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S. Thorsteinsdottir et al.
MM after 2000.19-21 These included the immunomodula- tors thalidomide and lenalidomide, and the proteasome inhibitor bortezomib, that were increasingly used during the later calendar period, and were used in over 80% of all MM patients in Sweden in 2013.31 Previous studies have shown that bortezomib can both inhibit growth of osteo- clasts and stimulate osteoblasts, thereby leading to bone healing in MM.32,33 Furthermore, the immunomodulators also seem to prompt the bone microenvironment towards bone formation.34,35 In addition to this, bisphosphonates, that are a well-established part of the treatment of MM patients, are known to reduce pathologic vertebral frac- tures, skeletal-related events, and pain.36 Moreover, zole- dronic acid, that was approved for MM in the later calen- dar period of the study, has shown a positive effect on overall survival.13 In 2010, Swedish national guidelines rec- ommended treatment with bisphosphonates from the time of MM diagnosis for all MM patients, irrespective of the presence of bone disease, and in the years 2008 to 2015, over 70% of MM patients received bisphosphonates as part of their disease management.31 In our study, even in 2000-2013, when we had information on outpatient visits for fractures for the whole period, we found no change over time in the association of fracture after MM diagnosis and survival. Thus, despite the increasing use of more effective treatment agents and more widespread use of bis- phosphonates, fractures are still an important predictor of overall survival.
The strengths of our study include the large population- based study design, including almost all patients diagnosed with MM in Sweden during a more than 20-year period.22 Using these real-world data, all MM patients are included, and the results therefore reflect the actual patient popula- tion. Because of the unique identification numbers assigned to every individual in Sweden, we have extensive and accurate follow up for the majority of this large group of patients. Furthermore, the high number of MM patients and fractures yields the study high statistical power to ana-
lyze the effect of different subgroups of fractures.
The limitations of our study include the fact that we do not have information on clinical stage, other prognos- tic factors, or on what treatment the MM patients received. Therefore, it is not possible to determine from our data whether fracture is an independent risk factor for death in MM. Because the fractures occurred after the MM diagnosis, there is a risk of immortal time bias in our survival analysis. To address this, we used both the method of time dependent co-variatesand landmark analysis to accurately analyze the difference in survival between the fractured and unfractured groups.24,37 In addition, we do not have access to radiographic images or individual patient records; therefore fractures, espe- cially asymptomatic fractures, might be relatively under- reported. In our study, a smaller proportion of patients were diagnosed with a fracture after MM diagnosis than had been previously reported.5 The difference between these results might be explained by the study designs, the fact that ours is a large database study using ICD- codes, and that, in the older study, all patient records were searched retrospectively for the occurrence of a fracture. Finally, a limitation of our study is that our fol- low up ended in 2013; although it would have been inter- esting to perform our analyses on more recent data, we did not have access to a more up-dated database at the
time of the study.
In conclusion, our population-based study shows that
MM patients with a fracture at MM diagnosis have an inferior survival than patients without a fracture at diag- nosis. Furthermore, we found that MM patients who develop a fracture after the time of MM diagnosis are at a 2-fold risk of dying compared to patients who do not develop a fracture, and that this risk did not decrease sig- nificantly after the introduction of more effective treat- ment agents in MM. Our results stress the importance of preventing bone disease in MM, not only to prevent the morbidity of fractures, but possibly to influence survival.
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