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Alendronate
Terms modified by Alendronate Selected AbstractsComparison of the Effect of Denosumab and Alendronate on BMD and Biochemical Markers of Bone Turnover in Postmenopausal Women With Low Bone Mass: A Randomized, Blinded, Phase 3 Trial,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 1 2009Jacques P Brown Abstract Denosumab is a fully human monoclonal antibody that inhibits bone resorption by neutralizing RANKL, a key mediator of osteoclast formation, function, and survival. This phase 3, multicenter, double-blind study compared the efficacy and safety of denosumab with alendronate in postmenopausal women with low bone mass. One thousand one hundred eighty-nine postmenopausal women with a T-score , ,2.0 at the lumbar spine or total hip were randomized 1:1 to receive subcutaneous denosumab injections (60 mg every 6 mo [Q6M]) plus oral placebo weekly (n = 594) or oral alendronate weekly (70 mg) plus subcutaneous placebo injections Q6M (n = 595). Changes in BMD were assessed at the total hip, femoral neck, trochanter, lumbar spine, and one-third radius at 6 and 12 mo and in bone turnover markers at months 1, 3, 6, 9, and 12. Safety was evaluated by monitoring adverse events and laboratory values. At the total hip, denosumab significantly increased BMD compared with alendronate at month 12 (3.5% versus 2.6%; p < 0.0001). Furthermore, significantly greater increases in BMD were observed with denosumab treatment at all measured skeletal sites (12-mo treatment difference: 0.6%, femoral neck; 1.0%, trochanter; 1.1%, lumbar spine; 0.6%, one-third radius; p , 0.0002 all sites). Denosumab treatment led to significantly greater reduction of bone turnover markers compared with alendronate therapy. Adverse events and laboratory values were similar for denosumab- and alendronate-treated subjects. Denosumab showed significantly larger gains in BMD and greater reduction in bone turnover markers compared with alendronate. The overall safety profile was similar for both treatments. [source] Recovery of Trabecular and Cortical Bone Turnover After Discontinuation of Risedronate and Alendronate Therapy in Ovariectomized RatsJOURNAL OF BONE AND MINERAL RESEARCH, Issue 10 2008Robyn K Fuchs Abstract Alendronate (ALN) and risedronate (RIS) are bisphosphonates effective in reducing bone loss and fractures associated with postmenopausal osteoporosis. However, it is uncertain how long it takes bone turnover to be re-established after treatment withdrawal, and whether this differs between the two drugs. The objective of this study was to determine the time required to re-establish normal bone turnover after the discontinuation of ALN and RIS treatment in an animal model of estrogen-deficiency osteoporosis. Two hundred ten, 6-mo-old female Sprague-Dawley rats were ovariectomized and 6 wk later were randomized into baseline controls (n = 10) and four treatment groups (n = 50/group): vehicle-treated controls (CON; 0.3 ml sterile water), ALN (2.4 ,g/kg), low-dose RIS (RIS low; 1.2 ,g/kg), and high-dose RIS (RIS high; 2.4 ,g/kg). Treatments were administered 3 times/wk by subcutaneous injection. Baseline controls were killed at the initiation of treatment. Other groups were treated for 8 wk, and subgroups (n = 10/ treatment group) were killed 0, 4, 8, 12, and 16 wk after treatment was withdrawn. Static and dynamic histological analyses were performed for cortical (tibial diaphysis) and trabecular (proximal tibia and L4 vertebrae) bone. DXA and mechanical testing was performed on the L5 vertebra. After 8 wk of treatment, trabecular bone turnover rates were significantly suppressed in all drug-treated animals. Trabecular bone formation rate (BFR/BS) remained significantly lower than vehicle in bisphosphonate-treated animals through 12 wk. Sixteen weeks after treatment withdrawal, trabecular BFR/BS in the proximal tibia was re-established in animals treated with RIS but not in animals treated with ALN compared with controls. BMD of the fifth lumbar vertebra remained significantly higher than controls 16 wk after treatment withdrawal in ALN-treated animals but not in RIS-treated animals. Despite reductions in BMD and increases in bone turnover, ultimate force of the fifth lumbar vertebra remained significantly higher in all drug-treated animals through 16 wk after withdrawal. [source] Effects of PTH and Alendronate on Type I Collagen Isomerization in Postmenopausal Women With Osteoporosis: The PaTH Study,,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 9 2008Patrick Garnero Abstract Fracture efficacy of PTH and alendronate (ALN) is only partly explained by changes in BMD, and bone collagen properties have been suggested to play a role. We analyzed the effects of PTH(1,84) and ALN on urinary ,,/,, CTX ratio, a marker of type I collagen isomerization and maturation in postmenopausal women with osteoporosis. In the first year of the previously published PaTH study, postmenopausal women with osteoporosis were assigned to PTH(1,84) (100 ,g/d; n = 119), ALN (10 mg/d; n = 60), or PTH and ALN together (n = 59). We analyzed patients on ALN alone (n = 60) and a similar number of patients assigned to PTH alone (n = 63). During the second year, women on PTH in the first year were reallocated to placebo (n = 31) or ALN (n = 32) and women with ALN continued on ALN. During the first year, there was no significant change in ,,/,, CTX ratio with PTH or ALN. At 24 mo, there was a marked increase of the ,,/,, CTX ratio in women who had received PTH during the first year, followed by a second year of placebo (median: +45.5, p < 0.001) or ALN (+55.2%, p < 0.001). Conversely, the ,,/,, CTX ratio only slightly increased (+16%, p < 0.05) after 2 yr of continued ALN. In conclusion, treatment with PTH(1,84) for 1 yr followed by 1 yr of placebo or ALN may be associated with decreased type I collagen isomerization. The influence of these biochemical changes of type I collagen on bone fracture resistance remains to be studied. [source] Long-Term Protective Effects of Zoledronic Acid on Cancellous and Cortical Bone in the Ovariectomized Rat,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 4 2008Jürg A Gasser PhD Abstract Current bisphosphonate therapies effectively prevent bone loss in postmenopausal women. We studied the effect of a single intravenous dose of ZOL in ovariectomized rats. Protection from bone loss was dose dependent, lasting for up to 32 weeks, supporting the rationale for an annual intravenous dosing regimen of ZOL for treatment of postmenopausal osteoporosis. Introduction: Once-yearly dosing with zoledronic acid (ZOL) 5 mg can increase BMD and reduce fracture rate in postmenopausal women with low BMD. The primary objective of this study was to determine the duration of bone protective effects of a single dose of ZOL in ovariectomized rats, an animal model of postmenopausal osteopenia. Secondary objectives were to determine the effects on bone turnover and mechanical properties. Materials and Methods: Female Wistar rats (10 per group) received single intravenous doses of ZOL 0.8, 4, 20, 100, or 500 ,g/kg, alendronate 200 ,g/kg, or isotonic saline 4 days before bilateral ovariectomy. Sham-operated controls were pretreated with saline. Mass and density of cancellous and cortical bone (pQCT) were measured at 4-wk intervals for 32 wk. Bone architecture (,CT), bone formation dynamics (fluorochrome label-based histomorphometry), and biomechanical strength in compression testing were also assessed at 32 wk. Results: Ovariectomy-associated BMD loss was significantly attenuated for 32 wk by ZOL ,4 ,g/kg for total BMD, ZOL ,20 ,g/kg for cortical BMD, and ZOL ,4 ,g/kg for cancellous BMD (p < 0.01 versus ovariectomized controls). Alendronate 200 ,g/kg was of equivalent potency to ZOL 20 ,g/kg. Ovariectomy-associated decreases in trabecular architectural parameters were dose-dependently attenuated by ZOL. Alendronate 200 ,g/kg was equivalent to ZOL 20 ,g/kg. The bone resorption marker TRACP5b indicated transient suppression of elevated osteoclast activity by ZOL relative to OVX-rats even at the lowest dose of 0.8 ,g/kg, whereas at 100,500 ,g/kg, the effect was significant relative to the OVX control for the entire duration of the study of 32 wk. Bone formation parameters were not significantly affected by ZOL 20 ,g/kg but were significantly reduced by ZOL 100,500 ,g/kg. Alendronate 200 ,g/kg was equivalent to ZOL 100 ,g/kg. ZOL produced dose-related improvements in bone strength parameters after ovariectomy. Alendronate 200 ,g/kg was of similar potency to ZOL 20 ,g/kg. Conclusions: The duration and magnitude of the bone-protecting effect of a single intravenous dose of ZOL in ovariectomized rats is dose dependent and lasts for up to 32 wk. Compared with alendronate, ZOL shows 10-fold higher potency in preventing bone loss. These data support the use of an annual intravenous ZOL dosing regimen for the treatment of osteoporosis. [source] Pretreatment Levels of Bone Turnover and the Antifracture Efficacy of Alendronate: The Fracture Intervention TrialJOURNAL OF BONE AND MINERAL RESEARCH, Issue 2 2006Douglas C Bauer MD Abstract The influence of pretreatment bone turnover on alendronate efficacy is not known. In the FIT, we examined the effect of pretreatment bone turnover on the antifracture efficacy of daily alendronate given to postmenopausal women. The nonspine fracture efficacy of alendronate was significantly greater among both osteoporotic and nonosteoporotic women with higher baseline levels of the bone formation marker PINP. Introduction: Previous trials have shown that high bone turnover is associated with greater increases in BMD among bisphosphonate-treated women. The influence of pretreatment bone turnover levels on antifracture efficacy has not been well studied. Materials and Methods: We randomized women 55,80 years of age with femoral neck BMD T scores , ,1.6 to alendronate (ALN), 5,10 mg/day (n = 3105), or placebo (PBO; n = 3081). At baseline, 3495 women were osteoporotic (femoral neck BMD T score , ,2.5 or prevalent vertebral fracture), and 2689 were not osteoporotic (BMD T score > ,2.5 and no prevalent vertebral fracture). Pretreatment levels of bone-specific alkaline phosphatase (BSALP), N-terminal propeptide of type 1 collagen (PINP), and C-terminal cross-linked telopeptide of type 1 collagen (sCTx) were measured in all participants using archived serum (20% fasting). The risk of incident spine and nonspine fracture was compared in ALN- and PBO-treated subjects stratified into tertiles of baseline bone marker level. Results and Conclusions: During a mean follow-up of 3.2 years, 492 nonspine and 294 morphometric vertebral fractures were documented. Compared with placebo, the reduction in nonspine fractures with ALN treatment differed significantly among those with low, intermediate, and high pretreatment levels of PINP levels (p = 0.03 for trend). For example, among osteoporotic women in the lowest tertile of pretreatment PINP (<41.6 ng/ml), the ALN versus PBO relative hazard for nonspine fracture was 0.88 (95% CI: 0.65, 1.21) compared with a relative hazard of 0.54 (95% CI: 0.39, 0.74) among those in the highest tertile of PINP (>56.8 ng/ml). Results were similar among women without osteoporosis at baseline. Although they did not reach statistical significance, similar trends were observed with baseline levels of BSALP. Conversely, spine fracture treatment efficacy among osteoporotic women did not differ significantly according to pretreatment marker levels. Spine fracture treatment efficacy among nonosteoporotic women was related to baseline BSALP (p = 0.05 for trend). In summary, alendronate nonspine fracture efficacy is greater among both osteoporotic and nonosteoporotic women with high pretreatment PINP. If confirmed in other studies, these findings suggest that bisphosphonate treatment may be most effective in women with elevated bone turnover. [source] Differential Effects of Teriparatide and Alendronate on Bone Remodeling in Postmenopausal Women Assessed by Histomorphometric Parameters,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 7 2005Monique Arlot MD Abstract An 18-month randomized double-blind study was conducted in postmenopausal women with osteoporosis to compare the effects of once-daily teriparatide 20 ,g 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 ,g 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. [source] Effect of Alendronate on the Age-Specific Incidence of Symptomatic Osteoporotic FracturesJOURNAL OF BONE AND MINERAL RESEARCH, Issue 6 2005Marc C Hochberg MD Abstract Analyses of data from 3658 postmenopausal women with osteoporosis enrolled in the Fracture Intervention Trial showed that alendronate is effective in reducing the risk of symptomatic osteoporotic fractures across a spectrum of ages. Introduction: Most osteoporosis studies examine the relative risk of fracture based on the entire duration of treatment. Because older patients tend to be at higher risk for osteoporosis-related fractures, this analysis examined the effect of alendronate treatment on the relative risk of fracture in terms of the age that patients attained during the study. Materials and Methods: We studied 3658 postmenopausal women with osteoporosis 55-80 years of age at baseline enrolled in the Fracture Intervention Trial, a large randomized, double-blind, placebo-controlled study. Patients were treated with placebo or with alendronate at a daily dose of 5 mg for 2 years followed by 10 mg for an additional 1-2.5 years, and monitored for clinical fractures. Age, rather than study time, was the dynamic variable in our analysis. Results: The relative risk reductions for hip, clinical spine, and wrist fractures were constant across age groups, without evidence of a decline at older ages. Specifically, alendronate reduced the risk of clinical fracture by 53% at the hip (relative risk [RR] = 0.47; 95% CI = 0.27-0.81; p < 0.01), 45% at the spine (RR = 0.55; 95% CI = 0.37-0.83; p < 0.01), and 31% at the wrist (RR = 0.69; 95% CI = 0.50-0.98; p = 0.038). In addition, alendronate produced a significant risk reduction of 40% (RR = 0.60; 95% CI = 0.47-0.77; p < 0.01) for the composite event of clinical hip, spine, and wrist fractures. As a consequence of the constant relative risk model, the absolute risk reduction with alendronate treatment increased with age because of the age-related increase in fracture risk in the placebo group. The absolute risk reduction for the composite event (hip, spine, and wrist fractures together) for alendronate treatment versus placebo was 65, 80, 111, and 161 women with fractures per 10,000 PYR for the 55 to <65, 65 to <70, 70 to <75, and 75-85 year age groups, respectively. Conclusions: These data show that alendronate is effective in reducing the risk of symptomatic osteoporotic fractures across a spectrum of ages. The effectiveness is somewhat greater in patients with femoral neck T score , ,2.5 than in those with a T score , ,2.0. [source] Alendronate Interacts With the Inhibitory Effect of 1,25(OH)2D3 on Parathyroid Hormone-Related Protein Expression In Human Osteoblastic Cells,,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 1 2003L Gómez-García Abstract 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 × 10,6 M), while it was eliminated by 5 × 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 × 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. [source] Two-Year Results of Once-Weekly Administration of Alendronate 70 mg for the Treatment of Postmenopausal OsteoporosisJOURNAL OF BONE AND MINERAL RESEARCH, Issue 11 2002R Rizzoli Abstract The aim of this study was to provide confirmation that once-weekly dosing with 70 mg of alendronate (seven times the daily oral dose) and twice-weekly dosing with 35 mg is equivalent to the 10-mg once-daily regimen and to gain more extensive safety experience with this new dosing regimen. Twelve hundred fifty-eight postmenopausal women (aged 42,95 years) with osteoporosis (bone mineral density [BMD] of either lumbar spine or femoral neck at least 2.5 SDs below peak young adult mean or prior vertebral or hip fracture) were assigned to receive oral once-weekly alendronate, 70 mg (n = 519); twice-weekly alendronate, 35 mg (n = 369); or daily alendronate 10 mg (n = 370) for a total of 2 years of double-blind experience. Mean BMD increases from baseline (95% CI) at 24 months in the once-weekly, twice-weekly, and daily treatment groups, respectively, were 6.8% (6.4, 7.3), 7.0% (6.6, 7.5), and 7.4% (6.9, 7.8) at the lumbar spine and 4.1% (3.8, 4.5), 4.3% (3.9, 4.7), and 4.3% (3.9, 4.7) at the total hip. These increases in BMD as well as the BMD increases at the femoral neck, trochanter, and total body and the reductions of biochemical markers of bone resorption (urinary cross-linked N-telopeptides of type I collagen [NTx]) and bone formation (serum bone-specific alkaline phosphatase [BSAP]) were similar for the three dosing regimens. All treatment regimens were well tolerated with a similar incidence of upper gastrointestinal (GI) adverse experiences. The incidence rates of clinical fractures, captured as adverse experiences, were similar among the groups. The 2-year results confirm the conclusion reached after 1 year that once-weekly alendronate is therapeutically equivalent to daily dosing, providing patients with a more convenient dosing option that may potentially enhance adherence to therapy. [source] Alendronate prevents femoral periprosthetic bone loss following total hip arthroplasty: Prospective randomized double-blind studyJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 7 2006Mohammad Arabmotlagh Abstract Following total hip arthroplasty (THA), femoral periprosthetic bone undergoes a remodeling process that results in bone loss in its proximal regions that may compromise the long-term outcome of THA. Periprosthetic bone loss mainly occurs during the first postoperative months. The question is whether a postoperative treatment with alendronate is effective in reducing periprosthetic bone loss and which doses and duration of treatment are required. In a 12-month prospective, randomized double-blind study, 51 patients undergoing cementless THA were treated postoperatively either with a daily dose of 20 mg alendronate for 2 months and 10 mg for 2 months thereafter (group I), with 20 mg of alendronate for 2 months and 10 mg for 4 months thereafter (group II), or treated with placebo (group III). Proximal femoral bone mineral density (BMD) was measured with dual-energy X-ray absorptiometry (DEXA) and serum biochemical markers of bone turnover bone specific alkaline phosphatase, osteocalcin, and C-terminal telopeptides (CTX-I) were assayed. Six months of alendronate treatment significantly reduced (p,<,0.001) bone loss in proximal medial region (,10%) compared with placebo (,26%). All biochemical markers of bone turnover were suppressed by alendronate. These data suggest that alendronate administered for the first 6 postoperative months following THA was effective in preventing early periprosthetic bone loss. © 2006 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 24:1336,1341, 2006 [source] Synergistic action of statins and nitrogen-containing bisphosphonates in the development of rhabdomyolysis in L6 rat skeletal myoblastsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 6 2009Sumio Matzno PhD Abstract Objectives Nitrogen-containing bisphosphonates, which are widely used to treat osteoporosis, act as inhibitors of farnesyl pyrophosphate synthase, one of the key enzymes of the mevalonate pathway, and thus may have the potential to enhance the effect of statins (inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase). In this study, we evaluated the synergistic effect of two nitrogen-containing bisphosphonates, alendronate and risedronate, in statin-induced apoptosis in rat skeletal L6 myoblasts. Methods L6 rat myoblasts were differentiated with drugs. DNA fragmentation was measured and small GTPase was detected by immunoblotting. Key findings Alendronate and risedronate caused dose-dependent apoptosis of L6 myoblasts. Risedronate induced detachment of rho GTPase from the cell membrane, followed by activation of the caspase-8-related cascade. Risedronate-induced apoptosis was synergistically enhanced with atorvastatin and significantly reduced by addition of geranylgeraniol. By contrast, alendronate did not reduce membrane GTPases and the apoptosis was caspase independent. Conclusions These results suggest that risedronate-induced apoptosis is related to geranylgeranyl pyrophosphate depletion followed by rho detachment, whereas alendronate affects are independent of rho. Our results suggest a risk of synergistic action between nitrogen-containing bisphosphonates and statins in the development of rhabdomyolysis when treating osteoporosis in women with hyperlipidaemia. [source] An Approach to Postmenopausal Osteoporosis Treatment: A Case Study ReviewJOURNAL OF THE AMERICAN ACADEMY OF NURSE PRACTITIONERS, Issue 12 2003Cathy Kessenich DSN Purpose To review and discuss the clinical evaluation and therapeutic options for a postmenopausal woman with osteoporosis. Data Sources Review of scientific literature, practice guidelines, and a case study. Conclusions To prevent and treat postmenopausal osteoporosis, women should be encouraged to per-form weight-bearing exercise, to not smoke, and to optimize calcium and vitamin D intake through diet and supplements. Drug regimens are effective and well tolerated in post-menopausal women with osteoporosis. Implications for Practice Drugs currently approved by the U.S. Food and Drug Administration for the treatment of postmenopausal osteoporosis include the bisphosphonates risedronate and alendronate; the selective estrogen receptor modulator, raloxifene; and intranasal calcitonin-salmon spray. Bisphosphonates have demonstrated the most impressive fracture risk reduction in prospective clinical trials of women with post-menopausal osteoporosis. Risedronate has consistently demonstrated significant reductions in vertebral fracture risk at 1 year and in vertebral and nonvertebral fracture risk at 3 years. Alendronate has demonstrated significant reductions in vertebral and nonvertebral fracture risk after 3 years. [source] Clinical trial: comparison of alendronate and alfacalcidol in glucocorticoid-associated osteoporosis in patients with ulcerative colitisALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 4 2009S. KITAZAKI Summary Background, Bone loss is often observed in patients with ulcerative colitis, particularly if they require glucocorticoids. Aim, To determine whether the bisphosphonate, alendronate, is safe and effective in preserving bone mass compared to the active vitamin D3, alfacalcidol, in ulcerative colitis patients receiving glucocorticoids. Methods, Thirty-nine patients with ulcerative colitis and treated with glucocorticoids were randomized to receive alendronate (5 mg/day) or alfacalcidol (1 ,g/day) daily for 12 months. Loss of bone mass was evaluated by bone mineral density, bone resorption by urinary N -telopeptide for type I collagen, and bone formation by serum bone alkaline phosphatase. Results, Alendronate, but not alfacalcidol, significantly increased bone mineral density in the lumbar spine. Alendronate decreased serum bone alkaline phosphatase levels, but alfacalcidol did not. Urinary N -telopeptide for type I collagen levels decreased in both groups, but were significantly lower in the alendronate group. There were no significant differences in the adverse events in the two groups. Conclusion, Our study indicates that alendronate is a safe, well-tolerated and more effective therapy than alfacalcidol for preventing glucocorticoid-associated bone loss in patients with ulcerative colitis. [source] Skeletal Integrity and Visceral TransplantationAMERICAN JOURNAL OF TRANSPLANTATION, Issue 10 2010J. Resnick Despite continuous improvement in long-term survival, there is no knowledge about risk of bone health impairment and management strategies before and after intestinal transplantation. Therefore, 147 adults were retrospectively studied via chart review; 70 long-term survivors, 53 candidates and 24 recipients with longitudinal follow-up. Evaluation process included measurement of bone mineral density (BMD) and allied biochemical markers. Both long-term survivors and candidates showed low bone mass with lower (p < 0.05) z-scores at hip, femoral neck and spine. Vitamin D deficiency and secondary hyperparathyroidism were observed in both groups. Prevalence of osteoporosis was 44% among long-term survivors and 36% in candidates with age, BMD, duration of parenteral nutrition, type of immunosuppression and rejection being significant risk factors. Fragility fractures occurred at a higher (p = 0.02) rate among long-term survivors (20%) compared to candidates (6%). The longitudinal study documented acceleration (p = 0.025) of bone loss after transplantation with a decline of 13.4% (femoral neck), 12.7% (hip) and 2.1% (spine). Alendronate reduced (p < 0.05) but did not prevent bone loss. In conclusion, intestinal transplant recipients are at risk of osteoporosis secondary to bone loss before and after transplantation. Accordingly, current management includes comprehensive preventive measures with prompt therapeutic intervention utilizing intravenous bisphosphonates or subcutaneous human PTH 1,34. [source] Effects of Bisphosphonate on the Endochondral Bone Formation of the Mandibular CondyleANATOMIA, HISTOLOGIA, EMBRYOLOGIA, Issue 5 2009M. S. Kim Summary The development of the mandibular condylar cartilage is important for the overall growth of the mandible. However, there have been a few researches into medical approaches aimed at controlling condylar growth. This study examined the effects of bisphosphonate on the growth of the condylar cartilage. Alendronate (3.5 mg/kg/week) was administered to postnatal day 1 SD rats for 7 and 10 days. The thickness of each chondrocyte layer and the level of MMP-9 expression were measured. The anteroposterior diameter of the developing condyle was unaffected by the alendronate treatment for 7 days (P > 0.05). The total thickness of the cartilage layers was also unaffected by the treatment for 7 days (P > 0.05). In particular, there was no change in the thickness of the perichondrium and reserve cell layer at the measured condylar regions (P > 0.05). However, the thickness of the proliferating cell layer was reduced significantly, whereas the thickness of hypertrophied cartilage layer was increased (P < 0.05). The number of chondroclasts engaged in hypertrophied cartilage resorption was reduced significantly by the alendronate treatment (P < 0.05). The level of MMP-9 expression was reduced at both the transcription and translation levels by the alendronate treatment for 7 and 10 days. These results indicate that alendronate (>3.5 mg/kg/week) inhibits the longitudinal growth of the mandibular condyle by inhibiting chondrocyte proliferation and the resorption of hypertrophied cartilage for ossification. [source] Effects of Alendronate on A Disintegrin and Metalloproteinase with Thrombospondin Motifs Expression in the Developing Epiphyseal Cartilage in RatsANATOMIA, HISTOLOGIA, EMBRYOLOGIA, Issue 2 2009M. S. Kim Summary A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) have been reported to play a role in the degradation of aggrecan, a major component of cartilage. This study was performed to examine the effects of alendronate on the expression of ADAMTS in developing femoral epiphyseal cartilage. Primary cultured chondrocytes from this cartilage were treated with alendronate in vitro and postnatal day 1 rats were injected subcutaneously with alendronate (1 mg/kg) every second day in vivo. The number of cultured chondrocytes and their aggrecan mRNA levels were unaffected by the alendronate treatment at 10,6 to 10,4 m concentrations. The mRNA levels of ADAMTS-1, -2 and -9 in chondrocytes were also unaffected. However, the levels of ADAMTS-5 and -4 were reduced significantly by the same treatment. The thickness of the proliferating chondrocyte layers and the aggrecan mRNA levels in the epiphysis were unaffected by the alendronate treatment in vivo. However, the hypertrophied chondrocyte layers became significantly thicker, and the size of the secondary ossification centre was reduced significantly by the same treatment (P < 0.05). Both ADAMTS-4 and -5 mRNA expressions were also reduced significantly in vivo. The immunoreactivity against ADAMTS-4 was seen in hypertrophied chondrocytes and reduced significantly by the alendronate treatment. These results suggested that alendronate can inhibit the degradation of aggrecan in the articular cartilage by downregulating the expression of matrix enzymes such as ADAMTS-4 and -5. [source] Successful treatment of multicentric reticulohistiocytosis with alendronate: Evidence for a direct effect of bisphosphonate on histiocytesARTHRITIS & RHEUMATISM, Issue 12 2003Hitoshi Goto We describe the case of a 44-year-old Japanese woman with severe nodular erythematous skin lesions and arthritis mutilans who was admitted for further treatment of multicentric reticulohistiocytosis. Skin and synovial biopsies showed heavy infiltration with tartrate-resistant acid phosphatase,positive histiocytes and multinucleated giant cells. Immunohistochemical analysis showed that some of the mononuclear cells in the skin were positive for RANKL. After 1 month of Alendronate, an aminobisphosphonate, given at a dosage of 10 mg once a week intravenously for the first 6 weeks and then once a month thereafter, the arthritis and skin nodules improved, and the remission has continued for more than 2 years. The findings in this patient suggest that osteoclast-like multinucleated giant cells differentiate locally in the skin from infiltrating histiocytes with the help of RANKL-positive stromal cells and that alendronate acts directly on cells of monocyte/macrophage lineage in humans. Thus, alendronate should be added to the list of drugs for the treatment of multicentric reticulohistiocytosis. [source] Preserving bone health in patients with hormone-sensitive prostate cancer: the role of bisphosphonatesBJU INTERNATIONAL, Issue 11 2009Fred Saad Men with prostate cancer initiating androgen-deprivation therapy (ADT) may have multiple factors that threaten their skeletal health, including increased fracture risk from bone loss during ADT and the propensity to develop bone metastases, which may lead to skeletal-related events (SREs). Bisphosphonates have utility in oncology for patients with bone metastases to prevent bone loss during hormonal therapy and in the benign setting to treat osteoporosis. These agents have an emerging role in patients with hormone-sensitive prostate cancer (HSPC). Etidronate, alendronate, pamidronate, and zoledronic acid have all shown efficacy in preventing ADT-related bone loss. Alendronate and zoledronic acid have also been shown to increase bone mineral density vs baseline during ADT. Patients with bone metastases from HSPC who received 4 mg zoledronic acid every 3 or 4 weeks had a low incidence of skeletal complications, although controlled study data have not been reported. Bisphosphonate treatment in men with HSPC may be effective for the prevention of ADT-related bone loss, underscoring the importance of treating early to avoid SREs and potentially delay disease progression to metastatic bone disease. [source] Biphasic Resorbable Calcium Phosphate Ceramic for Bone Implants and Local Alendronate Delivery,ADVANCED ENGINEERING MATERIALS, Issue 5 2010Shashwat S. Banerjee A novel biphasic calcium phosphate ceramic composed of tricalcium phosphate (TCP) and calcium pyrophosphate (CP) is synthesized in order to tailor the biodegradation behavior of the ceramic. The results show that biphasic TCP/CP ceramic has a strength of 62.2,±,2.1 MPa, which is superior to single-phase TCP and CP ceramics, which show strengths of 44.3,±,3.0 and 53.0,±,4.8 MPa, respectively. In addition, biphasic TCP/CP ceramic displays a controlled strength degradation from 62.2,±,2.1 to 40.5,±,1.0 MPa in stimulated body fluid over a period of 28 d. An in vitro cell materials interaction study using human fetal osteoblast cells indicates that TCP/CP ceramic is cytocompatible. TCP/CP ceramic also show a good loading capacity for alendronate. Adsorption of alendronate (AD) on the TCP/CP surface is found to proceed via ligand exchange mechanism and the in vitro release profile of AD from TCP/CP surface is characterized by an initial fast release followed by a slow and sustained release. Strong electrostatic interactions between AD groups and surface Ca2+ ions enable the slow and sustained release of AD. These results demonstrate that the newly developed biphasic ceramic, with its controlled strength degradation and drug release, shows promise for use in orthopedic and tissue engineering applications. [source] Osteoporosis medication profile preference: results from the PREFER-US studyHEALTH EXPECTATIONS, Issue 3 2007Thomas W. Weiss DrPH Abstract Objective, To assess patient preferences for two osteoporosis medications. Design, Women aged 50+ were surveyed via the Internet to assess preferences for two osteoporosis medication profiles. Drug A and Drug B, consistent with ibandronate and alendronate, respectively, differed by: time on market (recently vs. 10 years), dosing frequency (monthly vs. weekly), effectiveness (not proven vs. proven to reduce non-spine or hip fracture after 3 years) and dosing procedure (60 vs. 30 min wait before eating/drinking). Each profile had the same out-of-pocket costs, side-effects, potential for drug interaction and spine fracture efficacy. Patients force ranked and rated the importance of each attribute. Subgroup comparisons included diagnosed vs. at-risk respondents and treated vs. untreated respondents. Results, Among the 999 respondents, Drug B was preferred by 96%. Effectiveness was ranked as the most important determinant of preference (79% ranked it #1) compared with time on market (14%), dosing procedure (4%) and dosing frequency (3%). Effectiveness had the highest mean importance rating on a scale of 1 (extremely unimportant) to 7 (extremely important): mean (SD) = 6.1 (1.8), followed by time on market: 4.7 (1.7), dosing procedure: 4.6 (1.4) and dosing frequency: 4.5 (1.4). No significant differences in profile choice were found across study subgroups. Conclusions, The drug profile showing reductions in non-vertebral and hip fracture risk was chosen by almost all respondents. Drug effectiveness was the most important determinant of preference, while dosing frequency was the least important determinant. Incorporation of patient preferences in the medication decision-making process could enhance patient compliance and clinical outcomes. [source] Osteoporosis management: a perspective based on bisphosphonate data from randomised clinical trials and observational databasesINTERNATIONAL JOURNAL OF CLINICAL PRACTICE, Issue 12 2009S. Boonen Summary Aims:, The efficacy of treatments for osteoporosis can be evaluated using a variety of study designs. This article aims to comprehensively review the evidence for bisphosphonate anti-fracture efficacy in postmenopausal women, discussing the strengths and limitations associated with each study method. Methods:, Literature analysis included English-language publications reporting results of randomised controlled trials (RCTs), post hoc analyses, meta analyses and observational studies evaluating the efficacy of alendronate (ALN), ibandronate (IBN), risedronate (RIS) and zoledronate (ZOL), with an initial sample size , 100 patients, and follow-up data for at least 1 year. Results:, Primary and secondary analyses of RCT data suggest differences among bisphosphonates with regard to site-specific anti-fracture efficacy and onset of fracture risk reduction. While some observational studies indicate differences in clinical outcomes among these agents, others report similar effectiveness. ALN and RIS data demonstrate sustained fracture protection for up to 10 and 7 years of treatment respectively. The efficacy of IBN and ZOL has been evaluated for up to 3 and 5 years respectively. Conclusions:, Understanding of the benefits of bisphosphonate treatment can be maximised by evaluating complementary data from RCTs and observational database studies. Fracture risk reduction with bisphosphonates is shown in RCTs and in real-world clinical settings. [source] Effect of ipriflavone on pain due to recent osteoporotic vertebral crush fractureINTERNATIONAL JOURNAL OF RHEUMATIC DISEASES, Issue 1 2002Mohammad M. Rahman Abstract Aim:,Ipriflavone conserves bone mass in postmenopausal osteoporosis. Salmon calcitonin and alendronate, two other anti-resorptive drugs, have been found to have analgesic effects in osteoporotic acute vertebral fracture. This study aimed to determine if ipriflavone also possesses such an effect. Methods:,Thirty-two women with recent osteoporotic vertebral fractures were randomly assigned to ipriflavone treatment or placebo groups. Ipriflavone was given at the dose of 200 mg three times a day. Non-steroidal anti-inflammatory drugs were given ad libitum in both groups. Calcium carbonate (1 g daily) was administered to all subjects. Intensity of pain at rest, on movement and on pressure, pain rating on a 10-point visual analogue scale, degree of mobility impairment, and supplementary analgesic were assessed at the end of a 3-month period in both groups to assess the analgesic effect of ipriflavone. Results:,Fourteen subjects in the ipriflavone group and 12 in the placebo group completed the trial. After 3 months, all pain variables had decreased significantly in both groups. Intensity of pain at rest and on pressure and supplementary analgesic use were significantly lower in the ipriflavone group compared to the placebo group. Conclusion:,The study shows that ipriflavone has an analgesic adjuvant effect in acute osteoporotic vertebral fracture. [source] Effects of denosumab on bone mineral density and bone turnover in postmenopausal women transitioning from alendronate therapyJOURNAL OF BONE AND MINERAL RESEARCH, Issue 1 2010David L Kendler Abstract Patients treated with bisphosphonates for osteoporosis may discontinue or require a switch to other therapies. Denosumab binds to RANKL and is a potent inhibitor of bone resorption that has been shown to increase bone mineral density (BMD) and decrease fracture risk in postmenopausal women with osteoporosis. This was a multicenter, international, randomized, double-blind, double-dummy study in 504 postmenopausal women,,,55 years of age with a BMD T- score of ,2.0 or less and ,4.0 or more who had been receiving alendronate therapy for at least 6 months. Subjects received open-label branded alendronate 70,mg once weekly for 1 month and then were randomly assigned to either continued weekly alendronate therapy or subcutaneous denosumab 60,mg every 6 months and were followed for 12 months. Changes in BMD and biochemical markers of bone turnover were evaluated. In subjects transitioning to denosumab, total hip BMD increased by 1.90% at month 12 compared with a 1.05% increase in subjects continuing on alendronate (p,<,.0001). Significantly greater BMD gains with denosumab compared with alendronate also were achieved at 12 months at the lumbar spine, femoral neck, and 1/3 radius (all p,<,.0125). Median serum CTX levels remained near baseline in the alendronate group and were significantly decreased versus alendronate (p,<,.0001) at all time points with denosumab. Adverse events and serious adverse events were balanced between groups. No clinical hypocalcemic adverse events were reported. Transition to denosumab produced greater increases in BMD at all measured skeletal sites and a greater reduction in bone turnover than did continued alendronate with a similar safety profile in both groups. Copyright © 2010 American Society for Bone and Mineral Research [source] Comparison of the Effect of Denosumab and Alendronate on BMD and Biochemical Markers of Bone Turnover in Postmenopausal Women With Low Bone Mass: A Randomized, Blinded, Phase 3 Trial,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 1 2009Jacques P Brown Abstract Denosumab is a fully human monoclonal antibody that inhibits bone resorption by neutralizing RANKL, a key mediator of osteoclast formation, function, and survival. This phase 3, multicenter, double-blind study compared the efficacy and safety of denosumab with alendronate in postmenopausal women with low bone mass. One thousand one hundred eighty-nine postmenopausal women with a T-score , ,2.0 at the lumbar spine or total hip were randomized 1:1 to receive subcutaneous denosumab injections (60 mg every 6 mo [Q6M]) plus oral placebo weekly (n = 594) or oral alendronate weekly (70 mg) plus subcutaneous placebo injections Q6M (n = 595). Changes in BMD were assessed at the total hip, femoral neck, trochanter, lumbar spine, and one-third radius at 6 and 12 mo and in bone turnover markers at months 1, 3, 6, 9, and 12. Safety was evaluated by monitoring adverse events and laboratory values. At the total hip, denosumab significantly increased BMD compared with alendronate at month 12 (3.5% versus 2.6%; p < 0.0001). Furthermore, significantly greater increases in BMD were observed with denosumab treatment at all measured skeletal sites (12-mo treatment difference: 0.6%, femoral neck; 1.0%, trochanter; 1.1%, lumbar spine; 0.6%, one-third radius; p , 0.0002 all sites). Denosumab treatment led to significantly greater reduction of bone turnover markers compared with alendronate therapy. Adverse events and laboratory values were similar for denosumab- and alendronate-treated subjects. Denosumab showed significantly larger gains in BMD and greater reduction in bone turnover markers compared with alendronate. The overall safety profile was similar for both treatments. [source] Connexin 43 Is Required for the Anti-Apoptotic Effect of Bisphosphonates on Osteocytes and Osteoblasts In Vivo,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 11 2008Lilian I Plotkin Abstract Connexin (Cx)43 is required for inhibition of osteocyte and osteoblast apoptosis by bisphosphonates in vitro. Herein, we evaluated its requirement for the in vivo actions of bisphosphonates using mice in which Cx43 was deleted specifically from osteocytes and osteoblasts (Cx43,Ob,Ot/, mice). Effective removal of Cx43 was confirmed by the presence of the deleted form of the gene and by reduced mRNA and protein expression in osteoblastic cells and bones obtained from Cx43,Ob,Ot/, mice. The amino-bisphosphonate alendronate (2.3 ,mol/kg/d) was injected daily into 5-mo-old female mice (n = 6,11) for 31 days, starting 3 days before implantation of pellets releasing the glucocorticoid prednisolone (2.1 mg/kg/d). Cx43,Ob,Ot/, mice and their littermates (Cx43fl/,, Cx43,Ob,Ot/+, and Cx43fl/+) gained bone with similar kinetics and exhibited identical bone mass from 2 to 4.5 mo of age, indicating that Cx43 deletion from osteocytes and mature osteoblasts does not impair bone acquisition. In addition, prednisolone induced a similar increase in osteocyte and osteoblast apoptosis in Cx43,Ob,Ot/, or in control Cx43fl/, littermates. However, whereas alendronate prevented prednisolone-induced apoptosis in control Cx43fl/, mice, it was ineffective in Cx43,Ob,Ot/, mice. In contrast, alendronate inhibited glucocorticoid-induced bone loss in both type of animals, suggesting that inhibition of resorption is the predominant effect of alendronate against the early phase of glucocorticoid-induced bone loss. Taken together with earlier in vitro evidence, these findings show that Cx43 is required for the anti-apoptotic effect of bisphosphonates on osteocytes and osteoblasts. [source] Theoretical Implications of the Biomechanical Fracture ThresholdJOURNAL OF BONE AND MINERAL RESEARCH, Issue 10 2008Tony M Keaveny Abstract Because of the dichotomous nature of a bone fracture, when ,, the ratio of the applied impact force to the bone strength, is greater than a critical value,the biomechanical fracture threshold,fracture should occur. We sought to elucidate the conceptual implications of this biomechanical fracture threshold with application to hip fracture. We used data from the PaTH study, a 2-yr clinical trial in postmenopausal women treated with alendronate, PTH, or their combination. Outcomes included the force applied to the hip in a sideways fall as estimated from subject height and weight; femoral strength as determined by QCT-based finite element analysis; the load-to-strength ratio ,; and total hip areal BMD from DXA. Results indicated that those with "very low" femoral strength (<2000 N) invariably had load-to-strength ratio , values well above the theoretical biomechanical fracture threshold (, = 1), but those with "moderately low" femoral strength (2000,4000 N) displayed , values both above and below the theoretical biomechanical fracture threshold. This finding implies that the risk of a hip fracture can be high in those with only moderately low BMD because femoral strength can be low relative to fall impact forces. The observed weak correlation between areal BMD and the load-to-strength ratio , (r2 = 0.14) suggests that consideration of the biomechanical fracture threshold may improve fracture risk assessment, particularly for those in the osteopenic range. Regarding treatment effects, only those subjects having load-to-strength ratio , values within a relatively narrow "transition zone" of ±20% of the assumed biomechanical fracture threshold at baseline were predicted to change fracture status during the trial. In theory, outcomes of fracture trials may be dominated by the responses of those within the "transition zone" at baseline, and treatment benefits in terms of fracture efficacy may depend the patient's baseline status with respect to the biomechanical fracture threshold. We conclude that consideration of the theoretical implications of the biomechanical fracture threshold may lead to new insights and advances in the assessment and treatment of osteoporosis. [source] Effects of PTH and Alendronate on Type I Collagen Isomerization in Postmenopausal Women With Osteoporosis: The PaTH Study,,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 9 2008Patrick Garnero Abstract Fracture efficacy of PTH and alendronate (ALN) is only partly explained by changes in BMD, and bone collagen properties have been suggested to play a role. We analyzed the effects of PTH(1,84) and ALN on urinary ,,/,, CTX ratio, a marker of type I collagen isomerization and maturation in postmenopausal women with osteoporosis. In the first year of the previously published PaTH study, postmenopausal women with osteoporosis were assigned to PTH(1,84) (100 ,g/d; n = 119), ALN (10 mg/d; n = 60), or PTH and ALN together (n = 59). We analyzed patients on ALN alone (n = 60) and a similar number of patients assigned to PTH alone (n = 63). During the second year, women on PTH in the first year were reallocated to placebo (n = 31) or ALN (n = 32) and women with ALN continued on ALN. During the first year, there was no significant change in ,,/,, CTX ratio with PTH or ALN. At 24 mo, there was a marked increase of the ,,/,, CTX ratio in women who had received PTH during the first year, followed by a second year of placebo (median: +45.5, p < 0.001) or ALN (+55.2%, p < 0.001). Conversely, the ,,/,, CTX ratio only slightly increased (+16%, p < 0.05) after 2 yr of continued ALN. In conclusion, treatment with PTH(1,84) for 1 yr followed by 1 yr of placebo or ALN may be associated with decreased type I collagen isomerization. The influence of these biochemical changes of type I collagen on bone fracture resistance remains to be studied. [source] Long-Term Protective Effects of Zoledronic Acid on Cancellous and Cortical Bone in the Ovariectomized Rat,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 4 2008Jürg A Gasser PhD Abstract Current bisphosphonate therapies effectively prevent bone loss in postmenopausal women. We studied the effect of a single intravenous dose of ZOL in ovariectomized rats. Protection from bone loss was dose dependent, lasting for up to 32 weeks, supporting the rationale for an annual intravenous dosing regimen of ZOL for treatment of postmenopausal osteoporosis. Introduction: Once-yearly dosing with zoledronic acid (ZOL) 5 mg can increase BMD and reduce fracture rate in postmenopausal women with low BMD. The primary objective of this study was to determine the duration of bone protective effects of a single dose of ZOL in ovariectomized rats, an animal model of postmenopausal osteopenia. Secondary objectives were to determine the effects on bone turnover and mechanical properties. Materials and Methods: Female Wistar rats (10 per group) received single intravenous doses of ZOL 0.8, 4, 20, 100, or 500 ,g/kg, alendronate 200 ,g/kg, or isotonic saline 4 days before bilateral ovariectomy. Sham-operated controls were pretreated with saline. Mass and density of cancellous and cortical bone (pQCT) were measured at 4-wk intervals for 32 wk. Bone architecture (,CT), bone formation dynamics (fluorochrome label-based histomorphometry), and biomechanical strength in compression testing were also assessed at 32 wk. Results: Ovariectomy-associated BMD loss was significantly attenuated for 32 wk by ZOL ,4 ,g/kg for total BMD, ZOL ,20 ,g/kg for cortical BMD, and ZOL ,4 ,g/kg for cancellous BMD (p < 0.01 versus ovariectomized controls). Alendronate 200 ,g/kg was of equivalent potency to ZOL 20 ,g/kg. Ovariectomy-associated decreases in trabecular architectural parameters were dose-dependently attenuated by ZOL. Alendronate 200 ,g/kg was equivalent to ZOL 20 ,g/kg. The bone resorption marker TRACP5b indicated transient suppression of elevated osteoclast activity by ZOL relative to OVX-rats even at the lowest dose of 0.8 ,g/kg, whereas at 100,500 ,g/kg, the effect was significant relative to the OVX control for the entire duration of the study of 32 wk. Bone formation parameters were not significantly affected by ZOL 20 ,g/kg but were significantly reduced by ZOL 100,500 ,g/kg. Alendronate 200 ,g/kg was equivalent to ZOL 100 ,g/kg. ZOL produced dose-related improvements in bone strength parameters after ovariectomy. Alendronate 200 ,g/kg was of similar potency to ZOL 20 ,g/kg. Conclusions: The duration and magnitude of the bone-protecting effect of a single intravenous dose of ZOL in ovariectomized rats is dose dependent and lasts for up to 32 wk. Compared with alendronate, ZOL shows 10-fold higher potency in preventing bone loss. These data support the use of an annual intravenous ZOL dosing regimen for the treatment of osteoporosis. [source] Pretreatment Levels of Bone Turnover and the Antifracture Efficacy of Alendronate: The Fracture Intervention TrialJOURNAL OF BONE AND MINERAL RESEARCH, Issue 2 2006Douglas C Bauer MD Abstract The influence of pretreatment bone turnover on alendronate efficacy is not known. In the FIT, we examined the effect of pretreatment bone turnover on the antifracture efficacy of daily alendronate given to postmenopausal women. The nonspine fracture efficacy of alendronate was significantly greater among both osteoporotic and nonosteoporotic women with higher baseline levels of the bone formation marker PINP. Introduction: Previous trials have shown that high bone turnover is associated with greater increases in BMD among bisphosphonate-treated women. The influence of pretreatment bone turnover levels on antifracture efficacy has not been well studied. Materials and Methods: We randomized women 55,80 years of age with femoral neck BMD T scores , ,1.6 to alendronate (ALN), 5,10 mg/day (n = 3105), or placebo (PBO; n = 3081). At baseline, 3495 women were osteoporotic (femoral neck BMD T score , ,2.5 or prevalent vertebral fracture), and 2689 were not osteoporotic (BMD T score > ,2.5 and no prevalent vertebral fracture). Pretreatment levels of bone-specific alkaline phosphatase (BSALP), N-terminal propeptide of type 1 collagen (PINP), and C-terminal cross-linked telopeptide of type 1 collagen (sCTx) were measured in all participants using archived serum (20% fasting). The risk of incident spine and nonspine fracture was compared in ALN- and PBO-treated subjects stratified into tertiles of baseline bone marker level. Results and Conclusions: During a mean follow-up of 3.2 years, 492 nonspine and 294 morphometric vertebral fractures were documented. Compared with placebo, the reduction in nonspine fractures with ALN treatment differed significantly among those with low, intermediate, and high pretreatment levels of PINP levels (p = 0.03 for trend). For example, among osteoporotic women in the lowest tertile of pretreatment PINP (<41.6 ng/ml), the ALN versus PBO relative hazard for nonspine fracture was 0.88 (95% CI: 0.65, 1.21) compared with a relative hazard of 0.54 (95% CI: 0.39, 0.74) among those in the highest tertile of PINP (>56.8 ng/ml). Results were similar among women without osteoporosis at baseline. Although they did not reach statistical significance, similar trends were observed with baseline levels of BSALP. Conversely, spine fracture treatment efficacy among osteoporotic women did not differ significantly according to pretreatment marker levels. Spine fracture treatment efficacy among nonosteoporotic women was related to baseline BSALP (p = 0.05 for trend). In summary, alendronate nonspine fracture efficacy is greater among both osteoporotic and nonosteoporotic women with high pretreatment PINP. If confirmed in other studies, these findings suggest that bisphosphonate treatment may be most effective in women with elevated bone turnover. [source] Differential Effects of Teriparatide and Alendronate on Bone Remodeling in Postmenopausal Women Assessed by Histomorphometric Parameters,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 7 2005Monique Arlot MD Abstract An 18-month randomized double-blind study was conducted in postmenopausal women with osteoporosis to compare the effects of once-daily teriparatide 20 ,g 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 ,g 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. [source] | |||||||||||||||||||||||||||||||