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PubMed2004

Alendronate versus calcitriol for the prevention of bone loss after cardiac transplantation.

BACKGROUND: Osteoporosis is a well-known complication of cardiac transplantation. We conducted a randomized trial comparing alendronate with calcitriol for the prevention of bone loss during the first year after cardiac transplantation. METHODS: A total of 149 patients were randomly assigned to receive either alendronate (10 mg per day) or calcitriol (0.5 microg per day) a mean (+/-SD) of 21+/-11 days after transplantation. Estimates of bone loss and the incidence of fractures among untreated patients were obtained from a reference group of 27 prospectively recruited patients who received cardiac transplants within the same period as the intervention groups. RESULTS: At one year, the bone mineral density at the lumbar spine had decreased by a mean of 0.7 percent in the alendronate group and 1.6 percent in the calcitriol group (P=0.25 for the test of no difference). The bone mineral density at the femoral neck decreased by a mean of 1.7 percent in the alendronate group and 2.1 percent in the calcitriol group (P=0.69). In the reference group, the mean bone mineral density at the lumbar spine decreased by 3.2 percent (P=0.03 for the comparison with the alendronate group; P=0.15 for the comparison with the calcitriol group), and the mean density at the femoral neck decreased by 6.2 percent (P=0.001 for comparisons with both intervention groups). The incidence of vertebral fractures did not differ significantly among the groups (6.8 percent in the alendronate group, 3.6 percent in the calcitriol group, and 13.6 percent in the reference group). Hypercalciuria developed in 27 percent of the patients in the calcitriol group and 7 percent of those in the alendronate group (P=0.01). CONCLUSIONS: The degree of bone loss and the rates of fracture did not differ significantly between the intervention groups. Calcitriol was associated with a higher risk of hypercalciuria. Alendronate-treated patients sustained less bone loss at the spine than those in the reference group, and both intervention groups sustained less bone loss at the hip than the reference group. The requirement for monitoring the serum and urinary calcium levels in calcitriol-treated patients makes alendronate more attractive for the prevention of bone loss early after cardiac transplantation.

Alendronate↗
PubMed2005

Alendronate inhibits spine fusion in a rat model.

STUDY DESIGN: A posterolateral lumbar fusion model in rats. OBJECTIVE: To study the effects of alendronate on posterolateral lumbar fusion in rats. SUMMARY OF BACKGROUND DATA: To our knowledge, there are no studies that show a significant inhibition of manual palpation-assessed spine fusion by alendronate. METHODS: A total of 75 Sprague-Dawley rats underwent intertransverse fusion with 7-tailbone autograft at L4-L5. Animals received saline (control), alendronate equivalent to human dose (dose1, 5 microg/kg/day), or 10 times the human dose (dose10, 50 microg/kg/day) via subcutaneous osmotic pumps starting the day of surgery. Eight weeks after surgery, animals were euthanized, and fusion was assessed by manual palpation. Radiographic area and optical density of fusion masses were calculated. Histomorphometry was used to assess the percentage area of fusion masses occupied by bone or marrow tissues. RESULTS: Manual palpation fusion rates were lower in alendronate groups (50% and 40%, respectively) than in the control group (95%, P = 0.002). Interobserver and intraobserver kappa values were high (0.97-1.00). There were dose-dependent and statistically significant (P < 0.001) increases in fusion mass area and optical density with increasing alendronate dose. Fusion masses in dose10 animals had significantly higher percent area of bone tissue (P = 0.01) and lower percent area of marrow elements (P < 0.001) when compared to control animals. CONCLUSIONS: Alendronate inhibits spine fusion in rats. Fusion masses in alendronate-treated animals appeared radiographically larger and denser than those in control animals despite lower fusion rates. Quantitative histomorphometry confirmed that alendronate inhibited bone graft resorption and incorporation. We recommend that patients undergoing spine arthrodesis should not take alendronate until fusion is achieved.

Alendronate↗
PubMed2005

Comparative appraisal of clodronate, aspirin and dexamethasone as agents reducing alendronate-induced inflammation in a murine model.

Among the bisphosphonates, the nitrogen-containing bisphosphonates have much stronger anti-bone-resorptive activities than bisphosphonates containing no nitrogen, but nitrogen-containing bisphosphonates mostly have inflammatory side effects. Our previous murine-model experiments with a single intraperitoneal bisphosphonate injection demonstrated that (i) nitrogen-containing bisphosphonates induce various inflammatory reactions via an IL-1-dependent mechanism, (ii) alendronate (an nitrogen-containing bisphosphonate) produces a clear sclerotic line in the tibia that is easily detectable by radiography a few weeks later (tentatively called the bisphosphonate line, a useful marker for the anti-bone-resorptive activities of bisphosphonates), and (iii) clodronate (a non-nitrogen-containing bisphosphonate) reduces the inflammatory reactions induced by alendronate but does not reduce the bisphosphonate line formation induced by alendronate. We compared the effects of clodronate, aspirin and dexamethasone on the inflammatory reactions induced by alendronate (40 micromol/kg) (induction of the histamine-forming enzyme, accumulation of pleural exudate and splenomegaly) and on the bisphosphonate line formation induced by alendronate (0.1 micromol/kg). The effects of aspirin (833 micromol/kg) were weak. However, like clodronate, dexamethasone (10 micromol/kg, injected 5 min. after alendronate), strongly inhibited the alendronate-induced inflammatory reactions but did not reduce the alendronate-induced bisphosphonate line formation. Alendronate produced normal bisphosphonate lines in IL-1-deficient mice, too. These results suggest that clodronate and/or dexamethasone may be suitable for preventing or reducing the inflammatory side effects of nitrogen-containing bisphosphonates while preserving their powerful anti-bone-resorptive activities (although in practice the known side effects of dexamethasone may limit its use), and that the anti-bone resorptive activities of nitrogen-containing bisphosphonates are not influenced by IL-1.

Alendronate↗
PubMed2002

Physiological and morphological effects of alendronate on rabbit esophageal epithelium.

Alendronate, an aminobisphosphonate, produces as a side effect a topical (pill induced) esophagitis. To gain insight into this phenomenon, we assessed the effects of luminal alendronate on both esophageal epithelial structure and function. Sections of rabbit esophageal epithelium were exposed to luminal alendronate at neutral or acidic pH while mounted in Ussing chambers to monitor transmural electrical potential difference (PD), short-circuit current (I(sc)), and resistance (R). Morphological changes were sought by light microscopy in hematoxylin and eosin-stained sections. Impedance analysis was used for localization of alendronate-induced effects on ion transport. Luminal, but not serosal, alendronate (pH 6.9-7.2), increased PD and I(sc) in a dose- and time-dependent manner, with little change in R and mild edema of surface cell layers. The changes in I(sc) (and PD) were reversible with drug washout and could be prevented either by inhibition of Na,K-ATPase activity with serosal ouabain or by inhibition of apical Na channels with luminal acidification to pH 2.0 with HCl. An effect on apical Na channel activity was also supported by impedance analysis. Luminal alendronate at acidic pH was more damaging than either alendronate at neutral pH or acidic pH alone. These data suggest that alendronate stimulates net ion (Na) transport in esophageal epithelium by increasing apical membrane sodium channel activity and that this occurs with limited morphological change and no alteration in barrier function. Also alendronate is far more damaging at acidic than at neutral pH, suggesting its association with esophagitis requires gastric acid for expression. This expression may occur either by potentiation between the damaging effects of (refluxed) gastric acid and drug or by acid-induced conversion of the drug to a more toxic form.

Alendronate↗
PubMed2004

Upper gastrointestinal and overall tolerability of alendronate once weekly in patients with osteoporosis: results of a randomized, double-blind, placebo-controlled study.

OBJECTIVE: To compare the upper gastrointestinal (GI) and overall tolerability profiles of alendronate 70 mg once weekly with placebo. RESEARCH DESIGN AND METHODS: This 12-week international, multi-center, randomized, double-blind, placebo-controlled trial included 449 postmenopausal women and men with osteoporosis at 44 sites in 19 countries in Europe, the Americas, Africa, and Asia-Pacific. Subjects were randomized to alendronate 70 mg once weekly or matching placebo in a 1:1 ratio. MAIN OUTCOME MEASURES: The safety and tolerability of weekly alendronate and placebo were captured as clinical and laboratory adverse events. The primary endpoint was upper GI tolerability based on the incidence of upper GI tract adverse events. Secondary endpoints included the percentage of subjects who discontinued therapy due to a drug-related upper GI adverse event. Change from baseline in bone turnover as measured by the urinary N-telopeptide-collagen crosslinks corrected for creatinine (NTx/Cr) was assessed at 12 weeks as an indicator of efficacy. RESULTS: The percentages of subjects reporting an upper GI tract adverse event in the alendronate 70 mg once weekly group (9.8%) and the placebo group (9.4%) were similar. The risk difference between the two treatment groups (alendronate minus placebo) was 0.4% [95% confidence interval (CI), -5.1%, 5.9%]. Percentages of subjects who discontinued due to a drug-related upper GI adverse event were also similar (alendronate 2.7%; placebo 2.2%; risk difference 0.4%, 95% CI, -2.4, 3.3). The overall tolerability profile of alendronate 70 mg once weekly, as measured by the percentage 8.0% (95% CI, 1.4%, 15.0%) increase in the of subjects reporting any adverse event, was similar to that of placebo (risk difference 2.1%, 95% CI -6.9, 11.0). There was a significant 43.3% (95% CI, -47.9%, -38.3%) decrease from baseline in urinary NTx/Cr in the alendronate group compared with an placebo group at Week 12. CONCLUSION: Alendronate 70 mg administered once weekly to women and men with osteoporosis has an upper GI and overall tolerability profile similar to that of placebo.

Administration, Oral↗
PubMed2002

A randomized double-blind trial to compare the efficacy of teriparatide [recombinant human parathyroid hormone (1-34)] with alendronate in postmenopausal women with osteoporosis.

Teriparatide (rDNA origin) injection [recombinant human PTH (1-34)] stimulates bone formation, increases bone mineral density (BMD), and restores bone architecture and integrity. In contrast, bisphosphonates reduce bone resorption and increase BMD. We compared the effects of teriparatide and alendronate sodium on BMD, nonvertebral fracture incidence, and bone turnover in 146 postmenopausal women with osteoporosis. Women were randomized to either once-daily sc injections of teriparatide 40 micro g plus oral placebo (n = 73) or oral alendronate 10 mg plus placebo injection (n = 73). Median duration of treatment was 14 months. At 3 months, teriparatide increased lumbar spine BMD significantly more than did alendronate (P < 0.001). Lumbar spine-BMD increased by 12.2% in the teriparatide group and 5.6% in the alendronate group (P < 0.001 teriparatide vs. alendronate). Teriparatide increased femoral neck BMD and total body bone mineral significantly more than did alendronate, but BMD at the one third distal radius decreased, compared with alendronate (P < or = 0.05). Nonvertebral fracture incidence was significantly lower in the teriparatide group than in the alendronate group (P < 0.05). Both treatments were well tolerated despite transient mild asymptomatic hypercalcemia with teriparatide treatment. In conclusion, teriparatide, a bone formation agent, increased BMD at most sites and decreased nonvertebral fractures more than alendronate.

Adult↗
PubMed2001

Additional beneficial effects of alendronate in growth hormone (GH)-deficient adults with osteoporosis receiving long-term recombinant human GH replacement therapy: a randomized controlled trial.

We conducted a randomized controlled trial in osteoporotic adult GH-deficient (GHD) patients to assess whether additional treatment with a bisphosphonate would further favorably influence parameters of bone turnover and bone mineral density measurements (BMD). All patients were receiving stable recombinant human (rhGH) replacement therapy for 4 yr at the start of the study. Eighteen GHD patients with osteoporosis were randomized to continue their rhGH maintenance dose or to receive combination therapy with rhGH and alendronate for 12 months. All patients were calcium and vitamin replete, and there were no changes in calcium, vitamin D, or hormone replacement therapy for the duration of the study. At baseline there were no significant differences between the alendronate and the control group in parameters of bone turnover, BMD, or prevalence of vertebral fractures. Childhood-onset and adult-onset GHD were equally distributed between the groups, with no statistical differences in age and gender or other parameters between groups. Mean serum osteocalcin, serum bone-specific alkaline phosphatase, and urinary N-telopeptide/creatinine ratio were within the normal range at the start of the study. In the alendronate group all measured parameters of bone turnover, i.e. bone-specific alkaline phosphatase, osteocalcin, and urinary N-telopeptide/creatinine ratio, significantly decreased after 6 months, with no further decrease thereafter. No changes were observed in the control group. In the alendronate-treated patients serum bone-specific alkaline phosphatase decreased from 10.9 +/- 0.9 to 6.8 +/- 0.7 microg/L at 6 months (P < 0.001), serum osteocalcin decreased from 3.9 +/- 0.4 to 1.7 +/- 0.3 microg/L (P < 0.001), and the urinary N-telopeptide/creatinine ratio decreased from 27.3 +/- 7.0 to 6.4 +/- 0.8 nmol/mmol (P = 0.01). In this group, lumbar spine BMD significantly increased from baseline by 3.4% at 6 months (P = 0.001) and by 4.4% at 12 months (P < 0.001) of treatment, with no further significant increase between 6 and 12 months (P = 0.217). No changes in lumbar spine BMD were observed in the control group. There were no significant changes in femoral neck BMD in either group for the duration of the study. No incident vertebral or peripheral fractures were documented in either group at the end of the study. In summary, this is the first report indicating that treatment with alendronate was able to significantly increase BMD at the lumbar spine in GHD patients with osteoporosis receiving stable rhGH replacement for 4 yr. This increase was significantly greater in alendronate-treated patients than in patients maintained on rhGH. The increase in lumbar spine BMD in the alendronate-treated patients was associated with a decrease in the measured markers of bone turnover, whereas these markers did not change further in the patients maintained on rhGH. This controlled study suggests that additional treatment with alendronate in GHD patients with osteoporosis receiving stable rhGH replacement therapy is effective in increasing BMD at the lumbar spine. Further investigation is required to assess whether rhGH replacement alone or combined treatment with rhGH and alendronate is able to reduce the increased fracture risk associated with GHD.

Adult↗
PubMed2002

Alendronate increases bone mass and reduces bone markers in postmenopausal African-American women.

Previous studies indicated that aminobisphosphonate alendronate sodium, a potent inhibitor of bone resorption, increases bone mineral density (BMD) at the hip and spine, reduces markers of bone turnover, and reduces the risk of fractures in Caucasian postmenopausal women. The purpose of the present study was to investigate whether alendronate increases BMD and reduces markers of bone turnover in African-American postmenopausal women. In a multicenter, randomized, double-blind, placebo-controlled study, 65 African-American women, aged 45 to 88 yr, were randomly assigned to either placebo (n = 33) or alendronate 10 mg daily (n = 32) for 2 yr. Mean BMD T scores of the lumbar spine at baseline were -3.18 in the placebo-treated group and -3.09 in the alendronate-treated group. All women took 500 mg elemental calcium daily in the form of calcium carbonate and 500 IU vitamin D. Alendronate significantly increased BMD and reduced markers of bone formation and resorption, compared with placebo. At 2 yr, mean changes +/- SE in BMD were 6.5% +/- 0.7% for the lumbar spine (P < 0.001), 4.5% +/- 1.0% for the femoral neck (P < 0.001), 6.4% +/- 0.6% for the femoral trochanter (P < 0.001), 4.1% +/- 0.7% for the total hip (P < 0.001), 0.7% +/- 0.5% for the one third forearm (NS), and 2.0% +/- 0.4% for the total body (P < 0.001) in women treated with alendronate, compared with 0.9% +/- 0.6% (NS), 0.5% +/- 1.1% (NS), -0.2 +/- 0.8 (NS), -1.1 +/- 0.7% (NS), -0.8% +/- 0.6% (NS), and -1.2% +/- 0.6% (P < 0.05) for the lumbar spine, femoral neck, trochanter, total hip, one third forearm, and total body, respectively, in women treated with placebo. At 2 yr, mean serum bone-specific alkaline phosphatase had declined by 46.3% with alendronate (P < 0.001) and 13.6% with placebo (P < 0.01), and mean urinary N-telopeptide of type I collagen/creatinine ratio had declined by 70.5% with alendronate (P < 0.001) and 6.7% with placebo (NS). The incidence of adverse experiences was not different between the two groups. We conclude that in postmenopausal African-American women with osteoporosis, alendronate, 10 mg daily for 2 yr, increases BMD at the lumbar spine, hip, and total body and reduces markers of bone remodeling and is well tolerated.

Black or African American↗
PubMed2002

[Pharmacological and clinical properties of alendronate sodium hydrate].

Alendronate (alendronate sodium hydrate; Bonalon Tablet, 5 mg) is a nitrogen-containing bisphosphonate, which combines with the bone surface and reduces osteoclast-mediated bone resorption. It is a third-generation bisphosphonate compound, specifically distributed on the surface of bone resorption and taken into osteoclasts. Under the closed circumstances which is formed with osteoclast and the bone surface, alendronate becomes detached from the bone surface and taken into osteoclast since acid released from osteoclast leads to pH decrease (acidified). The uptaken alendronate blocks the pathway of mevalonic acid synthesis, which is cholesteric synthesis, inhibits the prenylation of GTP binding protein, and decreases the osteoclast's function by influencing the cytoskeleton. This restraint of alendronate in bone resorption against osteoclasts is reversible, showing no cytotoxicity at more than hundredfold concentration level at which action occurs. Alendronate is an agent for the treatment of osteoporosis that has established safety with regards to bone quality since it neither inhibits bone calcification nor influences fracture healing in chronic administration. The most serious morbidity in osteoporosis is developing fractures. The efficacy of alendronate on restraining fracture, as well as on increase in BMD, is evidenced in Japan. Recently, in addition to senile or postmenopausal osteoporosis, drug-induced osteoporosis, such as steroid-induced osteoporosis, has attracted attention. In this regard, alendronate has been found to be an effective agent for the treatment of osteoporosis overseas, being approved in over 90 countries and used by more than 4.5 million patients. This review will give an outline of alendronate, the preparation to have introduced a concept of Evidence Based Medicine earlier, from pharmacodynamic action to clinical efficacy.

Alendronate↗
PubMed2005

Differential effects of teriparatide and alendronate on bone remodeling in postmenopausal women assessed by histomorphometric parameters.

UNLABELLED: An 18-month randomized double-blind study was conducted in postmenopausal women with osteoporosis to compare the effects of once-daily teriparatide 20 microg with alendronate 10 mg on bone histomorphometry. Biopsies were obtained from 42 patients. Indices of bone formation were significantly higher after 6 or 18 months of teriparatide compared with alendronate treatment. INTRODUCTION: Alendronate and teriparatide increased BMD, assessed by DXA, by different mechanisms of action, supported by changes in biochemical markers of bone turnover. The purpose of this cross-sectional study was to explore the differential effects of these two osteoporosis treatments at the bone tissue level by examining bone histomorphometric parameters of bone turnover after either 6 or 18 months of treatment. MATERIALS AND METHODS: Patients were a cohort from a randomized parallel double-blind study conducted to compare the effects of once-daily teriparatide 20 microg and alendronate 10 mg in postmenopausal women with osteoporosis. Transiliac crest bone biopsies were obtained after tetracycline double labeling from 42 patients treated for 6 months (n = 23) or 18 months (n = 14); 5 additional patients were biopsied from contralateral sides at 6 and 18 months. Biopsy specimens adequate for quantitative analysis were analyzed by 2D histomorphometry from 17 patients at 6 months (teriparatide, n = 8; alendronate, n = 9) and 15 patients at 18 months (teriparatide, n = 8; alendronate, n = 7). Data were analyzed by two-sample tests. RESULTS: Histomorphometric indices of bone formation were significantly and markedly greater in the teriparatide group than in the alendronate group at 6 and 18 months, whereas indices of bone resorption were only significantly greater in the teriparatide group than in the alendronate group at 6 months. Bone formation and activation frequency were significantly lower at 18 months compared with 6 months in the teriparatide group, returning to levels comparable with untreated postmenopausal women. In the teriparatide group, the peak in histomorphometric bone formation indices coincided with peak levels for N-terminal propeptide of type I collagen, a biochemical marker of bone formation. The degree of mineralization was lower at 18 months than at 6 months with treatment in both groups but was not different between groups. CONCLUSIONS: These results confirm the opposite mechanisms of action of teriparatide and alendronate on bone remodeling and confirm the bone formation effect of teriparatide.

Absorptiometry, Photon↗
PubMed2000

Alendronate stimulates collagenase 3 expression in osteoblasts by posttranscriptional mechanisms.

Bisphosphonates inhibit bone resorption by reducing osteoclastic cell number and activity. Alendronate is a nitrogen-containing bisphosphonate analog used in the treatment of postmenopausal osteoporosis. The effects of alendronate in osteoclasts are well documented; however, there is limited information on the actions of alendronate in osteoblasts (Ob's). In this study, we investigated the effects of alendronate at concentrations of 1-100 microM on the synthesis of collagenase 3 or matrix metalloproteinase 13 (MMP-13) and tissue inhibitors of MMPs (TIMPs) 1, 2, and 3 in primary Ob-enriched cells from 22-day-old fetal rat calvariae. Alendronate at concentrations higher than 10 microM markedly stimulated the synthesis of collagenase messenger RNA (mRNA) and immunoreactive protein in Ob's. Alendronate did not stimulate the transcriptional rate of the collagenase 3 gene. However, in transcriptionally arrested cells, alendronate prolonged the half-life of collagenase transcripts. Alendronate did not alter the expression of TIMP 1 and 2, but modestly stimulated the expression of TIMP 3. The actions of alendronate in Ob's suggest potential additional effects in bone remodeling.

Alendronate↗
PubMed2003

Alendronate interacts with the inhibitory effect of 1,25(OH)2D3 on parathyroid hormone-related protein expression in human osteoblastic cells.

The bisphosphonate alendronate is a potent inhibitor of bone resorption by its direct action on osteoclasts. In addition, there is some data suggesting that alendronate could also inhibit bone resorption indirectly by interacting with osteoblasts. Parathyroid hormone-related protein (PTHrP) produced by osteoblasts and 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] are regulators of bone remodeling, which have interrelated actions in these cells. In this study, we assessed whether alendronate can affect PTHrP expression in the presence or absence of 1,25(OH)2D3 in human primary osteoblastic (hOB) cells from trabecular bone. Cell total RNA was isolated, and semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) was carried out using human PTHrP-specific primers. PTHrP in the hOB cell-conditioned medium was analyzed by a specific immunoradiometric assay. We found that PTHrP mRNA and secreted PTHrP were maximally inhibited by 10(-8) - 10(-6) M of 1,25(OH)2D3 treatment within 8-72 h in hOB cells. Alendronate (10(-14) - 10(-8) M) modified neither PTHrP mRNA nor PTHrP secretion, although it consistently abrogated the decrease in PTHrP production induced by 1,25(OH)2D3 in these cells. On the other hand, alendronate within the same dose range did not affect either the vitamin D receptor (VDR) mRNA or osteocalcin secretion, with or without 1,25(OH)2D3, in hOB cells. The inhibitory effect of alendronate on the 1,25(OH)2D3-induced decrease in PTHrP in these cells was mimicked by the calcium ionophore A23187 (5 x 10-6 M), while it was eliminated by 5 x 10(-5) M of nifedipine. Furthermore, although alendronate alone failed to affect [Ca2+]i in these cells, it stimulated [Ca2+]i after pretreatment of hOB cells with 10(-8) M of 1,25(OH)2D3, an effect that was abolished by 5 x 10(-5) M of nifedipine. These results show that alendronate disrupts the modulatory effect of 1,25(OH)2D3 on PTHrP production in hOB cells. Our findings indicate that an increase in calcium influx appears to be involved in the mechanism mediating this effect of alendronate.

Alendronate↗
PubMed2000

Effectiveness of local delivery of alendronate in reducing alveolar bone loss following periodontal surgery in rats.

BACKGROUND: Mucoperiosteal flaps are used to access bone and root surfaces for debridement, pocket elimination, management of periodontal defects, and in regenerative procedures, as well as in implant surgery. Many reports show that periodontal surgery stimulates osteoclast activity with varying amounts of alveolar bone loss. Alendronate given intravenously significantly reduced alveolar bone loss in mucoperiosteal flap procedures. In the present study, we explored the effectiveness of different concentrations of alendronate, delivered at the surgical site at the time of surgery, in distant delivery in reducing alveolar bone loss. METHODS: Following elevation of a mucoperiosteal flap next to molars of the rat mandible, a gelatin sponge soaked with different concentrations of alendronate (0, 1, 5, 20, or 40 mg/ml; experiment A) was applied to exposed bone on the experimental side. In the second group (experiment B), alendronate (0, 50, 200, or 400 microg) was topically delivered in the cheek submucosa on the left side (distant to the surgical site) in a small cut into which the gelatin sponge soaked with the drug was placed. RESULTS: Topical application of 200 microg and 400 microg doses of alendronate at the time of surgery was significantly effective (P <0.001) in reducing bone loss. Generally, the percentage of sections with mild bone loss (V1, V2) increased with an increase in the dose of alendronate, while the percentage of sections with severe bone loss (H1, H2) decreased with an increase in alendronate dose. Topical application of 400 microg of alendronate had a systemic effect. CONCLUSIONS: This study implies that topical delivery of alendronate at the time of surgery reduces bone loss in periodontal procedures involving mucoperiosteal flap surgery. The most effective dose is 200 microg for topical delivery at the surgical site and 400 microg for distant sites.

Administration, Buccal↗
PubMed2003

The influence of alendronate on bone formation and resorption in a rat ectopic bone development model.

BACKGROUND: Most bone grafting techniques that include bone marrow, alloplastic materials, and extracellular bone matrix produce new bone mass, filling bone defects unpredictably. In most cases, the new bone undergoes resorption due to low local strains, resulting in significant bone loss. Recently, it was shown that alendronate and other bisphosphonates reduce bone loss when administered systemically or locally. The aim of this study was to investigate whether alendronate is effective on bone formation or bone resorption. METHODS: A total of 64 rats were divided into 2 main groups. In all the rats, fresh bone marrow removed from DA young rats was placed into demineralized rat femur cylinders (DBMC) and implanted into subcutaneous sites of host DA rats, to form new bone. Group A served as an alendronate treatment group, and group B served as a non-treated control. Group A received 100 microl of 1.5 mg/ml alendronate solution at 1, 2, and 3 weeks (group A1) and at 3, 4, and 5 weeks (group A2). At designated times, the rats were sacrificed, and the implanted DBMC was dissected out of the thorax and processed for histological and microradiography image analysis. RESULTS: Alendronate given at 1, 2, and 3 weeks (during the bone formation phase) did not increase the amount of bone or the visual bone density in comparison to the time-matched control, after 4 and 8 weeks. When alendronate was injected at 3, 4, and 5 weeks, the bone mass increased by 70% and by 166% after 6 and 10 weeks, respectively, in comparison to the untreated control. The visual bone density in group A2 was maintained at the level of 140 +/- 15 at 6 weeks and 152 +/- 15 at 10 weeks. The matched, non-treated control group B2 was significantly lower, 106 +/- 20 and 108 +/- 15, respectively. The histological sections showed that alendronate treatment at 3, 4, and 5 weeks maintained the normal appearance of the ossicle at 6 and 10 weeks in comparison to the osteopenic bone appearance in the matched controls. CONCLUSIONS: This study suggests that alendronate is effective in inhibiting bone loss, but ineffective during the bone formation phase. We suggest, therefore, that alendronate should be administered in procedures where bone resorption is expected.

Alendronate↗
PubMed2003

A histopathological investigation on the effect of systemic administration of the bisphosphonate alendronate on resorptive phase following mucoperiosteal flap surgery in the rat mandible.

BACKGROUND: The present study was designed to assess histopathologically whether the systemic administration of aminobisphosphonate (alendronate), 0.5 mg/kg body weight, is effective in preventing alveolar bone resorption following mucoperiosteal flap surgery, and whether alendronate modulates tissue factors. METHODS: The effect of alendronate on bone resorption was evaluated in mucoperiosteal flaps used as a resorptive model. The animals were given subcutaneous injections of either saline (control group) or 0.5 mg/kg of alendronate (experimental group). The alendronate or saline was administered subcutaneously 1 week prior to surgery, immediately prior to surgery, and 1 week after surgery. The parameters determined with a semiquantitative subjective method for histopathological evaluation were as follows: inflammatory cell infiltration (ICI) of adjacent periodontal tissue, degree of fibrosis and collagen bundle formation, number and morphology of osteoclasts of the alveolar bone and interdental septum, resorption lacunae (osteoclast surfaces), and osteoblastic activity (forming surfaces). RESULTS: There were no statistically significant differences between the saline and alendronate groups with regard to inflammatory cell infiltration, number of osteoclasts, and osteoblastic activity. Fibrosis and collagen bundle formation, osteoclast morphologies, and resorption lacunae formation were significantly different between the two groups, in favor of the alendronate group. CONCLUSIONS: The systemic administration of 0.5 mg/kg alendronate was effective in preventing alveolar bone loss and in modulating tissue factors. These findings indicate that alendronate would be a valuable addition to the therapeutic armamentarium available for the treatment of periodontal diseases, either alone or in combination with regenerative components such as anti-inflammatory drugs, bone graft materials, and guided tissue regeneration techniques, and even with dental implants.

Alendronate↗
PubMed2004

Effects of combined systemic administration of low-dose doxycycline and alendronate on endotoxin-induced periodontitis in rats.

BACKGROUND: Doxycycline has been widely used in periodontal treatment for its antimicrobial and anti-enzymatic effects. Recently, bisphosphonates have been shown to inhibit alveolar bone resorption. The aim of the present study was to evaluate the effects of doxycycline and the bisphosphonate alendronate on the gingival tissue levels of prostaglandin E2 (PGE2), prostaglandin F2alpha (PGF2alpha), leukotriene B4 (LTB4), and platelet-activating factor (PAF) in endotoxin-induced periodontal breakdown in rats. METHODS: Experimental periodontitis was induced by repeated injection of Escherichia coli endotoxin (LPS) and 44 adult male Sprague-Dawley rats were divided into five study groups as follows: LPS, doxycycline + LPS, alendronate + LPS, doxycycline + alendronate + LPS, and saline control. Doxycycline and alendronate were given either as a single agent or as a combination therapy during the 7-day study period. At the end of the 1-week protocol, the rats were sacrificed, the gingival tissues were dissected and extracted, and the extracts were analyzed for PGE2, PGF2alpha, LTB4, and PAF levels. The defleshed jaws were analyzed morphometrically for alveolar bone loss. Data were evaluated statistically by using parametric tests. RESULTS: Alveolar bone loss measurements revealed significantly higher values in LPS, doxycycline + LPS, alendronate + LPS, and doxycycline + alendronate + LPS groups in comparison to the saline control group (P <0.05). Combined administration of doxycycline and alendronate exhibited the most prominent inhibition on gingival tissue levels of PGE2 and PGF2alpha (P<0.05). Doxycycline + alendronate + LPS group also significantly reduced LTB4 and PAF levels, although doxycycline provided the most reduction in the levels of these mediators (P <0.05). CONCLUSIONS: Alendronate and/or doxycycline may provide significant inhibition of the major inflammatory mediators of periodontal tissue destruction, and combined administration of these agents may provide beneficial effects in periodontal treatment. However, this hypothesis must be further verified by clinical human trials before introducing its use in dental practice.

Alendronate↗
PubMed2005

Systemic low-dose doxycycline and alendronate administration and serum interleukin-1beta, osteocalcin, and C-reactive protein levels in rats.

BACKGROUND: The aim of the present study was to evaluate the effects of systemic administration of low-dose doxycycline and a bisphosphonate, alendronate, on serum levels of interleukin-1beta (IL-1beta), osteocalcin (OC), and C-reactive protein (CRP) in experimental periodontitis in rats. METHODS: Experimental periodontitis was induced by repeated injection of purified lipopolysaccharide (LPS) derived from Escherichia coli endotoxin. Forty-seven adult male Sprague-Dawley rats were divided into five study groups and given LPS, LPS + doxycycline, LPS + alendronate, LPS + doxycycline + alendronate, and saline control. At the end of the 1-week protocol, blood samples were obtained, and the rats were sacrificed. Serum samples were analyzed for IL-1beta, OC, and CRP concentrations by enzyme-linked immunosorbent assay (ELISA). The jaws were defleshed, and alveolar bone loss was assessed morphometrically. Data were evaluated statistically by non-parametric tests. RESULTS: Morphometric measurements revealed significantly more bone loss in the LPS group compared to the saline control group (P <0.05). Alendronate revealed slight inhibition on alveolar bone loss either alone or in combination with doxycycline (alveolar bone loss: 0.41 mm in alendronate and combined drug treatment groups versus 0.45 mm in LPS and doxycycline groups). Significantly higher IL-1beta levels were observed with alendronate either alone or in combination with doxycycline than in the LPS group (P <0.05). Combined administration of doxycycline and alendronate showed significantly higher levels of OC than all of the other groups (P <0.01). Serum CRP levels did not exhibit significant differences between the study groups. CONCLUSIONS: Alendronate either alone or in combination with doxycycline provided slight inhibition on LPS-induced alveolar bone resorption. The significantly increased serum OC level observed in the combined drug treatment group suggests that combined administration of alendronate and doxycycline might increase bone remodeling and thereby inhibit the progression of alveolar bone resorption in rats.

Alendronate↗
PubMed2002

Effects of alendronate on particle-induced osteolysis in a rat model.

BACKGROUND: Particle-induced osteolysis is currently a major problem affecting the long-term survivorship of total joint replacements. Alendronate is a third-generation bisphosphonate that blocks osteoclastic bone resorption. The objective of this study was to determine whether alendronate could prevent particle-induced osteolysis or restore (reverse) bone loss in established osteolysis. METHODS: A rat model of particle-induced osteolysis was used. A specially designed polyethylene implant was placed in the proximal part of the right tibia of seventy-two animals. Following four weeks of healing, the animals were randomized into control groups, a prevention group, or a treatment group. In the prevention group, animals received intra-articular injections of high-density polyethylene particles (mean size, 2 m; all <10 m) at four, six, and eight weeks postoperatively. Alendronate (0.01 mg/kg/day) was administered concomitantly through an implantable pump from the fourth week through the tenth week. In the treatment group, animals were also exposed to polyethylene particles at four, six, and eight weeks, to establish bone loss, but they received alendronate subsequently, from the tenth week through the sixteenth week, to treat the bone loss. Positive (particle-only) and negative (saline-solution-only) control groups were assessed as well. Tissues were harvested at ten weeks in the prevention group and at sixteen weeks in the treatment group. Histological analyses and histomorphometric determinations of the periprosthetic bone volume were carried out. RESULTS: Histological examination showed a rim of new bone (neocortex) around the implant in the untreated and saline-solution-treated control animals (no polyethylene particles). Treatment with saline solution (no polyethylene particles) did not affect periprosthetic bone. Animals exposed to polyethylene particles had bone loss. In those that received alendronate, the bone loss was either prevented or reversed, and the quantity of neocortical and trabecular bone was increased compared with that of the controls. Alendronate effectively preserved periprosthetic bone in both the prevention and treatment groups. In the prevention arm, the mean periprosthetic bone volume of the neocortex and the surrounding trabecular bone, as determined with histomorphometry, was 21.5% +/- 6.5% in the saline-solution-treated controls (no particles), 13.1% +/- 5.9% in the particle-treated animals, and 32.6% +/- 6.4% in the alendronate-treated animals (p < 0.001). In the treatment arm, the mean periprosthetic bone volume was 27.2% +/- 5.6% in the saline-solution-treated controls, 17.7% +/- 6.2% in the particle-treated animals, and 30.2% +/- 5.9% in the alendronate-treated animals (p = 0.002). CONCLUSIONS: In our model, the intra-articular injection of polyethylene particles caused substantial bone loss around a loaded implant. Alendronate effectively prevented and treated the particle-induced periprosthetic bone loss.

Alendronate↗