The results from this matched case–control study provide evidence for the first time, to our knowledge, that comorbid PDB has a favourable effect on the overall survival time of patients with prostate cancer (11.8 years, Paget's group, vs 9.2 years, non-Paget's group; P=0.008). That observed improvement in overall survival time is consistent with our finding that the time from the diagnosis of prostate cancer to the development of bone metastasis was longer in the patients who had both diseases.
We recognise that cancer-specific survival time, not overall survival time, would have been a preferable end point in this study, but it was not possible to obtain that information because complete details of the cause of death were not available in the medical records. Considering that many patients with PDB likely died from causes unrelated to their cancer, we expect that their cancer-specific survival time would have been longer than their overall survival time. Thus, we believe that the results reported here could actually underestimate the cancer-specific survival time of prostate cancer patients with PDB. This would account for a merge of the survival curves after 10 years in .
The distinction between prostate cancer bone metastasis and PDB was subtle in some cases and required confirmation by experienced radiologists. It is true that the timing of radiographic studies could have affected the time between prostate cancer diagnosis and bone metastasis, but the likelihood of finding new bone lesions on a bone scan when the PSA concentration was increasing would be the same for both groups. Therefore, the chance that any lead-time bias favoured either group in this study was low. In fact, one would expect that the attention and scrutiny resulting from the identification of bony abnormalities in PDB would lead to a bias against patients with PDB for the early detection of prostate cancer bone metastasis.
It is important that the patients in the two groups were well matched for age at time of diagnosis, disease stage, Gleason grade, initial therapy, and Charlson comorbidity score. Although the baseline PSA concentration was slightly higher in the non-Paget's group, the difference was not statistically significant. Black patients tend to harbour a more aggressive form of prostate cancer than whites do, (Danley et al, 1995
; Clegg et al, 2002
), and there were more Black patients in our Paget's group than in the non-Paget's group (P
=0.096), but the better survival results in the Paget's group cannot be accounted for by this imbalance.
It remains unknown what effect the stage, location, or extent of PDB has on prostate cancer. Additional questions include whether treatment of PDB negates any benefits that PDB may have on prostate cancer and whether that treatment itself delays prostate cancer bone metastasis. However, our data do not suggest that the use of bisphosphonates either counteracts or causes any such effects, because this treatment is a relatively recent practice and most of the patients we studied never received it.
Our results suggest that PDB alters the bone microenvironment and interferes with the progression of prostate cancer in bone. Although a plethora of factors are involved in the progression of prostate cancer, it is unlikely that all of them actually have an effect on bone metastasis. We propose that PDB provides a unique experiment of nature through which we can identify factors that may be used to prevent the progression of prostate cancer to bone.
It is plausible that patients with PDB have a distinct bone condition or a unique bone microenvironment that protects them from prostate cancer bone metastasis. For instance, 67% of the genetic risk for PDB is derived from genetic variants close to four genes that are in some manner involved in osteoclastogenesis: CSF1
(macrophage colony-stimulating factor); OPTN
(optineurin, a nuclear factor-kappa B (NF-κ
B) essential-modulator-related polyubiquitin-binding protein); TM7SF4
(DC-STAMP, a dendritic cell-specific transmembrane protein, master regulator of osteoclast fusion); and TNFRSF11A
(a receptor activator of NF-κ
B or RANK) (Chung et al, 2010
Another factor for the apparent effect of PDB on progression of prostate cancer may be overproduction of Dickkopf-1 (DKK-1, a Wnt antagonist). Dickkopf-1 is implicated in osteolytic diseases, including PDB (Marshall et al, 2009
), multiple myeloma (Tian et al, 2003
), and rheumatoid arthritis (Diarra et al, 2007
), in which it enhances osteoclastic activity by inhibiting bone formation and stimulating its breakdown. In particular, osteoblasts from patients with PDB overexpress DKK-1, leading to elevated serum DKK-1 concentrations in such patients (Marshall et al, 2009
). We speculate that certain bone factors such as DKK-1, which are produced by pagetoid osteoblasts, myeloma plasma cells, and rheumatoid synovial fibroblasts, inhibit the progression of prostate cancer bone metastasis. Of note, elevated DKK-1 expression occurs early in prostate carcinogenesis; as the disease progresses, DKK-1 expression declines, particularly in advanced bone metastases (Hall et al, 2008
). This decline of DKK-1 in bone metastases coincides with a surge in Wnts and increased prostate-cancer-induced osteoblastic activity (Hall et al, 2005
). Likely, the overproduction of DKK-1 in PDB antagonises the osteogenic activity of the Wnts. Further, elevated levels of DKK1 may negatively influence several important steps of bone metastasis, such as mobilisation, engraftment, and proliferation of prostate cancer stem cells to and within the bone marrow (Tian et al, 2003
; Adams and Scadden, 2006
; Lee et al, 2011
It is of interest whether a delay in bone metastasis ensures an improvement in overall survival time of patients with prostate cancer. Recently, a randomised phase III trial demonstrated that denosumab delayed bone metastasis by 3.7 months, but did not affect the overall survival of men with castrate-resistant prostate cancer (Smith et al, 2012
). Currently, a randomised Zoledronic acid EUropean Study trial is being conducted to determine whether zoledronic acid can delay bone metastasis in high-risk patients with androgen-dependent prostate cancer. The fully human monoclonal antibody denosumab specifically inhibits osteoclastic activity by binding and inactivating the ligand of RANK. The bisphosphonate zoledronic acid also inhibits osteoclastic activity by reducing osteoclast development from precursor, disrupting bone resorption after internalisation by osteoclasts and inducing apoptosis of osteoclasts. Therefore, we anticipate that the effects of PDB on prostate cancer bone metastasis are more complex than merely increased osteoclastogenesis or osteoclastic activity in bone.
Further studies need to be performed to confirm the preliminary results of our exploratory retrospective study. Ideally, we would conduct a prospective clinical trial to validate our results. However, given the scarcity of patients who have prostate cancer with comorbid PDB, the relative longevity of these patients, and the logistics and cost that such studies will incur, we realise that it may not be feasible to conduct such a definitive prospective study. An alternative way to validate our findings is to discover disease correlations and stratify patient cohorts by using electronic patient records (Roque et al, 2011
In summary, for the first time, to our knowledge, we have obtained data showing that in patients with both prostate cancer and PDB, the time to develop bone metastasis is delayed and the overall survival time is longer than they are in men with prostate cancer alone. Our results suggest that certain bone factors related to the presence of PDB affect the progression of prostate cancer bone metastasis. Future study of these factors may enhance our understanding of the biology of prostate cancer bone metastasis and facilitate the discovery of relevant targets for use in developing effective prostate cancer treatments.