Abstract
Context
Cystic fibrosis (CF) transmembrane conductance (CFTR) dysfunction may play a role in CF-related bone disease (CFBD). Ivacaftor is a CFTR potentiator effective in improving pulmonary and nutritional outcomes in patients with the G551D-CFTR mutation. The effects of ivacaftor on bone health are unknown.
Objective
To determine the impact of ivacaftor on bone density and microarchitecture in children and adults with CF.
Design
Prospective observational multiple cohort study.
Setting
Outpatient clinical research center within a tertiary academic medical center.
Patients or Other Participants
Three cohorts of age-, race-, and gender-matched subjects were enrolled: 26 subjects (15 adults and 11 children) with CF and the G551D-CFTR mutation who were planning to start or had started treatment with ivacaftor within 3 months (Ivacaftor cohort), 26 subjects with CF were not treated with ivacaftor (CF Control cohort), and 26 healthy volunteers.
Interventions
All treatments, including Ivacaftor, were managed by the subjects’ pulmonologists.
Main Outcome Measures
Bone microarchitecture by high-resolution peripheral quantitative computed tomography (HR-pQCT), areal bone mineral density (aBMD) by dual-energy X-ray absorptiometry (DXA) and bone turnover markers at baseline, 1, and 2 years.
Results
Cortical volume, area, and porosity at the radius and tibia increased significantly in adults in the Ivacaftor cohort. No significant differences were observed in changes in aBMD, trabecular microarchitecture, or estimated bone strength in adults or in any outcome measures in children.
Conclusions
Treatment with ivacaftor was associated with increases in cortical microarchitecture in adults with CF. Further studies are needed to understand the implications of these findings.
Keywords: cystic fibrosis, Ivacaftor, bone mineral density, dual energy X-ray absorptiometry, high-resolution peripheral quantitative computed tomography, bone microarchitecture
Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (Cftr) gene, leading to abnormalities in chloride transport in the lungs, gut, and other tissues. Cystic fibrosis affects more than 30 000 people in the United States and 70 000 worldwide. Over the past several decades, the life expectancy for patients with CF has increased significantly, from an average of 10 years of age in 1962 to over 44 years of age in 2018 (1). As patients live longer, other comorbidities related to CF have become more prevalent, including CF-related bone disease (CFBD) (2, 3). Multiple clinical studies have reported that bone mineral density (BMD) measured by dual-energy X-ray absorptiometry (DXA) is lower (4–9) and that fracture rates are higher in patients with CF compared with healthy populations (9–12). Rib and vertebral fractures are common in adults with CF and may lead to pain, chest wall deformities, reduced lung volumes, ineffective cough and airway clearance, and ultimately compromised lung function.
Patients with CF frequently have known risk factors for low BMD, including vitamin D deficiency, delayed puberty, pancreatic insufficiency, malnutrition, glucocorticoid use, inflammation, and physical inactivity (2). Recent evidence indicates that the CFTR protein is expressed in human osteoclasts and osteoblasts (13) and may also play a causative role in CFBD. Cftr-/Cftr- mice have altered bone turnover and compromised bone mass even prior to the development of significant pulmonary and gastrointestinal disease (14). Similarly, studies in humans have shown increased markers of bone resorption and decreased markers of bone formation in subjects with CF (7, 15, 16).
Recently, new medications have been developed that pharmacologically improve CFTR function in patients with certain mutations in the Cftr gene. Ivacaftor, the first of these CFTR modulators to be developed, potentiates CFTR function and improves pulmonary function in CF patients with at least 1 copy of the G551D-CFTR mutation (roughly 5% of the CF population) (17, 18) as well as other gating and residual function mutations. If CFTR dysfunction also plays a role in CFBD, then enhancing CFTR activity with ivacaftor may also directly impact skeletal outcomes. At present, there are no published prospective clinical studies evaluating the effect of CFTR modulators on bone outcomes in patients with CF.
The goal of this prospective observational multiple cohort study was to evaluate the impact of treatment with ivacaftor on bone density, bone microarchitecture, and estimated bone strength in a clinical setting over 2 years in children and adults with CF and the G551D-CFTR mutation, compared with both age-, race-, and gender-matched subjects with CF not taking this medication and similarly matched healthy volunteers. We hypothesized that ivacaftor treatment would be associated with improved skeletal outcomes in children and adults with CF.
Materials and Methods
Subjects and eligibility criteria
Three cohorts of children and adults ages 6–75 years were recruited for this study. The 1st cohort (“Ivacaftor”) consisted of patients with CF and at least 1 copy of the G551D mutation who were planning to start or had started ivacaftor treatment as prescribed by their health care provider within 3 months of study enrollment. The 2nd cohort (“CF Control”) consisted of subjects with CF not treated with Ivacaftor, a majority of whom had CFTR mutations other than G551D and were thus not eligible to receive this medication. The 3rd cohort consisted of healthy volunteers. The CF Control and Healthy Volunteer cohorts were matched by age (±2 years and by Tanner stage in pediatric subjects), race, and gender to the Ivacaftor cohort. Subjects with CF were recruited from the Massachusetts General Hospital and Boston Children’s Hospital Cystic Fibrosis Centers. Exclusion criteria for all subjects with CF included a history of solid organ transplantation, current pregnancy, and Burkholderia dolosa infection (due to institutional infection control issues). Healthy volunteers were recruited from the community. Exclusion criteria for healthy volunteers included current pregnancy or a history of medication use or disorders known to affect bone metabolism, including osteoporosis, prolonged amenorrhea, hyperthyroidism, diabetes, hyperparathyroidism, Paget’s disease, chronic inflammatory disease, cancer, prolonged immobilization, or skeletal dysplasia. Healthy volunteers were also excluded if they had a history of nondigital fracture in the prior 6 months, a history of a pathological fracture, more than 4 total lifetime fractures, cumulative use of oral glucocorticoids for more than 2 months, or a body mass index (BMI) <18.5 or >30 kgm2 (or < 5th percentile or > 95th percentile for pediatric subjects) at the time of screening. The protocol was approved by the Partners Healthcare Human Research Committee with ceded review by the Boston Children’s Hospital Committee on Clinical Investigation and was registered on clinicaltrials.gov (NCT01549314). Written informed consent was obtained from all participants.
Clinical assessments
Subjects were followed prospectively with study visits at baseline, 12 months, and 24 months (±3 months). Subjects were queried at each visit regarding medical history; medications, including oral and inhaled glucocorticoids; alcohol and tobacco use; fractures; and pubertal and reproductive history. Subjects with CF were queried regarding baseline and interval CF exacerbations, defined as treatment with intravenous antibiotics and/or hospitalization. Additional data were obtained by chart review for subjects with CF, including CFTR genotype and the percentage of predicted forced expiratory volume in 1 second (FEV1) on most recent pulmonary function testing. A registered bionutritionist assessed calcium and vitamin D intake using the validated Nutrient Data System for Research (19) and physical activity using the Modified Activity Questionnaire (20). When available, reported fractures were confirmed with radiology reports. Fractures of the fingers, toes, hands, feet, skull, and face were excluded. In all subjects, height was measured on a wall-mounted stadiometer and weight was measured on an electronic scale. Race and ethnicity were self-reported.
Laboratory assessment
After fasting overnight, morning serum samples were obtained and were processed through the Brigham Research Assay Core at Brigham and Women’s Hospital in Boston, Massachusetts. Serum 25-hydroxyvitamin D (25(OH)D) levels were measured by liquid chromatography-tandem mass spectrometry. Parathyroid hormone (PTH) levels were obtained by access chemiluminescent immunoassay (Beckman Coulter, Fullerton, California). C-telopeptide levels were measured by immunoradiometric assay (Immunodiagnostic Systems, Fountain Hills, Arizona). Osteocalcin levels were measured by enzyme-linked immunosorbent assay (Wampole Laboratories, Princeton, New Jersey, and ALPCO Diagnostics, Salem, Massachusetts, respectively). Intact aminoterminal propeptide of type I collagen levels (P1NP) were measured by quantitative radioimmunoassay (Orion Diagnostica, Espoo, Finland).
Assessment of areal BMD and body composition
Areal BMD (aBMD) of the lumbar spine in the posterior-anterior (PA) projection, total hip, femoral neck, distal radius, and whole body along with body composition were measured using DXA (Discovery A; Hologic Inc, Bedford, Massachusetts). Vertebral fracture assessment (VFA) was obtained in all adult subjects over the age of 18 years at each study visit. Bone mineral density Z-scores were generated using Hologic gender-, race-, and age-specific normative databases. A standard quality control program was employed that included the daily measurement of a Hologic DXA anthropomorphic spine phantom and visual review of all images by an experienced investigator.
Assessment of volumetric bone mineral density, bone microarchitecture, and bone strength
Volumetric bone mineral density (vBMD) and bone microarchitecture of the distal radius and tibia were assessed by high-resolution peripheral quantitative computed tomography (HR-pQCT, Xtreme CT; Scanco Medical AG, Brütisellen, Switzerland). In adults, the standard regions of interest (ROI) were imaged at a fixed distance of 9.5 and 22.5 mm from the radial and tibial endplate, respectively, using previously described methods (21–23). To account for the changing extremity length in growing children and adolescents, the ROI was placed at the 8% site at the tibia in pediatric subjects under 18 years of age, as previously described (24). Due to considerable variability in ROI placement as well as a higher rate of movement artifact for radius scans in children, only tibia scans were included in analyses of HR-pQCT variables in pediatric subjects. Quality control was maintained with daily scanning of the manufacturer’s phantom. All HR-pQCT scans were reviewed for motion artifact and repeated if significant motion artifact was noted.
HR-pQCT scans were analyzed using Scanco software version 6.0 to provide total, cortical, and trabecular vBMD (mgHA/cm3), trabecular thickness (mm), trabecular number (mm-1), trabecular separation (mm), and trabecular distribution (mm). Cortical microarchitecture was characterized by processing HR-pQCT images with a semiautomated technique implemented in Scanco software (25–27). After image segmentation of cortical bone, the following measures were obtained: cortical thickness (mm), cortical and trabecular area (mm2), cortical volume (mm3), and cortical porosity (%). Microfinite element analysis (µFEA) was used to estimate failure load for radius and tibia under axial compression, as previously described (28, 29), providing estimated failure load (N).
In our laboratory, reproducibility for HR-pQCT measurements at the radius and tibia ranges from 0.2% to 1.4% for vBMD parameters, 0.3% to 8.6% for trabecular microarchitecture parameters, 0.6% to 2.4% for cortical microarchitecture parameters, 7.3% to 20.2% for cortical porosity measurements, and 2.1% to 3.0% for microfinite element analysis measures.
Statistical analysis
Statistical analysis was performed using SAS 9.4 software (SAS Institute Inc, Cary, North Carolina). Baseline characteristics of all 3 cohorts were compared using analysis of variance (ANOVA) for normally distributed data or Kruskal-Wallis for non-normally distributed data, followed by pairwise comparisons with Bonferroni correction. Categorical variables were compared using a chi-square test or Fisher’s exact test. For characteristics applying only to the 2 cohorts with CF, independent t-tests or a Wilcoxon rank-sum test was used to analyze normally or non-normally distributed data, respectively. The primary outcomes for this study were HR-pQCT-derived microarchitectural, vBMD, and strength measures at the radius and tibia, and secondary outcomes included aBMD by DXA, bone turnover markers, and fracture incidence. Other clinical outcomes of interest were examined as covariates, including FEV1, BMI, body composition (fat and lean mass), physical activity score, and 25(OH)D and PTH levels.
To minimize the effects of age, race and gender on skeletal outcomes, each subject in the ivacaftor group was matched to a CF Control subject and healthy volunteer. For the primary analysis, a random effects mixed model ANOVA accounting for matched subjects was used to compare the change in each outcome over the 3 study visits between the 3 cohorts,using the interaction term visit × cohort to identify significant differences in change in each parameter over time. Analyses of HR-pQCT outcomes were stratified by age (6–17 years and ≥18 years) due to the different ROI used for HR-pQCT scanning in pediatric and adult subjects. After unadjusted analyses, models were adjusted for BMI and FEV1, which were chosen because of clinical relevance and the expected impact from CFTR modulator therapy. In adult subjects, the change in outcomes from baseline to 2 years within each group was also compared by paired t-tests. Because bone outcomes are expected to increase over time in growing children, only between-group comparisons were performed in pediatric subjects.
Data are reported as mean ± standard deviation (SD) unless otherwise noted, and P-values < 0.05 are considered statistically significant. All supplementary material and tables are located in a digital research materials repository (30).
Results
Enrollment, retention, and study completion
As described in Fig. 1, 29 subjects with the G551D mutation were enrolled in the Ivacaftor cohort. One subject dropped out prior to any study procedures and was not included in the analyses. Two pediatric subjects enrolled into the Ivacaftor cohort decided not to start treatment with this medication and were moved to the CF Control cohort, leaving 26 subjects in the Ivacaftor cohort who were prospectively followed over 2 years. Twenty-six subjects matched by age, race, and gender were enrolled into the CF Control cohort and the Healthy Volunteer cohort. Ten of the 78 subjects (13%) were lost to follow-up: 3 adult subjects (1 male and 2 females) in the Ivacaftor cohort, 3 adult subjects (1 male and 2 females) and 2 pediatric subjects (both female) in the CF Control cohort, and 2 adult subjects (1 male and 1 female) in the Healthy Volunteer cohort. In the Ivacaftor cohort, 92% of subjects reported taking ivacaftor every day or almost every day during the 2-year period; 1 subject reported a rash requiring discontinuation of the medication for 6 months, and another reported running out of the medication for 6 weeks during the study period.
Figure 1.
Subject disposition. Abbreviation: CF, cystic fibrosis.
Demographics and clinical characteristics at baseline
Baseline clinical characteristics of all 3 cohorts are shown in Table 1. Subjects ranged in age from 6–56 years. In each cohort, 4 subjects were prepubertal (Tanner stage 1), 7 subjects were pubertal (Tanner stage 2–5), and 15 subjects were adults aged 18 years and older. All subjects were white and non-Hispanic, and 15 in each cohort (58%) were female. Weight, height, BMI, lean and percent fat mass by DXA, physical activity score, and reported age at menarche in females and pubarche in males were similar between the 3 cohorts. Healthy subjects consumed less calcium than subjects in the Ivacaftor cohort and less vitamin D than those in the CF Control cohort, though there were no differences between the 2 cohorts with CF. Mean 25(OH)D levels were ≥30 ng/mL in all cohorts without significant differences between them. Parathyroid hormone levels were higher in the CF Control cohort compared with the healthy volunteers but were not significantly different between the 2 cohorts with CF. Eight subjects reported 12 prevalent fractures (rib, clavicle, leg, and wrist) in the Ivacaftor cohort, 10 subjects reported 14 fractures (rib, leg, wrist, and vertebra) in the CF Control cohort, and 7 subjects reported 12 fractures (wrist, clavicle, leg, and femur) in the Healthy Volunteer cohort. All fractures were described as traumatic in nature with the exception of 1 subject in the Ivacaftor cohort who reported 3 atraumatic rib fractures and 1 subject in the CF Control cohort who reported 1 atraumatic rib fracture.
Table 1.
Baseline clinical characteristics
| Ivacaftor (n = 26) | CF Control (n = 26) | Healthy Volunteers (n = 26) | P-value | |
|---|---|---|---|---|
| Age (yr) | 23.1 ± 13.1 | 22.8 ± 13.1 | 23.8 ± 13.2 | 0.97 |
| Height | ||||
| Adult (cm) | 166.4 ± 8.3 | 167.3 ± 11.1 | 170.5 ± 8.9 | 0.46 |
| Pediatric (Z-score) | 0.10 ± 1.02 | -0.47 ± 0.92 | 0.09 ± 0.74 | 0.25 |
| Weight | ||||
| Adult (cm) | 58.8 ± 10.7 | 61.7 ± 14.7 | 65.3 ± 10.9 | 0.36 |
| Pediatric (Z-score) | 0.03 ± 0.77 | 0.05 ± 1.15 | 0.30 ± 0.66 | 0.73 |
| BMI | ||||
| Adult (cm) | 21.2 ± 3.6 | 21.9 ± 3.8 | 22.3 ± 3.8 | 0.67 |
| Pediatric (Z-score) | -0.11 ± 0.98 | 0.32 ± 1.04 | 0.31 ± 0.81 | 0.49 |
| Physical activity score | 23 ± 16 | 17 ± 14 | 14 ± 11 | 0.08 |
| Calcium intake (mg/day) | 2254 ± 1930 | 1937 ± 1108 | 1053 ± 442a | 0.006 |
| Vitamin D intake (IU/day) | 2177 ± 3123 | 3728 ± 3853 | 290 ± 436b | <0.001 |
| EtOH drinks/week (adult only) | 3 (0–24) | 1 (0–8) | 2 (0–10) | 0.15 |
| Fractures (n) | 12 | 14 | 12 | 0.52 |
| 25(OH)D (ng/mL) | 37 ± 19 | 33 ± 13 | 30 ± 10 | 0.30 |
| PTH (ng/mL) | 31.4 ± 16 | 40.3 ± 14.6 | 29.8 ± 12.5b | 0.02 |
| Lean mass (kg) | 39.6 ± 11.9 | 39.6 ± 12.2 | 42.8 ± 14.6 | 0.59 |
| Percent fat mass (%) | 25.0 ± 6.4 | 28.4 ± 7.7 | 27.1 ± 6.7 | 0.23 |
| CFTR mutation type (n,%) | ||||
| G551D/F508del | 16 (61.5%) | 0 | – | – |
| G551D/N1303K | 2 (7.5%) | 0 | – | – |
| G551D/G542X | 1 (4%) | 0 | – | – |
| G551D/Other | 7 (27%) | 2 (7.5%) | – | – |
| F508del/F508del | 0 | 10 (38.5%) | – | – |
| F508del/G542X | 0 | 1 (4%) | – | – |
| F508del/other | 0 | 11 (42%) | – | – |
| N1303K/other | 0 | 1 (4%) | – | – |
| Other/other | 0 | 1 (4%) | – | – |
| Predicted FEV1, % | 87.0 ± 30.8 | 71.8 ± 29.1 | – | 0.07 |
| Pancreatic insufficiency (n,%) | 23 (89%) | 19 (73%) | – | 0.29 |
| CFRD (n,%) | 1 (4%) | 5 (19%) | – | 0.19 |
| History of oral glucocorticoid use | ||||
| Ever use (n,%) | 22 (85%) | 16 (62%) | – | 0.13 |
| Estimated lifetime exposure (mo) | 8.6 ± 10.9 | 8.6 ± 10.9 | – | 0.13 |
| Use in the past 12 months (n,%) | 9 (35%) | 10 (38%) | – | 0.77 |
| Inhaled Glucocorticoids in the past 12 mo (n,%) | 16 (62%) | 18 (69%) | – | 0.55 |
| CF exacerbations in the past 12 mo | 1.0 ± 1.1 | 1.7 ± 1.8 | – | 0.29 |
Data are expressed as mean ± SD or median (range). P-values <0.05 are bolded. Abbreviations: 25(OH)D, 25-hydroxyvitamin D; BMI, body mass index; CF, cystic fibrosis; CFRD, cystic fibrosis related diabetes; CFTR, cystic fibrosis transmembrane conductance regulator; EtOH, alcohol; FEV1, forced expiratory volume in 1 second; mo, month; PTH, parathyroid hormone; SD, standard deviation; yr, year.
a P < 0.05 compared with Ivacaftor cohort.
b P < 0.05 compared with CF Control cohort.
Clinical characteristics specific to subjects with CF are presented in Table 1. A majority of subjects (81%) had pancreatic insufficiency requiring pancreatic enzyme replacement and 12% had CF-related diabetes, both similar between cohorts. There was a trend toward a higher FEV1 in the Ivacaftor cohort at baseline compared with the CF Control cohort (87% vs 72%, P = 0.07). Eighty-one percent of subjects in the CF Control cohort had at least 1 copy of the F508del allele, the most common CFTR mutation, and 38% had 2 copies. Four males in the CF Control cohort reported a history of delayed puberty compared with none in the Ivacaftor cohort (P = 0.08). Nine subjects in the Ivacaftor cohort were enrolled prior to starting Ivacaftor, and 17 subjects were enrolled on average 39 ± 24 days after starting treatment.
DXA, HR-pQCT, and bone turnover markers at baseline
There were no significant differences at baseline between the 3 cohorts in DXA aBMD and BMD Z-scores at the PA spine, total hip, femoral neck, distal radius, or total body. Low BMD (Z-score ≤ -2.0 at any site) was noted in 8 subjects in the CF Control cohort and in 2 subjects in the Ivacaftor cohort (P = 0.08). Stratifying DXA comparisons by age did not change the significance of these findings, with the exception that the femoral neck Z-score was lower in adults in the CF Control cohort than in healthy adults (-0.9 vs +0.2, respectively, P = 0.04, Table 2). Vertebral fracture assessment was negative for prevalent vertebral fracture in all adult subjects. Bone turnover markers (C-telopeptide, osteocalcin, and P1NP) were similar at baseline between cohorts, and no differences were noted after stratifying analyses for age (Table 2).
Table 2.
Baseline DXA and bone turnover markers
| Ivacaftor (n = 15) | CF Control(n = 15) | Healthy Volunteers(n = 15) | P-value | Ivacaftor(n = 11) | CF Control(n = 11) | Healthy Volunteers(n = 11) | P-value | |
|---|---|---|---|---|---|---|---|---|
| Adult subjects | Pediatric subjects | |||||||
| DXA | ||||||||
| Total body | ||||||||
| BMD (g/cm2) | 1.153 ± 0.074 | 1.101 ± 0.121 | 1.181 ± 0.122 | 0.14 | 0.921 ± 0.239 | 0.883 ± 0.162 | 0.943 ± 0.208 | 0.79 |
| Z-score | 0.5 ± 0.8 | -0.3 ± 1.3 | 0.7 ± 1.3 | 0.17 | -0.2 ± 1.8 | -0.7 ± 0.8 | 0.1 ± 1.0 | 0.30 |
| PA spine | ||||||||
| BMD (g/cm2) | 1.023 ± 0.087 | 0.997 ± 0.139 | 1.041 ± 0.132 | 0.61 | 0.794 ± 0.262 | 0.746 ± 0.167 | 0.814 ± 0.226 | 0.77 |
| Z-score | -0.2 ± 1.0 | -0.4 ± 1.5 | 0.0 ± 1.3 | 0.68 | -0.1 ± 1.7 | -0.5 ± 1.2 | 0.3 ± 0.8 | 0.39 |
| Total hip | ||||||||
| BMD (g/cm2) | 0.932 ± 0.111 | 0.872 ± 0.133 | 0.989 ± 0.161 | 0.08 | 0.833 ± 0.260 | 0.789 ± 0.157 | 0.833 ± 0.233 | 0.87 |
| Z-score | -0.3 ± 0.8 | -0.7 ± 1.2 | 0.2 ± 1.1 | 0.08 | -0.1 ± 1.8 | -0.4 ± 1.3 | -0.1 ± 1.2 | 0.85 |
| Femoral neck | ||||||||
| BMD (g/cm2) | 0.818 ± 0.121 | 0.749 ± 0.121 | 0.882 ± 0.193 | 0.06 | 0.758 ± 0.220 | 0.727 ± 0.119 | 0.774 ± 0.239 | 0.86 |
| Z-score | -0.4 ± 0.9 | -0.9 ± 1.2* | 0.2 ± 1.3 | 0.04 | -0.1 ± 1.6 | -0.3 ± 1.0 | -0.1 ± 1.4 | 0.94 |
| 1/3 distal radius | ||||||||
| BMD (g/cm2) | 0.749 ± 0.068 | 0.726 ± 0.093 | 0.750 ± 0.088 | 0.69 | 0.583 ± 0.142 | 0.574 ± 0.119 | 0.602 ± 0.124 | 0.88 |
| Z-score | 0.3 ± 0.8 | -0.1 ± 1.6 | 0.2 ± 1.1 | 0.37 | -0.4 ± 2.2 | -0.6 ± 1.6 | 0.2 ± 1.3 | 0.60 |
| Bone turnover markers | ||||||||
| Osteocalcin (ng/mL) | 12.2 ± 3.7 | 10.4 ± 4.6 | 11.2 ± 3.1 | 0.46 | 38.6 ± 13.5 | 40.9 ± 24.6 | 47.3 ± 20.6 | 0.60 |
| P1NP (ug/L) | 48.4 ± 20.9 | 40.7 ± 13.9 | 49.2 ± 12.8 | 0.30 | 299 ± 150 | 332 ± 224 | 417 ± 211 | 0.39 |
| C-telopeptide (ng/mL) | 0.50 ± 0.26 | 0.51 ± 0.29 | 0.51 ± 0.25 | 0.99 | 1.62 ± 0.77 | 1.96 ± 0.93 | 1.99 ± 0.61 | 0.50 |
Data are expressed as mean ± SD. P-values <0.05 are bolded. *P < 0.05 compared with the Healthy Volunteer cohort. Abbreviations: BMD, bone mineral density; CF, cystic fibrosis; DXA, dual-energy X-ray absorptiometry; P1NP, intact aminoterminal propeptide of type 1 collagen; PA, posterior-anterior; SD, standard deviation.
Baseline HR-pQCT measures for adult and pediatric subjects are presented in Table 3. At the tibia, adults in the CF Control cohort had lower total vBMD than both the ivacaftor and Healthy Volunteer cohorts (P = 0.003). Trabecular vBMD, cortical volume and thickness, and failure load of the tibia were lower in adult subjects in the CF Control cohort compared with healthy subjects (P < 0.05 for all). At the radius, adults in the CF Control cohort had lower total vBMD and lower cortical vBMD, area, volume, and thickness compared with healthy subjects (P < 0.05 for all). There were no differences in any HR-pQCT measures noted between the adults in the Ivacaftor cohort and healthy subjects.
Table 3.
Baseline HR-pQCT results at the tibia and radius
| Tibia | Radius | |||||||
|---|---|---|---|---|---|---|---|---|
| Ivacaftor(n = 15) | CF Control(n = 15) | Healthy Volunteers(n = 15) | P-value | Ivacaftor(n = 15) | CF Control(n = 15) | Healthy Volunteers(n = 15) | P-value | |
| Adult Subjects | ||||||||
| Total area (mm2) | 677 ± 163 | 678 ± 160 | 714 ± 166 | 0.781 | 281 ± 37 | 275 ± 68 | 287 ± 67 | 0.854 |
| Total vBMD (mgHA/cm3) | 316 ± 62a | 273 ± 38b | 335 ± 37 | 0.003 | 324 ± 58 | 285 ± 44b | 351 ± 49 | 0.004 |
| Trabecular vBMD mgHA/cm3) | 179 ± 36 | 155 ± 41b | 194 ± 34 | 0.022 | 180 ± 39 | 158 ± 30 | 187 ± 41 | 0.096 |
| Cortical vBMD (mgHA/cm3) | 872 ± 53 | 867 ± 30 | 892 ± 35 | 0.254 | 844 ± 59 | 817 ± 46b | 875 ± 43 | 0.009 |
| Trabecular number (mm-1) | 1.78 ± 0.26 | 1.71 ± 0.26 | 1.91 ± 0.32 | 0.157 | 2.03 ± 0.25 | 1.95 ± 0.24 | 2.00 ± 0.23 | 0.643 |
| Trabecular thickness (mm) | 0.08 ± 0.01 | 0.07 ± 0.01 | 0.09 ± 0.01 | 0.094 | 0.73 ± 0.01 | 0.67 ± 0.01 | 0.78 ± 0.14 | 0.050 |
| Trabecular spacing (mm) | 0.49 ± 0.09 | 0.52 ± 0.10 | 0.45 ± 0.08 | 0.108 | 0.43 ± 0.07 | 0.45 ± 0.07 | 0.43 ± 0.06 | 0.468 |
| Trabecular distribution (µm) | 0.22 ± 0.05 | 0.22 ± 0.05 | 0.19 ± 0.04 | 0.219 | 0.17 ± 0.03 | 0.18 ± 0.04 | 0.17 ± 0.03 | 0.771 |
| Trabecular area (mm2) | 561 ± 155 | 573 ± 139 | 585 ± 147 | 0.902 | 228 ± 35 | 227 ± 59 | 226 ± 57 | 0.995 |
| Cortical area (mm2) | 121 ± 23 | 109 ± 27 | 133 ± 28 | 0.053 | 56.0 ± 10.1 | 51.4 ± 12.8b | 64.8 ± 16.1 | 0.027 |
| Cortical volume (mm3) | 1031 ± 179 | 940 ± 226b | 1157 ± 277 | 0.046 | 450 ± 81 | 414 ± 82b | 530 ± 118 | 0.036 |
| Cortical thickness (mm) | 1.29 ± 0.24 | 1.11 ± 0.17b | 1.33 ± 0.19 | 0.011 | 0.84 ± 0.15 | 0.77 ± 0.12b | 0.95 ± 0.16 | 0.006 |
| Cortical porosity (%) | 4.44 ± 3.70 | 3.99 ± 2.02 | 3.86 ± 2.10 | 0.846 | 1.23 ± 0.98 | 1.46 ± 0.75 | 1.31 ± 0.92 | 0.781 |
| Endocortical perimeter (mm) | 94.4 ± 14.1 | 94.7 ± 12.7 | 97.5 ± 13.1 | 0.786 | 68.8 ± 6.2 | 68.2 ± 10.7 | 69.1 ± 9.6 | 0.963 |
| Failure load (N) | 10974 ± 2834 | 9701 ± 2822b | 12250 ± 3264 | 0.044 | 4176 ± 873 | 3604 ± 1182 | 4666 ± 1475 | 0.064 |
| Pediatric subjects | Ivacaftor(n = 11) | CF Control(n = 11) | Healthy Volunteers(n = 11) | P-value | ||||
| Total area (mm2) | 512 ± 95 | 481 ± 119 | 550 ± 135 | 0.397 | ||||
| Total vBMD (mgHA/cm3) | 281 ± 81 | 295 ± 80 | 293 ± 73 | 0.910 | ||||
| Trabecular vBMD mgHA/cm3) | 165 ± 53 | 170 ± 40 | 162 ± 28 | 0.908 | ||||
| Cortical vBMD (mgHA/cm3) | 798 ± 76 | 784 ± 69 | 778 ± 72 | 0.800 | ||||
| Trabecular number (mm-1) | 1.90 ± 0.21 | 1.79 ± 0.24 | 1.66 ± 0.21 | 0.068 | ||||
| Trabecular thickness (mm) | 0.08 ± 0.02 | 0.08 ± 0.02 | 0.08 ± 0.01 | 0.787 | ||||
| Trabecular spacing (mm) | 0.46 ± 0.07 | 0.49 ± 0.08 | 0.53 ± 0.08 | 0.114 | ||||
| Trabecular distribution (µm) | 0.19 ± 0.05c | 0.23 ± 0.05 | 0.25 ± 0.05 | 0.040 | ||||
| Trabecular area (mm2) | 402 ± 110 | 395 ± 115 | 395 ± 118 | 0.988 | ||||
| Cortical area (mm2) | 88.1 ± 33.4 | 90.0 ± 25.1 | 98.3 ± 34.9 | 0.738 | ||||
| Cortical volume (mm3) | 795 ± 302 | 812 ± 226 | 886 ± 315 | 0.738 | ||||
| Cortical thickness (mm) | 1.08 ± 0.35 | 1.13 ± 0.31 | 1.22 ± 0.37 | 0.612 | ||||
| Cortical porosity (%) | 2.81 ± 1.21 | 3.46 ± 1.65 | 4.47 ± 1.96 | 0.080 | ||||
| Endocortical perimeter (mm) | 77.1 ± 10.7 | 77.0 ± 10.8 | 77.1 ± 14.2 | 0.999 | ||||
| Failure load (N) | 7805 ± 3793 | 7734 ± 2533 | 8178 ± 3136 | 0.945 |
Data are expressed as mean ± SD. P-values <0.05 are bolded. Abbreviations: CF, cystic fibrosis; HR-pQCT, high resolution peripheral quantitative computed tomography; SD, standard deviation; vBMD, volumetric bone mineral density.
a P < 0.05 comparing Ivacaftor cohort with CF Control cohort.
b P < 0.05 comparing CF Control cohort with healthy volunteers.
c P < 0.05 comparing Ivacaftor cohort with healthy volunteers.
In pediatric subjects, trabecular distribution at the tibia was lower in the Ivacaftor cohort at baseline compared with the healthy subjects. All other HR-pQCT measures were similar between the 3 pediatric cohorts (Table 3).
Change in clinical covariates, DXA, and bone turnover markers over two years
There were no significant differences between the 3 cohorts in change over time in BMI, physical activity score, calcium and vitamin D intake, lean mass, percentage of fat mass, and PTH or 25OHD levels (P > 0.05 for all). Comparing the 2 cohorts with CF, there were no significant differences in change over time in FEV1, number of CF exacerbations, and oral glucocorticoid use between the ivacaftor and CF Control cohorts (P > 0.05 for all).
Change in aBMD and BMD Z-scores as measured by DXA did not differ significantly between the 3 cohorts over the 2-year period (P > 0.05 for all). Stratifying by age into pediatric and adult groups did not change the significance of these findings (Supplemental Table 1) (30). Areal BMD decreased by 3% at the femoral neck and 2% at the total hip in adults in the CF Control cohort from baseline to 2 years (P = 0.03 within group), whereas there was no significant change in aBMD in adults in the Ivacaftor cohort (P > 0.05 within group). Change in bone turnover markers also did not differ significantly between cohorts (P > 0.05 for all, before and after stratifying by age) (Supplemental Table 1) (30).
Change in vBMD, bone microarchitecture, and estimated bone strength over two years
The percentage change in HR-pQCT parameters from baseline to 2 years illustrating within-group changes in adult subjects are shown in Fig. 2, and the least squares means at the 1- and 2-year time points derived from longitudinal models comparing between-group changes are presented in Supplemental Table 2 (30). In adults treated with Ivacaftor, cortical area and volume at both the radius and tibia increased significantly over 2 years compared with the CF Control and Healthy Volunteer cohorts (P < 0.01 between groups). Compared with baseline, there was a 4% increase in both cortical area and volume at the radius, and a 6% increase at the tibia (P < 0.05 within group) in subjects in the Ivacaftor cohort, whereas there were no significant changes in the other 2 cohorts. There was a corresponding 1% decrease in trabecular area at the radius and tibia in adults in the Ivacaftor cohort (P < 0.05 within group), which was significantly different from the other 2 cohorts (P < 0.05 between group). Endocortical perimeter decreased by 1.5% at the radius in adults in the Ivacaftor cohort and increased by 1% in the CF Control cohort (P < 0.05 within group, P < 0.001 between group). At the radius, cortical porosity increased in the subjects treated with ivacaftor over the 2-year period (P = 0.02 within group), which was significantly different from the other 2 cohorts (P < 0.01 between group). Cortical porosity also increased significantly at the tibia in those treated with ivacaftor (P = 0.04 within group), though this change was not significantly different from the other 2 cohorts (P = 0.13 between group). There were no significant differences between adult cohorts in change over time in total, cortical, or trabecular vBMD or in trabecular microarchitecture at the radius or tibia. Change in estimates of bone strength also did not differ significantly over the course of the study between any of the 3 adult cohorts. Failure load at the tibia decreased in adults in the CF Control and Healthy Volunteer cohorts from baseline to 2 years (P < 0.05 within group), whereas there was no significant change in the Ivacaftor cohort despite the increase in cortical porosity (P > 0.05 within group). Adjustment of longitudinal models for changes in FEV1 and BMI did not affect the significance of these findings (data not shown).
Figure 2.
Mean percentage change (SEM) from baseline in HR-pQCT measures at the tibia (A) and radius (B) at 2 years in adult subjects. Cortical porosity results at the radius and tibia are presented in (C). *P < 0.05 for within-group comparisons to baseline. Abbreviations: CF, cystic fibrosis; HR-pQCT, high resolution peripheral quantitative computed tomography; SEM, standard error of the mean.
In pediatric subjects, there were no significant differences between the 3 cohorts with respect to change over time in any HR-pQCT outcomes at the tibia (Supplemental Table 3) (30).
Orkambi (Ivacaftor/lumacaftor) was approved by the Food and Drug Administration (FDA) in 2015 for patients with 2 copies of the F508del mutation. Three subjects (2 adult and 1 pediatric) in the CF Control cohort started treatment with this medication during the final year of their participation in the study. Sensitivity analysis excluding these data showed similar results as that obtained in the entire cohort (data not shown).
Fractures during the study period
There were no differences in fractures between cohorts during the study period. One subject in the Ivacaftor cohort reported an atraumatic rib fracture during the 2-year follow-up period, and 1 subject in the Healthy Volunteer cohort reported a traumatic femur fracture. No fractures were reported during the study period in the subjects in the CF Control cohort. Serial VFA assessments at each study visit showed no interval development of vertebral compression fractures in all subjects, with the exception of 1 male subject in the CF Control cohort in whom T12 and L1 abnormalities were noted on the VFA obtained at the 2-year follow-up visit; however, subsequent dedicated thoracolumbar spine X-rays showed normal vertebral bodies with no evidence of compression fractures.
Discussion
In this prospective, observational, multiple cohort study, ivacaftor treatment over a 2-year period increased cortical microarchitecture at both the radius and the tibia in adults with CF who were known to have the G551D-CFTR mutation, independent of pulmonary function and BMI. These changes brought measures of cortical area and volume in adults with CF closer to that of healthy volunteers. Cortical porosity increased at both the radius and the tibia after treatment with Ivacaftor, possibly reflecting increased metabolic activity within cortical bone, as observed with anabolic osteoporosis therapies such as teriparatide (31). Although higher cortical porosity has been associated with prevalent fracture in postmenopausal women and people with diabetes (32, 33), the absolute values in adults treated with ivacaftor remained small and were not associated with decrements in bone strength estimates, suggesting that the increase in cortical area and volume compensated for the increase in cortical porosity. Changes in other skeletal outcomes, including aBMD and trabecular microarchitecture, did not differ significantly in treated subjects compared with CF controls and healthy volunteers.
Recent data suggest that CFTR dysfunction may play a causative role in CF bone disease. Cystic fibrosis transmembrane conductance expression has been identified in murine osteoblasts (34) and in human osteoblasts and osteoclasts (13). Compared to wild type, Cftr-/Cftr- mice had a lower bone density and a reduced cortical and trabecular bone mass, as well as lower bone formation rates in the absence of significant gastrointestinal or pulmonary disease (14, 35–37). At birth, CFTR-deficient piglets had compromised cortical thickness compared to wild type littermates (38). Although the specific function of CFTR in bone has yet to be elucidated, several studies in rodents and in cultured human osteoblasts from patients with CF have found that CFTR dysfunction is associated with abnormal osteoprotegerin (OPG) levels and altered ratio of OPG and receptor activator of nuclear factor κβ ligand (RANKL) (34, 39, 40), which may lead to increased osteoclastogenesis and osteoclast activation. Improving CFTR activity increased bone formation, bone mass, and bone microarchitecture in CFTR mice with the F508del CFTR mutation (41) and improved underlying abnormalities in RANKL and OPG in cultured human F508del osteoblasts (42, 43).
Data describing the effect of CFTR modulators on skeletal outcomes in humans are limited. A retrospective study found a significant increase in lumbar spine BMD Z-score from -1.1 to -0.4 (P = 0.04) in 7 adults aged 26–65 years with the G551D mutation treated with ivacaftor for 1 to 3 years (43). In contrast, we did not identify any significant improvement in DXA outcomes in subjects treated with ivacaftor over a 2-year period compared with a control cohort of matched subjects with CF and healthy volunteers in this larger prospective study. However, significant increases in cortical bone microarchitecture were identified in this study using HR-pQCT. We and others have previously reported that patients with CF have abnormal cortical and trabecular microarchitecture and lower volumetric density compared with healthy volunteers, and these studies suggest that HR-pQCT provides unique information on bone integrity in patients with CF that is not fully captured by DXA (44–47).
The clinical effects of the cortical microarchitectural changes noted in subjects treated with ivacaftor in this study are unclear. The observed changes are of similar magnitude to those found in a study evaluating postmenopausal women treated with alendronate, where cortical thickness and area measured by HR-pQCT increased by 3% to 4% at the tibia over a 2-year period (48). Denosumab therapy over 2 years led to a 5% to 6% increase in cortical thickness at the radius and tibia (31). However, these osteoporosis medications also led to improvements in other microarchitectural outcomes, including vBMD and bone strength estimates (31, 48), which did not increase with ivacaftor treatment in this study. Cortical porosity at the radius and tibia increased significantly in the Ivacaftor cohort, suggesting an increase in skeletal remodeling, which is a finding also observed with treatment with anabolic agents such as teriparatide (31, 49). The increased cortical porosity was offset by increases in cortical bone volume to provide a maintenance of tibia bone strength estimates in the Ivacaftor cohort, whereas the strength estimates declined at this site in the CF Control cohort. A small decline in failure load at the tibia was also noted in the healthy adults, possibly related in part to age-related changes previously observed in healthy pre- and postmenopausal women and adult men (50, 51), particularly given that almost one-third of the adult subjects in this study were over the age of 40 at baseline.
Ivacaftor improves multiple aspects of health in patients with CF, including pulmonary function, nutritional status, and the frequency of CF exacerbations and hospitalizations (52); therefore, treatment with this medication may lead to an improvement in bone health apart from a direct effect of CFTR potentiation on bone cells. In longitudinal models, adjustment for FEV1 and BMI did not affect the significance of our findings, suggesting that the changes observed in cortical microarchitecture occurred independent of these factors. We collected prospective data on multiple additional clinical characteristics that may have been impacted by treatment with Ivacaftor, including physical activity levels, body composition, glucocorticoid use, CF exacerbations, and 25(OH)D and PTH levels. We did not find a significant change in any of these potential confounders in subjects in the Ivacaftor cohort compared with the other 2 cohorts, which may in part be due to the fact that the subjects in the Ivacaftor cohort were in relatively good health at baseline. In addition, because subjects were recruited up to 3 months after starting ivacaftor treatment, they may have had some degree of weight gain and FEV1 improvements occurring shortly after treatment initiation that were not captured at the baseline visit. Because of the observational study design and multiple potential confounders, the results from this study do not provide proof of a direct effect of CFTR modulation on bone. However, these findings do complement recent studies in animal models and cultured human cells and support the need for additional studies in humans. Regardless of specific etiology, the changes in bone microarchitecture noted with ivacaftor treatment in this study may have important clinical implications for long-term bone health in patients with CF, particularly in light of the new highly effective CFTR modulator therapy (Trikafta, Ivacaftor/tezacaftor/elexacaftor) that was recently FDA-approved for roughly 90% of patients with CF.
To our knowledge this is the only study comparing DXA and HR-pQCT results in children and adults with the G551D mutation compared with those with other CFTR mutations and healthy volunteers. The G551D mutation is a class III gating mutation, leading to diminished CFTR activity in response to adenosine triphosphate. Patients with this mutation often have less severe pulmonary disease than those with more severe mutation types such as F508del, reflected in the trend toward lower FEV1 noted in the CF Control cohort at baseline. However, there are limited data regarding skeletal phenotypes that occur with specific CFTR mutation types. In a cross-sectional study of 88 adults with CF, subjects who were homozygous or heterozygous for the F508del mutation had lower femoral neck and spine DXA BMD Z-scores than those without this allele, although this study did not investigate subjects with the G551D mutation (53). In our study, adults in the CF Control cohort had a lower total vBMD compared with the G551D subjects in the Ivacaftor cohort and healthy volunteers. In addition, compared with healthy volunteers, adults in the CF Control cohort had compromised cortical microarchitecture at both the radius and tibia and lower estimated failure load at the tibia. In contrast, there were no differences noted between healthy subjects and adults with the G551D mutation. These baseline microarchitectural differences between cohorts suggest that the G551D mutation may lead to an intermediate skeletal phenotype in adults with CF that is not as severe as those with other CFTR mutations and is closer to that of the healthy population.
In pediatric subjects in this study, DXA and HR-pQCT results at baseline and follow-up did not differ between the 3 cohorts. In general, children and adolescents with CF tend to be less affected by bone complications than adults. A recent systematic review and meta-analysis of matched cohort studies found that aBMD does not differ significantly in children and adolescents with CF compared with healthy peers (54), and bone accrual in children with CF is similar to healthy volunteers (55). Children and adolescents with CF had trabecular and cortical deficits noted on pQCT compared with healthy children (56), but only minimal microarchitectural abnormalities were identified using HR-pQCT (57). Due to improvements in clinical care, children and adolescents with CF today are likely to be healthier, more active, and with fewer risk factors for compromised bone accrual than several decades ago, which may explain why adults in this study had more skeletal findings than pediatric subjects. The wide range in age and pubertal status of pediatric subjects in this study also impacted the variability in bone outcomes, and this in combination with the small sample size, likely affected our ability to detect significant bone microarchitectural findings.
Strengths of this study include the comprehensive clinical and skeletal outcomes collected prospectively in a relatively large number of patients with the G551D mutation as they started ivacaftor treatment. The FDA approval of ivacaftor offered a unique, one-time opportunity to study the impact of this medication in a real-world setting, and to our knowledge this study represents the only prospectively collected data investigating bone outcomes in patients starting this treatment. However, important limitations of this study should be noted. The ideal study design would have been a double-blind, randomized, controlled trial comparing treated and untreated subjects with the G551D mutation, rather than an observational, multiple cohort study comparing cohorts of different mutation types. However, given the significant impact of this medication on pulmonary function and health, it would have been unethical to withhold this medication from subjects who qualify for it. Because of this, inherent differences may exist between the Ivacaftor cohort and the CF Control cohort due to differing genetic mutation types. Nonetheless, the fact that cortical microarchitecture increased in adults in the Ivacaftor cohort compared with the healthy volunteers suggest that these findings are not solely due to genetic differences between the 2 cohorts with CF. Because of this observational study design where ivacaftor treatment was managed by the subjects’ clinical providers, assessment of compliance was limited to subjects’ self-report. In addition, because ivacaftor was approved by the FDA sooner than anticipated, we could not enroll all subjects prior to starting treatment. Although this is unlikely to have significantly impacted DXA or HR-pQCT findings, this may have affected other baseline results, including pulmonary function, BMI, and bone turnover markers. Given the rarity of this mutation, a relatively large number of patients with G551D were enrolled in this single center study; however, the sample size was still small, the age range was large, and subjects were heterogeneous, which limit the conclusions that can be drawn from this study. It is possible that additional skeletal findings would be found if a larger number of subjects were studied or the follow-up period was longer. In addition, prior studies suggest a correlation between lung function and bone disease in patients with CF (58); therefore, it is possible that additional skeletal changes would have been identified if subjects with more severe lung disease were studied. Moreover, only peripheral skeletal sites were evaluated by HR-pQCT in this study. Although the similar changes in cortical bone observed at both a weight-bearing and nonweight-bearing site are compelling, further studies are needed to determine if these microarchitectural changes are representative of other skeletal regions. Finally, we used a fixed ROI for HR-pQCT scans in adults in this study instead of a relative site, as was used in pediatric subjects. Although some argue that a relative ROI may be more accurate in patient populations with shorter height and limb lengths, published data suggest that there is no difference noted between fixed and relative ROI placement in adults with CF (46). Moreover, primary analyses here focused on longitudinal changes, which would have not been influenced by use of the standard ROI placement in adults.
Conclusions
Treatment with ivacaftor was associated with significant increases in cortical area, volume, and porosity at the radius and tibia in adults with CF, independent of pulmonary function and BMI. As cortical bone contributes greatly to the strength of the peripheral skeleton, these changes may ultimately reduce fracture risk in patients with CF. Particularly as more patients with CF are treated with CFTR modulators at younger ages, early treatment may impact the development of bone disease later in life. Larger and longer-term studies are needed to understand the underlying pathophysiology and clinical implications of these findings.
Acknowledgments
We gratefully acknowledge the support of the dedicated staff of the Massachusetts General Hospital (MGH) Clinical Research Center and the Research Groups of the MGH and Boston Children's Hospital Cystic Fibrosis Centers. We thank the study volunteers for their participation.
Financial Support: This study was supported by the National Institutes of Health K23DK102600 and a Vertex Pharmaceuticals Investigator Initiated Studies Grant. Resources utilized for this study were provided by the Massachusetts General Hospital Clinical Research Center funded by the Harvard Catalyst 1UL1 TR001102. The HR-pQCT measurements were made possible by the National Center for Research Resources Shared Equipment Grant (1S10RR023405-01).
Clinical Trial Information: Clinical Trials Registration Number: NCT01549314.
Additional Information
Disclosure Summary: J.S.F. received research funding from Vertex Pharmaceuticals in the form of an Investigator Initiated Studies Grant supporting this project. G.S. and A.U. have served on advisory boards for Vertex Pharmaceuticals (unrelated to this work). G.S., A.U., and L.S. have received research funding from Vertex Pharmaceuticals (unrelated to this work). The other authors have nothing to disclose.
Data Availability
Some or all datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Some or all datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.