Risedronate Increases Bone Density and Reduces Vertebral Fracture Risk Within One Year in Men on Corticosteroid Therapy

Limited information is available on the effect of bisphosphonates in men receiving corticosteroid therapy. We studied 184 men among the patients enrolled in two, double-blind, placebo-controlled, 1-year studies with similar protocols. The studies evaluated the effects of risedronate in patients beginning corticosteroid treatment at a dose of at least 7.5 mg per day of prednisone or equivalent (prevention study) or continuing long-term treatment of corticosteroid at that dose (treatment study). The men received either placebo or risedronate (2.5 mg or 5 mg) daily, along with calcium supplementation (500-1000 mg). Endpoints included differences in bone mineral density (BMD) at the lumbar spine, femoral neck, and femoral trochanter, assessment of vertebral fractures, changes in biochemical markers of bone turnover, and overall safety. In the treatment study, risedronate 5 mg significantly (P < 0.01) increased lumbar spine BMD by 4.8% at the lumbar spine, 2.1% at the femoral neck, and 2.6% at the femoral trochanter compared with baseline values. In the prevention study, bone loss was prevented with risedronate 5 mg; in the placebo group, BMD decreased significantly (P < 0.01) by 3.4%, 3.3%, and 3.4% in the lumbar spine, femoral neck, and trochanter, respectively, at 1 year. The differences between risedronate 5 mg and placebo groups were significant at all skeletal sites in the prevention study (P < 0.01) and at the lumbar spine in the treatment study (P < 0.001). The 2.5 mg dose also had a positive effect on BMD, although of a lesser magnitude than the 5 mg dose. When the data from the two studies were combined, the incidence of vertebral fractures decreased 82.4% (95% confidence interval, 36.6%-95.1%) in the pooled risedronate groups compared with placebo (P = 0.008). Risedronate was well tolerated in men, with a similar incidence of upper gastrointestinal adverse events in the placebo and treatment groups. Daily treatment with risedronate increases bone density and decreases vertebral fracture risk within 1 year in men receiving corticosteroid therapy.     

Efficacy and safety of daily risedronate in the treatment of corticosteroid-induced osteoporosis in men and women: a randomized trial. European Corticosteroid-Induced Osteoporosis Treatment Study.

Long-term use of high-dose corticosteroids often results in bone loss, which may lead to osteoporosis-related fractures. This was a multicenter, double-blind study in which 290 ambulatory men and women receiving high-dose oral corticosteroid therapy (prednisone > or = 7.5 mg/day or equivalent) for 6 or more months were randomized to receive placebo, risedronate 2.5 mg/day, or risedronate 5 mg/day for 12 months. All patients received calcium 1 g and vitamin D 400 IU daily. The primary endpoint was lumbar spine bone mineral density (BMD) at month 12. Additional measurements included BMD at the femoral neck and trochanter and the incidence of vertebral fractures. Overall, there were statistically significant treatment effects on BMD at 12 months at the lumbar spine (p < 0.001), femoral neck (p = 0.004), and trochanter (p = 0.010). Risedronate 5 mg increased BMD at 12 months by a mean (SEM) of 2.9% (0.49%) at the lumbar spine, 1.8% (0.46%) at the femoral neck, and 2.4% (0.54%) at the trochanter, whereas BMD was maintained only in the control group. Although not powered to show fracture efficacy, we observed a reduction in the incidence of vertebral fractures of 70% in the combined risedronate treatment groups, relative to placebo (p = 0.042). Risedronate was well tolerated, had a good safety profile, and was not associated with gastrointestinal adverse events. We conclude that risedronate increases BMD and potentially reduces the incidence of vertebral fractures in patients with corticosteroid-induced osteoporosis.     

Prevention of Bone Loss with Risedronate in Glucocorticoid-Treated Rheumatoid Arthritis Patients

The aim of the study was to assess risedronate’s effect on bone mineral density in postmenopausal women with rheumatoid arthritis receiving glucocorticoids. We carried out a two center, 2 year, double-masked, placebo-controlled trial with a third year of nontreatment follow-up. We studied 120 women requiring long-term glucocorticoid therapy at >2.5 mg/day prednisolone randomized to treatment with daily placebo; daily 2.5 mg risedronate; or cyclical 15 mg risedronate (2 out of 12 weeks). At 97 weeks, bone mineral density was maintained at the lumbar spine (+1.4%) and trochanter (+0.4%) in the daily 2.5 mg risedronate group, while significant bone loss occurred in the placebo group (–1.6%, p= 0.03; and 4.0%, p<0.005, respectively). At the femoral neck, there was a nonsignificant bone loss in the daily 2.5 mg risedronate group (–1.0%) while in the placebo group bone mass decreased significantly (–3.6%, p<0.001). The difference between placebo and daily 2.5 mg risedronate groups was significant at the lumbar spine (p= 0.009) and trochanter (p= 0.02) but did not reach statistical significance at the femoral neck. Although not significantly different from placebo at the lumbar spine, the overall effect of the cyclical regimen was similar to that of the daily 2.5 mg risedronate regimen. Treatment withdrawal led to bone loss in the risedronate groups that was significant at the lumbar spine. A similar number of patients experienced adverse events (including upper gastrointestinal events) across treatment groups and risedronate was generally well tolerated. Thus risedronate preserves bone mass in postmenopausal women with rheumatoid arthritis receiving glucocorticoids while patients receiving a placebo have significant bone loss. Received: 2 June 1999 / Accepted: 29 September 1999     

Risedronate Reduces the Risk of First Vertebral Fracture in Osteoporotic Women

Risedronate treatment reduces the risk of vertebral fracture in women with existing vertebral fractures, but its efficacy in prevention of the first vertebral fracture in women with osteoporosis but without vertebral fractures has not been determined. We examined the risk of first vertebral fracture in postmenopausal women who were enrolled in four placebo-controlled clinical trials of risedronate and who had low lumbar spine bone mineral density (BMD) (mean T-score =–3.3) and no vertebral fractures at baseline. Subjects received risedronate 5 mg (n= 328) or placebo (n= 312) daily for up to 3 years; all subjects were given calcium (1000 mg daily), as well as vitamin D supplementation (up to 500 IU daily) if baseline serum 25-hydroxyvitamin D levels were low. The incidence of first vertebral fracture was 9.4% in the women treated with placebo and 2.6% in those treated with risedronate 5 mg (risk reduction of 75%, 95% confidence interval 37% to 90%; P= 0.002). The number of patients who would need to be treated to prevent one new vertebral fracture is 15. When subjects were stratified by age, similar significant reductions were observed in patients with a mean age of 64 years (risk reduction of 70%, 95% CI 8% to 90%; P= 0.030) and in those with a mean age of 76 years (risk reduction of 80%, 95% CI 7% to 96%; P= 0.024). Risedronate treatment therefore significantly reduces the risk of first vertebral fracture in postmenopausal women with osteoporosis, with a similar magnitude of effect early and late after the menopause. Received: 12 September 2001 / Accepted: 11 December 2001     

The Efficacy and Tolerability of Alendronate in Postmenopausal Osteoporotic Chinese Women: A Randomized Placebo-Controlled Study

Osteoporosis is a growing health problem in Asian women and it is expected that half of the world's hip fractures will occur in Asia in 50 years' time. As the use of hormonal replacement therapy (HRT) is extremely low in postmenopausal Asian women, nonhormonal agents will be more acceptable for the treatment and prevention of osteoporosis. The efficacy, tolerability, and acceptability of alendronate, an amino-bisphosphonate, for Asian women was evaluated in 70 osteoporotic southern Chinese women in a prospective, randomized, double-blind study. The subjects were randomized to receive either alendronate 10 mg daily or placebo, plus calcium supplementation 500 mg daily. The baseline L 1–4 and hip bone mineral density (BMD) were similar between both groups. At the end of 1 year, there was an increase of 5.8% in the lumbar spine BMD and 3.4% at the total hip with alendronate treatment when compared with baseline values (P < 0.001). Alendronate treatment for 1 year resulted in significant improvement in BMD at all sites measured when compared with placebo. There was also marked reduction in serum alkaline phosphatase (ALP) and urinary n-telopeptide (NTx) in the alendronate group when compared with the placebo group (ALP 25% versus 2%, NTx 75% versus 14%, both P < 0.005). The changes in ALP and NTx at 6 and 12 months correlated with the change in BMD at all sites measured at 1 year (P all <0.05). Alendronate was well tolerated and accepted, although two cases of gastric ulcer were reported. We conclude that alendronate is an effective and well-accepted agent for the treatment of osteoporosis in Asian women. Received: 30 September 1999 / Accepted 6 April 2000     

Cyclical Etidronate Therapy for Prevention of Postmenopausal Bone Loss: A 1-Year Open-Label Follow-Up Study

The objective of this study was to evaluate whether the pharmacological activity of cyclical etidronate therapy is sustained beyond the dosing period. A group of 121 postmenopausal women who had completed a 2-year, double-blind, placebo-controlled parallel study with etidronate or placebo (400 mg/day for 14 days every 3 months) and calcium agreed to participate in a 1-year open-label follow-up study to evaluate the effect of discontinuing etidronate treatment. Fifty-nine subjects in the former etidronate group and 62 in the placebo group received 500 mg/day of elemental calcium; 54/59 and 58/62 subjects, respectively, completed the study. Outcomes of the study were bone mineral density (BMD), measured by dual energy X-ray absorptiometry (DXA), and biochemical markers of bone turnover (urinary deoxypyridinoline/creatinine and serum osteocalcin). To determine whether there was a residual effect of previous therapy we compared mean percentage changes from baseline (year 0) to year 3 for both spinal and femoral neck BMD and markers of bone turnover in the former cyclical etidronate and placebo groups. To evaluate the carryover effect of treatment we compared the percent change from year 2 to year 3 for the same variables. Mean percentage change (SEM) from year 2 to year 3 for spinal BMD in the former cyclical etidronate group was −2.87% (0.48%) versus −0.99% (0.36%) in the placebo group (P= 0.0022). In the femoral neck, the BMD changes were −0.86% (0.42%) versus −1.01% (0.41%) (NS). Biochemical markers increased within 6 months toward baseline levels. Mean percentage changes from baseline (year 0) in both spinal and femoral neck BMD were significantly different between groups 1 year after treatment discontinuation. No differences between groups were maintained in deoxypyridinoline and osteocalcin. It is concluded that following withdrawal of cyclical etidronate therapy bone loss resumes at a normal and moderately accelerated rate in the proximal femur and lumbar spine, respectively. A positive effect on BMD at both cortical and trabecular sites is maintained for 1 year after treatment withdrawal. Received: 8 May 1999 / Accepted: 10 December 1999     

Randomized Trial of the Effects of Risedronate on Vertebral Fractures in Women with Established Postmenopausal Osteoporosis

The purpose of this randomized, double-masked, placebo-controlled study was to determine the efficacy and safety of risedronate in the prevention of vertebral fractures in postmenopausal women with established osteoporosis. The study was conducted at 80 study centers in Europe and Australia. Postmenopausal women (n= 1226) with two or more prevalent vertebral fractures received risedronate 2.5 or 5 mg/day or placebo; all subjects also received elemental calcium 1000 mg/day, and up to 500 IU/day vitamin D if baseline levels were low. The study duration was 3 years; however, the 2.5 mg group was discontinued by protocol amendment after 2 years. Lateral spinal radiographs were taken annually for assessment of vertebral fractures, and bone mineral density was measured by dual-energy X-ray absorptiometry at 6-month intervals. Risedronate 5 mg reduced the risk of new vertebral fractures by 49% over 3 years compared with control (p<0.001). A significant reduction of 61% was seen within the first year (p= 0.001). The fracture reduction with risedronate 2.5 mg was similar to that in the 5 mg group over 2 years. The risk of nonvertebral fractures was reduced by 33% compared with control over 3 years (p= 0.06). Risedronate significantly increased bone mineral density at the spine and hip within 6 months. The adverse-event profile of risedronate, including gastrointestinal adverse events, was similar to that of control. Risedronate 5 mg provides effective and well-tolerated therapy for severe postmenopausal osteoporosis, reducing the incidence of vertebral fractures and improving bone density in women with established disease. Received: 29 September 1999 / Accepted: 10 November 1999     

Fracture risk remains reduced one year after discontinuation of risedronate

Summary One year after discontinuation of three year’s treatment with risedronate, BMD decreased at the lumbar spine and femoral neck and bone turnover markers returned to control group levels. Despite these changes, the risk of new morphometric vertebral fractures remained lower in previous risedronate patients compared with previous control patients. Introduction Differences in bisphosphonate pharmacology and pharmacokinetics could influence persistence or resolution of the effects once treatment is stopped. We investigated changes in intermediate markers—bone mineral density (BMD) and bone turnover markers (BTM)—and fracture risk after discontinuation of treatment with risedronate. Methods Patients who received risedronate 5 mg daily (N = 398) or placebo (N = 361) during the VERT-NA study stopped therapy per protocol after 3 years but continued taking vitamin D (if levels at study entry were low) and calcium and were reassessed one year later. Results In the year off treatment, spine BMD decreased significantly, but remained higher than baseline (p ≤ 0.001) and placebo (p < 0.001), with similar findings at the femoral neck and trochanter. Urinary NTX and bone-specific alkaline phosphatase, which decreased significantly with treatment, were not significantly different from placebo after 1 year off treatment. Despite the changes in intermediate markers, the incidence of new morphometric vertebral fractures was 46% lower in the former risedronate group compared with the former placebo group (RR 0.54 [95% CI, 0.34, 0.86, p = 0.009]). Conclusions Despite the apparent resolution of effect on BMD and BTM, the risk reduction of new vertebral fractures remained in the year after treatment with risedronate was stopped. This study was funded by grants from Procter & Gamble Pharmaceuticals, Cincinnati, Ohio, and sanofi- aventis Pharma, Bridgewater, New Jersey.     

Bone Mass and Markers of Bone and Calcium Metabolism in Postmenopausal Women Treated with 1,25-Dihydroxyvitamin D (Calcitriol) for Four Years

To evaluate the long-term effect of calcitriol treatment on bone mineral density (BMD) of the femoral neck and lumbar spine and the parameters of calcium and bone metabolism in elderly women, 55 healthy, postmenopausal women, all aged 66 years, were enrolled in the study. Eighteen started a 4-year supplementation with 0.5 μg of calcitriol daily and 37 served as controls. Calcium intake of all the subjects was adjusted to 800 mg daily. In 4 years femoral neck BMD increased by 3.0% in the calcitriol group, but decreased by 1.6% in the control group (P= 0.009). The respective changes in lumbar spine BMD were +2.3% and +0.9% (P= 0.067). Two years' treatment with calcitriol increased the intestinal absorption of strontium by 57% (P < 0.001), doubled the urinary excretion of calcium (P < 0.001), and decreased the mean parathyroid hormone (PTH) level by 32% (P < 0.01). In the calcitriol group the marker of bone formation, serum osteocalcin, decreased by 27% (P < 0.01), and the marker of bone resorption, serum C-telopeptide of type I collagen (CTx), by 33% (P= 0.05) after 2 years. In two subjects the calcitriol dose had to be reduced because of hypercalciuria. We conclude that calcitriol treatment increases bone mass at the femoral neck and lumbar spine, the increases being maintained for up to 4 years. The gain in bone mass results from reduced bone turnover which is partly a consequence of the enhanced intestinal absorption of calcium and suppressed serum PTH levels. Received: 8 January 1999 / Accepted: 29 February 2000     

Bone Turnover and the Response to Alendronate Treatment in Postmenopausal Osteoporosis

This study investigated whether bone turnover influences the response to alendronate in women with postmenopausal osteoporosis. One hundred postmenopausal osteoporotic women were randomized to receive either alendronate (10 mg/day) plus calcium (1000 mg/day) (n = 50) or calcium alone (n = 50). Vertebral and radial bone density, measured by DXA, and markers of bone turnover were assessed at baseline and after 1 and 2 years. At the end of treatment, alendronate users showed an increase of 5.0% and 2.3%, respectively, at the lumbar spine and ultradistal radius; in the group treated only with calcium, bone mineral density (BMD) decreased by 1.6% at the lumbar spine and 1.3% at the ultradistal radius. The difference between the two groups was significant (P < 0.001). The patients were divided into high (HT) or low (LT) bone turnover groups, as assessed by 24-hour whole body retention (WBR%) of ^99mTc-methylene-diphosphonate. The response to alendronate treatment was greater in HT patients compared with LT patients. In fact, at the end of the study period, BMD at the lumbar spine had increased by 7.9% in HT patients and by 3.0% in LT patients; the difference between the two groups was significant (P < 0.001). No significant difference between the two groups was found for BMD at the ultradistal radius. In conclusion, the present study demonstrates that 2-year treatment with alendronate has highly positive effects on bone mass at both the lumbar spine and ultradistal radius. The increase in bone mass, especially at the axial level, is influenced by bone turnover. Therefore, the evaluation of bone turnover may be useful in predicting the response to alendronate treatment. Received: 23 April 1998 / Accepted: 10 June 1999     

Seven Years of Treatment with Risedronate in Women with Postmenopausal Osteoporosis

The effects of 7 years of risedronate treatment were evaluated in a second 2-year extension of a 3-year vertebral fracture study in women with osteoporosis. For the first 5 years of the study, women received risedronate 5 mg/day or placebo according to the original randomization, with maintenance of blinding. All the women who entered into the 6–7 years extension study received risedronate 5 mg/day. Endpoints included vertebral and nonvertebral fracture assessments, changes in biochemical markers of bone turnover, and bone mineral density (BMD) measurements. A total of 164 women (placebo/risedronate group, 81; risedronate group, 83) entered the 6–7 years extension study and 136 (83%) completed the study. Annualized incidence of new vertebral fractures during the 6–7 years was similar between the 2 treatment groups (3.8%). The incidence of vertebral fractures did not change in the 7-year risedronate group during the 6–7 years as compared to 4–5 years, while a significant reduction was observed in the placebo group that switched to risedronate treatment during years 6–7. The incidence of nonvertebral fractures was 7.4% and 6.0% in the placebo/risedronate and risedronate groups, respectively, during years 6–7. Urinary N-telopeptide decreased from baseline by 54% and 63% at 3 months and 7 years, respectively, in the risedronate group. The increases in BMD from baseline after 5 years of risedronate treatment were maintained or increased further during years 6–7; lumbar spine BMD after 5 and 7 years of risedronate treatment increased from baseline by 8.8% and 11.5%, respectively, for this extension study population. Risedronate was well tolerated and the occurrence of upper gastrointestinal adverse events was low. After 7 years of continuous risedronate treatment there were significant increases in BMD and decreases in bone turnover to within premenopausal levels and there was no indication of any loss of anti-fracture efficacy.     

Efficacy of risedronate administration in osteoporotic postmenopausal women affected by inflammatory bowel disease

Patients with inflammatory bowel disease (IBD) have frequently a bone mineral density (BMD) significantly lower than age-matched healthy subjects. The low BMD observed in IBD patients is related also to a higher incidence of bone fractures. In this prospective randomized study we evaluated the effect of 1-year risedronate administration on bone mass and turnover, and on vertebral fractures in osteoporotic postmenopausal women with IBD in remission. Ninety osteoporotic postmenopausal women were randomized to receive oral risedronate 35 mg/week (risedronate group) or placebo tablets (placebo group; one tab/week). The duration of treatment was 12 months. At entry and after treatment, lumbar spine and hip BMD, and serum osteocalcin (OC) and urinary deoxypyridinoline/creatinine ratio (DPD-Cr) levels were evaluated. Vertebral fractures were assessed from thoracic and lumbar lateral and anterior-posterior spinal radiographs taken at baseline, and from lateral spinal radiographs taken at the end of the study. At study entry, no difference between groups was also detected in BMD and in bone turnover markers. At the end of the study, lumbar spine, trochanter and femoral neck BMD was significantly ( p <0.05) higher in comparison with baseline in the risedronate group, whereas a significant ( p <0.05) decrease was observed in the placebo group. For the same visit, a significant ( p <0.05) difference in lumbar spine, trochanter and femoral neck BMD was detected between groups. After 12-month follow-up, serum OC and urinary DPD-Cr levels were significantly ( p <0.05) lower and higher in comparison with basal values in risedronate and placebo group, respectively. At the same time, a significant ( p <0.05) difference in serum OC and urinary DPD-Cr levels was observed between groups. Throughout the study, the incidence of vertebral fractures was significantly ( p <0.05) lower in the risedronate group than in the placebo group (12.5% vs 34.1%). The relative risk (RR) to develop a new vertebral fracture after 1 year of risedronate administration was of 0.36 (95% confidence interval, 0.14–0.85). In conclusion, risedronate administration is an effective anti-osteoporotic treatment in osteoporotic postmenopausal women with IBD in remission.     

Short-Term Effect of Vitamin K Administration on Prednisolone-Induced Loss of Bone Mineral Density in Patients with Chronic Glomerulonephritis

Glucocorticoid-induced osteoporosis has been reported to be caused by enhanced bone resorption and suppressed bone formation. To clarify whether administration of vitamin K, which enhances bone formation, prevents prednisolone-induced loss of bone mineral density (BMD), a randomized, prospective, controlled study was conducted on 20 patients with chronic glomerulonephritis scheduled for treatment with prednisolone. All patients were initially treated with 0.8 mg/kg body weight/day of prednisolone (maximum of 40 mg) for 4 weeks, tapering to 20 mg/day over approximately 6 weeks. Ten patients received prednisolone alone (Group 1), and the other 10 patients received prednisolone plus 15 mg of menatetrenone, vitamin K, three times per day (Group 2). BMD of the lumbar spine measured by dual-energy X-ray absorptiometry (DXA) and biochemical markers of bone metabolism in blood and urine were evaluated before and 10 weeks after administration of prednisolone alone or with menatetrenone. In Group 1, treatment with prednisolone significantly reduced BMD of the lumbar spine from 1.14 ± 0.12 to 1.10 ± 0.11 g/cm² (P= 0.0029). Serum intact osteocalcin and procollagen type I C-peptide (PICP) concentrations, biochemical markers of bone formation, were markedly reduced. A biochemical marker of bone resorption, urinary excretion of deoxypyridinoline, was significantly reduced. In Group 2, prednisolone-induced reduction of BMD was prevented by menatetrenone administration (1.09 ± 0.09 to 1.07 ± 0.07 g/cm², P= 0.153). Menatetrenone prevented reduction of PICP concentration by prednisolone but not in serum intact osteocalcin concentration and urinary excretion of deoxypyridinoline. Thus, treatment with prednisolone resulted in loss of BMD of the lumbar spine associated with suppression of both bone formation and bone resorption. Menatetrenone is a useful agent in preventing prednisolone-induced loss of BMD. Received: 7 July 1998 / Accepted: 13 August 1999     

The efficacy and tolerability of risedronate on bone mineral density and bone turnover markers in osteoporotic Chinese women: a randomized placebo-controlled study

Osteoporosis has become an important health problem in postmenopausal Asian populations as the prevalence of hip and vertebral fractures in some Asian countries has risen to approach that of Caucasian populations. Risedronate, a pyridinyl-bisphosphonate agent, is a potent inhibitor of bone resorption. Risedronate increases bone mineral density (BMD), reduces markers of bone turnover, and reduces the risk of fractures in Caucasian postmenopausal women. To determine the efficacy and tolerability of risedronate in Chinese, a multicenter, randomized, double blind, placebo controlled study was performed in Hong Kong. Sixty-five (65) postmenopausal osteoporotic Southern Chinese women, aged 67+/-6 years, were randomly assigned to receive either risedronate 5 mg daily (n=31) or placebo (n=34) for 12 months. All women received calcium carbonate 500 mg daily and vitamin D 400 IU daily. Mean baseline BMD T-score at the spine and total hip was -3.4 and -2.6, respectively. A significant increase in spine BMD was already evident at month 3 of risedronate treatment (P<0.001). Risedronate significantly increased BMD and reduced bone turnover markers as compared with placebo. The risedronate group had significant increase in BMD at 12 months at both the spine and hip when compared with the placebo group (L1-4 6.6% vs. 0.4%, P<0.001; total hip 2.7% vs. 0.3, P<0.0001; femoral neck 1.8% vs. 1.1%, P<0.02; trochanter 4% vs. 1.1%, P<0.0001, respectively). Significant changes in urine N-telopeptide (NTx) and serum osteocalcin were evident as early as 1 and 3 months, respectively, with risedronate treatment. No significant changes were seen in both BMD and bone markers in the placebo group. Risedronate was well tolerated without major adverse effects. We conclude that risedronate is an effective and well-tolerated agent for the treatment of postmenopausal osteoporosis in Asian population.     

A Comparison of the Effect of Risedronate and Etidronate on Lumbar Bone Mineral Density in Japanese Patients with Osteoporosis: A Randomized Controlled Trial

To demonstrate the clinical benefit of 2.5 mg daily risedronate in the treatment of involutional osteoporosis, the effect of risedronate on bone mineral density (BMD) of the lumbar spine was compared with that of etidronate, selected as a representative of the bisphosphonates currently marketed in Japan. In this multicenter, randomized, double-masked, active (etidronate) controlled comparative study, a total of 235 Japanese patients with involutional osteoporosis were randomized to receive either treatment with 2.5 mg/day of risedronate for 48 weeks or intermittent treatment with etidronate (4 cycles of 2 weeks of treatment with 200 mg/day followed by 10-week medication-free periods). All patients received 200 mg of calcium supplement daily in the form of the calcium lactate. Bone mineral density of the lumbar spine (L2–L4 BMD) was determined at 12, 24, 36 and 48 weeks by dual-energy X-ray absorptiometry. The primary endpoint was the percent change in L2–L4 BMD from baseline to the time of final evaluation. Changes in biochemical markers of bone turnover and safety profiles were also compared. A significant increase in L2–L4 BMD was observed at 12 weeks after initiation of therapy in both the risedronate (2.8%) and etidronate (1.8%) groups. The increase in L2–L4 BMD at the time of final evaluation in the risedronate group (4.9%) was significantly greater (p = 0.002) than that in the etidronate group (3.1%). The changes in bone resorption markers (urinary total deoxypyridinoline and N-terminal telopeptide of type I collagen) from baseline to 48 weeks were −37.6% and −41.3% for risedronate and −22.5% and −26.6% for etidronate, respectively. New vertebral fractures or deterioration of existing fractures were observed in 2.8% (3/106) of the patients in the etidronate group, while no such cases (0/101) were observed in the risedronate group. No significant difference in the incidence of adverse events was found between two treatments. Daily oral risedronate (2.5 mg) exhibited efficacy superior to that of intermittent cyclical etidronate (200 mg) in increasing L2–L4 BMD, and was well tolerated by Japanese patients with involutional osteoporosis. Received: 7 February 2002 / Accepted: 18 July 2002     

The Effectiveness of Cyclic and Continuous Oral Clodronate Therapy on Bone Density and Markers in Osteopenic Postmenopausal Women

Bisphosphonates have been used effectively to treat established osteoporosis and prevent postmenopausal bone loss. However, the optimal manner of its administration—whether cyclic or continuous—has not been well established. This study investigated the efficacy of cyclic and continuous oral administration of clodronate in 54 newly identified osteopenic postmenopausal women in a randomized, double-blind, crossover fashion. The participants were randomly separated into two groups. The cyclic group (n = 29) received 800 mg twice daily of oral clodronate for 2 weeks every 3 months for the first 12 months followed by placebo for the second 12 months. The continuous group (n = 25) received placebo in the first 12 months and ingested 400 mg of clodronate once daily for the second 12 months. The urinary amino-terminal (NTX™) and carboxy-terminal (CrossLaps™) cross-linked fragments of type I collagen, both markers of bone resorption, showed a marked decrease (25–50%) with both regimens during the period of active treatment. In the cyclic group, the levels of these two markers increased in the second 12 months with placebo, but did not return to the baseline completely. However, bone mineral density (BMD), determined by dual-energy X-ray absorptiometry (DXA), showed no significant change of BMD at various sites after 1 year of active treatment in both groups. Thoracic and lumbar spine X-ray showed no new vertebral fracture in either group after 2 years of treatment. With the two treatment protocols in this study, oral clodronate was effective in decreasing postmenopausal bone resorption, causing no significant changes in BMD at various sites. Received: 16 April 1997 / Accepted: 1 October 1998     

Prevention of Corticosteroid-Induced Osteoporosis with Alendronate in Sarcoid Patients

Prolonged corticosteroid administration, as often required in the treatment of sarcoidosis, increases the risk of osteoporosis and fracture. The aim of the present study was to evaluate the usefulness of alendronate, a third generation bisphosphonate, in preventing corticosteroid-induced osteoporosis. Forty-three consecutive, previously untreated, sarcoid patients (17 men and 26 premenopausal women) were included in the study: 13 needed no treatment and served as controls (Group 1) and 30 needed glucocorticoids (prednisone) and were randomly selected to also receive either placebo (n = 15, Group 2) or alendronate 5 mg/day (n = 15, Group 3). Bone mineral density (BMD) at the ultradistal radius by dual photon absorptiometry (Osteograph 1000, NIM, Verona, Italy) and biochemical markers of bone turnover were measured at baseline and after 6 and 12 months of glucocorticoid therapy. No significant difference was found between Groups 2 and 3 in the mean cumulative dose of prednisone (4945 ± 1956 mg and 5110 ± 2013 mg, respectively). At the end of the study period, BMD increased by 0.8% in the alendronate-treated group; in the placebo-treated group, BMD decreased by 4.5%. The difference between groups was significant (P < 0.01, ANOVA). A significant decrease in markers of bone formation was found in all patients treated with prednisone (Groups 2 and 3), independently of alendronate. Alendronate, however, counteracted the increase in markers of bone resorption induced by glucocorticoid therapy. Our data suggest that alendronate is effective in preventing glucocorticoid-induced bone loss in sarcoid patients. Further studies on alendronate use in steroid-induced osteoporosis are needed. Received: 30 September 1996 / Accepted: 30 April 1997     

Effects of Potassium Bicarbonate Supplementation on Axial and Peripheral Bone Mass in Rats on Strenuous Treadmill Training Exercise

We administered a potassium bicarbonate supplement to rats on strenuous treadmill training in order to determine the effect on bone mass and the metabolic acidosis seen with this type of training. A sample of 45 93-day-old female Wistar rats with a mean initial weight of 267 ± 17 g were studied. The control group (15 rats) was not exercised or given potassium bicarbonate (Ex− PB−). The experimental group (30 rats) was randomly divided into two subgroups of 15 rats each, one that exercised and did not receive potassium bicarbonate (Ex+ PB−) and one that exercised and received potassium bicarbonate (Ex+ PB+), at a dose of 0.05 mg/kg/day administered by esophageal catheter on exercise days. Training consisted of treadmill running on 5 out of 7 days for a period of 11 weeks. Running time, treadmill speed, and the percent grade were gradually increased until week 7, then maintained until rats were sacrificed at the ened of 11 weeks. The bone mineral content (BMC) and bone mineral density (BMD) of the whole right femur and 5th lumbar vertebra were measured. Femoral and vertebral length were also measured. Femur length, weight, BMC, and BMD, and femur BMC/final weight ratio, and vertebral weight, BMD, and BMC, and vertebral BMC/final weight ratio were lower in the Ex+ PB− group than in either the controls or the Ex+ PB+ group (P < 0.01–P < 0.0001); the length of the 5th lumbar vertebra did not differ between groups. Received: 21 July 1998 / Accepted: 12 March 1999     

Primary Prevention of Glucocorticoid-Induced Osteoporosis with Intermittent Intravenous Pamidronate: A Randomized Trial

The aim of this study was to assess whether early intermittent I.V. administration of disodium pamidronate can effectively achieve primary prevention of glucocorticoid-induced osteoporosis (GIOP). A total of 27 in- or outpatients who required first-time, long-term corticosteroid therapy at a daily dose of at least 10 mg prednisolone were studied. Patients were randomly selected to receive either pamidronate and calcium or calcium alone. Patients allocated to pamidronate treatment (pamidronate group) received a first intravenous infusion of 90 mg pamidronate simultaneously with the initiation of their steroid treatment. Subsequently, they received 30 mg pamidronate, intravenously, every 3 months, for as long as steroid therapy was continued. As with the control patients (calcium group), they were put on a daily 800-mg elemental calcium supplement given as calcium carbonate. Lumbar spine and hip (total and subregions) bone mineral densities (BMDs) were measured at the start and every 3-months by dual-energy X-ray absorptiometry (Hologic? QDR-2000). Over 1 year, the pamidronate group showed a significant BMD increase in the lumbar spine (3.6%), and at all sites of the hip (2.2% at the femoral neck). In the calcium group, a significant BMD reduction was registered at the lumbar spine (−5.3%) and at the femoral neck (−5.3%). Differences between the groups were significant at all sites measured. Intermittent intravenous pamidronate effectively achieves primary prevention of GIOP, as assessed by BMD measurements over 1 year. Received: 2 December 1996 / Accepted: 25 April 1997     

Long-term efficacy of risedronate: a 5-year placebo-controlled clinical experience

Limited placebo-controlled data are available to assess the long-term fracture efficacy of bisphosphonates. In order to determine the effects of 5 years of risedronate treatment, we extended a 3-year, placebo-controlled vertebral fracture study in osteoporotic women for an additional 2 years; women who entered the extension study continued to receive 5 mg risedronate or placebo according to the original randomization, with maintenance of blinding. End points included vertebral and nonvertebral fracture assessments, bone mineral density measurements, and changes in biochemical markers of bone turnover. A total of 265 women (placebo, 130; 5 mg risedronate, 135) entered the study extension and 220 (83%) completed the additional 2 years. Fracture results observed in the study extension were consistent with those observed in the first 3 years. The risk of new vertebral fractures was significantly reduced with risedronate treatment in years 4 and 5 by 59% (95% confidence interval, 19 to 79%, P = 0.01) compared with a 49% reduction in the first 3 years. Rapid and significant decreases in markers of bone turnover observed in the first 3 years were similarly maintained in the next 2 years of treatment. Increases in spine and hip bone mineral density that occurred in the risedronate group during the first 3 years were maintained or increased with a further 2 years of treatment. The mean increase from baseline in lumbar spine BMD over 5 years was 9.3% (P < 0.001). This study demonstrates that the effects of risedronate over 3 years on vertebral fracture and BMD are maintained with a further 2 years of treatment.