Table 5.

Prospective, retrospective, case control studies of steroid induced osteonecrosis in renal transplant patients.

Study/Ref.	Study design	No. of patients (+ ON/−ON)	Daily dose	Treatment duration	Cumulative dose	Site of lesion	Notes
Shibatani et al. [45]	Retrospective	37/150 (24%)	MPSL 500 mg IV during surgery, PSL 50 mg from the day after surgery, divided into 3 doses a day × 7 days (March 1989–Nov1996) or for 3 days (after Dec 1996). After that, PO dose gradually reduced to 40, 30, 25, 20, and 17.5 mg every 7 days, and maintenance dose of 10 mg was attained by the 6th week. In acute rejection: IV MPSL	2–8 weeks	The steroid doses (lower, middle, and upper thirds) at 2-week period: < 550, 550–650, and > 650 mg, respectively. At 4-week period: < 895, 895–1130, and > 1130 mg, respectively. At 6-week period: < 1165, 1165–1488, and > 1488 mg, respectively. At 8-week period: < 1400, 1400–1795, and > 1795 mg, respectively MPSL bolus in 24 pts at an average dose of 3111 mg	N/A	SS association between AVN incidence and the total dose of steroids in the first 2 months after transplantation, and there was a dose–response relationship. In the 2-week period after transplantation, odds ratios for AVN in the middle and upper-dose steroid groups rose, though not statistically significantly. In the 4 and 6-week periods after transplantation, ORs for the middle-dose group rose significantly and those for the upper-dose group also rose, but not significantly. In the 8-week period after transplantation, ORs for the middle- and upper-dose groups rose significantly, and a significant dose–response relationship was observed.
Hedri et al. [51]	Retrospective	15/326 (4.6%)	MPSL 1–2 mg/kg/day. CS dose gradually reduced over the next 8–12 weeks to a maintenance of 10–15 mg/day.	AVN diagnosed at a mean of 3.5 years after RT (range, 0.5–13 years)	Cumulative mean dose in AVN group 24,240 mg +/− 16,450 vs. 14,243 +/− 7530 in non-AVN group (P = 0.04)	Hip	Cumulative CS dose and the acute rejection rate were higher among the AVN group than the control group (P = 0.04 and P = 0.058, 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.
Tang et al. [46]	Retrospective Case control	16/397 (4.2%) control group 31	NA	NA	IV MPSL cumulative dose in 1st year in + AVN vs. − AVN: 2.97 +/− 2.48 vs. 1.42 +/− 2.01 (P = 0.026)	NA	Significantly higher body weight increments, rejection rate, mean daily oral prednisolone, and cumulative intravenous pulse methylprednisolone consumption in the first posttransplant year in AVN group
Saisu et al. [128]		Group A: 27% Group B: 100%		< 3 months	Group A: 0–4000 mg corticosteroid Group B: > 4000 mg IV methylprednisolone	Femoral head
Bradbury et al. [53]	Retrospective	3%	NA	NA	MPSL at 1 month in AVN+/AVN−:5371/2610 mg ( P = 0.0005) MPSL at 1 year in AVN+/AVN−: 6171/2966 mg Cumulative prednisone at 1 year was 5435 vs. 4540 for AVN− vs. AVN+	NA	+ Association between cumulative doses of IV MPSL in the first month after transplantation and the onset of osteonecrosis. No association between the cumulative doses of prednisone during the first year after transplantation and the development of osteonecrosis
Tervoven et al. [47]	Prospective	6/100 (6%)	NA	> 6 months mean time of exposure for AVN+ 9.5 years Mean time of exposure for AVN− 8.1 years	Mean 32.1 g for all comers Mean for AVN+ 40.9 g (p = 0.269)	HIP	No significant differences were found regarding the total dose of corticosteroids and AVN, but a trend towards higher dose and development of AVN was evident
Lausten et al. [48]	Retrospective	Group 1 (high dose steroid): 42/374 (11%) Group 2 (low dose steroid): 19/376 (5%) p = 0.002	34 mg/day 17 mg/day	Mean interval between treatment and ON—26 months in first group 21 months in second group	Average prednisone during 1st month, 1st year Group 1: 4224, 12,540 mg Group 2: 1712, 6481 mg	NA	Higher incidence with increased daily and cumulative dose of steroid The incidence of femoral head AVN was more than halved with reduction of cumulative steroid from 12 g to 6.5 g
Patton et al. [49]	Retrospective	52/444 (16%)	NA		NA		ON was associated with a history of early acute rejection (p less than 0.02), higher final serum creatinine (p = 0.07), and greater mean prednisone (p < 0.0001). The mean linear trend of daily pred dose was also significant (p < 0.03)
Felson et al. [21]	Metanalysis of 22 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 was 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!)
Metselaar et al. [50]	Retrospective	61/248 (24%)	Prednisone 30 mg/day after transplantation Rejection episodes treated with MPSL or increasing oral prednisone	NA	NA	Hip, knee, ankle, shoulder, elbow	Cumulative dose of steroids was not predictive of AVN Increase in body weight showed a strong correlation with AVN development at 6 months
Haajanen et al. [54]	Retrospective	29/546 (5.3%)	Until 1975, initial MPSL was 100–160 mg/day, where after 68–80 mg/day MPSL 1 month after transplant: 44–60 mg/day; 6 months after: 12–36 mg/day; 12 months after: 0–20 mg/day Rejections treated with IV MPSL 0.5–1 g/day (total 2–5 g)	NA	Total steroid without pulse at 12 months in + AVN/−AVN: 7716/7490 Total steroid with pulse doses at 12 months in + AVN/−AVN: 10,135/8912	Femoral Head	No significant difference in + AVN vs. − AVN in cumulative steroid without pulse dose group. Highly significant difference in + AVN/−AVN in cumulative steroid with pulse dose (IV MPSL)
Morris et al. [55]	Prospective	9/72 (12%) 8 patients in HD group and 1 patient in LD group	High dose (HD) regiment: 100 mg prednisolone daily in two doses started on the day after transplantation, reduced to 90 mg daily after 5 days and then by 5 mg every 5 days to 20 mg, after which the dose was reduced by 1 mg every 2 weeks down to a maintenance dose of 10 mg/day. Low dose (LD) regiment: 30 mg prednisolone daily in divided doses for 60 days, reduced to 25 mg daily for 2 weeks, and then to 20 mg/day. Subsequently, same taper as HD group. The LD patients received, in addition, 1 g MPSL IV on days 6, 7, and 8 after transplantation, and all patients were given 100 mg hydrocortisone i.v. during the operation.	NA	Cumulative dose in HD MPSL during first 6 months 8560 +/− 4500 mg; oral prednisone during first 6 months 6340 +/− 140 Cumulative steroid in LD group in first 6 months: methylprednisolone 9200 +/− 4000; prednisone 3950 +/− 110	NA	AVN is related mostly to the cumulative steroid dose received during the first few months after transplantation. Problems: low dose group with methylprednisolone may have actually gotten more total steroid. Only SS results were of prednisone data.
De Graaf et al. [52]	Retrospective	52/170 (30%)	Initial prednisone dose posttransplant: 80 mg/day, reduced within 6 days to 25–30 mg/day. Subsequently reduced each month by 2.5 mg until min daily dose of 7.5–10 mg was reached. Rejection: IV MPSL 125–200 mg/day × 5 days and then tapered. Mean prednisone dose in + AVN:6300 +/− 990 mg	1, 3, and 6 months	Total prednisone in first 3 months: 2380–9230 mg	Hip > knee > ankle	+ Correlation between cumulative prednisone in 1st 3 months and with the incidence of AVN. (p < 0.001) Statistically significant correlation between number of rejection treatments and incidence of AVN Dosages > 5000 mg during first 3 months appears to be critical dose cut off above which AVN may develop
Hely et al. [129]	Retrospective	29 total children; 21% AVN.	NA	NA	NA	Femoral head	The presence of osteodystrophy prior to transplant was strongly correlated with osteonecrosis Extensive reviews of their records failed to clearly identify other predisposing factors
Elmsted et al. [130]	Retrospective Case control	19 with AVN compared to 125 without AVN	NA	NA	NA	NA	A direct relationship between dose of steroids and the development of AVN not consistently demonstrated
Ibels et al. [41]	Prospective Case control	40/194	Prednisone 2.5–40 mg/day (mean 15.9) Rejection treated with MPSL	NA	NA	Multi sites. Hips most common.	No significant correlation seen in prednisone dose and AVN even in patients treated with MSPL for acute rejection
Potter et al. [131]	Retrospective Case control	11/100 (11%)	At the time of transplantation, treatment with prednisone, 2 to 4 mg/kg The prednisone dose is rapidly decreased to 0.8 to 1.0 mg/kg at the end of one month and more slowly thereafter to a minimum dose of 0.1 to 0.3 mg/kg Rejection treated with MPSL	< 12 months	Cumulative prednisone dose at 3, 6, 12, and 24 months in + AVN/−AVN, respectively. 3368/3466, 5018/4211, 8336/8086, 11,893/14,087 Total dose in + AVN/−AVN: 14,207/12,432	femoral heads, 14; femoral condyles, 12; tall, two; and carpal naviculars, two.	Although the prevalence of AVN decreased after 1967 coincident with a decrease in prednisone dose, children with AVN received the same cumulative prednisone dose as children in a control group.
Levine et al. [42]	Retrospective Case control	16 pts with + AVN compared with 16 control	Mean daily steroid dose for each of the first 14 28-day periods after transplantation was calculated for each patient. Exact numbers not described	NA	The total dosage of CS received by each patient with AVN was estimated in an arbitrarily chosen period of the first 392 days following transplantation. Exact numbers not described	Femoral heads, femoral condyles and humerus in 1	No significant difference between AVN+ and control patients in either total steroid dose or average daily dose over the first 392 days following transplant.
Bewit et al. [43]	Retrospective	13 patients developed AVN	NA		NA		No correlation between steroid dose and AVN
Pierides [44]	Retrospective Case control	11/78 (14%) 11 patients with A.N. were compared with two control groups of unaffected renal transplant patients.	Exact mean not recorded	NA	Exact mean not recorded	NA	the cumulative dose of prednisone received by affected patients during the first three posttransplant months was found to be significantly higher than that for both control groups (P less than 0.05 No significant difference was found between the daily dose of prednisone received by affected patients and control group II
Troche et al. [132]		13/90 patients	Prednisolone 50 mg/day with gradual reduction to 10–20 mg/day over one year Rejection treated with high dose prednisolone	NA	NA	NA	No SS difference in amount of CS received by 13 patients with osteonecrosis and unaffected patients over a comparable period.
Harrington et al. [133]	Retrospective	18/150	NA	> 3 weeks	Of 50 patients who had received an average total dose of steroids of 2960 mg in the 3-week period after transplant 16 developed AVN Of 101 patients who had received an average total dose of steroids of 1180 mg in the 3-week period after transplantation, only 2 developed AVN	NA	Total steroid dose in the 3-week period after transplantation was an etiological factor in the development of AVN.