By Crystal Phend, Senior Staff Writer, MedPage Today
Published: April 29, 2010
Reviewed by Zalman S. Agus, MD; Emeritus Professor
University of Pennsylvania School of Medicine and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner
- Explain to interested patients that long-term glucocorticoid treatment may be part of the therapy for asthma, ulcerative colitis, kidney diseases, and rheumatologic disorders.
Patients on chronic glucocorticoid therapy often develop osteonecrosis of the hip, but injections of adrenocorticotropic hormone (ACTH) might prevent that devastating complication, a preclinical study showed.
Rabbits treated with depot methylprednisolone acetate (Depo Medrol) showed half as much necrotic surface area on the femoral head when also given the synthetic cosyntropin (Cortrosyn) form of ACTH (P<0.05), Mone Zaidi, MD, PhD, of the Mount Sinai School of Medicine in New York City, and colleagues found.
The protective effect weakened for deeper bone, with all rabbits in both groups showing focal necrotic spots.
But these deeper areas of necrosis were smaller and generally not consolidated in ACTH-treated rabbits compared with prominent consolidated areas of necrosis in those that got only the glucocorticoid, Zaidi's group reported online in the Proceedings of the National Academy of Sciences.
These results provide a rationale for extended use of cosyntropin to decrease the risk of osteonecrosis for human patients who have to be on long-term glucocorticoid treatment, they suggested.
"The results are very promising because this is the first proof-of-concept of any medical therapy" in this setting, Zaidi said in an interview.
The only treatment for this debilitating, painful condition has been surgical debridement, the researchers explained.
The rate of osteonecrosis of the hip induced by long-term glucocorticoid use isn't clear, but it is thought to account for about 10% of hip replacements in the U.S. each year, Zaidi noted.
The mechanism appears to be different than with osteoporosis from long-term glucocorticoid treatment, which occurs largely due to osteocyte apoptosis, his group wrote.
The researchers started looking into the the role of ACTH after noting that ACTH-producing adenomas result in a profound glucocorticoid excess but not osteonecrosis.
They gave rabbits 10 mg/kg depot methylprednisolone acetate, which consistently produced damage to bone in the femoral head within 28 days.
Half the rabbits also received 0.2 μg/kg ACTH in the form of subcutaneous cosyntropin injections daily, which normalized ACTH serum levels for about three hours.
Bone scans showed a small effect of ACTH on density of the femoral head: it was 10% greater with the hormone.
There was a highly significant approximately 50% reduction in the necrotic surface area in femora from the rabbits treated with MPA plus ACTH compared with those given the glucocorticoid alone.
The explanation for this and the other morphological results appeared to be that ACTH supported osteoblast activity, the researchers wrote.
Quantitative PCR indicated significantly greater vascular endothelial growth factor (VEGF) mRNA expression in bone marrow of rabbits that got ACTH compared with those on methylprednisolone alone.
VEGF might maintain viability of components of the bone matrix given its central role in bone development and homeostasis, Zaidi's group noted.
"The femoral head is a site of high bone turnover, with formation and resorption occurring continuously over a large fraction of the total surface area," they explained in the paper. "This surface area is also embedded with an extensive capillary network; this means that the maintenance and regeneration of capillaries requires support by molecules such as VEGF."
Further testing suggested that ACTH stimulated production of VEGF in osteoblasts, not monocytes, and that the glucocorticoid dexamethasone profoundly inhibited monocyte-induced VEGF production, "probably as one of several mechanisms that initiate osteonecrosis," the researchers wrote.
The effect of ACTH appeared VEGF-dependent in cell line experiments with ACTH-stimulated VEGF production apparently through the ACTH receptor MC2R.
The investigators didn't look at whether this mechanism is a normal feature of bone mass regulation in the absence of glucocorticoid treatment. They noted, though, that results from patients with familial glucocorticoid deficiency and adrenal Cushing's syndrome support "at least a small anabolic effect of ACTH, which seemingly counteracts the bone loss due to cortisol."
Zaidi said that because synthetic ACTH would be dosed to restore the naturally occurring hormone levels and is already in clinical use for testing adrenal sufficiency there shouldn't be any safety concerns with long-term use in patients on glucocorticoids.
However, the protective effect wouldn't extend to patients who already have developed osteonecrosis, he told MedPage Today.
"The idea is to prevent," he said in the interview. "Once that part of the bone is dead, I can't see any logical way to bring it back to life again."
The study was supported by grants from the National Institutes of Health and by the American Federation for Aging Research.
Primary source: Proceedings of the National Academy of Sciences
Zaidi M, et al "ACTH protects against glucocorticoid-induced osteonecrosis of bone" Proc Natl Acad Sci 2010; DOI:10.1073/pnas.0912176107