Cystic Fibrosis-related Bone Disease Research Articles

Effects of modulator therapies on endocrine complications in adults with cystic fibrosis: a narrative review.

Cystic fibrosis is a monogenic disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein, which transports chloride ions in secretory organs. Modulator therapies are small molecules that correct CFTR dysfunction and can lead to a wide range of benefits for both pulmonary and extrapulmonary complications of cystic fibrosis. With advancements in airway, antimicrobial and nutritional therapies and now introduction of modulator therapies, most people living with cystic fibrosis in Australia are now adults. For adults with cystic fibrosis, endocrine manifestations such as cystic fibrosis-related diabetes, metabolic bone disease, and reproductive health are becoming increasingly important, and emerging evidence on the endocrine effects of CFTR modulator therapies is promising and is shifting paradigms in our understanding and management of these conditions. The management of cystic fibrosis-related diabetes will likely need to pivot for high responders to modulator therapy with dietary adaptions and potential use of medications traditionally reserved for adults with type 2 diabetes, but evidence to support changing clinical care needs is currently lacking. Increased attention to diabetes-related complications screening will also be required. Increased exercise capacity due to improved lung function, nutrition and potentially direct modulator effect may have a positive impact on cystic fibrosis-related bone disease, but supporting evidence to date is limited. Fertility can improve in women with cystic fibrosis taking modulator therapy. This has important implications for pregnancy and lactation, but evidence is lacking to guide pre-conception and antenatal management. Provision of multidisciplinary clinical care remains ever-important to ensure the emergence of endocrine and metabolic complications are optimised in adults with cystic fibrosis.

Cystic fibrosis related bone disease in children: Can it be predicted?

Cystic fibrosis (CF) -related bone disease (CFBD) is an important complication of CF, and low BMD in childhood is a precursor of CFBD. Here, we aimed to investigate bone turnover biomarkers, including osteocalcin (OC), receptor activator of nuclear factor kappa B ligand (RANKL) and osteoprotegerin (OPG) in relation to low BMD in children with CF (cwCF). We also evaluated factors which could affect bone turnover with particular emphasis on fat-free mass (FFM), forced expiratory volume in 1s (FEV1), hand grip strength (HGS), and functional capacity and physical activity. Sixteen cwCF aged 8-18 years with moderate low BMD (group1) and 64 cwCF with normal BMD (group2) were enrolled. Serum RANKL, OC, and OPG were determined by immunoenzymatic assays. Multiple parameters including pancreatic status, lung functions, body mass index (BMI), FFM measured by bioelectric impedance analysis (BIA), 6-minute walk test, vitamin D, nutritional intake, HGS, functional capacity and physical activity, serum and urine biomarkers were compared between the two groups. We found similar serum levels of RANKL (p=0.501), OC (p=0.445), OPG (p=0.380), and RANKL/OPG ratio (p=0.449) between group1 and group2 in cwCF. BMI z-score (p<0.001), FFMI z-score (p<0.001), FEV1 z-score (p=0.007), and right-HGS (%pred) (p=0.009) significantly differed between the two groups. Multivariate linear regression revealed that the only factors that predicted BMD were FFMI z-score and HGS %pred. Serum OC, OPG, RANKL and RANKL/OPG ratio did not predict BMD in cwCF. FFMI z-score and HGS %pred measured by non-invasive and practical methods were the best predictors of BMD.

P314 Cystic fibrosis related to bone disease in children: can it be predicted?

Cystic fibrosis (CF) -related bone disease (CFBD) is an important complication of CF, and low BMD in childhood is a precursor of CFBD. Here, we aimed to investigate bone turnover biomarkers, including osteocalcin (OC), receptor activator of nuclear factor kappa B ligand (RANKL) and osteoprotegerin (OPG) in relation to low BMD in children with CF (cwCF). We also evaluated factors which could affect bone turnover with particular emphasis on free fat mass (FFM), forced expiratory volume in 1 s (FEV1), hand grip strength (HGS), and functional capacity and physical activity.

Clinical relevance of low bone density in cystic fibrosis adult patients: A pilot study

Survival improvement in cystic fibrosis (CF) is associated with more frequent long-term complications, including CF related bone disease (CFBD). Impact of CFBD on global health outcome remains poorly described. We aimed to assess the relationship between low bone mineral density (BMD) and spinal pain, disability, and quality of life in CF adult patients. This monocentric cross-sectional study with prospective data collection was conducted from November 2016 to December 2019 in the Department of Respiratory Diseases at the University Hospital of Reims (NCT02924818). BMD was assessed by X-ray absorptiometry (DXA). Disability was assessed by the Health Assessment Questionnaire (HAQ). Quality of life was assessed by both the St George's Respiratory Questionnaire and the Cystic Fibrosis Questionnaire for teenagers and adults (CFQ 14+). Forty patients were analyzed, 68% of men, with a median age of 25 years, a median body mass index of 21 kg/m² and a median FEV1% of 54%. Nine patients (23%) had spinal pain. Ten patients (25%) had a low BMD. Compared with patients with normal BMD, patients with low BMD had a significantly lower BMI (22 vs 19 kg/m²; P = .006) and less vitamin D supplementation (33% vs 0%; P = .035). Low BMD was not associated with spinal pain, disability and quality of life. Low BMD is frequent in CF, affecting 1-quarter of adult patients. No significant association was found between low BMD and spinal pain, disability or quality of life.

Management of Cystic Fibrosis-related bone disease with bisphosphonates: An audit in a tertiary care hospital in the UK

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Osteoblasts and osteoclasts generation from iPSCs to study CFTR role in cystic fibrosis-related bone disease

Osteoblasts and osteoclasts generation from iPSCs to study CFTR role in cystic fibrosis-related bone disease

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.

Treatment of cystic fibrosis related bone disease

The advent of highly effective CFTR modulator therapies has slowed the progression of pulmonary complications in people with cystic fibrosis. There is increased interest in cystic fibrosis bone disease (CFBD) due to the increasing longevity of people with cystic fibrosis. CFBD is a complex and multifactorial disease. CFBD is a result of hypomineralized bone leading to poor strength, structure and quality leading to susceptibility to fractures. The development of CFBD spans different age groups. The management must be tailored to each group with nuance and based on available guidelines while balancing therapeutic benefits to risks of long-term use of bone-active medication. For now, the mainstay of treatment includes bisphosphonates. However, the long-term effects of bisphosphonate treatment in people with CF are not fully understood. We describe newer agents available for osteoporosis treatment. Still, the lack of data behooves trials of monoclonal antibodies treatments such as Denosumab and Romozosumab and anabolic bone therapy such as teriparatide and Abaloparatide. In this review, we also summarize screening and non-pharmacologic treatment of CFBD and describe the various options available for the pharmacotherapy of CFBD. We address the prospect of CFTR modulators on bone health while awaiting long-term trials to describe the effects of these medications on bone health.

An update on methods for assessing bone quality and health in Cystic fibrosis

With increasing life expectancy in people with Cystic fibrosis (CF), the focus of clinical care has shifted to management and prevention of non-pulmonary comorbidities. CF related bone disease, defined by low bone mineral density (BMD), is prevalent across all age groups and acknowledges the increased fractures rates that negatively impact lung function and quality of life. Dual energy X-ray absorptiometry (DXA) measurement of bone mineral content (BMC) and “areal” BMD (aBMD) is recommended for identifying and monitoring bone health in children and adults due to its low cost, low radiation exposure, and widespread availability. Recent studies in children and adolescents with chronic illness focus on adjustment of BMC and aBMD measurements for height due to the effects of short stature and delayed maturation on bone size. Expanded reference databases for alternate imaging sites such as the ultradistal radius and hip present opportunities for research and long-term monitoring. As the two-dimensional nature of DXA imposes limitations, we highlight other imaging modalities including peripheral quantitative computed tomography QCT (pQCT), magnetic resonance imaging, and quantitative ultrasound (QUS). These tools, while primarily used in a research setting, can impart information on true volumetric bone density and bone microarchitecture as well as contribute to fracture assessment and prediction. Due to the high morbidity and mortality associated with vertebral and hip fracture, we will present on vertebral fracture assessment (VFA) in both children and adults as well as applied analyses including hip structural analysis (HSA), trabecular bone score (TBS), and fracture risk assessment (FRAX) for high risk groups. Questions remain on the future clinical applicability and accessibility of these assessment and prediction tools, longitudinal monitoring through adolescence and adulthood, and how outcome measures may guide bone modifying therapies.

Findings from a feasibility study of estradiol for hypogonadal women with cystic fibrosis-related bone disease

BackgroundAdvancements in therapies for patients with cystic fibrosis (CF) have decreased mortality, leading to increased prevalence of chronic complications including bone disease. CF-related bone disease (CFBD) is characterized by low bone mineral density (BMD) and fragility fractures. Estrogen deficiency increases bone resorption, resulting in decreased BMD that can be restored with estrogen replacement. Current CF guidelines recommend treating female hypogonadal patients with CFBD with estrogen replacement, but no prospective study has investigated the effects of estrogen supplementation on CFBD. Estrogen is known to modulate inflammatory markers and autoimmune diseases.We proposed to test the hypothesis that estrogen status plays a critical role in optimizing bone health, modulating inflammation, preserving lung function, and maximizing quality of life in premenopausal women with CF.MethodsWe planned a randomized, placebo-controlled, investigator- and patient-blinded, pilot trial with two parallel arms. Eligible subjects were women with CF 18–50 years old with hypogonadism and low BMD who were not taking systemic glucocorticoids, had not had a prior transplant, and did not have contraindications to oral estradiol. Subjects would be block randomized to receive oral estradiol or placebo for 6 months. The primary outcome was feasibility metrics. Secondary outcomes included relative changes in estradiol, bone turnover markers, lung function, inflammatory markers, and quality of life metrics. The study was funded through departmental funds.ResultsOf 233 subjects screened, 86 subjects were women with CF 18–50 years old and none were eligible for participation. Most subjects were excluded due to absent DXA report (24%), normal BMD (22%), or use of systemic estrogen (16%). Due to difficulty recruiting the planned 52 subjects, the trial was closed for recruitment and no subjects were randomized.ConclusionThis study was designed to investigate the feasibility of a safety and efficacy trial of estrogen therapy for women with CF. Unfortunately, due to eligibility criteria, the study was unable to recruit subjects. This feasibility study highlights the need for improved BMD screening in young women with CF. Future study designs may require the incorporation of a screening DXA as part of subject recruitment.Trial registrationThe study was registered on ClinicalTrials.gov (NCT03724955).

Magnesium implantation or supplementation ameliorates bone disorder in CFTR-mutant mice through an ATF4-dependent Wnt/β-catenin signaling

Magnesium metal and its alloys are being developed as effective orthopedic implants; however, the mechanisms underlying the actions of magnesium on bones remain unclear. Cystic fibrosis, the most common genetic disease in Caucasians caused by the mutation of CFTR, has shown bone disorder as a key clinical manifestation, which currently lacks effective therapeutic options. Here we report that implantation of magnesium-containing implant stimulates bone formation and improves bone fracture healing in CFTR-mutant mice. Wnt/β-catenin signaling in the bone is enhanced by the magnesium implant, and inhibition of Wnt/β-catenin by iCRT14 blocks the magnesium implant to improve fracture healing in CFTR-mutant mice. We further demonstrate that magnesium ion enters osteocytes, increases intracellular cAMP level and activates ATF4, a key transcription factor known to regulate Wnt/β-catenin signaling. In vivo knockdown of ATF4 abolishes the magnesium implant-activated β-catenin in bones and reverses the improved-fracture healing in CFTR-mutant mice. In addition, oral supplementation of magnesium activates ATF4 and β-catenin as well as enhances bone volume and density in CFTR-mutant mice. Together, these results show that magnesium implantation or supplementation may serve as a potential anabolic therapy for cystic fibrosis-related bone disease. Activation of ATF4-dependent Wnt/β-catenin signaling in osteocytes is identified as a previously undefined mechanism underlying the beneficial effect of magnesium on bone formation.

S1P serum concentration is increased in CFTR-F508DEL patients: A novel biomarker of cystic fibrosis related bone disease

S1P serum concentration is increased in CFTR-F508DEL patients: A novel biomarker of cystic fibrosis related bone disease

P260 Elevated circulating sphingosine 1-phosphate in CFTR-F508del patients: a new biomarker leading to cystic fibrosis-related bone disease?

P260 Elevated circulating sphingosine 1-phosphate in CFTR-F508del patients: a new biomarker leading to cystic fibrosis-related bone disease?

SUN-337 Low Dose Ethinyl Estradiol in Women with Cystic Fibrosis Does Not Preserve Bone Mass

BACKGROUND: Cystic fibrosis-related bone disease (CFBD) affects 26% of adults with cystic fibrosis (CF). CFBD increases the risk for fractures, which in turn limits patients’ ability to effectively perform daily therapies necessary to maintain health. Factors contributing to CFBD include nutritional deficiencies, inflammation, glucocorticoid use, CF-related diabetes and untreated hypogonadism. Hypogonadism in CF is thought to be functional, although the distribution of etiologies of female hypogonadism in the modern era of CF therapies is unknown. Estrogen supplementation is commonly prescribed in the form of oral contraceptives to women with low bone mineral density (BMD). At our CF center, the average dose of ethinyl estradiol prescribed to women is 20 mcg. Recent evidence suggests that oral estrogen is ineffective for restoring bone health in women with functional hypogonadism and specifically that doses < 30 mcg oral ethinyl estradiol are inadequate. It is unknown if estradiol supplementation will restore and/or maintain BMD in women with CFBD. METHODS: The purpose of this study was to examine the skeletal health of a cross-section of premenopausal women seen at a single CF center taking 20 mcg or less of ethinyl estradiol daily (low-dose estrogen) compared to women not taking estrogen supplement. As screening for an IRB-approved intervention study, we collected health information by chart review. RESULTS: In a 12-week period, 98 women were seen in CF clinic. Of women 18 - 50 years old with CF and a documented DXA, 37 women were not taking estrogen supplement (mean age 30.8 ± 5.9 years) and 6 women were taking low-dose estrogen (mean age 30.4 ± 7.1 years). There were not statistically significant differences in other baseline characteristics known to modify CFBD. Women not taking estrogen had higher lumbar spine z-score: -0.04 ± 1.0, compared to women taking low-dose estrogen, z-score: -0.7 ±, 0.5 (p-value 0.01). Women not taking estrogen had higher BMD at the lumbar spine: 1.02 ± 0.1 g/cm2, compared to women taking low-dose estrogen: 0.95 ± 0.1 g/cm2 (p-value 0.03). Similar trends were seen at the total hip and femoral neck (p-values > 0.05). DISCUSSION: In this retrospective single-center chart review, women not taking estrogen supplement compared to women taking low-dose estrogen supplement had higher BMD. This was statistically significant at the lumbar spine, the DXA site with mostly trabecular bone. Estrogen deficiency causes trabecular bone loss, which can be restored with estrogen supplementation. These findings raise concern that low-dose estrogen supplementation for women with CF is inadequate for optimal bone accrual and may be detrimental. The ideal route and dose of estrogen supplementation for skeletal health of premenopausal women with CF still needs to be clarified. REFERENCES: CFF Patient Registry 2017; Aris JCEM 2005; Ackerman JCEM 2019; Anabtawi J CF 2019; Hughan J CF 2019

SUN-LB72 The Relationship Between Estrogen Exposure and Bone Health in Women With Cystic Fibrosis

Patients with cystic fibrosis (CF) are at risk for cystic fibrosis-related bone disease (CFBD) characterized by low bone mineral density and fractures. Nutritional status, cystic fibrosis-related diabetes (CFRD), lung health, and sex hormone insufficiency affect CFBD. CF Foundation guidelines recommend exogenous estrogen treatment for women with CFBD and sex hormone deficiency. There is a lack of data regarding effects of exogenous estrogen supplementation on the bone health of CF women. This Emory IRB approved case-control study examined the association of estrogen on bone health in CF women. Data included demographics, sex hormone treatments, CFBD modifiers, and bone mineral density. 35 estrogen exposed subjects were matched 1:2 to 70 estrogen unexposed subjects for age, BMI, and transplant status. Statistical tests analyzed differences in bone health outcomes between the estrogen and non-estrogen exposed groups. At baseline, age, BMI, transplant status, and CFRD were not statistically different (p>0.05) between the two groups. The unexposed group had higher rates of pancreatic insufficiency (p=0.02). The exposed and unexposed subjects did not have statistically significant differences in areal bone mineral density at lumbar spine, femoral neck, or total hip (p>0.05). Our study demonstrates that there are no differences in bone mineral density at 3 different sites between estrogen exposed versus estrogen unexposed women. One limitation is that factors that may also influence bone density including vitamin D status, family history, and severity of CF mutation were not corrected for. Future longitudinal studies should determine if estrogen treatment can increase bone density over time in CF women.

Prevention of osteoporosis in cystic fibrosis.

The increased life span of patients with cystic fibrosis has lead to the detection of new complications. Osteopenia is present in up to 50% of adult patients with cystic fibrosis, and osteoporosis in 10-34% and can cause a difficult management problem. In children, defects in bone health become apparent generally at adolescence because of suboptimall bone peak mass achievement. Malnutrition, inflammation, vitamin D and vitamin K deficiency, altered sex hormone production, glucocorticoid therapy, and physical inactivity potentiate poor bone health. Monitoring bone mineral density and preventive care of osteoporosis are necessary from childhood to minimize cystic fibrosis-related bone disease in adult cystic fibrosis patients.

WS11-4 Current clinical practice in the management of cystic fibrosis-related bone disease in a regional UK adult cystic fibrosis centre

WS11-4 Current clinical practice in the management of cystic fibrosis-related bone disease in a regional UK adult cystic fibrosis centre

Bone involvement in young adults with cystic fibrosis awaiting lung transplantation for end-stage respiratory failure.

The assessment of the prevalence of cystic fibrosis-related bone disease (CFBD) and its associated risk factors in young adults with cystic fibrosis (CF) awaiting lung transplantation for end-stage respiratory failure. Clinical characteristics, bone mineral density (BMD), the parameters of calcium metabolism, including vitamin D (25OHVitD) levels, and the presence of fragility fractures were evaluated in 42 CF patients (24 females, age 34.0 ± 8.4years) consecutively referred as lung transplant candidates. Mean 25OHVitD levels (54.9 ± 26.2nmol/L) were below the reference range and hypovitaminosis D (25OHVitD < 75nmol/L) was found in 34 patients (81%) and daily calcium intakes (median 550mg/day) were lower than recommended. A BMD below the expected range for age (Z-score of - 2.0 or lower) and at least one prevalent fragility fracture were found in 22 patients (52.4%) and 18 patients (45.2%), respectively. The coexistence of low BMD and the presence of fracture was observed in 13 patients (31.0%). In these patients, the prevalence of nephrolithiasis was higher than in the remaining ones (p = 0.046). The presence of kidney stones was associated with a worse bone status and with severe vitamin D deficiency. In the whole sample, femoral BMD Z-scores were directly correlated with albumin-adjusted calcium (p < 0.05) and 25OHVitD levels (p < 0.01). Despite the improvement of CF care, CFBD is still highly prevalent in young adults awaiting lung transplantation for end-stage CF. Suboptimal 25OHVitD levels could significantly contribute to the development of CFBD. The presence of nephrolithiasis could be an additional warning about the need for a careful evaluation of bone health in CF patients.

P163 Cystic Fibrosis-Related Diabetes, chronic lung infection and low nutritional status increase the risk of cystic fibrosis related bone disease

P163 Cystic Fibrosis-Related Diabetes, chronic lung infection and low nutritional status increase the risk of cystic fibrosis related bone disease

Cystic fibrosis-related bone disease in young adults affected with cystic fibrosis awaiting lung transplantation for end-stage respiratory failure

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)