Do bisphosphonates alter the clinico-radiological profile of children with Perthes disease? A systematic review and meta-analysis.

This meta-analysis is aimed to analyze the efficacy of bisphosphonates in the management of Perthes disease. A total of 8 animal and 7 human studies have been shortlisted for this analysis. In human studies, common variables for pain, Harris Hip Score (HHS), propensity for femoral head collapse, and total hip arthroplasty (THA), were assessed. In contrast, in animal studies, the data was recorded for epiphyseal quotient, trabecular volume, trabecular separation, trabecular thickness, and trabecular number. Meta-analysis of human studies on ONFH (Osteo-Necrosis of Femoral Head) revealed a statistically significant outcome in HHS [p<0.001; (95% CI: 4.79 - 8.87)], collapse of the femoral head [p=0.079; (95% CI: -0.16 - 0.01)], and THA [p=0.002; (95% CI: -0.19 - -0.04)] whereas the pain score showed an insignificant outcome [p=0.067; (95% CI: -0.62 - 0.04)]. The meta-analysis of selected variables in animal studies revealed a noteworthy outcome in bone volume (p<0.001, 95% Cl), trabecular number (p<0.001, 95% Cl), trabecular thickness (p<0.013, 95% Cl) and trabecular separation (p<0.026, 95% Cl) but not in epiphyseal quotient. Further, analysis of stratified datasets in animal studies revealed a contradictory outcome with significant observations described later in the paper. The use of bisphosphonates holds a promising treatment option in Perthes disease. Although, good quality RCTs are needed to validate it further.

Severe bilateral Legg-Calvé-Perthes resolved with pamidronate in combination with casts, physiotherapy and adductor tenotomy: a pictorial essay over 11 years.

We describe an 11-year prospective clinical and radiologic course of a 6-year-old boy with bilateral Legg-Calvé-Perthes disease, who was treated with intravenous pamidronate (IV-PAM). His baseline radiographs showed grade IV avascular necrosis/Catterall stage IV, and at worst he progressed to lateral pillar/Herring stage C bilaterally. His disease initially was extremely functionally limiting with expected poor outcome with eventual joint replacement. Because IV-PAM stops bone breakdown and allows for ongoing bone formation while revascularisation of bone occurs, we hypothesised that IV-PAM could act as an adjunct to traditional treatment to help heal the femoral heads. Our patient received nine once monthly doses of IV-PAM (1 mg/kg/dose) over 13 months, along with Petrie/broomstick casts and physiotherapy. Remarkably, over time, his femoral heads healed. Now, at 11-year follow-up, he has excellent functional and radiologic outcome with congruence between femoral head and acetabulum, no residual osteonecrosis and minimal loss of femoral head sphericity.

[A boy with a white striped knee on a radiograph]. / Witte strepen op een röntgenfoto van de knie.

A 10-year-old boy presented at the radiology department with pain in the right knee. Radiographs of the knee revealed dens metaphyseal bands and subchondral epiphyseal sclerosis as a result of periodic bisphosphonate administration for the treatment of Legg-Calvé-Perthes disease three years ago.

Local administration of bone morphogenetic protein-2 and bisphosphonate during non-weight-bearing treatment of ischemic osteonecrosis of the femoral head: an experimental investigation in immature pigs.

BACKGROUND: Non-weight-bearing decreases the femoral head deformity but increases bone resorption without increasing bone formation in an experimental animal model of Legg-Calvé-Perthes disease. We sought to determine if local administration of bone morphogenetic protein (BMP)-2 with or without bisphosphonate can increase the bone formation during the non-weight-bearing treatment in the large animal model of Legg-Calvé-Perthes disease. METHODS: Eighteen piglets were surgically induced with femoral head ischemia. Immediately following the surgery, all animals received an above-the-knee amputation to enforce local non-weight-bearing (NWB). One to two weeks later, six animals received local BMP-2 to the necrotic head (BMP group), six received local BMP-2 and ibandronate (BMP+IB group), and the remaining six received no treatment (NWB group). All animals were killed at eight weeks after the induction of ischemia. Radiographic, microcomputed tomography (micro-CT), and histomorphometric assessments were performed. RESULTS: Radiographic assessment showed that the femoral heads in the NWB, BMP, and BMP+IB groups had a decrease of 20%, 14%, and 10%, respectively, in their mean epiphyseal quotient in comparison with the normal control group. Micro-CT analyses showed significantly higher femoral head bone volume in the BMP+IB group than in the BMP group (p = 0.02) and the NWB group (p < 0.001). BMP+IB and BMP groups had a significantly higher trabecular number (p < 0.01) and lower trabecular separation (p < 0.02) than the NWB group. In addition, the osteoclast number per bone surface was significantly lower in the BMP+IB group compared with the NWB group. Calcein labeling showed significantly higher bone formation in the BMP and BMP+IB groups than in the NWB group (p < 0.05). Heterotopic ossification was found in the capsule of four hips in the BMP+IB group but not in the BMP group. CONCLUSIONS: Administration of BMP-2 with bisphosphonate best decreased bone resorption and increased new bone formation during non-weight-bearing treatment of ischemic osteonecrosis in a pig model, but heterotopic ossification is a concern. CLINICAL RELEVANCE: This preclinical study provides new evidence that BMP-2 with bisphosphonate can effectively prevent the extreme bone loss associated with the non-weight-bearing treatment and increase new bone formation in the femoral head in this animal model of ischemic osteonecrosis.

Use of bisphosphonates in orthopedic surgery: pearls and pitfalls.

Bisphosphonates are medications known to decrease bone resorption by inhibiting osteoclastic activity. They are the first-line therapy for the treatment of osteoporosis because a significant body of literature has proved their efficacy in reducing the risk of fracture in the hip, spine and other nonvertebral osseous sites. In addition, the use of bisphosphonates has significantly decreased morbidity and increased survival, and they have also proved to be cost-effective. Unexpected adverse effects have been reported recently, but the benefit of bisphosphonates use outweighs the risks. This article reviews the current use of bisphosphonates in orthopedic surgery.

Local delivery of recombinant human bone morphogenetic proteins and bisphosphonate via sucrose acetate isobutyrate can prevent femoral head collapse in Legg-Calve-Perthes disease: a pilot study in pigs.

PURPOSE: Legg-Calve-Perthes disease is a paediatric condition encompassing idiopathic osteonecrosis of the femoral head (ONFH). Preventing collapse and the need for subsequent joint replacement remains the major goal of clinical management. This exploratory study utilises a porcine model of surgically induced ONFH. METHODS: rhBMP-2 with and without zoledronic acid (ZA) was delivered by intra-osseous injection in the phase-transitioning sucrose acetate isobutyrate (SAIB) in an attempt to prevent femoral head collapse. Epiphyseal quotient (EQ) at eight weeks post-surgery was the primary outcome measure. Heterotopic ossification in the joint capsule and bisphosphonate retention in the femoral head were key secondary outcomes. RESULTS: Femoral heads with ONFH and no treatment all collapsed (3/3, EQ < 0.4, P < 0.05 compared to no ONFH). Local delivery of rhBMP-2/SAIB into the femoral head prevented collapse by EQ measurement one of four samples; however, this specimen still showed evidence of significant collapse. In contrast, the combination of local rhBMP-2 and local ZA prevented collapse in two of four samples. Confocal fluorescence microscopy showed locally dosed bisphosphonate entered and was retained in the femoral head. This group also showed strong Calcein signal, indicating new bone formation. Treatment with rhBMP-2 was associated with a limited amount of heterotrophic ossification in the joint capsules in some specimens. CONCLUSIONS: Operators reported SAIB to be an efficient way to deliver rhBMP-2 to the femoral head. These data suggest that rhBMP-2 is ineffective for preventing femoral head collapse without the addition of bisphosphonate. Further research will be required to validate the clinical efficacy of a combined local rhBMP-2/bisphosphonate approach.

[Complex conservative treatment of legg-calve-perthes disease with dona--glucosamine sulfate (sachet)].

The experience of 10 year application of the preparation dona - glucosamine sulphate (Sachet) Rottapharm, Italy among the children age group during the conservative treatment of thighbone head osteochondropathy (Pertes disease) at the Tbilisi, Children's Sanatorium "Gazapkhuli" orthopedic department is described in the article. In the article, it is mentioned the great importance of glicosaminglycans (GAG) in the matter of formation and existence of connective tissue, their greatest role in the metabolism of bone and cartilaginoid tissue, the considerable importance of preparation dona components (glucosamine, sulphate group) in biochemical processes that proceeds in cartilaginoid tissue - in the gialuroni acid and glicosaminglycans synthesis (the substances that the proteoglycans are composed of). The experience that the Department has in the application of polysulphate glicosaminglycan - preparation rumalon (Russia), during the conservative treatment of Pertes disease, is mentioned. Taking into account the afore-mentioned, the preparation dona was introduced into the scheme of conservative treatment of 300 child patients within 5-14 age group having different stages of Pertes disease. During 5-6 years after the treatment cessation, observation on children patients showed that during the lasting treatment period with the preparation, the hypersensitivity, negative circumstances and complications were not observed. The positive results of the treatments (90-92%), structural restoration processes both in bone and cartilaginoid tissue after the intake of roentgenologically approved preparation, gives the basis for the author of the article to express its opinion on the possibility of application of preparation dona - glucosamine sulphate (Sachet)-1500, as a structural-modified preparation, during the complex conservative treatment of Pertes disease among children within 5-14 age group.

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

BACKGROUND: The rationale for using bisphosphonate (BP) therapy for Legg-Calvé-Perthes disease (LCPD) is the potential to prevent substantial femoral head deformity during the fragmentation phase by inhibiting osteoclastic bone resorption. However, it is unclear whether BP therapy decreases femoral head deformity. QUESTIONS/PURPOSES: In this systematic review, we answered the following questions: (1) Does bisphosphonate (BP) therapy decrease femoral head deformity and improve pain and function in LCPD or other juvenile osteonecrotic conditions? And (2) does BP therapy decrease femoral head deformity in experimental studies of juvenile femoral head osteonecrosis? METHODS: We searched the literature from 1966 to 2011 for clinical and experimental studies on BP therapy for juvenile femoral head osteonecrosis. Studies specifically addressing clinical and/or radiographic/histologic outcomes pertaining to pain and function and femoral head morphology were analyzed. RESULTS: Three Level IV clinical studies met our inclusion criteria. Only one study initiated BP therapy during the precollapsed stage of osteonecrosis and reported prevention of femoral head deformity in nine of 17 patients. All studies noted subjective improvements of pain and gait in patients treated with intravenous BPs. Of the eight experimental studies reviewed, seven reported reduced femoral head deformity and six found better preservation of trabecular framework in animals treated with BPs. CONCLUSIONS: Clinical evidence lacks consistent patient groups and drug protocols to draw definitive conclusions that BP therapy can decrease femoral head deformity in juvenile osteonecrotic conditions. Experimental studies suggest BP therapy protects the infarcted femoral head from deformity, but it lacks bone anabolic effect. Further basic and clinical research are required to determine the potential role of BPs as a medical treatment for LCPD.

Potential for bisphosphonate treatment in Legg-Calve-Perthes disease.

BACKGROUND: The observation that the pathogenesis of femoral head deformity in Legg-Calve-Perthes disease (LCPD) relates to bone resorption without subsequent coupled bone formation leads quickly to the hypothesis that antiresorptive agents may provide a useful adjunctive avenue for therapy. Robust bone catabolism in the absence of anabolism can only lead to femoral head deformity. METHODS: The published data on bisphosphonate use in models of LCPD was reviewed. RESULTS: Multiple animal studies support the further investigation of bisphosphonates and other anticatabolic agents in LCPD. Clinical data is only now starting to be gathered on the basis of animal and safety data.Rodent studies of traumatic and spontaneous osteonecrosis confirm that femoral head shape can be preserved by systemic bisphosphonate administration. Large animal piglet studies also show better preservation of the femoral head shape with systemic and local bisphosphonate administration, and also illustrate that systemic therapy requires initial revascularization of the necrotic head before its distribution within the head-a potential drawback of systemic therapy. Timing of effective dosing is likely to be very important. If the goal of treatment is to prevent deformity, then the window of therapy may be limited to an early stage of the disease before the significant collapse of the head.Although limiting bone resorption and preserving femoral head shape with bisphosphonates or other anticatabolic drugs may be of use, anabolic stimulation to speed up healing and new bone formation may also be desirable. Physical factors such as weight relief and activity modification may be important as the mechanical properties of the necrotic femoral head are significantly compromised during healing. The inflammatory nature of early LCPD is likely to also play a role in pathogenesis. These factors cannot be addressed by the use of antiosteoclastic therapy alone. CLINICAL RELEVANCE: Further basic science and clinical studies are required to clarify the role of bisphosphonates as adjunctive therapy in LCPD.

A case of frequently relapsing nephrotic syndrome combined with Perthes disease.

Orally-administered steroids often induce osteonecrosis of the femoral head. In cases of Perthes disease, osteonecrosis of the femoral head occurs in children due to an unknown cause. Our subject was a 4-year-old boy who had to be given large amounts of steroids because of frequently relapsing nephrotic syndrome (FRNS) developed after the onset of Perthes disease. One month earlier, he would limp with his right leg, but his radiographs were normal. Later, facial edema appeared and he was brought to our hospital with heavy proteinuria. He was diagnosed with NS and prescribed prednisolone for 2 months. As he would limp occasionally during the treatment, he had an orthopedic examination at our hospital, and shrinkage of the right femoral head was disclosed. Perthes disease was diagnosed on the basis of his MRI and clinical history. Meanwhile, NS relapsed twice over a half year, and he was diagnosed as having FRNS. Cyclophosphamide was administered for 12 weeks. Four years later, MRI indicated that the femoral head slowly improved and he was able to walk without prosthetic support. These results suggest that in the course of healing from Perthes disease, the conventional method of using prednisolone has little impact on the femoral head.

Systemic effects of zoledronic acid in children with traumatic femoral head avascular necrosis and Legg-Calve-Perthes disease.

BACKGROUND: Intravenous bisphosphonate therapy is associated with preservation of femoral head sphericity and congruence in 77% of children with traumatic avascular necrosis. The aim was to describe the systemic effects of intravenous zoledronic acid (ZA) on bone and mineral metabolism in otherwise normal children and adolescents with femoral head AVN. MATERIAL AND METHODS: 37 children (age 10.8+/-2.76 years) diagnosed with avascular necrosis AVN (Slipped Capital Femoral Epiphysis (SCFE), N=20 or Legg-Calve-Perthes disease (LCPD), N=17) were treated with at least 12 months of ZA. Bone mineral density (BMD) by DXA, bone morphometry and mineral homeostasis were evaluated at baseline, 6, 12 and 18 months. Data was retrieved retrospectively. RESULTS: All children maintained height SD during treatment. BMI SD increased in the SCFE subgroup during the first 12 month period. Bone age increased appropriately. Age adjusted total body BMD, lumbar spine BMD and lean tissue mass adjusted bone mineral content (BMC) Z-scores increased significantly over the 18 months of treatment. The LS.BMD increase was greater in LCPD than in SCFE leading to more individuals with LCPD having a LS.BMD((age))Z-score over 2 SD at 12 months follow-up. Biochemical markers of bone turnover were decreased and PTH increased during the first 12 months of treatment and bone modeling was reduced. All markers stabilised over the next 6 months. There were no incidences of fracture, spondylolisthesis or osteonecrosis of the jaw. CONCLUSION: We here report that ZA in otherwise healthy children with femoral head AVN increases BMD - most pronounced in the LCPD group - and reduces bone modeling and turnover. Further efficacy and safety data are required before this therapy can be widely recommended.

RANKL inhibition: a novel strategy to decrease femoral head deformity after ischemic osteonecrosis.

UNLABELLED: A novel therapeutic strategy to decrease the development of femoral head deformity after ischemic osteonecrosis was studied in a large animal model of total head infarction. RANKL inhibition through exogenous osteoprotegerin administration significantly decreased pathologic bone resorption and deformity during repair of the infarcted head. INTRODUCTION: Legg-Calvé-Perthes disease (LCPD) is a juvenile form of osteonecrosis of the femoral head that can produce permanent femoral head deformity (FHD) and premature osteoarthritis. The development of FHD in LCPD is closely associated with the repair process, characterized by a predominance of bone resorption in its early stage that produces a fragmented appearance and collapse of the femoral head. We present here a novel strategy to preserve the femoral head structure after ischemic osteonecrosis based on inhibition of interaction between RANK and RANKL using exogenous administration of osteoprotegerin (OPG-Fc) in a large animal model of ischemic osteonecrosis. MATERIALS AND METHODS: Ischemic osteonecrosis was surgically induced in 18 male piglets by placing a ligature tightly around the right femoral neck to disrupt the blood flow to the right femoral head. Two weeks after the induction of total head infarction, OPG-Fc or saline was administered subcutaneously to nine animals per group for 6 weeks. The contralateral, normal (left) femoral heads from the animals treated with saline served as normal, nondisease controls. All animals were killed at 8 weeks when severe FHD has been previously shown to occur because of the repair process dominated by osteoclastic bone resorption. Radiographic, histomorphometric, and immunohistochemical assessments were performed. RESULTS: Radiographic assessment showed significantly better preservation of the femoral head structure in the OPG-Fc group compared with the saline group. Epiphyseal quotient (the ratio of epiphyseal height to diameter) was significantly higher in the OPG-Fc group (0.41 +/- 0.09) compared with the saline group (0.24 +/- 0.08, p < 0.001). Histomorphometric assessment revealed a significant reduction in the number of osteoclasts present in the OPG-Fc group (5.9 +/- 5.3mm(-2)) compared with the saline group (39.6 +/- 13.8 mm(-2), p < 0.001). Trabecular bone volume, number, and separation were significantly better preserved in the OPG-Fc group compared with the saline group (p < 0.001). No significant difference in femoral length was observed between the OPG-Fc and saline groups. Immunostaining revealed the presence of OPG-Fc only within the blood vessels, with no apparent staining of bone matrix or trabecular bone surfaces. CONCLUSIONS: To our knowledge, this is the first study to show that RANKL inhibition decreases bone resorption and FHD after ischemic osteonecrosis. Because RANKL inhibitors do not bind to bone, their effects on resorption are reversible as the drug is cleared from circulation. The reversible nature of RANKL inhibitors is very appealing for treating pediatric bone diseases such as LCPD, where the resorptive stage of the disease lasts for 1-2 years.

Use of bisphosphonates in a case of Perthes disease.

Bisphosphonates are a group of drugs that have been used extensively for more than 10 years to treat adults with osteoporosis. Use of bisphosphonates in pediatrics has generally been confined to conditions such as osteogenesis imperfecta or other conditions with bone density problems. Bisphosphonates increase bone density, bone mineral content, and strength; improve mobility; reduce fracture rates; and are effective agents in combating bone pain. Bisphosphonates inhibit osteoclastic action, thereby increasing bone density (Rauch & Glorieux 2004). Recently there has been interest in the effect of bisphosphonates in localized disorders of bone, including avascular necrosis. The third-generation bisphosphonate zoledonic acid is currently being explored as a treatment for children presenting with Perthes disease at the Children's Hospital at Westmead, Sydney, Australia, and this is a report of that experience.

Zoledronic acid improves femoral head sphericity in a rat model of perthes disease.

We hypothesized that the bisphosphonate zoledronic acid (ZA) could improve femoral head sphericity in Perthes disease by changing the balance between bone resorption and new bone formation. This study tests the effect of ZA in an established model of Perthes disease, the spontaneously hypertensive rat (SHR). One hundred and twenty 4-week old SHR rats were divided into three groups of 40: saline monthly, 0.015 mg/kg ZA weekly, or 0.05 mg/kg ZA monthly. At 15 weeks DXA measurements documented that femoral head BMD was increased by 18% in ZA weekly and 21% in ZA monthly compared to controls (p<0.01). Femoral head sphericity in animals with osteonecrosis was improved in ZA-treatment groups (p<0.01) as measured by epiphyseal quotient (EQ). The proportion of "flat" heads (EQ0.40) was significantly reduced from 32% in saline-treated animals to 12% in weekly ZA and 3% in monthly ZA (p<0.01). Histologically there was a similar prevalence of osteonecrosis in all groups. The prevalence of ossification delay was significantly reduced by ZA treatment (p<0.01). Zoledronic acid favorably altered femoral head shape in this spontaneous model of osteonecrosis in growing rats. Translation of these results to Perthes disease could mean that deformity of the femoral head may be modified in children, perhaps reducing the need for surgical intervention in childhood and adult life.

[Clinical observation on effect of gufusheng capsule in treating early stage Legg-Calve-Perthes disease].

OBJECTIVE: To evaluate the clinical efficacy of Gufusheng capsule (GFSC) in treating early stage Legg-Calve-Perthes disease. METHODS: Adopting randomized single controlled trial, 45 cases with Legg-Calve-Perthes disease in early stage were randomly divided into 2 groups, 23 patients in the control group were treated with arthrectomy hip synovial membrane excision of affected lateral, femoral head decompression and transplantation of muscle-bone flap from ileum, above treatment were also given to the 22 patients in the treated group but combined with orally taking of GFSC. The treatment course for both groups was 6 months. RESULTS: Short-term effect after 6 months' treatment showed that the total effective rate in the treated group and the control group was 90.9% and 78.3% respectively, and the excellent rate was 72.7% and 60.9% respectively. The pain visual analogue scoring, clinical symptom and syndrome scoring markedly decreased before and after treatment, showing significant difference between the two groups (P < 0.05, P < 0.01). Long-term effect after 1-year to 4-year follow-up showed that the total effective rate and excellent rate between the treated group and the control group was significantly different ( chi2 = 8. 5976, P < 0.05). CONCLUSION: GFSC has marked effect in alleviating pain and ameliorating function of hip joint, being an effective compound recipe for treatment of early stage Legg-Calve-Perthes disease. Therefore, it is worthy of researching and developing furthermore.

[Early results in the treatment of Legg-Calvé-Perthes disease using intra-articular injections of aqueous propolis extract]. / Frühzeitige Ergebnisse der Behandlung der Legg-Calvé-Perthes Krankheit mittels Gelenkinjektion von wässrigem Extrakt von Propolis.

Authors presented results in conservative treatment of 54 cases of hip joint with aseptic necrosis of thigh bone. In 22 hips, excluding the typical conservative treatment, EEP injections were given. However, in the remaining 32, different forms of relieve were used. The obtained results in the first group (A) confirm the purpose of enrichment in conservative treatment by adapting intra- articular injections of EEP especially in advanced stages of necrosis (III-IV period of illness) and also in those whose parents did not express their consent on surgery in the early stage of the illness.