This retrospective, open-label and observational analysis is part of an ongoing quality assurance measure managed by the University Hospital Basel initiated in April 2017. The analysis was approved by the regional ethics committee (EKNZ no. 2017-00338) and followed applicable law, the principles of good clinical practise, and the Declaration of Helsinki.
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.
At baseline, all 43 patients reported pain as their predominant symptom. Thirty-eight clinical follow-up visits were recorded for the 34 patients treated. At each follow-up visit, the course of pain was rated as improved, unchanged, or worsened. To evaluate the appearance of adverse events (yes/no), patient records were screened for reports on typical symptoms of an acute phase reaction such as flu-like symptoms, myalgia, exhaustion, or fever.
MRI examinations were available for all patients at baseline and for 18 patients during follow-up. Central reassessment was performed by one trained musculoskeletal radiologist (K. A.) who was presented the MRI data in random order without patient identifiers or date. Thus, the radiologist was blinded to clinical and laboratory data as well as to the course of MRI examinations.
Currently, there is no standardised evaluation method for quantifying and comparing BML in MR images. The Whole-Organ Magnetic Resonance Imaging Score (WORMS) was applied to describe and quantify BML . WORMS represents a semiquantitative evaluation method originally developed for research purposes in cartilage evaluation of osteoarthritic knees. The knee was divided into different compartments. The lesion volume was evaluated by the percentage of the compartment’s affected volume and scored from 0 to 3 (0 = none, 1 = affected volume < 25%, 2 = 25% ≤ affected volume < 50%, and 3 = affected volume ≥ 50%). Figure 3 illustrates examples of WORMS scorings 1–3.
At baseline, all patients underwent laboratory analysis of bone metabolism. During follow-up, 39 laboratory analyses were performed at the osteological outpatient clinic under well-defined, standardised conditions (fasting, between 08.00 a.m. and 10.00 a.m.). In each laboratory analysis, creatinine for calculating glomerular filtration rate (GFR), 25-OH-vitamin-D3, albumin-corrected calcium in serum, CTx, and P1NP were extracted. Reference values of these laboratory parameters are presented in Table 1. Daily calcium intake by regular meals and current medication—including any type of supplements—was obtained by a standardised questionnaire and documented to complete the bone metabolic workup. CTx proved to be more sensitive than P1NP and was, thus, used as bone turnover marker in the analysis.
Decision on antiresorptive treatment indication
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:
Response to treatment
The primary outcome was change of patient-reported pain. Alternatively, the combination of pain relief, reduction in WORMS, and reduction in CTx levels of at least 50% was used to document response to treatment.
Diagnostic methods at baseline
To assess if laboratory analyses could replace or supplement semiquantitative evaluation of BML expansion on MRI using WORMS, correlations between WORMS and CTx were calculated at baseline. Levels for 25-OH-vitamin-D3 were measured at baseline.
Diagnostic methods during follow-up
To assess a diagnostic technique’s potential in treatment monitoring, the respective values of WORMS and CTx or P1NP at baseline and during follow-up were compared. Correlations between these methods were calculated for values during follow-up. To investigate the potential of laboratory analysis and/or MRI to objectively support the patient-reported primary outcome, correlations between changes in pain, WORMS, and CTx were calculated, as well. Levels for 25-OH-vitamin-D3 were measured during follow-up.
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:
Patients treated with intravenous ibandronic acid only, multiple applications possible, and, therefore, resulting in multiple follow-up visits.
Patients treated with intravenous zoledronic acid once only.
Patients initially treated with intravenous ibandronic acid followed by one single administration of intravenous zoledronic acid. This group is called sequential (I → Z) in the following. Due to multiple applications of ibandronic acid and the change in medication, multiple follow-up visits possible.
Patients treated with subcutaneous administration of denosumab once only.
Patients treated with oral alendronic acid only.
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.