Intravenous Bisphosphonate Therapy for Traumatic Osteonecrosis of the Femoral Head in Adolescents

Ramachandran, Manoj FRCS(Tr&Orth); Ward, Kate MPH; Brown, Richard R. FRCS(Tr&Orth); Munns, Craig F. FRACP; Cowell, Christopher T. FRACP; Little, David G. FRACS(Orth)

Journal of Bone & Joint Surgery - American Volume: August 2007 - Volume 89 - Issue 8 - p 1727–1734
doi: 10.2106/JBJS.F.00964
Scientific Articles

Background: Femoral head osteonecrosis as a result of trauma in adolescents has a poor prognosis as a result of femoral head collapse and subsequent degenerative change of the hip. There are currently no satisfactory treatments for adolescents with this condition, although bisphosphonate therapy has improved the outcome in animal models of osteonecrosis. We evaluated bisphosphonate therapy for femoral head osteonecrosis following trauma in adolescents.

Methods: We established a protocol for identifying adolescents with osteonecrosis of the femoral head with use of bone scans immediately after surgical treatment of hips at risk for the development of osteonecrosis following trauma. In a consecutive group of twenty-eight patients with an unstable slipped capital femoral epiphysis (twenty-two patients), femoral neck fracture (four), or traumatic hip dislocation (two), seventeen patients with osteonecrosis were identified. These patients (thirteen boys and four girls with a mean age of 12.7 years) and their families gave consent for the patients to receive treatment with intravenous bisphosphonates. The average duration of the bisphosphonate treatment was 20.3 months (range, seven to thirty-nine months). All patients were followed clinically and radiographically for a minimum of two years.

Results: After a mean duration of follow-up of 38.7 months, fourteen patients were pain-free. Clinically, all seventeen patients had a good or excellent outcome. On the average, the Harris hip score was 91.2 points, the Iowa Hip Rating was 92.1 points, and the Global Pediatric Outcomes Data Collection Instrument (PODCI) score was 91.5 points. According to the radiographic classification system of Stulberg et al., nine hips were rated as Class I or II; six, as Class III; and two, as Class IV.

Conclusions: Bisphosphonate therapy may play an adjunctive role in the treatment of adolescents with osteonecrosis of the femoral head following trauma.

Level of Evidence: Therapeutic Level IV. See Instructions to Authors for a complete description of levels of evidence.

1 The Children's Hospital at Westmead, Locked Bag 4001, Westmead NSW 2145, Australia. E-mail address for D.G. Little: DavidL3@chw.edu.au

2 Cheltenham General Hospital, Sandford Road, Cheltenham, Gloucestershire GL53 7AN, United Kingdom

Article Outline

Osteonecrosis of the femoral head following trauma is a rare yet severe disorder in children, occurring after an unstable slipped capital femoral epiphysis, a femoral neck fracture, or a traumatic hip dislocation. The reported prevalence of osteonecrosis in patients with a slipped capital femoral epiphysis is 3% to 58%, depending on the severity and stability of the slip and the initial treatment1,2. There are severe long-term consequences, such as femoral head collapse and degenerative changes of the hip, but no clear guidelines for treatment3. Osteonecrosis of the femoral head has also been shown to occur in up to 40% of hips with a femoral neck fracture and 12% of those with a dislocation and is associated with a poor clinical outcome4-7.

Bone resorption and femoral head collapse can be rapid in children with femoral head osteonecrosis. Osteoclasts resorb necrotic bone during revascularization in an attempt at repair; however, this usually occurs before new bone has been laid down in a sufficient amount to maintain structural integrity8,9. Attempts have therefore been made to slow osteoclastic resorption with nitrogen-containing bisphosphonates, in the hope of maintaining femoral head sphericity and allowing eventual revascularization and ossification without collapse of the femoral head.

In a bone-chamber study of rats, Astrand and Aspenberg10 documented that high-dose systemic alendronate treatment led to the retention of trabecular bone structure and encouraged new bone formation onto structural frozen bone grafts, indicating that repair was possible in this model as long as the bone template was present. One of us (D.G.L.) and colleagues11 applied the same hypothesis in a rat model of traumatic osteonecrosis of the femoral head treated with zoledronic acid, a high-potency bisphosphonate. Parenteral treatment with zoledronic acid resulted in better preservation of both histological architecture and macroscopic femoral head sphericity compared with those seen in control animals, and prophylactic treatment led to a further improvement toward the condition in intact controls. Kim et al.12 expanded these concepts to a large-animal (piglet) ischemic osteonecrosis model, in which parenteral ibandronate treatment was effective in increasing the retained trabecular number and bone volume of the femoral head, with improved preservation of the epiphyseal quotient (the height of the femoral head divided by its diameter). Treatment resulted in an improvement compared with the status of control ischemic femoral heads, but the results were still not identical to those in intact controls; prophylactic treatment provided a further improvement in outcome.

We are aware of three recent human trials of alendronate for the treatment of femoral head osteonecrosis in adults. In a case series of sixty patients (100 hips) with osteonecrosis who were treated with alendronate, and in which twelve patients had a history of trauma, Agarwala et al.13 concluded that early surgical intervention could be avoided in most patients. Lai et al.14 assessed alendronate for the treatment of nontraumatic osteonecrosis of the femoral head in a randomized controlled trial with a minimum duration of follow-up of twenty-four months. Only two of twenty-nine femoral heads in the group treated with alendronate collapsed (with one requiring a subsequent total hip arthroplasty) compared with nineteen of twenty-five hips in the control group (with sixteen needing arthroplasty). Nishii et al.15 treated twenty hips with osteonecrosis of the femoral head with alendronate for one year and compared the results with those in thirteen control hips that had not received treatment. In the alendronate group, the biochemical markers of bone resorption (N-telopeptide of Type-I collagen) decreased more than did those of bone formation (alkaline phosphatase). The alendronate group also showed a lower frequency of femoral head collapse (5% compared with 46% in the control group) and reported less hip pain at one year.

We are not aware of any previous reports on the use of bisphosphonates for the treatment of osteonecrosis of the femoral head after trauma in children. The goal of this prospective series was to determine whether bisphosphonates could preserve femoral head sphericity in children with traumatic osteonecrosis. At our institution, our clinical experience has been focused on the use of pamidronate and zoledronic acid for pediatric orthopaedic conditions such as osteogenesis imperfecta and osteopenic disorders. Furthermore, the preclinical evidence was based on the results of parenteral administration of either high-dose or high-potency bisphosphonates. We therefore decided to carry out a prospective trial of these bisphosphonates as an adjunctive treatment for our patients.

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Materials and Methods

Approvals

The Hospital Pharmacy Committee at our institution considered the protocol for the treatment of traumatic osteonecrosis with bisphosphonates and granted approval on an individual basis for patients who had provided written informed consent. Approval for review of this prospective case series was also obtained from the local Institutional Ethics Committee. All of the study patients presented to our institution between October 2000 and December 2003.

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Treatment Protocol

Before treatment was commenced, we instituted a protocol for identifying patients with femoral head osteonecrosis, as the preclinical evidence had suggested that early treatment would be necessary. Technetium-99m bone scans have been documented to reliably predict femoral head osteonecrosis in this patient group16. Therefore, all children who were at risk for the development of osteonecrosis underwent bone scans as soon as feasible after surgical treatment. Technetium-99m conjugated with methylene diphosphonate was injected intravenously, and a standard three-phase whole-body bone scan was obtained, including pinhole images of both hips. The delayed-phase pinhole images were assessed for ischemia of the femoral head by a nuclear medicine physician. Single-photon-emission computed tomography (SPECT) was used in selected cases as determined by the nuclear medicine physician. One patient's scan was equivocal and was repeated three days later. The repeat scan showed no osteonecrosis, and the patient was not included in the treatment group. Differentiation between partial and total femoral head osteonecrosis was not feasible with this technique.

The protocol for commencing bisphosphonate therapy during the study period is shown in Figure 1. If the bone scan did not show ischemia (i.e., was “hot”), the patient was observed and no adjunctive therapy was offered. If the bone scan showed ischemia (i.e., was “cold”), the patient was offered adjunctive treatment with bisphosphonates. Patients with osteonecrosis were advised to remain partially weight-bearing for the first year, but compliance was not measured. When a patient had a slipped capital femoral epiphysis, the stability of the slip was classified according to the definitions described by Loder et al.1. The slip was classified as unstable if the patient had such severe pain that walking was not possible, even with crutches, regardless of the duration of symptoms. The slip was classified as stable if walking and weight-bearing were still possible with or without crutches. Only patients with an unstable slipped capital femoral epiphysis were considered to be at risk for the development of osteonecrosis.

Treatment with pamidronate (ten patients) or, later, zoledronic acid (seven patients) was begun within three months after the initial traumatic event. Bisphosphonates were administered intravenously in order to improve absorption and bioavailability and to ensure patient compliance. The primary rationale for changing to zoledronic acid when it became available to us was a theoretical increase in potency and shorter infusion times. Prospective clinical and radiographic evaluations were carried out every three months following the initiation of the bisphosphonate therapy.

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Assessment

The primary clinical outcome measures were the Harris hip score17, the Iowa Hip Rating18, and the Global Pediatric Outcomes Data Collection Instrument (Global PODCI)19, administered at the time of final follow-up by a pediatric orthopaedic fellow. The sphericity and congruence of the affected hips were assessed on the final follow-up radiographs with use of the consensus radiographic classification described by Stulberg et al.20 (see Appendix). This scoring system is widely used to assess radiographic outcomes in hips affected by Legg-Calvé-Perthes disease, and it has acceptable intraobserver reliability21. It is useful for assessing outcomes in adolescents with femoral head osteonecrosis, as sphericity and congruence are of paramount importance in the evaluation of long-term outcomes of treatment of any pediatric hip condition, and we could find no other available validated scoring system. We also applied the staging system of Ficat22, as it is more commonly used to evaluate femoral head osteonecrosis in adults. As our patients all presented with an acute traumatic event, they all had a Ficat stage-1 hip at presentation. All radiographs were also reviewed for the presence of femoral head resorption.

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Adverse Effects

Because of concern over theoretical adverse renal effects, including nephrocalcinosis and renal insufficiency, all patients had a baseline renal ultrasound examination and renal function blood tests before treatment. Because of the risk of hypocalcemia, total serum calcium levels were monitored on the first and third days following infusion of the bisphosphonate23. In addition, the patients were monitored clinically every three months for growth abnormalities and any other rare bisphosphonate-associated complications, such as uveitis and osteonecrosis of the jaw.

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Statistical Analysis

Means and standard deviations are reported. Unpaired t tests were used to compare the primary outcome measure scores between the subgroups in the study. The Fisher exact test was used for tests of proportions. Paired t tests were employed to compare patient height Z scores at the commencement of bisphosphonate treatment with those at one and two years following treatment24. A p value of <0.05 was selected as the level of significance for this study before the data analysis.

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Results

Of the twenty-eight patients at risk, seventeen (thirteen boys and four girls with a mean age of 12.7 years at the onset of the disease) were diagnosed with femoral head osteonecrosis following initial surgical treatment and subsequently were treated with intravenous bisphosphonates. This group included twelve of twenty-two patients with a severe unstable slip of the femoral capital epiphysis, four of four patients with a transcervical hip fracture, and one of two patients with a hip dislocation seen at our institution during the study period (Fig. 1). All of the slipped capital femoral epiphyses had been unstable at the initial presentation to either the referring hospital or our unit, and an attempt had been made to pin the femoral head in situ. Five of these index procedures had failed at other institutions, and therefore these patients underwent a single subsequent operation (repinning in situ and injection of bone marrow from the ipsilateral iliac crest) at our institution before starting bisphosphonate treatment. The transcervical hip fractures were all displaced and were treated with closed reduction and cannulated screw fixation. The hip dislocation was posterior and treated with closed reduction.

All patients who were entered into the study had a “cold” femoral head on the delayed pinhole image produced with the technetium-99m bone scan. Typical appearances were a variable decrease in isotope uptake on the blood pool phase and a complete absence of isotope uptake in the femoral head and growth plate on the affected side on the delayed pinhole images. During the study period, twenty-two patients with an unstable slipped capital femoral epiphysis presented to our institution. Ten of them had a “hot” femoral head on bone scanning and were therefore not offered bisphosphonate therapy. All had a Stulberg Class-I outcome with no complications at the time of follow-up, at a minimum of two years. Of the four patients presenting with a femoral neck fracture, all had femoral head osteonecrosis, as did one of two patients presenting with a traumatic hip dislocation.

The average duration of bisphosphonate treatment was 20.3 months (range, seven to thirty-nine months). The first ten patients in the study received a dose of 1.0 mg/kg of intravenous pamidronate over three to four hours on alternate months. Later, as patient responses and safety data were reviewed, this dose was increased to 1.5 mg/kg on alternate months. The average number of infusions of pamidronate was 9.6 (range, seven to thirteen), with an average total dose of 10.8 mg/kg (range, 3.9 to 18.2 mg/kg). The last seven patients were treated with zoledronic acid at a dose of 0.025 to 0.05 mg/kg (maximum, 2.0 mg) given over thirty minutes after the initial diagnosis, at six weeks after the injury, at three months after the injury, and every three months thereafter. The average number of infusions of zoledronic acid was 8.1 (seven, eight, or nine), and the average total dose was 0.23 mg/kg (range, 0.17 to 0.34 mg/kg).

The clinical and radiographic outcomes are presented in the Appendix. At an average of 38.7 months (range, 25.6 to 58.3 months) following the start of bisphosphonate therapy, fourteen of the seventeen patients were completely pain-free. Thirteen of the seventeen patients walked with a clinically normal gait. Of these thirteen patients, nine had equal limb lengths and four had a 1-cm limb-length discrepancy. Three patients had a short-leg gait (2 cm of limb-shortening in two patients and 2.5 cm in one), and one had a Trendelenburg gait due to hip abductor muscle dysfunction. The mean Harris hip score was 91.2 ± 11.2 points (range, 65 to 100 points), the mean Iowa Hip Rating was 92.1 ± 8.9 points (range, 66 to 100 points), and the mean Global PODCI score was 91.5 ± 8.3 points (range, 77 to 100 points).

At the latest radiographic follow-up evaluation, nine hips were rated as Stulberg Class I or II; six, as Stulberg Class III; and two, as Stulberg Class IV (see Appendix). No areas of femoral head resorption were seen on the radiographs in nine of the seventeen patients. The absence of noticeable areas of resorption in the femoral head on radiographs was associated with an increased number of femoral heads being classified as Stulberg Class I or II. Eight of nine femoral heads without resorption had a Stulberg Class-I or II outcome. In contrast, only one of eight heads displaying resorption had a Stulberg Class-I or II outcome (p < 0.01). The absence of femoral head resorption was also associated with an improvement in the mean Harris hip score (96.0 points compared with 85.8 points for the hips with resorption; p < 0.05) and the mean Global PODCI score (96.0 compared with 86.4 points; p < 0.01), although, with the numbers studied, the difference in the mean Iowa Hip Rating was not significant (94.0 compared with 89.9 points; p = 0.18). Case examples are shown in Figures 2 and 3.

Four patients with a slipped capital femoral epiphysis eventually underwent a flexion/valgus femoral osteotomy for the treatment of posterior angulation and impingement in flexion, and one additional patient was a candidate for such intervention at the time of writing. In two patients with a slipped capital femoral epiphysis, a stable slip of the contralateral hip developed during the study period, one at six months and the other at seven months following the initial slip. Both cases were treated with pinning in situ without complications.

After the initial bisphosphonate infusion, most patients had an acute-phase response, including fever (nine patients), headache (ten), nausea or vomiting (thirteen), or general malaise (thirteen), which lasted less than seventy-two hours and had no apparent long-term effects. Hypocalcemia (<2.1 mmol/L) occurred after the initial dose of bisphosphonates in thirteen of the patients, but it did not occur following subsequent doses. There were no adverse renal effects and no clinically symptomatic cases of uveitis or osteonecrosis of the jaw.

Follow-up bone scans were performed on all patients, typically ordered between four to six months following the injury and repeated until photopenia was no longer seen on the pinhole views (Figs. 2 and 3). In one patient with a basicervical femoral neck fracture, photopenia was still present at seventeen months after the injury. For the remaining sixteen patients, the mean time of documented revascularization was 6.3 ± 3.1 months. In one of these patients, the growth plate signal partially recovered, but the remaining patients showed increased uptake in the femoral head, no growth plate signal, and variable changes attributable to remodeling in the femoral head and neck.

Analysis of the growth data for the study patients revealed no adverse effects. The height Z scores actually increased from a baseline mean of 0.09 ± 1.97 at the initiation of treatment to a mean of 0.43 ± 1.62 at one year (p < 0.05) and a mean of 0.90 ± 1.63 at two years (p < 0.01) following treatment.

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Discussion

The rationale for adjunctive bisphosphonate therapy for adolescents with femoral head osteonecrosis after an injury is that it may slow resorption of necrotic bone (catabolism) and allow revascularization and subsequent bone formation (anabolism) to occur before there is collapse of the femoral head. Investigations of novel treatment strategies such as administration of bisphosphonates are of paramount importance as there is currently no effective treatment for traumatic femoral head osteonecrosis in adolescents.

It is widely accepted that the long-term prognosis for traumatic femoral head osteonecrosis in this age group is commonly collapse and deformity of the femoral head with secondary degenerative changes in the hip and a poor clinical outcome3,25-27. For example, Krahn et al.27, in a thirty-one-year retrospective study of thirty-six patients with slipped capital femoral epiphysis that led to femoral head osteonecrosis, reported that 75% of the patients had evidence of marked degenerative change on radiographs of the hip. Salvage surgery, such as proximal femoral realignment osteotomy or hip arthrodesis, may be required at an early age to prevent or treat progression of hip osteoarthritis28, although these secondary procedures may increase the technical difficulty of any future joint arthroplasty29.

Bisphosphonates are metabolically stable analogs of inorganic pyrophosphate in which the P-O-P bond has been replaced with a nonhydrolyzable P-C-P bond30. They are versatile and potent antiresorptive (anticatabolic) agents, exerting their effects by inhibiting components of the intracellular mevalonate pathway and preventing prenylation of intracellular proteins in osteoclasts. Bisphosphonates have been shown to improve bone density in a variety of conditions, such as osteogenesis imperfecta31 and Gaucher disease32, and bone strength in preclinical models of distraction osteogenesis and fracture repair33-35. In patients with femoral head osteonecrosis, because osteoclastic resorption of necrotic subchondral bone may lead to mechanical weakening and subsequent collapse of the femoral head, inhibition of osteoclastic activity by bisphosphonates may attenuate or prevent the progression of the collapse associated with this repair process.

During the time course of this study, twenty-two patients presented with an unstable slipped capital femoral epiphysis. Twelve of these twenty-two patients had a “cold” bone scan consistent with femoral head osteonecrosis. Published rates of osteonecrosis in patients presenting with unstable slipped capital femoral epiphysis range from 47% to 58%1,36,37. The authors of those reports assumed that all of the femoral heads with osteonecrosis went on to collapse and those that did not collapse did not have osteonecrosis, but it is not possible to be certain of this on the basis of the methodologies employed in those studies. Technetium-99m bone scanning has been shown to be a reliable predictor, with excellent sensitivity and predictive value, of femoral heads at risk for collapse16,38. In one study16, osteonecrosis developed in five of six hips that had had “cold” pretreatment bone scans. The same outcome was seen in three “cold” hips scanned following surgical fixation in another study38.

Our results require careful interpretation in the light of this literature. We did not treat the ten patients who presented with an unstable slipped capital femoral epiphysis and a “hot” bone scan during the period of our study. Had we reported our outcomes simply in terms of the rate of femoral head collapse in all patients with an unstable slipped capital femoral epiphysis, we would have stated that seventeen (77%) of twenty-two femoral heads remained spherical and five (23%) of the twenty-two collapsed. The rate of femoral head collapse in this raw evaluation is lower than the 47% to 58% rates reported in the literature on unstable slipped capital femoral epiphysis. It should be noted that the duration of follow-up in the current investigation was shorter than that in some of the other studies, so caution in the interpretation of these comparisons is needed.

However, because we used bone scanning, we are able to state more precisely how the patients fared depending on whether or not they had evidence of osteonecrosis on the bone scan. None of the ten patients with an unstable slipped capital femoral epiphysis and “hot” bone scans showed any resorption or collapse. Of the twelve patients with an unstable slipped capital femoral epiphysis and “cold” bone scans, seven had a Stulberg Class-I or II outcome, which is possibly an improvement over the natural history.

We can thus confirm that children who present with an unstable slipped capital femoral epiphysis and have normal bone scans following surgical fixation do not require further adjunctive treatment such as administration of bisphosphonates. We treated all patients with an unstable slipped capital femoral epiphysis, a femoral neck fracture, or a hip dislocation and a “cold” bone scan with bisphosphonate therapy. Restrictions were placed on weight-bearing for the first year following the injury. Despite the common belief that necrotic bone is strong, Pringle et al.9 showed, in a piglet model of ischemic necrosis, that the indentation stiffness of the femoral head is reduced by 74% compared with controls by four weeks after the induction of osteonecrosis and considerable deformity is present by eight weeks. Ideally, we would have insisted on weight-bearing restrictions for eighteen months, as radiographic evidence of bone resorption was observed in this study group up to this time. This length of time was, however, impractical in an adolescent population, and we became concerned about the general effects of inactivity. The desirability of preventing radiographically obvious resorption in the femoral head was reinforced by our findings of increased rates of sphericity and higher Harris hip and Global PODCI scores in patients without resorption.

The Stulberg classification was useful for defining which femoral heads were spherical and which were not. A limitation of using this classification in this patient cohort is that it could not account for areas of resorption seen in some femoral heads. We are uncertain that there will be a significant difference in the long-term outcomes between hips graded as Stulberg Class III and those graded as Stulberg Class IV in our patient cohort. However, we assume that the hips graded as Stulberg Class I or II will have a better prognosis because of the maintenance of sphericity, as these hips were nearly all graded as Ficat stage I. Although our cohort had very good hip function overall, hip function in these patients with osteonecrosis of the femoral head may decrease over time, even when the femoral head has remained spherical.

The choice of bisphosphonate was limited to those with which we were familiar. Pamidronate has been used commonly for patients with osteogenesis imperfecta31, and many centers would be more familiar with this drug than with the newer, more potent zoledronic acid. The advantages of using zoledronic acid at our institution were a shorter infusion time and less frequent dosing than with pamidronate, but these advantages may not be relevant in all centers.

There were no major adverse effects of the bisphosphonate therapy in this study. The frequency of acute flu-like effects was similar to that previously reported in the literature23. In particular, no renal effects, uveitis, or osteonecrosis of the jaw39,40 was noted in our small series of subjects. We are not aware of any reports of bisphosphonate-associated osteonecrosis of the jaw in children; however, information about this risk should be provided to patients and their families. It remains possible that subclinical events did occur and were not noted by our surveillance.

Animal studies have shown diminution of growth with the use of potent bisphosphonates41. However, human studies have shown that this growth disturbance is not clinically measurable42,43. While our study revealed no negative effects on growth and provided further evidence that this problem does not seem to translate from animals to children, the continued monitoring of growth of children being treated with bisphosphonates remains advisable.

It was difficult to ascertain the exact dose and duration of bisphosphonate treatment required for these patients, as this question is not answered by the available preclinical data. We saw radiographic evidence of resorption up to eighteen months after the initial injury. A higher dose of bisphosphonates may have provided stronger inhibitory effects on osteoclast activity and enhanced the ability to protect against progression of femoral head collapse. For example, clinical trials of osteoporosis treatment with alendronate have shown a dose-related increase in bone mineral density in the lumbar spine44. However, a higher dose or longer duration of treatment must be balanced against a higher risk of adverse effects. Bisphosphonates do not distribute in high concentration to necrotic bone and only penetrate the revascularizing femoral head45. This would appear to mandate continued administration of the drug until revascularization has occurred. Although the follow-up bone scans documented apparent revascularization by six months, bone scans do not have sufficient resolution to show if revascularization is fully complete. However, the findings on these scans confirm that systemically administered bisphosphonate is usually being distributed to the femoral head by six to nine months.

Alternative future approaches that require investigation include local bisphosphonate delivery with or without follow-up systemic treatment. Furthermore, rather than relying on the natural bone-forming (anabolic) response, which took up to eighteen months to repair the femoral head according to our radiographic observations, the addition of a properly timed anabolic therapy may be useful. A few patients in this study had bone marrow injections in concert with additional necessary surgery for screw placement, but we cannot determine if these interventions had useful effects on the basis of this small number of patients.

More than half of the hips with femoral head osteonecrosis in this study had a Stulberg Class-I or II outcome, which we believe may be better than the described natural history of this severe disorder. The positive nature of this observational series supports the need for larger multicenter randomized trials in the future.

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Appendix

A table showing clinical details on all study patients and a figure depicting the Stulberg classification are available with the electronic versions of this article, on our web site at jbjs.org (go to the article citation and click on “Supplementary Material”) and on our quarterly CD-ROM (call our subscription department, at 781-449-9780, to order the CD-ROM). ▪

Disclosure: The authors did not receive any outside funding or grants in support of their research for or preparation of this work. One or more of the authors, or a member of his or her immediate family, received, in any one year, payments or other benefits in excess of $10,000 or a commitment or agreement to provide such benefits from commercial entities (Novartis Pharma, Ingham Enterprises, and Smith and Nephew). No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, division, center, clinical practice, or other charitable or nonprofit organization with which the authors, or a member of their immediate families, are affiliated or associated.

A commentary is available with the electronic versions of this article, on our web site (www.jbjs.org) and on our quarterly CD-ROM (call our subscription department, at 781-449-9780, to order the CD-ROM).

Investigation performed at The Children's Hospital at Westmead, Sydney, Australia

1. , Richards BS, Shapiro PS, Reznick LR, Aronson DD. Acute slipped capital femoral epiphysis: the importance of physeal stability. J Bone Joint Surg Am. 1993;75: 1134-40.
2. , Weiner DS, Green NE, Terry CL. Acute slipped capital femoral epiphysis: the value and safety of urgent manipulative reduction. J Pediatr Orthop. 1997;17: 648-54.
3. , Weinstein SL, Noble J. Long-term follow-up of slipped capital femoral epiphysis. J Bone Joint Surg Am. 1991;73: 667-74.
4. . Complications of fracture of the neck of the femur in children. A long-term follow-up study. Injury. 2001;32: 45-51.
5. , Guille JT, Kumar SJ, Rhee KJ. Complications associated with fracture of the neck of the femur in children. J Pediatr Orthop. 1992;12: 503-9.
6. , Broughton NS. Traumatic hip dislocation in childhood. J Pediatr Orthop. 1998;18: 691-4.
7. , Hubbard GW, Crawford AH, Roy DR, Wall EJ. Traumatic hip dislocation in children. Long-term followup of 42 patients. Clin Orthop Relat Res. 2000;376: 68-79.
8. , Su PH. Development of flattening and apparent fragmentation following ischemic necrosis of the capital femoral epiphysis in a piglet model. J Bone Joint Surg Am. 2002;84: 1329-34.
9. , Koob TJ, Kim HK. Indentation properties of growing femoral head following ischemic necrosis. J Orthop Res. 2004;22: 122-30.
10. , Aspenberg P. Systemic alendronate prevents resorption of necrotic bone during revascularization. A bone chamber study in rats. BMC Musculoskelet Disord. 2002;3: 19.
11. , 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: 2016-22.
12. , Randall TS, Bian H, Jenkins J, Garces A, Bauss F. Ibandronate for prevention of femoral head deformity after ischemic necrosis of the capital femoral epiphysis in immature pigs. J Bone Joint Surg Am. 2005;87: 550-7.
13. , Jain D, Joshi VR, Sule A. Efficacy of alendronate, a bisphosphonate, in the treatment of AVN of the hip. A prospective open-label study. Rheumatology (Oxford). 2005;44: 352-9. Erratum in: Rheumatology (Oxford). 2005;44:569.
14. , Shen WJ, Yang CY, Shao CJ, Hsu JT, Lin RM. The use of alendronate to prevent early collapse of the femoral head in patients with nontraumatic osteonecrosis. A randomized clinical study. J Bone Joint Surg Am. 2005;87: 2155-9.
15. , Sugano N, Miki H, Hashimoto J, Yoshikawa H. Does alendronate prevent collapse in osteonecrosis of the femoral head? Clin Orthop Relat Res. 2006;443: 273-9.
16. , Davidson RS, Heyman S, Dormans JP, Drummond DS. Pretreatment bone scan in SCFE: a predictor of ischemia and avascular necrosis. J Pediatr Orthop. 1999;19: 164-8.
17. . Traumatic arthritis of the hip after dislocation and acetabular fractures: treatment by mold arthroplasty. An end-result study using a new method of result evaluation. J Bone Joint Surg Am. 1969;51: 737-55.
18. . Rating scale for hip disabilities. Clin Orthop Relat Res. 1963;31: 85-93.
19. , Young NL, Owen JL, Wright JG. Comparison of three outcomes instruments in children. J Pediatr Orthop. 2001;21: 425-32.
20. , Cooperman DR, Wallensten R. The natural history of Legg-Calvé-Perthes disease. J Bone Joint Surg Am. 1981;63: 1095-108.
21. , Weinstein SL, Spratt KF, Dolan L, Morcuende J, Dietz FR, Guyton G, Hart R, Kraut MS, Lervick G, Pardubsky P, Saterbak A. Stulberg classification system for evaluation of Legg-Calvé-Perthes disease: intra-rater and inter-rater reliability. J Bone Joint Surg Am. 1999;81: 1209-16.
22. . Idiopathic bone necrosis of the femoral head. Early diagnosis and treatment. J Bone Joint Surg Br. 1985;67: 3-9.
23. , Yap F, Little D, Ambler G, McQuade M, Cowell CT. Short-term safety assessment in the use of intravenous zoledronic acid in children. J Pediatr. 2004;145: 701-4.
24. , Ogden CL, Grummer-Strawn LM, Flegal KM, Guo SS, Wei R, Mei Z, Curtin LR, Roche AF, Johnson CL. CDC growth charts: United States. Adv Data. 2000;314: 1-27.
25. , Mickelson MR, Ponseti IV. Slipped capital femoral epiphysis. Long-term follow-up study of one hundred and twenty-one patients. J Bone Joint Surg Am. 1981;63: 85-95.
26. , Lyne ED, Morawa LG. Slipped capital femoral epiphysis long-term results after 10-38 years. Clin Orthop Relat Res. 1979;141: 176-80.
27. , Canale ST, Beaty JH, Warner WC, Lourenco P. Long-term follow-up of patients with avascular necrosis after treatment of slipped capital femoral epiphysis. J Pediatr Orthop. 1993;13: 154-8.
28. , Sood M, Hashemi-Nejad A, Catterall A. The management of avascular necrosis after slipped capital femoral epiphysis. J Bone Joint Surg Br. 2005;87: 1669-74.
29. , Clarke NM. Joint replacement for sequelae of childhood hip disorders. J Pediatr Orthop. 2004;24: 235-40.
30. , Einhorn TA. Bisphosphonates in orthopaedic surgery. J Bone Joint Surg Am. 2005;87: 1609-18.
31. , Bishop NJ, Plotkin H, Chabot G, Lanoue G, Travers R. Cyclic administration of pamidronate in children with severe osteogenesis imperfecta. N Engl J Med. 1998;339: 947-52.
32. , Cuttini M, Bembi B. Short-term effects of pamidronate in patients with Gaucher's disease and severe skeletal involvement. N Engl J Med. 1997;337: 712.
33. , Cornell MS, Briody J, Cowell CT, Arbuckle S, Cooke-Yarborough CM. Intravenous pamidronate reduces osteoporosis and improves formation of the regenerate during distraction osteogenesis. A study in immature rabbits. J Bone Joint Surg Br. 2001;83: 1069-74.
34. , Smith NC, Williams PR, Briody JN, Bilston LE, Smith EJ, Gardiner EM, Cowell CT. Zoledronic acid prevents osteopenia and increases bone strength in a rabbit model of distraction osteogenesis. J Bone Miner Res. 2003;18: 1300-7.
35. , Brown R, Bilston LE, Little DG. A single systemic dose of pamidronate improves bone mineral content and accelerates restoration of strength in a rat model of fracture repair. J Orthop Res 2005;23: 1029-34.
36. , Loder RT. Treatment of the unstable (acute) slipped capital femoral epiphysis. Clin Orthop Relat Res. 1996;322: 99-110.
37. , Stanton RP, Mason DE. Factors influencing the development of osteonecrosis in patients treated for slipped capital femoral epiphysis. J Bone Joint Surg Am. 2003;85: 798-801.
38. , Chotel F, Vargas Barreto B, Berard J. The value of early postoperative bone scan in slipped capital femoral epiphysis. J Pediatr Orthop B. 2001;10: 51-5.
39. , Mehrotra B, Rosenberg TJ, Engroff SL. Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg. 2004;62: 527-34.
40. . Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg. 2003;61: 1115-7.
41. , Lau ST, Oberbauer AM, Martin RB. Alendronate affects long bone length and growth plate morphology in the oim mouse model for Osteogenesis Imperfecta. Bone. 2003;32: 268-74.
42. , Rauch F, Plotkin H, Glorieux FH. Height and weight development during four years of therapy with cyclical intravenous pamidronate in children and adolescents with osteogenesis imperfecta types I, III, and IV. Pediatrics. 2003;111: 1030-6.
43. , Hamdy NA, Papapoulos SE. Long-term effects of bisphosphonates on the growing skeleton. Studies of young patients with severe osteoporosis. Medicine (Baltimore). 1997;76: 266-83.
44. , Meunier PJ, Emkey R, Rodriguez-Portales JA, Menkes CJ, Wasnich RD, Bone HG, Santora AC, Wu M, Desai R, Ross PD. Skeletal benefits of alendronate: 7-year treatment of postmenopausal osteoporotic women. Phase III Osteoporosis Treatment Study Group. J Clin Endocrinol Metab. 2000;85: 3109-15.
45. , 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: 205-12.
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