Table 4.

Prospective, retrospective, case control studies of steroid induced osteonecrosis in SLE.

Study/Ref.	Study design	No. of patients (+ ON/−ON)	Daily dose	Treatment duration	Cumulative dose (steroid equivalent in prednisone)	Site of lesion	Remarks
Uea-areewongsa et al. [35]	Retrospective Case control	41/186 only 20 patient included in data analysis	NA	NA	NA		Use of steroids (recorded as evidenced by maximum and mean daily prednisolone dose) was significantly higher in the ON group than in controls
Nakamura et al. [26]	Prospective	169 pts ON in 260 of 676 pts (38%) Pediatric: 4/72 joints (6%) Adolescent: 49/100 joints (49%) Adult: 207/504 joints (41%)	The mean highest daily corticosteroid dosages were 51.4, 60.4, 57.4 mg/day in pediatric, adolescent, adults, respectively. The mean highest daily corticosteroid dosage according to body weight was 1.5 mg/kg/day (range 0.7–3.0) in pediatric patients, 1.2 mg/kg/day (range 0.6–2.0) in adolescent patients, and 1.1 mg/kg/day (range 0.4–1.9) in adult patients. (P = 0.0001).	NA	NA	Hips and knees	Rate of ON and mean highest daily steroid dose significantly lower in pediatrics vs. adolescent and adult (p < 0.0001) However: Highest daily dose of steroid not SS different in + AVN vs. − AVN in mean daily dose (P = 0.072) and according to body weight. (P = 0.820) Limitations: MPSL pulse therapy not studied or reported
Jaovisidha [37]	Prospective	2/11	NA	NA	4920 mg	NA	The 2 AVN patients had longest duration of steroid treatment before MR study (105 and 99 days) and higher cumulative dose of prednisolone compared to non-AVN patients.
Gladman et al. [36]	Retrospective Case control	95/744	Maximum daily dose in + AVN/−AVN: 44.4/28.1 mg	NA	IN + AVN/−AVN: 23.1/15 g	Hip most common	AVN significantly associated with the use of CS (OR = 19), maximal dose of steroids (OR = 1.02), cumulative dose (OR = 1.04) and duration of therapy (OR = 1.15); however, in the multivariate analyses, only the use of corticosteroids remained significantly associated with osteonecrosis (OR = 18.5). cushingoid appearance OR 3.8
Oinuma et al. [27]	Prospective	32/72 (44%)	40 mg/day or more equivalent prednisolone The initial mean (SD) CS dose 58.2 (10.1)/58.6 (16.6) mg/day in the + AVN/−AVN 17 pts in ON group 18 in non-ON group treated with MPPT	AVN onset after 39.6 and 100.2 days of treatment.	NA	Multi-joint	Early development of ON in SLE was related to an event just after high dose CS treatment, and was not related to the total treatment period, the highest daily dose, a continuous high dose, or the cumulative dose of corticosteroid. SLE ON lesions developed very early (1–2 months) after starting high dose CS treatment.
Zonana-Nacach et al. [32]	Retrospective	47/539 (8.7%)	Prednisone high dose (> 60 mg/day for > 2 months) in 21% of total cohort Pulse MPSL (1–3 g IV) in 30% of total cohort	NA	Converted to relative risk.	NA	The risk significantly increased with exposure to a high dose of prednisone. Each 2 mo of exposure to > 60 mg of prednisone was associated with 1.2-fold increased risk for development of AVN Risk was not associated with cumulative dose or pulse therapy
Mok et al. [24]	Retrospective	38/143 (26%)	NA	NA	AVN+ vs. AVN− in 1 and 4 month cumulative dose:1.8 vs. 1.1 and 4.5 vs. 2.8 g, respectively; P < 0.01 in both	NA	Highest cumulative prednisolone dose in 1 and 4 mo was significantly higher in SLE patients with ON vs. without ON (1.8 vs. 1.1 and 4.5 vs. 2.8 g, respectively). + Correlation with cushingoid habitus and ON
Mont et al. [34]	Cohort	31/72 (43%)	Mean maximal prednisone dose was 60 vs. 37 mg for SLE patients + AVN vs. − AVN	NA	NA	NA	SLE pts with osteonecrosis had significant increases in cushingoid body habitus and higher maximal prednisone doses compared with SLE patients without osteonecrosis.
Rascu et al. [38]	Retrospective	6/280 (2.1%)	Mean daily dose 21.3 mg Max daily dose 72 mg	NA	Mean cumulative dose 38,614 mg IV MPSL in 2/6	Hip most common	+ Correlation between steroid dose and development of AVN, BUT other factors likely play role as well. Drawbacks: only analyzed symptomatic ON
Migliaresi et al. [33]	Prospective	7/69 (10%)	NA	3–12 month	Total corticosteroid dose including MPSL therapy in + AVN vs. − AVN was 20.6 +/− 14.9 g vs. 29.1 +/− 29 g Total corticosteroid therapy in those not treated with MPSL pulse therapy in AVN+ vs. − AVN was 20.6 +/− 14.9 vs. 15.8 +/− 17.7	NA	+ Relationship between AVN and conventional CS treatment. No increased risk of AVN in MPPT-treated patients, even though they cumulated the highest CS doses. Shortcomings: study might have underestimated the true occurrence of AVN because it was performed by radiographs and/or bone scan and in the follow up it included only symptomatic AVN.
Massardo et al. [25]	Retrospective	Total 17/176 Group A (MPSL): 7/36 patients (19%) Group B (no MPSL): 10/154 (6%) patients P < 0.04	Group A: pulse methylprednisolone Group B: no pulse methylprednisolone Steroid dose > 40 mg/day in 1st month: 57%/37% in AVN+/AVN−	NA	NA	Femoral head most common	Patients who developed AVN received a higher dose of steroid in a shorter period of time. + Correlation with + AVN and cushingoid appearance, use of MPSL (P < 0.045), steroid doses > or = 40 mg/day during the first month of treatment, a ratio of steroid dose in grams/year > or = 12 SS only with MSPL and cushingoid appearance
Ono et al. [31]	5 year prospective study	9/62 total patients (14%)	Prednisone/MPSL at dose of > 30 mg/day	> 1 month	NA	NA	Both IV pulse CS and oral prednisolone therapy at a dose > 30 mg/day for at least 1 month were risk factors for ON. However, it is unclear whether short term high dose MPSL pulse therapy is a risk factor.
Weiner et al. [39]	Retrospective	28/172 (16.3%)	Prednisone/MPSL	NA		NA	CS intake during the first 1.5 years after diagnosis of SLE and during the third year after diagnosis was significantly greater for the patients AVN+ vs. AVN−.
Felson et al. [21]	Metanalysis of 22 studies (SLE, renal transplant, BMT, Hodgkin's)	AVN range 0–31%	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 have different risks!)
Zizic et al. [22]	Prospective	28/54 total patients (52%) 3/6 patients on MPSL developed AVN	The mean daily dose of prednisone for the highest month of therapy was > 40 mg/day in 93% and > 20 mg/day in all patients with ischemic necrosis of bone.	NA	NA	Multifocal	Cushingoid changes in 24 (86%) of the 28 patients with AVN vs. 4 (15%) of the 26 patients without AVN (p < 0.0001). The duration of steroid therapy, total cumulative steroid dose, and the mean daily prednisone dose for the first 1–12 months of therapy were not significantly different between the two groups. Mean daily prednisone dose for the highest single month as well as the highest consecutive three, six, and 12 months of therapy was significantly higher in patients with ischemic necrosis of bone. A lower mean dose of prednisone was required to produce ischemic necrosis of bone in patients with Reynaud's phenomenon.
Abeles [40]	Retrospective	17/365 (4.7%)	NA	1, 3, and 6 months Average duration of therapy 4.3 years	Mean total dose in first 1, 3, and 6 mo in + AVN vs. − AVN: 1.4 vs. 0.6 g; 3.5 vs. 1.9 g; 6.4 vs. 3 g	NA	Severity of disease and duration of therapy were not found to correlate with AN. High initial corticosteroid dosages in patients with SLE seem to be associated with the development of AN.
Dimant et al. [29]	Retrospective Case control	22/234 (9%)	NA	NA	NA	NA	No correlation was found with duration, peak dose, or cumulative dose of corticosteroid therapy.
Smith et al. [30]	Retrospective case control	7/99 (7%)	Patients with AVN: 11.88 mg prednisone Patients without AVN: 14.18 mg prednisone	Patients with AVN: 19.86 months of treatment 22.86 months of treatment	Patients with AVN: 13.83 g prednisone Patients without AVN 18.18 g prednisone	NA	No correlation between steroid dose and AVN.
Bergstein et al. [19]	Prospective	14/35	Prednisone 2 mg/kg per day in divided doses. Following remission of activity prednisone was “tapered.”	NA	NA	Most common site distal femur	No difference was found in the age of onset of SLE, the duration of prednisone or the average annual dose of prednisone between patients with and without bone disease. + Correlation with total cumulative dose up until dx of ON
Dubois et al. [28]	Retrospective	11/400	NA	NA	NA	NA	No association of AVN with steroid therapy