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.
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.
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.
Copyright 2007 by The Journal of Bone and Joint Surgery, Incorporated
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.