Evidence for using bisphosphonate to treat Legg-Calvé-Perthes disease

Abstract

Background: The rationale for using bisphosphonate (BP) therapy for Legg-Calvé-Perthes disease (LCPD) is the potential to prevent substantial femoral head deformity during the fragmentation phase by inhibiting osteoclastic bone resorption. However, it is unclear whether BP therapy decreases femoral head deformity.

Questions/purposes: In this systematic review, we answered the following questions: (1) Does bisphosphonate (BP) therapy decrease femoral head deformity and improve pain and function in LCPD or other juvenile osteonecrotic conditions? And (2) does BP therapy decrease femoral head deformity in experimental studies of juvenile femoral head osteonecrosis?

Methods: We searched the literature from 1966 to 2011 for clinical and experimental studies on BP therapy for juvenile femoral head osteonecrosis. Studies specifically addressing clinical and/or radiographic/histologic outcomes pertaining to pain and function and femoral head morphology were analyzed.

Results: Three Level IV clinical studies met our inclusion criteria. Only one study initiated BP therapy during the precollapsed stage of osteonecrosis and reported prevention of femoral head deformity in nine of 17 patients. All studies noted subjective improvements of pain and gait in patients treated with intravenous BPs. Of the eight experimental studies reviewed, seven reported reduced femoral head deformity and six found better preservation of trabecular framework in animals treated with BPs.

Conclusions: Clinical evidence lacks consistent patient groups and drug protocols to draw definitive conclusions that BP therapy can decrease femoral head deformity in juvenile osteonecrotic conditions. Experimental studies suggest BP therapy protects the infarcted femoral head from deformity, but it lacks bone anabolic effect. Further basic and clinical research are required to determine the potential role of BPs as a medical treatment for LCPD.

Fig. 1A–B

(A) A diagram represents normal bone remodeling where bone formation and resorption are equal. Because of equal bone anabolic and catabolic activities, there is no change in the bone mass. (B) A diagram represents pathologic bone remodeling observed after femoral head osteonecrosis. Increased bone catabolism and decreased bone anabolism produce a net bone loss and weakening of the femoral head.

Fig. 2

A flow diagram demonstrates the method of article selection for clinical study inclusion.

Fig. 3

A flow diagram demonstrates the method of article selection for experimental study inclusion.

Fig. 4A–B

(A) Radiographic findings from a study using a surgically induced osteonecrosis model in immature rats shows the animals receiving zoledronic acid either postoperatively (ZA Post) or preoperatively and postoperatively (ZA Pre-Post) had better preservation of the femoral head architecture compared to the animals receiving saline. The nonoperated femoral heads (Non-Op) from the animals receiving saline were used as normal controls. (B) Histologic sections (stain, von Kossa; original magnification ×25) show increased bone resorption in the femoral head of a saline-treated animal compared to the femoral head of an animal treated with zoledronic acid postoperatively (ZA Post) or preoperatively and postoperatively (ZA Pre-Post). Reprinted with permission by The American Society of Bone and Mineral Research from Little DG, Peat RA, McEvoy A, Williams PR, Smith EJ, Baldock PA. Zoledronic acid treatment results in retention of femoral head structure after traumatic osteonecrosis in young Wistar rats. J Bone Miner Res. 2003;18:2016–2022.

Fig. 5A–B

(A) Autoradiographic images show the three regions (necrotic bone, revascularized marrow space, and newly formed bone) found in the infarcted femoral heads of piglets at 6 weeks after ischemia induction. ¹⁴C-labeled ibandronate was administered intravenously 24 hours before sacrifice to determine its localization within the necrotic head. Arrows indicate the presence of silver grains (indicating ¹⁴C radioactivity) on the trabecular surfaces. A dense concentration of the silver grains was present on the newly formed bone but not on the necrotic bone. (B) A bar graph shows the mean silver grain counts obtained from the background and from the three regions found in the infarcted head at 6 weeks. ^ap = 0.02 versus background and p = 0.05 versus necrotic region; ^bp = 0.000001 versus all groups; HPF = high-power field. Reprinted with permission from Kim HK, Sanders M, Athavale S, Bian H, Bauss F. Local bioavailability and distribution of systemically (parenterally) administered ibandronate in the infarcted femoral head. Bone. 2006;39:205–212. Copyright Elsevier (2006).

Fig. 6A–B

(A) A radiograph demonstrates an intraosseous needle placed in the central region of the femoral head used to locally deliver BP. (B) Autoradiographic sections from a control femoral head and an infarcted femoral head injected with ¹⁴C-ibandronate show a wide distribution of ¹⁴C-ibandronate, marked by diffuse staining of the trabecular bone with black silver grains, in the femoral head after a single intraosseous injection. (C) A representative radiograph and photomicrographs (stain, von Kossa and McNeal’s tetrachrome; original magnifications, ×5 and ×100) obtained from an infarcted femoral head injected with saline or 560 μg ibandronate 7 weeks before the sacrifice show femoral head structure and trabecular bone are better preserved in the ibandronate group than in the saline group. Reprinted with permission by The American Society of Bone and Mineral Research from Aya-ay JP, Athavale S, Morgan-Bagley S, Bain H, Bauss F, Kim HK. Retention, distribution and effects of intraossseously administered ibandronate in the infarcted femoral head. J Bone Miner Res. 2007;22:93–100.