If you don't remember your password, you can reset it by entering your email address and clicking the Reset Password button. You will then receive an email that contains a secure link for resetting your password
If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password
The aim of this study was to assess the efficacy, tolerability and safety of risedronate in adults with CF.
Methods
Patients with a lumbar spine (LS), total hip (TH) or femoral neck (FN) bone mineral density (BMD) Z-score of −1 or less were randomised to receive risedronate 35 mg weekly or placebo, and calcium (1 g)+vitamin D3 (800 IU).
Results
At baseline, BMD Z-scores in the risedronate (n=17) and placebo (n=19) groups were similar. By 24 months, 7/17 risedronate patients vs 0/19 placebo patients stopped the study medication due to bone pain. After 24 months treatment, the mean difference (95% CI) in change in LS, TH and FN BMD between the risedronate vs placebo groups was 4.3% (0.4, 8.2) p=0.03; 4.0% (−0.5, 8.6) p=0.08; and 2.4% (-3.5, 8.2) p=0.41.
Conclusions
After two years treatment there was a significant increase in LS BMD with weekly risedronate compared to placebo.
], it is not known if it affects bone cell activity. However, recent data suggest that CFTR dysfunction may lead to reduced expression of osteoprotegerin, the soluble decoy receptor for RANKL and this may result in increased osteoclastic bone resorption [
]. Chronic pulmonary infection is also thought to stimulate bone resorption through the effects of pro-inflammatory cytokines on osteoclast maturation and activity [
Bisphosphonates are potent inhibitors of osteoclastic bone resorption and are effective in the prevention of fragility fractures in postmenopausal women, male osteoporosis and glucocorticoid induced osteoporosis [
National Institute for Health and Clinical Excellence. Final appraisal determination. Alendronate, etidronate, risedronate, raloxifene and strontium ranelate for the primary prevention of osteoporotic fragility fractures in postmenopausal women. NICE,
LondonJune 2007
National Institute for Health and Clinical Excellence. Final appraisal determination. Alendronate, etidronate, Risedronate, raloxifene, strontium ranelate and teriparatide for the secondary prevention of osteoporotic fragility fractures in postmenopausal women. NICE,
LondonJune 2007
]. Previous studies have also shown that three monthly bisphosphonate infusions (pamidronate and zoledronic acid) and oral alendronate (taken daily and weekly) are effective in increasing BMD in adults with CF [
]. To date there have been no studies of the oral bisphosphonate risedronate in adults with CF. Risedronate is an aminobisphosphonate which is approved for the prevention and treatment of osteoporosis in men and postmenopausal women and glucocorticoid induced osteoporosis [
National Institute for Health and Clinical Excellence. Final appraisal determination. Alendronate, etidronate, risedronate, raloxifene and strontium ranelate for the primary prevention of osteoporotic fragility fractures in postmenopausal women. NICE,
LondonJune 2007
National Institute for Health and Clinical Excellence. Final appraisal determination. Alendronate, etidronate, Risedronate, raloxifene, strontium ranelate and teriparatide for the secondary prevention of osteoporotic fragility fractures in postmenopausal women. NICE,
LondonJune 2007
Efficacy and safety of daily risedronate in the treatment of corticosteroid-induced osteoporosis in men and women: a randomized trial. European Corticosteroid-Induced Osteoporosis Treatment Study.
]. It is believed to have a shorter half life in bone than alendronate, which is relevant to females who wish to become pregnant following cessation of bisphosphonate therapy. The aim of this study was to assess the long term efficacy, tolerability and safety of risedronate administered once weekly in adults with CF.
2. Methods
2.1 Participants
Adults with CF aged 18 years and over were recruited between November 2005 and June 2007 from four UK adult CF centres: Papworth Hospital, Cambridge; The Royal Brompton Hospital, London; St James's University Hospital, Leeds; and Belfast City Hospital, Belfast. The diagnosis of CF was made on the basis of a positive sweat test or gene analysis and a consistent CF phenotype.
Eligibility was assessed at a screening visit. Patients were included if their lumbar spine (LS) or total hip (TH) or femoral neck (FN) BMD Z-score was −1.0 or less. Exclusion criteria were the prescription of daily oral glucocorticoids for six weeks or more in the 12 months preceding the study; breast feeding, pregnancy, desire to become pregnant within three years; listed for, or recipient of solid organ transplant; history of gastroscopy proven oesophageal abnormalities; renal impairment (elevated serum creatinine and an estimated creatinine clearance of 30 ml/min or less); hypocalcaemia; previous prescription of bone active drugs (bisphosphonates, hormone replacement therapy, raloxifene, calcitriol, calcitonin, teriparatide); biochemical evidence of vitamin D deficiency in the 12 months prior to the screening visit (25-hydroxyvitamin D level<10 ng/ml and PTH >45 pg/ml); previous poor clinic attendance; previous poor adherence; pre-terminal illness or other serious concomitant illness. The study was approved by the local ethics committee (Cambridge, UK) and submitted to www.clinicaltrials.gov.
2.2 Study protocol
Patients were randomised to receive once weekly risedronate 35 mg or identical placebo (Procter & Gamble, Norwich, USA). Both groups were prescribed Calcichew D3 Forte two tablets daily (Shire Pharmaceuticals, Hampshire, UK) which provides 1000 mg calcium+800 IU vitamin D3/day. Patients were advised to continue their standard multivitamin supplements. Female participants of reproductive age were advised not to become pregnant for at least 12 months after study completion.
Participants commenced the study medication within six weeks of the screening visit. Study visits were conducted after 3, 6, 12, 18 and 24 months of treatment and included a clinical assessment and a pregnancy test (in females). X-ray confirmed fractures, concomitant medications and adverse events were also recorded.
The serum concentration of C-terminal cross-linked telopeptide of collagen type 1 (CTX), a biochemical marker of bone resorption, was measured at the baseline and six month visits in 24 patients (12 risedronate, 12 placebo). CTX was measured using the serum CrossLaps ELISA kit (IDS Ltd, UK), which has an intra-assay variation of 1.8–3.0%.
Adherence was measured through performing a residual tablet count at each study visit.
2.3 Bone densitometry
The primary outcome measure was change in BMD (LS) measurements at 24 months of treatment, adjusted for baseline measurement, using dual energy X-ray absorptiometry (DXA). Secondary outcome variables included change in BMD (TH and FN) at 24 months, change in BMD at 12 months and new vertebral fractures during the 24 months of treatment.
DXA scans were performed on the Hologic Discovery (Hologic Inc, Bedford, MA) at Belfast City Hospital and Papworth Hospital, on the GE Lunar DPX-IQ (GE Healthcare, WI) at the Royal Brompton Hospital and the GE Lunar Prodigy (GE Healthcare, WI) at St James Hospital. The European spine phantom (ESP) was scanned at each centre at the start and end of the study and these data were used to standardise measurements between the different densitometers [
European Semi-Anthropomorphic spine phantom for the calibration of bone densitometers—assessment of precision, stability, and accuracy—the European Quantitation of Osteoporosis Study Group.
]. BMD was reported as g/cm2 and as Z-scores. Z-scores were calculated using Hologic reference data for the lumbar spine and National Health and Nutrition Examination Survey (NHANES) reference data for the proximal femur [
]. To monitor quality assurance, a manufacturer specific spine phantom was scanned at each site three or more times each week during the study period [
]. There were no significant drifts or jumps in quality assurance data from each centre and the precision (CV%) of the spine phantom measurements was 0.35% at Belfast City Hospital, 0.40% at St James Hospital, 0.42% at Papworth Hospital and 0.69% at The Royal Brompton Hospital.
2.4 Fracture determination
Lateral thoracic and lumbar spine X-rays were performed at the baseline visit and after 24 months of treatment. A blinded radiologist (PB) assessed all X-rays for vertebral fractures using the semi quantitative method of Genant et al. [
]. The assumed mean change (SD) in LS BMD was 5% (3%) in the risedronate arm and −2% (4%) in the placebo arm. Assuming two-sided significance of 5% and 90% power, we aimed to recruit 40 patients, allowing for 25% dropping out during the two year trial. Patients were allocated to risedronate or placebo using a computer programme to minimise differences between groups in treatment centre, sex and baseline LS BMD. Only the study pharmacist had access to the treatment allocation.
Study data were analysed using STATA version 11.0. Data were summarised as the mean (SD), median (interquartile range), or number (%). In exploratory analysis differences between groups were assessed using Fisher's exact test, Mann–Whitney U test and the Student t-test. For inference mean differences with 95% confidence intervals are presented. The differences in BMD measurements were estimated using general linear models, including baseline values and treatment group as covariates. Adverse events were tabulated for each treatment group and incidence rates were compared using log-linear regression.
The statistical design and analysis followed CONSORT guidelines [
]. An intention to treat principle was used to compare the treatment groups. Only patients who completed 24 months of follow up were included in the initial analysis of primary outcome (n=24). Multiple imputation analyses were undertaken to estimate primary outcomes for all patients, whilst incorporating the full variation in measurement. Imputed values were based on baseline BMD, treatment group, spirometry and treatment centre. Since these analyses gave very similar results only the completers analysis is included.
3. Results
The preliminary results of this study were presented at the European and North American Cystic Fibrosis conferences in 2010 [
Multicentre randomised double blind placebo controlled trial assessing the effect of weekly risedronate on bone mineral density in adults with cystic fibrosis.
Two-year multicenter, randomised, double-blind, placebo-controlled trial assessing the effect of weekly risedronate on bone mineral density in adults with CF.
The CONSORT diagram is shown in Fig. 1. Forty-six patients were screened for the study. Of these, 8 patients were excluded due to very low BMD (n=1), BMD Z-score in the LS and proximal femur>−1 (n=4) and biochemical evidence of vitamin D deficiency (n=3). A further two patients decided not to take part in the trial. The remaining 36 patients were recruited and randomised to risedronate (n=17) or placebo (n=19). Recruitment became increasingly difficult as the trial progressed due to the adverse events (bone pain) reported by some of the initial participants (see below).
Fig. 1CONSORT flow diagram. (NB one placebo patient at 12 months had incomplete follow up due to illness).
Immediately after randomisation one patient in the placebo group withdrew consent before taking the study medication. Therefore, only 18 patients were commenced on placebo. By 12 months, 16/19 (84%) placebo patients remained in the study, two patients had withdrawn consent and one patient had died.
At 12 months, 14/17 (82%) risedronate patients remained in the study, 11 of whom were still taking the study medication. Three patients had withdrawn from the study completely (due to bone pain) and three patients discontinued the study medication (one patient citing bone pain and two patients citing muscle aches/generalised pain) but remained in the study for follow up.
By 24 months, 12/19 (63%) placebo patients remained in the study, three patients had withdrawn consent and four patients had died.
By 24 months, 12/17 (71%) risedronate patients remained in the study, nine of whom were still taking the study drug. Between 12 and 24 months one further patient withdrew from the study (citing bone pain) and one patient died.
3.1 Demographic and clinical characteristics
The baseline demographic and clinical characteristics of the 36 patients who were randomised are summarised in Table 1, Table 2. There were no significant differences in demographic or clinical characteristics between participants randomised to the risedronate or placebo groups.
Table 1Demographic and clinical details of patients in risedronate and placebo groups.
The percentage changes in BMD from baseline in the risedronate and placebo groups after 12 and 24 months treatment are summarised in Table 3. Primary outcome data were available for 12/17 (71%) of the risedronate group and 12/19 (63%) of the placebo group. Treatment with risedronate led to a significant increase in the primary outcome (LS BMD), compared to placebo (mean difference 4.3 (95% CI 0.4, 8.2) %, p=0.03) over a two-year period. There was a non-significant improvement in TH BMD in risedronate treated patients compared to placebo (mean difference 4.0 (95% CI −0.5, 8.6) %, p=0.08), and in FN BMD (mean difference 2.4 (95% CI −3.5, 8.2) %, p=0.41).
Table 3Percentage change from baseline in absolute bone mineral density in the risedronate and placebo groups after 12 and 24 months treatment.
Risedronate
Placebo
Difference R—P adjusted for baseline (95% CI)
p
Change from baseline in lumbar spine BMD after 12 months
4.3 (7.0)%
−1.2 (6.4)%
5.8 (1.2, 10.4)%
0.02
(n=14)
(n=15)
Change from baseline in lumbar spine BMD after 24 months
3.1 (5.5)%
0.1 (4.3)%
4.3 (0.4, 8.2)%
0.03
(n=12)
(n=12)
Change from baseline in total hip BMD after 12 months
2.1 (7.3)%
−1.7 (2.9)%
3.6 (−1.1, 8.3)%
0.13
(n=13)
(n=15)
Change from baseline in total hip BMD after 24 months
2.0 (5.8)%
−2.0 (3.6)%
4.0 (−0.5, 8.6)%
0.08
(n=11)
(n=12)
Change from baseline in femoral neck BMD after 12 months
2.5 (7.3)%
−1.1 (4.7)%
3.5 (−1.7, 8.7)%
0.18
(n=13)
(n=15)
Change from baseline in femoral neck BMD after 24 months
Fig. 2 shows the mean percentage change (95% CI) in LS, TH and FN BMD from baseline in the risedronate and placebo groups after 12 and 24 months treatment.
Fig. 2Mean percentage change (95% CI) in bone mineral density from baseline to 12 and 24 months for completers at A) the lumbar spine B) the total hip and C) the femoral neck.
The median (IQR) serum CTX concentrations in the risedronate and placebo groups at baseline were: 0.32 (0.64) ng/ml vs 0.37 (0.55) ng/ml, p=1.00, respectively. The median (IQR) serum CTX concentrations in the risedronate and placebo groups after six months treatment were: 0.15 (0.22) ng/ml vs 0.46 (0.75) ng/ml, p=0.02, respectively.
3.4 Fractures
One patient had a vertebral fracture identified at the baseline visit. There were no new vertebral fractures identified at the end of the study. There were no new rib or long bone fractures reported during the study period.
3.5 Adherence
Participants were considered adherent if the residual tablet count at a study visit suggested that study medication had been taken correctly >80% of the time. Of the 12 placebo patients who remained on the study medication throughout the study, four were adherent at each study visit. Of the nine risedronate patients who remained on the study medication throughout the study, five were adherent at each study visit.
3.6 Adverse events
Three hundred and forty six adverse events were recorded within two years of randomisation. Most events were classed as respiratory exacerbations (n=230) and there was no difference in incidence between the two groups. Gastrointestinal symptoms were also common (n=42) and there was an excess in the risedronate group (26 vs. 16). These events corresponded to the same number of patients in each study group (nine in risedronate, nine in placebo).
Bone pain was recorded 19 times by nine different risedronate patients in the first year after randomisation, while there were no episodes of bone pain in the placebo group. Fourteen of 19 (74%) episodes occurred within the first 56 days after randomisation. Five events (26%) were classified as severe and led to the discontinuation of the study medication. Of the other events, ten were classified as moderate and four as mild. Only two (11%) events were considered to be unrelated to the study medication. There were no differences in baseline CRP, 25-hydroxyvitamin D, PTH or CTX levels between the risedronate patients that experienced bone pain and those that did not (p>0.5 for all). However, the median (IQR) number of intravenous antibiotic days in the year prior to randomisation was 28 (42) for risedronate treated patients that developed bone pain vs 0 (3) for those that did not (p=0.01).
Overall in the two-year follow up, there was an excess of events in the risedronate arm, mostly due to bone pain and gastrointestinal problems. This was significant for the non-serious adverse events (Relative Risk=1.52, 95% CI 1.18 to 1.96, p=0.0008), but not for the serious adverse events (Relative Risk=1.17, 95% CI 0.76 to 1.79, p=0.46).
4. Discussion
This is the first trial assessing the efficacy, safety and tolerability of risedronate in adults with CF. The results show that treatment with risedronate led to a significant increase in LS BMD compared to placebo (mean difference 4.3 (95% CI 0.4, 8.2) %, p=0.03) over a two-year period. Similar but non-significant trends were seen at the proximal femur. The significant reduction in serum CTX in the risedronate treated patients after six months is consistent with inhibition of osteoclastic bone resorption.
There was no excess of serious adverse events associated with the use of risedronate. However, seven out of 17 (41%) patients in the risedronate group discontinued the study drug or withdrew from the study completely, citing bone pain or muscle aches / generalised pain as the reason. Flu-like symptoms occur in approximately 30% of postmenopausal women following the first dose of intravenous zoledronic acid [
]. It remains unclear why bone pain should occur more commonly with risedronate than alendronate in people with CF. Potential explanations include differences in the populations studied, medication specific differences or differences in the definitions of adverse events. Baseline vitamin D levels were suboptimal in some risedronate treated patients which could predispose patients to develop bone pain through bisphosphonate induced osteomalacia or bisphosphonate induced secondary hyperparathyroidism, but there were no differences in baseline vitamin D, PTH or CTX levels between those that developed pain and those that did not. Furthermore, bone pain was a common adverse event in the Australian study of intravenous zoledronic acid, the participants of which were vitamin D replete [
]. While there was also no difference in baseline CRP between risedronate treated patients that developed bone pain and those that did not, the significantly greater requirement for intravenous antibiotic treatment in the year prior to randomisation in those that developed bone pain suggests that an individual's antibiotic history (a possible surrogate marker of pulmonary inflammation) may be useful in predicting the likelihood of bone pain after starting bisphosphonate therapy.
], bone pain in the current study involved the vertebrae, ribs and long bones. It usually started within 24 h of the first dose of risedronate and lasted for approximately 72 h. Five events were classified as severe and led to discontinuation of the study medication. There were no reported episodes of bone pain in the placebo group. The prescription of paracetamol and ibuprofen prior to and after taking risedronate appeared to reduce the severity of bone pain / flu like symptoms in some patients. In a previous study, intravenous antibiotics and / or oral glucocorticoids administered before the first dose of intravenous pamidronate appeared to reduce the likelihood of bone pain in adults with CF [
], but Chapman and colleagues found no such effect when oral glucocorticoids were given for a short time before and after the first infusion of zoledronic acid [
]. It is now clear that bone pain occurs after both intravenous and oral bisphosphonates in patients with CF and it is possible that a course of intravenous antibiotics administered before starting bisphosphonate therapy may reduce the likelihood of bone pain through decreasing pulmonary inflammation.
The magnitude of change in BMD in the current study is broadly comparable to that observed in the other oral bisphosphonate studies in CF. In a 12-month study comparing the effect of alendronate 70 mg once weekly with placebo, alendronate patients gained 5.2 (3.7) and 2.1 (3.3)% in the LS and TH BMD, versus placebo patients who lost 0.08 (3.9) (p<0.001) and 1.3 (2.7)% (p<0.001), respectively [
]. In a 12-month study comparing the effect of alendronate 10 mg daily with placebo, alendronate treated patients gained 4.9 (3.0)% and 2.8 (3.2)% in spine and femur BMD versus placebo patients who lost 1.8 (4.0)% (p<0.001) and 0.7 (4.7)% (p=0.003), respectively [
]. However, the magnitude of change in BMD appears greater following intravenous bisphosphonates in patients with CF, particularly in the proximal femur where rates of bone loss tend to be highest in untreated CF patients [
]. In a 24-month trial comparing the effect of intravenous zoledronic acid with placebo, the zoledronic acid group gained 6.1 (1.9)% and 4.2 (1.3)% in LS and FN BMD, versus placebo patients who gained 0.44 (0.10)% (p=0.021) and lost 2.5 (1.4)% (p=0.0028), respectively [
]. This apparent difference between the oral and intravenous preparations does not reflect the longer duration of the intravenous zoledronic acid study as the majority of change in BMD was evident after 12 months treatment [
]. This observation is further supported by the findings of a six-month trial investigating the effect of three monthly pamidronate infusions on BMD in adults with CF. Pamidronate treated patients showed a significant increase in BMD compared to controls in the LS (mean difference 5.8%, 95% CI 2.7% to 8.9%) and total hip (mean difference 3.0%, 95% CI 0.3% to 5.6%) after only two doses [
], intravenous bisphosphonates are likely to be more effective at increasing BMD in patients with CF.
This study has several limitations. Although the primary outcome measure was met, the sample size was small. The high incidence of bone pain made recruitment to the study increasingly difficult and ultimately reduced its power. Suboptimal adherence may also have diluted the treatment effect, but reflects the reality of prescribing a medicine with a complex administration regimen in an already overburdened patient population. As with other bisphosphonate studies in CF [
], the current study was not powered to demonstrate a change in fracture incidence and relies on BMD as a surrogate marker of bone health. Furthermore, the BMD threshold at which bisphosphonate treatment should be initiated and the duration of treatment has not been addressed by this study.
In conclusion, after two years treatment there was a significant increase in LS BMD with weekly risedronate compared to placebo. As risedronate is believed to have a shorter half life in bone than other more potent bisphosphonates, risedronate may be a preferable option for females who wish to become pregnant (following cessation of bisphosphonate therapy) in the future. Strategies to reduce the incidence of bone pain following bisphosphonate treatment need to be evaluated in adults with CF.
Conflict of interest statement
Charles Haworth received an unrestricted educational grant from Proctor & Gamble to fund this study.
Linda Sharples—no conflicts of interest
Vikki Hughes—no conflicts of interest
Sarah Elkin—no conflicts of interest
Margaret Hodson—no conflicts of interest
Steven Conway—no conflicts of interest
Christine Etherington—no conflicts of interest
Stuart Elborn—no conflicts of interest
Jackie Rendall—no conflicts of interest
Ella Wheaton—no conflicts of interest
Emma Kadri—no conflicts of interest
Jane Elliott—no conflicts of interest
Helen Barker—no conflicts of interest
Philip Bearcroft—no conflicts of interest
Thinn Hlaing—no conflicts of interest
Juliet Compston received an unrestricted educational grant from Proctor & Gamble to fund this study. Juliet Compston has also received fees for attending / speaking at symposia from Proctor & Gamble and fees from Sanofi Aventis for consultancy work.
Acknowledgements
We would like to thank Proctor & Gamble (Norwich, USA) and the Cystic Fibrosis Trust for unrestricted educational grants to fund this study.
We would like to thank Professor Judith Adams, Elizabeth Harrison, Elaine Gunn, Katherine Treacy, Valerie Bell, Fiona Kerr, Myril Fairhurst and Sandra Scott for their invaluable help in conducting the study.
JEC and PB acknowledge the support of the NHS National Institute of Health Research (UK). Ella Wheaton completed statistical analysis during a Medical Research Council Clinical Trials Trainee Fellowship funded by the UK National Institute for Health Research.
References
Aris R.M.
on behalf of the Cystic Fibrosis Foundation Consensus Bone Health Group. Guide to bone health and disease in cystic fibrosis.
National Institute for Health and Clinical Excellence. Final appraisal determination. Alendronate, etidronate, risedronate, raloxifene and strontium ranelate for the primary prevention of osteoporotic fragility fractures in postmenopausal women. NICE,
LondonJune 2007
National Institute for Health and Clinical Excellence. Final appraisal determination. Alendronate, etidronate, Risedronate, raloxifene, strontium ranelate and teriparatide for the secondary prevention of osteoporotic fragility fractures in postmenopausal women. NICE,
LondonJune 2007
Efficacy and safety of daily risedronate in the treatment of corticosteroid-induced osteoporosis in men and women: a randomized trial. European Corticosteroid-Induced Osteoporosis Treatment Study.
European Semi-Anthropomorphic spine phantom for the calibration of bone densitometers—assessment of precision, stability, and accuracy—the European Quantitation of Osteoporosis Study Group.
Multicentre randomised double blind placebo controlled trial assessing the effect of weekly risedronate on bone mineral density in adults with cystic fibrosis.
Two-year multicenter, randomised, double-blind, placebo-controlled trial assessing the effect of weekly risedronate on bone mineral density in adults with CF.
00130-5&id=gr1.jpg){kind=link}
00130-5&id=gr2.jpg){kind=link}