Table 6.
Prospective, retrospective, case control studies of steroid dosing and osteonecrosis in bone marrow transplant, cardiac transplant, lung transplant, liver transplant, acute lymphocytic leukemia, Hodgkin's disease, Multiple myeloma undergoing chemotherapy, SARS, multiple sclerosis, neurosurgical patients.
| Study/Ref. | Study design | No. of patients (+ ON/−ON) | Underlying disease | Daily dose | Treatment duration | Cumulative dose | Site of lesion | Notes |
|---|---|---|---|---|---|---|---|---|
| Lieberman et al. [56] | Retrospective | 6/204 (3%) | Cardiac transplant | Three 125 mg doses of IV MPSL q 12 h starting immediately after surgical procedure. On postop day 2, prednisone 70 mg/day and then tapered to 20 mg/day by postoperative day 14. Taper regimen over the next 180 days down to a maintenance dose of prednisone 5 mg/day. For transplant rejection: IV MPSL bolus of 1500 to 3000 mg over 3 days and a bolus of prednisone 770 mg over 16 days. |
Most weaned off of steroids by 1–2 years post op. Some required continued maintenance dose prednisone 5 mg/day. | Cumulative steroid (MPSL and prednisone over 2 years) —in AVN+ 5560 mg; in AVN− 5866 mg. Cumulative dose of MPSL at 2 years 881 vs. 1188 in AVN− vs. AVN+, respectively. Cumulative dose of prednisone at 2 years was 4984 mg vs. 4372 for AVN − vs. AVN+ |
N/A | No relationship between either the prednisone or IV MPSL dose and the development of osteonecrosis of the hip or knee. |
| Chan et al. [75] | Prospective | 7/69 | SARS | prednisolone 0.5–1.0 mg/kg of body weight daily, or IV hydrocortisone 100 mg every 8 h with step-down titration starting at the third week of admission. For patients with clinical deterioration including desaturation (oxygen saturation, 90% using pulse oximetry) or development of new infiltrates in chest radiograph, pulse steroid using MPSL 0.5 g daily × 3 days Daily hydrocortisone equivalent (mg/day) 572 (326–749) |
The median hospital-day on maintenance and/or pulse CS therapies was 17 | Hydrocortisone equivalent for all corticosteroids (mg)* 9520 (4580–16,600) | N/A | Cumulative doses of > 2000 mg of MPSL, > 1900 mg of hydrocortisone, > 13,340 mg of hydrocortisone equivalent, and > 18 days on corticosteroid therapy are significant risk predictors for ON, while pulse steroid therapy is not. Hydrocortisone and hydrocortisone equivalent not SS |
| Ce et al. [134] | Prospective cohort | 5/33 | Multiple sclerosis; tobacco+ | N/A | N/A | Total CS dosage varied between 10 and 62 g | N/A | No meaningful relationship between dosing and AVN. Given trends, very high doses of steroids given in a short-time course constitutes an independent risk for AVN. |
| Wong et al. [58] | Retrospective | 4/1352 (0.3%) | Neurosurgical patients | High dose, short course Dexamethasone | Duration of steroid treatment ranged from 15 to 27 days (mean 20 days). | The steroid dose as dexamethasone equivalent ranged from 59 to 150 mg (mean 102 mg) | Femoral head | Though data failed to establish a relationship between steroid dosage and the risk of AVN, experience of long term steroid management indicates that the duration and dosage of steroids are factors contributing to AVN. |
| Talamo et al. [60] | Prospective | 49/553 | Multiple myeloma undergoing antineoplastic therapy | Dexamethasone in 4 phases. | N/A | The cumulative dexamethasone dose ranged from 800 to 2880 mg, with a median cumulative dose to onset of AVN of 1120 mg. | NA | When adjusted for body weight, the cumulative dexamethasone dose remained significantly associated with an increased probability of AVN (OR, 1.030; 95% CI, 1.005–1.055; P = 0.0201). Higher cumulative dexamethasone dose (odds ratio [OR], 1.028; 95% CI, 1.012 to 1.044; P = 0.0006 [per 40 mg of dexamethasone]) A logistic regression equation predicted that a patient receiving a cumulative dexamethasone dose of 2880 mg had a 20% chance of developing AVN, a probability that was 4.2-fold higher than that of a patient treated with a cumulative dexamethasone dose of 800 mg. |
| Li et al. [135] | Retrospective | 12/40 | SARS | N/A | average course of treatment was (24 +/− 5) days (16 to 30 days). | average total dosage of methylprednisolone was (4949 +/− 2959) mg | N/A | The cumulative dosage and duration of therapy denoted highest risk of AVN |
| Arico et al. [61] | Retrospective | 15/1421 (1/0.1%) | Chemotherapy in childhood acute lymphoblastic leukemia | N/A | N/A | AIEOP–ALL-95 regiment: 3250–6420 mg/m2 | N/A | Cumulative dose is a risk factor Noted decreased incidence with comparison between other chemotherapy regiments (CCG vs. DFCI) where cumulative dose is higher (5885–9050 mg/m2 vs. 7600–21,240, respectively) |
| Koo et al. [7] | Retrospective | 22 total | Renal transplant (7), aplastic anemia (6) nephrotic syndrome (3) liver transplantation (1), Crohn's (1) eosinophilic granuloma in (1), pemphigus vulgaris (1), MS (1), ALL (1) | During 1st month mean daily dose was 76 mg (range 60–145 mg) | The duration of steroid treatment within this period (mean 4.5 months). Start of steroid treatment to the diagnosis by MRI mean 5.3 months |
1800–15,505 mg (mean 5928 mg). During 1st month: mean dose 2267 mg Until the diagnosis on magnetic resonance imaging, the total dose \of steroid mean 5928 mg |
Femoral head, other | The high dose of steroid during the first several weeks seems to be more important than the total cumulative dose. |
| Torii et al. [62] | Retrospective | 19/100 (19%) | Post-BMT | NA | NA | NA | Femoral head | Four factors were found to be SS different between patients who had osteonecrosis develop and those who did not: younger age at the time of bone marrow transplantation, chronic graft-versus-host disease, cumulative dose of steroid, and intravenous pulse therapy with methylprednisolone. It was concluded that a low rate of complications and low dose steroid administration would reduce the incidence of osteonecrosis after bone marrow transplantation. |
| Lieberman et al. [57] | Retrospective | 3/203 (2%) | Liver transplant | MPSL preoperative dose 50–1000 mg of MPSL IV, followed by a 6-day tapered dose as follows: day 1, 200 mg; day 2, 160 mg; day 3, 120 mg; day 4, 80 mg; day 5, 40 mg; and day 6, 20 mg IV. On post op day 7, Prednisone 20 mg/day × 30 days. Followed by taper of 15 mg/day down to 2.5 mg at 180 days after transplant. |
Up to 2 years | Prednisone + MPSL at 2 years in AVN+/AVN−: 9678/10,552 MPSL alone at 2 years in AVN+/AVN−: 9678/10,552 (mg/m2) Prednisone alone at 2 years in AVN+/AVN−: 7,688/7,152 |
Hip | No relationship between either parenteral or oral steroid dose and the development of osteonecrosis of the hip |
| Mattano et al. [63] | Retrospective | 111/140 (9.3%) | ALL-pediatric | NA | NA | (mg/m2) Induction prednisone: 1815 Delayed intensification dexamethasone 235 in group A and B and 470 in group C Maintenance Prednisone in males/females: 7000/4400 in group A and B and 6200/3600 in group C |
NA | Incidence of ON higher for patients randomized to receive two 21-day dexamethasone courses versus one course (23.2% +/− 4.8% vs. 16.4% +/− 4.3%, respectively; P = 0.27). Patients 10–20 years old randomized to receive DDI (2 dexamethasone pulses) exhibited a 1.4-fold higher incidence of symptomatic ON compared with those who received SDI (1 dexamethasone pulse), although this did not reach a conventional significance level. This effect was accentuated in females and in those 16 to 20 years of age at diagnosis of ALL. Conclusion: children ages 10 to 20 years who receive intensive ALL therapy, including multiple courses of corticosteroid, are at significant risk for developing ON. |
| Ojala et al. [64] | Prospective | 9/24 (34%) | ALL | Induction phase: prednisone 60 mg/day; delayed intensification phase, which includes intensive dexamethasone medication. | 4–5 weeks for induction phase; unclear duration of intensification phase Interval between treatment and osteonecrosis—within a few months |
NA | NA | Corticosteroids may cause osteonecrosis in cancer patients. |
| Wiesman et al. [65] | Retrospective | 17/272 (6%) | Post allogenic BMT | High dose prednisolone The mean maximal dose of prednisolone was 3 mg/kg/day (range 2–27). |
NA | Total dose 189 mg/kg (range 13–555 mg/kg) The median total dosage of prednisolone at the time of diagnosis was 189 mg/kg (single manifestation 150 mg/kg; multiple manifestations 313 mg/kg) with a total range of 13–555 mg/kg. |
Femoral head most common, multifocal. | Significant difference in median total dosage of prednisolone at the time of diagnosis between single and multifocal AVN |
| Enrici et al. [66] | Retrospective | 9/784 (1%) | Hodgkin's disease | NA | Between treatment and ON—35 months | Prednisone 2725–5250 mg | Head of femur; 1 humeral head | Osteonecrosis is rare in CS treated Hodgkin's disease |
| Wing et al. [59] | Prospective cohort study | 0/59 | Spinal Cord Injury | Methylprednisolone | 24 h | MPSL 11,000–15,000 mg over 24 h | NA | Using binomial distribution, we conclude that the true incidence of AVN among the methylprednisolone treated group is less than 5% (a50.05) and therefore continue to recommend short term (24 h) methylprednisolone therapy. Shortcomings: very poor follow up. |
| Vaidya et al. [67] | Retrospective | 850 (0.6%) | ALL | NA | Duration of chemotherapy regiment including steroid 24–30 months Between treatment and ON—29 months |
Prednisolone cumulative dose from 4.5 to 7 g | NA | The data suggests that patients receiving combination chemotherapy, especially those with high cumulative doses of steroids, run an increased risk of developing AVN Drawback: radiography and bone scans were performed on symptomatic patients only. |
| Fink et al. [68] | Case control | 87/1939 (5%) | ALL | NA | Between treatment and ON—26 months | NA | NA | Corticosteroids are a high-risk factor for developing osteonecrosis in ALL. Posttransplant steroid use was a risk factor for the occurrence of AVN (adjusted OR, 14.4; 95% CI, 2.8–73.2), with the greatest risk associated with those receiving steroids at the time of diagnosis of AVN (adjusted OR, 31.9; 95% CI, 4.4–248.9). There was no further increasing risk associated with increasing duration of steroid use. |
| Socie et al. [69] | Multicenter retrospective | 77/4388 (4%) | Post-BMT | NA | Mean of 15 months Time delay between steroid and ON—22 months |
NA | Hip most often affected (88%) | In multivariate logistic regression analysis, five factors remained significantly associated with an increased risk for developing avascular necrosis: chronic GvHD (odds ratio (OR) 3.52), acute GvHD (OR 3.73), age > 16 years (OR 5.81), aplastic anemia (OR 3.90), and acute leukemia (OR 1.72) Steroids are part of treatment for GVHD. Steroids dose and exact relation not examined. Steroids are a significant risk factor for developing AVN in post-BMT patients. |
| Ojala et al. [70] | Prospective | 9/28 (32%) | ALL-pediatric | High dose dexamethasone 3 different regiment: all the regimens included 4–5 weeks of prednisone at a dose of 60 mg/m2 per day in the induction phase 2/3 regiments with Intensification phase and high dose dexamethasone |
NA | NA | NA | A significant risk of developing AVN exists in patients on intensive CS treatment for ALL. All of our patients with AVN had been treated with IR or HR protocols, which include a delayed intensification phase with intensive dexamethasone medication, whereas no typical AVN were found in the SR patients, who had not received dexamethasone |
| Thornton et al. [74] | Retrospective Case series |
8/12 patients | ALL or NHL | High dose dexamethasone These phases: 28 days of prednisolone 60 mg/m 2 body area daily at the induction phase, 4 weeks of dexamethasone at 10 mg/m 2 body area daily at the intensification phase and 5-day pulses of prednisolone 10rag daily every month for 2 years in the maintenance phase. |
NA | NA | 11 knees, seven hips, five shoulders and five ankles | AVN in these patients is most likely due to the high dose dexamethasone therapy as in all eight cases symptoms followed this stage of the regimen. |
| Bradbury et al. [53] | retrospective | 5/168 (3%) | Cardiac/pulmonary transplant | NA | NA | Total MPSL dose at 1 month: 2610 mg in patients who did not develop osteonecrosis and 5371 milligrams in those patients who developed osteonecrosis ( P = 0.0005) Total MPSL at 1 year: 2966 mg vs. 6171 mg for AVN− vs. AVN+. Total prednisone at 1 year: 5435 vs. 4540 for AVN− vs. AVN+ |
NA | + Association between cumulative doses of IV MPSL in the first month and 1 year after transplantation and the onset of AVN. No association between the cumulative doses of prednisone during the first year after transplantation and the development of osteonecrosis |
| Socie et al. [71] | Retrospective | 27/727 | Post-BMT | First line therapy for GVHD was 2 mg/kg × 10 days and then tapered Severe or progressive GVHD was treated with Prednisone 5 mg/kg |
NA | Mean cumulative dose 14.3 g/patient (range 2.5–50.5 g). According to body weight, Mean total dose of 200 mg/kg, range 60–840 mg/kg. | Hip most common in 69% | 3 factors with increased risk for developing avascular necrosis by multivariate analysis: male gender (relative risk (RR) 4.72, P = 0.002), age older than 16 (RR = 3.87, P = 0.004), and acute graft-versus-host disease requiring steroid therapy (RR = 6.30, P = 0.0002). |
| Chan-lam et al. [72] | Retrospective | 5/9 (55%) | ALL and high grade malignant Lymphoma | 28 days of prednisolone at the dose of 60 mg/m2 daily in the induction phase, 4 weeks of dexamethasone at 10 mg/m2 daily at the intensification phase and 5-day prednisolone pulses every month in the maintenance phase for 2 years. | ~ 2 years | NA | Hips, knees, ankles | The relatively high incidence of AVN in our series could be explained by the dose of corticosteroids used in the BFM protocol which is 1.5–1.75× greater than the doses used in conventional chemotherapy schedules like the MRC ALL × protocol. Three out of the four patients who did not develop clinical AVN did not receive the late intensification block which contains high dose dexamethasone and this would further support the role of high doses of steroids in causing AVN. |
| Marsh et al. [76] | Retrospective | Group A: 21% Group B: 0% |
Aplastic anemia | Group A: methylprednisolone 5 mg/kg/day Group B: methylprednisolone 1 mg/kg/day |
2–4 weeks | NA | Femoral head most common, knee, 1 patient with humeral head | AVN only seen in high dose group. |
| Enright et al. [73] | Retrospective | 28/902 | Post-BMT | Mean dose/day in 1st month: 0.82 mg/kg/day, and was 2.2 mg/kg/day during the second 30 days after transplantation (reflecting increased steroid need for GVHD) | NA | The mean cumulative dose of steroids to onset of avascular necrosis was 19.8 g/patient (range 9 to 70.0 g) | The hip joint was most often involved (64% of patients), followed by knee (61%), ankle (29%), shoulder (21%), and elbow (7%). | Significant correlation between the total cumulative dose of steroids and number of joints involved (p < 0.01). A multivariate analysis (allogeneic transplant patients only) identified acute or chronic GVHD requiring steroid therapy (p = 0.003), and increasing age (p = 0.002) as significant and independent risk factors. |
| Felson et al. [21] | Metanalysis of 22 studies | 22 pooled studies | AVN range 0–31% (SLE, renal transplant, BMT, Hodgkin's) | 1st month, 3 months, 6 months, and 12 months (total steroid/oral steroid), respectively were 127/80, 74/50, 49/34, 29/25. | 1-, 3-, 6-, and 12-month periods | NA | NA | + Relationship between oral dose in each time period and development of AVN Comparing steroid dose and bolus steroids indicated that a 9000 mg prednisone (equivalent) cumulative dosage given in a month had a 22% incidence of AVN. Bolus dose was not associated with AVN. This quantitative review strongly suggests that steroid dose is the major predictor of the risk of AVN. The oral dose effect amounts to a 4.6% increase in the risk of AVN for every 10 mg/day rise in oral steroids during the first 6 months of therapy Draw backs: only a small number of non-renal cohorts in study (SLE patients shave different risks!) |
| Atkinson et al. [136] | Retrospective | 5/50 | Aplastic anemia–post-BMT | NA | > 14 days | Total dose of 14 mg/kg | Femoral head | Minimization of steroids in prophylaxis of GVHD to prevent AVN complication |