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Published ahead of print on October 16, 2003, doi:10.1164/rccm.200307-1049OC
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American Journal of Respiratory and Critical Care Medicine Vol 169. pp. 77-82, (2004)
© 2004 American Thoracic Society

Efficacy of Alendronate in Adults with Cystic Fibrosis with Low Bone Density

Robert M. Aris, Gayle E. Lester, Melissa Caminiti, A. Denene Blackwood, Margaret Hensler, Robert K. Lark, Travis M. Hecker, Jordan B. Renner, Ursula Guillen, Sue A. Brown, Isabel P. Neuringer, Worakij Chalermskulrat and David A. Ontjes

Divisions of Pulmonary Medicine and Endocrinology; the Cystic Fibrosis and Pulmonary Research and Treatment Center; the Departments of Radiology and Orthopedics; and the School of Medicine, The University of North Carolina at Chapel Hill, North Carolina

Correspondence and requests for reprints should be addressed to Robert Aris, M.D., CB# 7020, 4131 Bioinformatics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7524. E-mail: aris{at}med.unc.edu


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
As adults with cystic fibrosis (CF) have enjoyed incremental increases in longevity over the last few decades, they have also been suffering from low bone density and its clinical manifestations, fractures and kyphosis. We conducted a placebo-controlled, randomized, double-blinded trial of alendronate (10 mg/day orally) (n = 24) compared with placebo (n = 24) for 1 year in 48 patients to improve bone mineral density at the spine as the primary endpoint. All patients received 800 IU of cholecalciferol and 1,000 mg of calcium carbonate. Both groups were similar in age, sex, CF mutations, bone density T scores, renal function, and body mass index at study onset. The alendronate-treated patients gained (mean ± SD) 4.9 ± 3.0% and 2.8 ± 3.2% bone density after 1 year versus placebo, which lost (mean ± SD) 1.8 ± 4.0% and 0.7 ± 4.7%, in spine and femur bone density, respectively (p <= 0.001 for the spine; p = 0.003 for the femur). Urine N-telopeptide, a bone resorption marker, levels declined in the treatment group more than in the control group (p = 0.002), consistent with the known antiresorptive effects of bisphosphonates. Alendronate was more effective than placebo in improving spine and femur bone mineral density and is a promising agent for the long-term prevention and management of bone disease in patients with CF.

Key Words: osteoporosis • cystic fibrosis • bisphosphonates • bone metabolism • alendronate

Cystic fibrosis (CF) is the most common recessive genetic mutation in the white population that leads to respiratory failure early in life. The worldwide prevalence of CF is more than 50,000 individuals. Advancements in the treatment of patients with CF have increased the median life expectancy by more than 25 years in the last four decades (1). Consequently, the clinical management of these patients has evolved to encompass many nonrespiratory problems such as distal intestinal obstruction syndrome, cirrhosis, and bone disease—to name a few. Low bone mineral density (BMD) was first reported in patients with CF in 1979 (2). It is now recognized that bone disease is a major affliction within the adult population with CF. A recent consensus conference adopted the term bone disease to describe low BMD in CF because the exact pathophysiology of this disorder is not known (3). Delayed pubertal maturation, malabsorption of vitamin D, poor nutritional status, physical inactivity, hypogonadism, and glucocorticoid therapy are all potential etiologic factors (4–13). In addition, and possibly most importantly, chronic pulmonary infection increases bone resorption and suppresses bone formation through the activity of inflammatory cytokines (11). Thus, CF represents a potential paradigm for bone disease that arises from sustained, chronic inflammation. Low BMD in patients with CF can lead to pathologic fractures, kyphosis, and even exclusion from lung transplantation candidacy (14).

The foundation for lifetime bone health is established during infancy, childhood, and adolescence. Children with CF appear to achieve a lower peak bone mass than healthy individuals (7, 15). Added to this problem, adults with CF lose BMD three to five times faster than patients who are healthy (16). For these reasons, many of the clinical manifestations of low BMD, namely fractures and kyphosis, occur very early in life in patients with CF (from adolescence to young adulthood) and decades before they typically occur in normal adults (6, 17, 18). Therefore, clinicians need to be aware of this problem and its early presentation to screen for and treat low BMD before fractures occur.

Therapeutic trials using bisphosphonates to improve BMD in postmenopausal, idiopathic male, and glucocorticoid-induced osteoporosis have provided encouraging results (19–21). Due to the relatively recent attention given to bone disease in patients with CF, there have been few therapeutic trials in this population. The question of whether bisphosphonates administered orally for adult patients with CF, who commonly have gastroesophageal reflux disease and malabsorption, would be safe and beneficial was addressed by the study reported herein. Our primary goal in this investigator-initiated, randomized, double-blind, placebo-controlled, clinical trial was to determine if alendronate, a second-generation oral bisphosphonate, could improve BMD at the spine after 1 year in adult patients with CF.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients
All ambulatory, adults with CF were recruited from the Adult CF Center from 1996 to 2001 and underwent a screening dual-energy X-ray absorptiometry (DXA) scan if they did not have any of the following exclusionary criteria: active upper gastrointestinal disease, chronic oral glucocorticoid usage (> 10 mg every day), organ transplantation, renal insufficiency (serum creatinine > 3.0 mg/dl), a history of bisphosphonate intolerance or use, and pregnancy. All subjects signed an Institutional Review Board–approved consent form. The patients were included if the screening DXA showed a spine or femur T score of -1 or less. The diagnosis of CF was confirmed as described previously (22).

Clinical Protocol
Subjects were stratified by sex and severity of bone disease (mild: spine T score of -1 to -2 or severe: spine T score < -2) and randomized in a blocks-of-four design to receive either daily oral alendronate (10 mg) or placebo (Merck and Co. Inc., Whitehouse Station, NJ). The patients were instructed to take alendronate/placebo with a full 250-mL glass of water on an empty stomach and not to eat or drink for at least half an hour. All subjects were prescribed 800 IU of cholecalciferol (Scandipharm, Birmingham, AL) and 1,000 mg of calcium carbonate (CVS Pharmacy Inc., Woonsocket, RI). Subjects were evaluated at visits on 45 and 90 days and 6 and 12 months with an option to participate at 18 and 24 months. The protocol was originally designed to be 2 years in length, but few subjects were willing to consent to such a lengthy study, so the protocol was revised. Compliance was evaluated by pill counting.

The primary endpoint was change in spine BMD at 12 months. Secondary endpoints included spine BMD at 24 months, proximal femur BMD, urine bone metabolic markers, and vertebral and long bone fractures. Data were collected from computerized medical records that contain all outpatient and inpatient visits, pulmonary function, laboratory tests and medications, and by interview for potentially confounding variables including corticosteroid use, renal insufficiency, weight loss, and evidence of clinical deterioration.

Bone Densitometry
Spine and femur measurements were made on all patients at baseline and every 6 months using DXA as described previously (4, 17, 22, 23). The coefficient of variation for our Hologic 4500 is 0.6%, and the reference limits for variation are ± 1.5%. In general, for patients under the age of 20, Z scores should be used, and for patients over the age of 30, T scores should be used. For those in between, T and Z scores are virtually identical. The position statement, Guide to Bone Health and Disease in Cystic Fibrosis, written by domestic and international authorities and sponsored by the U.S. Cystic Fibrosis Foundation (3), will promulgate these recommendations. Because we only had three patients younger than 20, we believed that using T scores was most appropriate in the clinical protocol but have included both Z and T scores in Table 1 .


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  		TABLE 1. Patient baseline physical characteristics (mean ± sd)

 
Fracture Determination Methods
Baseline and end-of-study chest radiographs were analyzed for thoracic spine curvature (i.e., kyphosis angle) and vertebral and rib fractures by a single, blinded musculoskeletal radiologist as described previously (24, 25). Clinical fractures were recorded.

Serum and Urine Biochemical Measurements
Fasting serum was stored at -80°C and analyzed for parathyroid hormone, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D, osteocalcin, and bone-specific alkaline phosphatase, and fasting urine was stored and measured for cross-linked N-telopeptides and deoxypyridinoline as described previously (11, 22, 23, 26, 27).

Medical Management for CF
Physicians from the division of pulmonary medicine who were not part of the study, and who specialized in CF care, primarily managed the medical problems of the patients in our study.

Statistical Analysis
An intention-to-treat principle was used in the analyses of the treatment endpoints. Differences in the primary endpoint were compared between the alendronate and the control arm with a repeated measures analysis of variance analyzing for the effects of time, treatment, and time x treatment interactions. Potentially confounding variables were included in the analysis as covariates. Longitudinal changes in the biochemical markers of bone metabolism were compared with separate repeated measures analysis of variance. Fracture rates were compared with Fisher's Exact tests. To determine if clinical or demographic variables predicted the treatment response to alendronate, univariate linear regression analyses using potential predictor variables were performed. All analyses were performed with SAS (v6.12; SAS Institute, Cary, NC) or SigmaStat (v2.03; SPSS, Inc., Chicago, IL) (28).


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient Characteristics
One hundred and one adults with CF were screened by DXA and 86 (85%) of them had osteopenia (T score between -1.0 and -2.5) or osteoporosis (T score < -2.5) at either the spine or femur site as defined by the World Health Organization. Figure 1 shows the flow of patients through the study. Of the 86 patients who had osteopenia or osteoporosis, 53 agreed to participate in this study. The most common reasons for nonparticipation were that the patients were unable to meet the time commitments of the study (n = 10), did not want to receive additional medications (n = 12), desired to become pregnant (n = 2), and other (n = 9). Of the 53 subjects who began the protocol, five patients dropped out before their 6-month DXA. The reasons for dropping out included: pregnancy (n = 1), diarrhea and mild weight loss (n = 3), and dysphagia (n = 1). No one dropped out from gastroesophageal reflux symptoms. The pregnant patient had a spontaneous abortion in her first trimester. The three patients with diarrhea reported abdominal cramping, loss of appetite, and diarrhea before the medications began that worsened during the study but persisted after the study medications were discontinued; one patient was on alendronate and two on placebo. Forty-eight subjects completed at least one DXA beyond baseline, and their baseline characteristics are included in Table 1. At baseline, osteoporosis was found in 4 subjects and osteopenia was present in 20 subjects in both the treatment and control groups.



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  		Figure 1. Patient flow diagram of this single-center randomized, double-blind, placebo-controlled trial comparing alendronate at 10 mg/day plus calcium (1,000 mg/day) and cholecalciferol (800 IU/day) to calcium and cholecalciferol and placebo. The diagram includes detailed information on the patients who qualified for the study, drop-outs, and endpoints achieved.

 
The CF genotypes for the treatment arm (n = 24) were: 15 (63%) DF508 homozygotes, 6 (25%) DF508 compound heterozygotes, 1 was R347P/unknown (4%), and 2 were not tested (8%). The genotype frequencies for the control arm (n = 24) were: 12 (50%) DF508 homozygotes, 10 (42%) compound heterozygotes, and 2 were not tested (8%). Pancreatic insufficiency in the treatment arm was present in 96% of the patients, and in the control arm it was present in 92% of the patients.

Serum Calcium, Vitamin D, and Parathyroid Hormone Levels
Baseline serum calcium, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and parathyroid hormone levels are shown in Table 2 .


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  		TABLE 2. Patient characteristics: baseline serum and urine (mean ± sd)

 
Treatment Compliance and Safety
By defining medication compliance as patients who took at least 80% of their pills, 42 of the 48 (21 in each arm) patients who were included in Table 1 were compliant. A single patient reported that the first pill was difficult to swallow despite the use of 250 mL of water. This patient also reported difficulty swallowing other tablets. Therapy was discontinued. There were no episodes of significant bone pain, fever, or other systemic side effects due to alendronate. One patient developed nephrolithiasis after 1 year of therapy and discontinued the study. He had a family history of nephrolithiasis, and a literature search and complete search of the Merck and Co., Inc. Safety Database revealed no association between alendronate and nephrolithiasis. The reasons for participants withdrawing after the 6-month but before the 12-month DXA are summarized in Figure 1.

Efficacy in Improving BMD
The alendronate-treated patients (n = 24) experienced increases in spine and femur BMD (mean ± SD) 4.9 ± 3.0% and 2.8 ± 03.2% BMD after 1 year in comparison with control subjects, which changed (mean ± SD) -1.8 ± 4.0% and -0.7 ± 4.7%, in spine and proximal femur BMD, respectively (p < 0.001 for spine and p = 0.003 for femur) (Figure 2) . The absolute spine BMD (mean ± SD) values for the alendronate and placebo arms were 0.876 ± 0.094 versus 0.855 ± 0.073 g/cm2 at 0 months, 0.913 ± 0.098 and 0.844 ± 0.076 g/cm2 at 6 months, and 0.916 ± 0.701 versus 0.839 ± 0.0752 g/cm2 at 12 months. At the femur, the alendronate and placebo BMD (mean ± SD) values were 0.794 ± 0.092 versus 0.791 ± 0.091 g/cm2 at 0 months, 0.808 ± 0.0932 versus 0.787 ± 0.103 g/cm2 at 6 months, and 0.815 ± 0.794 versus 0.771 ± 0.103 g/cm2 at 12 months, respectively. By the end of 1 year, 100 and 78% patients in the alendronate group as opposed to 50 and 35% of the patients in the control group had increased BMD at the spine and femur, respectively. To determine if a particular treatment arm subgroup had a greater response to alendronate, predictor variables were correlated with the 12-month spine and femur BMD change (%). This analysis was conducted to help clinicians predict the response to alendronate for any given patient on the basis of their underlying characteristics. The initial BMI trended toward a negative correlation with spine BMD change (%) and proximal femur change (%) (r values -0.38 and -0.47; p = 0.13 and 0.06). Also, the initial FEV1% and FVC% trended toward a negative correlation with spine and femur BMD changes (%) (r values, -0.30 to -0.54; p values, 0.02–0.16). The baseline spine T score was negatively correlated with the spine BMD change (%) (r = -0.72, p < 0.001). Baseline proximal femur T scores trended toward predicting the femur responses in an inverse fashion. In addition, males tended to respond better than females at the spine, but not at the femur, at the 12-month measurement (p = 0.08). Nonetheless, the alendronate-treated females had significantly better responses at the spine than the placebo-treated females (+3.0 ± 0.8% vs. -1.8 ± 4.4%, p < 0.001), indicating that the male response did not account for the entire treatment effect within the alendronate group. Variables such as baseline age and percent changes in FEV1 and FVC, home intravenous administration days, and hospitalization days across the study were not associated with BMD changes in the alendronate group. For the patients who remained in the study for 2 years, spine and femur BMD increased in treated patients at the 2-year time point (mean ± SD) 4.5 ± 3.3% and 2.8 ± 3.0% (n = 11), respectively, and were still significant (p < 0.001) when compared with the control subjects, which decreased (mean ± SD) 1.2 ± 5.9% and 2.3 ± 7.8% (n = 13).



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  		Figure 2. Mean ± SE change in A spine and B femur bone mineral density (BMD) (expressed as a percent of baseline) over time in subjects on alendronate plus calcium and vitamin D (dashed line) compared with placebo and calcium and vitamin D (solid line), demonstrating significantly greater improvements at the spine (p < 0.001) and femur (p = 0.003) with alendronate.

 
Potential Confounding Variables
Potential confounding variables (Table 3) , including glucocorticoid usage, changes in lung function and BMI, and hospital and home intravenous antibiotic administration days (n) were analyzed as covariates and did not significantly impact the spine and femur BMD results.


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  		TABLE 3. Patient and treatment variables

 
Fractures and Kyphosis Angles
There were two new fractures in different patients reported in the alendronate arm (arm and rib) and a single toe fracture reported in the control group (p = not significant). The kyphosis angles did not change significantly during the study in either group.

Bone Biomarkers
Urine N-telopeptides fell in the alendronate group significantly (Figure 3) . After initiating alendronate, N-telopeptides levels changed from baseline (mean ± SE) -36 ± 25% and -28 ± 14%, respectively, whereas N-telopeptides levels in control subjects changed -12.4 ± 28% and +6 ± 16%, respectively, at the 45- and 90-day measurement points (p = 0.002). Deoxypyridinoline levels followed a similar trend: alendronate versus control group: (mean ± SD) -33 ± 36% versus -14 ± 37% at 45 days and -29 ± 36% versus -26 ± 38% at 90 days (p = 0.10).



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  		Figure 3. Mean ± SE changes in urine N-telopeptides of type I collagen (NTx) (expressed as a percent of baseline) over time on alendronate (dashed line) and placebo (solid line), demonstrating significant declines in NTx in the alendronate arm compared with placebo (p = 0.002).

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The results of this study demonstrate that alendronate, a second-generation bisphosphonate, is safe and effective for improving spine and proximal femur BMD in adult patients with CF. Alendronate significantly reduced urinary markers of bone resorption. These results are consistent with our understanding of the basic pathogenesis of this disorder derived from bone biomarker studies, which have found that increased bone resorption occurs even during quiescence of lung disease and escalates during periods of lung infection (8, 10, 11, 22). Univariate analyses suggested that patients with CF with lower baseline T scores, BMI, or lung function responded better to alendronate. Consistent with previous alendronate studies outside of CF, spine BMD increased more than proximal femur BMD with alendronate therapy. These results strongly suggest that bone disease in CF, despite the presence of intestinal malabsorption, is a treatable medical complication that can be improved with oral bisphosphonates. Although this study was not powered to demonstrate efficacy in reducing the fracture rates of osteoporosis, the improvements in BMD should translate into reductions in fractures because improvements in BMD are usually highly correlated with reduction in fracture risk (29, 30).

We chose to study adult patients with CF because the majority of this population suffer from low BMD and represent a relatively homogenous population. In addition, alendronate has Food and Drug Administration approval for adult use. There are few studies addressing bisphosphonate therapy for bone disease in patient populations with CF. Because less than 1% of alendronate is absorbed in healthy individuals, bioavailability was a concern in this study design. However, the long half-life of alendronate had a cumulative protective effect on BMD, which mitigated the aforementioned absorption issues. Also, bone pain associated with the use of the intravenous bisphosphonate, pamidronate, was a significant limitation to the broadscale use of this therapy (31). Last, alendronate should not be used for osteomalacia due to vitamin D or calcium deficiency, a condition that has rarely been reported in CF.

The beneficial effects of alendronate in our study compare favorably with other studies using bisphosphonates specifically targeting the population with CF. Haworth and coworkers enrolled patients with CF having a Z score lower than -2.0 in the lumbar spine, proximal femur, or distal forearm and randomized them to receive either 30 mg intravenous pamidronate every 3 months and 1 g calcium daily (pamidronate group) or 1 g calcium daily alone (control group) (32). After 6 months of treatment, the pamidronate group (n = 13) showed a significant increase in BMD compared with the control group (n = 15) in the lumbar spine (mean difference 5.8% [CI, 2.7–8.9%]) and total hip (mean difference 3.0% [CI, 0.3–5.6%]). Unfortunately, significant adverse events occurred in association with pamidronate. These events included fever, phlebitis, and moderate to severe bone pain, which led to 7/12 patients becoming transiently bedridden with "excruciating" pain that was unresponsive to both paracetamol and diclofenac (31). Three of the four patients who were taking prednisolone long term remained pain free, suggesting that prednisone therapy had a protective effect (33).

In a preliminary report using a nonrandomized case–control design, Conway and coworkers treated 30 patients (21 with osteoporosis and 9 with osteopenia) with oral bisphosphonates (etidronate or alendronate) and 9 patients, 8 of whom had normal BMD, received no treatment (34). Two years later, the bisphosphonate group had a significant increase in both the total body and lumbar spine BMD (p = 0.001 and 0.007, respectively) but not the proximal femur BMD, whereas the control group did not change at the spine but declined significantly at the femur (p = 0.01). Although the groups differed significantly in their BMD at study entry, encouraging preliminary results were seen with oral bisphosphonates in patients with CF with low BMD.

Bisphosphonates have also been shown to be effective in postlung transplant patients with CF. End-stage patients with CF who opt for lung transplantation must adhere to lifelong immunosuppressant therapies that may have a detrimental effect on BMD. In a study by our group, 34 ambulatory adults (18–38 years old) with CF (18 men, 16 women) were randomized to receive calcium carbonate (1 g/day) and ergocalciferol (800 IU/day) orally with or without pamidronate 30 mg intravenously every 3 months for 2 years (23). The patients treated with pamidronate gained on average (± SD) 8.8 ± 2.5% and 8.2 ± 3.8% in spine and femur BMD after 2 years in comparison with control subjects, who gained, on average (± SD), 2.6 ± 3.2 and 0.3 ± 2.2%, respectively (p < 0.015 for both).

The benefits of alendronate have also been examined in patients with glucocorticoid-induced osteoporosis. Because up to 40% of patients with CF may be prescribed oral glucocorticoid therapy at some time, they may also suffer from glucocorticoid-induced osteoporosis (17). Saag and coworkers reported that 5 and 10 mg daily of alendronate improved spine BMD by 2.1 ± 0.3% and 2.9 ± 0.3%, respectively, after 1 year in a large cohort of patients chronically treated with glucocorticoids (p < 0.001 compared with placebo) (21). The femoral neck BMD increased by 1.2 ± 0.4% and 1.0 ± 0.4% in the 5 and 10 mg alendronate groups, respectively, (p < 0.01 compared with placebo). Also, there were proportionally fewer new vertebral fractures in the alendronate groups (overall incidence of 2.3% compared with 3.7% in the placebo group).

Several potential limitations of this study exist. First, we only studied adult patients, and we cannot extrapolate to younger patients with CF with bone disease. However, bisphosphonates have been used in children with conditions other than CF and appear to be relatively safe and effective. Second, the number of patients in this study is relatively small, and the number of potentially confounding variables is relatively large. Because the weight of each confounder on BMD is unknown, stochastic variation in individual patterns could have a cumulative effect on treatment versus control responses. Nonetheless, statistical efforts to analyze the effects of confounding variables on the main outcome measures did not reduce the significance of our findings. The third limitation, and probably most important, is intrinsic to the underlying disease. Patients with CF often experience frequent hospitalizations, prolonged oral glucocorticoid therapy, lung transplantation, and a variety of other factors that make compliance with chronic medication (including alendronate) difficult. Thus, the dropout rate in this study was high. Once-weekly bisphosphonate therapy may improve compliance in CF without compromising efficacy as it does in patients with osteoporosis not suffering from CF (35). Last, the low rate of bone formation in adults with CF reported by Elkin and colleagues (12) would not be expected to be altered by alendronate or other bisphosphonates but may be amenable to anabolic bone medications if demonstrated by controlled clinical trials.

In summary, our results demonstrate a favorable impact of alendronate on bone density in CF adults who suffer from chronic lung infection and inflammation. This finding adds support to the idea that low BMD that results, at least in part, from chronic inflammatory diseases may be effectively slowed with bisphosphonate therapy acting on the common pathway of increased osteoclast activity. Therefore, our results may hold promise for the treatment of bone disease in patients with other chronic inflammatory disorders including sarcoidosis and inflammatory interstitial diseases (lupus erythematosis, scleroderma, and rheumatoid arthritis). Whereas our sample size was too small to detect a fracture benefit, the increase in BMD seen in the alendronate group might be expected to reduce fractures. More aggressive surveillance for, and targeted management of, bone disease in patients with CF will probably mitigate the clinical ramifications of low BMD. No doubt, further experience with alendronate or other newer bisphosphonates will be necessary to determine their long-term usefulness in the population with CF. Multiple bisphosphonate studies are underway that will shed important light on the usefulness of these drugs in patients with CF.


   Acknowledgments
 
The authors thank Kathy Hohneker, our CF nurse-clinician; Ken Davis and Brandi Mueller, the lung transplant coordinators at UNC hospitals; the nursing staff at the GCRC; and Steffen Baumann, the DXA technician, for their assistance during this study.


   FOOTNOTES
 
Supported by the U.S. Food and Drug Administration (FD-R-001518-01), Merck and Co, Inc. (Medical School Grants Program), the Clinical Nutrition Research Unit (NIDDK 56350), the Verne S. Caviness General Center for Clinical Research at UNC (NIH RR00046), the Cystic Fibrosis Foundation (A936), and a Medical Student Training Grant (5 T35 DK07386) from the NIDDK.

Conflict of Interest Statement: R.M.A. received $30,000 from the Merck Medical School Grants Program in order to provide "seed" money to initiate this clinical trial, this grant program is investigator-initiated and competitive; G.E.L. has no declared conflict of interest; M.C. has no declared conflict of interest; A.D.B. has no declared conflict of interest; M.H. has no declared conflict of interest; R.K.L. has no declared conflict of interest; T.M.H. has no declared conflict of interest; J.B.R. has no declared conflict of interest; U.G. has no declared conflict of interest; S.A.B. has no declared conflict of interest; I.P.N. has no declared conflict of interest; W.C. has no declared conflict of interest; D.A.O. has no declared conflict of interest.

Received in original form July 30, 2003; accepted in final form October 9, 2003


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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