Poor Fat Metabolism and Insulin Resistance Linked to Bone Loss, Fracture Risk in Cushing’s Patients

Abnormal fat accumulation, including increased bone marrow fat and insulin resistance,  can lead to bone loss and a greater likelihood of fractures in people with Cushing’s disease, researchers report.

Their study, “Beyond the metabolic syndrome: Visceral and marrow adipose tissues impair bone quantity and quality in Cushing’s disease,” was published in the journal PLOS ONE.

The high cortisol levels seen in Cushing’s patients can lead to obesity, increasing their risk of cardiovascular diseases (heart attack and stroke), high blood pressure, metabolic disorders such as type 2 diabetes, and fractures due to bone loss (osteoporosis).

A connection is known to exist between Cushing’s disease and bone loss, but details relating to the accumulation of body fat in these people and its effect on bone health are still lacking.

Researchers at the University of São Paulo in Brazil designed a study to evaluate the relationship between bone health and fat accumulation, as well as insulin resistance (a precursor of diabetes), in women with Cushing’s disease by comparing them to healthy women.

They recruited 53 women – matched for age and height – and split them into three groups. The first group, a control group, was composed of 27 women with a healthy body mass index (BMI) of less than 24 (BMI is a measure of body fat based on weight and height). The second and patient-paired group consisted of 16 control individuals all with an average BMI scores greater than 30 (obese), and the third group had 10 Cushing’s patients with an average BMI of over 30. 

People in the control and paired groups were older than 18, and did not have bone disease.

Cushing’s patients ranged in age from 18 to 65. Hypercortisolism, or excess cortisol levels, was confirmed in all these women, and all had undergone surgery to remove a pituitary tumor.

Bone mineral density (BMD) was measured in the lumbar spine (L1–L4), total hip, and femoral neck (top of the thigh bone). From this, a Trabecular Bone Score (TBS) — a measure of the inner porous bone — was calculated.

Results revealed that Cushing’s patients had lower BMD in the lumbar spine (L1–L4) compared to both control and paired groups. No differences in BMD were found in the femoral neck and total hip areas.

TBS values in Cushing’s patients were also significantly lower than those in the control and paired groups, suggesting a higher risk of bone fractures.

Two types of body fat tissue were measured — subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) — the latter relating to truncal obesity. Fat accumulation in the liver and bone marrow fat were also determined.

These tests identified differences between the amount and distribution of body fat, finding that Cushing’s patients had higher fat accumulation in their trunk, liver, and bone marrow compared to women in the other groups.  

While visceral fat (fat stored in the abdominal cavity) was higher in the paired control group than in normal-weight controls, no differences between marrow and liver fat were seen in either of these control groups (obese paired or normal weight). 

Insulin resistance was estimated using the homeostasis model assessment of insulin resistance (HOMA-IR) and blood samples were analyzed to determine the amount of various components such as total calcium, phosphorus, glucose, 25-hydroxyvitamin D (a metabolite of vitamin D), parathyroid hormone (PTH), insulin, and a marker for bone formation called osteocalcin. 

Levels of glucose, insulin, and insulin resistance were all significantly higher in Cushing’s patient than in women in the other two groups. While the levels of calcium, phosphorus, and PTH were similar among all three groups, patients had lower levels of vitamin D and lower levels of osteocalcin.

A statistical analysis of these results showed that lower TBS scores were linked to greater visceral adipose tissue, marrow fat, insulin resistance, and lower lumbar bone mineral density and osteocalcin levels. Increased marrow fat was also related to more visceral adiposity and liver fat accumulation. 

“CD [Cushing’s disease] not only accentuates the accumulation of fat in liver and visceral pad; it also increases bone marrow adiposity [fat cells],” the researchers concluded. “CD exacerbates several negative traits present in primary obesity.”

And, they added, “insulin resistance and dysfunctional adipose tissue are active players on bone deterioration” in Cushing’s patients.