During the past century, orthopaedic surgery has made major advances in many diseases and now has satisfactory treatments available to restore function for most diseases and injuries. However, one problem area that has not advanced as rapidly is osteonecrosis. Despite many years of basic and clinical research, minimal progress has been made in the understanding and treatment of this disease. The barriers to progress and potential solutions that might lead to breakthroughs will be explored and presented. Promising therapeutic pathways will be debated.

Introduction: Osteonecrosis (ON) is a disabling disease, which often affects young adults after corticosteroid immunosuppression for organ transplantation. Reducing risk factors remains the only preventive measure for this condition. Our goal was to determine if diabetes has any influence in developing ON after kidney transplantation.

Materials and Methods: We identified 2881 renal transplantation patients with the following inclusion criteria: age > 16 years, no history of corticosteroid exposure. There were 1762 (61%) diabetics and 1119 (39%) non-diabetics. Mean age was 43 years (range, 16 to 77) and mean follow-up was 128 months (range, 36 to 242). Osteonecrosis free survivorship was defined as time from transplant to diagnosis of ON.

Results: Kaplan-Meier life table analysis at 5 years revealed that the incidence of ON was 4% for diabetics vs. 9% for non-diabetics (ON- free survivorship 96%, [95% confidence interval 0.952 to 0.970] vs. 91% [95% C.I. 0.896 to 0.929], respectively [p < 0.0001]). At 10 years, the ON incidence was 5% for diabetics vs. 10% for non-diabetics representing a 50% reduction.

Diabetes was the strongest independently predictive factor for ON-free survival (relative risk 0.47, p< 0.0001), while other factors were also independently significant but had a weaker relationship; (rejection episodes [RR 1.17, p=0.009], year of transplantation [RR 0.96, p=0.01]).

Discussion: Although the most common reason for renal transplantation, in adults, is diabetic nephropathy (61%), only a small fraction actually developed ON as compared to the non-diabetic population. The reason for this is unknown but might be related to lipid metabolism, high glucose levels, or neovascularization analogous to diabetic retinopathy.

Presence of diabetes is associated with a dramatic risk reduction in developing ON. The magnitude of the risk reduction was greatest for diabetes as compared to all other risk factors analyzed.

Introduction: The relationship between corticosteroids and osteonecrosis (ON) is well known. Limited data have suggested that statins modulate cholesterol metabolism and may protect against ON. We analyzed our, NIH supported, prospective renal transplant database to determine if statin usage reduces the incidence of corticosteroid-related osteonecrosis.

Materials and Methods: We identified 2881 renal transplantation patients who met our inclusion/exclusion criteria. There were 1752 male and 1129 female patients with mean age 43 years (range, 16 to 77). Mean follow-up was 128 months (range, 36 to 242 months). We identified 338 of 2881 patients as being on statins for over 1 year, commencing within 31 days of their transplant.

Results: Among the 338 patients on statins, 15 (4.4%) developed osteonecrosis vs. 180 of 2543 (7%) not on statins. Kaplan-Meier life table analysis of ON-free survival did not show a statistically significant relationship between statin exposure and development of ON (p=0.14, Log-Rank).

Discussion: We conclude that among our renal transplant patients, an association between statin usage and lower risk of osteonecrosis was not found, and if a reduction in incidence of ON actually exists, it is likely to be quite small. In addition, male gender and higher number of rejection episodes were independent predictive factors for ON.

Introduction: The treatment of asymptomatic osteonecrosis of the femoral head (ONFH) is controversial. The primary aim of this study was to define the optimal management of osteonecrotic lesions in patients with asymptomatic ONFH by determining the incidence of disease progression and the factors that might predict its occurrence. In order to assess the indications and timing for surgical intervention in these patients, the secondary aim was to determine whether or not pain precedes subchondral fracture in patients with asymptomatic disease.

Methods: The subjects in this study were patients with asymptomatic ONFH who were derived from two separate prospective, institutional review board-approved investigations in our institution. We determined the incidence of pain development and radiographic evidence of fracture and the temporal relationship of these events. Statistical analyses were performed to determine what factors affected either radiographic progression or the appearance of symptoms.

Results: Of the 37 hips, 12 (32%) were symptomatic at 2 years. Of these painful hips, six (50%) were associated with the simultaneous presence of a subchondral fracture. When analyzing the relationship of pain with fracture, 5 of 6 hips developed symptoms at an average of 8.1 months (1 to 28 months) prior to fracture. Three symptomatic patients had spontaneous resolution of the ONFH. Cox regression analysis revealed that an index of necrosis of > 50 and a greater extent of radiographic involvement correlate with a higher risk for developing symptoms and a subchondral fracture. If an index of necrosis of 50 is set as the lower limit for intervention, 78% of hips that fractured and 93% of hips that did not were identified.

Discussion: Asymptomatic ONFH with small lesions are amenable to observation, and intervention may be withheld until the appearance of symptoms. Asymptomatic ONFH with extensive femoral head involvement has a high probability of early progression to symptomatic ONFH and subchondral fracture. In these cases, early intervention may be beneficial in preventing fractures which may occur without any preceding symptoms. An index of necrosis of 50 is proposed as a threshold for intervention, as it is a good discriminator between those that did and did not fracture, and had a positive predictive value of 77.8%. The only independent predictor of both pain and collapse was the extent of femoral head involvement.

Introduction: Whether or not to surgically treat osteonecrosis of femoral head (ONFH) when patients are asymptomatic is controversial. The goal of this study was to determine: 1) if spontaneous resolution of ONFH does occur, 2) how long does it take for resolution to occur, and 3) if there are predictors of spontaneous resolution.

Materials and Methods: For this prospective study, patients with asymptomatic ONFH were identified from two National Institute of Health funded, Institutional Review Board approved screening studies. A prospective screening study for ONFH after organ transplantation was begun in 1997 by performing routine MRI examinations after transplantation. In a second prospective study on surgical treatment for symptomatic ONFH, the contralateral hip was screened for asymptomatic disease. A cohort of patients having hips with asymptomatic ONFH was then analyzed.

Results: As of December 2000, 13 asymptomatic hips in 10 patients were identified from the prospective screening study after organ transplantation and 17 hips in 17 patients were identified from the contralateral hip screening study. There were 3 hips with ARCO stage I disease showing evidence of spontaneous resolution. The modified index of necrotic extent measured 11.10, 12.72, and 20.83, with the estimated femoral head involvement being 15–30% in 2 of the hips and less than 15% in the third. Resolution on MRI was complete in 2 of the 3 hips, and nearly complete in the third.

Discussion: Spontaneous resolution of ONFH does occur. Factors associated with resolution are early, asymptomatic disease (ARCO stage I), small lesion size (modified index of necrotic extent < 25), and the absence of symptomatic disease in the contralateral hip. Initial signs of resolution may take up to one year to occur. For patients fitting these criteria, we recommend withholding surgery and monitoring hips with serial MRI observation to monitor the course of their disease.

Introduction: Osteoneocrosis of the femoral head (ONFH) is difficult to treat as collapse frequently occurs after core decompression. This may be due to the failure to provide structural support during revascularization and healing after core decompression. Cement (PMMA) packing for giant cell tumors of bone has been shown to provide adequate support of the subchondral bone. This study was undertaken to determine whether or not the addition of PMMA packing provides any benefit to the outcome of core decompression for ONFH. Secondary objectives were to assess various factors for prognostic significance.

Materials and Methods: A prospective, randomized trial of core decompression ± cement (PMMA) packing for ARCO stage I or II ONFH was conducted. Outcome measures were: radiographic (XR) progression, conversion to hip arthroplasty (THA), WOMAC, SF 36, and Harris Hip scores (HHS). Survivorship analysis using Kaplan-Meier estimates was performed.

Results: The time to XR progression at 3 years for the core vs. core + PMMA cohorts was 42 ± 11 mo vs. 45 ± 12 mo, p=0.68, respectively. The time to THA at 3 yrs for the core vs. core± PMMA groups was 42 ± 11 mo vs. 67 ± 12 mo, p=0.17, respectively. Comparing pre vs.1 year postoperative WOMAC scores, for the core + PMMA group, there were statistically significant improvements in pain (p=0.082), stiffness (p=0.03), physical function (p= 0.05) and total score (p=0.03) whereas for the core decompression group, there was no significant difference noted among the same domains (p=0.06, 0.25, 0.74, 0.88) respectively. The SF 36 role physical domain score was higher for the core + PMMA group at 1 year (p=0.07) and 15 mos (p=0.09) but was no different at 3 yrs (p=85). For the physical function and bodily physical domains, there was no difference at any time point. The factors of smoking (y/n) p=0.003, location (central/ medial/lateral) p=0.03, per cent femoral head involvement (< 15, 15–30, > 30%) p=0.05, age (< 40, ≥40 yrs), and necrotic arc (< 40, ≥40) p=0.005, were significant predictors for XR progression on univariate analysis but upon Cox multivariate regression, only age (p=0.09), smoking (p=0.07), and necrotic arc (p=0.04) remained independently, statistically significant.

Discussion: The addition of PMMA packing to core decompression for pre-collapse ONFH (ARCO I/II) does not improve the outcome of treatment as measured by XR progression and conversion to THA. There is a benefit to PMMA packing for pain relief at 12–15 mos. as measured by the mean WOMAC, HHS and SF 36/role physical scores but this benefit ceases at 3 years after treatment. Age ≥40 years, smoking, and necrotic arc ≥40 are all predictive of eventual progression of disease on XR.