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PubMed1995

The bone-specific estrogen centchroman inhibits osteoclastic bone resorption in vitro.

There is considerable interest in identifying bone-specific estrogen-like compounds with beneficial activities on bone and the cardiovascular system, but lacking side effects on the reproductive system. Two such compounds are currently under clinical investigation -raloxifene (Lilly) and centchroman (Novo-Nordisk). There is evidence suggesting that 17 beta-estradiol can inhibit osteoclastic bone resorption although this is somewhat controversial. Therefore, we examined the effect of centchroman and raloxifene, as well as 17 beta-estradiol, in the in vitro bone slice assay, where the direct effect of compounds on osteoclast activity can be assessed. Centchroman (0.001 - 1 microM) dose-dependently inhibited osteoclastic bone resorption up to 70% at 1 microM (p = 0.007) with an IC50 = 0.1 microM, while in contrast, raloxifene had no significant effect on bone resorption over the same dose range. 17 beta-estradiol (0.0001 - 1 microM) had a modest but significant inhibitory effect on resorption (40%, p < 0.05) at 1 microM, but no effect at lower physiological/therapeutic concentrations. Centchroman (1 microM) inhibited osteoclast cytoplasmic spreading by 32%, while raloxifene and 17 beta-estradiol were without effect. These results show that centchroman at therapeutic concentrations (ED50 approximately 1 mg/kg in animal models) is a potent inhibitor of osteoclastic bone resorption in vitro, suggesting that bone-specific estrogen-like molecules may have different mechanisms of action.

Animals↗

PubMed2000

Prostaglandins regulate acid-induced cell-mediated bone resorption.

Metabolic acidosis induces bone calcium efflux initially by physicochemical dissolution and subsequently by cell-mediated mechanisms involving inhibition of osteoblasts and stimulation of osteoclasts. In rat kidney, acidosis increases endogenous prostaglandin synthesis, and in bone, prostaglandins are important mediators of resorption. To test the hypothesis that acid-induced bone resorption is mediated by prostaglandins, we cultured neonatal mouse calvariae in neutral or physiologically acidic medium with or without 0.56 microM indomethacin to inhibit prostaglandin synthesis. We measured net calcium efflux and medium PGE(2) levels. Compared with neutral pH medium, acid medium led to an increase in net calcium flux and PGE(2) levels after both 48 h and 51 h, a time at which acid-induced net calcium flux is predominantly cell mediated. Indomethacin inhibited the acid-induced increase in both net calcium flux and PGE(2). Net calcium flux was correlated directly with medium PGE(2) (r = 0.879, n = 29, P < 0.001). Exogenous PGE(2), at a level similar to that found after acid incubation, induced net calcium flux in bones cultured in neutral medium. Acid medium also stimulated an increase in PGE(2) levels in isolated bone cells (principally osteoblasts), which was again inhibited by indomethacin. Thus acid-induced stimulation of cell-mediated bone resorption appears to be mediated by endogenous osteoblastic PGE(2) synthesis.

Acidosis↗

PubMed1993

Role of dual signal transduction systems in the stimulation of bone resorption by parathyroid hormone-related peptide. The direct involvement of cAMP-dependent protein kinase.

The present study was performed to compare the effect of parathyroid hormone-related peptide (PTHrP) on bone resorption with that of parathyroid hormone (PTH) and clarify the participation of PTHrP-responsive dual signal transduction systems involving cAMP-dependent protein kinase (PKA) and calcium/protein kinase C (Ca/PKC) in the stimulation of bone resorption by PTHrP. Bone resorbing activity was estimated as the number of pits formed on the dentine slice and total area of pits per slice in bone cells derived from 2 week-old mice. Human (h)PTHrP-(1-34) (10(7) M) stimulated bone resorption as potent as hPTH-(1-34) (10(7) M) did. The stimulation of bone resorption by hPTHrP-(1-34) and hPTH-(1-34) was equally blocked by either simultaneous treatment with 10(-8) M Elcatonin (eel calcitonin derivative; from Asahi Chemical Industry, Tokyo, Japan) [corrected] or pretreatment with 10(-7) M [Nle8,18Tyr34]hPTH-(3-34)amide. Rp-cAMPs, an antagonist in the activation of PKA, equally attenuated bone resorption stimulated by PTHrP as well as by PTH. A23187 (10(-7) M) caused a significant stimulation of bone resorption. These findings indicate the direct involvement of PKA activation and a contributory role of an increase in cytosolic calcium in the stimulation of bone resorption by PTHrP and suggest that PTHrP stimulates bone resorption presumably through the same mechanism as PTH does.

Animals↗

PubMed2006

Herbal formulation, Yukmi-jihang-tang-Jahage, regulates bone resorption by inhibition of phosphorylation mediated by tyrosine kinase Src and cyclooxygenase expression.

Anti-bone resorption properties of the Korean herbal medicine, Yukmi-jihang-tang (YJ), which is comprised of seven herbs such as Rehmannia glutinosa Libosch, Dioscorea japonica THUNB, Cornus officinalis SIEB et. ZUCC, Smilax glabra ROXB, Paeonia suffruticosa ANDR, Alisma platago-aquatica var. orientale SAMUELS and Hominis placenta, were investigated. Cyclooxygenase-2 (COX-2) and tyrosine kinase involve on prostaglandin E2 (PGE2) production in mouse calvarial osteoblasts stimulated by cytokine interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha) and/or interleukin-6 (IL-6). IL-1beta and IL-6 and to a lesser extent TNF-alpha, enhanced COX-2 mRNA levels in calvarial osteoblasts. TGF-beta, YJ (100microg/ml) and their combinations of YJ+TGF-beta reduced the COX-2 mRNA level, PGE2 biosynthesis and bone resorption induced by IL-1beta, TNF-alpha, IL-6 or their combination. Finally, YJ inhibits in vitro and in vivo bone resorption by inhibition of phosphorylation of peptide substrates. The parathyroid hormone-induced bone resorption in mouse fetal long bone cultures was inhibited with an IC(50) of 16microg/ml. YJ dose-dependently reduced the hypercalcemia induced in mice by IL-1beta and partly prevented bone loss and microarchitectural changes in young ovariectomized rats, showing that the protective effect on bone was exerted via the inhibition of bone resorption. These results indicate that the synergy between IL-beta, TNF-alpha, IL-6 on PGE2 production is due to an enhanced gene expression of COX-2 and that tyrosine kinase(s) are involved in the signal transduction of COX-2 in mouse calvarial osteoblasts. Thus, YJ as a possible Src family kinase inhibitor may be useful for the treatment of diseases associated with elevated bone loss. This result also suggested that the YJ extracts is effective for bone resorptive action in bone cells.

Animals↗

PubMed1996

[Cell biology of osteoclasts and molecular mechanisms of bone resorption].

The maintenance of a normal skeletal shape and bone mass closely depends on a normal osteoclastic activity, as do bone growth and repair. Thus, the improvement of our means of therapeutic intervention will depend on our better understanding of the molecular basis of bone resorption and of the cellbiology of the osteoclast. This review-article presents our current opinion of the molecular mechanisms of bone resorption by the osteoclast. After describing the morphological features of the osteoclast, aspects as cell mobility, attachment, enzymesynthesis, transmembrane transport, osteoclast differentiation and function, as well as the protooncogenes c-src and c-cbl and their role for bone resorption are presented in detail.

Animals↗

PubMed1986

Comparative study of the effects of cyclic nucleotide phosphodiesterase inhibitors on bone resorption and cyclic AMP formation in vitro.

The relation between the level of cyclic AMP and bone resorption was studied in a bone organ culture system, using calvaria from newborn mice. Two methylxanthines, iso-butyl-methylxanthine and theophylline and two non-xanthine inhibitors of cyclic AMP phosphodiesterase, Ro 20-1724 and rolipram, stimulated the release of [45Ca] and [3H] from bones prelabelled in vivo with [45Ca]- and [3H]proline, respectively. The release occurred after a delay of more than 24 hr. In 120-hr cultures, theophylline, IBMX, rolipram and Ro 20-1724, all stimulated the release of stable calcium, inorganic phosphate and the lysosomal enzymes, beta-glucuronidase and beta-N-acetylglucosaminidase from mouse calvarial bones. In addition, all four phosphodiesterase inhibitors decreased the amount of hydroxyproline in the bones at the end of the culture period. The release of minerals and the decrease of hydroxyproline was abolished by indomethacin. In short-term cultures (24 hr), rolipram and Ro 20-1724 did not reduce PTH-stimulated mineral mobilization, whereas the two methylxanthines, and dibutyryl cyclic AMP and 8-bromo cyclic AMP, did cause a reduction of PTH-stimulated mineral release during the first 24 hr. All four phosphodiesterase inhibitors increased the accumulation of cyclic AMP in the calvaria and inhibited cyclic AMP hydrolysis in extracts of calvarial bone. There was a correlation between the magnitude of the initial rise in cyclic AMP and the delayed stimulation of bone resorption. However, much lower concentrations of the PDE inhibitors were sufficient to produce a delayed increase in bone resorption than to block phosphodiesterase and significantly raise cyclic AMP levels. It is suggested that the elevation of cyclic AMP in a subset of bone cells results in an acute reduction of bone mobilization and the cAMP elevation in another subset to a delayed rise in bone resorption.

1-Methyl-3-isobutylxanthine↗

PubMed1992

The activation of cAMP-dependent protein kinase is directly linked to the stimulation of bone resorption by parathyroid hormone.

The present study was performed to characterize the direct involvement of cAMP in the stimulation of bone resorption by parathyroid hormone (PTH), using Sp-cAMPS and Rp-cAMPS, which were the direct agonist and antagonist in the activation of cAMP-dependent protein kinase (PKA), respectively. Bone resorbing activity was estimated as the number of pits formed on the dentine slice and total area of pits per slice in bone marrow cells derived from 2 week-old mice. Dibutyryl cAMP (dbcAMP)(10(-4)M) and Sp-cAMPS (10(-4)M) caused the remarkable stimulation of bone resorption. Although Rp-cAMPS (10(-4)M) did not affect bone resorption by itself, it significantly inhibited dbcAMP- and Sp-cAMPS-induced stimulation of bone resorption. Moreover, Rp-cAMPS (10(-4)M) antagonized 10(-7)M human PTH-(1-34)-induced stimulation of bone resorption, although it did not affect 10(-8)M 1,25(OH)2D3-induced stimulation of bone resorption. Present study indicates the direct involvement of PKA in the stimulation of bone resorption by PTH.

Animals↗

PubMed2001

Bisphosphonates alendronate and ibandronate inhibit artery calcification at doses comparable to those that inhibit bone resorption.

The present experiments were carried out to test the hypothesis that artery calcification is linked to bone resorption by determining whether the selective inhibition of bone resorption with the bisphosphonates alendronate and ibandronate will inhibit artery calcification. Artery calcification was first induced by treatment of 42-day-old male rats with warfarin, a procedure that inhibits the gamma-carboxylation of matrix Gla protein and has been shown to cause extensive calcification of the artery media within 2 weeks. These experiments revealed that ibandronate (0.05 mg. kg(-1). d(-1)) and alendronate (0.1 mg x kg(-1) x d(-1)) completely inhibited calcification of all arteries and heart valves examined after 2 and 4 weeks of warfarin treatment. A 10-fold lower dose of alendronate reduced artery calcification by 50% (P<0.005). These bisphosphonate doses are comparable to those that inhibit bone resorption in rats of this age. More rapid artery calcification was induced by treatment with warfarin together with high doses of vitamin D, a procedure that causes extensive artery calcification by 84 hours. Alendronate and ibandronate again completely inhibited calcification of all arteries and heart valves examined. The subcutaneous doses of alendronate and ibandronate necessary to inhibit artery calcification are comparable to the daily subcutaneous doses of these drugs that have previously been shown to inhibit bone resorption in rats of the same age, with 50% inhibition of artery calcification at 20 microg alendronate x kg(-1) x d(-1) and at 1 microg ibandronate x kg(-1) x d(-1) x Bisphosphonate treatment did not affect serum calcium and phosphate, and so the inhibition of artery calcification cannot be due to a simple lowering of the serum calcium phosphate ion product. We conclude that bisphosphonates inhibit the calcification of arteries and heart valves at doses comparable to the doses that inhibit bone resorption. These results support the hypothesis that artery calcification is linked to bone resorption. The mechanism of this linkage remains to be established, however, and an alternative explanation for the present results is also considered.

Alendronate↗

PubMed2001

Serum bone sialoprotein: a marker of bone resorption in postmenopausal osteoporosis.

Thirty healthy perimenopausal women who had normal lumber spine bone mineral density (LS-BMD) measured by dual energy X-ray absorptiometry (DEXA) participated in this study as controls. The pathological group comprised 50 postmenopausal osteoporotic women who had LS-BMD more that 2 SD below the normal mean of healthy perimenopausal women. Postmenopausal osteoporotic patients were allocated to three different therapeutic modalities (hormone replacement therapy HRT, alendronate or combined HRT and alendronate). Blood and urine samples were collected from all groups before and 12 months after treatment. Serum bone sialoprotein (BSP) was measured by a specific radioimmunoassay and urinary pyridinoline (Pyr), deoxy-pyridinoline (DPyr) and N-telopeptide of type 1 collagen (NTX) were determined as biomarkers of bone resorption. In addition, serum IL-11 and TGFbeta2 were measured by enzyme immunoassays. The results obtained showed that serum BSP was significantly elevated in postmenopausal osteoporosis compared to that of healthy perimenopausal controls. Significant positive correlations exist between serum BSP and biomarkers of bone resorption (Pyr,DPyr,NTX) as well as bone resorptive cytokines (IL-11,TGFbeta2). Serum BSP decreased after different antiresorptive treatments and this decrease paralleled the decrease of bone resorption markers and the increase of LS-BMD. Based on these data, circulating BSP appears to be a valuable marker of bone resorption and monitoring therapy with antiresorptive drugs in postmenopausal osteoporosis.

Adult↗

PubMed1971

2-Thiophenecarboxylic acid: inhibitor of bone resorption in tissue culture.

In tissue culture 2-thiophenecarboxylic acid inhibited both spontaneous resorption of bone and that induced by parathyroid hormone. Its action was to inhibit calcium transfer out of bone.

Animals↗

PubMed1976

Bone resorption in organ culture: inhibition by the divalent cation ionophores A23187 and X-537A.

The ionophores A23187 and X-537A were used as probes to investigate the possible role of calcium uptake by bone as a mediator for the stimulation of bone resorption induced by parathyroid hormone (PTH) and other agents in cultured mouse calvaria. The ionophores alone at concentrations from 1 nM to 20 muM did not stimulate bone resorption, nor did they potentiate bone resorption stimulated by submaximal concentrations of PTH after either brief (15-60 min) or extended (1-3 day) exposure to the ionophores. Unexpectedly, we found that the ionophores inhibit in a dose-dependent manner bone resorption stimulated by PTH and a wide variety of other compounds (prostaglandin E2, 1alpha-hydroxycholecalciferol, 3-isobutyl-1-methyl-xanthine, and phorbol myristate acetate). This inhibition was not due to irreversible damage to the bones by the ionophores, because the inhibition was reversible even after 24 h of treatment. Inhibition of bone resorption by the ionophores was observed in media of both high and low calcium concentration, indicating that the inhibition was not due to a critical extracellular calcium concentration. Inhibition by the ionophores differs qualitatively in several ways from that produced by calcitonin, a natural inhibitor of bone resorption. Furthermore, A23187 at 1.0 mug/ml had no effect on the accumulation of cyclic AMP in the medium of either control, PTH- or calcitonin treated calvaria. We conclude that the ionophores A23187 or X537A do not stimulate bone resorption nor potentiate the effects of stimulators of bone resorption; instead they are inhibitors of bone resorption stimulated by a wide variety of compounds.

Animals↗

PubMed2002

Reduction of instability-induced bone resorption using bisphosphonates: high doses are needed in rats.

Bone resorption associated with prosthetic loosening can be reduced by giving bisphosphonates since they bind to bone surfaces and inactivate osteoclasts when bisphosphonate-containing bone is resorbed. During loosening, an increase in osteoclastic activity can be triggered by mechanical instability, fluid pressure or wear particles. We used a rat model in which a titanium surface can be made to slide over a bone surface and cause instability-induced bone resorption. 111 rats were operated on with a plate implant and treated with alendronate or clodronate injections in different doses or saline controls. After 4 weeks of osseointegration, the plate was moved during 2 weeks and the findings evaluated with histomorphometry. The percentage of persisting bone-metal contact and the soft tissue area at the interface were measured to estimate bone loss. Low or intermediate doses of the bisphosphonates increased the ash weight of untraumatized bone, but did not inhibit resorption at the unstable interface. Only rats treated with the highest doses of alendronate or clodronate had more bone-metal contact than controls. Instability-induced bone resorption therefore seems to be reduced by bisphosphonates, but higher doses are needed to obtain this effect than to reduce bone resorption associated with normal remodeling of untraumatized bone.

Alendronate↗

PubMed2003

An immunoassay for type I collagen alpha 1 helicoidal peptide 620-633, a new marker of bone resorption in osteoporosis.

Type I collagen fragments are the most sensitive markers of bone resorption in osteoporosis. Currently, all available type I collagen-related bone resorption markers detect in serum and/or urine fragments arising from the telopeptide region of the molecule. Our aim was to evaluate the technical and clinical performances of a new assay detecting in urine a degradation fragment originating from the helical part of type I collagen and consisting of the 620-633 sequence of the alpha1 chain. Urinary helical peptide was measured with a new ELISA (Metra Helical peptide, Quidel Corporation). Results were compared with those of urinary C-terminal cross-linking type I collagen of type I collagen (CTX), an established bone resorption marker. We measured urinary helical peptide levels in 89 healthy women (age 31-89 years) and in 59 postmenopausal women involved in two randomized studies of the efficacy of alendronate (10 mg/day; n = 20) and transdermal 17beta estradiol (50 microg/day; n = 39). The within-run and between-run CVs were < or = 7.3 and 8.7%, respectively. In 59 healthy women, urinary helical peptide levels highly correlated with those of urinary CTX (r = 0.78, P < 0.0001). The long-term intraindividual variability assessed over 6 months in 18 untreated postmenopausal women was 24%. Compared to 24 premenopausal women, urinary helical peptide was 42% (P < 0.0001) higher in 65 postmenopausal women (mean age, 60 years), an increase comparable to that of urinary CTX (+ 47%, P < 0.0001). Urinary helical peptide levels decreased by 72% (P < 0.0001) after 3 months of alendronate treatment and by 59% (P < 0.0001) after 6 months of transdermal estrogen therapy. These changes were of similar magnitude to those of urinary CTX (-69 and -62%, respectively; NS compared with changes in helical peptide). In women treated with transdermal 17beta estradiol, the percentage of change of urinary helical peptide and urinary CTX at 6 months significantly correlated with the change in spinal bone mineral density after 2 years (r = -0.58, P = 0.002, and r = -0.52, P = 0.006, for urinary helical peptide and CTX, respectively). This new assay for type I collagen helical peptide has demonstrated adequate analytical performance and was highly correlated with urinary CTX, an established type I collagen C-telopeptide bone resorption marker. The test was a sensitive indicator of the antiresorptive effects of bisphosphonate and estrogens in postmenopausal women. This new bone resorption marker should be useful for the clinical investigation of patients with osteoporosis.

Adult↗

PubMed1987

Palytoxin: an extraordinarily potent stimulator of prostaglandin production and bone resorption in cultured mouse calvariae.

Palytoxin, a nonphorbol ester-type tumor promoter, stimulated the production of prostaglandin E2 (PGE2) and bone resorption in neonatal mouse calvariae in organ culture. The action of palytoxin on bone resorption occurred at extraordinarily low concentrations; enhanced resorption was regularly observed at 0.5 pg/ml, and the ED50 was 1-2 pg/ml (approximately 3 X 10(-13) M). Palytoxin-induced formation of PGE2 and bone resorption were inhibited completely by indomethacin (200 ng/ml). Concentrations of palytoxin above 10 pg/ml led to progressively decreasing enhancement of bone resorption; by 100-250 pg/ml no stimulation of resorption was observed despite continued high production of PGE2. Treatment with high concentrations of palytoxin (100 or 250 pg/ml) for 24-72 h inhibited cAMP accumulation stimulated by exogenous PGE2 or PTH and inhibited bone resorption induced by PGE2, PTH, or an analog of cAMP. Thus, palytoxin exhibited a biphasic dose-response curve for enhanced bone resorption, with stimulation at low concentrations (0.5-10 pg/ml) and toxic inhibition at high concentrations (greater than 50 pg/ml). Palytoxin is one of the most potent stimulators of bone resorption yet identified.

1-Methyl-3-isobutylxanthine↗

PubMed1990

Na+/H+ antiporter is the primary proton transport system used by osteoclasts during bone resorption.

We have examined the effects of inhibitors of proton transport systems on osteoclastic bone resorption using an in vitro bone slice assay, where osteoclasts (OCs) are free from the influence of other bone cells. Amiloride (AM) and dimethylamiloride (DMA), inhibitors of the Na+/H+ antiporter, were potent inhibitors of bone resorption (IC50 approximately 9 and 0.7 microM for AM and DMA, respectively). Omeprazole (OM), a potent inhibitor of parietal cell K+/H+(-)ATPase, was a poor inhibitor of OC bone resorption (IC50 approximately 100 microM). These results strongly suggest that the Na+/H+ antiporter is the primary proton system used by OCs during bone resorption.

Adenosine Triphosphatases↗

PubMed1990

Osteopetrosis in the rat: coexistence of reductions in osteocalcin and bone resorption.

Osteocalcin, one of the vitamin K-dependent bone proteins, has recently been implicated in bone resorption. To explore this hypothesis, bone and serum osteocalcin were measured in three different osteopetrotic rat mutations characterized by reduced bone resorption. These three mutations (ia/ia, tl/tl, and op/op) exhibit heterogeneity with respect to osteoclast number and activity and response to being cured by bone marrow transplantation. Calvarial bone osteocalcin was present in normal amounts, but difficult to extract, in ia/ia rats that have increased numbers of inactive osteoclasts. Bone osteocalcin was greatly decreased in op/op (53-60% of control) and tl/tl (64-73% of control) osteopetrotic rats, in which osteoclasts are both reduced in number and inactive. These decreases in osteocalcin levels in bone coexist with elevated serum levels of osteocalcin in all three mutations. Since osteocalcin synthesis is known to be stimulated by 1,25(OH)2D3, the increase in serum osteocalcin may be a reflection of the elevated blood levels of 1,25(OH)2D3 known to occur in each of these mutations. These findings indicate that the composition of osteopetrotic bone is abnormal with respect to osteocalcin in the two rat osteopetrotic mutations showing decreased osteoclast numbers. Considered together with the emerging evidence that the extracellular matrix in many developing tissues plays a role in cell recruitment and differentiation, these data suggest that osteocalcin abnormalities may be a contributing factor to the spectrum of osteoclast aberrations in osteopetrosis.

Aging↗

PubMed1995

Antithetic effects of ryanodine and ruthenium red on osteoclast-mediated bone resorption and intracellular calcium concentrations.

In the process of bone remodeling, osteoclasts are responsible for resorption of bone. High levels of intracellular calcium decrease the bone resorbing activity of osteoclasts and increase detachment of osteoclasts from the bone surface. The regulatory role of intracellular calcium in bone resorption is not clearly understood. To understand this phenomenon, we studied the effects of the intracellular calcium modulators ryanodine and ruthenium red on bone resorption using the disaggregated osteoclast pit assay. Changes in intracellular calcium concentrations after treatment with these compounds were detected with the fluoroprobe fura2. With ryanodine, a significant, dose-dependent decrease in bone resorption was detected. This inhibition of bone resorption was reversible upon the removal of ryanodine. Ryanodine increased intracellular calcium concentrations, suggesting that the mechanism of inhibition by ryanodine was via alterations in intracellular stores of calcium. After treatment with ruthenium red, osteoclasts resorbed significantly more bone compared to vehicle-treated cells. This increase in bone resorption correlated with a decrease in intracellular calcium concentrations. The addition of parathyroid hormone or ruthenium red to osteoclast cultures containing ryanodine did not attenuate the decrease in bone resorption caused by ryanodine, suggesting that the mechanism of ryanodine inhibition of bone resorption may involve the "locking" of a calcium channel in an open position.

Analysis of Variance↗

PubMed1984

Reconstruction of the resorptive site in iliac trabecular bone: a kinetic model for bone resorption in 20 normal individuals.

The variations with time in function and morphology at the resorptive site in normal iliac crest trabecular bone were reconstructed from tetracycline double-labeled iliac crest bone biopsies from 20 normal individuals. Resorption depths below osteoclasts, mononuclear cells, and preosteoblast-like cells were measured by counting the number of lamellae of known thickness eroded. Mean resorption depth below osteoclasts was 19.0 (+/- 4.9) micron. Lacunae containing mononuclear cells were deeper (P less than less than 0.0001), with a mean resorption depth of 49.1 (+/- 10.2) micron. The deepest lacunae were lacunae containing preosteoblast-like cells, with a mean resorption depth of 62.6 (+/- 12.5) micron. This depth was significantly deeper (P less than 0.001) than the resorption depth found below mononuclear cells. Median total resorption period was 48 days (31-68; 95% confidence interval). Median osteoclastic function period was 8 days (6-12), median mononuclear cell function period was 34 days (24-48), and median period where preosteoblast-like cells were present in lacunae before matrix synthesis started was 9 days (6-13). Distribution curves describing the occurrence of the three cell types in relation to resorption depth showed that osteoclasts occupied the more superior parts of the resorption lacunae, with mononuclear cells and preosteoblast-like cells situated in the deeper parts. The distribution curves support the hypothesis that osteoclasts precede mononuclear cells, which again precede preosteoblast-like cells. Based on this hypothesis, curves showing the variation in resorption depth with time were constructed in duplicate. Resorption rates were calculated for three periods.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗