Cystic fibrosis (CF) is a life-limiting genetic disorder resulting from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The defective or absent CFTR protein disrupts chloride and bicarbonate transport across epithelial cell surfaces, leading to the accumulation of thick, tenacious mucus in the lungs, pancreas, liver, intestines, and reproductive organs. Historically, progressive lung disease dominated the clinical picture and drove mortality. However, with the advent of more effective airway clearance techniques, aggressive antibiotic regimens, and CFTR modulator therapies, the median predicted survival for individuals with CF has risen dramatically into the fifth decade of life. This extended lifespan has unmasked a cascade of comorbid conditions that were previously less prevalent or less recognized. Among these, cystic fibrosis-related diabetes (CFRD) stands out as one of the most consequential. CFRD affects approximately 20% of adolescents with CF and up to 50% of adults over the age of 30, making it one of the most common extrapulmonary complications of the disease.

The metabolic derangements of CFRD extend far beyond glucose dysregulation. Patients with CFRD face a markedly elevated risk of skeletal complications, including reduced bone mineral density (BMD), osteoporosis, and fragility fractures. These bone health issues compound the existing burden of CF by impairing respiratory mechanics, limiting mobility, and diminishing overall quality of life. The relationship between CFRD and bone deterioration is multifactorial, involving nutritional deficiencies, chronic inflammation, hormonal imbalances, medication side effects, and direct cellular toxicity from hyperglycemia. Understanding these interconnected pathways is essential for clinicians who care for CF patients, as early identification and proactive management of bone disease can significantly alter the trajectory of the disease.

CFRD is a distinct form of diabetes that cannot be neatly categorized as type 1 or type 2. Its pathophysiology is unique and reflects the underlying exocrine and endocrine pancreatic damage inherent to CF. The primary mechanism is progressive destruction of the pancreatic islets due to fibrosis, fatty infiltration, and chronic inflammation. This process gradually erodes the population of insulin-producing beta cells, leading to a relative or absolute deficiency of insulin secretion. Unlike type 1 diabetes, the loss of beta-cell mass in CFRD is gradual, occurring over years to decades, and some degree of endogenous insulin secretion is often preserved well into the course of the disease.

Insulin resistance also plays a role, though it is generally less pronounced than in type 2 diabetes. During periods of acute illness, pulmonary exacerbation, or systemic inflammation, counter-regulatory hormones such as cortisol, growth hormone, and catecholamines drive transient but significant insulin resistance, unmasking the underlying insulin secretory defect. This results in episodes of hyperglycemia that may initially be intermittent. Over time, however, as beta-cell mass continues to decline, hyperglycemia becomes persistent and progressive. CFRD is further distinguished from type 2 diabetes by the absence of obesity in most patients. In fact, many individuals with CFRD have low or low-normal body mass index (BMI), which reflects the chronic energy deficit caused by malabsorption and increased metabolic demands from chronic lung disease.

The clinical presentation of CFRD is often subtle. Classic diabetes symptoms such as polyuria, polydipsia, and weight loss may be masked by concurrent CF symptoms or mistakenly attributed to the underlying disease. More commonly, CFRD is detected through routine surveillance. The Cystic Fibrosis Foundation recommends annual screening for CFRD using the oral glucose tolerance test (OGTT) in all patients aged 10 years and older. HbA1c is not reliable as a standalone screening test in CF because of altered red blood cell turnover due to chronic inflammation, nutritional deficits, and the use of supplemental oxygen, all of which can falsely lower HbA1c values. The consequences of untreated or poorly controlled CFRD are severe: accelerated decline in pulmonary function, worsening nutritional status, increased frequency of pulmonary exacerbations, and elevated mortality. Among the emerging complications that demand attention is the profound impact of CFRD on the skeletal system.

Bone is a metabolically active tissue that undergoes continuous remodeling throughout life. The process is tightly regulated by the balance between osteoclast-mediated bone resorption and osteoblast-mediated bone formation. In patients with CF who develop diabetes, a constellation of factors disrupts this balance, leading to impaired attainment of peak bone mass during adolescence and accelerated bone loss in adulthood. The result is a skeleton that is structurally compromised and more susceptible to fracture.

Malabsorption of Key Nutrients

Exocrine pancreatic insufficiency is a hallmark of CF, affecting more than 85% of individuals. The inability to secrete adequate pancreatic enzymes leads to profound malabsorption of dietary fats, proteins, and, critically, the fat-soluble vitamins A, D, E, and K. Vitamin D deficiency is almost ubiquitous in the CF population, with prevalence rates ranging from 60% to 90% depending on the study population and the threshold used for definition. Inadequate vitamin D levels reduce intestinal absorption of calcium, triggering a compensatory rise in parathyroid hormone (secondary hyperparathyroidism). Parathyroid hormone, in turn, mobilizes calcium from the skeletal reservoir by increasing osteoclastic bone resorption, thereby accelerating bone loss. Vitamin K deficiency is also common and particularly deleterious because vitamin K is required for the gamma-carboxylation of osteocalcin, a non-collagenous bone matrix protein that binds calcium and is essential for proper bone mineralization. Without adequate vitamin K, osteocalcin remains undercarboxylated and functionally impaired, reducing bone strength even when BMD appears normal. Magnesium depletion, another frequent finding in CF due to intestinal losses and loop diuretic use, further compromises bone health by impairing parathyroid hormone secretion and reducing the conversion of vitamin D to its active form.

Chronic Inflammation and Pro-inflammatory Cytokines

CF is characterized by persistent endobronchial infection and an associated chronic systemic inflammatory state. Circulating levels of pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β), are chronically elevated. These cytokines act directly on bone cells to promote resorption and suppress formation. TNF-α and IL-1β are potent stimulators of osteoclast differentiation and activation, while simultaneously inhibiting osteoblast function and promoting osteoblast apoptosis. IL-6 enhances the expression of receptor activator of nuclear factor kappa-B ligand (RANKL), the key cytokine that drives osteoclastogenesis. The arrival of CFRD intensifies this pro-inflammatory milieu. Hyperglycemia triggers the non-enzymatic formation of advanced glycation end-products (AGEs), which bind to their receptor (RAGE) on immune cells and further amplify the production of inflammatory cytokines. Additionally, hyperglycemia-induced oxidative stress contributes to a self-perpetuating cycle of inflammation and tissue damage. Studies using bone turnover markers have confirmed the synergistic effect of CF and diabetes on bone resorption. For example, urinary N-telopeptide, a specific marker of bone resorption, has been shown to be significantly higher in CF patients with CFRD than in those without diabetes, indicating a state of heightened bone turnover that favors net bone loss.

Hormonal Disruptions

Insulin is not only a metabolic hormone but also has significant anabolic effects on bone. It directly stimulates osteoblast proliferation, differentiation, and the synthesis of type I collagen, the primary structural protein of bone. In CFRD, the progressive decline in insulin secretion results in a state of relative insulin deficiency at the bone tissue level. This reduces the anabolic drive necessary for maintaining bone mass and repairing microdamage. The situation is compounded by reduced levels of insulin-like growth factor 1 (IGF-1). IGF-1 is synthesized in the liver in response to growth hormone, and its production is highly dependent on nutritional status and insulin signaling. In CF, malnutrition and chronic illness suppress the growth hormone-IGF-1 axis, leading to low circulating IGF-1 levels. IGF-1 is critical for achieving peak bone mass during adolescence and for preserving bone density in adulthood. Low IGF-1 levels are associated with reduced bone formation and increased fracture risk.

Sex hormones also play a fundamental role in skeletal health. Estrogen in women and testosterone in men exert protective effects on bone by inhibiting osteoclast activity and promoting osteoblast function. Delayed puberty is a well-recognized complication of CF, resulting from the combined effects of malnutrition, chronic inflammation, and glucocorticoid therapy. Hypogonadism can persist into adulthood, with many women with CF experiencing secondary amenorrhea and many men having low testosterone levels. CFRD may further disrupt the hypothalamic-pituitary-gonadal axis, compounding the hormonal deficiency state. The net effect is a skeleton that lacks the protective influence of both insulin, IGF-1, and sex steroids, leaving it vulnerable to unchecked resorption and inadequate formation.

Impact of Corticosteroid Use

Systemic glucocorticoids are frequently used in the management of CF-related complications, including allergic bronchopulmonary aspergillosis (ABPA), refractory airway inflammation, and acute pulmonary exacerbations. The deleterious effects of glucocorticoids on bone are well documented and occur through multiple mechanisms. Glucocorticoids directly suppress osteoblast activity by inhibiting the Wnt-beta-catenin signaling pathway, which is essential for osteoblastogenesis. They prolong the lifespan of osteoclasts, thereby enhancing bone resorption. In the intestine, glucocorticoids reduce calcium absorption, and in the kidney, they increase calcium excretion, leading to a net negative calcium balance that further stimulates secondary hyperparathyroidism. Glucocorticoids also suppress the secretion of gonadotropins (luteinizing hormone and follicle-stimulating hormone), leading to reduced production of estrogen and testosterone. The combination of CFRD and corticosteroid therapy is particularly detrimental because steroids induce insulin resistance, exacerbating hyperglycemia and creating a vicious cycle in which higher glucose levels cause further toxicity to bone cells. Patients who require frequent or high-dose corticosteroid courses represent a population at extreme risk for bone loss and fracture.

Direct Effects of Hyperglycemia on Bone Cells

Beyond its systemic effects, hyperglycemia exerts direct toxic effects on bone cells. High extracellular glucose concentrations impair osteoblast differentiation by downregulating the expression of Runx2 (runt-related transcription factor 2), a master transcriptional regulator of osteoblastogenesis. Glucose also promotes apoptosis of mature osteoblasts through the activation of caspases and the induction of oxidative stress. In the bone marrow microenvironment, hyperglycemia shifts the RANKL/osteoprotegerin (OPG) balance in favor of RANKL, thereby promoting osteoclast differentiation and activity. The accumulation of AGEs on bone collagen fibers alters the material properties of the bone matrix, increasing its brittleness and reducing its ability to absorb energy before fracturing. This is a critical concept: even in a patient whose BMD is only modestly reduced, the quality of the bone may be severely compromised, leading to a fracture risk that is disproportionate to the BMD measurement. These direct cellular effects of hyperglycemia underscore the importance of achieving and maintaining excellent glycemic control as a core component of bone health management in CFRD.

Clinical Implications: Fracture Risk and Osteoporosis in CFRD

The convergence of the mechanisms described above translates into a clinically significant increase in fracture risk. Large cohort studies and registry analyses have consistently demonstrated that CF patients with CFRD have a substantially higher incidence of fractures compared to their non-diabetic counterparts. Vertebral fractures are a particular concern because they are frequently asymptomatic and may go undetected, yet they can have profound consequences for pulmonary function. Compression fractures of the thoracic spine cause kyphosis, reduce thoracic cavity volume, and impair the mechanical efficiency of the diaphragm and chest wall muscles. This can accelerate the decline in forced expiratory volume in one second (FEV1), independent of airway disease. Non-vertebral fractures, especially of the ribs and extremities, are also more common in CFRD and can lead to prolonged immobility, reduced physical activity, and further deterioration of both bone and muscle health.

The prevalence of osteoporosis (defined as a BMD T-score of -2.5 or lower at the hip or spine) in the adult CF population ranges from 30% to 50%, and the presence of CFRD increases that prevalence by an additional 15 to 20 percentage points. Longitudinal studies indicate that BMD declines at a faster rate in patients with CFRD compared to those with CF alone, and this accelerated loss is evident even after adjusting for age, sex, BMI, and pulmonary function. The risk factors for bone disease in CFRD include longer duration of diabetes, higher HbA1c, lower BMI, history of corticosteroid use, and hypogonadism. Despite the clear epidemiological signals, screening for osteoporosis in CF remains suboptimal. The Cystic Fibrosis Foundation recommends that DXA (dual-energy X-ray absorptiometry) be performed at age 18 and repeated every two to five years thereafter. Additional screening is recommended in the presence of risk factors such as a history of fractures, chronic corticosteroid use, or malnutrition. However, many patients with CFRD are not referred for DXA until after a fracture has occurred. Given the additive risk conferred by diabetes, a more aggressive screening strategy is warranted. Ideally, patients should undergo baseline DXA at the time of CFRD diagnosis, regardless of age, with follow-up intervals determined by the initial BMD and the presence of additional risk factors.

Vertebral fracture assessment (VFA) using DXA technology should be considered as an adjunct to standard BMD measurement, as it can detect vertebral deformities that may not be apparent on routine radiographs. Laboratory assessment should include serum 25-hydroxyvitamin D, calcium, phosphate, parathyroid hormone, and markers of bone turnover such as serum procollagen type I N-terminal propeptide (P1NP) and C-terminal telopeptide (CTX-1), though the role of turnover markers in clinical decision-making for individual patients remains a subject of investigation. Integrating the results of annual OGTTs with bone health surveillance is a practical strategy for identifying at-risk patients earlier in the disease course.

Comprehensive Management Strategies for Bone Health in CFRD

Managing bone health in the setting of CFRD requires a coordinated, multidisciplinary approach that addresses nutrition, glycemic control, pharmacologic therapy, physical activity, and the minimization of iatrogenic risk factors. No single intervention is sufficient; instead, a portfolio of strategies must be implemented simultaneously to achieve the best outcomes.

Nutritional Optimization

Ensuring adequate intake of bone-essential nutrients is the foundation of any bone health program in CFRD. Calcium requirements are approximately 1,200 to 1,500 mg per day, which can be challenging to meet through diet alone given the prevalence of lactose intolerance and altered gastrointestinal function in CF. Calcium supplements should be used as needed, but they must be taken separately from pancreatic enzyme supplements and CFTR modulators to avoid interference with absorption. Vitamin D supplementation is almost universally required, and many patients need doses of 2,000 to 5,000 IU per day of vitamin D3 (cholecalciferol) to achieve and maintain a serum 25-hydroxyvitamin D level above 30 ng/mL. In cases of severe deficiency or malabsorption, high-dose bolus therapy under medical supervision may be necessary. Vitamin K supplementation, typically as phytonadione (vitamin K1), at doses of 90 to 120 mcg per day for women and 120 to 150 mcg per day for men, should be considered, especially in patients with evidence of osteocalcin undercarboxylation. Magnesium levels should be monitored and repleted as needed, aiming for a serum magnesium concentration in the normal range. A registered dietitian with expertise in CF care should guide caloric intake to achieve and maintain a healthy body weight, as low BMI is an independent and potent risk factor for low BMD and fracture.

Glycemic Control

Tight glycemic control is a cornerstone of bone health management in CFRD. Insulin therapy is the mainstay of treatment, as it corrects the underlying insulin deficiency and provides the anabolic signals that bone cells require. The goal of therapy is to achieve near-normal glycemic profiles while minimizing the risk of hypoglycemia. Continuous glucose monitoring (CGM) has become an invaluable tool for guiding insulin dosing and assessing time-in-range. Studies have shown that patients with CFRD who are treated with insulin have better BMD outcomes compared to those with untreated hyperglycemia, providing clinical evidence for the bone-protective effects of glycemic management. The choice of insulin regimen should be individualized, with many patients requiring both basal insulin (e.g., insulin glargine or insulin degludec) and prandial insulin (e.g., insulin lispro or insulin aspart) to cover meals and correct hyperglycemia. Metformin is generally avoided in CF because of the risk of lactic acidosis in patients with impaired liver function or hypoxemia. SGLT2 inhibitors and GLP-1 receptor agonists have not been adequately studied in CFRD and carry risks such as euglycemic diabetic ketoacidosis and gastrointestinal side effects, respectively. Thus, insulin remains the preferred and safest pharmacologic option for glucose control in this population.

Pharmacologic Interventions for Bone Density

When BMD is low (T-score less than -1.5) or when a fragility fracture has occurred, pharmacologic therapy for osteoporosis should be considered. Bisphosphonates are the most extensively studied agents in CF. Both oral alendronate and intravenous zoledronic acid have been shown to increase BMD in CF patients, and while fracture reduction data specific to CF are limited, the efficacy of bisphosphonates in reducing vertebral and non-vertebral fractures in other forms of osteoporosis is well established, with risk reductions of 40% to 50%. Before initiating bisphosphonate therapy, it is essential to correct vitamin D deficiency and ensure adequate calcium intake to prevent hypocalcemia. The choice between oral and intravenous bisphosphonates should take into account patient preference, gastrointestinal tolerance, and adherence. For patients with severe osteoporosis or those who cannot tolerate bisphosphonates, teriparatide (recombinant human parathyroid hormone 1-34), an anabolic agent that stimulates bone formation, may be considered. Denosumab, a RANKL inhibitor, is another option, though its use in patients with CF requires careful consideration of infection risk due to its effects on the immune system. Given that many CF patients are already immunosuppressed due to corticosteroid use, denosumab should be used with caution.

Physical Activity and Mechanical Loading

Weight-bearing exercise is a potent stimulus for bone formation and should be encouraged in all patients with CFRD, provided they do not have established osteoporosis or a recent fracture. Activities such as walking, jogging, stair climbing, dancing, and resistance training impose mechanical loads on the skeleton that activate osteoblast-mediated bone formation. Exercise also improves insulin sensitivity, reduces systemic inflammation, and enhances muscle strength, which further protects against falls and fractures. In patients with advanced lung disease, exercise tolerance may be limited, and a tailored program supervised by a physical therapist is recommended. High-impact activities should be approached with caution in patients with low BMD to avoid precipitating a fracture, but the overall message should be one of encouragement to remain as physically active as the underlying pulmonary disease allows.

Minimizing Corticosteroid Exposure

Clinicians should make every effort to limit the dose, duration, and frequency of systemic corticosteroid use. When steroids are necessary for conditions such as ABPA or severe exacerbations, the lowest effective dose should be used for the shortest possible duration. Inhaled corticosteroids, which have minimal systemic bioavailability, are preferred for chronic airway inflammation when possible. For patients who require repeated courses of systemic steroids, bone-protective therapy with a bisphosphonate should be initiated early, and calcium and vitamin D supplementation should be optimized. The recent availability of biologic therapies such as omalizumab and mepolizumab for ABPA has provided steroid-sparing alternatives that may reduce the burden of corticosteroid-induced bone disease.

Future Directions and Research Opportunities

The advent of CFTR modulator therapies has revolutionized the care of individuals with CF. Agents such as ivacaftor, lumacaftor, tezacaftor, and the highly effective triple combination elexacaftor-tezacaftor-ivacaftor correct the underlying protein defect in a significant proportion of patients. Early data suggest that modulator therapy improves pancreatic endocrine function, leading to improved insulin secretion and better glycemic control in some patients with CFRD. Moreover, by reducing systemic inflammation and improving nutritional status, modulators may have favorable downstream effects on bone metabolism. Preliminary studies have shown stabilization or even modest improvements in BMD among patients treated with modulators, but long-term data are needed to confirm these findings. The impact of modulators on fracture risk, which is the most clinically relevant endpoint, has not yet been reported.

Research into novel biomarkers of bone disease in CF is ongoing. Sclerostin, a glycoprotein secreted by osteocytes that inhibits the Wnt signaling pathway and suppresses bone formation, has emerged as a potential therapeutic target. Monoclonal antibodies against sclerostin (e.g., romosozumab) have been shown to increase BMD and reduce fracture risk in postmenopausal osteoporosis, and their role in CF-related bone disease is an area of active investigation. The gut-bone axis, mediated by the intestinal microbiome and its influence on nutrient absorption and immune function, is another frontier. The altered gut microbiome in CF, resulting from chronic antibiotic use and intestinal inflammation, may influence bone health through effects on calcium absorption and the production of short-chain fatty acids that modulate bone cell activity. Finally, the optimization of bone health in the context of the multidisciplinary CF care team, integrating endocrinology, gastroenterology, pulmonology, and physical therapy, remains a priority for improving outcomes.

For a deeper understanding of the mechanisms linking CF to metabolic bone disease, readers are referred to the comprehensive review of CFRD pathophysiology published in the Journal of Cystic Fibrosis. Clinical practice guidelines from the Cystic Fibrosis Foundation provide detailed evidence-based recommendations for bone health screening and management. The relationship between diabetes medications and skeletal outcomes is explored in depth in a review published in Osteoporosis International.

Conclusion

Cystic fibrosis-related diabetes is far more than a metabolic complication of CF. It is a potent and independent driver of bone deterioration that significantly elevates the risk of osteoporosis and fragility fractures in a population already vulnerable to skeletal compromise. The mechanistic pathways linking CFRD to bone disease are diverse and interconnected, encompassing malabsorption of vitamin D, calcium, and vitamin K; chronic systemic inflammation driven by both CF and hyperglycemia; hormonal deficiencies involving insulin, IGF-1, and sex steroids; the catabolic effects of corticosteroid therapy; and the direct toxic effects of high glucose concentrations on bone-forming cells. The clinical consequence is a marked increase in fracture incidence that accelerates the decline in pulmonary function, impairs mobility, and diminishes quality of life.

Clinicians caring for patients with CF must adopt a proactive and integrated approach to bone health. Annual screening for CFRD using OGTT should begin at age 10, and DXA screening for bone density should be initiated at the time of CFRD diagnosis, regardless of age. Nutritional status must be optimized with adequate calcium, vitamin D, vitamin K, and magnesium. Glycemic control using insulin therapy should be pursued aggressively to limit the direct and indirect damage to bone. When BMD is low or a fragility fracture has occurred, bisphosphonate therapy should be initiated. Corticosteroid use should be minimized whenever possible. As CFTR modulator therapies continue to transform the landscape of CF care, their effects on endocrine and skeletal endpoints will become increasingly important to monitor. Until long-term data are available, a comprehensive, team-based approach that coordinates the efforts of pulmonologists, endocrinologists, dietitians, and physical therapists remains the most effective strategy for preserving bone health and reducing fracture risk in patients living with cystic fibrosis and diabetes.