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Persistent use of glucocorticoid drugs is associated with bone loss and increased fracture risk. Concurrent oral bisphosphonates increase bone mineral density and reduce frequency of vertebral fractures, but are associated with poor compliance and adherence. We aimed to assess whether one intravenous infusion of zoledronic acid was non-inferior to daily oral risedronate for prevention and treatment of glucocorticoid-induced osteoporosis. This 1-year randomised, double-blind, double-dummy, non-inferiority study of 54 centres in 12 European countries, Australia, Hong Kong, Israel, and the USA, tested the effectiveness of 5 mg intravenous infusion of zoledronic acid versus 5 mg oral risedronate for prevention and treatment of glucocorticoid-induced osteoporosis. 833 patients were randomised 1:1 to receive zoledronic acid (n=416) or risedronate (n=417). Patients were stratified by sex, and allocated to prevention or treatment subgroups dependent on duration of glucocorticoid use immediately preceding the study. The treatment subgroup consisted of those treated for more than 3 months (272 patients on zoledronic acid and 273 on risedronate), and the prevention subgroup of those treated for less than 3 months (144 patients on each drug). 62 patients did not complete the study because of adverse events, withdrawal of consent, loss to follow-up, death, misrandomisation, or protocol deviation. The primary endpoint was percentage change from baseline in lumbar spine bone mineral density. Drug efficacy was assessed on a modified intention-to-treat basis and safety was assessed on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT00100620. Zoledronic acid was non-inferior and superior to risedronate for increase of lumbar spine bone mineral density in both the treatment (least-squares mean 4·06% [SE 0·28] vs 2·71% [SE 0·28], mean difference 1·36% [95% CI 0·67–2·05], p=0·0001) and prevention (2·60% [0·45] vs 0·64% [0·46], 1·96% [1·04–2·88], p<0·0001) subgroups at 12 months. Adverse events were more frequent in patients given zoledronic acid than in those on risedronate, largely as a result of transient symptoms during the first 3 days after infusion. Serious adverse events were worsening rheumatoid arthritis for the treatment subgroup and pyrexia for the prevention subgroup. A single 5 mg intravenous infusion of zoledronic acid is non-inferior, possibly more effective, and more acceptable to patients than is 5 mg of oral risedronate daily for prevention and treatment of bone loss that is associated with glucocorticoid use. Novartis Pharma.

This study compared a single intravenous infusion of zoledronic acid with daily oral risedronate in patients with Paget's disease. At six months, 96 percent of patients receiving zoledronic acid had a therapeutic response, as compared with 74 percent of patients given risedronate. Single-infusion zoledronate produces more rapid, complete, and sustained responses than does daily risedronate and may increase adherence to bisphosphonate therapy. Single-infusion zoledronate produces more rapid, complete, and sustained responses than does daily risedronate and may increase adherence to bisphosphonate therapy. Paget's disease of bone is characterized by a dramatic increase in bone turnover (both formation and resorption) at one or more sites. Measurement of biochemical markers of bone turnover is used to assess disease activity and monitor the response to therapy. About 2 percent of the U.S population older than 60 years of age have Paget's disease, 1 as do up to 6 or 7 percent of the elderly population in western Europe. 2 The bone pain, skeletal deformity, pathologic fractures, secondary arthritis, neurologic complications, and deafness that may accompany this disease contribute to substantial morbidity in the older population. Bisphosphonate therapy . . .

Aromatase inhibitors prevent breast cancer in postmenopausal women at high risk of the disease but are associated with accelerated bone loss. We assessed effectiveness of oral risedronate for prevention of reduction in bone mineral density (BMD) after 3 years of follow-up in a subset of patients in the IBIS-II trial. The double-blind IBIS-II trial recruited 3864 healthy, postmenopausal women at increased risk of breast cancer and randomly allocated them oral anastrozole (1 mg/day) or matched placebo. 1410 (36%) postmenopausal women were then enrolled in a bone substudy and stratified at baseline according to their lowest baseline T score at spine or femoral neck (stratum I: T score at least −1·0; stratum II: T score at least −2·5 but less than −1·0; stratum III: T score less than −2·5 but greater than −4·0). Women in stratum I were monitored only; women in stratum III were all given risedronate (35 mg/week). Women in stratum II were randomly assigned (1:1) to risedronate (35 mg/week) or matched placebo by use of a block randomisation schedule via a web-based programme. The primary outcome of this per-protocol analysis (done with all women with a baseline and 3 year DXA assessment) was the effect of risedronate versus placebo for osteopenic women in stratum II randomly allocated to anastrozole (1 mg/day). Secondary outcomes included effect of anastrozole (1 mg/day) on BMD in women not receiving risedronate (strata I and II) and in osteoporotic women who were all treated with risedronate (stratum III). The trial is ongoing, but no longer recruiting. This trial is registered, number ISRCTN31488319. Between Feb 2, 2003, and Sept 30, 2010, 150 (58%) of 260 women in stratum II who had been randomly allocated to anastrozole and either risedronate or placebo had baseline and 3 year assessments. At the lumbar spine, 3 year mean BMD change for the 77 women receiving anastrozole/risedronate was 1·1% (95% CI 0·2 to 2·1) versus −2·6% (−4·0 to −1·3) for the 73 women receiving anastrozole/placebo (p<0·0001). For the total hip, 3 year mean BMD change for women receiving anastrozole/risedronate was −0·7% (−1·6 to 0·2) versus −3·5% (−4·6 to −2·3) for women receiving anastrozole/placebo (p=0·0001). 652 (65%) of 1008 women in strata I and II who were not randomly allocated to risedronate had both baseline and 3 year assessments. Women not receiving risedronate in stratum I and II who received anastrozole (310 women) had a significant BMD decrease after 3 years of follow-up compared with women who received placebo (342 women) at the lumbar spine (−4·0% [–4·5 to −3·4] vs −1·2% [−1·7 to −0·7], p<0·0001) and total hip (−4·0% [–4·4 to −3·6] vs −1·8% [−2·1 to −1·4], p<0·0001). 106 (79%) of 149 women in stratum III had a baseline and a 3 year assessment. The 46 women allocated to anastrozole had a modest BMD increase of 1·2% (−0·1 to 2·6) at the spine compared with a 3·9% (2·6 to 5·2) increase for the 60 women allocated to placebo (p=0·006). For the total hip, a small 0·3% (−0·9 to 1·5) increase was noted for women allocated anastrozole compared with a 1·5% (0·5 to 2·5) increase for women allocated placebo, but the difference was not significant (p=0·12). The most common adverse event reported was arthralgia (stratum I: 94 placebo and 114 anastrozole; stratum II: 39 placebo/placebo, 25 placebo/risedronate, 34 anastrozole/placebo, and 34 anastrozole/risedronate; stratum III: 21 placebo/risedronate, 17 anastrozole/risedronate). Other adverse events included hot flushes, alopecia, abdominal pain, and back pain. Risedronate counterbalances the effect of anastrozole-induced bone loss in osteopenic and osteoporotic women and might be offered in combination with anastrozole treatment to provide an improved risk–benefit profile. Cancer Research UK (C569/A5032), National Health and Medical Research Council Australia (GNT300755, GNT569213), Sanofi-Aventis, and AstraZeneca.

PurposeThis randomized controlled trial compared changes in bone mineral density (BMD) and bone turnover in postmenopausal women with low bone mass randomized to 12 months of either risedronate, exercise, or a control group.MethodsTwo hundred seventy-six women with low bone mass, within 6 years of menopause, were included in analysis. Treatment groups were 12 months of (a) calcium and vitamin D supplements (CaD) (control), (b) risedronate + CaD (risedronate), or (c) bone-loading exercises + CaD (exercise). BMD and serum markers for bone formation (Alkphase B) and resorption (Serum Ntx) were analyzed at baseline, 6, and 12 months.ResultsUsing hierarchical linear modeling, a group by time interaction was found for BMD at the spine, indicating a greater improvement in the risedronate group compared to exercise (p ≤ .010) or control groups (p ≤ .001). At 12 months, for women prescribed risedronate, changes in BMD at the spine, hip, and femoral neck from baseline were + 1.9%, + 0.9%, and + .09%; in exercise group women, + 0.2%, + 0.5%, and − 0.4%; and in control group women, − 0.7%, + 0.5%, and − 0.5%. There were also significant differences in reductions in Alkphase B (RvsE, p < .001, RvsC, p < .001) and Serum Ntx (RvsE, p = .004, RvsC, p = .007) in risedronate women compared to exercise and control groups. For risedronate, 12-month changes in Alkphase B and Serum Ntx were − 20.3% and − 19.0%; for exercise, − 6.7% and − 7.0%; and for control, − 6.3% and − 9.0%.ConclusionPostmenopausal women with low bone mass should obtain adequate calcium and vitamin D and participate in bone-loading exercises. Additional use of BPs will increase BMD, especially at the spine.

Summary Managing osteoporotic patients suboptimally adherent to bisphosphonates (BPs) is difficult. Such patients who remained at higher risk for fracture (≥1 risk factor) were transitioned to denosumab or a monthly oral BP. Denosumab-treated subjects had significantly greater increases in bone mineral density and decreases in bone turnover in this 12-month study. Introduction A clinical need exists to manage patients who are suboptimally adherent to oral BPs and remain at higher risk for fracture. Here, we compare the effects on bone mineral density (BMD) and bone turnover of transitioning such patients to denosumab or monthly oral BP (ibandronate or risedronate). Methods In two previous multicenter, open-label studies, postmenopausal women ≥55 years previously treated with, though suboptimally adherent to, a daily or weekly BP were randomized to denosumab 60 mg subcutaneously every 6 months ( N =  852) or oral BP 150 mg monthly ( N =  851) for 12 months. In this combined post-hoc analysis, a subset of higher risk subjects was identified, and the percentage changes from baseline in BMD and serum C-telopeptide of type I collagen (sCTX-1) were assessed. Results In the overall population, denosumab was associated with greater gains in BMD at 12 months than monthly oral BP at the total hip, femoral neck, and lumbar spine ( p  < 0.0001 for all). In higher risk subjects, denosumab led to greater gains in BMD than oral BPs at the total hip (2.2 vs 0.8 %), femoral neck (1.8 vs 0.3 %), and lumbar spine (3.7 vs 1.4 %) ( p  < 0.0001 for all). Denosumab also led to greater decreases in sCTX-1 in the overall population and higher risk subjects at months 1 and 6 ( p  < 0.0001 for both). Adverse events and serious adverse events were generally similar between treatment groups. Conclusions Transitioning to denosumab was well tolerated and more effective in increasing BMD and reducing bone turnover than cycling to a monthly oral BP treatment in subjects who remained at higher fracture risk despite suboptimal BP treatment.

Summary The effect of teriparatide and risedronate on back pain was tested, and there was no difference in the proportion of patients experiencing a reduction in back pain between groups after 6 or 18 months. Patients receiving teriparatide had greater increases in bone mineral density and had fewer vertebral fractures. Introduction This study aimed to understand the effect of teriparatide in reducing back pain in patients with prevalent back pain and vertebral fracture compared to risedronate. Methods In an 18-month randomized, double-blind, double-dummy trial, we investigated the effects of teriparatide (20 μg/day) vs. risedronate (35 mg/week) in postmenopausal women with back pain likely due to vertebral fracture. The primary objective was to compare the proportion of subjects reporting ≥30% reduction in worst back pain severity from baseline to 6 months as assessed by a numeric rating scale in each treatment group. Pre-specified secondary and exploratory outcomes included assessments of average and worst back pain at additional time points, disability and quality of life, bone mineral density, incidence of fractures, and safety. Results At 6 months, 59% of teriparatide and 57% of risedronate patients reported ≥30% reduction in worst back pain and there were no differences between groups in the proportion of patients experiencing reduction in worst or average back pain at any time point, disability, or quality of life. There was a greater increase from baseline in bone mineral density at the lumbar spine ( p  = 0.001) and femoral neck ( p  = 0.02) with teriparatide compared to risedronate and a lower incidence of vertebral fractures at 18 months (4% teriparatide and 9% risedronate; p  = 0.01). Vertebral fractures were less severe ( p  = 0.04) in the teriparatide group. There was no difference in the overall incidence of adverse events. Conclusions Although there were no differences in back pain-related endpoints, patients receiving teriparatide had greater skeletal benefit than those receiving 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.

Background Fahr’s disease and syndrome are rare disorders leading to calcification of the small arteries in the basal ganglia of the brain, resulting in a wide range of symptoms comprising cognitive decline, movement disorders and neuropsychiatric symptoms. No disease-modifying therapies are available. Studies have shown the potential of treatment of ectopic vascular calcifications with bisphosphonates. This paper describes the rationale and design of the CALCIFADE trial which evaluates the effects of etidronate in patients with Fahr’s disease or syndrome. Methods The CALCIFADE trial is a randomised, placebo-controlled, double-blind trial which evaluates the effects of etidronate 20 mg/kg during 12 months follow-up in patients aged ≥ 18 years with Fahr’s disease or syndrome. Etidronate and placebo will be administered in capsules daily for two weeks on followed by ten weeks off. The study will be conducted at the outpatient clinic of the University Medical Center Utrecht, the Netherlands. The primary endpoint is the change in cognitive functioning after 12 months of treatment. Secondary endpoints are the change in mobility, neuropsychiatric symptoms, volume of brain calcifications, dependence in activities of daily living, and quality of life. Results Patient recruitment started in April 2023. Results are expected in 2026 and will be disseminated through peer-reviewed journals as well as presentations at national and international conferences. Conclusions Fahr’s disease and syndrome are slowly progressive disorders with a negative impact on a variety of health outcomes. Etidronate might be a new promising treatment for patients with Fahr’s disease or syndrome. Trial registration ClinicalTrials.gov, NCT05662111. Registered 22 December 2022, https://clinicaltrials.gov/ct2/show/NCT01585402 .

Summary Bone mineral density response to once weekly delayed-release formulation of risedronate, given before or following breakfast, was non-inferior to that seen with traditional immediate-release risedronate given daily before breakfast. Delayed-release risedronate is a convenient dosing regimen for oral bisphosphonate therapy that might avoid poor compliance. Introduction This 2-year, randomized, controlled, non-inferiority study assessed the efficacy and safety of a delayed-release (DR) 35-mg weekly oral formulation of risedronate that allows subjects to take their weekly risedronate dose before or immediately after breakfast. Results from the first year of the study were published previously (McClung et al. Osteoporos Int 23(1):267-276, 2012 ); we now report the final results after 2 years. Methods Women with postmenopausal osteoporosis were randomly assigned to receive risedronate 5 mg immediate-release (IR) daily ( n  = 307) at least 30 min before breakfast, or risedronate 35 mg DR weekly, either immediately following breakfast (FB, n  = 307) or at least 30 min before breakfast (BB, n  = 308). Bone mineral density (BMD), bone turnover markers (BTMs), fractures, adverse events, and bone histomorphometry were evaluated. Results A total of 248 subjects (80.8 %) in the IR daily group, 234 subjects (76.2 %) in the DR FB weekly group, and 240 subjects (77.9 %) in the DR BB weekly group completed the 2-year study. After 2 years of treatment, BMD increases at the lumbar spine and total hip with the weekly DR doses similar to or greater than that with the IR daily dose. Decreases in BTMs were similar or significantly lower in the DR groups. Bone histomorphometry results did not differ among the DR weekly and the IR daily formulations. The three regimens were similarly well tolerated. Conclusions Risedronate 35 mg DR weekly is as effective and as well tolerated as risedronate 5 mg IR daily, and will allow subjects to take their weekly risedronate dose immediately after breakfast.

The purposes of the study were to review available published literature on magnitude of non-adherence with osteoporosis regimens and to determine the association between frequency and modality of medication administration with patient preference and adherence. We searched peer-reviewed journal databases--MEDLINE, EMBASE, Biosis and Derwent Drug File for publications (January 1979 to January 2009) including MeSH terms--“patient preference”, “adherence” and “compliance” based on “dosing frequency” and “modality”. Since adherence was difficult to accurately quantify, preference, compliance and persistence were evaluated. Patients' preference and adherence at 12 months were higher with weekly over daily bisphosphonates (≥84% preference for weekly, medication possession ratios (MPR) 60-76% vs 46-64%; persistence 43.6-69.7% vs 31.7-55.7%). MPR reported for oral bisphosphonates were 68-71% at 12 months. At 2 years, only 43% of patients had MPR ≥80% for daily and weekly bisphosphonates. Observational studies (6-12 months) reported discontinuation rates of 18-22% for daily and 7% for weekly bisphosphonates. Data on monthly bisphosphonates are conflicting and confounded by cost differences, patient support programmes and definition of persistence. Studies suggest patient preference for annual zoledronic acid infusions over weekly bisphosphonates (66.4-78.8% vs 9.0-19.7%, respectively), but no data on compliance or persistence are available. Drug effectiveness, side effects and route of administration were more important than frequency. Although less frequent dosing is preferred, other factors such as perceived efficacy, side effects, medication cost, availability of patient support programmes and route of delivery are equally important. Adherence is complex and difficult to quantify and may not be exclusively influenced by frequency of medication administration.