How is bone mineral density loss managed in patients with Cushing disease?

Management of Bone Mineral Density Loss in Cushing Disease

Conventional osteoporosis treatments, particularly bisphosphonates, should be initiated for patients with Cushing disease who have decreased bone mineral density, even if BMD is in the normal range, due to the increased fracture risk associated with cortisol excess. 1

Pathophysiology of Bone Loss in Cushing Disease

• Skeletal fragility is a frequent and early complication of hypercortisolism, with vertebral fractures occurring in 30-50% of patients, correlating with hypercortisolism severity 1
• Bone loss occurs through multiple mechanisms:
  • Suppression of growth hormone (GH)/insulin-like growth factor (IGF-I) axis 1
  • Suppression of hypothalamic-pituitary-gonadal axes 1
  • Altered parathyroid hormone pulsatility 1
  • Decreased osteoblast number and function, evidenced by reduced serum levels of bone formation markers (osteocalcin and alkaline phosphatase) 2

Assessment of Bone Health

• Dual X-ray absorptiometry (DXA) of the lumbar spine should be performed in all patients with Cushing disease 2
• Standard DXA alone may not be sufficiently informative; consider bone quality assessment (microscanner or trabecular bone score) or morphometric vertebral assessment where available 1
• Consider BMD assessment prior to adult transition in pediatric patients at high risk for bone fragility 1
• Fractures may occur even in patients with BMD in the normal or osteopenic range, making comprehensive assessment crucial 1

Treatment Approach

First-line Management

• The primary treatment for bone mineral density loss is addressing the underlying hypercortisolism through:
  • Surgical resection of the adenoma (first-line therapy) 1
  • Radiotherapy for recurrent disease not amenable to curative surgery 1
  • Medical therapy to control hypercortisolemia while awaiting definitive treatment 1

Specific Bone-Directed Therapies

• Bisphosphonates are recommended for patients with persistent Cushing disease even if BMD is normal due to increased fracture risk 1
• Bisphosphonates induce more rapid improvement in BMD than cortisol normalization alone 2
• Calcium and vitamin D supplementation should be provided as supportive treatment 1

Special Considerations in Children and Adolescents

• Growth failure and resultant short stature are almost always present at diagnosis in pediatric patients 1
• After normalization of cortisol, children with growth retardation should be evaluated for GH deficiency with dynamic testing 1
• Early GH replacement therapy should be initiated in GH-deficient children or those who fail to show catch-up growth 1
• Consider gonadotropin-releasing hormone analogue therapy to delay puberty and epiphyseal closure in appropriate cases 1
• Combined treatment with GH and aromatase inhibitors may be considered in pubertal patients to reduce bone maturation induced by estradiol 1

Recovery of Bone Mass

• Bone mineral density recovery after successful treatment of Cushing disease is slow, taking approximately ten years to become complete 2
• During this recovery period, patients with severe osteopenia remain at high risk for fracture 2
• Most patients show substantial improvement in BMD following cure of Cushing syndrome 3, 4
• Post-menopausal women may have more difficulty recovering bone mass and remain at higher risk for fractures 3

Long-term Follow-up

• Radiological follow-up of the skeleton should be included in management not only during the active phase but also after cure 2
• Monitor and follow-up as for all adult high-risk populations 1
• The decision to discontinue antiresorptive therapy should be based on clinical monitoring and DEXA measurements 2
• Lifelong follow-up is essential as recurrence of Cushing disease can occur up to 15 years after apparent surgical cure 1

Pitfalls and Caveats

• Fractures may occur even in patients with normal BMD, making standard DXA assessment alone potentially insufficient 1
• The FRAX tool to assess fracture risk is not validated for Cushing disease 1
• Growth hormone deficiency is common after treatment and may contribute to persistent bone issues if not addressed 1
• Normal body composition and BMD are more difficult to achieve than catch-up growth in pediatric patients 1
• Patients with subclinical hypercortisolism may also experience bone mineral density loss and should be evaluated 5