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Topical, single dose bisphosphonate treatment reduced bone resorption in a rat model for prosthetic loosening.

Fluid pressure, instability or particles have been suggested to cause peri-prosthetic bone resorption. High intracapsular pressures have been reported in hip joints with loose prosthetic components, and oscillating fluid pressure has been shown to cause dramatic bone resorption in animal models. Resorption can be reduced by systemic bisphosphonate treatment in rat models with oscillating fluid pressure, but this has required higher doses than needed to inhibit normal remodelling. Bisphosphonates have high affinity to bone mineral. Topical application of the drug is therefore feasible. We used a previously described rat model where oscillating fluid pressure causes bone resorption. Before pressurization, a 1 mg/ml solution of alendronate was applied onto the bone surface for 1 min, after which excess bisphosphonate was rinsed away. Bone resorption was measured on histological slides as soft tissue area at the interface. Rats treated with topical alendronate had soft tissue areas reduced by half. Topical bisphosphonate treatment before cementing a joint implant could possibly reduce the risk of later loosening.

Administration, Topical↗

Effects of the prostacyclin products, 6-keto prostaglandin E1 and 6-keto prostaglandin F1 alpha, on bone resorption in vitro.

Previous studies have suggested that prostacyclin (PGI2) can stimulate bone resorption in vitro. However, this effect required repeated administration, perhaps because PGI2 is rapidly degraded or converted to other products, including 6-keto prostaglandin F1 alpha (6K-PGF1 alpha) and possibly 6-keto prostaglandin E1 (6K-PGE1). We therefore tested the ability of 6K-PGF1 alpha and 6K-PGE1 to stimulate bone resorption as measured by the release of previously incorporated 45Ca from 19-day fetal rat long bone cultures and compared their effects with those of PGE1 and PGF1 alpha. As reported previously, PGE1 was the most potent of the monoenoic prostanoids. PGF1 alpha was somewhat less potent. Of the PGI2 products 6K-PGE1 was an effective stimulator, but less potent than PGE1 or PGF1 alpha. Thus, the potency ratios were approximately 100:10:1 for PGE1, PGF1 alpha and 6K-PGE1. In contrast, 6K-PGF1 alpha did not produce a maximal resorptive response and its effects were not dose-related. We conclude that 6K-PGE1 is an effective stimulator of bone resorption in vitro, while 6K-PGE1 alpha is only a partial agonist. The formation of these compounds might account for some of the effects of PGI2 reported previously.

6-Ketoprostaglandin F1 alpha↗

A pharmacokinetic model in the rat and rabbit of the direct measurement of mature bone resorption in vivo with [3H]tetracycline.

This report presents a pharmacokinetic model in the rat and rabbit of the direct quantification of mature bone resorption in vivo. This is based on a first-order reaction rate describing the release of [3H]tetracycline from bone. Compared with the previous method, the model has two new means of expressing bone resorption. First, resorption rate of bone is precisely represented by explicit parameters derived from the model. Second, resorption rate of the whole skeletal system is measured and demonstrated by means of plasma, renal, and bone kinetics of elimination of the isotope. These are represented by the model parameters, the elimination constant, and the half-life of [3H]tetracycline for plasma, urine, and bone. Four ages of normal Sprague Dawley rats and one age of New Zealand white rabbits of both sexes were prelabeled extensively with [3H]tetracycline in utero or during 10 to 84 d of age. Following 1-21 d after the end of prelabeling, the loss of the isotope from femur into plasma and urine was measured at weekly intervals to determine bone resorption of mineral in vivo. The elimination constants of the isotope per day in plasma were -0.148 in weaning rats (4-7 weeks), -0.071 in adolescent rats (10-14 weeks), and -0.025 in mature rats (15-23 weeks). The urinary elimination constants of the isotope per day were 74, 76, and 76% of those in plasma in weaning, adolescent, and mature rats, respectively. The half-lives of the isotope in the femur were 10 d in neonatal rats (0-2 weeks), 32 d in weaning rats, 63 d in adolescent rats, and 198 d in mature rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Bradykinin, a new potential mediator of inflammation-induced bone resorption. Studies of the effects on mouse calvarial bones and articular cartilage in vitro.

The effect of bradykinin and desArg9-bradykinin on bone was studied in cultures of calvarial bones taken from 6-7-day-old mice. Bradykinin, at and above a 3-nM concentration, caused a dose-dependent stimulation of bone mineral mobilization and matrix degradation. Bradykinin-stimulated resorption was inhibited by calcitonin, an increased concentration of phosphate in the culture medium, hydrocortisone, dexamethasone, indomethacin, meclofenamic acid, naproxen, and 5, 8, 11, 14-eicosatetraenoic acid. The results suggest that bradykinin stimulates osteoclast-mediated bone resorption by a process that is dependent on endogenous prostaglandin production. The stimulatory effect of bradykinin, but not of parathyroid hormone and prostaglandin E2, was potentiated by the angiotensin-converting enzyme inhibitor, BPP5a. Treatment with carboxypeptidase B did not affect the capacity of the peptide to stimulate 45Ca release. DesArg9-bradykinin (1 mumole/liter) stimulated 45Ca release to the same degree as did bradykinin. Bradykinin (3 microM) did not affect the degradation of cartilage proteoglycans, as assessed by the release of 35S-sulfate from prelabeled calf articular cartilage in organ culture. These findings suggest that generation of bradykinin in inflammatory lesions of rheumatoid arthritis and periodontitis may contribute to the bone resorptive process seen in the joints and alveolar bone; however, bradykinin does not directly activate chondrocytes into a catabolic state.

Animals↗

In vitro and in vivo studies of the effect of a Chinese herb medicine on osteoclastic bone resorption.

OBJECTIVE: To study the effect of a Chinese herb on osteoclastic bone resorption and osteoporosis. MATERIALS AND METHODS: Osteoclasts were isolated and cultured for in vitro study of the effect of the Chinese herb Guizhou epimedium (Epimedium Leptorrhizum Stearn). The in vivo effect of this Chinese herb was also investigated in rats in whom osteoporosis was induced by ovariectomy; these results were then compared with the effects of estradiol in the same group of rats. RESULTS: The in vitro study showed that the epimedium inhibited the osteoclastic resorption of bone. The in vivo investigation demonstrated that both the epimedium and estradiol were able to increase mineral content and promote bone formation. CONCLUSION: The Chinese herb Guizhou epimedium is of potential use in the treatment of osteoporosis.

Animals↗

Grafting of deproteinized bone particles inhibits bone resorption after maxillary sinus floor elevation.

OBJECTIVES: To evaluate the value of deproteinized bone particles on bone resorption in the augmented space after maxillary sinus floor elevation in rabbits. MATERIAL AND METHODS: A total of 20 rabbits underwent bilateral grafting, using blood clots (control group) and deproteinized bone particles (experimental group), and followed with histologic and histomorphometric analysis. RESULTS: Two weeks after grafting, the augmented space was almost completely obliterated by both newly formed bone and fibrous connective tissue in the control group. Some osteoclasts were found on the surface of newly formed bone, especially near the elevated sinus membrane. In the experimental group, newly formed bone was found along the elevated sinus membrane, the cortical wall of the augmented space, and the surface of deproteinized bone particles near the cortical wall. Some osteoclasts were found along the deproteinized bone particles and a few adhered to the surface of the newly formed bone. Eight to 10 weeks after implantation in the control group, most of the newly formed bone had been resorbed. In the experimental group, newly formed bone was found in most parts of the convex augmented space. Histomorphometrical analysis showed that the augmented height was significantly higher in the experimental group than in the control group at all evaluation times. Bone area was significantly higher in the experimental group than in the control group at 6, 8, and 10 weeks after implantation. The area of grafted deproteinized bone particles did not change significantly from 2 to 10 weeks. CONCLUSION: Slowly resorbed deproteinized bone particles contribute to stable augmentation of the maxillary sinus floor by inhibiting bone resorption.

Animals↗

Prostaglandin E2, interleukin 1alpha, and tumor necrosis factor-alpha increase human osteoclast formation and bone resorption in vitro.

Prostaglandin E2 (PGE2) and the cytokines interleukin (IL) 1alpha and tumor necrosis factor (TNF)alpha increase bone resorption in vivo, but the effect of these agents on osteoclastic bone resorption has never been studied in an in vitro human system. Our recently described human bone marrow culture system, in which osteoclasts are generated (vitronectin and calcitonin receptor-positive cells which resorb bone), was used to study the effects of these agents. Addition of indomethacin to macrophage colony-stimulating factor (M-CSF)-treated cultures nearly abolished osteoclast parameters, indicating that prostaglandins are virtually essential for human osteoclast formation. Additionally, PGE2 dose responsively increased osteoclast numbers and bone resorption. The effects of M-CSF and PGE2 are independent, as demonstrated by unaltered PGE2 concentrations in culture supernatants in spite of the dose-responsive increase in osteoclast parameters in response to M-CSF. The generation of osteoclasts in the presence of PGE2 occurred in favor of CD 14-positive macrophage formation. IL 1alpha and TNFalpha increased osteoclast parameters in a dose-responsive manner. Maximum stimulation yielded culture supernatant levels of PGE2 approximately the same as those concentrations of exogenous PGE2 that dramatically induced osteoclast formation. This osteoclast-inducing effect was inhibited both by indomethacin and by the specific inhibitor of inducible prostaglandin G/H synthase, NS398, and this was reversed by addition of exogenous PGE2. These results demonstrate unequivocally that IL 1alpha and TNFalpha enhance human osteoclast formation and suggest that they mediate their effects through PGE2.

Antibodies, Monoclonal↗

The effects of soy protein containing isoflavones on lipids and indices of bone resorption in postmenopausal women.

OBJECTIVE: To assess the effect of a dietary soy protein supplement containing isoflavones on lipids and indices of bone resorption in postmenopausal women. DESIGN: Placebo-controlled, double-blind, randomized study. PATIENTS: One hundred and six postmenopausal women were randomized to dietary soy supplementation (n = 51) or placebo (n = 55) for 3 months, of which 78 were included in the final analysis. MEASUREMENTS: Lipid profiles including total, low-density lipoprotein (LDL) and HDL cholesterol as well as triacylglycerol were measured. Pyridinoline and deoxypyridinoline were used as markers of bone resorption. Urinary isoflavone excretion was measured to assess compliance. RESULTS: There was a significantly greater increase in urinary isoflavone excretion detected in the soy group compared to placebo. Lipid profiles improved with significant decreases in LDL cholesterol (-0.60 +/- 0.10 vs.-0.29 +/- 0.09 mmol/l, P < 0.05), triacylglycerol (-0.22 +/- 0.07 vs. +0.01 +/- 0.05 mmol/l, P < 0.005) and the LDL : HDL ratio (-0.32 +/- 0.10 vs. +0.20 +/- 0.10, P < 0.005) in the soy group compared to placebo. There were no significant differences between the soy and placebo groups for urinary excretion of pyridinoline (-3.8 +/- 3.1 vs.-0.8 +/- 3.1 nmol/mmolCr, P = 0.4) or deoxypyridinoline (-0.8 +/- 0.9 vs.-0.3 +/- 0.7 nmol/mmolCr, P = 0.4). CONCLUSIONS: In postmenopausal women, dietary supplementation with soy protein containing isoflavones does not appear to have oestrogenic effects on markers of bone resorption. Soy protein favourably affected lipids; however, these effects (fall in triacylglycerol and no change in HDL) differ from those observed with oral oestrogen. These findings suggest that soy may not have biologically significant oestrogenic effects on bone resorption and we hypothesize that the lipid effects may be mediated, at least in part, through nonoestrogenic mechanisms.

Aged↗

Bafilomycin A1 inhibits bone resorption and tooth eruption in vivo.

It has been shown that a specific inhibitor of vacuolar H(+)-ATPases, bafilomycin A1, inhibits bone resorption by isolated chicken osteoclasts by blocking the proton pump in the ruffled border membrane. We report here the effects of bafilomycin A1 on bone resorption in vivo. Using a cannulated osmotic minipump delivery system, we infused bafilomycin locally to the eruption pathway of permanent premolars of beagle dogs. We used pit formation by osteoclasts in vitro to estimate the concentrations and heat stability of bafilomycin to be used in vivo. In this model, osteoclasts were cultured on thin bone slices, in which they form pits indicative of resorption. After 2 weeks preincubation at 37 degrees C, bafilomycin concentrations of 10(-6) and 10(-7) M but not 10(-8) M completely inhibited the resorptive activity of cultured osteoclasts, and the two larger doses were chosen for use in vivo. Local delivery of 10(-6) M bafilomycin to the eruption pathway of the fourth permanent mandibular premolar during mideruption inhibited tooth eruption by blocking bone resorption as assayed by radiography, light microscopy, and scanning electron microscopy. Bafilomycin at 10(-7) M had similar but less intensive effects. Moreover, osteoclasts in the alveolar bone of crypts treated with 10(-7) M bafilomycin A1 stained very weakly for tartrate-resistant acid phosphatase. The effect of bafilomycin on bone resorption was shown to be very local, and no side effects of treatment with bafilomycin were observed in adjacent teeth or the behavior of dogs. We report here, for the first time, inhibition of tooth eruption caused by inhibited bone resorption using bafilomycin A1 in vivo.

Animals↗

Bone resorption and osteoporotic fractures in elderly men: the dubbo osteoporosis epidemiology study.

UNLABELLED: Among the potential risk factors for fragility fractures, bone turnover is considered an important determinant. In a case-cohort control study of 151 elderly men followed prospectively over 6.3 years, high bone resorption as assessed by S-ICTP was associated with increased risk of osteoporotic fracture, independent of BMD. Combining measurements of BMD and bone turnover may improve fracture prediction in elderly men. INTRODUCTION: Approximately one-third of osteoporotic fractures occur in men. Among the potential risk factors for fragility fractures, bone turnover is considered an important determinant. The association between fracture risk and rates of bone turnover has not been well established in men. We examined this relationship in elderly community-dwelling men. MATERIALS AND METHODS: This case-cohort control study included 50 men with incident low-trauma fractures (cases; age, 72.3 +/- 6.7 years) and 101 men without fracture (controls; age, 70.4 +/- 4.1 years), who have been prospectively followed in the Dubbo Osteoporosis Epidemiology Study for a median of 6.3 years (range, 2-13 years). BMD at the lumbar spine (LSBMD) and at the femoral neck (FNBMD) and markers of bone turnover were measured at baseline. Bone resorption was assessed by measuring nonfasting serum concentrations of the carboxyterminal cross-linked telopeptide of type I collagen (S-ICTP) and of a linear octapeptide derived from the carboxyterminal type I collagen telopeptide (S-CTX). Bone formation was assessed by measuring the serum levels of the aminoterminal propeptide of type I procollagen (S-PINP). RESULTS: Men with subsequent fractures had lower BMD at baseline, both at the femoral neck and the spine, lower dietary calcium intake, and higher S-ICTP levels than age-and weight-matched controls. Smoking habits, S-CTX, and S-PINP did not differ between groups. Based on univariate regression analyses, S-ICTP (relative risk [RR] for 1 SD change: 1.8; 95% CI, 1.4-2.3) and serum creatinine levels (RR, 1.4; 95% CI, 1.1-1.7) were associated with increased risk of fracture. In multivariate regression analyses, S-ICTP (RR, 1.4; 95% CI, 1.0-1.9) and FNBMD (RR, 1.8; 95% CI, 1.4-2.3) remained independent predictors of fracture risk. Men within the highest quartile of S-ICTP had a 2.8-fold (95% CI 1.4-5.4) increased risk of fracture compared with those in the lowest quartile. The incidence of osteoporotic fractures was 10 times higher in men with high S-ICTP and low FNBMD compared with men with low S-ICTP and high FNBMD. Of the fracture risk in the population, 20% was attributable to high S-ICTP and low FNBMD, and S-ICTP contributed 17% to this increased risk. CONCLUSION: High bone resorption is associated with an increased risk of osteoporotic fracture in elderly men, independent of BMD. Combining measurements of BMD and bone turnover, which correlated with fracture in this cohort, could improve fracture risk prediction in elderly men.

Aged↗

The effect of modifying dietary calcium intake pattern on the circadian rhythm of bone resorption.

In order to assess day-to-day variations of the circadian rhythm of biochemical bone resorption markers, urinary morning (6-8 a.m.) and evening (7-10 p.m.) samples from 35 individuals were monitored during 3 subsequent days. The bone-specific deoxypyridinoline (DPD) crosslinks of type I collagen followed a circadian rhythm in all individuals. In contrast, no such pattern was observed in the urinary hydroxyproline/creatinine and calcium/creatinine measurements. The DPD crosslink measurements showed a much larger difference between the morning and evening samples collected within 1 day compared with the variation between the samples collected in the morning or evening on subsequent days, indicating the importance of adequate timing of urine sampling for clinical trials aiming to monitor effects on bone resorption. The analysis of DPD crosslinks was then used to evaluate the effects of different patterns of dietary calcium intake on the circadian rhythm of bone resorption in osteoporotic patients. No significant effect on the circadian rhythm of the DPD crosslinks was found after concentrating the normal daily calcium intake to the evening (6-10 p.m.) during 8 days (n = 7). Ingestion of a dietary calcium supplement (600 mg) at 10 p.m. during 8 days (n = 7) resulted in an increased urinary calcium excretion in the morning, and a flattening of the circadian peak and nadir concentrations of urinary DPD/creatinine. The absolute levels of DPD/creatinine in the morning and evening urine samples, respectively, were not significantly altered compared with the control day. We conclude that dietary calcium supplementation in the evening only marginally affects the circadian rhythm of urinary DPD crosslinks in established osteoporosis patients.

Aged↗

The effect of fish oil on bone resorption following pulp exposure in rats.

The aim of this study was to determine whether treatment with fish oil may alter the periapical bone resorption following pulp exposure in rats. Untreated and pulp-exposed animals served as the negative and positive control, respectively. Other pulp-exposed animals were orally treated with fish oil at different concentrations and frequencies. Periapical tissue sections were stained with tartrate-resistant acid phosphatase (TRAP), and then the numbers of both periapical osteodasts and preosteoclasts were determined. The levels of bone resorption were assessed using the osteoclast-bone interface (OBI) index. The results showed that no differences between the numbers of both osteoclasts and preosteoclasts in the fish oil-treated animals and the negative control at day 14 could be found. Similarly, the periapical bone resorption in the animals treated with fish oil for 14 days significantly reduced to the levels of that in the negative control. The results of the present study, therefore, suggest that oral treatment with fish oil may inhibit bone resorption following pulp exposure in rats and hence, may have a therapeutic modality for inflamed periradicular tissue.

Alveolar Bone Loss↗

In vitro effect of KCA-098, a derivative of coumestrol, on bone resorption of fetal rat femurs.

The effects of 3,9-bis(N,N-dimethylcarbamoyloxy)-5H-benzofuro[3,2-c]quinoli ne-6-one (KCA-098), a derivative of coumestrol, on bone resorption was studied in organ cultures of 20-day fetal rat femora. KCA-098 increased the length, dry weight, and calcium and phosphorus contents of parathyroid hormone (PTH)-treated fetal rat femur. As PTH significantly reduced the calcium and phosphorus contents of the femora, probably by stimulating bone resorption, KCA-098 seems to inhibit bone resorption. In fact, KCA-098 inhibited the PTH-induced release of 45Ca from pre-labeled fetal rat femora into the medium in organ culture. Coumestrol also inhibited the release of 45Ca from bone into the medium. However, KCA-098 did not increase the uterine weight of ovariectomized rats, whereas coumestrol did so. Thus KCA-098 is a unique, new inhibitor of bone resorption that has no estrogenic activity.

Animals↗

[Alveolar bone resorption process in molar tooth region in calcium-deficient rats].

The present study was carried out to investigate the alveolar bone resorption in the molar tooth region in the rats fed a low calcium diet. Male Wistar rats (70-85g in body weight) were either fed a low calcium diet (0.05% Ca, 0.35% P) or a control diet (0.5% Ca, 0.35% P) by using a pair feeding technique. The rats were sacrificed at intervals of 3, 6, 9 and 20 days during the experimental period. Contact microradiograph of the second molar region of the mandible showed that the cancellus bone as well as the endosteal surface of the cortical bone were progressively resorbed soon after the start of low calcium feeding. At day 9, the amount of bone was reduced to about half of the control rats and 80% of the bone was diminished at day 20. In spite of the severe bone resorption, the alveolar bone proper that surrounds the molar sockets and a few cancellus bone were seen remaining and the occlusal function of the molar tooth seemed to be maintained. These results suggest that the alveolar bone quickly responded to the low calcium diet resulting in bone resorption and that the bone in the supporting tissues of the molar tooth seems to be not affected by the calcium deficiency.

Alveolar Bone Loss↗

In vivo administration of IL-1 beta accelerates silk ligature-induced alveolar bone resorption in rats.

The effects of recombinant human interleukin-1 beta (rhIL-1 beta) on alveolar bone resorptive activity in rats were examined. Continuous administration of rhIL-1 beta or phosphate-buffered saline (PBS) was given via osmotic pumps for 3, 7 and 14 days to rats with silk ligatures around second maxillary molars. Other animals without ligatures received insertion of pumps containing rhIL-1 beta or remained untreated. Sections were subject to three different stains:--hematoxylin and eosin (H-E) for histology, acid phosphatase (ACPase) activity for osteoclast detection, and immunohistochemistry using anti-rat monocyte/macrophage monoclonal antibody (ED 1). In addition, body weight, plasma calcium and phosphorus levels were monitored. The mean body weight of rats receiving rhIL-1 beta was significantly lower (P < 0.05 to P < 0.01) compared with untreated rats throughout the experimental period. On Day 7, plasma calcium and phosphorus levels were significantly lower in rats receiving rhIL-1 beta than in rats receiving PBS only (P < 0.05). Sections revealed a moderate inflammatory cell infiltrate reaching near the alveolar crest in both groups with ligatures on Day 3. Only rats receiving rhIL-1 beta exhibited enhancement of inflammatory cell invasion on Days 7 and 14. In rats receiving rhIL-1 beta with ligatures, numerous resorption lacunae containing ACPase-positive multinucleated giant cells (MNGCs), coinciding with ED1-positive cells, were located on the mesial side of the septum where extensive bone resorption had occurred throughout the experimental period. In animals receiving rhIL-1 beta without ligatures, compared with untreated rats, increased ACPase-positive cells were observed on the mesial side of the septum on Day 3. In animals receiving PBS only, a few ACPase-positive cells were observed confined to the mesial regions where slight bone resorption occurred on Days 7 and 14. These results indicate that the administration of rhIL-1 beta accelerated alveolar bone destruction in ligature-induced periodontal tissue inflammation over a two-week period.

Acid Phosphatase↗

Urinary N-telopeptides to monitor bone resorption while on GnRH agonist therapy.

OBJECTIVES: To assess the utility of urinary cross-linked N-telopeptides in monitoring bone resorption and predicting bone loss during GnRH agonist administration. METHODS: Ninety patients who were prescribed GnRH agonist therapy for 3-6 months for treatment of endometriosis, leiomyomas or other gynecologic disorders participated in this prospective multicenter study. N-telopeptides, serum estradiol (E2), and bone mineral density were monitored before, during and up to 3 months after the course of GnRH agonist therapy. RESULTS: N-telopeptide levels increased significantly throughout GnRH agonist therapy and returned to baseline levels by 3 months after treatment was completed. A significant negative correlation was seen between N-telopeptide and E2 measurements after 3 months (r=-0.23, P<.05), 4 months (r=-0.32, P < .05), and 5 months (r=-0.41, P<.005) of GnRH agonist therapy. The percent change in bone mineral density at L1-L4 at 6 months of GnRH agonist treatment correlated inversely with the percent change in N-telopeptides from baseline to 2,3,4, and 5 months of treatment; the percent change of bone mineral density at the femoral neck at 6 months correlated inversely with the percent change of N-telopeptides from baseline to month 4. CONCLUSIONS: Urinary N-telopeptide determinations provide a quantitative measure of bone resorption, due to GnRH agonist-induced hypoestrogenism. Increases in resorption as measured by N-telopeptides parallel decreases in in E2 levels. Increases in N-telopeptides on GnRH agonist therapy may provide a tool to predict decreases in bone mineral density.

Adult↗

Mandibular bone resorption in patients treated with tissue-integrated prostheses and in complete-denture wearers.

Mandibular bone resorption was studied in patients treated with tissue-integrated prostheses (TIP) and in complete-denture wearers by distance and area measurements on cephalometric radiographs. The area measurements were performed by means of a computer. Two TIP groups with short and long periods (mean = 2.4 and 23.9 years) of edentulousness and wearing complete dentures before fixture installation were followed up over 7-8 years. Mandibular bone resorption was remarkably small behind the distally positioned fixtures in comparison with the corresponding region in complete-denture wearers. Patients with complete dentures showed a continuous resorption of the mandibular alveolar ridge over 21 years, even though there were great individual variations. The bone loss was most pronounced anteriorly and during the first 2 years after extraction of the residual teeth. It is concluded that treatment with tissue-integrated prostheses seems to reduce bone resorption in the mandible, probably owing to favorable load conditions and adequate stimulation of the bone.

Bone Resorption↗

Alendronate distributed on bone surfaces inhibits osteoclastic bone resorption in vitro and in experimental hypercalcemia models.

Alendronate is an aminobisphosphonate that acts as a potent inhibitor of osteoclastic bone resorption. To understand the mechanism of action of alendronate in vivo, in this study we investigated the relationship between distribution of [14C]-alendronate in rat bone and its effects on bone resorption in vitro or in rat hypercalcemic models. A single IV dose of 0.05 approximately 1.25 mg/kg inhibited the increase in plasma calcium level induced by bovine PTH or 1 alpha(OH)D3. The minimal effective dose of pamidronate (1.25 mg/kg) and etidronate (over 31.25 mg/kg) were at least 5 times and 25 times, respectively, higher than the dose of alendronate in the rat hypercalcemic model prepared by 1 alpha(OH)D3. The relative potencies of compounds in the hypercalcemic rat models reflected those of inhibitory effects on bone resorption in vitro. We conducted the ivory-slice assay under two conditions: (a) addition of a given bisphosphonate after adherence of the osteoclasts; and (b) preincubation of the ivory slices with a given bisphosphonate. The inhibitory IC50 values of alendronate under condition (b) were similar to those under condition (a). To evaluate the interaction between osteoclasts and alendronate in bone, we investigated the localization of [14C]-alendronate in the tibia of growing rats (4-day-old rats). Alendronate did not distribute uniformly in the tibia. At 1 day after injection (0.05 mg SC), dense labeling was seen primarily under osteoclasts. We injected 0.05 mg/kg of [14C]-alendronate (single i.v.) into rats [14C]-alendronate was rapidly eliminated from plasma, and mainly distributed to the bone in rats. These data suggest that alendronate which distributed on bone surface mainly contributed to the antihypercalcemic action in vivo.

Alendronate↗