ACTH protects against glucocorticoid-induced osteonecrosis of bone

Abstract

We report that adrenocorticotropic hormone (ACTH) protects against osteonecrosis of the femoral head induced by depot methylprednisolone acetate (depomedrol). This therapeutic response likely arises from enhanced osteoblastic support and the stimulation of VEGF by ACTH; the latter is largely responsible for maintaining the fine vascular network that surrounds highly remodeling bone. We suggest examining the efficacy of ACTH in preventing human osteonecrosis, a devastating complication of glucocorticoid therapy.osteoporosis | osteoclast | osteoblast T he use of glucocorticoids for medical conditions as diverse as asthma, ulcerative colitis, kidney diseases, and rheumatologic disorders causes not only a variety of metabolic and medical complications, including diabetes and osteoporosis, but also a painful debilitating condition, osteonecrosis, usually affecting the femoral head (1). Osteonecrosis almost invariably requires surgical debridement of dead bone and contributes to approximately 10% of the more than 500,000 hip replacements annually in the United States (2). In addition, 30-50% patients on long-term glucocorticoids sustain a hip fracture with a 2-to 2.5-fold increased risk (3).Osteocyte apoptosis is thought to be the key determinant of glucocorticoid-induced cortical bone loss (4). Reduced osteoblast function manifesting in attenuated bone formation has also been documented in trabecular bone in rodents and humans (5). In contrast to glucocorticoid-induced osteoporosis, the pathogenesis of glucocorticoid-induced osteonecrosis is unclear (6). It resembles the osteonecrosis caused by traumatic damage to the artery that supplies the femoral head, hence the name, avascular necrosis (3), but the necrosis actually begins as regional trabecular death (6), likely from osteoblast and osteocyte apoptosis. However, there is strong evidence for an ischemic component. For example, studies using a rat model of Legg-Calve-Perthe's disease suggest that the intracortical blockade of lateral epiphyseal arteries that supply approximately 80% of the femoral head (7) can, in part, be attributed to their anatomical predisposition. It is nonetheless unclear whether ischemia is the initiating event or is secondary to local cellular or vascular bed damage (8).It is further surprising that osteonecrosis is not a cardinal feature of adrenocorticotropic hormone (ACTH)-producing adenomas (9), where glucocorticoid excess is profound. A question therefore arises-does ACTH protect against glucocorticoid-induced osteonecrosis? Indeed, one of our groups has documented functional ACTH receptors (MC2Rs) on osteoblasts; their activation enhances cell proliferation (10). These data are consistent with the presence of receptors for other anterior pituitary hormones, FSH and TSH, on bone cells, as well as with the description of another pituitary-bone axis, in which these hormones bypass traditional endocrine targets to regulate bone mass directly (11-13).We were thus prompted to investigate whether glucocorticoidinduced osteonecrosis could, i...

Risk factors for fractures and avascular osteonecrosis in type 1 Gaucher disease: A study from the International Collaborative Gaucher Group (ICGG) Gaucher Registry

“…(40) Interestingly, increased osteoblast apoptosis and resulting loss of vascular endothelial growth factordependent angiogenesis support has been implicated in humans and in animal models of AVN receiving glucocorticoids. (41)(42)(43) Osteoblastic dysfunction (17) and abnormalities of mesenchymal stem cells (44) have been described in animal models of GD and in a human patient, respectively. Both these cell types are essential components of the hematopoietic microenvironment, and dysfunction of either or both could conceivably link AVN and anemia as secondary phenomena.…”

Pituitary-bone connection in skeletal regulation

“…We showed that as with the adrenal cortex, ACTH induces Vascular endothelial growth factor (VEGF) production in osteoblasts through its action on MC2Rs [87]. This likely translates into the protection by ACTH of glucocorticoidinduced osteonecrosis in a rabbit model [87].…”

Functions of vasopressin and oxytocin in bone mass regulation

“…osteoporosis | osteoblast | skeleton O ver the past decade, we have described direct actions of anterior and posterior pituitary hormones on the skeleton (1)(2)(3)(4)(5)(6)(7)(8). We have shown that these actions are exerted via G protein-coupled receptors resident on both osteoblasts and osteoclasts.…”

“…Apart from the known actions of growth hormone on the skeleton, Tsh, Fsh, Acth, Oxt, and vasopressin (Avp) have all been shown to regulate the formation and/or function of both osteoblasts and osteoclasts and thus to control bone remodeling in vivo (2)(3)(4)(6)(7)(8). The two neurohypophyseal hormones Oxt and Avp have opposing functions (2,3).…”