Bridging the osteoporosis treatment gap: performance and cost-effectiveness of a fracture liaison service.

Individuals who sustain fragility fractures are at high risk of refracture. However, osteoporosis treatment rates remain low for these patients. Therefore, we aimed to assess the performance and cost-effectiveness of introducing a fracture liaison service (FLS) into a tertiary hospital. In "nonhospitalized" ambulatory patients who had sustained fragility fractures, we assessed baseline osteoporosis investigation and treatment rates, and subsequently, the impact of introducing an orthopedic osteoporosis policy and an FLS. Outcomes measured were uptake of osteoporosis intervention, patient satisfaction, and quality-adjusted life years (QALYs) gained. QALYs were calculated over 5 years using predicted fracture risks without intervention and estimated fracture risk reduction with intervention. At baseline (n = 49), 2% of ambulatory patients who had sustained fragility fractures underwent dual-energy X-ray absorptiometry (DXA) and 6% received osteoporosis-specific medication. After introduction of an osteoporosis policy (n = 58), 28% were investigated with DXA (p < 0.0001). However, treatment rates were unchanged. An FLS was introduced, reviewing 203 new patients over the inaugural 2 years (mean age [standard deviation], 67 (11) years; 77% female). All underwent DXA, and criteria for osteoporosis and osteopenia were identified in 44% and 40%, respectively. Osteoporosis medications were prescribed to 61% patients (risedronate: 22%, alendronate: 16%, strontium ranelate: 13%, zoledronic acid: 8%, other: 2%). Eighty-five of 90 questionnaire respondents were very satisfied or satisfied with the FLS. With the treatment prescribed over 5 years, we conservatively estimated that this FLS would reduce nonvertebral refractures from 59 to 50, improving QALYs by 0.054 and costing $1716 per patient (incremental cost-effectiveness ratio: $31749). This FLS model improves uptake of osteoporosis intervention guidelines, is popular among patients, and improves cost-effectiveness. Thus, it has the capacity to substantially improve health in a cost-effective way.

Compliance, persistence, and preference outcomes of postmenopausal osteoporotic women receiving a flexible or fixed regimen of daily risedronate: A multicenter, prospective, parallel group study.

OBJECTIVE: The aim of this study was to examine the level of compliance and persistence in patients with postmenopausal osteoporosis (OP) receiving daily risedronate (5 mg) with either fixed dosing of three different timing regimens (A: before breakfast; B: in-between meals; C: before bedtime) or with flexible dosing and the effect on urinary N-terminal telopeptide of Type 1 collagen (NTX-1). METHODS: The study included 448 patients with postmenopausal OP. Patients were randomly assigned into six treatment groups each with a permutation of the treatment sequence (ABC, BCA, etc.) in the crossover phase (3 x 1 week) and randomized to 23 weeks of either the daily flexible (either regimen A, B or C) or fixed timing (only regimen A, B, or C) in the patient's preference phase. Urinary NTX-1 was tested. RESULTS: A total of 433 patients participated in the patient's preference phase (49.7% preferred flexible and 50.3% fixed timing). There was no significant difference between the proportion of responders who were both compliant and persistent in the flexible (54.4%) and fixed regimens (53.7%) (p=0.8803). A significant difference between the flexible and fixed regimens was seen in persistence in favor of the flexible regimen (p=0.0306). There was no significant difference between the flexible and fixed regimens in terms of compliance (p=0.4611). Change in urinary NTX-1 did not show any difference between the two regimens. At the final visit, 51% of patients in the flexible and 55% in the fixed regimen group considered the used risedronate regimen as excellent or very good (p=0.1440). CONCLUSION: A flexible dosing with daily risedronate appears be a valuable option in terms of compliance and persistence for patients with postmenopausal OP.

Risedronate as an intra-abdominal sepsis mimic: a case report.

UNLABELLED: This case report highlights the potential severity of bisphosphonate-associated reactions. CASE REPORT: A 76-year-old lady underwent several hospital admissions for investigation of fever associated with rigors, abdominal pain, and vomiting. DISCUSSION: Despite multiple investigations, no cause was found, but the timing of the symptoms coincided with monthly risedronate administration.

Cranial base pathology in pediatric osteogenesis imperfecta patients treated with bisphosphonates.

OBJECT: Cranial base pathology is a serious complication of osteogenesis imperfecta (OI). Our aim was to analyze whether bisphosphonate treatment, used to improve bone strength, could also prevent the development of craniocervical junction pathology (basilar impression, basilar invagination, or platybasia) in children with OI. METHODS: In this single-center retrospective study the authors analyzed the skull base morphology from lateral skull radiographs and midsagittal MR images (total of 94 images), obtained between the ages of 0 and 25 years in 39 bisphosphonate-treated OI patients. The results were compared with age-matched normative values and with findings in 70 OI patients who were not treated with bisphosphonates. In addition to cross-sectional data, longitudinal data were available from 22 patients with an average follow-up period of 7.6 years. The patients, who had OI types I, III, IV, VI, and VII, had been treated with zoledronic acid, pamidronate, or risedronate for 3.2 years on average. RESULTS: Altogether 33% of the 39 bisphosphonate-treated patients had at least 1 cranial base anomaly, platybasia being the most prevalent diagnosis (28%). Logistic regression analysis suggested a higher risk of basilar impression or invagination in patients with severe OI (OR 22.04) and/or older age at initiation of bisphosphonate treatment (OR 1.45), whereas a decreased risk was associated with longer duration of treatment (OR 0.28). No significant associations between age, height, or cumulative bisphosphonate dose and the risk for cranial base anomaly were detected. In longitudinal evaluation, Kaplan-Meier curves suggested delayed development of cranial base pathology in patients treated with bisphosphonates but the differences from the untreated group were not statistically significant. CONCLUSIONS: These findings indicate that cranial base pathology may develop despite bisphosphonate treatment. Early initiation of bisphosphonate treatment may delay development of craniocervical junction pathology. Careful followup of cranial base morphology is warranted, particularly in patients with severe OI.

Risk of atypical femoral fracture during and after bisphosphonate use.

BACKGROUND AND PURPOSE: Use of bisphosphonates in women is associated with higher risk of atypical femoral fractures. The risk in terms of timing of use and type of bisphosphonate, and in men, remains unclear. PATIENTS AND METHODS: We reviewed radiographs of 5,342 Swedish women and men aged 55 years or more who had had a fracture of the femoral shaft in the 3-year period 2008-2010 (97% of those eligible), and found 172 patients with atypical fractures (93% of them women). We obtained data on medication and comorbidity. The risk of atypical fracture associated with bisphosphonate use was estimated in a nationwide cohort analysis. In addition, we performed a case-control analysis with comparison to 952 patients with ordinary shaft fractures. A short report of the findings has recently been presented (Schilcher et al. 2014a). Here we provide full details. RESULTS: The age-adjusted relative risk (RR) of atypical fracture associated with bisphosphonate use was 55 (95% CI: 39-79) in women and 54 (CI: 15-192) in men. In bisphosphonate users, women had a 3-fold higher risk than men (RR = 3.1, CI: 1.1-8.4). Alendronate users had higher risk than risedronate users (RR = 1.9, CI: 1.1-3.3). The RR after 4 years or more of use reached 126 (CI: 55-288), with a corresponding absolute risk of 11 (CI: 7-14) fractures per 10,000 person-years of use. The risk decreased by 70% per year since last use. INTERPRETATION: Women have a higher risk of atypical femoral fracture than men. The type of bisphosphonate used may affect risk estimates and the risk decreases rapidly after cessation.

Stimulation of in-vitro angiogenesis by low concentrations of risedronate is mitigated by 1,25-dihydroxyvitamin D3 or 24,25-dihydroxyvitamin D3.

The nitrogen-containing or nitrogenous bisphosphonates (N-BF) are currently the main class of drugs used for the treatment of diseases characterized by an increased bone resorption. Preliminary data suggest that N-BF have also direct or indirect anti-tumoral effects, and recent evidence suggests that part of the anti-tumoral activity of N-BF may be attributed to their anti-angiogenic capacity when they are used at high concentrations. On the other hand, an optimal vitamin-D status seems to be necessary to maximize the bone response to N-BF. Our aim has been to evaluate the effect of risedronate, alone or in combination with either 1,25(OH)2D3 or 24,25(OH)2D3 (two main vitamin-D metabolites) on parameters related to the angiogenic capacity of human umbilical-vein endothelial cells (HUVEC). The studies of tube formation through in-vitro angiogenesis assays with Matrigel, chemotaxis and migration in a scratch assay showed that low concentrations of risedronate (0.01 to 1µM) stimulated angiogenesis and cellular migration in vitro. The presence of 1,25(OH)2D3 in the medium inhibited tubular-structure formation and cellular migration. In addition, the presence of 1,25 or 24,25(OH)2D3 in the culture medium also decreased the pro-angiogenic effects of low-concentrations of risedronate. These data show the differential effects of different concentrations of vitamin-D metabolites and risedronate on angiogenesis, thus stressing the importance of an adequate vitamin D status during medical treatment with risedronate. This article is part of a Special Issue entitled '17th Vitamin D Workshop'.

Timing of the initiation of bisphosphonates after surgery for fracture healing: a systematic review and meta-analysis of randomized controlled trials.

SUMMARY: We performed a systematic review and meta-analysis of randomized clinical trials. Early administration of bisphosphonates (BPs) after surgery did not appear to delay fracture healing time either radiologically or clinically. Furthermore, the anti-resorptive efficacy of BPs given immediately after surgical repair should positively affect the rate of subsequent fractures. INTRODUCTION: Bisphosphonates (BPs) are widely used in the prophylaxis and treatment of osteoporosis. However, early administration of BPs after surgical repair of a fracture may limit the reserve capacity of bone to heal. The aim of this review and meta-analysis was to analyze the benefits and adverse effects of early administration of BPs and give recommendations regarding when BPs should be utilized. METHODS: We identified randomized controlled trials comparing the early administration of BPs to placebo, delayed BP treatment, or no therapy in adult patients after surgery. The search was performed in PubMed, the Cochrane Library, and Embase. RESULTS: Ten studies with 2888 patients were included. Four trials used alendronate, three trials used zoledronic, two trials used risedronate, and one trial used etidronate. Early administration of BPs was considered less than 3 months after surgery. Patients treated with BP therapy had no significant differences in radiological fracture healing times compared with patients in the control group (mean difference [MD] 0.47, 95% confidence interval [CI] -2.75 to 3.69). There were also no significant differences in the rate of delay or nonunion of fracture healing (odds ratio [OR] 0.98, 95% CI 0.64 to 1.50). However, the bone mineral density (BMD) of total hips did significantly improve after 12 months of treatment with BPs. And most bone turnover markers of patients in the study group were significantly decreased. CONCLUSIONS: Early administration of BPs after surgery did not appear to delay fracture healing time either radiologically or clinically. Furthermore, according to the changes in BMD and bone turnover markers, the anti-resorptive efficacy of BPs given immediately after surgical repair should positively affect the rate of subsequent fractures.

Residual effect after oral bisphosphonate treatment and healthy adherer effects--the Swedish Adherence Register Analysis (SARA).

UNLABELLED: Little is known of the effect of alendronate and risedronate on osteoporotic fractures after discontinuation of therapy. We found that time on treatment was significantly inversely associated with the incidence of hospitalized fractures during posttreatment follow-up. Our results will inform health economic analysis of osteoporosis interventions. INTRODUCTION: Real-world persistence to treatment of osteoporosis is well-understood, but little is known of the posttreatment residual effect on fractures. The objective of this study was to investigate the residual effect of alendronate and risedronate on fractures and assess whether a healthy adherer effect confounds the association between persistence and residual anti-fracture effect. METHODS: A treatment-naïve cohort from the Swedish Prescribed Drug Register was identified through prescriptions for alendronate or risedronate between 2005 and 2009. Persistence was estimated, and patients were stratified by time on treatment (<1 month, 1-6 months, 7-12 months, and >12 months). Survival analysis was used to study hospitalized fractures and mortality up to 18 months after treatment discontinuation. RESULTS: The crude incidence proportion of fractures the first 6 months after treatment discontinuation ranged from 2.26% (<1 month of treatment) to 1.16% (>12 months). The corresponding estimates for month 7 to 12 after discontinuation was 3.18 to 1.96%, and for month 13 to 18 after discontinuation 2.69 to 1.95%. Adjusted regression results showed that patients persisting with therapy for >12 months had 60% lower fracture risk the first six months after treatment discontinuation (RR 0.40, p = 0.001). Patient characteristics, including prevalent fractures and co-morbidities, and posttreatment mortality were comparable across persistence durations, and we found no evidence of a healthy adherer effect. CONCLUSIONS: Time on bisphosphonate treatment was significantly inversely associated with the incidence of hospitalized fractures during posttreatment follow-up. We found no evidence of a healthy adherer effect confounding the relationship between treatment persistence and fracture risk.

Bone safety with risedronate: histomorphometric studies at different dose levels and exposure.

UNLABELLED: This report describes bone safety and histomorphometric data across different dose levels and dosing frequencies of risedronate. Normal bone structure and histomorphometric data were observed, with ongoing bone remodeling and mineralization regardless of dose. These data are reassuring and do not suggest compromised bone remodeling during treatment with established risedronate regimens. INTRODUCTION: The efficacy and bone safety of risedronate 5 mg daily were established in pivotal phase III randomized, placebo-controlled clinical studies. Histomorphometric analysis of paired biopsies demonstrated bone safety as reflected by presence of fluorescent tetracycline double-labels in all evaluable biopsies. This report describes bone safety and histomorphometric data across studies of various dose regimens of risedronate. METHODS: Bridging studies, with bone mineral density as the primary endpoint, demonstrated non-inferiority of risedronate 35 mg and 50 mg once a week, risedronate 150 mg once a month, and a risedronate 75-mg dose on two consecutive days a month versus risedronate 5 mg daily. The low oral bioavailability and known dosing limitations due to food interactions of bisphosphonates have led to development of an oral delayed-release dose form of risedronate 35 mg to be taken weekly, before or after breakfast. Bone biopsies were collected at 24 months in studies involving these risedronate dosing regimens; bone safety and histomorphometric data were evaluated. RESULTS: Qualitative bone histology showed normal mineralization of newly formed bone without evidence of pathological findings, such as osteomalacia, bone marrow dyscrasia, or bone marrow fibrosis. Importantly, ongoing bone remodeling, based on fluorochrome labeling, was observed in all patients regardless of dose and exposure. Key histomorphometric variables were comparable to those observed with the risedronate 5 mg daily dose and were within the range seen in healthy pre- and post-menopausal women. CONCLUSIONS: Overall, the results are reassuring with respect to bone safety and histomorphometric data, and do not suggest oversuppression of bone remodeling during treatment with these established risedronate regimens.

Risedronate therapy for neurofibromatosis Type 1-related low bone mass: a stitch in time saves nine.

Neurofibromatosis Type 1 (NF1) is a common hereditary disease characterized by disorders regarding the skin, neural, and skeletal systems. Osteoporosis is one of the skeletal manifestations of NF1, which is associated with increased fracture risk. The management of NF1-related low bone mass has been less studied in the literature. We present a 19-year-old patient with severe low bone mass complicating NF1. The patient received 1-year course of 35 mg risedronate sodium once per week along with a daily regimen of 1200 mg calcium and 800 IU vitamin D. Significant improvement with regard to the Z-scores and bone mineral density values was achieved. Besides, rapid favourable biochemical response was obtained. The patient experienced 24·4 and 15·0% improvements in bone mineral density at the lumbar site and hip, respectively, at the first year of therapy. No adverse effect was observed. Since increased bone turnover is the primary contributor of osteoporosis in NF1, antiresorptive agents such as bisphosphonates can be considered for treatment. Despite the lack of consensus on the treatment of osteoporosis in NF1, risedronate may hold a promise as a potential therapy for osteoporosis complicating NF1. This is the first report of risedronate therapy in a case with NF1-associated low bone mass in the literature.

The osteogenic activity of human mandibular fracture haematoma-derived progenitor cells is affected by bisphosphonate in vitro.

It is known that bisphosphonates (BPs) suppress the activity of osteoclasts; however, it has not been reported whether BPs affect the potential of human mandibular fracture haematoma-derived cells (MHCs) for bone differentiation. In this study, we examined whether the degree of bone differentiation changes following the administration of BP in vitro. The effects of alendronate and risedronate (10(-8) to 10(-7)M (mol/l)) on cell proliferation were evaluated at 4 and 8 days, after which BP treatment was applied for 4, 8, 14, and 20 days prior to assessing the alkaline phosphatase (ALP) activity and performing the mineralization assay. Alendronate 10(-8) and 10(-7)M and risedronate 10(-7)M decreased the degree of cell proliferation on day 8 (P<0.05). Using an ELISA, the ALP activity of the control, alendronate 10(-8)M, risedronate 10(-8)M, and risedronate 10(-7)M groups were 112.1±10.2%, 156.1±24.3%, 138.8±16.5%, and 133.3±10.3%, respectively, at 14 days after treatment (day 0 in each group was considered to be 100%). ALP activity was significantly higher in the alendronate 10(-8)M and risedronate 10(-8) and 10(-7)M groups than in the control group (P=0.010, 0.014, and 0.009, respectively). It is possible that BPs increase the potential of MHCs for osteogenic differentiation depending on the concentration of the drug.

Treatment satisfaction in postmenopausal women suboptimally adherent to bisphosphonates who transitioned to denosumab compared with risedronate or ibandronate.

CONTEXT: For many patients, adhering to postmenopausal osteoporosis treatment is a challenge. Higher treatment satisfaction is associated with greater persistence with these therapies, which is associated with better outcomes. OBJECTIVE: This study aimed to evaluate the change in treatment satisfaction in postmenopausal women who were suboptimally adherent to daily or weekly oral bisphosphonates and who transitioned to denosumab vs a monthly oral bisphosphonate. DESIGN AND SETTING: Pooled data of outpatients from two international, multicenter, randomized, open-label studies were analyzed. PATIENTS: Postmenopausal women (n = 1703) age 55 years or greater with low bone mineral density who were suboptimally adherent with prior oral bisphosphonate therapy, as assessed by the Osteoporosis-Specific Morisky Medication Adherence Scale, were included in the study. INTERVENTIONS: Patients received denosumab, a fully human monoclonal antibody to receptor activator of nuclear factor-kappa B ligand, 60 mg s.c. every 6 months vs the oral bisphosphonates ibandronate or risedronate, 150 mg once monthly for 12 months. MAIN OUTCOME MEASURES: Change in treatment satisfaction scores from baseline to months 6 and 12 were measured using the Treatment Satisfaction Questionnaire for Medication (TSQM). The TSQM is a validated tool that measures perception of four domains of treatment satisfaction: effectiveness, side effects, convenience, and global satisfaction. RESULTS: Patients in both treatment groups showed improvement from baseline for all four TSQM domains at 6 and 12 months. However, the denosumab group had significantly (all P < .001) greater improvements among all four TSQM domains at 6 and 12 months compared with the oral bisphosphonate group. CONCLUSIONS: Women with low adherence to oral bisphosphonates reported greater treatment satisfaction when transitioned to denosumab vs switching to a monthly oral bisphosphonate.

Efficacy, effectiveness and side effects of medications used to prevent fractures.

There is an increasing number of effective therapies for fracture prevention in adults at risk of osteoporosis. However, shortcomings in the evidence underpinning our management of osteoporosis still exist. Evidence of antifracture efficacy in the groups of patients who most commonly use calcium and vitamin D supplements is lacking, the safety of calcium supplements is in doubt, and the safety and efficacy of high doses of vitamin D give cause for concern. Alendronate, risedronate, zoledronate and denosumab have been shown to prevent spine, nonspine and hip fractures; in addition, teriparatide and strontium ranelate prevent both spine and nonspine fractures, and raloxifene and ibandronate prevent spine fractures. However, most trials provide little information regarding long-term efficacy or safety. A particular concern at present is the possibility that oral bisphosphonates might cause atypical femoral fractures. Observational data suggest that the incidence of this type of fracture increases steeply with duration of bisphosphonate use, resulting in concern that the benefit-risk balance may become negative in the long term, particularly in patients in whom the osteoporotic fracture risk is not high. Therefore, reappraisal of ongoing use of bisphosphonates after about 5 years is endorsed by expert consensus, and 'drug holidays' should be considered at this time. Further studies are needed to guide clinical practice in this area.

[Osteodeficiency in chronic pancreatitis: ways of correction].

The expediency of Vitrum Calcium 600 + D400 and Risendros using in the complex treatment of the patients with a chronic pancreatitis and osteodeficiency syndrome has been proved. As a result the status of the bone mineralization is improved, the mineral density of the bone tissue is increased.

Probenecid as a sensitizer of bisphosphonate-mediated effects in breast cancer cells.

BACKGROUND: Anti-resorptive bisphosphonates (BP) are used for the treatment of osteoporosis and bone metastases. Clinical studies indicated a benefit in survival and tumor relapse in subpopulations of breast cancer patients receiving zoledronic acid, thus stimulating the debate about its anti-tumor activity. Amino-bisphosphonates in nM concentrations inhibit farnesyl pyrophosphate synthase leading to accumulation of isopentenyl pyrophosphate (IPP) and the ATP/pyrophosphate adduct ApppI, which induces apoptosis in osteoclasts. For anti-tumor effects µM concentrations are needed and a sensitizer for bisphosphonate effects would be beneficial in clinical anti-tumor applications. We hypothesized that enhancing intracellular pyrophosphate accumulation via inhibition of probenecid-sensitive channels and transporters would sensitize tumor cells for bisphosphonates anti-tumor efficacy. METHOD: MDA-MB-231, T47D and MCF-7 breast cancer cells were treated with BP (zoledronic acid, risedronate, ibandronate, alendronate) and the pyrophosphate channel inhibitors probenecid and novobiocin. We determined cell viability and caspase 3/7 activity (apoptosis), accumulation of IPP and ApppI, expression of ANKH, PANX1, ABCC1, SLC22A11, and the zoledronic acid target gene and tumor-suppressor KLF2. RESULTS: Treatment of MDA-MB-231 with BP induced caspase 3/7 activity, with zoledronic acid being the most effective. In MCF-7 and T47D either BP markedly suppressed cell viability with only minor effects on apoptosis. Co-treatment with probenecid enhanced BP effects on cell viability, IPP/ApppI accumulation as measurable in MCF-7 and T47D cells, caspase 3/7 activity and target gene expression. Novobiocin co-treatment of MDA-MB-231 yielded identical results on viability and apoptosis compared to probenecid, rendering SLC22A family members as candidate modulators of BP effects, whereas no such evidence was found for ANKH, ABCC1 and PANX1. CONCLUSIONS: In summary, we demonstrate effects of various bisphosphonates on caspase 3/7 activity, cell viability and expression of tumor suppressor genes in breast cancer cells. Blocking probenecid and novobiocin-sensitive channels and transporters enhances BP anti-tumor effects and renders SLC22A family members as good candidates as BP modulators. Further studies will have to unravel if treatment with such BP-sensitizers translates into preclinical and clinical efficacy.

Changes in bone mineral density at 3 years in postmenopausal women receiving anastrozole and risedronate in the IBIS-II bone substudy: an international, double-blind, randomised, placebo-controlled trial.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: Cancer Research UK (C569/A5032), National Health and Medical Research Council Australia (GNT300755, GNT569213), Sanofi-Aventis, and AstraZeneca.