This detailed quantitative analysis has demonstrated that NBF is closely related to other features of joint disease in gout. The most common features of NBF in gout are sclerosis, osteophyte and spur. The finding that bone erosion is strongly associated with all features of NBF suggests that loss of bone and formation of new bone may be connected during the joint remodelling process in joints affected by gout.
Although tophus size was not strongly associated with features of NBF in this analysis, joints with intraosseous tophus were more likely to have associated NBF, compared with those joints without tophus. These data suggest that the tophus may play a role in development of these features, particularly spur, periosteal NBF, ankylosis and sclerosis. The tophus represents a foreign body granulomatous response to collections of monosodium urate crystals, involving innate and adaptive immune cells [17
]. It seems unlikely that MSU crystals within tophi have a direct effect on bone cells to promote NBF, as these crystals promote osteoclastogenesis and inhibit osteoblast differentiation, survival and function, resulting in net bone resorption [18
]. MSU crystals within the tophus are surrounded by an inflammatory cell rim (the corona zone) which, in turn, is surrounded by a fibrovascular zone with organized deposition of collagen [22
]. It is conceivable that the processes that contribute to formation of the fibrovascular zone also contribute to the development of some forms of NBF, such as bone sclerosis. In addition to expression of cytokines typically associated with bone resorption, such as IL-1 and TNF-α [17
], transforming growth factor β (TGFβ) is also expressed in the tophus [17
]. TGFβ has various effects on bone homeostasis, but may contribute to NBF under certain conditions [24
]. Other pathways implicated in NBF in other arthropathies such as the bone morphogenetic proteins (BMPs) and Wnt signalling pathways have not been explored to date in patients with gout; activation of these pathways may also contribute to the patterns of NBF in joints affected by gout [25
Magnetic resonance imaging studies have demonstrated a close relationship between resolution of inflammatory bone lesions and development of new bone formation in ankylosing spondylitis [28
]. Our study was not able to address bone inflammation at sites of NBF, as this feature is not visualized using CT. The current study has defined the features of NBF that occur in patients with gout. Longitudinal multimodality imaging studies are now needed to understand the mechanisms of NBF in gout, and the impact of treatment on these features.
It is also possible that elevated circulating concentrations of soluble urate contribute to NBF in patients with gout. Several studies have reported that serum urate concentrations positively correlate with total body bone mineral density [30
]. A large observational study of older men has demonstrated that higher serum urate concentrations are associated with lower prevalence of osteoporosis and osteoporotic fractures [31
]. These findings persisted after adjusting for potential confounders including body mass index, alcohol use, diuretic therapy and kidney disease. The mechanisms of this relationship are not fully understood, but analysis of bone turnover markers showed that serum urate negatively correlated with urinary NTX-1, a marker of bone resorption [31
]. In contrast, there was no relationship observed between serum urate concentrations and P1NP, a marker of osteoblast activity. These observations suggest that urate may have opposing effects on bone, leading to erosion at local sites in the context of MSU crystals in tophi, but also maintenance of total bone density in response to high soluble urate concentrations. It is unknown whether the mechanisms of local NBF within joints affected by MSU crystals are the same as those influencing total body bone density. In this analysis, we did identify a weak relationship between serum urate and the number of joints affected by bone spur and ankylosis, but not other forms of NBF.
It is well documented that gout is more likely to present in joints previously affected by osteoarthritis [32
]. Consistent with these observations, osteophytes were associated with the presence of joint space narrowing, erosion and intraosseous tophus in the site-by-site analysis. However, the relationship of erosion and intraosseous tophus with osteophyte was much weaker than with the other forms of NBF. Furthermore, in the overall patient level analysis, a relationship between osteophyte and NBF was not observed. The analysis of different joint areas showing a relationship between erosion and tophus with osteophytes at sites other than the DIP and PIP joints suggests that these processes may be related in some circumstances and not in others.
This study shows that erosion, tophus and certain features of NBF (periosteal new bone formation and sclerosis) are more common at the radius/ulna region compared with the distal interphalangeal joints. It is possible this difference may have been due to improved resolution at the larger site, compared with the small DIP joints. However, it is more likely that this represents a real difference. Potential explanations for this observation are that local factors such as biomechanical strain at the distal radioulnar region contribute to formation of MSU crystals, or promotion of tophus formation in the presence of MSU crystals at this site.
Patients in this study had longstanding gout with a mean disease duration of almost 20 years and high serum urate levels. Although we did not observe a relationship between disease duration and NBF features in the patient level analysis, the results described in this paper may not necessarily be applied to patients with early disease or with well controlled disease. Similarly, this study only included joints of the hands, and it is possible that NBF changes may occur at different rates in the feet, which are more frequently affected by gout. Analysis of the feet is planned in future studies.
A further question that arises from this work is whether CT is preferable to plain radiography to accurately detect features of NBF. CT was able to detect more osteophytes and spurs than plain radiography. However, the inter-reader agreement was similar between XR and CT, with reasonable agreement between the methods for detection of the various features of NBF, suggesting that plain radiographs may be sufficient. The additional cost and radiation exposure from CT further supports plain radiography as the method of choice.
The strong relationship between bone loss (erosion) and NBF observed in this cross-sectional study suggests that NBF features such as sclerosis and spur formation may be repair phenomena triggered by joint destruction. At present, it is unclear whether NBF in gout occurs before bone erosion and tophus formation, develops concurrently with bone erosion, or occurs as part of tissue remodelling in response to tophus and erosion. Exploration of the temporal relationship between tophus, NBF and bone erosion now requires detailed longitudinal studies. Ideally these will be multimodality imaging studies which include plain radiography, MRI and dual energy CT, an advanced imaging method that allows visualization of urate deposits [33
]. Intervention studies are also needed to address whether effective urate-lowering therapy can prevent or reverse features of NBF, and to understand the impact of these changes on musculoskeletal function. Evaluation of NBF as part of the imaging assessment in future studies of gout may clarify the pathogenesis and impact of NBF in this disease.