Studies into the pathogenesis of femoral head deformity in Legg-Calve-Perthes disease (LCPD) have led to the consideration of bisphosphonates as a potential therapeutic adjunctive therapy. Although the cause of LCPD remains unknown, the pathogenesis of the response to the avascular insult is becoming better understood.
PATHOGENESIS OF FEMORAL HEAD DEFORMITY BASED ON THE PIGLET MODEL OF ISCHEMIC NECROSIS
Studies using a piglet model of ischemic necrosis have highlighted the pathogenesis, mechanical, and radiologic consequences of infarction of the growing capital epiphysis.1,2 The radiologic manifestations closely resemble those of LCPD, with the phases of resorption (fragmentation) and reossification being most prominent. The model uses a resorbable ligature placed tightly around the femoral neck to disrupt the blood supply to the capital femoral epiphysis (Fig. 1). Mild femoral head flattening is observed by 4 weeks after the induction of ischemia, and severe flattening and fragmentation are observed by 8 weeks (Fig. 2).
The predominant repair response observed after revascularization is osteoclastic bone resorption. Before the development of flattening, a large area of osteoclastic bone resorption is observed in the central region of the femoral head. Many osteoclasts are present along the revascularization front, which are responsible for active resorption of the necrotic trabecular bone.
Appositional new bone formation is not observed in the area of bone resorption. Instead, the areas of resorbed bone are replaced with a fibrovascular tissue that persisted for up to 8 weeks. Any appositional new bone formation that was observed was limited to small areas in which revascularization was not followed by osteoclastic bone resorption and in which necrotic trabecular bone was still present. The simultaneous presence of the areas of bone resorption, new bone formation, and necrotic bone contributed to the fragmented radiographic appearance of the femoral head. Decreases in mechanical strength come rapidly, with decreases over control values of 50% by 2 weeks and 75% by 4 weeks.
Thus, the predominant repair response observed in the piglet model of ischemic necrosis is osteoclastic bone resorption. The early bone loss, the lack of new bone formation, and the persistence of fibrovascular tissue in the areas of bone resorption compromised the structural integrity of the femoral head and produce progressive femoral head flattening over time.
OTHER MODELS OF LCPD
The spontaneous hypertensive rat (SHR) has been proposed as a model of spontaneous osteonecrosis in growing animals. Fifty percent of male SHRs undergo a necrotic event during the first 9 weeks of life, and this leads to femoral head deformity by 15 weeks.3 The SHR displays delayed femoral head ossification. Weight bearing has been shown to be critical in the pathogenesis of osteonecrosis in SHRs; prevention of weight bearing by knee amputation provides 100% protection against the onset of osteonecrosis.4
EFFECTS OF BISPHOSPHONATES IN ANIMAL MODELS OF LCPD AND OSTEONECROSIS
Bisphosphonates (BPs) are synthetic analogs of pyrophosphate that bind with high affinity to hydroxyapatite. The selectivity of BPs for osteoclasts is due to the fact that they distribute almost exclusively to the skeleton and osteoclasts resorb bone and are exposed to high concentrations of the drug. Newer bisphosphonates have increased potency due to the presence of a nitrogen-containing side chain.5 Nitrogen-containing bisphosphonates (N-BPs) [(pamidronate, alendronate, risedronate, ibandronate, zoledronic acid (ZA)] inhibit an enzyme called FFP synthase which leads to cellular dysfunction and apoptosis, whereas the older non-N-BPs produce toxic metabolites in the mitochondria.6
Rat Femoral Head Studies
Rat studies have been performed in 2 different scenarios. In one scenario, the osteonecrosis of the femoral head is surgically induced traumatically. In another scenario, a group of SHRs with a predilection for osteonecrosis were studied.
ZA Treatment Results in Retention of Femoral Head Structure after Traumatic Osteonecrosis in Young Wistar Rats7
In this study, rats were subjected to a surgically induced osteonecrosis. Control femoral heads showed loss of trabecular structure and deformation. ZA treatment resulted in significant increase in trabecular number (trabecular retention) and an improvement in femoral head shape over saline (Fig. 3). Prophylactic ZA almost completely preserved femoral head structure. The native anabolic response was very strong in this model with robust new bone formation by week 4.
Alendronate Treatment Maintains Femoral Head Shape in Traumatic Model of Osteonecrosis8,9
In 2 closely related studies, alendronate given subcutaneously (200 μg/kg/d) was able to preserve femoral head structure in Sprague-Dawley rats. Alendronate and avascular and vascular heads did not differ in shape, whereas untreated femoral heads were flatter than the contralateral nonoperated side.
ZA Improves Femoral Head Sphericity in a SHR Perthes Model10
SHRs develop a Perthes-like osteonecrosis in 50% of male animals. In this study, 120 rats were treated with either saline, ZA 0.05 mg/kg every 4 weeks, or 0.015 mg/kg ×10 doses given weekly. ZA treatment resulted in a significant improvement in the epiphyseal quotient, a measure of femoral head flattening (Fig. 4). More importantly, the number of animals with “flat” femoral heads was reduced from 33% in controls to 6% to 14% in treated groups, suggesting that ZA can preserve femoral head shape in response to spontaneous osteonecrosis.
These studies confirm that bisphosphonates can protect against collapse in a loaded large animal model. Although the osteonecrosis in these animals was induced surgically, the disease in the piglet femoral head closely resembles LCPD radiographically.
Ibandronate Decreases Femoral Head Deformity After Ischemic Necrosis of the Capital Femoral Epiphysis in Immature Pigs11
In this study, a well-characterized model of LCPD in the piglet was subjected to 3 treatment arms, which were compared with normal femoral heads.
The saline group showed moderate-to-severe deformity of the femoral head with a mean epiphyseal quotient of 0.28±0.10 (vs. 0.48±0.02 in the normal controls), which is consistent with the natural course of the piglet model at 8 weeks. In comparison with the saline group, the prophylactic and the postischemia ibandronate dose groups had significantly higher mean epiphyseal quotients (0.45±0.05 and 0.39±0.09, respectively) indicating less deformity of the femoral head.
Histomorphometric assessment revealed that changes in the trabecular bone volume, trabecular number, and separation were preserved in the femoral heads of the animals treated with prophylactic and postischemic doses of ibandronate compared with the animals that received saline only (P<0.05).
In this study, the long bone growth was found to be decreased by repeated systemic administration of bisphosphonate. The mean length of the femur from the nonoperated side was 1.7 cm (P<0.00001) and 0.8 cm (P=0.01) shorter in the animals receiving prophylactic and postischemic doses of ibandronate, respectively, in comparison with the animals receiving saline.
BIODISTRIBUTION OF SYSTEMIC AND LOCALLY ADMINISTERED BISPHOSPHONATES
Bisphosphonates preferentially bind in areas that are vascularized and their access to the nonvascularized regions of the infracted head is limited. This presents a potential limitation if treatment is only given systemically. In the rat models above, revascularization was rapid, potentially underestimating this concern. However, in the piglet model where revascularization is slower, studies indicate that the necrotic bone receives less bisphosphonate than revascularized bone.12
More recently, local administration of bisphosphonates has been studied. 99Tc-labeled pamidronate given locally increased the efficiency of delivery of the drug to the femur in rats.13 The local distribution was further increased when a fracture was present.
Locally administered C14-ibandronate was largely retained in the injected head and almost negligible amount of radioactivity was present in the bone and organs elsewhere at 48 hours.14 At 3 and 7 weeks, 50% and 30% of the C14-drug were found to be retained in the infarcted heads, respectively. Retention of femoral head structure was evident in locally ibandronate treated femoral heads (Fig. 5). Revascularization was observed at 8 weeks after infarction, but little new bone formation was yet evident in this model.
OTHER ANTICATABOLIC AGENTS
The effects of bisphosphonates are dependent on their binding to the bone of the femoral head. Another potential strategy is to decrease bone resorption by limiting osteoclastogenesis. In a further study, inhibition of RANK ligand by OPG-Fc significantly preserved the femoral heads of piglets with ischemic necrosis.15 The study showed significant reduction in the number of osteoclasts in the OPG-Fc group compared with the saline group (P<0.001) with significantly better preservation of the femoral head structure (P<0.001). Furthermore, OPG-Fc administration did not affect long bone growth during the study period. At 8 weeks, little anabolic response had occurred.
The osteoclast number was seen to be very high in the saline treated infracted femoral heads—a standard response to ischemic necrosis. OPG-Fc eliminated osteoclastogenesis and preserved femoral head morphology. This study confirms that antiosteoclastic therapy (other than bisphosphonates) may be of benefit on ischemic necrosis.
Summary Of Animal Studies
Taken together, these studies show that
- Bisphosphonates decreased femoral head deformity in animal models of osteonecrosis and LCPD
- Bisphosphonate administration delays resorption of necrotic bone, which may allow more time for revascularization to occur before structural failure
- Trabecular number is maintained in the normal range whereas this variable is consistently decreased in saline-treated animals.
- Anabolism (new bone formation in the area of repair) is not enhanced
- Other forms of anticatabolic (antiosteoclastic) therapy are also effective, reinforcing the hypothesis that control of catabolism is a useful step in maintaining femoral head structure in ischemic necrosis.
CLINICAL STUDIES OF BISPHOSPHONATES FOR OSTEONECROSIS IN CHILDREN
In children, bisphosphonate therapy has been used to treat LCPD,16 traumatic osteonecrosis,17 and osteonecrosis as a complication of chemotherapy for childhood leukemia and non-Hodgkin lymphoma.18–20 These case series and case reports do not provide a high level of evidence for clinical use. A prospective case series of adolescent traumatic osteonecrosis due to unstable slipped capital femoral epiphysis, hip fracture, or dislocation treated with intravenous bisphosphonate (pamidronate or ZA) did better than expected from historical controls at the minimum follow-up of 2 years.17 Nine of 17 patients had a spherical femoral head and 14 of 17 patients were pain free. The mean Harris hip score, Iowa hip rating, and global Pediatrics Outcomes Data Collection Instrument score were all over 90. In an observational study of 17 patients with osteonecrosis as a complication of chemotherapy childhood leukemia,19 improvements in the pain scores, analgesic requirement, and function were found in the 9 patients who received bisphosphonate therapy, whereas 7 of 8 patients who did not receive bisphosphonate therapy showed clinical deterioration. No radiographic improvements were noted. Another small study of childhood leukemic patients found a reduction of pain and increased mobility in 4 of the 6 patients treated with pamidronate for 2 years, however, 3 of the 6 patients had a progression and required hip replacement.20
CLINICAL STUDIES OF BISPHOSPHONATES FOR OSTEONECROSIS IN ADULTS
There have been 3 recent human studies of N-BPs (alendronate) for osteonecrosis in adults. In a case series of 60 patients (100 hips) with osteonecrosis who were treated with alendronate, of which 12 patients had a history of trauma, Agarwala et al21 concluded that early surgical intervention could be avoided in most patients. In an updated study that included 294 patients (395 hips), when treatment was ceased at year 3, stage III hips had largely progressed over 8 years, whereas 56% (72 of 129) of stage II hips progressed.22 Only 13% (27 of 215) stage I hips had collapsed up to 8 years later. A minority of patients had undergone arthroplasty at a mean of 4 years—2% (4 of 215), 8% (10 of 129), and 33% (17 of 51) of hips had been replaced in stage 1, 2, and 3 hips, respectively. Although a large study, it suffers from the major limitations in that the extent of the femoral head involvement was not assessed and that it is a cohort study with no control group.
Lai et al23 compared alendronate with nonplacebo in the treatment of nontraumatic osteonecrosis of the femoral head in a randomized controlled trial with a minimum follow-up of 24 months. Only 2 of 29 femoral heads in the alendronate group collapsed (of which 1 required subsequent total hip arthroplasty) compared with 19 of 25 in the control group (of which 16 needed arthroplasty).
Nishii et al24 treated 20 hips with osteonecrosis of the femoral head with alendronate for 1 year and compared their results with 13 control hips that did not receive treatment. The alendronate group showed a greater decrease of the biochemical markers of bone resorption (N-telopeptide of type I collagen) than those of bone formation (alkaline phosphatase). The alendronate group also showed a lower frequency of femoral head collapse (5% compared with 46%) and reported less hip pain than the control group at 1-year follow-up.
As noted, many animal experiments document that bisphosphonates can decrease longitudinal growth in experimental animals.10,11,25,26 It should be noted that these animals are growing rapidly, that bisphosphonate doses given are often above those used clinically and more frequent than used clinically. Some studies show no effect on longitudinal growth. The inhibition seems to recover once dosing is ceased, but there is no evidence of catch up.27
Safety Data in Children
Zeitlin et a28 have documented increased height in children with Osteogenesis Imperfecta after 4 years therapy with pamidronate. In a cohort of children treated for fibrous dysplasia with pamidronate, growth was normal after 1 to 9 years of treatment.29 A recent review of patients with osteonecrosis and LCPD treated with bisphosphonates noted maintenance of height Z scores.30
The impairment in longitudinal growth seen in some rapidly growing animals has not been seen in studies of children on bisphosphonates. Continued monitoring of longitudinal growth of children on bisphosphonates remains standard practice.
Bone Mineral Density Increases
Increase in bone mineral density (BMD) is not the primary aim of the treatment. BMD increases from baseline over 12 months ZA treatment from a Z score 0.03±0.93 to 0.92±0.9230. Lumbar spine BMD rose even further from 0.33±1.02 to 1.54±0.91. Treatment for more than 1 year is likely to be undesirable in terms of increases in BMD in the spine.
Renal Function, Hypocalcaemia
In a study of 34 children who received ZA infusions for a variety of benign indications, no effect on renal function was noted.31
Calcium and phosphorus levels decreased significantly between baseline and 48 hours post ZA infusion (P<0.001) and were still significantly below baseline after 72 hours. Subsequent infusions demonstrated a smaller drop in serum calcium. These data indicate that maintaining adequate oral intake, and calcium and vitamin D are important. These safety aspects need to be monitored in children on IV bisphosphonates.
Osteonecrosis of the Jaw
A new complication known as osteonecrosis of the jaw has been recently described. Patients who are on bisphosphonates for cancer and who have had a recent tooth extraction are at the highest risk. Nonhealing of the tooth socket or other open mucosal lesions occurs, which is often painful and effects eating. Associated infection is common. To date, no reported cases have occurred in children but routine disclosure, informed consent, and observation for this complication is standard practice.
SUMMARY AND FUTURE DIRECTIONS
The above body of work shows consistent results from rat models of traumatic and spontaneous osteonecrosis to large animal studies in the piglet model. The hypothesis that outcome can be improved by decreasing the catabolic effects on the femoral head by osteoclast inhibition is supported by the animal models. Continued research is needed to optimize the delivery of bisphosphonate to the femoral head and minimize any unwanted effects. Local administration may meet these requirements but has not been trialed in children with LCPD to date.
Complimentary anabolic strategies will also need to be developed, as although bisphosphonates have a positive effect in preserving femoral head architecture, the anabolic response remains deficient. The delay in new bone formation after resorption in LCPD is clearly a major part of the pathogenesis.
The role of inflammation and decreased range of movement in subluxation and deformity are not directly addressed by anticatabolic strategies. However, these are temporary problems and preservation of a near spherical femoral head may obviate the need to address them.
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