Clinician perspectives and practices related to sexual and reproductive care provision for males with cystic fibrosis.

BACKGROUND: Males with cystic fibrosis (MwCF) have unique sexual and reproductive health (SRH) concerns. This study investigates multidisciplinary CF clinician perspectives related to SRH for MwCF in the current era of CF care. METHODS: We surveyed multidisciplinary clinicians exploring attitudes, practices, and preferences toward male CF SRH care. We compared responses across groups by population served (pediatric vs. adult vs. both pediatric and adult MwCF) using chi square/Fisher's exact tests. RESULTS: A total of 297 clinicians completed the survey (41 % pediatric, 36 % adult, 23 % both; 27 % physicians, 24 % social workers, 11 % nurses, 41 % other). Nearly all (98 %) believed the CF team had a role in SRH care with 75 % believing they should be primarily responsible. Pediatric clinicians were less likely to deem SRH topics important and less likely to report annual discussions compared to adult colleagues (all p<0.05). Pediatric clinicians reported less comfort in their SRH knowledge than adult colleagues (p<0.001) and in their ability to provide SRH care (p<0.05). Common barriers endorsed by respondents included lack of SRH knowledge (75 %) and presence of family/partners in exam room (64 %). A majority rated SRH screening tools (91 %), partnerships with SRH specialists (90 %), clinician training (83 %), and management algorithms (83 %) as potential facilitators. CONCLUSION: Multidisciplinary CF clinicians perceive SRH for MwCF as important but report suboptimal SRH discussions. Pediatric clinicians report significantly less comfort and skill in discussing and managing male SRH. Identified barriers and facilitators should be used to improve SRH care for MwCF.

Elexacaftor/tezacaftor/ivacaftor and gastrointestinal outcomes in cystic fibrosis: Report of promise-GI.

BACKGROUND: Elexacaftor/tezacaftor/ivacaftor (ETI) improves pulmonary disease in people with cystic fibrosis (PwCF), but its effect on gastrointestinal symptoms, which also affect quality of life, is not clear. METHODS: PROMISE is a 56-center prospective, observational study of ETI in PwCF >12 years and at least one F508del allele. Gastrointestinal symptoms, evaluated by validated questionnaires: Patient Assessment of Upper Gastrointestinal Disorders-Symptom (PAGI-SYM), Patient Assessment of Constipation-Symptom (PAC-SYM), Patient Assessment of Constipation-Quality of Life (PAC-QOL)), fecal calprotectin, steatocrit and elastase-1 were measured before and 6 months after ETI initiation. Mean difference and 95% confidence intervals were obtained from linear regression with adjustment for age and sex. RESULTS: 438 participants fully completed at least 1 questionnaire. Mean (SD) for baseline PAGI-SYM, PAC-SYM, and PAC-QOL total scores were 0.56 (0.59), 0.47 (0.45), and 0.69 (0.53) out of maximum 5, 4, and 5, respectively (higher score indicates greater severity). Corresponding age- and sex-adjusted 6 months mean changes (95% CI) in total scores were -0.15 (-0.21, -0.09) for PAGI-SYM, -0.14 (-0.19, -0.09) for PAC-SYM, and -0.15 (-0.21, -0.10) for PAC-QOL. While statistically significant, changes were small and unlikely to be of clinical importance. Fecal calprotectin showed a change (95% CI) from baseline of -66.2 µg/g (-86.1, -46.2) at 6 months, while fecal elastase and steatocrit did not meaningfully change. CONCLUSIONS: After 6 months of ETI, fecal markers of inflammation decreased. Gastrointestinal symptoms improved, but the effect size was small. Pancreatic insufficiency did not improve.

Endocrine Complications of Cystic Fibrosis.

Endocrine comorbidities have become increasingly important medical considerations as improving cystic fibrosis (CF) care increases life expectancy. Although the underlying pathophysiology of CF-related diabetes remains elusive, the use of novel technologies and therapeutics seeks to improve both CF-related outcomes and quality of life. Improvements in the overall health of those with CF have tempered concerns about pubertal delay and short stature; however, other comorbidities such as hypogonadism and bone disease are increasingly recognized. Following the introduction of highly effective modulator therapies there are many lessons to be learned about their long-term impact on endocrine comorbidities.

Men's sexual and reproductive health in cystic fibrosis in the era of highly effective modulator therapies-A qualitative study.

BACKGROUND: As people with cystic fibrosis (CF) are living longer, men with CF increasingly face both general and disease-specific sexual and reproductive health (SRH) concerns. This study explored the SRH experiences and preferences of men with CF in health care in the era of widespread use of highly effective CF modulator therapies. METHODS: We recruited men with CF aged 18 years and older to participate in a qualitative descriptive study using semi-structured telephone interviews to explore experiences and preferences related to CF SRH care. Two independent researchers coded interview transcripts and conducted content and thematic analysis using an inductive approach. FINDINGS: We interviewed 24 participants (mean age 33.7 ± 11.8 years, range 19-60) and identified five major themes: 1) CF SRH concerns, specifically infertility, can have negative impacts on men's perceptions of masculinity, relationships, and mental health; 2) As life expectancy increases, addressing male SRH is increasingly important in CF care; 3) Men with CF experience lack of SRH counseling and care; 4) Conversations about SRH should begin in early adolescence and be addressed regularly by CF providers in a stepwise fashion; 5) Men with CF value peer support and SRH information featuring the experiences of other men with CF. CONCLUSIONS: Men with CF acknowledge the need for comprehensive CF care that includes SRH and value early, stepwise, provider-initiated SRH conversations. Future work should seek a broader understanding of the impact of SRH on the mental health of men with CF as these concerns can have significant effects on the lives and self-identities of men with CF.

Exploring provider attitudes and perspectives related to men's health in cystic fibrosis.

BACKGROUND: New modulator therapies have markedly improved the health of people with cystic fibrosis (CF), allowing an increased focus on quality-of-life improvements for men with CF, including those related to sexual and reproductive health (SRH). This study explored CF providers' attitudes and experiences with addressing men's health in CF. METHODS: We interviewed geographically diverse adult and pediatric United States (U.S.) CF program directors via semi-structured telephone interviews exploring their perspectives and practices related to men's SRH in CF. Two coders analyzed transcribed interviews and created a codebook to identify key themes. RESULTS: We interviewed 20 providers and identified the following themes: 1) Men's SRH is important to address within CF care, but there is no standardization around this aspect of care; 2) There is no consensus about the recommendation or utilization of semen analysis to assess men's infertility; 3) There are many barriers to men's SRH care provision in CF centers, including the low priority of SRH concerns and provider discomfort and lack of expertise in SRH; 4) Providers desire clear evidence-based guidelines and patient resources related to men's SRH in CF; and 5) Providers believe future research should focus on testosterone and the impact of modulators on men's SRH. CONCLUSIONS: CF center directors acknowledge the importance of addressing SRH with men with CF, but there is a lack of standardization and research in this aspect of care. Existing barriers to optimal SRH care and identified facilitators in this study can serve as targets for interventions in the CF care model.

Bone mineral density screening by DXA for people with cystic fibrosis: A registry analysis of patient and program factors influencing rates of screening.

BACKGROUND: Current guidelines recommend screening for Cystic Fibrosis (CF) related bone disease (CFBD) using dual-energy x-ray absorptiometry (DXA) for all people ≥ 18 years of age and select people ≥ 8 years of age. However, adherence to these guidelines is variable. This study aims to evaluate screening practices among adult programs in the US and identify patient and program-based characteristics which may influence screening. METHODS: The CF Foundation Patient Registry (CFFPR) was used to identify all people over the age of 18 who were seen at adult CF programs and received screening for CFBD using DXA at least once between 2014 and 2018. Associations with patient and program level characteristics were assessed using the Chi Square test. Patient level variables were also examined using standardized difference to assess for meaningful clinical differences in rates of screening. RESULTS: From 2014 to 2018, a total of 15,134 people over the age of 18 were identified in the CFFPR. Of these people, 9,023 (60%) received a DXA during the time period. The median rate of screening by program was 66% and programs in the highest quartile of screening obtained DXAs on >76% of their population. At the program level, larger size and increased adherence to other guideline practices such as OGTT screening and 4 visits, 4 cultures in a year correlated with higher rates of screening for CFBD. At the patient-level, people with lower lung function (FEV1 <90%) and those with CF related diabetes were more likely to be screened. People without health insurance were less likely to receive recommended screening. CONCLUSION: Screening practices for CFBD vary widely across adult programs in the US despite recommendations to screen all people over the age of 18. Factors identified in this analysis may be used to identify those people at highest risk of missing appropriate screening. CFBD has significant implications for our patients and therefore routine screening should be emphasized as part of standard care moving forward.

Clinical Effectiveness of Elexacaftor/Tezacaftor/Ivacaftor in People with Cystic Fibrosis: A Clinical Trial.

Rationale: The cystic fibrosis (CF) modulator drug, elexacaftor/tezacaftor/ivacaftor (ETI), proved highly effective in controlled clinical trials for individuals with at least one F508del allele, which occurs in at least 85% of people with CF. Objectives: PROMISE is a postapproval study to understand the broad effects of ETI through 30 months' clinical use in a more diverse U.S. patient population with planned analyses after 6 months. Methods: Prospective, observational study in 487 people with CF age 12 years or older with at least one F508del allele starting ETI for the first time. Assessments occurred before and 1, 3, and 6 months into ETI therapy. Outcomes included change in percent predicted FEV1 (ppFEV1), sweat chloride concentration, body mass index (BMI), and self-reported respiratory symptoms. Measurements and Main Results: Average age was 25.1 years, and 44.1% entered the study using tezacaftor/ivacaftor or lumacaftor/ivacaftor, whereas 6.7% were using ivacaftor, consistent with F508del homozygosity and G551D allele, respectively. At 6 months into ETI therapy, ppFEV1 improved 9.76 percentage points (95% confidence interval [CI], 8.76 to 10.76) from baseline, cystic fibrosis questionnaire-revised respiratory domain score improved 20.4 points (95% CI, 18.3 to 22.5), and sweat chloride decreased -41.7 mmol/L (95% CI, -43.8 to -39.6). BMI also significantly increased. Changes were larger in those naive to modulators but substantial in all groups, including those treated with ivacaftor at baseline. Conclusions: ETI by clinical prescription provided large improvements in lung function, respiratory symptoms, and BMI in a diverse population naive to modulator drug therapy, using existing two-drug combinations, or using ivacaftor alone. Each group also experienced significant reductions in sweat chloride concentration, which correlated with improved ppFEV1 in the overall study population. Clinical trial registered with www.clinicaltrials.gov (NCT NCT04038047).

Most Short Children with Cystic Fibrosis Do Not Catch Up by Adulthood.

Poor linear growth is common in children with cystic fibrosis (CF) and predicts pulmonary status and mortality. Growth impairment develops in infancy, prior to pulmonary decline and despite aggressive nutritional measures. We hypothesized that growth restriction during early childhood in CF is associated with reduced adult height. We used the Cystic Fibrosis Foundation (CFF) patient registry to identify CF adults between 2011 and 2015 (ages 18-19 y, n = 3655) and had height for age (HFA) records between ages 2 and 4 y. We found that only 26% CF adults were ≥median HFA and 25% were <10th percentile. Between 2 and 4 years, those with height < 10th percentile had increased odds of being <10th percentile in adulthood compared to children ≥ 10th percentile (OR = 7.7). Of HFA measured between the 10th and 25th percentiles at ages 2-4, 58% were <25th percentile as adults. Only 13% between the 10th and 25th percentile HFA at age 2-4 years were >50th percentile as adults. Maximum height between ages 2 and 4 highly correlated with adult height. These results demonstrate that low early childhood CF height correlates with height in adulthood. Since linear growth correlates with lung growth, identifying both risk factors and interventions for growth failure (nutritional support, confounders of clinical care, and potential endocrine involvement) could lead to improved overall health.

Barriers to retinopathy screening in youth and young adults with type 1 diabetes.

Early detection of diabetic retinopathy (DR) is imperative; however, adherence to screening guidelines is poor. We hypothesized that youth and young adults with type 1 diabetes (T1D) who met American Diabetes Association criteria for recommended DR screening at the time of the study (10 years old or greater with diabetes duration of 5 years or more) would report multiple barriers to screening and that targeted barriers and subpopulations could be identified to improve access to care. 271 youth aged 10 to 26 years with T1D of at least 5 years duration were recruited from clinic, diabetes camp, and a diabetes conference and completed a patient-reported questionnaire. 113 (41.7%) reported at least one barrier to DR screening, with missed school and work being the most common (20.7%). Older participants (P = 0.007) and those with a longer diabetes duration (P = 0.018) were more likely to report barriers to screening. Recruitment location, sex, race and ethnicity, HbA1c, insulin regimen, and clinic visit frequency were not associated with reporting at least one barrier. Slightly less than two-thirds (62.1%) of participants who responded (n = 235 out of 271) adhered to recommended screening guidelines of the time and reported having an eye exam within the past year, 24.7% 12-23 months ago, 9.8% 2 years ago or more, and 3.4% had never had a DR exam. As older patients and those with longer duration of diabetes are more likely to have DR, targeted interventions to address barriers to care, such as, missed school and work should be implemented in these groups.

PROMISE: Working with the CF community to understand emerging clinical and research needs for those treated with highly effective CFTR modulator therapy.

Highly effective CFTR modulator drug therapy is increasingly available to those with cystic fibrosis. Multiple observational research studies are now being conducted to better understand the impacts of this important therapeutic milestone on long-term outcomes, patient care needs, and future research priorities. PROMISE is a large, multi-disciplinary academic study focused on the broad impacts of starting elexacaftor/tezacaftor/ivacaftor in the US population age 6 years and older. The many areas of investigation and rationale for each are discussed by organ systems, along with recognition of remaining important questions that will not be addressed by this study alone. Knowledge gained through this and multiple complementary studies around the world will help to understand important health outcomes, clinical care priorities, and research needs for a large majority of people treated with these or similarly effective medications targeting the primary cellular impairment in cystic fibrosis.

Real-World Screening for Retinopathy in Youth With Type 1 Diabetes Using a Nonmydriatic Fundus Camera.

OBJECTIVE: To assess the use of a portable retinal camera in diabetic retinopathy (DR) screening in multiple settings and the presence of associated risk factors among children, adolescents, and young adults with type 1 diabetes. DESIGN AND METHODS: Five hundred youth with type 1 diabetes of at least 1 year's duration were recruited from clinics, diabetes camp, and a diabetes conference and underwent retinal imaging using a nonmydriatic fundus camera. Retinal characterization was performed remotely by a licensed ophthalmologist. Risk factors for DR development were evaluated by a patient-reported questionnaire and medical chart review. RESULTS: Of the 500 recruited subjects aged 9-26 years (mean 14.9, SD 3.8), 10 cases of DR were identified (nine mild and one moderate nonproliferative DR) with 100% of images of gradable quality. The prevalence of DR was 2.04% (95% CI 0.78-3.29), at an average age of 20.2 years, with the youngest affected subject being 17.1 years of age. The rate of DR was higher, at 6.5%, with diabetes duration >10 years (95% CI 0.86-12.12, P = 0.0002). In subjects with DR, the average duration of diabetes was 12.1 years (SD 4.6, range 6.2-20.0), and in a subgroup of clinic-only subjects (n = 114), elevated blood pressure in the year before screening was associated with DR (P = 0.0068). CONCLUSION: This study in a large cohort of subjects with type 1 diabetes demonstrates that older adolescents and young adults (>17 years) with longer disease duration (>6 years) are at risk for DR development, and screening using a portable retinal camera is feasible in clinics and other locations. Recent elevated blood pressure was a risk factor in an analyzed subgroup.

Growth failure and treatment in cystic fibrosis.

Poor growth has long been a characteristic feature of cystic fibrosis (CF) and is significantly linked to lung function and overall health status. Improvements in pulmonary and nutrition care for patients with cystic fibrosis (CF) have resulted in better growth outcomes; however, height gains have not paralleled the improvements in weight in children with CF, and patients with more severe CF mutations remain significantly more affected. Many factors affect the growth hormone-IGF-1 axis and the growth plate of the long bones, including the chronic inflammatory state associated with CF. There are also increasing data on the direct effects of CFTR on bone and implications for CFTR modulators in attaining optimal growth. Treatments aimed at improving growth in CF are also reviewed here.

Reduced bone length, growth plate thickness, bone content, and IGF-I as a model for poor growth in the CFTR-deficient rat.

BACKGROUND: Reduced growth and osteopenia are common in individuals with cystic fibrosis (CF). Additionally, improved weight and height are associated with better lung function and overall health in the disease. Mechanisms for this reduction in growth are not understood. We utilized a new CFTR knockout rat to evaluate growth in young CF animals, via femur length, microarchitecture of bone and growth plate, as well as serum IGF-I concentrations. METHODS: Femur length was measured in wild-type (WT) and SD-CFTRtm1sage (Cftr-/-) rats, as a surrogate marker for growth. Quantitative bone parameters in Cftr-/- and WT rats were measured by micro computed tomography (micro-CT). Bone histomorphometry and cartilaginous growth plates were analyzed. Serum IGF-I concentrations were also compared. RESULTS: Femur length was reduced in both Cftr-/- male and female rats compared to WT. Multiple parameters of bone microarchitecture (of both trabecular and cortical bone) were adversely affected in Cftr-/- rats. There was a reduction in overall growth plate thichkness in both male and female Cftr-/- rats, as well as hypertrophic zone thickness and mean hypertrophic cell volume in male rats, indicating abnormal growth characteristics at the plate. Serum IGF-I concentrations were severely reduced in Cftr-/- rats compared to WT littermates. CONCLUSIONS: Despite absence of overt lung or pancreatic disease, reduced growth and bone content were readily detected in young Cftr-/- rats. Reduced size of the growth plate and decreased IGF-I concentrations suggest the mechanistic basis for this phenotype. These findings appear to be intrinsic to the CFTR deficient state and independent of significant clinical confounders, providing substantive evidence for the importance of CFTR on maintinaing normal bone growth.

Effects of Diagnosis by Newborn Screening for Cystic Fibrosis on Weight and Length in the First Year of Life.

Importance: Since the implementation of universal newborn screening (NBS) for cystic fibrosis (CF), the timing and magnitude of growth deficiency or its association with correlates of disease among infants with CF who underwent NBS has not been well described. Objective: To examine incremental weight gain, linear growth, and clinical features in the first year of life among infants with CF who underwent NBS. Design, Setting, and Participants: The Baby Observational and Nutrition Study (BONUS), a multicenter, longitudinal, observational cohort study, was conducted during regular CF clinic visits in the first 12 months of life at 28 US Cystic Fibrosis Foundation-accredited Care Centers from January 7, 2012, through May 31, 2015. Participants included 231 infants younger than 3.5 months who underwent NBS and had confirmed CF, with a gestational age of at least 35 weeks, birth weight of at least 2.5 kg, and toleration of full oral feeds. Of these, 222 infants (96.1%) had follow-up beyond 6 months of age and 215 (93.1%) completed 12 months of follow-up. Exposure: Cystic fibrosis. Main Outcome and Measures: Attained weight and length for age and World Health Organization normative z scores at ages 1 to 6 and 8, 10, and 12 months (defined a priori). Results: Of the 231 infants enrolled, 110 infants (47.6%) were female and 121 (52.4%) were male, with a mean (SD) age of 2.58 (0.69) months. BONUS infants had lower than mean birth weights (mean z score, -0.15; 95% CI, -0.27 to -0.04) and higher birth lengths (mean z score, 0.44; 95% CI, 0.26 to 0.62). They achieved normal weight by 12 months, a significant improvement over a prescreening cohort of newborns with CF from 20 years before the contemporary cohort (mean z score increase, 0.57; 95% CI, 0.37-0.77). However, length was lower than the mean at 12 months (mean z score, -0.56; 95% CI, -0.70 to -0.42). Only 30 infants (13.6%) were at less than the 10th percentile of weight for age, whereas 53 (23.9%) were at less than the 10th percentile of length for age at more than half their visits. Male sex, pancreatic insufficiency, meconium ileus, histamine blocker use, and respiratory Pseudomonas aeruginosa infection were associated with lower weight or length during the first year. Insulinlike growth factor 1 levels were significantly lower among low-length infants. Persistently low-weight infants consumed significantly more calories, and weight and length z scores were negatively correlated with caloric intake. Conclusions and Relevance: Since initiation of universal NBS for CF, significant improvement has occurred in nutritional status, with normalization of weight in the first year of life. However, length stunting remains common.

Growth in Prepubertal Children With Cystic Fibrosis Treated With Ivacaftor.

BACKGROUND AND OBJECTIVES: Cystic fibrosis (CF) is known for its impact on the lung and pancreas of individuals; however, impaired growth is also a common complication. We hypothesized that targeting the biological defect in the CF transmembrane conductance regulator (CFTR) protein may affect growth outcomes. METHODS: In this post hoc analysis, we assessed linear growth and weight in 83 children (aged 6-11 years) enrolled in 2 clinical trials, the longitudinal-observation GOAL study and the placebo-controlled ENVISION study, to evaluate the effects of ivacaftor, a CFTR potentiator. We calculated height and weight z scores and height and weight growth velocities (GVs). RESULTS: In ivacaftor-treated children in GOAL, height and weight z scores increased significantly from baseline to 6 months (increases of 0.1 [P < .05] and 0.26 [P < .0001], respectively); height GV increased significantly from 3 to 6 months (2.10-cm/year increase; P < .01). In ivacaftor-treated children in ENVISION, height and weight z scores increased significantly from baseline to 48 weeks (increases of 0.17 [P < .001] and 0.35 [P < .001], respectively). Height and weight GVs from baseline to 48 weeks were also significantly higher with ivacaftor than with placebo (differences of 1.08 cm/year [P < .05] and 3.11 kg/year [P < .001], respectively). CONCLUSIONS: Ivacaftor treatment in prepubescent children may help to address short stature and altered GV in children with CF; results from these analyses support the existence of an intrinsic defect in the growth of children with CF that may be ameliorated by CFTR modulation.

Osteoblast CFTR inactivation reduces differentiation and osteoprotegerin expression in a mouse model of cystic fibrosis-related bone disease.

Low bone mass and increased fracture risk are recognized complications of cystic fibrosis (CF). CF-related bone disease (CFBD) is characterized by uncoupled bone turnover--impaired osteoblastic bone formation and enhanced osteoclastic bone resorption. Intestinal malabsorption, vitamin D deficiency and inflammatory cytokines contribute to CFBD. However, epidemiological investigations and animal models also support a direct causal link between inactivation of skeletal cystic fibrosis transmembrane regulator (CFTR), the gene that when mutated causes CF, and CFBD. The objective of this study was to examine the direct actions of CFTR on bone. Expression analyses revealed that CFTR mRNA and protein were expressed in murine osteoblasts, but not in osteoclasts. Functional studies were then performed to investigate the direct actions of CFTR on osteoblasts using a CFTR knockout (Cftr-/-) mouse model. In the murine calvarial organ culture assay, Cftr-/- calvariae displayed significantly less bone formation and osteoblast numbers than calvariae harvested from wildtype (Cftr+/+) littermates. CFTR inactivation also reduced alkaline phosphatase expression in cultured murine calvarial osteoblasts. Although CFTR was not expressed in murine osteoclasts, significantly more osteoclasts formed in Cftr-/- compared to Cftr+/+ bone marrow cultures. Indirect regulation of osteoclastogenesis by the osteoblast through RANK/RANKL/OPG signaling was next examined. Although no difference in receptor activator of NF-κB ligand (Rankl) mRNA was detected, significantly less osteoprotegerin (Opg) was expressed in Cftr-/- compared to Cftr+/+ osteoblasts. Together, the Rankl:Opg ratio was significantly higher in Cftr-/- murine calvarial osteoblasts contributing to a higher osteoclastogenesis potential. The combined findings of reduced osteoblast differentiation and lower Opg expression suggested a possible defect in canonical Wnt signaling. In fact, Wnt3a and PTH-stimulated canonical Wnt signaling was defective in Cftr-/- murine calvarial osteoblasts. These results support that genetic inactivation of CFTR in osteoblasts contributes to low bone mass and that targeting osteoblasts may represent an effective strategy to treat CFBD.

Cystic fibrosis-related bone disease: insights into a growing problem.

PURPOSE OF REVIEW: This review will describe the clinical significance, pathogenesis and treatment of cystic fibrosis related bone disease (CFBD). RECENT FINDINGS: CFBD continues to increase as the life expectancy of individuals with cystic fibrosis increases. According to clinical guidelines, individuals with cystic fibrosis should be initially screened at the age of 18 years via dual-energy x-ray absorptiometry, if not done so previously. The underlying pathogenesis of CFBD appears to be multifactorial, but increasing data imply a direct impact by the cystic fibrosis transmembrane conductance regulator (CFTR). CFTR deficiency and/or dysfunction impair osteoblast activity and differentiation, and indirectly promote osteoclast formation. Unfortunately, once diagnosed with CFBD, few cystic fibrosis tested medical therapies exist. SUMMARY: CFBD is an increasingly recognized complication that has a significant impact on the overall health of the individual. Recommendations to identify patients with cystic fibrosis who are at risk for fracture using dual-energy x-ray absorptiometry have been established. Therapeutic agents directly studied in patients with cystic fibrosis are limited to bisphosphonates, although other potential treatment agents exist. Finally, an improved understanding of the pathologic mechanisms will aid in the study and development of therapies.

A multi-center controlled trial of growth hormone treatment in children with cystic fibrosis.

OBJECTIVES: We evaluated safety and efficacy of recombinant human growth hormone (rhGH) for improving growth, lean body mass (LBM), pulmonary function, and exercise tolerance in children with cystic fibrosis (CF) and growth restriction. STUDY DESIGN: Multicenter, open-label, controlled clinical trial comparing outcomes in prepubertal children <14 years with CF, randomized in a 1:1 ratio to receive daily rhGH (Nutropin AQ) or no treatment (control) for 12 months, followed by a 6-month observation (month 18). Safety was monitored at each visit, including assessments of glucose tolerance. RESULTS: Sixty-eight subjects were randomized (control n = 32; rhGH n = 36). Mean height standard deviation score (SDS) in the rhGH group increased by 0.5 ± 0.4 at 12 months (mean ± SD, P < 0.001); the control group height SDS remained unchanged. Weight increased by 3.8 ± 1.8 versus 2.8 ± 1.5 kg, (mean ± SD, P = 0.0356) and LBM increased by 3.8 ± 1.8 versus 2.1 ± 1.4 kg (P = 0.0002) in the rhGH group versus controls, respectively. Forced vital capacity increased by 325 ± 319 in the rhGH group compared with 178 ± 152 ml in controls (mean ± SD, P = 0.032). Forced expiratory volume in 1 sec improved in both groups with a significant difference between groups after adjustment for baseline severity (LS mean ± SE: rhGH, 224 ± 37, vs. controls, 108 ± 40 ml; P = 0.04). There was no difference between groups in exercise tolerance (6-min walk distance) at 1 year. Changes in glucose tolerance for the two groups were similar over the 12-month study period, with three subjects developing IGT and one CFRD in each group. One rhGH-treated patient developed increased intracranial pressure. CONCLUSIONS: Treatment with rhGH in prepubertal children with CF was effective in promoting growth, weight, LBM, lung volume, and lung flows, and had an acceptable safety profile.

Endocrine parameters of cystic fibrosis: back to basics.

Dramatic changes in the life expectancy of cystic fibrosis (CF) patients are occurring, creating a cohort of aging individuals experiencing long-term complications of this chronic disease. The two most common of these complications include CF-related diabetes and CF bone disease. The clinical implications of each have become better understood, as have potential therapies. However, data obtained from the basic science studies of both diseases have not been widely recognized. In this review, we focus on the known and hypothesized pathogenesis of these two disorders. Additionally, the molecular underpinnings of CF will be explained along with the potential interactions with endocrine disease phenotypes.

Murine model for cystic fibrosis bone disease demonstrates osteopenia and sex-related differences in bone formation.

As the incidence of cystic fibrosis (CF) bone disease is increasing, we analyzed CF transmembrane conductance regulator (CFTR) deficient mice (CF mice) to gain pathogenic insights. In these studies comparing adult (14 wk) CF and C57BL/6J mice, both bone length and total area were decreased in CF mice. Metaphyseal trabecular and cortical density were also decreased, as well as diaphyseal cortical and total density. Trabecular bone volume was diminished in CF mice. Female CF mice revealed decreased trabecular width and number compared with C57BL/6J, whereas males demonstrated no difference in trabecular number. Female CF mice had reduced mineralizing surface and bone formation rates. Conversely, male CF mice had increased mineralizing surface, mineral apposition, and bone formation rates compared with C57BL/6J males. Bone formation rate was greater in males compared with female CF mice. Smaller bones with decreased density in CF, despite absent differences in osteoblast and osteoclast surfaces, suggest CF transmembrane conductance regulator influences bone cell activity rather than number. Differences in bone formation rate in CF mice are suggestive of inadequate bone formation in females but increased bone formation in males. This proanabolic observation in male CF mice is consistent with other clinical sex differences in CF.