosphatase (TRAP)-positive or vitronectin receptor-positive cells after 18 h in M-CSF-free cultures. The number of nuclei per osteoclast after 2 or 18 h in M-CSF was also similar and there was no difference in the number of vitronectin receptor-positive mononucleate cells at 2 and 18 h. This suggests that the increased bone resorption is likely to be accounted for by enhanced osteoclast survival in M-CSF compared with controls rather than by formation of new osteoclasts.

Acid Phosphatase↗

PubMed1998

Bisphosphonates in bone cement inhibit PMMA particle induced bone resorption.

OBJECTIVE: Wear particle induced bone resorption is thought to be one of the mechanisms that contribute to implant loosening. It has previously been shown that macrophages, in response to polymethylmethacrylate (PMMA) particles, differentiate into bone resorbing osteoclasts, and that this process is inhibited by a bisphosphonate, etidronate (EHDP). The aim of this study was to determine whether incorporating EHDP in bone cement could reduce PMMA associated bone resorption. METHODS: Two concentrations of EHDP were mixed with PMMA monomer before polymerisation. Particles of PMMA (1-10 microns) were generated then added to mouse monocytes cocultured with UMR106 rat osteoblast-like cells and the extent of osteoclast differentiation was determined by assessing the extent of tartrate resistant acid phosphatase (TRAP) staining and measuring the amount of lacunar bone resorption. RESULTS: The addition of PMMA to monocyte-UMR106 cocultures resulted in a marked increase in the number of TRAP positive osteoclast-like cells and a significant increase in the number of lacunar resorption pits compared with control cultures to which no particles had been added. After the addition of particles of PMMA + 20 mg EHDP, significantly fewer lacunar pits (p = 0.00006) and fewer TRAP positive cells were noted compared with cocultures containing PMMA particles alone. CONCLUSIONS: These results indicate that by mixing a bisphosphonate with bone cement, it is possible to inhibit PMMA particle induced bone resorption. This bisphosphonate inhibition of PMMA biomaterial wear particle containing macrophage-osteoclast differentiation and bone resorption may provide a possible therapeutic strategy to prevent or to control the osteolysis of aseptic loosening.

Animals↗

PubMed2000

Proposed standard nomenclature for new tumor necrosis factor members involved in the regulation of bone resorption. The American Society for Bone and Mineral Research President's Committee on Nomenclature.

Recently, three new family members of the tumor necrosis factor (TNF) ligand and receptor signaling system that play a critical role in the regulation of bone resorption have been identified and cloned. These also have been shown to play an important role in regulating the immune system. A proliferation of synonyms for these molecules has led to miscommunication and redundancy. To resolve this, the President of the American Society for Bone and Mineral Research (ASBMR) appointed a special committee to recommend a standard nomenclature. After considerable deliberation and after vetting by workers in the field, the Committee recommends the names of receptor activator of NF-kappaB (RANKL) for the membrane receptor, RANK ligand (RANK) for the ligand, and osteoprotegerin (OPG) for the decoy receptor.

Bone Resorption↗

PubMed2000

Proposed standard nomenclature for new tumor necrosis factor family members involved in the regulation of bone resorption. The American Society for Bone and Mineral Research President's Committee on Nomenclature.

Recently, three new family members of the tumor necrosis factor (TNF) ligand and receptor signaling system that play a critical role in the regulation of bone resorption have been identified and cloned. These also have been shown to play an important role in regulating the immune system. A proliferation of synonyms for these molecules has led to miscommunication and redundancy. To resolve this, the President of the American Society for Bone and Mineral Research (ASBMR) appointed a special committee to recommend a standard nomenclature. After considerable deliberation and after vetting by workers in the field, the Committee recommends the names of receptor activator of NF-kappaB (RANK) for the membrane receptor, RANK ligand (RANKL) for the ligand, and osteoprotegerin (OPG) for the decoy receptor.

Bone Resorption↗

PubMed1999

Acute fasting diminishes the circadian rhythm of biochemical markers of bone resorption.

OBJECTIVE: Biochemical markers of bone turnover exhibit circadian rhythms with the peak during the night/early morning and the nadir in the late afternoon. The nocturnal increase in bone resorption could theoretically be caused by the absence of food consumption which brings about a decrease in net calcium absorption and an increase in parathyroid hormone (PTH), followed by increased bone resorption in response to the body's demand for calcium. The aim of the present study was to assess the influence of a 33-h fast on the circadian variation in biochemical markers of bone turnover. DESIGN: Eleven healthy premenopausal women (age: 24+/-5 years) participated in a randomised, cross-over study consisting of two periods: either 33h of fasting (fasting) followed 1 week later by a 33-h period with regular meals eaten at 0800-0830h, 1130-1230h and 1800-1900h (control) or vice versa. METHODS: Urinary CrossLaps (U-CL/Cr) corrected with creatinine, as a marker of bone resorption; serum osteocalcin (sOC) as a marker of bone formation; serum intact PTH (iPTH); serum phosphate; and serum calcium corrected with albumin. RESULTS: Both the fasting and the control periods showed a significant circadian rhythm in U-CL/Cr (P<0.001), but the decrease was significantly less pronounced in the morning hours during the fasting period. Fasting resulted in a significant decrease in serum iPTH (throughout the study period) as compared with the control period (P<0.05-0.001). No change was observed in sOC by fasting. CONCLUSION: Food consumption has a small influence on the circadian variation in bone resorption, independent of PTH. The fall in iPTH during fasting may be secondary to an increased bone resorption produced by fasting.

Adult↗

PubMed1987

Calcitonin gene-related peptide inhibits osteoclastic bone resorption: a comparative study.

Besides the calcitonin (CT) precursor, the calcitonin gene also encodes another peptide--calcitonin gene-related peptide (CGRP). We have previously reported that CGRP lowers plasma calcium in the rat. In the present study we have evaluated the effect of CGRP on resorption of bone by isolated rat osteoclasts and have compared these effects to those produced by calcitonins from three species (salmon, pig, and human calcitonins). There was a significant inhibition of bone resorption with rat calcitonin gene-related peptide (rCGRP) at a 1000-fold higher dose than that used for human CT. This effect well explains the CT-like effect of CGRP seen in the in vivo rat CT bioassay. Our results suggest that though CGRP may not be involved in the hormonal control of plasma calcium, the peptide may be an important local regulator of bone cell function.

Animals↗

PubMed2006

Vertebral bone resorption after transforaminal lumbar interbody fusion with bone morphogenetic protein (rhBMP-2).

OBJECTIVE: Bone morphogenetic protein (rhBMP-2) has demonstrated an increased rate of interbody fusion when placed in the intervertebral space. Owing to this advantage, rhBMP-2 is being implanted with increasing frequency in the lumbar spine. The purpose was to quantify and describe the presence of bone resorption within the vertebral body after transforaminal lumbar interbody fusion with placement of rhBMP-2 within the disc space. METHODS: Twenty-six patients were selected from a clinical database. Patients included in the study had undergone a transforaminal lumbar interbody fusion with BMP. Interbody implants included allograft dowels or interbody cages augmented with autograft or allograft bone. A computed tomography study of the lumbar spine a minimum of 3-month postoperatively was another inclusion criterion. Osteolytic defects were grouped into 3 categories on the basis of the size and extent of involvement in the vertebral body. RESULTS: A total of 32 lumbar levels were reviewed. Fourteen males and 12 females with an average age of 46.0 years were included in the study. Bone resorption defects were noted in 22 of the 32 levels reviewed (69%). The defects were characterized as mild in 50% (11 of 22), moderate in 18% (4 of 22), and severe in 31% (7 of 22). CONCLUSIONS: The benefit of rhBMP-2 to promote interbody fusion in the lumbar spine has been well documented. BMP has demonstrated an increased fusion rate and the ability to produce a robust fusion mass. rh-BMP-2's osseous remodeling potential may lead to bone resorption within the vertebral body.

Adolescent↗

PubMed1997

Estrogen inhibits bone resorption by directly inducing apoptosis of the bone-resorbing osteoclasts.

Estrogen deficiency causes bone loss, which can be prevented by estrogen replacement therapy. Using a recently developed technique for isolation of highly purified mammalian osteoclasts, we showed that 17 beta-estradiol (E2) was able to directly inhibit osteoclastic bone resorption. At concentrations effective for inhibiting bone resorption, E2 also directly induced osteoclast apoptosis in a dose- and time-dependent manner. ICI164,384 and tamoxifen, as pure and partial antagonists, respectively, completely or partially blocked the effect of E2 on both inhibition of osteoclastic bone resorption and induction of osteoclast apoptosis. These data suggest that the protective effects of estrogen against postmenopausal osteoporosis are mediated in part by the direct induction of apoptosis of the bone-resorbing osteoclasts by an estrogen receptor- mediated mechanism.

Animals↗

PubMed1995

C-type natriuretic peptide increases bone resorption in 1,25-dihydroxyvitamin D3-stimulated mouse bone marrow cultures.

Most agents that regulate osteoclast bone resorption exert their effects indirectly, through the osteoblast. Nitric oxide, which stimulates soluble guanylyl cyclase, has been reported to inhibit osteoclast bone resorption directly, by a cGMP-independent mechanism (1). In this report, we demonstrate that C-type natriuretic peptide (CNP), an activator of membrane-bound guanylyl cyclase, stimulates bone resorption by osteoclast-containing 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3)-stimulated mouse bone marrow cultures. Quantitative reverse transcription polymerase chain reaction assays and anti-CNP immunocytochemistry were used to demonstrate that CNP is expressed in mouse marrow cells cultured in the presence, but not the absence, of, 1,25-(OH)2D3. mRNA for guanylyl cyclase type B, the receptor for CNP, was expressed in cultures independent of 1,25-(OH)2D3. CNP (1 and 10 microM) elevated cGMP production in marrow cultures to 350 and 870%, respectively, of control values. 10 microM CNP increased osteoclast bone resorptive activity, measured by the resorption area on whale dentine wafers, or by the NH4Cl-inhibitable release of [3H]proline from radiolabeled bone chips, to 214 and 557% of control, respectively, without affecting osteoclast formation. Bone resorption by the marrow cultures was inhibited by 7F9.1, a monoclonal antibody raised against CNP, but not by control antibodies. These results indicate that CNP is a potent activator of osteoclast activity and may be a novel local regulator of bone remodeling.

Animals↗

PubMed2006

A highly potent inhibitor of cathepsin K (relacatib) reduces biomarkers of bone resorption both in vitro and in an acute model of elevated bone turnover in vivo in monkeys.

Cathepsin K is an osteoclast-derived cysteine protease that has been implicated as playing a major role in bone resorption. A substantial body of evidence indicates that cathepsin K is critical in osteoclast-mediated bone resorption and suggests that its pharmacological inhibition should result in inhibition of bone resorption in vivo. Here we report the pharmacological characterization of SB-462795 (relacatib) as a potent and orally bioavailable small molecule inhibitor of cathepsin K that inhibits bone resorption both in vitro in human tissue and in vivo in cynomolgus monkeys. SB-462795 is a potent inhibitor of human cathepsins K, L, and V (K(i, app)=41, 68, and 53 pM, respectively) that exhibits 39-300-fold selectivity over other cathepsins. SB-462795 inhibited endogenous cathepsin K in situ in human osteoclasts and human osteoclast-mediated bone resorption with IC50 values of approximately 45 nM and approximately 70 nM, respectively. The anti-resorptive potential of SB-462795 was evaluated in normal as well as medically ovariectomized (Ovx) female cynomolgus monkeys. Serum levels of the C- and N-terminal telopeptides of Type I collagen (CTx and NTx, respectively) and urinary levels of NTx were monitored as biomarkers of bone resorption. Administration of SB-462795 to medically ovariectomized or normal monkeys resulted in an acute reduction in both serum and urinary markers of bone resorption within 1.5 h after dosing, and this effect lasted up to 48 h depending on the dose administered. Our data indicate that SB-462795 potently inhibits human cathepsin K in osteoclasts, resulting in a rapid inhibition of bone resorption both in vitro and in vivo in the monkey. These studies also demonstrate the therapeutic potential of relacatib in the treatment of postmenopausal osteoporosis and serves to model the planned clinical trials in human subjects.

Administration, Oral↗

PubMed2002

Effects of dose and timing of calcium supplementation on bone resorption in early menopausal women.

Bone resorption follows a circadian rhythm that peaks at night, reflecting the circadian rhythm of serum parathyroid hormone. Our previous studies in early postmenopausal women have established that 1000 mg of calcium given at 9 p. m. reduced bone resorption markers overnight, but not during the day. In contrast, 1000 mg given as a divided dose (500 mg doses at 9 a. m. and 9 p. m. each) reduced bone resorption markers during the day, but not during the night. We have now evaluated the effect of 1500 mg of calcium given as a divided dose of 500 mg in the morning and 1000 mg in the evening on bone resorption. We studied 26 healthy women (median age 56 years) whose menopause was less than five years before. On two days, urine was collected from 9 a. m. to 9 p. m. (day collection), and from 9 p. m. to 9 a. m. (night collection); a further fasting (spot) urine sample was obtained at 9 a. m. at the end of the night collection. On the second day, 500 mg of calcium in the carbonate form was taken at 9 a. m. (at the start of the collection) and a further 1000 mg at 9 p. m. (at the start of the second night collection). Calcium supplementation decreased urinary deoxypyridinoline (DPyr/Cr) during the day (p = 0.08) and night (p < 0.05), as well as urinary pyridinoline (Pyr/Cr) both by day (p < 0.05) and night (p < 0.001). There were also decreases in urine hydroxyproline. We conclude that the acute administration of 500 mg of calcium in the morning and 1000 mg in the evening to early postmenopausal women suppresses bone resorption markers during both the day and night.

Amino Acids↗

PubMed1995

Diminished bone resorption in rats after oral xylitol administration: a dose-response study.

The effects of 5, 10, and 20% dietary xylitol supplementations on the resorption of bone were studied. The resorption was measured by the urinary excretion of [3H] radioactivity from [3H]tetracycline-prelabeled rats. The 10 and 20% oral xylitol administrations caused a significant decrease in the excretion of [3H] as compared with the control group with no xylitol supplementation. The effect was detected as early as 2 days after the beginning of xylitol-feeding and was maintained throughout the experimental period of 31 days. The retarding effect on bone resorption was about 25% in the 10% xylitol group, about 40% in the 20% xylitol group, and undetectable in the 5% xylitol group. The amount of preserved [3H] radioactivity in the tibiae of the 10 and 20% xylitol groups after the experiment clearly exceeded the values of the control group. The mechanism of the retarded bone resorption caused by dietary xylitol still remains obscure, but an increased absorption of calcium may be involved. In conclusion, dietary xylitol supplementation in rats seems to retard the bone resorption in a dose-dependent way. The effect is achieved rapidly and is maintained at least over a period of 1 month xylitol feeding.

Administration, Oral↗

PubMed1980

Ouabain effects on hormonally-stimulated bone resorption and cyclic AMP content in cultured fetal rat bones.

Ouabain in concentrations from 20-100 micromoles produced a dose-related inhibition of in vitro stimulation of bone resorption by parathyroid hormone, 1,25-dihydroxyvitamin D3 and calcium ionophore A23187, as measured by 45Ca and [3H]-hydroxyproline release in 5-day cultures of fetal rat forelimb rudiments. The inhibitory effect on 45Ca release was completely reversed by subsequent incubation in ouabain-free medium. At a concentration of 100 micromoles ouabain virtually abolished active bone resorption; however, basal and stimulated bone cyclic AMP (cAMP) content were significantly increased above levels observed in the absence of ouabain. The increased cAMP content did not appear to be the result of phosphodiesterase inhibition. It is concluded that intact Na/K ATPase function is required for hormonally-stimulated bone resorptive processes and that the inhibitory effect of ouabain on bone resorption is produced at a point subsequent to cyclic AMP generation.

Animals↗