‘Striking’ BMD increase follows surgical remission in endogenous Cushing’s syndrome
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A cohort of adults with endogenous Cushing’s syndrome experienced a high rate of bone turnover immediately after surgical remission, resulting in a “striking” net increase in bone mineral density for most patients, researchers reported.
“Guidelines for the management of osteoporosis due to endogenous Cushing’s syndrome are still missing,” Martin Reincke, MD, chairman of the department of medicine at Klinikum der Universität München, Germany, and colleagues wrote in the study published in the Journal of Bone and Mineral Research. “In terms of risk assessment, the subtype of Cushing’s syndrome does not seem to influence osteoporosis risk, whereas the morning cortisol levels are negatively correlated with lumbar bone mineral density. The duration of endogenous Cushing’s syndrome (or the duration of exogenous replacement therapy after successful surgery) obviously affects bone mineral density. Whether the T-score is the best predictor for fracture risk, is not quite clear.”
Reincke and colleagues analyzed data from 89 adults with confirmed Cushing’s syndrome with BMD and fracture information at the time of diagnosis and 2 years after successful tumor resection (74% women; mean age, 44 years; mean BMI, 30 kg/m²), along with 71 age-, sex- and BMI-matched controls. Researchers measured levels of plasma osteocalcin, alkaline bone phosphatase, C-terminal telopeptide of type 1 collagen (CTX-1), procollagen type 1 N-terminal propeptide (P1NP) and the osteoclast enzyme tartrate-resistant acid phosphatase (TRAcP) 5b at the time of diagnosis, 1 and 2 years after surgery. Researchers used multiple regression analysis to investigate differences in bone turnover markers between adults with Cushing’s syndrome and controls, with findings adjusted for sex, age and BMI.
Within the Cushing’s syndrome cohort, 65% had pituitary Cushing’s syndrome, 28% had adrenal Cushing’s syndrome and 7% had ectopic Cushing’s syndrome.
Overall, BMD for adults in the Cushing’s syndrome cohort was decreased vs. controls, with an average lowest T-score of –1.4. BMD was lower at the femoral neck (mean T-score = –0.9; P = .001) and at the spine (mean T-score = –1) compared with the total femur (mean T-score = –0.5). More than half of adults with Cushing’s syndrome had osteopenia (52%), 32% had normal BMD and 17% had osteoporosis, defined as a T-score of –2.5. Researchers also observed that men with Cushing’s syndrome were more likely to sustain fractures vs. women with Cushing’s syndrome (35% vs. 14%; P = .03).
Surgical tumor resection leading to biochemical remission was followed by a “strong increase” in bone formation markers tested at the 1-year follow-up, according to researchers. At 2 years, bone turnover markers decreased slightly, but remained elevated.
“The bone formation markers showed a three- to fourfold increase 1 year postoperatively, with a moderate decline thereafter,” the researchers wrote. “The bone resorption markers showed a similar but less pronounced course.”
BMD improved 2 years after surgery for 78% of patients with Cushing’s syndrome. T-score improved by at least 0.5 for 45% of adults at the 2-year follow-up. Between diagnosis and 2-year follow-up, mean z score at the femoral neck decreased from –0.59 to –0.28 (P = .02); mean BMD at the femoral neck increased from 0.91 g/cm² to 0.95 g/cm² (P = .16).
Researchers did not observe any clinical fractures after successful treatment of Cushing’s syndrome.
“The unique and comprehensive data show that, initially, bone metabolism is characterized by decreased bone formation and increased bone resorption, in line with the classical action of glucocorticoids,” the researchers wrote. “Successful treatment of endogenous Cushing’s syndrome leads to a strong activation of bone turnover, characterized by increased bone formation and bone resorption, a process which [is] continuous beyond year 2 following remission of Cushing’s syndrome, although at a reduced activity level. In parallel, bone mineral density increases in the majority of patients.”
The researchers wrote that the data give new insight into bone healing after surgical remission in Cushing’s syndrome.
“Our data support a wait and watch strategy despite a high endogenous risk for additional fractures, based on the baseline assessment,” the researchers wrote. “This observation will influence future therapeutic strategies in patients with Cushing’s syndrome.” – by Regina Schaffer
Perspective
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Joseph L. Shaker, MD
steoporosis is a well-recognized manifestation of endogenous Cushing’s syndrome, as well as exogenous glucocorticoid therapy. Harvey Cushing described dramatic skeletal complications in his initial report of the disease, and vertebral compression fractures and rib fractures are well-known complications of glucocorticoid excess. Bone resorption is increased early in glucocorticoid therapy; however, the most important causes of bone disease are decreased bone formation related to decreased osteoblastogenesis as well as osteoblast and osteocyte apoptosis.Bone density has been found to improve after surgical remission in Cushing’s syndrome. The 2-year follow-up study by Braun and colleagues also demonstrates improved bone density after Cushing’s syndrome cure. The authors provide additional insight into the mechanism of the bone density changes after Cushing’s syndrome cure. The authors measured both bone resorption and bone formation markers and demonstrated a marked increase in bone formation markers with a less dramatic increase in bone resorption markers, suggesting that increased bone formation explains the increase in bone density after cure of Cushing’s syndrome.
These findings raise the possibility that observation — rather than pharmacologic therapy — may be appropriate management of osteoporosis in the setting of Cushing’s syndrome cure.
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