0
Commentary and Perspective   |    
Commentary on an article by Jacob S. Vandermeer et al.: “Local Administration of Ibandronate and Bone Morphogenetic Protein-2 After Ischemic Osteonecrosis of the Immature Femoral Head. A Combined Therapy That Stimulates Bone Formation and Decreases Femoral Head Deformity”
Keith M. Baumgarten, MD
View Disclosures and Other Information

The author received no payments or services, either directly or indirectly (i.e., via his institution), from a third party in support of any aspect of this work. Neither the author nor his institution has had any financial relationship, in the thirty-six months prior to submission of this work, with any entity in the biomedical arena that could be perceived to influence or have the potential to influence what is written in this work. Also, the author has not had any other relationships, or engaged in any other activities, that could be perceived to influence or have the potential to influence what is written in this work. The complete Disclosures of Potential Conflicts of Interest submitted by the author of this commentary are available with the online version of this article at jbjs.org.


Copyright © 2011 by The Journal of Bone and Joint Surgery, Inc.
J Bone Joint Surg Am, 2011 May 18;93(10):e57 1-2. doi: 10.2106/JBJS.K.00270
The main article is available here
5 Recommendations (Recommend) | 3 Comments | Saved by 3 Users Save Case
Osteonecrosis of the immature femoral head is a condition that occurs spontaneously with Legg-Calvé-Perthes disease and after a traumatic insult from an unstable slipped capital femoral epiphysis, a femoral neck fracture, or a hip dislocation. Unfortunately, femoral head collapse and deformity are potential outcomes of this disorder. The severity of the residual femoral head deformity has been shown to be the most important prognostic indicator of long-term outcome, with severe cases requiring hip arthroplasty as early as the third decade of life.
Maintenance of femoral head sphericity is currently the main focus in the treatment of Legg-Calvé-Perthes disease. The aim of current treatments is to restore containment of the femoral head, so that remodeling takes place in close conformation with the acetabulum. The ideal treatment would prevent or minimize loss of sphericity and containment1. In their study, Vandermeer et al. utilized a bisphosphonate (ibandronate) to minimize bone resorption and an osteoinductive agent (bone morphogenetic protein-2 [BMP-2]) to enhance bone formation in an attempt to maintain head sphericity.
The authors of previous basic-science studies have examined the use of bisphosphonates in isolation as a means of maintaining femoral head sphericity. Little et al. demonstrated, in both a spontaneous model of osteonecrosis1 and a traumatic model of osteonecrosis2, that zoledronic acid improved femoral head shape compared with that in saline-solution-treated animals. Similarly, Hofstaetter et al. utilized a rabbit model of hip osteonecrosis to demonstrate that alendronate treatment increased bone volume and density and significantly reduced porosity when compared with values in animals treated with a placebo3.
Clinical studies of the efficacy of bisphosphonates for treatment of pediatric femoral head osteonecrosis are rare. Ramachandran et al. treated twenty-eight patients with traumatic osteonecrosis of the femoral head with intravenous bisphosphonates for a mean of twenty months4. Nine of seventeen patients followed for a mean of thirty-eight months had no evidence of femoral head resorption. Although this study was limited by the lack of a comparison group, the authors believed that it demonstrated a lower incidence of femoral head collapse compared with historical data.
To the best of our knowledge, there have not been any studies on the use of BMP in the treatment of pediatric osteonecrosis of the femoral head. The few studies evaluating BMP treatment of femoral head osteonecrosis have involved adults5-7.
Over the last decade, Dr. Kim and his colleagues have performed pioneering work that has increased our understanding of the pathophysiology and potential treatments of Legg-Calvé-Perthes disease and ischemic necrosis of the femoral head in the pediatric population. In 2001 and 2002, they further developed the piglet model of ischemic necrosis of the capital femoral epiphysis initially developed by Salter8,9. This model has been shown to produce histopathologic and radiographic changes resembling Legg-Calvé-Perthes disease. In 2004 and 2007, biomechanical studies in which this model was used demonstrated that the femoral head was structurally compromised as a result of osteoclastic bone resorption that occurs after an ischemic insult10,11. The authors theorized that treatments aimed at retarding bone resorption and stimulating bone formation would be beneficial in minimizing the mechanical compromise of the infarcted femoral head.
Dr. Kim and colleagues further pursued this theory by analyzing the effects of bisphosphonates on post-ischemic bone properties and histomorphology in the immature femoral head. In 2005, they reported that subcutaneous administration of ibandronate prophylactically and postoperatively significantly preserved femoral head structure compared with that following treatment with a placebo12. In 2006, Kim et al. showed that parenterally administered ibandronate cannot gain access to the infarcted femoral head unless revascularization of the femoral head is initiated13. To address this concern, an intraosseous method of administering bisphosphonate was developed14. Radiographic and histomorphometric assessments showed that infarcted heads treated with intraosseous administration of ibandronate were significantly better preserved than were those treated with saline solution injection. The fact that intraosseous administration avoids systemic distribution of the drug makes it preferable for children. The intraosseous route also has the advantage of directly delivering a therapeutic dose of the drug to the epiphysis of the infarcted femoral head even prior to its revascularization.
In their current study, Vandermeer et al. combined reduction of bone resorption with concomitant stimulation of new bone formation by simultaneously using ibandronate and BMP-2 for treatment of ischemic necrosis in the immature femoral head. Compared with the use of ibandronate alone, as reported in their study published in 200714, the combination of ibandronate and BMP-2 significantly improved osteoblast surface number, mean trabecular thickness, and enchondral ossification after ischemic insult. The mean trabecular bone volume was also increased compared with that following treatment with ibandronate alone, but not to the level of significance.
The current study is the latest in a decade's worth of dedication to investigating ischemic necrosis of the immature femoral head. I look forward to the possible future studies by these authors, further investigating techniques for preventing femoral head deformity after ischemic necrosis, including biomechanical analyses, further refinement of the administration of BMP to reduce the risk of heterotopic ossification, and translation of this research to clinical trials in children with Legg-Calvé-Perthes disease and posttraumatic osteonecrosis.
Little  DG;  McDonald  M;  Sharpe  IT;  Peat  R;  Williams  P;  McEvoy  T. Zoledronic acid improves femoral head sphericity in a rat model of Perthes disease. J Orthop Res.  2005;23:862-8.[CrossRef][PubMed]
 
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;18:2016-22.[CrossRef]
 
Hofstaetter  JG;  Wang  J;  Yan  J;  Glimcher  MJ. The effects of alendronate in the treatment of experimental osteonecrosis of the hip in adult rabbits. Osteoarthritis Cartilage.  2009;17:362-70.[CrossRef]
 
Ramachandran  M;  Ward  K;  Brown  RR;  Munns  CF;  Cowell  CT;  Little  DG. Intravenous bisphosphonate therapy for traumatic osteonecrosis of the femoral head in adolescents. J Bone Joint Surg Am.  2007;89:1727-34.[CrossRef]
 
Tingart  M;  Beckmann  J;  Opolka  A;  Matsuura  M;  Wiech  O;  Grifka  J;  Grässel  S. Influence of factors regulating bone formation and remodeling on bone quality in osteonecrosis of the femoral head. Calcif Tissue Int.  2008;82:300-8.[CrossRef]
 
Ma  HZ;  Zeng  BF;  Li  XL;  Chai  YM. Temporal and spatial expression of BMP-2 in sub-chondral bone of necrotic femoral heads in rabbits by use of extracorporeal shock waves. Acta Orthop.  2008;79:98-105.[CrossRef]
 
Lieberman  JR;  Conduah  A;  Urist  MR. Treatment of osteonecrosis of the femoral head with core decompression and human bone morphogenetic protein. Clin Orthop Relat Res.  2004;429:139-45.[CrossRef]
 
Kim  HK;  Su  PH;  Qiu  YS. Histopathologic changes in growth-plate cartilage following ischemic necrosis of the capital femoral epiphysis. An experimental investigation in immature pigs. J Bone Joint Surg Am.  2001;83:688-97.
 
Kim  HK;  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.
 
Pringle  D;  Koob  TJ;  Kim  HK. Indentation properties of growing femoral head following ischemic necrosis. J Orthop Res.  2004;22:122-30.[CrossRef]
 
Koob  TJ;  Pringle  D;  Gedbaw  E;  Meredith  J;  Berrios  R;  Kim  HK. Biomechanical properties of bone and cartilage in growing femoral head following ischemic osteonecrosis. J Orthop Res.  2007;25:750-7.[CrossRef]
 
Kim  HK;  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.[CrossRef]
 
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;39:205-12.[CrossRef]
 
Aya-ay  J;  Athavale  S;  Morgan-Bagley  S;  Bian  H;  Bauss  F;  Kim  HK. Retention, distribution, and effects of intraosseously administered ibandronate in the infarcted femoral head. J Bone Miner Res.  2007;22:93-100.[CrossRef]
 

Submit a comment

References

Little  DG;  McDonald  M;  Sharpe  IT;  Peat  R;  Williams  P;  McEvoy  T. Zoledronic acid improves femoral head sphericity in a rat model of Perthes disease. J Orthop Res.  2005;23:862-8.[CrossRef][PubMed]
 
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;18:2016-22.[CrossRef]
 
Hofstaetter  JG;  Wang  J;  Yan  J;  Glimcher  MJ. The effects of alendronate in the treatment of experimental osteonecrosis of the hip in adult rabbits. Osteoarthritis Cartilage.  2009;17:362-70.[CrossRef]
 
Ramachandran  M;  Ward  K;  Brown  RR;  Munns  CF;  Cowell  CT;  Little  DG. Intravenous bisphosphonate therapy for traumatic osteonecrosis of the femoral head in adolescents. J Bone Joint Surg Am.  2007;89:1727-34.[CrossRef]
 
Tingart  M;  Beckmann  J;  Opolka  A;  Matsuura  M;  Wiech  O;  Grifka  J;  Grässel  S. Influence of factors regulating bone formation and remodeling on bone quality in osteonecrosis of the femoral head. Calcif Tissue Int.  2008;82:300-8.[CrossRef]
 
Ma  HZ;  Zeng  BF;  Li  XL;  Chai  YM. Temporal and spatial expression of BMP-2 in sub-chondral bone of necrotic femoral heads in rabbits by use of extracorporeal shock waves. Acta Orthop.  2008;79:98-105.[CrossRef]
 
Lieberman  JR;  Conduah  A;  Urist  MR. Treatment of osteonecrosis of the femoral head with core decompression and human bone morphogenetic protein. Clin Orthop Relat Res.  2004;429:139-45.[CrossRef]
 
Kim  HK;  Su  PH;  Qiu  YS. Histopathologic changes in growth-plate cartilage following ischemic necrosis of the capital femoral epiphysis. An experimental investigation in immature pigs. J Bone Joint Surg Am.  2001;83:688-97.
 
Kim  HK;  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.
 
Pringle  D;  Koob  TJ;  Kim  HK. Indentation properties of growing femoral head following ischemic necrosis. J Orthop Res.  2004;22:122-30.[CrossRef]
 
Koob  TJ;  Pringle  D;  Gedbaw  E;  Meredith  J;  Berrios  R;  Kim  HK. Biomechanical properties of bone and cartilage in growing femoral head following ischemic osteonecrosis. J Orthop Res.  2007;25:750-7.[CrossRef]
 
Kim  HK;  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.[CrossRef]
 
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;39:205-12.[CrossRef]
 
Aya-ay  J;  Athavale  S;  Morgan-Bagley  S;  Bian  H;  Bauss  F;  Kim  HK. Retention, distribution, and effects of intraosseously administered ibandronate in the infarcted femoral head. J Bone Miner Res.  2007;22:93-100.[CrossRef]
 
Accreditation Statement
These activities have been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Academy of Orthopaedic Surgeons and The Journal of Bone and Joint Surgery, Inc. The American Academy of Orthopaedic Surgeons is accredited by the ACCME to provide continuing medical education for physicians.
CME Activities Associated with This Article
Submit a Comment
Please read the other comments before you post yours. Contributors must reveal any conflict of interest.
Comments are moderated and will appear on the site at the discretion of JBJS editorial staff.

* = Required Field
(if multiple authors, separate names by comma)
Example: John Doe





Related Content
The Journal of Bone & Joint Surgery
JBJS Case Connector
Related Audio and Videos
Clinical Trials
Readers of This Also Read...
JBJS Jobs
03/19/2014
NY - KINGS COUNTY HOSPITAL CENTER
03/26/2014
MA - Boston University Orthopedic Surgical Associates
04/02/2014
WV - Charleston Area Medical Center
11/15/2013
LA - Ochsner Health System