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Rheumatology Advance Access published online on July 17, 2007
Rheumatology, doi:10.1093/rheumatology/kem172
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© The Author 2007. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Short-term outcome of painful bone marrow oedema of the knee following oral treatment with iloprost or tramadol: results of an exploratory phase II study of 41 patients

M. E. Mayerhoefer1, J. Kramer2, M. J. Breitenseher1,3, C. Norden4, A. Vakil-Adli5, S. Hofmann6, R. Meizer7, H. Siedentop4, F. Landsiedl7 and N. Aigner7

1Department of Radiology, Medical University of Vienna, Vienna, 2Institute of CT and MRI Diagnostics Schillerpark, Linz, 3Institute of Radiology, Waldviertelklinikum Horn, Horn, Austria, 4Bayer Schering Pharma AG, Specialized Therapeutics, Berlin, Germany, 5Department of Orthopaedics, Hospital of the Sisters of Charity Linz, Linz, Austria, 6Department of Orthopaedics, LKH Stolzalpe, Stolzalpe and 7First Orthopaedic Department, Orthopaedic Hospital Speising, Vienna, Austria

Correspondence to: Marius E. Mayerhoefer, Department of Radiology, Vienna General Hospital (AKH), Waehringer Guertel 18-20, 1090 Vienna, Austria. E-mail: marius.mayerhoefer{at}meduniwien.ac.at


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 
Objectives. To compare the therapeutic effects of oral iloprost and tramadol on the outcome of bone marrow oedema (BME) of the knee by MR imaging and clinical assessment.

Methods. Forty-one patients with painful ischemic or mechanical BME of the knee were enrolled in a double-blind, randomized controlled study. Patients were randomized either to iloprost (n = 21, group 1) or tramadol (n = 20, group 2). The treatment duration was 4 weeks. The Larson knee score was used to assess function before treatment and then 3 days, 1, 2, 3, 4 weeks and 3 months after the start of treatment. Short tau inversion recovery and T1-weighted MR images of the affected knees were obtained before and 3 months after the start of treatment. Bone marrow oedema was assessed visually and by computer-assisted quantification for baseline and follow-up MR examinations.

Results. Thirty-three patients completed the study as scheduled. The mean Larson score improved from 58.6 points to 81.8 points in group 1, and from 59.6 points to 86.8 points in group 2, after 3 months (no significant difference between the treatment groups). On MR images, complete BME regression in at least one bone was observed in nine patients (52.9%) in group 1, as opposed to three patients (18.7%) in group 2, after 3 months (P = 0.034). Correspondingly, the median BME volume decreased by 58.0% in group 1, and by 47.5% in group 2.

Conclusions. The analgesic effect of iloprost and tramadol was similar. BME regression on MR images was more pronounced under iloprost treatment.

KEY WORDS: Knee, Bone marrow cells, MRI, Drug therapy


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Acknowledgements
 References
 
The typical MR imaging pattern of what is commonly referred to as ‘bone marrow oedema’ (BME) is often observed in patients with severe joint pain. Based on its aetiology, BME may be classified as ischaemic [‘bone marrow oedema syndrome (BMES),’ osteonecrosis], mechanical (bone bruise, stress and microfractures), or reactive (osteoarthritis, tumor and infection) [1]. Histological analyses have revealed that, at the cellular level, BMES (idiopathic BME, ‘transient osteoporosis’), osteonecrotic and osteoarthritic BME share several of the most striking features, such as fat cell destruction and fibrovascular regeneration, while the actual amount of fluid accumulation in the bone marrow cavities varies [2–4].

Although BME is generally considered to be a self-limiting entity [5–8], progression to irreversible osteonecrosis has occasionally been observed in the femoral head [5, , 9–12]. In patients with knee osteoarthritis, BME has also been identified as a potent risk factor for structural deterioration [13]. For these reasons, and because of the disabling character of BME, different therapeutic attempts have been made to provide relief of pain and/or accelerate the natural time course of healing [2, 14–16].

The conservative standard treatment of ischaemic and mechanical BME consists of analgesic or anti-inflammatory medications in combination with reduced weight-bearing and physical therapy until symptoms disappear [6, 17, 18], which usually takes 3–18 months [6, 7, 19]. For the management of BMES of the femoral head, surgical intervention has also been proposed by several authors, with core decompression the current standard technique [2, 16, 17, 20–22]. In recent studies, intravenous administration of the vasoactive prostacyclin analogue iloprost has been presented as an effective, non-invasive treatment alternative for BME of different aetiologies [21, 23, 24].

The primary aim of our study was to investigate, in patients with isolated ischaemic or mechanical BME of the knee, the effect of oral iloprost on pain and joint function, compared with the opioid analgesic tramadol. Our secondary aim was to determine the effects of the two drugs on MRI findings in these patients. The greater benefit of oral administration of iloprost, which has a pharmacodynamic profile similar to that of intravenous iloprost, but does not require hospitalization of patients suffering from BME, justified the exploration of this subject.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Acknowledgements
 References
 
Patients and study design
Recruiting of patients with painful BME of the knee consisted of two steps: first, patients presented to the orthopaedic surgeon with typical knee pain (see inclusion criteria subsequently) during regular out-patient hours (there was no special advertising for the study); second, these patients were referred to an MR imaging centre, and if a typical BME pattern (see inclusion criteria subsequently) was observed on the MR images by the radiologist, they were asked to participate in the study.

Forty-one patients enrolled in a two-arm prospective double-blind randomized controlled phase II study, which was exploratory in nature. The study was approved by the Institutional Review Boards of the two referring hospitals, and written informed consent was obtained from each patient examined according to the Declaration of Helsinki. The primary study objective for proof of the clinical concept was to compare the effects of oral iloprost and tramadol on pain and joint function in patients with painful BME, including MRI findings as a secondary variable. The sample size was not determined to detect differences between oral iloprost and tramadol in terms of a pre-defined primary efficacy end-point related to pain and joint function. A study population of 41 patients, divided into two treatment groups, was considered sufficient to obtain first information on the potential benefits and the safety of treatment with oral iloprost in patients with painful BME, compared with analgesic treatment with tramadol.

Criteria for inclusion in the study were: severe knee joint pain on exertion and at rest, aggravated by percussion over the affected bones of the knee joint (as verified by two board-approved orthopaedic surgeons); the presence of a typical BME pattern on MR images [ill defined areas that are hyperintense on short tau inversion recovery (STIR) images and hypointense on T1-weighted images] in at least one part of the bony structures of the knee (as verified by two board-approved musculoskeletal radiologists); and age between 19 and 70 yrs.

Criteria for exclusion from the study were: demarcated areas indicative of manifest osteonecrosis on X-ray radiographs or MR images, signs of osseous infection/inflammation, or cartilage damage visible on MR images (as verified by two board-approved musculo-skeletal radiologists); a history of trauma or chronic inflammatory or degenerative diseases of the knee joint; pregnancy/positive pregnancy test; fertile women without adequate contraception; heart failure NYHA class III–IV; unstable angina pectoris, myocardial infarction; coronary reconstructive measures within 3 months of baseline; severe cardiac arrhythmia; hypertension (systolic, ≥180 bpm; diastolic, ≥110 bpm); symptomatic hypotension; cerebrovascular events within 3 months of baseline; bleeding disorder; total bilirubine and/or GPT above twice the upper normal limit; creatinine ≥180 µmol/l or dialysis therapy; surgical intervention within 4 weeks of baseline; treatment with prostacyclin analogss or neuroleptics within 3 months of baseline; alcohol or drug abuse; inability to understand patient information or give informed consent.

After the initial X-ray (antero-posterior and lateral) and MR examinations (imaging protocols: see subsequently) of the knee, patients were randomized to either group 1 (n = 21) or group 2 (n = 20), and received study medication over a period of 4 weeks, administered orally with food. The possibility of a drug administration longer than 4 weeks was excluded by the study design.

In group 1, the treatment consisted of 50 µg of iloprost clathrate (Schering AG, Berlin, Germany) three times daily on days 1–3; after day 3, individual dose adjustment was allowed (range: 50 µg twice daily up to 2 x 50 µg three times daily). The oral extended-release formulation of iloprost was developed to mimic the plasma concentration time curve of intravenous iloprost during a 6 h infusion at a dose rate of 1.5 ng/kg/min. The absolute bioavailability of oral iloprost ranges from 16 to 19% [25]. In group 2, where patients received tramadol (Heumann Pharma GmbH, Nuernberg, Germany), the same dosage scheme was used, with 50 mg of tramadol matching 50 µg of iloprost clathrate. Both iloprost and tramadol were provided as gelatin-coated capsules of identical appearance. To preserve the double-blind character of the study, both the iloprost and the tramadol capsules received an additional outer size 3 capsule of hard gelatin. The treatment was followed by an 8-week period without treatment. No additional therapeutic measures for joint immobilization or reduction of weight bearing were taken.

The safety of treatment was assessed by recording of adverse events both elicited and volunteered. Vital signs were measured at each visit. Physical examinations, blood sampling for haematology and clinical chemistry as well as urine tests were performed prior to, at the end of treatment and at the end of the follow-up.

Clinical and statistical assessment
Pain at rest and effort-induced pain were assessed by the patients at each visit during the double-blind study and follow-up using a visual analogue scale (VAS). Changes over time relative to baseline were compared between the two groups using the Mann–Whitney U-test. As a measure of disease activity, the Larson score [26] was assessed at each visit during the study and follow-up. The four categories, function (50 points), range of movement (10 points), pain (30 points) and anatomy (10 points), and the sum of these categories (100 points) were evaluated descriptively at each time, and the changes of the Larson score relative to baseline were compared between the two groups using the Mann–Whitney U-test.

Assessment and statistical evaluation of BME on MR images
Coronal turbo SE (spin echo) STIR and T1-weighted MR images of the affected knees were acquired at two centres. Patients were examined at either of the two MR imaging centres. At Centre A, a 1.0 Tesla MR scanner (Philips/Marconi, Best, The Netherlands) equipped with a dedicated knee coil was used. For the STIR sequence, parameters were: repetition time (TR), 2500 ms; echo time (TE), 10 ms and inversion time (TI), 100 ms. For the T1-weighted sequence, parameters were: TR, 498–750 ms; and TE, 10 ms. At Centre B, a 1.5 Tesla MR scanner (Siemens, Erlangen, Germany) equipped with a dedicated knee coil was used. For the STIR sequence, parameters were: TR, 4100–4700 ms; TE, 26–28 ms and TI, 130 ms. For the T1-weighted sequence, parameters were: TR, 410–520 ms; and TE, 11 ms. At both centres, a 256 x 256 matrix and a slice thickness of 4 mm were used for both sequences. Both MR examinations (baseline and follow-up) of a particular patient were always performed with the same MR scanner (either Centre A or Centre B).

Three months (range, 82–102 days) after the baseline examinations, follow-up MR images were obtained, using the same acquisition protocols as described earlier. Both a visual and a recently described computer-assisted, quantitative method [27] were used to determine the presence and extent of BME in patients’ knees at both points in time. This strategy was used because our experience shows that the computer-assisted method is prone to detecting extremely small and clinically irrelevant clusters of pixels with abnormal signal, and thus, results of BME quantification are always slightly above zero, even in healthy bones. For this reason, the computer-assisted method was used primarily for confirmation of the visually assessed results.

Visual assessment of BME
This was performed in consensus by a team consisting of two radiologists and two orthopaedic surgeons. Femoral and tibial epiphyses were classified independently as either ‘affected by BME’ or ‘healthy’, using the STIR images. Because of the ill-defined borders and, in some cases, multi-focal appearance of the BME, no further grading of BME size and signal was attempted with this method. During review of the follow-up MR images, the team members were blinded to the results assessed at baseline as well as to the treatment administered.

To determine the treatment effects of iloprost and tramadol with regard to BME affection, the numbers of patients with ‘complete regression of BME in at least one bone’, ‘no change of BME affection’ and ‘new bone affected by BME’ were calculated for each treatment group. Fisher's exact test was used for evaluating the results of visual assessment.

In addition to BME, the presence of subchondral bands of very low signal intensity, which represent focal subchondral stress fractures, was assessed on the T1-weighted baseline and follow-up MR images, and their rates of complete healing in both treatment groups were calculated.

Computer-assisted quantitative assessment of BME
For MR examinations of patients whose images were available in DICOM format (n = 37), computer-assisted quantification of BME volume and signal contrast, based on calculation of a gray-scale threshold value separating healthy from oedematous bone marrow, was performed using the STIR images, as described in a recent study [27]. BME volume was defined as the percentage of oedema of each epiphysis (femoral or tibial), while signal intensity was defined as difference between mean gray-scale value of the epiphysis’ BME and the previously calculated threshold value.

For verification of the results of the visual assessment, the median BME volume, as assessed by computer-assisted quantification, of all bones visually described as ‘healthy’ was calculated and compared with the median BME volume of all bones described as ‘affected by BME’. To provide more detailed information regarding the change in BME in primarily affected bones (visually described as ‘affected by BME’ at the baseline examination) between baseline and follow-up examinations, the median rates of regression of BME volume and signal intensity were calculated for each treatment group. The Wilcoxon signed ranks test and the Mann–Whitney U-test were used for statistical evaluation.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Acknowledgements
 References
 
Patient characteristics
Of the 41 patients included in the study, 21 (15 men and 6 women; age range: 23–66 yrs) were randomized to group 1, and 20 patients to group 2 (12 men and 8 women; age range: 29–68 yrs). MR examinations of 25 patients were performed at Centre A (group 1, n = 13; group 2, n = 12), and MR examinations of the remaining 16 patients were performed at Centre B (group 1, n = 8; group 2, n = 8). The incidence and distribution of BME in the two treatment groups is given in Table 1.


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  		TABLE 1. Incidence and distribution of BME in the two treatment groups

 
Five patients in either treatment group presented with an unremarkable medical history. Arterial hypertension was the most frequent comorbidity in both groups (group 1, 38%; group 2, 20%). Lipid disorders (group 1, 33%; group 2, 25%) and hyperuricaemia (group 1, 24%; group 2, 5%) were also common in the study population.

Eight patients in either treatment group were smokers, but the number of daily cigarettes was higher in group 1 (25.0 ± 9.6) than in the group 2 (16.9 ± 11.8). More patients in group 1 consumed alcohol occasionally (group 1, 47.6%; group 2, 30%) or regularly (group 1, 19%; group 2, 15%) than in the group 2.

No treatment with bone active drugs was reported in the patient population, including corticosteroids. Four patients in either treatment group received non-steroidal antiphlogistic medication before the start of the study. According to the study protocol, this medication was discontinued prior to the start of treatment.

Clinical assessment
Seven patients received intravenous iloprost infusions as rescue therapy (group 1, n = 4; group 2, n = 3) due to persistent pain, and their clinical data were only included in the analysis up to the switch to intravenous iloprost. Further, one patient from group 2 withdrew consent and no follow-up MR was available.

In group 1, the severity of pain at rest (VAS) decreased from a mean of 41.2 mm (S.D. ± 21.9 mm) at baseline to 6.5 mm (S.D. ± 13.5 mm) after 1 month, and increased to 14.3 mm (S.D. ± 28.1 mm) after 3 months. The severity of pain on exertion fell from a mean of 62.5 mm (S.D. ± 20.4 mm) to 18.2 mm (S.D. ± 20.6 mm) after 1 month, and slightly increased to 23.5 mm (S.D. ± 31.2 mm) after 3 months. The Larson score improved from a mean of 58.6 points (S.D. ± 13.2 points) to 86.2 points (S.D. ± 10.0 points) after 1 month, and then slightly decreased to 81.8 points (S.D. ± 19.6) after 3 months.

In group 2, the severity of pain at rest decreased from a mean of 33.9 mm (S.D. ± 20.2 mm) to 5.5 mm (S.D. ± 7.0 mm) after 1 month, and to 5.1 mm (S.D. ± 9.9 mm) after 3 months. The severity of pain on exertion fell from a mean of 60.1 mm (S.D. ± 20.6 mm) to 18.8 mm (S.D. ± 26.8 mm) after 1 month, and to 14.1 mm (S.D. ± 24.8 mm) after 3 months. The Larson score improved from a mean of 59.6 points (S.D. ± 10.4 points) to 84.2 points (S.D. ± 10.4 points) after 1 month, and then to 86.8 points (S.D. ± 12.2 points) after 3 months.

The differences between the groups were not statistically significant with regard to the changes in pain at rest, pain on exertion and the Larson score.

Assessment of BME on MR images
Of the 33 patients (group 1, n = 17; group 2, n = 16) who completed the study as scheduled and whose MR images were used to determine the rates of BME regression, 20 (group 1, n = 10; group 2, n = 10) were examined at Centre A and 13 (group 1, n = 7; group 2, n = 6) were examined at Centre B. Twenty-six bones of the 17 patients in group 1 (femur only, n = 8; tibia only, n = 0; femur and tibia, n = 9) and 18 bones of the 16 patients in group 2 (femur only, n = 8; tibia only, n = 6; femur and tibia, n = 2) were classified as ‘affected by BME’ by visual assessment at the baseline examination. Radiographs did not show any abnormalities in the regions corresponding to those that showed BME on baseline and follow-up MR images. In group 1, 52.9% (n = 9) of the patients showed complete regression of BME in a least one bone, opposed to only 18.7% (n = 3) in group 2. No change of BME affection was observed in 29.7% (n = 5) in group 1 and 75.0% in group 2 (n = 12). New areas of BME (in primarily unaffected bones) were detected in four patients, with three of them belonging to group 1. These differences between the two groups in regard to healing of BME were statistically significant (P = 0.034).

The number of subchondral stress fractures in group 1 decreased from 11 at baseline to eight after 3 months (healing rate, 27.3%). In group 2, none of the five subchondral stress fractures observed at baseline showed signs of healing after 3 months. None of the patients in our study population showed signs of osteonecrosis on MR images or radiographs.

The visually assessed findings were supported by the computer-assisted method of BME quantification. While for bones described as ‘healthy’, a median BME volume of only 1.1% [interquartile range (IQR) 0.7–1.9%] was calculated, a median volume of 15.7% (IQR 4.7–31.6%) was found for bones described as ‘affected by BME’. This difference between the two categories of visual assessment was statistically significant (P < 0.001). The trend towards better healing of BME after iloprost treatment was also confirmed by the quantitative data with regard to the median rate of BME volume regression, which was 58.0% (IQR 19.3–86.9%) in group 1 and 47.5% (IQR 1.1–84.2%) in group 2. Reduction of BME signal intensity in primarily affected bones was also slightly more pronounced in group 1 (median 50.4%; IQR 23.9–63.3%; P < 0.001) than in group 2 (median 42.5%; IQR 17.0–60.6%; P < 0.01) after 3 months.

There was no statistically significant difference in the regression of BME between knees with and knees without subchondral stress fractures.

Safety
No serious adverse events were reported in the patient population. Oral iloprost was well tolerated and no safety concerns arose.


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Acknowledgements
 References
 
It was the goal of this study to compare the effect of oral treatment with the vasoactive iloprost to the effect of symptomatic treatment with tramadol, with regard to the outcome of painful isolated BME of the knee. While we were able to exclude all causes for reactive BME, and also a history of trauma suggesting mechanical BME, we were not able to reliably exclude minor to moderate axis deviations compatible with mechanical BME, because only standard antero-posterior and lateral radiographs of the knee joint, but no long radiographs of the entire lower limb, were available. Therefore, the BME observed in our patient population was regarded as either ischaemic or mechanical.

In recent studies, iloprost, which is currently registered for the intravenous therapy of peripheral arterial occlusive disease, thrombangiitis obliterans and Raynaud's phenomenon, has been presented as an effective novel approach for the management of BME [21, 23, 24, 28]. Iloprost inhibits platelet and leucocyte activation, induces vasodilatation, counteracts vasospasm, protects the endothelium and reduces vessel wall permeability [29]. Because it is believed that the main factors responsible for the development of BME are thrombo-, fat- and air-embolization, obstruction of venous and pre-capillary drainage or elevated venous pressure and decreased arterial perfusion, vessel wall injuries and decreased fibrinolysis [2, , 30–32], iloprost may represent a truly causative treatment option.

Meizer et al. [24] reported good results in BME of different joints with the administration of intravenous iloprost, with regard to pain reduction and normalisation of MR pattern. Aigner et al. [12] investigated the outcome of BMES of the femoral head after treatment with either intravenous iloprost or core decompression, and found an equal effect for both treatment strategies, with even slightly better results for iloprost, after a period of 3 months. Disch et al. [23] also used iloprost infusions for treatment of patients with isolated BME and patients with necrosis-associated BME of the proximal femur, and found a significant improvement in both groups after 3 months, surpassing results achieved with standard conservative treatment. In these studies, intravenous administration of iloprost was carried out slowly and cautiously (6 h/day, on five consecutive days). While reduction of weight-bearing, which is mandatory for up to 6 weeks following core decompression [12, 17, 24], is not necessary after intravenous iloprost infusions [23], hospitalization of patients for the duration of the treatment period is thus practically unavoidable [29].

To overcome this limitation, the present study evaluated the efficacy of oral iloprost on the outcome of isolated painful BME of the knee. Due to the considerable pain and disability associated with BME, it was regarded inappropriate to introduce an untreated control group. For this reason, patients who did not receive oral iloprost were treated with the centrally active opioid analgesic tramadol, for which no vasoactive effects are known, and which thus represents an entirely symptomatic method of treatment. A treatment duration of 4 weeks was considered appropriate since a rapid onset of pain relief could be expected based on previous experience with oral iloprost in rheumatoid arthritis [33, 34]. Our present study results confirm this assumption, because almost complete pain reduction was achieved by a 4-week iloprost administration. Despite the fact that more patients in the iloprost group showed BME of both femur and tibia, there was no significant difference between the iloprost and the tramadol group after 4 weeks of treatment, with regard to improvement of symptoms and normalization of knee function (see Fig. 1). These results indicate that oral iloprost possesses an analgesic effect similar to that of morphine, although its mircrocirculatory mode of action differs from the centrally active opioid. When aiming at structural repair, however, iloprost treatment for more than 4 weeks may be indicated, but additional studies are needed to determine the value of this substance in this regard.


Figure 1
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  		FIG. 1. Clinical outcome of patients with BME of the knee after 3 months: no significant differences were observed, with regard to pain at rest, pain on exertion and the Larson score, between the two treatment groups (iloprost/tramadol).

 
The results of both visual and computer-assisted quantitative assessment of BME on MR images demonstrated higher rates of BME regression after iloprost treatment than after tramadol treatment (Figs 2 and 3). On the other hand, three patients in the iloprost group showed new areas of BME in a primarily unaffected bone at follow-up, and only one showed this in the tramdol group. However, healing of subchondral stress fractures, which is of clinical significance because these lesions can directly precede the development of osteonecrosis [35, 36], was observed exclusively in the iloprost group (Fig. 4). It is interesting to note that the presence of subchondral stress fractures appears not to have an effect on the rates BME regression.


Figure 2
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  		FIG. 2. Coronal STIR MR images of a 65-yr-old male patient from group 1 (Iloprost) with BME of the distal femur. The BME pattern observed at baseline (A) has completely vanished after 3 months (B).

 

Figure 3
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  		FIG. 3. Coronal STIR MR images of a 54-year-old male patient from group 2 (tramadol) with BME of the distal femur. While the BME pattern observed at baseline (A) is still visible after 3 months (B), a reduction of its volume (–41.7%) and signal intensity (–63.5%) was found by the computer-assisted method of quantification.

 

Figure 4
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  		FIG. 4. Coronal T1-weighted spin echo MR images of a 42-year-old male patient from group 1 (iloprost) with a focal subchondral stress fracture of the medial femoral condyle (black arrow), observed at the baseline examination (A). After 3 months, the subchondral stress fracture is not visible anymore (B).

 
The main limitation to the results of this study, despite randomization of patients to the two groups, is the fact that the number of bones primarily affected by BME was higher in the iloprost group (n = 26) than in the tramadol group (n = 18). However, the use of the category ‘complete regression of BME in at least one bone’ may have lessened the possible impact of this uneven distribution, because it favoured neither group. Another limitation refers to the fact that eight patients were lost to follow-up, which reduced the number of patients, and consequently, the significance of our results. Finally, we were unable to accurately identify the subchondral weight bearing portions of the fermoral and tibial condyles, because no long radiographs of the entire lower limb were available to determine the mechanical axes of the bones. As a consequence, we could not investigate whether the spatial relation of the BME to these weight bearing portions of subchondral bone has a significant influence on the rates of BME regression.

In conclusion, the results of the current study indicate that, with regard to relief of pain and normalization of joint function, results achieved by treatment with oral iloprost are comparable with those achieved by treatment with the opioid analgesic tramadol. Better healing rates of BME and subchondral stress fractures were achieved with iloprost than with tramadol treatment, but the rate of new BME formation in previously healthy areas of bone marrow was also higher. Nevertheless, the findings of this study are encouraging and warrant further exploration of iloprost in larger studies.

Formula


   Acknowledgements
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
References
 
This study was funded by Bayer Schering Pharma AG (formerly Schering AG), Berlin, Germany.

RM, SH, AV-A, MM, MB and NA have received honoraria for participation in the randomized clinical trial from Bayer Schering Pharma AG, Berlin, Germany. CN is a consultant to Bayer Schering Pharma AG, Berlin, Germany. HS is a senior statistician employed by Bayer Schering Pharma AG, Berlin, Germany.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 

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Submitted 17 January 2007; revised version accepted 30 May 2007.
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