Glucocorticoid-induced osteonecrosis

Abstract

Awareness of the need for prevention of glucocorticoid-induced fractures is growing, but glucocorticoid administration is often overlooked as the most common cause of nontraumatic osteonecrosis. Glucocorticoid-induced osteonecrosis develops in 9-40% of patients receiving long-term therapy although it may also occur with short-term exposure to high doses, after intra-articular injection, and without glucocorticoid-induced osteoporosis. The name, osteonecrosis, is misleading because the primary histopathological lesion is osteocyte apoptosis. Apoptotic osteocytes persist because they are anatomically unavailable for phagocytosis and, with glucocorticoid excess, decreased bone remodeling retards their replacement. Glucocorticoid-induced osteocyte apoptosis, a cumulative and unrepairable defect, uniquely disrupts the mechanosensory function of the osteocyte-lacunar-canalicular system and thus starts the inexorable sequence of events leading to collapse of the femoral head. Current evidence indicates that bisphosphonates may rapidly reduce pain, increase ambulation, and delay joint collapse in patients with osteonecrosis.

Fig. 1

MRI of osteonecrosis. The acetabular fat pad (blue arrow) shown in the left panel gives an intense white signal with MRI as shown in the right panel (small arrow), while the loss of marrow fat (large arrow) gives a dark signal typical of edema with T1 MRI imaging

Fig. 2

Glucocorticoid-induced osteonecrosis is osteocyte apoptosis. Abundant apoptotic osteocytes are present in sections of whole femoral heads obtained during total hip replacement for glucocorticoid- induced osteonecrosis (a, b). In c is a prevalence map of osteocyte apoptosis made from the section of the femoral head shown in (a). Osteocyte apoptosis was most prevalent (3?) adjacent to the subchondral crescent and fracture cleft and decreased (1?) as the examination progressed more distally. Osteocyte apoptosis was anatomically juxtaposed to the osteonecrotic fracture (adapted from Weinstein et al. [40]. Copyright 2000. The Endocrine Society)

Fig. 3

A major problem in the field of osteonecrosis is the lumping together of multiple etiologies. Femoral head core samples taken from patients with sickle cell disease show a empty osteocytic lacunae, oil cysts (arrow), and necrosis (asterisk), and b widely separated double tetracycline labels (arrows). Apoptotic cells were absent. In glucocorticoidinduced osteonecrosis (c), virtually all the osteocytes are apoptotic and remain present in their lacunae. Apoptotic osteocytes were uncommon in alcohol-induced (d) and absent in post-traumatic osteonecrosis (e) (d and e were adapted from Weinstein et al. [40]. Copyright 2000. The Endocrine Society)

Fig. 4

Osteocytic lacunae are rarely empty in glucocorticoid-induced osteonecrosis. Condensed chromatin in apoptotic osteocytes shows intense blue fluorescence after staining with Hoechst nuclear dye 33258 (a). Osteocytes in the same section viewed with visible light (b) are barely visible and their lacunae could be incorrectly thought to be empty. The osteocytes (arrows) recently buried in a new packet of bone are already apoptotic as shown by the nuclear dye (c). As a result, after chronic glucocorticoid therapy, the osteocyte–canaliculi– lining cell network links dead cells (brown staining indicates apoptotic cells; toluidine blue counterstain) (d) (adapted from Weinstein et al. [40]. Copyright 2000. The Endocrine Society)