There has been focus on the risk for cancer after insertion of joint replacements [2-4]. The majority of studies are from the national arthroplasty registries in Finland [9, 10, 12, 15, 16], Scotland , England and Wales , and Sweden . All but one of these studies conclude that there is no (or a negligible) increased risk for cancer after insertion of joint replacements. On the other hand, Wagner and colleagues have reported an overall increased cancer risk for total knee arthroplasty (TKA) patients compared to the general population. In addition, they reported findings of specific cancer types, which they argue can be a result of TKA exposure . Our study supports previous findings showing no overall increased risk for cancer after THR, neither before nor after 10 years follow-up. For uncemented THRs we found an association with a small increased risk for cancer for males.
There are limitations in this study. As shown by Lie and colleagues , patients with a THR have reduced overall mortality compared to the general population, while THR patients under 60 years have increased mortality and patients over 80 years of age have considerably reduced mortality compared to the population in general. Furthermore, uncemented prostheses have predominantly been given to younger and healthier patients, while cemented prostheses have been given to elderly and frailer patients . Consequently, adjusting for the risk for cancer, the first 10 years after primary THR (difference-in-difference model) would adjust for (unknown) risk factors contributing to the baseline risk for cancer for the different categories of patients. Still, there is a potential for a complex selection mechanism for receiving a THR and also for receiving the different types of THR, which we are not able to adjust for. Hypothetically, receiving a THR can increase the attention to own health. Subsequently, this can lead to more visits for medical care (e.g. general practitioner), which may increase the number of tests and also the probability of being tested for cancer. This would particularly be the case for prostate cancer in men.
Recently, Cartilage Oligomeric Matrix Protein (COMP), which plays an important role in the organization of the extracellular matrix of cartilage, has been identified as a potent driver of the progression of prostate cancer, acting in an anti-apoptotic fashion by interfering with the Ca2+ homeostasis of cancer cells . In a retrospective case control series in prostate cancer patients with and without osteoarthritis, this condition was identified as an independent risk factor for metastatic disease. However, when joint arthroplasty was included in the model, osteoarthritis was no longer an independent risk factor . It is unlikely that this association can explain the small increase in cancer risk in men with uncemented compared to cemented THR in our study.
The common analytical approach to study cancer risk for THR and TKA patients is to compare the observed cancer risk for arthroplasty patients with cancer rates in the general population. When SIRs are used to compare the cancer risk for the patients studied with the cancer risk in the population, it is assumed that prosthesis patients are comparable to the general population. Previous studies find no increase in risk for cancer after an arthroplasty compared to the general population [6-18]. Overall, this agrees with our finding, using the same analyses techniques.
From studies of secondary cancer related to anti-neoplastic treatment, it is known that the latency from the first to the subsequent malignant tumour is 10 years or more [32, 33]. In the regression models in this study, we took into consideration that the development of cancer related to arthroplasty can take at least one decade, and that cancer diagnoses during the first years after a THR operation are most likely related to factors other than the arthroplasty itself. To compare the different types of fixations, we therefore used baseline cancer risk at the first 10 years follow-up as a reference. In these analyses we thus compared the difference in cancer risk between different types of fixations, and other factors, adjusting for the crucial selection for receiving the THR.
We found an increased cancer risk for patients with two uncemented prostheses components, compared to patients where both prostheses components were cemented. Patient with hybrid prostheses had not a statistically increased risk for cancer compared to patients with two cemented components.
In analyses of cancer after THR, death is a competing risk. For the present analyses we did not take competing risks into account. The reason is that since there are differences in selection mechanisms between the different prosthesis, which will be apparent in analyses with death as endpoint, death may also be a collider in causal terminology when we study the risk for receiving cancer. Accordingly, using models for competing risks, a false and elevated risk between the types of THR and cancer was present (analyses not shown). The relative differences in the SIRs in our analyses correspond to the findings from the Cox model with time-dependent adjustment, which we consider strengthen our findings.
There has been a concern about cancer risks associated with metal on metal articulations for THRs [9, 10, 14, 34], but other and newer types of articulations should also be studied . Articulation has not been included in the present study since the majority of THR prostheses in the Norwegian Arthroplasty Register have a metal head and polyethylene cup, and other articulations have lower numbers or shorter follow-up . Metal-on-metal has rarely been used in Norway in the study period. Only approximately 200 cemented and less than 200 uncemented implants of this type, most of which with small heads (<32 mm) were used in the time period studied . Metal on metal resurfacing implants were excluded from the study, because this type of THR is a marginal problem in this study, and omitting these implants would not alter our findings.
In the present study we found no increased risk for cancer in THR patients compared to the general population. However, we found a small increased risk for cancer after insertion of THR where both components were uncemented, compared to prostheses where both were cemented. In gender stratified analysis this increased risk was only found for men, but not found in age stratified analysis for men. The difference was small and prone to unmeasured confounding. The risk for cancer after joint replacements and possible mechanisms related to cancer for patients with musculoskeletal diseases and/or joint replacements should be studied further. Surveillance of new products, materials and prostheses, with respect to rare and adverse outcomes like cancer, is important, also in the future.