A meta-analysis characterizing the dose–response relationships for three oral nitrogen-containing bisphosphonates in postmenopausal women

Summary

A meta-analysis of spine BMD dose–response relationships for alendronate, risedronate, and ibandronate was performed. Data from all three oral bisphosphonates conform to a log–linear relationship between dose and change in spine BMD relative to placebo at 1 year, with an incremental gain of about 1 % for each doubling of dose.

Introduction

Animal data suggesting differences in potency and differences in approved oral dosage strengths for alendronate, risedronate, and ibandronate in the treatment of osteoporosis raise questions about their dose–response relationships and relative potencies in humans.

Methods

A meta-analysis of dose–response relationships for spine BMD increases for these three bisphosphonates was performed using data from 21 placebo-controlled trials that collectively included over 13,000 patients on active treatment and over 8,000 on placebo.

Results

For alendronate over the range of 1 to 20 mg/day, there was a strong log–linear relationship between dose and the increase in spine BMD relative to placebo at 1 year (R ²?=?0.994 using sample-weighted means). For each doubling in alendronate dose, there was an incremental gain of about 1 % in spine BMD. On the same scale, risedronate and ibandronate are approximately equipotent to alendronate on a weight-for-weight basis. The increases in BMD efficacy with each doubling of dose are parallel for all three nitrogen-containing bisphosphonates (NCBPs).

Conclusions

All three NCBPs are approximately equipotent and exhibit a log–linear relationship between dose and the increase in spine BMD. Differences in efficacy between the available oral bisphosphonate regimens appear to be a function of dose rather than inherent differences in therapeutic potential.     

Longitudinal change in clinical fracture incidence after initiation of bisphosphonates

Summary

There are differences in the risk profile of patients prescribed alendronate, risedronate, or ibandronate. Observed reductions in fracture incidence over time suggest that the effectiveness of each bisphosphonate in clinical practice has been consistent with their efficacies demonstrated in randomized controlled trials.

Introduction

Observational studies of bisphosphonate effectiveness for fracture prevention are subject to bias from unknown characteristics of baseline fracture risk at the start of therapy. The fracture incidence during the short period after starting a bisphosphonate and before any expected clinical benefit likely reflects baseline fracture risk. Bisphosphonate effectiveness may then be estimated by measuring the change in fracture incidence over time on therapy.

Methods

Administrative billing data were used to follow three cohorts of women aged 65 and older (total n?=?210,144) after starting therapy either on alendronate, risedronate, or ibandronate in the USA between market introduction and 2006. Within each cohort, the baseline incidence of clinical fractures at the hip, vertebral, and nonvertebral sites was defined by the initial 3-month period after starting therapy. Relative to these baselines, we then compared the fracture incidence during the subsequent 12 months on therapy.

Results

At the start of therapy, the ibandronate cohort was younger and had fewer prior fractures than either the risedronate or alendronate cohorts. Accordingly, the baseline incidence of hip fractures was higher in the risedronate cohort (0.90 per 100 person-years) and in the alendronate cohort (0.77) than in the ibandronate cohort (0.64). Relative to the baseline incidence, fracture incidence was significantly lower in the subsequent 12 months in both cohorts of alendronate (18% lower at hip, 28% at nonvertebral sites, and 57% at vertebral sites) and risedronate (27% lower at hip, 21% at nonvertebral sites, and 54% at vertebral sites). In the ibandronate cohort, the fracture incidence was lower (31%) only at vertebral sites.

Conclusions

Differences in the baseline fracture incidence among the cohorts may reflect differences in the risk profile of patients prescribed each bisphosphonate. The reductions observed in fracture incidence over time within each cohort suggest that the effectiveness of each bisphosphonate in clinical practice has been consistent with their efficacies demonstrated in randomized controlled trials.     

Regional bone metabolism at the lumbar spine and hip following discontinuation of alendronate and risedronate treatment in postmenopausal women

Summary

The aim of this study was to examine the effects of bisphosphonate discontinuation on bone metabolism at the spine and hip measured using ¹⁸?F-fluoride PET. Bone metabolism at the spine remained stable following discontinuation of alendronate and risedronate at 1?year but increased in the hip in the alendronate group only.

Introduction

Bisphosphonates such as alendronate (ALN) or risedronate (RIS) have persistent effects on spine BMD following discontinuation.

Methods

Positron emission tomography (PET) was used to examine regional bone metabolism in 20 postmenopausal women treated with ALN (n?=?11) or RIS (n?=?9) for a minimum of 3?years at screening (range 3–9?years, mean 5?years for both groups). Subjects underwent a dynamic scan of the lumbar spine and a static scan of both hips at baseline and 6 and 12?months following treatment discontinuation. ¹⁸?F-fluoride plasma clearance (K_i) at the spine was calculated using a three-compartment model. Standardised uptake values (SUV) were calculated for the spine, total hip, femoral neck and femoral shaft. Measurements of BMD and biochemical markers of bone turnover were also performed.

Results

With the exception of a significant decrease in spine BMD in the ALN group, BMD remained stable. Bone turnover markers increased significantly from baseline by 12?months for both study groups. Measurements of K_i and SUV at the spine and femoral neck did not change significantly in either group. SUV at the femoral shaft and total hip increased significantly but in the ALN group only, increasing by 33.8% (p?=?0.028) and 24.0% (p?=?0.013), respectively.

Conclusions

Bone metabolism at the spine remained suppressed following treatment discontinuation. A significant increase in SUV at the femoral shaft and total hip after 12?months was observed but for the ALN group only. This study was small, and further clinical studies are required to fully evaluate the persistence of BP treatment.     

Response of bone turnover markers to three oral bisphosphonate therapies in postmenopausal osteoporosis: the TRIO study

Summary

We used bone turnover markers to identify women who responded to bisphosphonate treatment for osteoporosis. Response was more likely with alendronate and ibandronate than risedronate. There was a greater decrease in bone markers if baseline bone turnover markers were higher and if the patient took more than 80 % of her medication.

Introduction

Biochemical response to bisphosphonate therapy can be assessed using either a decrease in bone turnover marker beyond the least significant change (LSC) or a reduction to within a reference interval (RI). We compared the performance of these target responses and determined whether response was related to the type of bisphosphonate, compliance and baseline bone turnover markers.

Methods

Biochemical responses to three oral bisphosphonates were assessed in an open, controlled trial comprising 172 postmenopausal osteoporotic women (age 53–84 years), randomised to alendronate, ibandronate or risedronate, plus calcium and vitamin D supplementation for 2 years. The LSC for each marker was derived within the study population, whereas RIs were obtained from a control group of healthy premenopausal women (age 35–40 years).

Results

Over 70 % of women achieved a target response for serum CTX and PINP, irrespective of the approach used. The percentage decrease at 12 weeks was greater for women with baseline PINP above the RI ?63 % (difference 13 %, 95 % CI 0 to 27.1, P?=?0.049) and good compliance ?67 % (difference 15.9 %, 95 % CI 6.3 to 25.5, P?=?0.001). Responders had a greater increase in spine bone density compared to nonresponders; for example 6.2 vs. 2.3 % (difference 3.9 %, 95 % CI 1.6 to 6.3, P?=?0.0011) for PINP LSC. The magnitude of change in bone markers was greater with ibandronate and alendronate than risedronate.

Conclusions

Both approaches to response identified similar proportions of women as responders. Nonresponders had smaller increases in BMD, and we suggest that biochemical assessment of response is a useful tool for the management of women with postmenopausal osteoporosis.

     

Use of risedronate to prevent bone loss following a single course of glucocorticoids: findings from a proof-of-concept study in inflammatory bowel disease

Summary

We performed a randomised controlled trial (RCT) to determine whether risedronate 35 mg once weekly prevents bone loss following an 8-week reducing course of prednisolone given for an exacerbation of inflammatory bowel disease (IBD). The greatest change in bone mineral density (BMD) was at Ward’s triangle (WT), which fell by 2.2% in the placebo group, compared with a reduction of 0.8% in the risedronate group.

Introduction

Whether bisphosphonates can prevent bone loss associated with intermittent glucocorticoid (GC) therapy is unknown, reflecting the difficulty in performing RCTs in this context.

Method

To explore the feasibility of RCTs to examine this question, lumbar spine (LS; L2–4) and hip dual X-ray absorptiometry (DXA) scans were performed in 78 patients commencing a GC therapy course for a relapse of IBD. They were then randomised to receive placebo or risedronate 35 mg weekly for 8 weeks, after which the DXA scan was repeated.

Results

For LS BMD, there was no change in the placebo group (0.1?±?0.4, p?=?0.9), but there was an increase after risedronate (0.8?±?0.4, p?=?0.04; mean%?±?SEM by paired Student’s t test). There were small decreases in both groups at the total hip (?0.5?±?0.3, p?=?0.04; ?0.5?±?0.3, p?<?0.05, placebo and risedronate, respectively). At WT, BMD fell after placebo (?2.2?±?0.5, p?=?0.001) but not risedronate (?0.8?±?0.5, p?=?0.09; p?=?0.05 for between-group comparison).

Conclusion

RCTs can be used to examine whether bisphosphonates prevent bone loss associated with intermittent GC therapy, providing metabolically active sites such as WT are employed as the primary outcome.     

Denosumab significantly increases bone mineral density and reduces bone turnover compared with monthly oral ibandronate and risedronate in postmenopausal women who remained at higher risk for fracture despite previous suboptimal treatment with an oral bisphosphonate

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.     

Are changes in bone mineral density different between groups of early rheumatoid arthritis patients treated according to a tight control strategy with or without prednisone if osteoporosis prophylaxis is applied?

Summary

Addition of 10 mg prednisone daily to a methotrexate-based tight control strategy does not lead to bone loss in early rheumatoid arthritis (RA) patients receiving preventive treatment for osteoporosis. A small increase in lumbar bone mineral density (BMD) during the first year of treatment was recorded, regardless of use of glucocorticoids.

Introduction

This study aims to describe effects on BMD of treatment according to EULAR guidelines with a methotrexate-based tight control strategy including 10 mg prednisone daily versus the same strategy without prednisone in early RA patients who received preventive therapy for osteoporosis.

Methods

Early RA patients were included in the CAMERA-II trial: a randomized, placebo-controlled, double-blind 2-year trial, in which effects of addition of 10 mg prednisone daily to a methotrexate-based tight control strategy were studied. All patients received calcium, vitamin D and bisphosphonates. Disease activity was assessed every 4 weeks. Radiographs of hands and feet and dual-energy X-ray absorptiometry of lumbar spine and left hip were performed at baseline and after 1 and 2 years of treatment.

Results

BMD increased significantly over time in both treatment groups at the lumbar spine with a mean of 2.6 % during the first year (p?<?0.001), but not at the hip; at none of the time points did BMD differ significantly between the prednisone and placebo group. Higher age and lower weight at baseline and higher disease activity scores during the trial, but not glucocorticoid therapy, were associated with lower BMD at both the lumbar spine and the hip in mixed-model analyses.

Conclusion

Addition of 10 mg prednisone daily to a methotrexate-based tight control strategy does not lead to bone loss in early RA patients on bisphosphonates. A small increase in lumbar BMD during the first year of treatment was found, regardless of use of glucocorticoids.     

Efficacy and safety of a novel delayed-release risedronate 35 mg once-a-week tablet

Summary

Dosing regimens of oral bisphosphonates are inconvenient and contribute to poor compliance. The bone mineral density response to a once weekly delayed-release formulation of risedronate given before or following breakfast was non-inferior to traditional immediate-release risedronate given daily before breakfast. Delayed-release risedronate is a convenient regimen for oral bisphosphonate therapy.

Introduction

We report the results of a randomized, controlled, clinical study assessing the efficacy and safety of a delayed-release (DR) 35 mg weekly oral formulation of risedronate that allows patients to take their weekly risedronate dose before or immediately after breakfast.

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 at least 30 min before breakfast (BB, n?=?308) or immediately following breakfast (FB, n?=?307). Bone mineral density (BMD), bone turnover markers (BTMs), fractures, and adverse events were evaluated. The primary efficacy variable was percent change from baseline in lumbar spine BMD at Endpoint.

Results

Two hundred fifty-seven subjects (83.7%) in the IR daily group, 252 subjects (82.1%) in the DR FB weekly group, and 258 subjects (83.8%) in the DR BB weekly group completed 1 year. Both DR weekly groups were determined to be non-inferior to the IR daily regimen. Mean percent changes in hip BMD were similar across groups. The magnitude of BTM response was similar across groups; some statistical differences were seen that were small and deemed by investigators to have no major clinical importance. The incidence of adverse events leading to withdrawal and serious adverse events were similar across treatment groups. All three regimens were well tolerated.

Conclusions

Risedronate 35 mg DR weekly is similar in efficacy and safety to risedronate 5 mg IR daily, and will allow patients to take their weekly risedronate dose immediately after breakfast.     

Factors associated with bisphosphonate treatment failure in postmenopausal women with primary osteoporosis

Summary

Among 97 postmenopausal women with primary osteoporosis, adequate calcium and vitamin D supplementation, and good compliance to a 36-month bisphosphonate treatment, the 25.8 % of patients are inadequate responders. Current smoking and a bone turnover in the upper part of the normal range increase the risk of treatment failure.

Introduction

To evaluate the prevalence of the bisphosphonate treatment failure and its possible associated factors in women with primary osteoporosis (PO).

Methods

We studied 97 previously untreated postmenopausal women with PO and fragility fractures and/or a FRAX® 10-year probability of a major osteoporotic fracture ≥7.5 %, before and after a 36-month treatment with alendronate or risedronate and adequate vitamin D supplementation with good compliance. At baseline and after 36 months, lumbar spine (LS) and femoral bone mineral density (BMD) were assessed by Dual X-ray absorptiometry and vertebral fractures by spinal radiographs. Spinal deformity index (SDI) was calculated. Treatment failure was defined by the presence of ≥2 incident fragility fractures and/or a BMD decrease greater than the least significant change.

Results

Bisphosphonate treatment failure was observed in 25.8 % of patients. Age, body mass index, years since menopause, familiar history of hip fracture, number of falls, type of bisphosphonate used, 25-hydroxyvitamin D levels (25OHVitD), BMD, SDI, and FRAX® score at baseline were not different between responders and inadequate responders. Treatment failure was associated with current smoking (OR 3.22, 95 % CI 1.10–9.50, P?=?0.034) and baseline alkaline phosphatase total activity levels ≥66.5 U/L (OR 4.22, 95 % CI 1.48–12.01, P?=?0.007), regardless of age, number of falls, LS BMD, and baseline SDI.

Conclusions

The 25.8 % of PO postmenopausal women inadequately responds to bisphosphonates, despite a good compliance to therapy and normal 25OHVitD levels. The current smoking and bone turnover in the upper part of the normal range are associated with the inadequate response to bisphosphonates.     

The limited effects of anti-tumor necrosis factor blockade on bone health in patients with rheumatoid arthritis under the use of glucocorticoid

We investigated the effects of biologics for rheumatoid arthritis (RA) patients on bone mineral density (BMD) and bone metabolic markers (BMM), retrospectively, and also clarified the effects of bisphosphonates (alendronate or risedronate 35 mg/week) and glucocorticoids. Participants in this study comprised 219 patients with RA, including 117 patients treated with biologics (infliximab, n = 90; etanercept, n = 27) and 102 patients with conventional disease-modifying anti-rheumatic drugs (DMARDs) for 1 year. Changes in BMD at the lumbar spine and total hip and BMMs [urinary type I collagen cross-linked N-telopeptide (NTX) and bone-specific alkaline phosphatase] were measured. BMD of the lumbar spine in both groups and total hip BMD in the biologics group were unchanged during treatment with biologics. However, BMD of the total hip was significantly decreased in the DMARDs group (from 0.731 ± 0.135 to 0.706 ± 0.135 g/cm²). Patients receiving glucocorticoids without bisphosphonates showed significant decrease in BMD of the total hip compared with patients not receiving glucocorticoids or receiving glucocorticoids with bisphosphonates in both biologics and DMARDs groups. Furthermore, BMD of the lumbar spine increased (p < 0.05) for patients in the biologics group who received bisphosphonates. NTX was significantly decreased only in the biologics group. Multiple regression analysis showed that BMD and bone metabolic marker levels correlated positively with bisphosphonate and biologics use and negatively with glucocorticoid use. BMD of the total hip was maintained in the patients using biologics without glucocorticoids or with bisphosphonates, but it was not maintained in the DMARDs patients, even without glucocorticoids or with bisphosphonates. Even if biologics have protective effect against bone loss of RA patients, we should consider reducing the dose of glucocorticoids and adding bisphosphonates for the treatment of osteoporosis.     

Determinants of change in bone mineral density and fracture risk during bisphosphonate holiday

Summary

In a retrospective analysis of 208 osteoporotic patients followed during a bisphosphonate holiday, lower body weight and risedronate use were associated with a more rapid decline in bone mineral density during the bisphosphonate holiday, while bone mineral density (BMD) trends were similar in patients who sustained vs. did not sustain a fracture.

Introduction

A drug holiday has been suggested for some bisphosphonate-treated patients with osteoporosis to minimize potential side effects from prolonged use. However, there is limited information on the evolution of BMD during a bisphosphonate holiday. Our study analyzed the longitudinal course of BMD following bisphosphonate discontinuation and assessed its determinants.

Methods

Retrospective single-center cohort study of osteoporosis patients treated with alendronate or risedronate for at least 2 years and then discontinued their bisphosphonate for a drug holiday. Patients were stratified by bisphosphonate type and by fracture occurrence during drug holiday.

Results

A total of 208 patients were included in this analysis (87.5 % female). At the time of bisphosphonate cessation, mean?±?SD age was 66.9?±?8.9 years and BMI 24.5?±?4.4 kg/m². Duration of bisphosphonate treatment was 5.2?±?2.3 years, and follow-up during holiday was 3.3?±?1.7 years. During the first 2 years of the holiday, BMD remained stable at the lumbar spine and femoral neck, but declined significantly at the total hip. BMD declined significantly at all sites thereafter. Significant predictors of BMD decline during bisphosphonate holiday included lower BMI at the start of the holiday and change in body weight during the holiday. BMD decline was more pronounced in former risedronate compared to former alendronate users. BMD trends were similar in patients who sustained vs. did not sustain a fracture during the holiday.

Conclusions

BMD at the total hip declines significantly within 1 year of bisphosphonate discontinuation, particularly in lean patients. Additional studies are needed to identify predictors of fracture incidence during a bisphosphonate holiday.

     

Efficacy and safety of risedronate 150-mg once a month in the treatment of postmenopausal osteoporosis: 2-year data

Summary

This study showed that risedronate 150-mg once a month provides similar efficacy and safety at 2 years compared with risedronate 5-mg daily for the treatment of postmenopausal osteoporosis. This adds to the range of risedronate dosing options and provides an alternative for patients who prefer once-a-month dosing.

Introduction

Risedronate is effective in the treatment of postmenopausal osteoporosis in oral daily, weekly, or on two consecutive days per month doses. This 2-year randomized, double-blind, multicenter study assesses the efficacy and safety of a single risedronate 150-mg once-a-month oral dose compared with the 5-mg daily regimen.

Methods

Women with postmenopausal osteoporosis were randomly assigned to receive risedronate 5-mg daily (n?=?642) or 150-mg once a month (n?=?650) for 2 years. Bone mineral density (BMD), bone turnover markers, new vertebral fractures, and adverse events were evaluated. The primary efficacy endpoint was the mean percent change from baseline in lumbar spine BMD after 1 year.

Results

Four hundred ninety-eight subjects in the daily group (77.6 %) and 513 subjects in the once-a-month group (78.9 %) completed the study. After 24 months, the mean percent change in lumbar spine BMD was 3.9 % (95 % confidence interval [CI], 3.43 to 4.42 %) and 4.2 % (95 % CI, 3.68 to 4.65 %) in the daily and once-a-month groups, respectively. The once-a-month regimen was determined to be non-inferior to the daily regimen. The mean percent changes in BMD at the hip were similar in both dose groups, as were changes in biochemical markers of bone turnover. The incidence of adverse events, adverse events leading to withdrawal, and upper gastrointestinal tract adverse events were similar in the two treatment groups.

Conclusions

After 2 years, treatment with risedronate 150-mg once a month provided similar efficacy and tolerability to daily dosing and provides an alternative for patients who prefer once-a-month oral dosing.     

The non-interventional BonViva Intravenous Versus Alendronate (VIVA) study: real-world adherence and persistence to medication, efficacy, and safety, in patients with postmenopausal osteoporosis

Summary

Adherence and persistence to oral bisphosphonates in women with postmenopausal osteoporosis is suboptimal. In this study, patients were treated with either oral or intravenous bisphosphonates. The increased adherence and persistence observed in patients receiving intravenous medication compared with those receiving oral medication may improve health outcomes.

Introduction

Poor adherence and persistence to oral medication are often observed in women with postmenopausal osteoporosis (PMO). The purpose of the non-interventional BonViva Intravenous Versus Alendronate (VIVA) study was to determine whether, in a real-world setting, (1) increased adherence and persistence to medication would be observed in women with PMO receiving intravenous (i.v.) ibandronate versus oral alendronate, (2) a correlation exists between adherence and persistence to medication and drug efficacy, and (3) any unexpected adverse events/serious adverse events (AEs/SAEs) may occur.

Methods

The study was conducted in 632 centers in Germany. A total of 6,064 females with PMO were enrolled and recruited into one of two treatment arms: quarterly i.v. administration of 3 mg ibandronate or weekly oral medication of 70 mg alendronate, for 12 months. At the end of the study, adherence and persistence to medication, new osteoporotic fractures, mobility, use of analgesics, and AEs/SAEs were determined.

Results

Greater adherence and persistence to medication were observed in the ibandronate treatment arm compared with the alendronate treatment arm. Although there was no significant difference in the number of patients with new vertebral, hip, or forearm fractures between treatment arms, a significantly greater increase in mobility and decrease in the use of analgesics were reported in the ibandronate treatment arm. No unexpected AEs/SAEs occurred in either arm.

Conclusions

Adherence and persistence to medication were greater in women with PMO receiving i.v. ibandronate compared with those receiving oral alendronate. This may have led to an increase in mobility and a decrease in pain in these patients.     

Effect of alendronate in elderly patients after low trauma hip fracture repair

Summary

One year of once weekly alendronate, when given shortly after the surgical repair of a hip fracture, produces reductions in bone markers and increases proximal femoral bone density. The therapy was well tolerated.

Introduction

Hip fracture is the most devastating type of osteoporotic fracture and increases notably the risk of subsequent fractures. The aim of this paper was to evaluate the effects of 1 year therapy with a weekly dose of alendronate in the bone mineral density and bone markers in elderly patients after low trauma hip fracture repair.

Methods

Two hundred thirty-nine patients (81?±?7 years; 79.8% women) were randomized to be treated either with calcium (500 mg/daily) and vitamin D₃ (400 IU/daily; Ca–Vit D group) or with alendronate (ALN, 70 mg/week) plus calcium and vitamin D₃ (500 mg/daily and 400 IU/daily, respectively; ALN + Ca–Vit D group).

Results

One hundred forty-seven (61.5%) patients completed the trial. Alendronate increased proximal femoral bone mineral density (BMD) in the intention-to-treat analysis (mean difference (95% confidence interval); total hip 2.57% (0.67; 4.47); trochanteric 2.96% (0.71; 5.20), intertrochanteric 2.32% (0.36; 4.29)), but the differences were not significant in the BMD of the femoral neck (0.47%; (?2.03; 2.96) and the lumbar spine (0.69%; (?0.86; 2.23)). Bone turnover markers decreased during alendronate treatment.

Conclusion

The present study demonstrates for the first time the anti-resorptive efficacy of alendronate given immediately after surgical repair in an elderly population with recent hip fracture. This effect should positively affect the rate of subsequent fractures.     

Comparative efficacy of bisphosphonates in short-term fracture prevention for primary osteoporosis: a systematic review with network meta-analyses

Summary

Our network meta-analyses compared the efficacy of different bisphosphonates preventing fractures for primary osteoporosis. By including 36 studies, we found that zoledronic acid seemed the most effective in preventing vertebral fracture, nonvertebral fracture, and any fracture, and alendronate or zoledronic acid seemed the most effective in preventing hip fracture.

Introduction

This study was conducted in order to analyze the available evidence on the efficacy of bisphosphonates for preventing fractures.

Methods

We considered randomized trials comparing any bisphosphonate with other bisphosphonate or placebo. We searched Cochrane Library, Embase, and PubMed and manually searched reference list of relevant articles. Pairwise and network meta-analyses were performed. The primary outcome is vertebral fracture. Secondary outcomes include nonvertebral fracture, hip fracture, wrist fracture, and any fracture.

Results

Thirty-six studies were included. Significant difference was found between bisphosphonates for vertebral fracture and nonvertebral fracture (P?<?0.0001 and P?=?0.04, respectively). Compared with placebo, alendronate, clodronate, ibandronate, minodronate, pamidronate, risedronate, and zoledronic acid significantly prevented vertebral fracture. Zoledronic acid significantly reduced the risk of vertebral fracture, compared with alendronate, clodronate, etidronate, ibandronate, risedronate, and tiludronate (0.65 (0.46, 0.91), 0.53 (0.33, 0.86), 0.45 (0.27, 0.74), 0.52 (0.36, 0.75), 0.59 (0.42, 0.83), and 0.31 (0.21, 0.48), respectively). Compared with etidronate, clodronate and zoledronic acid significantly prevented nonvertebral fracture. Compared with alendronate, zoledronic acid significantly prevented any fracture. The possibility rankings showed that zoledronic ranked first in preventing vertebral fracture, hip fracture, and any fracture, and pamidronate ranked first in preventing nonvertebral fracture and wrist fracture. In the sensitivity analyses, zoledronic acid ranked first in preventing nonvertebral fracture, and alendronate ranked first in preventing hip fracture and wrist fracture.

Conclusion

Zoledronic acid seemed the most effective in preventing vertebral fracture, nonvertebral fracture, and any fracture, and alendronate or zoledronic acid seemed the most effective in preventing hip fracture. Uncertainty still remains and future studies are needed to accurately evaluate the comparative efficacy of bisphosphonates.

     

Evaluation of urinary N-telopeptide of type I collagen measurements in the management of osteoporosis in clinical practice

Summary

We measured urinary N-telopeptide of type I collagen (U-NTX) to monitor response to bisphosphonates for osteoporosis. Decrease in U-NTX was associated with increase in spine bone density. A lesser response in U-NTX was more likely in those with secondary osteoporosis or with poor compliance. U-NTX may be a useful early indicator of treatment non-compliance or secondary osteoporosis.

Introduction

This study aims to determine the utility of the bone resorption marker, U-NTX, in the clinical setting, to monitor the response to bisphosphonate therapy (alendronate and risedronate) for osteoporosis.

Methods

A retrospective evaluation of data collected as part of the bone turnover marker monitoring service in the Metabolic Bone Centre, Sheffield, UK. Treatment compliance, underlying causes of osteoporosis, change in U-NTX/creatinine (Cr) at 4 months and change in spine and hip bone mineral density (BMD) by dual-energy X-ray absorptiometry were recorded. Treatment response was defined as either a change in U-NTX/Cr greater than a pre-defined least significant change (LSC) of 54 % or to within the lower half of a pre-defined pre-menopausal reference interval (≤30 nM BCE/mmol Cr).

Results

A greater decrease in U-NTX/Cr at 4 months was associated with a greater increase in spine BMD at 18 months (r?=??0.33; P?<?0.0001, Pearson’s correlation). The mean U-NTX/Cr at 4 months was higher in patients with secondary osteoporosis compared with those with primary osteoporosis (P?<?0.01, ANOVA). A lesser response in U-NTX/Cr increased the likelihood of secondary osteoporosis or poor treatment compliance (P?=?0.04, Fisher’s exact test). A lack of response in U-NTX/Cr to within the lower half of the reference interval was a better indicator of secondary osteoporosis and treatment non-compliance than a change in U-NTX/Cr greater than LSC.

Conclusions

Treatment monitoring using U-NTX/Cr has a place in clinical practice for the early identification of non-compliance or presence of secondary osteoporosis.     

Comparative effects of teriparatide and ibandronate on spine bone mineral density (BMD) and microarchitecture (TBS) in postmenopausal women with osteoporosis: a 2-year open-label study

Summary

Treatment effects over 2 years of teriparatide vs. ibandronate in postmenopausal women with osteoporosis were compared using lumbar spine bone mineral density (BMD) and trabecular bone score (TBS). Teriparatide induced larger increases in BMD and TBS compared to ibandronate, suggesting a more pronounced effect on bone microarchitecture of the bone anabolic drug.

Introduction

The trabecular bone score (TBS) is an index of bone microarchitecture, independent of bone mineral density (BMD), calculated from anteroposterior spine dual X-ray absorptiometry (DXA) scans. The potential role of TBS for monitoring treatment response with bone-active substances is not established. The aim of this study was to compare the effects of recombinant human 1–34 parathyroid hormone (teriparatide) and the bisphosphonate ibandronate (IBN), on lumbar spine (LS) BMD and TBS in postmenopausal women with osteoporosis.

Methods

Two patient groups with matched age, body mass index (BMI), and baseline LS BMD, treated with either daily subcutaneous teriparatide (N?=?65) or quarterly intravenous IBN (N?=?122) during 2 years and with available LS BMD measurements at baseline and 2 years after treatment initiation were compared.

Results

Baseline characteristics (overall mean ± SD) were similar between groups in terms of age 67.9?±?7.4 years, body mass index 23.8?±?3.8 kg/m², BMD L1–L4 0.741?±?0.100 g/cm², and TBS 1.208?±?0.100. Over 24 months, teriparatide induced a significantly larger increase in LS BMD and TBS than IBN (+7.6 %?±?6.3 vs. +2.9 %?±?3.3 and +4.3 %?±?6.6 vs. +0.3 %?±?4.1, respectively; P?<?0.0001 for both). LS BMD and TBS were only weakly correlated at baseline (r ²?=?0.04) with no correlation between the changes in BMD and TBS over 24 months.

Conclusions

In postmenopausal women with osteoporosis, a 2-year treatment with teriparatide led to a significantly larger increase in LS BMD and TBS than IBN, suggesting that teriparatide had more pronounced effects on bone microarchitecture than IBN.     

Effect of oral monthly ibandronate on bone microarchitecture in women with osteopenia—a randomized placebo-controlled trial

Summary

We have examined the effect of oral monthly ibandronate on distal radius and tibia microarchitecture with high-resolution peripheral quantitative tomography compared with placebo, in women with osteopenia, and found that ibandronate did not significantly affect trabecular bone but improved cortical density and thickness at the tibia.

Methods

We have examined the effect of ibandronate on bone microarchitecture with peripheral high-resolution quantitative computed tomography (HR-pQCT) in a randomized placebo-controlled trial among 148 women with osteopenia. Patients received either oral 150 mg monthly ibandronate or placebo over 24 months. Bone microarchitecture was assessed at baseline, 6, 12, and 24 months, using HR-pQCT at the distal radius and tibia; areal bone mineral density (aBMD) was measured with DXA at the spine, hip, and radius.

Results

At 12 months, there was no significant difference in trabecular bone volume at the radius (the primary end point) between women on ibandronate (10.8?±?2.5%) and placebo (10.5?±?2.9%), p?=?0.25. There was no significant difference in other radius trabecular and cortical microarchitecture parameters at 12 and 24 months. In contrast, at the tibia, cortical vBMD in the ibandronate group was significantly greater than in the placebo group at 6, 12, and 24 months, with better cortical thickness at 6, 12, and 24 months. With ibandronate, aBMD was significantly increased at the hip and spine at 12 and 24 months but at the radius was significantly superior to placebo only at 24 months. Most of the adverse events related to ibandronate were expected with bisphosphonate use, and none of them were serious.

Conclusion

We conclude that 12 months of treatment with ibandronate in women with osteopenia did not affect trabecular bone microarchitecture, but improved cortical vBMD at the tibia at 12 and 24 months, and preserved cortical thickness at the tibia.     

Treatment of postmenopausal osteoporosis with delayed-release risedronate 35 mg weekly for 2 years

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.