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PubMed1994

Reversibility of the inhibitory effect of salmon calcitonin on bone resorption in rats.

Inhibition of osteoclastic bone resorption has been induced in growing rats with high doses of salmon calcitonin. This effect was evaluated by measuring the perichondrial ring height of the proximal tibial metaphysis. The aim was to assess whether osteoclastic activity resumed after a period of inhibition with high doses of calcitonin. 20 male Sprague-Dawley rats were treated for 21 days with 100 units/kg/day of salmon calcitonin subcutaneously and killed after 0-60 days, together with non-treated controls at 0 and 60 days. Arrest of metaphyseal modeling and increased height of the perichondrial ring at the end of the period of therapy (P 0.002 versus controls) were observed. Recovery of bone resorption was evident 20 and 40 days after withdrawal of calcitonin.

Animals↗

PubMed1996

Hydrogen peroxide, but not superoxide, stimulates bone resorption in mouse calvariae.

Reactive oxygen species such as superoxide and hydrogen peroxide have been implicated as regulatory factors in the control of osteoclastic bone resorption. While superoxide radicals have been suggested to be the main bone resorbing species in organ culture and in vivo, hydrogen peroxide (H2O2) has recently been shown to activate isolated osteoclasts in vitro. In this study, we investigated the effects of hydrogen peroxide and superoxide on bone resorption in mouse calvarial organ cultures. Hydrogen peroxide stimulated bone resorption in a concentration-dependent manner in calvarial organ cultures with a maximal effect at 1 mumol/L (45Ca release; treated/control = 1.6 +/- 0.07; p < 0.001 from control). Bone resorption induced by H2O2 was significantly inhibited by catalase to 1.2 +/- 0.05; p < 0.02. In contrast, the combination of xanthine and xanthine oxidase, which generates superoxide anions, failed to stimulate bone resorption, except in the presence of superoxide dismutase (SOD), which resulted in a modest increase in bone resorption to a treated/control ratio of 1.2 +/- 0.05; p < 0.02. Analysis of calvarial bones which were exposed to H2O2 showed a significant increase in osteoclast numbers suggesting that H2O2 may be capable of stimulating osteoclast formation in addition to enhancing activity of mature osteoclasts. Our data are consistent with previous work, which has shown that H2O2 is a bone resorbing factor with effects on both osteoclast formation and in activity of mature osteoclasts. The experiments with SOD further suggest that the enhancement of bone resorption previously noted with superoxide generating systems may be due in part to generation of H2O2.

Analysis of Variance↗

PubMed1996

Prediction of the outcome of treatment of Paget's disease of bone with bisphosphonates from short-term changes in the rate of bone resorption.

In Paget's disease of bone, bisphosphonate therapy is usually given for 3-6 months, at which point the success of treatment is assessed by measuring serum alkaline phosphatase activity. The changes, however, in bone resorption and formation after bisphosphonate therapy are predictable, and their correct interpretation may allow a rational therapeutic approach applicable to the individual patient. We addressed this issue in 21 patients with active Paget's disease treated with 2 different nitrogen-containing bisphosphonates for 10 days. Urine samples were collected daily before and during treatment for the measurement of the following collagen degradation products, as indexes of bone resorption; cross-linked N-telopeptide of collagen type I (NTx), free deoxypyridinoline with 2 different assays, and hydroxyproline. Independently of the structure of the bisphosphonate used, the magnitude of decrease in urinary NTx with treatment was greater than that of both deoxypyridinoline assays and practically identical to the decrease in excess of urinary hydroxyproline. The degree of suppression of NTx on the 9th and 10th days of treatment correlated with the lowest serum alkaline phosphatase activity obtained during 1 yr of follow-up. All patients in whom serum alkaline phosphatase activity normalized during follow-up showed a suppression of NTx greater than 75% of the initial values after 10 days of treatment. We conclude that urinary NTx is a sensitive and specific index to follow the efficacy of bisphosphonate therapy in patients with Paget's disease and that measurements of its values before and after a short period of treatment can provide a simple and convenient way to predict the final therapeutic outcome and to avoid unnecessary continuation of treatment in many patients with Paget's disease of bone.

Adult↗

PubMed1995

Taxol inhibits osteoclastic bone resorption.

We have examined the effect of the anti-tumor compound taxol, on osteoclastic bone resorption. In the bone slice assay, taxol (0.1-0.001 microM) dose-dependently inhibited bone resorption with an IC50 of 0.08 microM. Osteoclast survival on bone slices was unaffected by 0.01-1 microM taxol, but 10 microM was cytotoxic. Taxol (1 microM) also inhibited osteoclast spreading (45%) on fibronectin-coated slides. The antiproliferative effects of taxol are due to its unique ability to stabilize microtubules. Primary osteoclasts are nonproliferating end cells, so taxol probably inhibits bone resorption by interfering with other microtubule-dependent functions such as cell polarization, motility or vesicle exocytosis. Since these inhibitory effects on osteoclasts in vitro are seen with therapeutically relevant concentrations, taxol therapy may have beneficial side-effects e.g. inhibition of hypercalcemia and bone metastases.

Animals↗

PubMed2002

Characterization of the bone-resorptive effect of interleukin-11 in cultured mouse calvarial bones.

Interleukin-11 (IL-11) is a stromal cell-derived cytokine that can enhance osteoclast formation and stimulate bone resorption. In the present study, the characteristics of the resorptive effect of IL-11 in mouse calvarial bones were investigated. Both recombinant mouse IL-11 and human IL-11 caused concentration- and time-dependent stimulations of (45)Ca release from prelabeled mouse calvariae. Half-maximal responses were obtained at 0.7 ng/mL (approximately 40 pmol/L). Mouse and human IL-11 also stimulated release of (3)H from [(3)H]-proline-labeled bones. The magnitude of the (45)Ca and (3)H release (1.4-1.6-fold) caused by a maximally effective concentration of IL-11 was less than the stimulation (2.5-4.0-fold) elicited by a maximum concentration of parathyroid hormone (PTH). Release of (45)Ca by IL-11 was unaffected by the mitotic inhibitors, hydroxyurea and aphidicolin. In addition to resorption of bone, IL-11 caused a small (1.5-2.0-fold) enhancement of prostaglandin E(2) (PGE(2)) biosynthesis in calvariae, but had no effect on the mRNA expression of cyclooxygenase-1 and -2, or cytosolic phospholipase A(2). Indomethacin and flurbiprofen abolished the formation of PGE(2) and partially reduced (45)Ca release stimulated by IL-11. When either mouse interleukin-4 (IL-4) or interleukin-13 (IL-13) was added to calvariae treated with IL-11, (45)Ca release was inhibited. Resorption caused by IL-11 was also inhibited by both anti-mouse glycoprotein 130 (gp130) and an antibody neutralizing IL-11, but these agents had no effect on (45)Ca release caused by PTH or 1,25(OH)(2)vitamin D(3) (D(3)). Real-time, quantitative polymerase chain reaction (PCR) analysis (TaqMan PCR) and semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) demonstrated that IL-11 caused concentration-dependent enhancements of receptor activator of nuclear factor-kappaB ligand (RANKL) and osteoprotegerin (OPG) mRNA, without affecting the mRNA expression of RANK. Mouse RANKL stimulated (45)Ca release in the calvarial bones. The stimulatory effects of RANKL and IL-11 were inhibited by mouse OPG. These data demonstrate that IL-11 stimulates osteoclastic resorption in mouse calvariae by mechanisms that are independent of cell proliferation; partially dependent on prostaglandin biosynthesis; sensitive to inhibition by IL-4, IL-13, and OPG; and associated with enhanced expression of RANKL and OPG. In addition, IL-11 was not found to play an essential role in resorption stimulated by other calciotropic agents in calvariae.

Animals↗

PubMed1980

Basal bone resorption in the rat fetus related to the hormonal status of the mother.

Fetal bone resorption was measured by an organ culture technique using fetuses from thyroparathyroidectomized (TPTX) pregnant rats to investigate the roles of fetal and maternal hormones in the regulation of basal bone resorption in utero. Thyroparathyroidectomized female rats were treated with thyroxine and/or metabolites of vitamin D3. Basal bone resorption was greatly increased in fetuses from TPTX mothers. Administration of 1,25-dihydroxycholecalciferol or 1,24,25-trihydroxycholecalciferol to TPTX female rats normalized the basal bone resorption of the fetus whereas injection of 24,25-dihydroxycholecalciferol was without effect. Treatment of the TPTX mothers with thyroxine was also shown to normalize basal bone resorption in the fetus.

24,25-Dihydroxyvitamin D 3↗

PubMed1991

BM 21.0955, a potent new bisphosphonate to inhibit bone resorption.

A total of 300 new bisphosphonates were screened for their effect on bone resorption in the rat. Among these, 1-hydroxy-3-(methylpentylamino)propylidenebisphosphonate (BM 21.0955) was selected for detailed investigation. It inhibited arotinoid-stimulated bone resorption as assessed by calcemia in thyroparathyroidectomized rats at a SC dose as low as 0.001 mg P (0.016 mumol) per kg body weight per day. The compound was thus about 2, 10, 50, and 500 times more potent than risedronate, alendronate, pamidronate, and clodronate, respectively. Intravenous administration was as effective as subcutaneous, and oral administration was 100 times less effective. The effect after one administration decreased with time but was still measurable after 2 weeks. Nonstimulated bone resorption assayed by the urinary excretion of radiolabeled tetracycline from lifelong prelabeled animals was also inhibited. This effect started 3 days after a single dose and was still maximal after 7 days. Histomorphometric analysis of the tibial metaphysis in growing intact rats also showed an inhibition of bone resorption along with an increase in bone mass. The number of osteoclasts increased in animals treated with 0.01 and 0.1 mg P per kg (0.16 and 1.6 mumol/kg) body weight SC but decreased in animals given 1 mg P per kg (16.1 mumol/kg), showing that the inhibition of bone resorption was not due to an inhibition of osteoclast recruitment. No inhibition of mineralization occurred. This new bisphosphonate appears to have great potential for use in human bone disease.

Alendronate↗

PubMed1997

Ipriflavone inhibits bone resorption in intact and ovariectomized rats.

The aim of this study was to investigate the possible inhibitory effect of ipriflavone on bone resorption in rats. For this purpose, 10-week-old, intact and ovariectomized (OVX) rats, prelabeled from birth with [3H]-tetracycline, were used. Bone resorption was monitored by measuring the urinary excretion of [3H]. The animals were fed a purified diet devoid of naturally occurring flavonoids. In the intact rats, the daily meal was given either as a single portion or divided into four portions, a procedure known to lead by itself to a decrease in bone resorption. Ipriflavone, given 7 days after OVX at the dose of 400 mg/kg B.W. daily mixed with the food, led within 2-3 days to a significant decrease in bone resorption equivalent to that of 27.2 micrograms/kg s.c. of 17 beta-estradiol. The inhibition was sustained for the length of the experiment, up to 21 days. Ipriflavone given 7 days before OVX prevented the increase in bone resorption induced by castration, the effect being dose-dependent between 50 and 400 mg/kg B.W. In contrast to 17 beta-estradiol, a 5-week treatment with ipriflavone failed to prevent the OVX-induced uterine atrophy. Significant inhibition of bone resorption was also seen in intact animals, provided they rapidly ingested the daily meal. Actually, the decrease in bone resorption induced by portioning the daily food masked the inhibitory effect of ipriflavone in intact animals. In conclusion, ipriflavone can decrease bone resorption in both intact and OVX animals given a purified diet as a single daily meal. In the OVX model, ipriflavone mimics the osteoprotective effect of estrogen. However, the lack of a uterotropic effect suggests that the compound can discriminate between bone and reproductive tissues.

Administration, Oral↗

PubMedDate not supplied

Pressure-induced bone resorption in the middle ear.

Osteoclastic activity is seen in areas of bone resorption which are the result of experimental and human cholesteatoma. Many factors may induce osteoclasts, including transmitted pressure. The purpose of this study was to determine if transmitted pressure, in the absence of cholesteatoma, could cause localized bone resorption in the middle ear. Surgical grade silicone was implanted into the middle ear of gerbils without cholesteatoma. Bone resorption was observed only in areas where the implants exerted pressure on bone. It was estimated that pressures of 50 to 120 mm Hg (6.7 X 10(4) to 16 X 10(4) dynes/cm2) resulted in the induction of osteoclastic bone resorption.

Animals↗

PubMed1999

Effect of MALP-2, a lipopeptide from Mycoplasma fermentans, on bone resorption in vitro.

Mycoplasmas may be associated with rheumatoid arthritis in various animal hosts. In humans, mycoplasma arthritis has been recorded in association with hypogammaglobulinemia. Mycoplasma fermentans is one mycoplasma species considered to be involved in causing arthritis. To clarify which mycoplasmal compounds contribute to the inflammatory, bone-destructive processes in arthritis, we used a well-defined lipopeptide, 2-kDa macrophage-activating lipopeptide (MALP-2) from M. fermentans, as an example of a class of macrophage-activating compounds ubiquitous in mycoplasmas, to study its effects on bone resorption. MALP-2 stimulated osteoclast-mediated bone resorption in murine calvaria cultures, with a maximal effect at around 2 nM. Anti-inflammatory drugs inhibited MALP-2-mediated bone resorption by about 30%. This finding suggests that MALP-2 stimulates bone resorption partially by stimulating the formation of prostaglandins. Since interleukin-6 (IL-6) stimulates bone resorption, we investigated IL-6 production in cultured calvaria. MALP-2 stimulated the liberation of IL-6, while no tumor necrosis factor was detectable. Additionally, MALP-2 stimulated low levels of NO in calvaria cultures, an effect which was strongly increased in the presence of gamma interferon, causing an inhibition of bone resorption. MALP-2 stimulated the bone-resorbing activity of osteoclasts isolated from long bones of newborn rats and cultured on dentine slices without affecting their number. In bone marrow cultures, MALP-2 inhibited the formation of osteoclasts. It appears that MALP-2 has two opposing effects: it increases the bone resorption in bone tissue by stimulation of mature osteoclasts but inhibits the formation of new ones.

Animals↗

PubMed2002

High bone resorption in adult aging transgenic mice overexpressing cbfa1/runx2 in cells of the osteoblastic lineage.

The runt family transcription factor core-binding factor alpha1 (Cbfa1) is essential for bone formation during development. Surprisingly, transgenic mice overexpressing Cbfa1 under the control of the 2.3-kb collagen type I promoter developed severe osteopenia that increased progressively with age and presented multiple fractures. Analysis of skeletally mature transgenic mice showed that osteoblast maturation was affected and that specifically in cortical bone, bone resorption as well as bone formation was increased, inducing high bone turnover rates and a decreased degree of mineralization. To understand the origin of the increased bone resorption, we developed bone marrow stromal cell cultures and reciprocal coculture of primary osteoblasts and spleen cells from wild-type or transgenic mice. We showed that transgenic cells of the osteoblastic lineage induced an increased number of tartrate-resistant acid phosphatase-positive multinucleated cells, suggesting that primary osteoblasts as well as bone marrow stromal cells from transgenic mice have stronger osteoclastogenic properties than cells derived from wild-type animals. We investigated the candidate genes whose altered expression could trigger this increase in bone resorption, and we found that the expression of receptor activator of NF-kappaB ligand (RANKL) and collagenase 3, two factors involved in bone formation-resorption coupling, was markedly increased in transgenic cells. Our data thus suggest that overexpression of Cbfa1 in cells of the osteoblastic lineage does not necessarily induce a substantial increase in bone formation in the adult skeleton but has a positive effect on osteoclast differentiation in vitro and can also dramatically enhance bone resorption in vivo, possibly through increased RANKL expression.

Aging↗

PubMed2000

Relative contributions of testosterone and estrogen in regulating bone resorption and formation in normal elderly men.

Young adult males who cannot produce or respond to estrogen (E) are osteopenic, suggesting that E may regulate bone turnover in men, as well as in women. Both bioavailable E and testosterone (T) decrease substantially in aging men, but it is unclear which deficiency is the more important factor contributing to the increased bone resorption and impaired bone formation that leads to their bone loss. Thus, we addressed this issue directly by eliminating endogenous T and E production in 59 elderly men (mean age 68 years), studying them first under conditions of physiologic T and E replacement and then assessing the impact on bone turnover of withdrawing both T and E, withdrawing only T, or only E, or continuing both. Bone resorption markers increased significantly in the absence of both hormones and were unchanged in men receiving both hormones. By two-factor ANOVA, E played the major role in preventing the increase in the bone resorption markers, whereas T had no significant effect. By contrast, serum osteocalcin, a bone formation marker, decreased in the absence of both hormones, and both E and T maintained osteocalcin levels. We conclude that in aging men, E is the dominant sex steroid regulating bone resorption, whereas both E and T are important in maintaining bone formation.

Aged↗

PubMed1990

Osteoclast bone resorption is enhanced in the presence of osteoblasts.

Bone resorption activity by osteoclasts has been evaluated in a co-culture system in which osteoclasts have been plated in the presence of osteoblasts. The system prevents cell-cell contact but permits diffusion of molecules through the pores of a millipore membrane that separates the two compartments in which the two cell types have been plated. Results demonstrated that osteoblasts exert a stimulatory effect over osteoclast bone resorption due to soluble molecules capable of passing through the membrane pores. The effect is specific since periosteal cells, which do not express osteoblastic characteristics, fail to induce changes in the osteoclast activity. PTH does not affect osteoblast-mediated enhancement of bone resorption, indicating that the stimulatory effect that the hormone exert in vivo occurs via a different cellular system.

Animals↗

PubMed1986

Actions of recombinant interleukin 1, interleukin 2, and interferon-gamma on bone resorption in vitro.

Human peripheral blood cells, when cultured in vitro, release bone-resorbing factors, which have been called osteoclast-activating factors (OAF) but remain unidentified. We showed previously that a monocyte product, similar to interleukin 1 (IL 1), is a powerful stimulator of bone resorption in vitro. However, the possibility remained that other immune cell products may contribute to OAF activity. We have therefore tested three recombinant cytokines; IL 1, interleukin 2 (IL 2), and interferon-gamma (IFN-gamma) for their activity in a neonatal mouse bone resorption assay. We report here that purified recombinant murine IL 1 is a potent and powerful stimulator of bone resorption in vitro, active over a concentration range of 0.14 to 33 U/ml (1.3 X 10(-12) to 3.1 X 10(-10) M). IL 1-stimulated bone resorption was unaffected by cyclooxygenase inhibition but was inhibited by calcitonin and IFN-gamma. IL 2 had no effect on bone resorption.

Animals↗

PubMed1989

Membrane IL-1 induces bone resorption in organ culture.

We have studied the role of the membrane-associated form of IL-1 on bone resorption in vitro. Murine macrophages of the P388D1 cell line stimulated with LPS, subsequently fixed with paraformaldehyde, induced the proliferation of C3H/HeJ mouse thymocytes in the presence of a submitogenic concentration of Con A. Membrane IL-1 on P388D1 cells stimulated with LPS induced bone resorption in organ cultures of neonatal BALB/c mouse calvaria. Polyclonal antibodies directed against membrane IL-1 and soluble IL-1 from P388D1, and monospecific rabbit anti-murine rIL-1 alpha serum neutralized the membrane IL-1 activity, as measured by the thymocyte proliferation. In addition, these antibodies suppressed the bone resorption induced by membrane IL-1. The bone resorption induced by membrane IL-1 required direct contact between mouse calvaria and membrane IL-1. Salmon calcitonin strongly suppressed the calcium release from mouse calvaria in the presence of membrane IL-1. Indomethacin partially inhibited the bone resorption induced by membrane IL-1 on P388D1 cells. Moreover, membrane IL-1 on LPS-stimulated BALB/c mouse peritoneal macrophages or LPS-stimulated osteoblastic cells from BALB/c mouse calvaria induced bone resorption in vitro. These results suggest that membrane IL-1 on macrophages and osteoblastic cells may have a significant role in inflammatory bone resorption in vivo.

Animals↗

PubMed1993

The majority of osteoclasts require mRNA and protein synthesis for bone resorption in vitro.

Mithramycin is an mRNA synthesis inhibitor that has been used to decrease bone resorption in patients with humoral hypercalcemia and Paget's disease. During studies on the mechanism of action of mithramycin it became clear that the compound has a direct inhibitory effect on osteoclastic bone resorption in the in vitro bone slice assay. At concentrations of 0.1-100 nM mithramycin directly inhibited osteoclastic bone resorption dose-dependently up to 66 +/- 5% at 100 nM (mean +/- SEM, 3 expts.). Another mRNA synthesis inhibitor, actinomycin D (0.1-100 nM) and the protein synthesis inhibitor, cycloheximide (0.1-10 microM), also dose-dependently inhibited osteoclastic bone resorption by 78 +/- 7% at 100 nM and 76 +/- 7% at 10 microM, respectively. Mithramycin and actinomycin D at 100 nM did not affect osteoclast survival on bone slices and were therefore not cytotoxic at the concentrations used. Mithramycin (100 nM) and cycloheximide (10 microM) both slightly decreased osteoclast cytoplasmic spreading. Addition of 100 nM mithramycin 6 hr after osteoclast adhesion to bone slices still inhibited subsequent resorption by 50%, indicating a continued but lesser requirement for mRNA synthesis during bone resorption. These results show that approximately 75% of osteoclasts obtained from neonatal rat long bones are activated by adhesion to mineralized bone surfaces and require mRNA and protein synthesis in order to resorb bone in vitro.

Animals↗

PubMed2003

Subchondral bone resorption in temporomandibular joint disorders.

Several tissues are involved in temporomandibular joint (TMJ) health, including synovial fluid, the TMJ disc, articular cartilage, and subchondral bone. This article focuses upon bone resorption in temporomandibular joint disorders (TMD) and has the following objectives: (1) to provide a brief review of the current understanding of bone formation and bone resorption (bone remodeling); (2) to present selected case studies which illustrate the spectrum of bone resorption patterns in TMD patients of various ages; (3) to review previous reports in the literature describing loss of subchondral bone in TMD, and (4) to discuss the interaction between osteoporosis and TMD and the potential role for antiresorbing agents in TMD therapy.

Bone Resorption↗

PubMed1993

Intranasal calcitonin suppresses increased bone resorption during short-term immobilization: a double-blind study of the effects of intranasal calcitonin on biochemical parameters of bone turnover.

Immobilization is associated with increased bone resorption and decreased bone formation. We evaluated in a double-blind trial the effect of intranasal administration of salmon calcitonin on biochemical parameters of bone turnover in 32 patients immobilized for a prolapsed intervertebral disk. Calcitonin in a dose of two times 200 IU/day partially inhibited the increase in the fasting 2 h urinary hydroxyproline/creatinine ratio (OHPr/Cr) and calcium/creatinine ratio (Ca/Cr). The increase in OHPr/Cr was 40% less in the calcitonin group compared to the placebo group (P = 0.01), and the increase in Ca/Cr was 80% less in the calcitonin group (P = 0.04). Calcitonin also partially inhibited the increase in serum cross-linked carboxyl-terminal telopeptide of collagen type I (P < 0.05). The decrease in serum 1,25-dihydroxyvitamin D after 10 days of immobilization was significantly less in the calcitonin-treated group than in the placebo group (14 versus 29%, respectively; P < 0.05). Intranasal calcitonin did not influence the pain scores as measured with a visual analog scale (VAS). The tolerability of the nasal calcitonin preparation was excellent. We conclude that nasal salmon calcitonin counteracts the early increase in bone resorption induced by immobilization.

Administration, Intranasal↗