The use of etidronate and calcium versus calcium alone in the treatment of postmenopausal osteopenia: results of three years of treatment. Effects of cyclical etidronate therapy on bone loss in early postmenopausal women who are not undergoing hormonal replacement therapy. Intermittent cyclical etidronate treatment of postmenopausal osteoporosis. Prevention of early postmenopausal bone loss with cyclical etidronate therapy (a double-blind, placebo-controlled study and 1-year follow-up) Effect of intermittent cyclical treatment with etidronate disodium (HEBP) and calcium plus alphacalcidol in postmenopausal osteoporosis. Effect of intermittent cyclical etidronate therapy on bone mass and fracture rate in women with postmenopausal osteoporosis. Comparative efficacy of hormone replacement therapy, etidronate, calcitonin, alfacalcidol, and vitamin K in postmenopausal women with osteoporosis: The Yamaguchi Osteoporosis Prevention Study. The effect of a modified etidronate cyclical regimen on postmenopausal osteoporosis: a four-year study. Coherence therapy does not prevent axial bone loss in osteoporotic women: a preliminary comparative study. A four-year randomized controlled trial of hormone replacement and bisphosphonate, alone or in combination, in women with postmenopausal osteoporosis. The prevention of early postmenopausal bone loss by cyclical etidronate therapy: a 2-year, double-blind, placebo-controlled study.
The purpose of this open, prospective, controlled, randomized trial was to study the effect of intermittent, cyclic etidronate on the bone mass of osteoporotic postmenopausal women with or without fractures. Eligible subjects were asymptomatic women less than 75 years old who had been amenorrhoeic for at least 1 year. Those with secondary osteoporosis were excluded. Subjects also had to be ambulant with a bone mineral density (BMD) of the lumbar spine > 1 SD below that of age matched controls (Z-score < -1 SD). Eighty patients were enrolled, of whom 65 were recruited through a screening programme conducted in the practices of two general practitioners. The remaining patients were from other referrals. The subjects were randomized to two groups of 40 women. Treatment regimens were as follows. The etidronate group was treated with etidronate 400 mg once daily for 14 days followed by 76 days of 500 mg of elementary calcium once daily; this cycle was repeated every 3 months. The calcium group took 500 mg of elementary calcium once daily. The groups were not different in age, height, weight, time since menopause. BMD at baseline and prevalent vertebral fractures. In 50 patients (28 in the etidronate group and 22 in the calcium group) no vertebral fractures were present (67%). Sixty-four patients (35 in the etidronate group and 29 in the calcium group) completed the 3 years of the study. In the etidronate group the mean BMD of the lumbar spine, femoral neck, trochanter and Ward's triangle increased by 5.7%, 1.4%, 7.1% and 10.9% from baseline values respectively (p < 0.05 at all sites except for the femoral neck). In the calcium group no significant changes from baseline were found at any time point at any site after 3 years, except for the femoral neck, where BMD at 156 weeks decreased significantly by 3% (p < 0.003). In 3 patients, all in the calcium group, six new fractures were found. There were no serious adverse effects. We conclude that intermittent, cyclic treatment with etidronate causes a significant increase in the BMD of the lumbar spine and the proximal femur in osteopenic postmenopausal women, and that treatment is safe and has no serious adverse effects. This study was carried out to investigate the effectiveness and tolerability of cyclical etidronate therapy in the prevention of bone loss occurring in early postmenopausal women who are not undergoing hormone replacement therapy (HRT). A total of 109 Caucasian women aged 45-60 years were treated with etidronate 400 mg/day or placebo for 14 days followed by calcium supplementation 500 mg/day for 77 days. Ninety-one women completed the 2 years of the study. After 2 years, the estimated difference between the two groups as regards lumbar spine bone mineral density (BMD) was 2.53% (SEM 1.07%; p = 0.01); BMD of the hip and wrist were not significantly different between treatment groups. A clear reduction in bone turnover was obtained as evidenced by a significant decrease in serum alkaline phosphatase level and in urinary N-telopeptide/ creatinine ratio in the etidronate group; the difference between the two groups was -12% +/- 3.2% for serum alkaline phosphatase level (p = 0.019) and -22.9% +/- 13.7% for the urinary N-telopeptide/creatinine ratio (p = 0.047). There was no statistically significant difference between the two groups in terms of the serum osteocalcin levels and urinary hydroxyproline/ creatinine and calcium/creatinine ratios. Etidronate was generally well tolerated and its adverse event profile was similar to that of placebo. The results of this study indicate that cyclic etidronate therapy can prevent trabecular bone loss, with no deleterious effect on cortical bone, in the first 5 years of menopause and that it has a very high safety margin. To determine the effects of etidronate (a bisphosphonate that inhibits osteoclast-mediated bone resorption) in the treatment of postmenopausal osteoporosis, we conducted a prospective, two-year, double-blind, placebo-controlled, multicenter study in 429 women who had one to four vertebral compression fractures plus radiographic evidence of osteopenia.
                The patients were randomly assigned to treatment with phosphate (1.0 g) or placebo twice daily on days 1 through 3, etidronate (400 mg) or placebo daily on days 4 through 17, and supplemental calcium (500 mg) daily on days 18 through 91 (group 1, placebo and placebo; group 2, phosphate and placebo; group 3, placebo and etidronate; and group 4, phosphate and etidronate). The treatment cycles were repeated eight times. The bone density of the spine was measured by dual-photon absorptiometry, and the rates of new vertebral fractures were determined from sequential radiographs.
                After two years, the patients receiving etidronate (groups 3 and 4) had significant increases in their mean (+/- SE) spinal bone density (4.2 +/- 0.8 percent and 5.2 +/- 0.7 percent, respectively; P less than 0.017). The rate of new vertebral fractures was reduced by half in the etidronate-treated patients (groups 3 and 4 combined) as compared with the patients who did not receive etidronate (groups 1 and 2 combined) (29.5 vs. 62.9 fractures per 1000 patient-years; P = 0.043); the effect of treatment was most striking in the subgroup of patients with the lowest spinal bone mineral density at base line, in whom fracture rates were reduced by two thirds (42.3 vs. 132.7 fractures per 1000 patient-years; P = 0.004). The addition of phosphate provided no apparent benefit. There were no significant adverse effects of treatment.
                Intermittent cyclical therapy with etidronate for two years significantly increases spinal bone mass and reduces the incidence of new vertebral fractures in women with postmenopausal osteoporosis. The objective of the study was to evaluate the effects of cyclical therapy with etidronate and calcium on spinal and femoral bone loss in the early post menopausal period. Fifty-four women, 53 +/- 2.8 yr old (mean +/- SD) and 2.3 +/- 1.3 yr post menopause received oral doses of either 400 mg/day etidronate for 2 weeks followed by 500 mg/day elemental calcium for 11 weeks, or placebo for 14 days followed by calcium for 11 weeks, repeated over a total of 24 months. A statistically significant increase in spinal bone mineral density (BMD) was observed after 6 months in the etidronate group. At 2 yr, the mean treatment differences in spinal and femoral neck BMD were +2.93% (P < 0.02) and 2.02% (P < 0.03), respectively. Serum osteocalcin and urinary crossLaps/creatinine excretion were decreased significantly by etidronate. Etidronate was well tolerated with a safety profile similar to that of placebo. Thirty-seven women participated in a 1-yr open-label follow-up study. Twelve months after treatment withdrawal, spinal BMD in the former etidronate group decreased by 1.43% and serum osteocalcin and urinary crossLaps returned to pretreatment values. In conclusion, cyclical etidronate is an effective therapy for the prevention of both trabecular and cortical bone loss in the early menopause and has a good safety profile. We evaluated intermittent cyclical treatment with etidronate disodium (HEBP) and calcium plus alphacalcidol in postmenopausal osteoporosis, with special reference to bone mineral density (BMD) and prevention of spinal fracture. The patients were 40 women, over 50 years of age, with lumbo-dorsal pain and low BMD (less than 0.70 g/cm(2)), measured by dual-energy X-ray absorptiometry (DXA). The patients were randomly assigned to two groups. The first group (HEBP) received 200 mg of HEBP per day for 2 weeks, followed by 2 g calcium lactate and 0.5 microg alphacalcidol per day for the next 10 weeks. This 12-week cycle was repeated eight times for 2 years. The second group (Ca. D) received 2 g calcium lactate and 0.5 microg alphacalcidol per day for 2 years. Lumbar BMD was measured before the treatment and every 6 months during the treatment until 24 months, and changes were evaluated. The number of fractured vertebrae was counted on X-ray films before treatment and at the final assessment. After 6 months of treatment, a significant and continuous increase in BMD was observed in the HEBP group. Moreover, the percentage of patients with new vertebral compression fractures in the HEBP group was one-tenth of that in the Ca. D group. These results suggest that intermittent cyclical treatment with HEBP and calcium plus alphacalcidol may be effective for increasing BMD and preventing fractures in postmenopausal osteoporosis. Progressive bone loss in osteoporosis results from bone resorption in excess of bone formation. We conducted a double-blind study in 66 women with postmenopausal osteoporosis of therapy with etidronate, a diphosphonate compound that reduces bone resorption by inhibiting osteoclastic activity. The patients were randomly assigned in equal numbers to receive oral etidronate (400 mg per day) or placebo for 2 weeks, followed by a 13-week period in which no drugs were given. This sequence was repeated 10 times, for a total of 150 weeks. Daily oral supplementation with calcium and vitamin D was given throughout the study to both groups. Vertebral bone mineral content was measured by dual-photon absorptiometry; spinal radiographs were assessed to identify new vertebral fractures. Vertebral bone mineral content increased significantly (P less than 0.01) after 150 weeks of etidronate therapy (5.3 percent; 95 percent confidence interval, 2.0 to 8.6; n = 20) but decreased with placebo (-2.7 percent; 95 percent confidence interval, -7.3 to 1.9; n = 20). The difference between groups was 8.0 percentage points (P less than 0.01; 95 percent confidence interval, 2.4 to 13.6). The rates of fracture were significantly different for the period from week 60 to week 150 between the etidronate and placebo groups (6 vs. 54 fractures per 100 patient-years; P = 0.023). No adverse clinical, biochemical, or bone histomorphometric effects of treatment were observed. We conclude that at the end of nearly three years, etidronate therapy for postmenopausal osteoporosis results in significant increases in vertebral bone mineral content and, after approximately one year of treatment, a significant decrease in the rate of new vertebral fractures. To assess the comparative effectiveness of several medications on bone mineral density, biochemical bone markers, and the incidence of vertebral fractures in postmenopausal women with osteoporosis.
                A total of 396 postmenopausal women, aged 50 to 75 years, were allocated randomly to six equal-sized groups: hormone replacement therapy, etidronate, eel calcitonin, alfacalcidol, vitamin K (menatetrenone), or control (no treatment). Thoracic and lumbar spine radiographs, bone mineral density at the distal radius, and markers of bone turnover were assessed at baseline and every 3 months during the 2-year study.
                Compared with baseline, the 2-year mean changes in bone mineral density were 2.0% for hormone replacement therapy, -0.5% for etidronate, 1.6% for calcitonin, -3.6% for alfacalcidol, -1.9% for vitamin K, and -3.3% for control. Seventeen (26%) of the 66 control patients developed new vertebral fractures. Compared with controls, the relative risks of vertebral fracture were 0.35 (95% confidence interval [CI]: 0.14 to 0.83) for hormone replacement therapy, 0.40 (95% CI: 0.17 to 0.92) for etidronate, 0.41 (95% CI: 0.17 to 0.93) for calcitonin, 0.56 (95% CI: 0.26 to 1.12) for alfacalcidol, and 0.44 (95% CI: 0.20 to 0.99) for vitamin K.
                We observed significant reductions in the incidence of vertebral fractures with hormone replacement therapy, etidronate, and calcitonin, and significant improvements in bone mineral density with hormone replacement therapy and calcitonin. To develop an improved treatment schedule for osteoporosis, a study was undertaken in 100 postmenopausal women using a modified ADFR 90-day cyclical regimen with etidronate. After one year of treatment, the etidronate-treated group showed a significant increase in bone density of the spine, which continued over the following 2 years of treatment and remained stable during the fourth year. In contrast, in the non-etidronate group, bone density decreased significantly after four years. In addition, the fracture rate was significantly lower in the etidronate group than in the non-etidronate group. Side effects were minimal in both groups and no serious adverse reactions were reported. In conclusion, it appears that a cyclical regimen using 1,25-dihydroxyvitamin D3, etidronate and calcium increases bone mass and reduces fractures with no significant side effects, thus making a useful contribution in the treatment of postmenopausal osteoporosis. Coherence therapy, also known as ADFR (activate, depress, free, repeat) therapy, has been proposed as a new form of treatment for osteoporosis. We compared the effects of this therapy with those of gonadal steroid and calcium and of calcium alone in 93 osteoporotic women. Thirty women were treated for 1 yr with ADFR, in the form of K-phosphate (1.5 g/day), for 3 days followed by etidronate, (400 mg/day) for 14 days, followed by 8 weeks of neither drug, plus continuous calcium carbonate therapy (1 g/day). Thirty-six women received conjugated estrogens (0.625 mg/day) for 25 days/month plus medroxyprogesterone acetate (10 mg/day) for 10 days/month and calcium, while 27 women received calcium carbonate (500 mg, twice daily). Sixteen women in the ADFR group, 15 in the calcium group, and 19 in the hormone-calcium group completed 2 yrs of treatment. Spinal bone mineral density was measured by single energy quantitative computerized tomography (QCT) and in the proximal and distal radius by single energy photon absorptiometry. The 3 groups were similar in age, initial bone mass, years since menopause, and dietary calcium intake. After 2 yrs, the mean women in the ADFR therapy group had a mean reduction of 8.0% in spinal QCT (P less than 0.05), and no change in proximal radius mineral content/bone width (BMC), and distal radius BMC. The group treated with calcium only had a decrease of 3.8% in QCT (P less than 0.05), of 5.6% in proximal BMC (P less than 0.05), and of 4.9% in distal BMC (P less than 0.05). The group treated with hormonal replacement and calcium had no change in any of their measurements. The relative bone loss in the spine at the end of the study was greater in the ADFR group than in the hormone-calcium group (P less than 0.05). Bone loss in the calcium group was slightly but not significantly greater than that in the hormone group and lower than that in the ADFR group. In conclusion, these preliminary results indicate that the ADFR regimen using phosphate and etidronate in doses of 1.5 g/day for 3 days and 400 mg/day for 14 days, respectively, is not as effective as hormonal replacement in preventing trabecular bone loss in osteoporosis, nor it is any more effective than calcium supplementation alone. Hormone replacement therapy (HRT) with estrogen and treatment with bisphosphonates have been shown to increase bone mineral density (BMD) in postmenopausal women. This 4-year prospective randomized study was carried out to assess the effectiveness of the combined HRT plus etidronate on BMD in postmenopausal women with established osteoporosis.
                Seventy-two postmenopausal women (mean age 64.9+/-0.5 years) attending metabolic bone disease outpatient clinics with established osteoporosis were randomly allocated into one of four treatment groups and monitored for 4 years. All patients enrolled in this study including the control group (n=18) received 1.0 g elemental calcium and 400 units vitamin D per day. The HRT group (n=18) received cyclical estrogen and progesterone; the etidronate group (n=17) received intermittent cyclical etidronate; and the combined therapy group (n=19) received both HRT and etidronate. BMD was measured in the lumbar spine and the hip before treatment and at 2 and 4 years after treatment. Changes in height were recorded, and the occurrence of new vertebral fractures were documented in comparison with the baseline radiographic evaluation. In 40 patients (10 patients per group), analysis of bone histomorphometry was carried out after 4 years of treatment.
                In patients who received the combined therapy, BMD increased in the lumbar spine by 10.4% (P <0.001) and in the hip by 7.0% (P <0.001) at 4 years. For patients treated with ICE, these increases were 7.3% (P <0.001) and 0.9% (P <0.05), and with HRT, the increases were 7.0% (P <0.001) and 4.8% (P <0.01) in the vertebrae and femora, respectively. The group treated with calcium and vitamin D lost 2.5% (P <0.05) and 4.4% (P <0.01) of BMD in the vertebrae and femora, respectively, after 4 years. Patients who received combined therapy had significantly higher BMD in both the vertebrae and in the femora (P <0.05) in comparison with patients who were treated with HRT or etidronate alone after 4 years. In comparison with patients in the control group, there was a trend toward a lower rate of new vertebral fractures in the treatment groups. Height loss was significantly less in all three active treatment groups (HRT [P <0.001], etidronate [P <0.02], and combined therapy group [P <0.0001]), in comparison with the control group. The combined therapy group did not have a significant height loss, in comparison with the HRT (P <0.02) and the etidronate (P <0.001) groups. None of the patients had histomorphometric evidence of osteomalacia.
                This 4-year randomized study showed an additive effect of etidronate and HRT on hip and spine BMD in postmenopausal women with established osteoporosis. To determine whether intermittent cyclical etidronate therapy can prevent early postmenopausal bone loss.
                This was a 2-year outpatient, randomized, double-blind, placebo-controlled clinical trial. The subjects were 152 women within 1 to 10 years of the onset of menopause and bone mineral density (BMD) between 0 and -2 SD of normal values for a 50 year old woman. The women were stratified according to years since the menopause (1 to 3 years: n = 43; 4 to 6 years: n = 53; 7 to 10 years: n = 56). Measurements of lumbar spine, proximal femur and total body BMD were performed at baseline, 12 and 24 months by dual x-ray absorptiometry. Biochemical markers of bone resorption and bone formation were measured on the same visits.
                One hundred thirty-five subjects completed the study. Mean percentage change in lumbar spine BMD (and SEM) at 2 years was +2.14 (0.47)% in the etidronate group and -1.72 (0.41)% in the placebo group. Results for lumbar spine BMD in the treated and control groups stratified according to years since the menopause were: 1 to 3 years: +1.73 (0.84)% and -3.30 (0.70)%; 4 to 6 years: +1.37 (0.88)% and -1.80 (0.61)%; 7 to 10 years: +3.42 (0.61)% and -0.38 (0.70)%. The effect of both treatment group and menopausal stratum were highly statistically significant for lumbar spine and total body BMD. Treatment group, but not stratum, was significant for BMD in the proximal femur. Markers of bone resorption and bone formation were significantly decreased by etidronate therapy.
                Cyclical etidronate prevents bone loss in the total skeleton and at the clinically relevant sites (spine and proximal femur) even in the early postmenopausal years. Hence, it appears to be an effective and safe nonhormonal therapy in postmenopausal women with normal or low BMD.
Etidronate, at 400 mg per day, demonstrated a statistically significant and clinically important benefit in the secondary prevention of vertebral fractures. No statistically significant reductions in vertebral fractures were observed when it was used for primary prevention. In addition, no statistically significant reductions in non-vertebral, hip, or wrist fractures were found, regardless of whether etidronate was used for primary or secondary prevention. The level of evidence for all outcomes is Silver (www.cochranemsk.org.)