Bone Damage Runs Deep in Cushing’s Syndrome, Even When Scans Look Normal

Skeletal fragility is emerging as one of the most serious and still under-recognized complications of endogenous Cushing’s syndrome, the rare disorder caused by the body’s chronic overproduction of cortisol. A comprehensive review published in Frontiers in Endocrinology pulls together the available evidence on how excess cortisol dismantles bone strength, why standard bone density scans fail to capture the true danger, and why fracture risk lingers for years even after the disease itself has been cured. The picture that emerges is one of a skeleton under attack on multiple fronts, with damage that begins silently and often outlasts treatment.

The numbers are striking. Across published observational series, densitometric osteoporosis by dual-energy X-ray absorptiometry, or DXA, is present in roughly 30 to 50 percent of patients with endogenous Cushing’s syndrome, with the lumbar spine the most commonly affected site. Fragility fracture prevalence varies widely across studies, from 11 to 76 percent, a spread that reflects differences in the populations studied and the small number of investigations specifically designed to assess skeletal outcomes. Vertebral fractures, often multiple, and rib fractures dominate the clinical picture, and either can be the first sign that something is wrong. Many vertebral fractures are asymptomatic or only mildly symptomatic, going undetected unless clinicians actively look for them with lateral spine radiographs or vertebral fracture assessment.

The disconnect between what densitometry shows and what actually breaks is central to the problem. Observational data indicate that about 40 percent of patients with fragility fractures in endogenous Cushing’s syndrome have bone mineral density values in the osteopenic or even normal range at diagnosis, rather than the osteoporotic range. This mirrors what is well established in exogenous glucocorticoid-induced osteoporosis, where fractures frequently occur at bone density levels only mildly reduced or within normal limits. The explanation lies in bone quality: glucocorticoid excess degrades trabecular and cortical microarchitecture, bone geometry, and the material properties of mineralized matrix and collagen, none of which standard DXA adequately captures.

At the cellular level, the review describes a coordinated cascade of direct damage. Excess cortisol acts through the glucocorticoid receptor on all skeletal cell populations. Early in the course of hypercortisolism, bone resorption rises rapidly, driven by enhanced secretion of RANKL and a drastic reduction of its decoy receptor osteoprotegerin, an imbalance that accelerates osteoclast maturation and activity. The core of the damage, however, is suppression of the osteoblast lineage at every developmental stage. Glucocorticoids push bone marrow mesenchymal stem cells away from osteoblast differentiation toward the fat lineage, inducing pro-adipogenic transcription factors such as PPARgamma2 and C/EBPalpha while downregulating Runx2, the essential driver of bone formation. The clinical correlate is increased bone marrow fat that correlates inversely with bone mass.

The suppression does not stop there. Committed osteoblasts are paralyzed: glucocorticoids arrest the cell cycle in the G1 phase by downregulating cyclins and cyclin-dependent kinases while promoting inhibitors such as p21, p27, and p53. They also interfere with the Wnt and bone morphogenetic protein signaling pathways, increasing production of the Wnt antagonists sclerostin and Dickkopf-1, which suppresses expression of type I collagen and osteocalcin. Osteocytes, which make up over 95 percent of bone cells and act as guardians of bone quality and mechanotransduction, undergo apoptosis in a time- and dose-dependent manner, degrading the lacuno-canalicular network and increasing tissue fragility regardless of remaining mineral mass. Early high-turnover bone loss eventually evolves into a low-turnover state in which both formation and resorption are suppressed.

Indirect systemic mechanisms amplify the skeletal assault. Chronic cortisol excess suppresses hypothalamic GnRH secretion and pituitary gonadotropin release, producing functional hypogonadotropic hypogonadism in many patients, particularly consequential in younger men and premenopausal women. The growth hormone and IGF-1 axis is also impaired, removing anabolic input from both bone and muscle; in one recent study of patients with Cushing’s disease, lower IGF-1 levels were independently associated with low bone mass. Calcium metabolism suffers too, with reduced intestinal absorption and increased urinary excretion creating a chronic negative calcium balance, while hypophosphatemia has been reported in active Cushing’s disease and improves after treatment. Vitamin D metabolism is disrupted through increased catabolism, downregulation of the vitamin D receptor, and suppression of renal 1alpha-hydroxylase, and patients typically show lower 25-hydroxyvitamin D levels than controls.

Muscle adds another dimension. Cushing’s-associated myopathy, marked by painless proximal muscle weakness especially in the lower limbs, impaired chair-rise and stair-climbing ability, and muscle atrophy with fat infiltration, is detected objectively in most patients with active disease and may persist for years after biochemical remission. Sarcopenia and myopathy impair the muscle-bone crosstalk mechanically and through endocrine pathways, increasing the likelihood of falls and fractures. Metabolic comorbidities, including central obesity, insulin resistance, and diabetes, further damage bone through chronic inflammation, marrow adiposity, and accumulation of advanced glycation end products in bone collagen. The review frames skeletal fragility in Cushing’s syndrome as the product of this disease-specific network rather than a simple copy of classic glucocorticoid-induced osteoporosis.

Because bone mineral density alone cannot predict fracture risk in these patients, the review highlights complementary assessment tools. The Trabecular Bone Score, derived from texture analysis of DXA images, is reduced in most available studies of Cushing’s syndrome and correlates inversely with disease duration, severity, and vertebral fracture number, although some authors have not confirmed it as an independent fracture predictor. Quantitative computed tomography and high-resolution peripheral quantitative CT confirm reduced vertebral trabecular density and impaired cortical microarchitecture, but cost, radiation dose, and limited availability rule them out as screening tools. MRI-based bone marrow fat assessment correlates with vertebral fracture prevalence independently of density. The review also stresses that vertebral morphometry, by X-ray or DXA-based vertebral fracture assessment using the Genant semi-quantitative method, should be recommended in all patients at diagnosis given the low cost and the frequent, often silent, occurrence of vertebral fractures. No validated fracture prediction algorithm exists for endogenous hypercortisolism, and FRAX cannot be applied because cortisol exposure cannot be quantified as it can with prescribed steroids.

Remission triggers a genuine but imperfect healing process. After successful control of hypercortisolism, bone formation markers surge ahead of resorption markers in an anabolic window beginning within the first three to six months. A German prospective study of 89 patients documented lumbar T-score improvement in 78 percent of subjects two years after surgical cure, and a Dutch cohort of 231 patients found lumbar Z-score improvements still significant 20 years after remission, with men recovering more robustly than women. Recovery is faster at the lumbar spine than the femoral neck. Yet density gains do not equal restored strength: finite element analysis of the proximal femur in 32 women in long-term remission showed significantly worse biomechanical parameters than controls even when density and Trabecular Bone Score matched, and impact microindentation revealed a lower Bone Material Strength Index than in matched controls. In a Swedish nationwide study of 419 patients with a median remission duration of 13 years, fracture incidence remained 1.7 times that of the general population.

Treatment options remain frustratingly thin. Correcting cortisol excess is the first-line therapy, and general measures apply: adequate calcium intake of 1000 to 1200 milligrams daily, vitamin D supplementation targeting levels above 30 nanograms per milliliter, smoking cessation, reduced alcohol consumption, and resistance and balance exercise. Bisphosphonates are the most widely prescribed bone-active agents in practice, but evidence in endogenous disease is limited to a single randomized trial of 39 patients with Cushing’s disease, in which alendronate combined with ketoconazole produced greater lumbar and femoral neck density gains at 12 months than placebo, while a recent retrospective study found no significant difference in density recovery after surgical remission. Denosumab has no controlled data in this population, and teriparatide evidence is confined to case reports. Registry data underline the systemic gap: in the European Registry on Cushing’s Syndrome, a DXA scan at diagnosis was performed in only 45 percent of patients and spinal radiographs in 29 percent. No Cushing’s-specific skeletal guidelines exist, and the authors argue that prospective studies, standardized diagnostic pathways, and updated regulatory frameworks are urgently needed for this high-risk population.

Subject of Research: Skeletal fragility and fracture risk in endogenous Cushing's syndrome

Article Title: The complexity of skeletal fragility in overt endogenous Cushing’s syndrome: how much do we know?

Article References: Voltan, G., Mogno, C., Contini, G., Tizianel, I., Ferrarese, M., & Camozzi, V. (2026). The complexity of skeletal fragility in overt endogenous Cushing’s syndrome: how much do we know?. Frontiers in Endocrinology, 17, Article 1918392. https://doi.org/10.3389/fendo.2026.1918392

Image Credits: AI Generated

DOI: 10.3389/fendo.2026.1918392

Keywords: Cushing's syndrome, skeletal fragility, fragility fractures, glucocorticoids, bone quality, osteoporosis, DXA, trabecular bone score, osteoblasts, bone remodeling, hypercoortisolism, vertebral fractures