RANKL inhibition: a novel strategy to decrease femoral head deformity after ischemic osteonecrosis.
A novel therapeutic strategy to decrease the development of femoral head deformity after ischemic osteonecrosis was studied in a large animal model of total head infarction. RANKL inhibition through exogenous osteoprotegerin administration significantly decreased pathologic bone resorption and deformity during repair of the infarcted head.


BACKGROUND
Legg-Calvé-Perthes disease (LCPD) is a juvenile form of osteonecrosis of the femoral head that can produce permanent femoral head deformity (FHD) and premature osteoarthritis. The development of FHD in LCPD is closely associated with the repair process, characterized by a predominance of bone resorption in its early stage that produces a fragmented appearance and collapse of the femoral head. We present here a novel strategy to preserve the femoral head structure after ischemic osteonecrosis based on inhibition of interaction between RANK and RANKL using exogenous administration of osteoprotegerin (OPG-Fc) in a large animal model of ischemic osteonecrosis.


METHODS
Ischemic osteonecrosis was surgically induced in 18 male piglets by placing a ligature tightly around the right femoral neck to disrupt the blood flow to the right femoral head. Two weeks after the induction of total head infarction, OPG-Fc or saline was administered subcutaneously to nine animals per group for 6 weeks. The contralateral, normal (left) femoral heads from the animals treated with saline served as normal, nondisease controls. All animals were killed at 8 weeks when severe FHD has been previously shown to occur because of the repair process dominated by osteoclastic bone resorption. Radiographic, histomorphometric, and immunohistochemical assessments were performed.


RESULTS
Radiographic assessment showed significantly better preservation of the femoral head structure in the OPG-Fc group compared with the saline group. Epiphyseal quotient (the ratio of epiphyseal height to diameter) was significantly higher in the OPG-Fc group (0.41 +/- 0.09) compared with the saline group (0.24 +/- 0.08, p < 0.001). Histomorphometric assessment revealed a significant reduction in the number of osteoclasts present in the OPG-Fc group (5.9 +/- 5.3mm(-2)) compared with the saline group (39.6 +/- 13.8 mm(-2), p < 0.001). Trabecular bone volume, number, and separation were significantly better preserved in the OPG-Fc group compared with the saline group (p < 0.001). No significant difference in femoral length was observed between the OPG-Fc and saline groups. Immunostaining revealed the presence of OPG-Fc only within the blood vessels, with no apparent staining of bone matrix or trabecular bone surfaces.


CONCLUSIONS
To our knowledge, this is the first study to show that RANKL inhibition decreases bone resorption and FHD after ischemic osteonecrosis. Because RANKL inhibitors do not bind to bone, their effects on resorption are reversible as the drug is cleared from circulation. The reversible nature of RANKL inhibitors is very appealing for treating pediatric bone diseases such as LCPD, where the resorptive stage of the disease lasts for 1-2 years.
Kim
Harry K W
HK
Center for Research in Skeletal Development and Pediatric Orthopaedics, Shriners Hospitals for Children, FL 33612, USA. hkim@shrinenet.org
Morgan-Bagley
Stephanie
S
Kostenuik
Paul
P
D000818:Animals; D020520:Brain Infarction / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005270:Femur Head / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007511:Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D007873:Legg-Calve-Perthes Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053244:Osteoprotegerin / Q000494:pharmacology*; D053245:RANK Ligand / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013552:Swine; D013997:Time Factors
D053244:Osteoprotegerin; D053245:RANK Ligand; C506030:TNFRSF11B protein, human