Zoledronic acid is more efficient than ibandronic acid in the treatment of symptomatic bone marrow lesions of the knee

At an osteological outpatient clinic, 43 patients (27 male; mean age 45 ± 15 years) with symptomatic BML of the knee radiologically diagnosed by means of fluid-sensitive MRI sequences were retrospectively identified. Patients were referred from three sports clinics during a 5-year observational period (February 2012–September 2017). Patients were included independent of potential aetiology, duration of symptoms, or final decision with respect to pharmaceutical treatment options. The same osteological consultant (N. S.) had personally evaluated all patients. Thirty-four patients were treated with antiresorptive medication. An overview of treatment options applied, follow-up visits, and examinations performed is given in Fig. 2.

All data were extracted from patient records not specifically filed for scientific purposes. Records available both at the osteological outpatient clinic and at referring institutions were included. Initial examinations at referring institutions and laboratory analysis performed at the osteological outpatient clinic prior to treatment are named baseline visits for this analysis. Subsequent visits during/or at the end of treatment, performed at the osteological outpatient clinic or at referring institutions, are named follow-up visits throughout the article. Appraisal of the course of symptoms and laboratory follow-up were routinely conducted 4 weeks after application of antiresorptive medication or after treatment was ended. In case of persisting pain or dissatisfying course of treatment, multiple follow-up visits were necessary. In some cases, follow-up MRI examinations were ordered by referring physicians, particularly in cases of suspected aggravation or lack of pain reduction, but also for follow-up to assess response to treatment. Because the patient reporting on adverse events was potentially subjective, these were documented but not quantified.

According to the guidelines of the osteological outpatient clinic, an indication for antiresorptive treatment initiation was based on the following criteria:

Three different aspects (response to treatment, methods at baseline, and methods during follow-up) were analysed for this article:

Prior to the implementation of antiresorptive treatment, all patients received vitamin D supplementation (1000 IU/d). In patients with insufficient vitamin D levels at baseline, a loading dose (45,000 IU) was also administered. Five treatment groups were considered:

The distribution of binary and categorical variables was described by absolute and relative frequencies. Median, mean, or range was used to describe the distribution of continuous variables. Wilcoxon and the Kruskal–Wallis tests were used to compare the distribution of ordinal and continuous variables between groups. The Pearson correlation coefficient was used to assess the association between variables. Some patients showed BML on both femoral as well as on tibial compartments of the knee. For this analysis, WORMS was applied to the more severely affected compartment. Hence, one value for WORMS for each patient was entered into the analysis. The change from baseline was quantified by the relative change expressed in per cent. Because of the retrospective nature of the study, no formal a priori sample size calculation was performed.

The primary outcome assessed the failure of treatment based on clinical reporting of pain, or alternatively on all three methods together (“Overall”). Zoledronic acid was found to be more or at least equally effective compared to other treatment regimens (Table 2). Among the 12 patients treated with zoledronic acid, one failure due to the insufficient reduction of WORMS was noted. In all other treatment groups except for alendronic acid, higher failure rates based on missing pain relief or lack of reduction in CTx were observed. The highest rate of adverse events was noted in patients with zoledronic acid (Table 2).

Very low correlations between WORMS and CTx (r = 0.13) were noted (Table 3a). With a mean value of 37.3 nmol/l, vitamin D levels were mostly found to be below reference (Table 1).

Moderate correlations between WORMS and CTx (r = 0.48) were noted (Table 3b). In Fig. 4 a diagnostic method’s potential to illustrate treatment response is presented. WORMS and CTx differentiated well between responders and non-responders, whereas P1NP was not able to do so. Moderate correlations between changes in pain and WORMS (r = − 0.32), but only little correlation between changes in pain and CTx (r = − 0.13) were observed. Little correlations between changes in WORMS and CTx (r = 0.14) were noted as well. During follow-up, mean levels of vitamin D were elevated to 57.3 nmol/l (Table 1).

Several studies have considered BML as a preamble to later development of osteonecrosis. Different antiresorptive medications have been applied to treat BML and osteonecrosis as a possible endpoint, because antiresorptive medications inhibit bone resorption [10, 18]. Mixed results have been reported for treatment with ibandronic acid [10, 18], which may be explained by its limited capacity in suppressing bone resorption [6, 17]. In contrast, zoledronic acid features a higher antiresorptive capacity. In agreement with the above-presented results, previous studies have reported an advantage of zoledronic acid above other antiresorptive medications in inhibiting bone specific pain and in suppressing bone resorption [3, 4, 8].

Simon et al. [18] have shown that balanced vitamin D homeostasis is essential prior to the administration of antiresorptive treatment. Also in line with the above-presented findings, most patients suffering from BML who had not recently undergone vitamin D supplementation exhibited vitamin D insufficiency or even deficiency [12, 18]. Contrary to the other reports [18], reconstitution of sufficient 25-OH-vitamin-D3 levels was more difficult than expected in this study’s patient population. The finding of incomplete normalisation is supported by Oehler et al. [12]. 58% of their patient population had insufficient or even deficient levels of vitamin D despite ongoing supplementation [12]. From an osteological point of view, the combined application of vitamin D supplementation and antiresorptive medication is, therefore, mandatory.

Response to treatment of symptomatic BML with antiresorptive medications according to this study’s indication consequently would have to be monitored with adapted tools. It was hypothesised that methods for monitoring response to treatment were interchangeable. However, this analysis failed to prove significant correlations amongst the diagnostic techniques applied. This result is in line with the current literature reporting on difficulties to establish a correlation between diagnosed BML, pain, and MRI findings [7, 9]. An explanation for these difficulties may be differences in the dynamics when the diagnostic techniques are applied. For instance, Simon et al. [18] found that the intensity of BML and/or expansion on MRI persist over a longer period of time, even when patients were already relieved from pain. Furthermore, bone turnover markers are known for different dynamics under treatment: the bone resorption marker CTx is suppressed much faster than the bone formation marker P1NP [21]. Hence, the time gaps between the onset of symptoms, diagnostic techniques performed at baseline or during follow-up, and the implementation of medication treatment may be relevant with respect to the correlations found [18].

In contrast to the previous studies [10, 16, 18], scorings such as the visual analogue scale (VAS) to objectively report on pain at baseline or to quantify changes during follow-up were not applied. Patients suffering from symptomatic BML of the knee report on pain as a complex symptom emphasising the existence of two qualities. First, they describe a sharp, intense pain that may be triggered by physical examination as well as by unintended movements. Second, they experience a deep, numb continuous pain at lower level. Because of this clinical observation, it seemed inappropriate to quantify “pain” with just a number. Moreover, patients sense pain to be modulated by activity level or by the consumption of analgesic medication. Therefore, the patient’s overall judgement of pain as “improved”, “unchanged” or “worse” was favoured over VAS values.

This analysis was based on a retrospective design without a control group. The spontaneous course of BML, therefore, still necessitates clarification. Patients were referred from three sports clinics, thereby causing inconsistencies with respect to the quality of external documentation, type of pre-treatment, and possible etiopathology of BML. There were no complete follow-up data for all patients. This was mainly caused by lacking patients’ compliance to attend planned follow-up examinations. Despite the limited sample size in our retrospective study, these results are relevant, because they suggest that when zoledronic acid is considered for therapy in a case of symptomatic BML, the patient needs to be informed about the balance between effectiveness and risk of adverse events.