Idiopathic and secondary bone marrow lesions of the knee treated by oral bisphosphonates: an observational pilot study.
M. Rotini1, G. Papalia1, N. Setaro1, D. Pigliapoco1, C. Urbinati2 and A. Gigante1
1Department of Clinical and Molecular Sciences, School of Medicine, Università Politecnica delle Marche, Ancona, Italy
2 S.O.D. Radiologia Specialistica e Pediatrica, A.O.U. Ospedali Riuniti Ancona, Ancona, Italy
Bone Marrow Lesions (BMLs) have a low prevalence but distinctive alteration in MRI which can develop primarily or as epiphenomenon of an underlying disease. Their presence has been associated with pain and functional impairment. Although these lesions appear to resolve over time, it has been suggested that conservative treatment might improve symptom severity and duration. The aim of this study was to clinically and radiologically evaluate a group of patients affected by BMLs treated by oral alendronate and to assess eventual differences between patients affected by primary BMLs and secondary forms. We evaluated 19 patients with BMLs of the knee. At the time of diagnosis, MRI was assessed by a radiologist to define the Whole-Organ Magnetic Resonance Imaging Score (WORMS). Patients were divided into two groups according to Roemer’s classification: idiopathic BMLs and secondary BMLs. Data on smoking habit, diabetes, osteoporosis and chronic corticosteroid intake were collected. Therapy included administration of oral bisphosphonates (alendronate 70mg 1/week for one month), in addition to NSAIDs as needed. VAS and WOMAC scores were collected both at T0 and at 9-months of follow-up. Nine patients (47.5%) were considered idiopathic BMLs, 4 (21%) secondary to knee osteoarthritis, 2 (10.5%) as consequence of trauma, 2 (10.5%) inflammatory and 2 (10.5%) developed in a contest of spontaneous osteonecrosis of the knee (SONK). Six patients were affected by primary osteoporosis, 7 underwent chronic corticosteroid intake, 3 were affected by diabetes and 2 were cigarette smokers. VAS and WOMAC showed a statistically significant reduction from T0 to follow-up values. ΔVAS and ΔWOMAC in idiopathic BMLs were statistically superior to ΔVAS and ΔWOMAC of the secondary BMLs, with p <0.05 for both. Apparently, average WORMS >10 has a direct influence on baseline VAS and WOMAC, although a statistically significant correlation was not possible. The present study suggests that oral administration of alendronate could be useful in significantly relieving pain for patients with BMLs of the knee and reduce duration of the symptoms, especially in patients with primary BMLs. Cortisone therapy might be a risk factors for the disease, although no statistically significant correlation has been possible.
Key words: knee, MRI, bone edema, bone marrow lesions, bisphosphonates, alendronate
The term “Bone Marrow Edema” was first used by Wilson et al. in 1988 as they needed to define alterations of MRI signal (T2-weighted hyperintensities) in patients with joint pain and normal results at conventional RX. This definition of the lesions was based on their radiological appearance, suggestive of the increase of fluid inside the bone marrow (1). In the following years many authors tried to correlate the MRI imaging with histological findings (2–4) and the actual edema content was questioned. Today, these lesions are more correctly defined in the context of Bone Marrow Lesions (BMLs), a radiological finding that is commonly associated with a wide range of pathological conditions, such as osteoarthritis (OA), trauma, infections, neoplasia, enthesitis, necrosis, and other causes, but which can also be an isolated finding. In secondary forms, clinical presentation is usually determined by the underlying cause. When occurring as a primary event, unrelated to other recognizable causes, it is accompanied by debilitating local pain exacerbated by load or pressure and therefore defined as a separate clinical-radiological entity known as “Bone Marrow Edema Syndrome” (BMES) or “idiopathic BML” (5). Due to the incomplete knowledge on etiology and pathogenesis of the disease, there is still no universally accepted classification; to date, the one that provides a more complete distinction and logical subdivision was described by Roemer et al. in 2009 (6). A recognized therapy is not available but, given the self-limiting evolution of the disease, NSAIDs and functional rest are reported in literature as first line treatment (7). In the attempt to reduce the duration of symptoms, some authors investigated the ability of I.V. bisphosphonates (8–10), prostaglandin inhibitors (11, 12), pulsed electromagnetic field therapy (PEMFT) (13) and subchondroplasty (14, 15) to modify the natural progression of the disease.
It is clear that, despite receiving growing interest in recent literature, BMLs do not meet a unified consensus regarding classification, etiology, pathogenesis, treatment and outcome. The primary endpoint of this study was to evaluate a group of patients affected by edematous lesions of the subchondral knee bone, assessing their clinical and radiological outcome after conservative treatment with oral alendronate. The secondary endpoint was to highlight differences in clinical outcome and imaging between patients affected by primary BMLs and secondary forms.
MATERIALS AND METHODS
Patients with subchondral bone marrow lesions of the knee joint were evaluated after conservative treatment at our centre between 2016 and 2018. Inclusion criteria were acute onset of spontaneous knee pain of at least 4 points on the Visual Analog Scale with MRI findings characteristic of BMLs. Exclusion criteria were disorders of the upper gastrointestinal tract in active phase, renal dysfunction, serious cardiovascular diseases, alcohol consumption, pregnant and/or lactating women, hypersensitivity to alendronate, to other bisphosphonates or to any of the excipients. Every patient underwent MRI with T1 weighted, T2 weighted and STIR sequences, that were subsequently classified according to Whole-Organ Magnetic Resonance Imaging Score (WORMS) (16) by a radiologist expert in osteoarticular pathology. Each lesion was identified according to Roemer’s classification and patients were divided into two groups: idiopathic BMLs (after the exclusion of other causes) and secondary BMLs. Patients were asked to complete an anamnestic form to evaluate smoking habit, diabetes, primary or secondary osteoporosis and chronic corticosteroid intake as possible risk factors for the development of BMLs. Treatment consisted of the administration of oral bisphosphonates (Alendronate 70mg 1/week for 3 months). In addition, patients used non-steroidal anti-inflammatory drugs (NSAIDs) as needed and crutches with weight-bearing as tolerated for 30 days. Outcome evaluation was performed using VAS and WOMAC scores, collected both before starting the therapy and at 9-months of follow-up.
Student’s t-test for paired samples was used to compare scores obtained before the treatment and those at the follow-up. Student’s t-test for unpaired samples was instead used to compare the scores obtained in the different groups between the first evaluation and the follow-up. A 95% confidence interval was set. Statistical significance was set at p<0.05.
Among the patients evaluated during the course of this study, 19 (8 males, 11 females) met the inclusion criteria and attended until the last follow-up. Of these, 3 patients (16%) underwent total knee arthroplasty during the follow-up and were therefore excluded from subsequent evaluation. The mean age at the time of diagnosis was 69 years (range 49-82 years). The mean BMI at the time of first evaluation was 28 kg/m2. According to Roemer’s classification (6), in 9 patients (47.5%) the BML was considered idiopathic, in 4 (21%) it was secondary to knee osteoarthritis, in 2 (10.5%) it was the consequence of a traumatic event, in 2 (10.5%) it was linked to an inflammatory state and in 2 (10.5%) it developed in a context of SONK. The lesion involved the medial compartment in 16 patients (84%): in 7 cases (37%) it was limited to the femur, in 6 (31.5%) to the tibia, while in 3 (16%) cases both were involved. By contrast, the lateral compartment was affected in 2 patients (10.5%): in the first one both segments were involved, while in the second one the tibia alone was affected. Finally, in 1 patient (5%) the subchondral lesion extended to medial and lateral tibial plateau. VAS score decreased from a mean value of 7.8 at the time of diagnosis to a value of 2.3 at the control time (Δ = 5.5). WOMAC score also decreased from 59.2 to 23.5 (Δ = 35.7). More specifically, in the group of the idiopathic form the mean ΔVAS was 7.3 and the mean ΔWOMAC was 47.5. Within the group with osteoarthritis, 2 patients underwent total knee replacement and were excluded from scores evaluation; in the remaining 2 patients the ΔVAS was 1 and the ΔWOMAC was 12. In the BMLs resulting from a traumatic event the ΔVAS was 3.5 and the ΔWOMAC was 21.5. In presence of lesions associated with inflammatory diseases the ΔVAS resulted 4 and ΔWOMAC was 18. Regarding the lesions in the contest of SONK, 1 patient had to undergo total knee arthroplasty, while the other patient resulted in a ΔVAS of 4 and a ΔWOMAC of 5. Fig. 1 shows the mean VAS score at T0 and after treatment in idiopathic forms (VAS T0 = 8.5; VAS control = 1.3) compared to secondary forms (VAS T0 = 5.9; VAS control = 3.5). Fig. 2 shows the mean WOMAC score at T0 and after treatment in idiopathic forms (WOMAC T0 = 63.2; WOMAC control = 15.8) compared to secondary forms (WOMAC T0 = 50; WOMAC control = 33.4). In patients with idiopathic lesion, as well as in those with secondary BML, the values of VAS and WOMAC scores at the end of the follow-up time were significantly lower than those calculated at the time of diagnosis, with p <0.05 for both. Fig. 3 shows the mean difference between VAS and WOMAC at T0 and after treatment in idiopathic forms (ΔVAS = 7.3; ΔWOMAC = 47,4) compared to secondary forms (ΔVAS = 2,9; ΔWOMAC = 15,4). ΔVAS and ΔWOMAC in idiopathic BMLs were statistically superior to ΔVAS and ΔWOMAC of the secondary BMLs, with p <0.05 for both.
The correlation between risk factors and the onset of BMLs revealed that 6 patients (31.5%) were affected by primary osteoporosis, 7 (37%) had undergone chronic corticosteroid intake in the previous 2 years, 3 (16%) were affected by diabetes and 2 (10.5%) were cigarette smokers. The average total WORMS was 7.8, with a maximum of 15 points and a minimum of 2 points. The mean total WORMS for patients with idiopathic BML was 8 points; while in the secondary forms it was slightly lower (7.7).
Alendronate was well tolerated by all patients and no adverse events related to the administration were observed. The results of the study are shown in detail in Tables I and II.
BMLs have been identified in a wide range of bone disorders, whether based on traumatic injuries, mechanical stress, inflammatory or vascular diseases. The primary form, Bone Marrow Edema Syndrome, is a rare but under-diagnosed cause of pain, mainly involving lower limb joints (17, 18). The debate on the pathogenesis and clinical implications of BMLs is still open and this is reflected by the lack of gold standard recommendations or guidelines in the treatment of this condition (7). To shorten the clinical course of BMLs, frequently associated with severe and mid-term disability, various treatments have been proposed. Most authors, due to the alleged self-limiting nature of the disease, agree on the usefulness of functional rest and intake of NSAIDs.
Surgical approach is controversial and not a main topic of this study. Surgical decompression and subchondroplasty for the treatment of BMLs have proven useful, especially in cases of recurrent or persistent lesions (14, 15). However, their real advantages as first line treatment for these lesions are questioned due to the generally benign course and the availability of alternative pharmacological and physical therapies. Moreover, these procedures are not without risk (19).
The administration of drugs such as intravenous bisphosphonates sees its rationale in the evidence that local bone resorption in BMLs is increased (7) and their benefits have been repeatedly demonstrated (9, 10, 20), despite a lack of evidence to indicate which bisphosphonate and which regimen of administration represents the best therapeutic choice. Furthermore, some sources suggest that BMLs are less frequent in patients who are already in therapy with bisphosphonates (21), supporting them as potential therapeutic candidates.
Alendronate is a bisphosphonate with a favorable, effective and generally well-tolerated pharmacological profile (22). The use of oral alendronate for the treatment of transient osteoporosis has been reported in a few studies: Kibbi et al. (24) described 3 cases (two hips and one knee), Emad et al. (23) reported their experience with 8 patients while Miltner et al. (25) described a cases-report supporting the idea that even oral bisphosphonates may be useful in reducing the duration of BMLs. Intravenous bisphosphonates are reportedly more effective than oral administration (26), however oral intake is associated with a lower risk of complications (27). As the need for frequent intravenous infusions could compromise patient compliance, orally administrated alendronate may offer a simple and convenient treatment option. Clearly, the main drawback compared to intravenous administration is the eventuality of altered absorption due to gastrointestinal disorders.
In our experience, after therapy with Alendronate, at 9-month follow-up all the patients suffering from primary BMLs had already recovered a good level of autonomy in their daily lives with an important reduction in pain, as denoted by the improvement in VAS and WOMAC scores. While still significant, in patients with secondary BMLs the improvement was lower and 3 of them needed to undergo total knee replacement. When comparing the ΔVAS and ΔWOMAC of idiopathic and secondary BMLs respectively, the relatively poor efficacy of the treatment in patients with secondary forms supports the hypothesis that this kind of lesion is an epiphenomenon of underlying disease and has therefore a different origin from idiopathic ones.
The total WORMS was averagely higher in idiopathic forms (8 points) compared to the secondary ones (7.7 points), this was probably due to the typical presentation of idiopathic forms, which are characterized by widespread and large BMLs (6). There was a great heterogeneity at WORMS evaluation and therefore in the extension of the lesions, ranging from a minimum of 2 points to a maximum of 15 points. Notably, the group of patients with WORMS >10 points displayed a mean VAS score at T0 slightly higher (8.83) than the group of patients with WORMS <10 (7.73). Similarly, mean WOMAC at T0 of the group patients with WORMS >10 was greater (63.8) than in the group of patients with WORMS <10 (58.6). These data could suggest that the extent of the BML, both in primary and secondary forms, might have a direct influence on the level of pain and therefore on joint function. However, due to the small sample size, it was not possible to demonstrate a statistically significant correlation between the WORMS and the VAS and WOMAC scores.
In 2016, Trevisan et al. (28), with a retrospective observational cohort study on outpatient data on 23 patients with BMLs at MRI, investigated the following risk factors: bone metabolism disorders; cigarette smoke; recent excessive use of the lower limbs; osteoporosis/osteopenia. In their study, the most frequent risk factor was excessive use, while the second most frequent risk factors were bone metabolism disorders and smoking habit. In the present study, cigarette smoking did not emerge as a risk factor (2 patients, 10.5%), whereas the intake of cortisones (7 patients, 37%) and osteoporosis (6 patients, 31.5%) appeared to be frequent in these patients. However, the small number of the patients did not allow to statistically assess whether these factors could be related to BMLs.
This study presents several limitations, mainly the absence of a control group, the lack of a radiological follow-up by MRI, the limited number of patients and the short follow-up. Some studies in the literature have used bisphosphonates at relatively high doses, which expose to possible side effects. In patients with a self-limiting condition this treatment may not be justified in our opinion. Since the optimal alendronate posology for treating BMLs is not established, the administration employed in the present study was chosen based on the currently recommended regimen for the treatment of idiopathic osteoporosis.
In agreement with other studies in literature, we believe conservative therapy to be the most reasonable approach in the treatment of BMLs. The use of I.V. bisphosphonates is widely reported in literature, whereas oral intake has been described only by a few studies (23–25). The present study allowed to show that oral administration of alendronate may be a useful addition in significantly relieving pain for patients with BMLs of the knee and reduce duration of the symptoms. However, the treatment appears to be more effective in patients with primary BMLs who achieved a near complete resolution of clinical symptoms after 9 months, in comparison to secondary forms. Cortisone therapy in the 2 years before the onset of pain and osteoporosis emerged as possible factors associated with BMES, but it was not possible to demonstrate whether they significantly increase the risk of BMES in the general population.
We believe that BMES is a nosological entity to be discovered from the etiological and therapeutic point of view. The close collaboration between clinician and radiologist is strategic in order to homogenize the diagnosis and to determine the correlation between clinical data and imaging findings. Further controlled studies are needed to confirm these results and further explore the appropriate dose and duration of treatment.
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