Lessons learnt from basic sciences

It is hypothesized that cascades of maladaptive bone-related processes, most prominent in entheses, are triggered by biomechanical factors. McGonagle et al. [22] proposed a model of enthesitis-based pathogenesis for SpA over 20 years ago. It underlined a possible association of repetitive compressive and shear forces occurring in entheses, in close relationship to bone and tendon, with microtrauma and activation of proinflammatory genes and healing responses. The authors emphasized that the sites of internal organ involvement in ankylosing spondylitis (AS), the radiographic subtype of axSpA (r-axSpA), e.g. the aortic root, the lung apex, the ciliary body in the eye and skin extensor surfaces are places of repetitive biomechanical forces [22].

Since that discovery, researchers have been examining the correlation between mechanical stress and SpA with regard to its potential role in the pathogenesis of the disease and its impact on disease-associated factors, including disease activity, physical functionality, pain and radiographic damage [15–17, 23]. The outcomes so far are diverse, and the impact of mechanical stress on immune system interactions and bone remodelling seems to have both positive and negative effects simultaneously [24].

Jacques et al. [5] performed an important basic science study concerning whether mechanical stress triggers inflammation and new bone formation in SpA. By molecular modification of tumour necrosis factor (TNF) production, mouse models of SpA-like arthritis were obtained. Histopathological examination of tissue specimens resulted in a conclusion that early signs of inflammation were present at entheses, eventually spreading out into the synovium. Moreover, it was found that a lack of mechanical stress prevented the development of signs of inflammation, measured both clinically and histopathologically.

In 2008, McGonagle et al. [25] confirmed a physiological reaction to repetitive biomechanical stress by discovering the formation of small spurs in healthy individuals in microanatomic studies of cadaveric entheses. In this study of SpA patients with enthesitis using ultrasound (US), McGonagle et al. [25] proved that bone erosions and osteoproliferation are distinct anatomically and temporally. He noted that erosions and new bone formation are linked to biomechanics since erosions occurred in areas of compression, while spur formation took place in regions where tensile forces are likely to be greater.

In a 2014 animal study, Jacques et al. [5] proved that mechanical load is necessary for disease onset and correlates with arthritis and new bone progression. In tail-suspended TNF delta AU-rich element (TNFΔARE) mice (with chronic and deregulated TNF production), clinical signs of arthritis in the hind paws were not observed on clinical examination, and inflammatory changes on histological examination were minor. In collagen antibody-induced arthritis tail-suspended mice, osteophytes were markedly smaller on radiological and histopathological evaluation.

The author corroborated the role of stromal cells in the initiation of enthesitis. In mature T-cell-deficient mouse models [recombination activating gene 1 (RAG-1) deficient TNFΔARE], the incidence of enthesitis was similar to that in the control group, which indicates that both T-cell-dependant and -independent mechanisms lead to enthesitis [5].

Conclusions drawn from clinical research

The evaluation of SpA imaging measures supports the hypothesis of biomechanics-related osteoproliferation in SpA. Tan et al. [19] analysed the spatial distribution of spine syndesmophytes in r-axSpA. He found that syndesmophytes occur and first develop along the vertebral rim, a place exposed to mechanical forces. Therefore, this particular occurrence suggests a possible role of biomechanics in the development of syndesmophytes in axSpA. Moreover, Tan et al. [26] observed syndesmophytes, which were less common and smaller and were located at the thoracolumbar vertebral rim near the aorta. This observation added further evidence that not only inflammation but also biomechanical forces extrinsic to the spine play a role in new bone formation in axSpA. A key topic in many studies is the presence of bone marrow oedema (BME) in sacroiliac joints (SIJ) on magnetic resonance imaging (MRI). The bone marrow oedema is hallmark of axSpA, but it may also be present in healthy individuals such as postpartum women, athletes and others [27, 28]. The bone marrow oedema is often present in SIJ exposed to high biomechanical forces found in postpartum women, patients with disc herniation, athletes (runners, hockey players), military recruits and professionals, which suggests an impact of mechanical stress [27, 28]. Although in the study by Varkas et al. [29], no differences were observed in SIJ MRI findings in military recruits after 6 weeks of intense physical training, it is noteworthy that a high prevalence of MRI lesions (40.9%) was already present in this population before the training began.

In studies investigating the correlation between the presence of syndesmophytes in patients with r-axSpA, associations were found with disease duration, patient age, and elevated levels of osteocalcin (a marker of osteoproliferation), whereas no association was observed with disease activity or low BMD [30, 31].

Obesity has been associated with higher disease activity and with axial and peripheral osteoproliferation and entheseal inflammation, as reported by Maas et al. [32] and Bakirci et al. [33]. Although involved in immunological reactions [34], obesity increases biomechanical forces in axial and peripheral joints.

Bone density in spondyloarthropathies

Low BMD is already present in 47% of patients with early SpA (with a median disease duration of 6 years), including osteoporosis in 9–18% [7, 9]. It is associated with male sex, in contrast to the healthy population, as well as with high disease activity and decreased functional performance [7, 31]. However, in PsA, osteopenia and osteoporosis appear to occur with a prevalence similar to that of the general population [9]. Current studies underline the role of proinflammatory cytokines in bone resorption and the pathogenesis of low bone mass in SpA [35]. Studies on bone turnover markers indicate that the level of N-terminal telopeptide – a marker of bone resorption – in patients with r-axSpA is associated with disease activity, C-reactive protein levels, low BMD, and the occurrence of fractures, while it is not associated with the presence of syndesmophytes [30].

Inflammatory cytokines elevated in SpA, such as TNF and interleukin-17, impact bone remodelling. Under physiological conditions, inflammation, bone resorption, and formation are essential for tissue healing. In pathological conditions, however, these processes contribute to low BMD, osteoporosis, syndesmophyte formation, and ankylosis. Several osteoimmunological pathways play a role in r-axSpA, including bone morphogenetic proteins (BMPs), the Wnt signalling pathway, and Hedgehog signalling (Hh) [36]. A fundamental pathway in bone metabolism is Wnt. In the presence of inflammation, TNF promotes the expression of Dickkopf-1 (DKK1) and sclerostin (Wnt inhibitors), inhibits osteoblast differentiation, and enhances bone resorption by increasing the receptor activator of nuclear factor kappa-B ligand (RANKL)/osteoprotegerin (OPG) ratio [36].

Physical activity acts in the opposite manner: it reduces the expression of DKK1, sclerostin, and RANKL; increases the expression of OPG; and overall promotes osteoblast proliferation and activity while inhibiting osteoclast differentiation and activation [37, 38].

Molecular mechanisms of the effect of physical activity on bone metabolism are shown in Figure 1.

Fig. 1

Molecular mechanisms underlying the effects of physical activity on bone metabolism [37, 38].

DKK1 – Dickkopf-1, LRP5/6 – low-density lipoprotein receptor-related protein 5 and 6, OPG – osteoprotegerin, RANKL – receptor activator of nuclear factor κ-B ligand, Wnt/β-catenin – Wnt/β-catenin signalling pathway.

Tumour necrosis factor blockers in r-axSpA lower DKK1 and BMP 7 levels [39], decrease expression of Indian Hh [40], and increase the OPG/sRANKL ratio [41]. Several meta-analyses have demonstrated that anti-TNF agents improve BMD [42, 43].

The effect of antiresorptive drugs on bone metabolism in r-axSpA remains insufficiently explored. To date, no double-blind randomized clinical trial evaluating the impact of bisphosphonates or RANKL inhibitors on BMD in SpA patients has been conducted. In a meta-analysis comparing outcomes of r-axSpA patients treated with and without bisphosphonates, published between January 2000 and March 2020, only 6 comparative studies were identified [44]. According to this meta-analysis, bisphosphonates do not improve lumbar or femoral BMD or disease activity in r-axSpA; however, limitations such as small sample sizes and short follow-up durations should be taken into consideration [44].

In spondyloarthritis, bone loss is driven by inflammation, which promotes increased osteoclastogenesis through both RANKL-dependent and -independent pathways, while simultaneously limiting osteoblast formation [45]. Thus, antiresorptive therapies, such as bisphosphonates and RANKL inhibitors, may be expected to improve bone mass in patients with low BMD and active inflammation.

Studies investigating the effects of denosumab in SpA are scarce. A South Korean pilot study demonstrated the efficacy of denosumab in improving lumbar and total hip BMD, without affecting disease activity or spinal new bone formation [46]. One case series reported an increase in BMD, measured by quantitative computed tomography, after 1 and 2 years of denosumab treatment [47]. Large, long-term randomised clinical trials evaluating the effect of denosumab in SpA are required. Considerably more data are available regarding the efficacy of denosumab in rheumatoid arthritis: a meta-analysis of 6 randomised controlled trials showed that denosumab improves BMD and prevents joint erosions in patients with osteoporosis and rheumatoid arthritis [48].

Numerous clinical studies have shown that physical activity increases peak bone mass and reduces the risk of osteoporosis; therefore, it is recommended for both its treatment and prevention in the general population [49]. Given the inflammatory nature of osteoporosis in SpA, it is important to further explore the effects of physical activity on both disease activity and bone density in this population.

Characteristics of included studies

The analysed populations varied significantly. Three studies included patients with PsA, including one with axial PsA, while the remaining three involved patients with r-axSpA. The characteristics of the patients also differed significantly. Three studies focused on early SpA (2 on PsA and 1 on r-axSpA), with a median disease duration of 3–6 years [54–56], whereas three other studies examined longstanding SpA (2 on r-axSpA and 1 on PsA), with a mean disease duration ranging from 11 to 32 years [19–21]. Notably, the proportion of patients treated with bDMARDs differed across studies. In 1 study, none of the patients received bDMARD treatment at baseline, whereas in the others, this percentage ranged from 27% to 48%. Among the analysed studies, only 1 provided information about steroid therapy; moreover, not all of them reported on the use of NSAIDs or synthetic DMARDs. In the study by Ward [19], glucocorticosteroids were used in only 7% of patients [57–59].

Two of the included studies were randomized controlled trials exploring the impact of high-intensity interval training (HIIT) on numerous outcomes, including radiographic structural damage, among PsA patients. Thomsen et al. [56] assessed the impact of 11 weeks of HIIT on imaging of the spine, peripheral joints and entheses in MRI (axial) and US (peripheral) compared to the control group. The analysed cohort comprised early PsA patients, and 31% of them were treated with bDMARDs. Similarly, Chronaiou et al. [55] analysed the impact of 11 weeks of HIIT on MRI of the spine in early axial PsA patients compared to the control group. In both studies, early inflammatory changes of the spine were scored using the Spondylarthritis Research Consortium of Canada (SPARCC) BME score, and inflammation of peripheral joints and entheses was assessed using semiquantitative gradation of brightness mode and Power Doppler images from 0 to 3. In the study by Chronaiou et al. [55], the images were scored by 1 reader in radiological evaluation for BME using the Assessment in SpondyloArthritis International Society criteria, by another reader in SPARCC score and by extraction of textural features.

Slouma et al. [54] investigated a correlation between levels of physical activity measured by 2 scales, the University of California and Los Angeles activity scale and the Tegner activity scale, supplemented with information regarding the weekly duration of exercise and physical activity, and disease progression as assessed by US imaging of 14 predefined entheses in patients with early r-axSpA. Ultrasound imaging was scored using the Spanish Enthesitis Index, Glasgow Ultrasound Enthesitis Scoring System and Madrid Sonographic Enthesitis Index.

The remaining 3 studies analysed the association between professional work and radiographic structural damage. Participants were categorized by their occupational activity into 2 groups: blue-collar workers with physically demanding jobs and white-collar workers with physically undemanding jobs. The rationale for this approach is that physically demanding jobs are presumably associated with more mechanical stress to the spine than sedentary ones. In a study by Ramiro et al. [21], the job type was determined by consensus, and Zhou et al. [20] and Ward et al. [19] used the Occupational Information Network (job classification database) to determine specific attributes of jobs (such as workers’ abilities, measures of work context, etc.) and found associations between particular activities and radiographic progression. The included studies involved participants with longstanding r-axSpA [19, 21] and PsA [20]. Radiograms were taken every 2 years in the Ramiro et al. [21] and Zhou et al. [20] studies and once in the study by Ward et al. [19] Cervical and lumbar spine X-rays were scored using the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) [21, 20] or the Bath Ankylosing Spondylitis Radiology Index for the spine (BASRI-s) [19]. Peripheral joint radiograms were scored using the modified Steinbrocker score [20]. Of concern, in the study by Ward et al. [19], the images were scored by only 1 reader.

Both scoring systems, mSASSS and BASRI-s, rate the degree of structural damage (including erosions, sclerosis or fusion) in the cervical and lumbar spine. The Bath Ankylosing Spondylitis Radiology Index for the spine additionally rates damage to SIJ. Detailed characteristics of the included studies are presented in Table I.

Outcomes of the analysed studies

Detailed information about the results of the analysed studies is presented in Table II.

Briefly, in a study by Thomsen et al. [56], the authors concluded that there is no significant influence of HIIT on the severity of inflammation in the peripheral joints, entheses, SIJ and spine assessed by US and MRI.

In an analysis by Chronaiou et al. [55], the number of participants with BME changes on radiological evaluation, in SPARCC scores or in textural features did not differ significantly between the 11-week HIIT group and the control group.

Slouma et al. [54] found no significant differences in US image of entheses in patients with r-axSpA between individuals practising and not practising exercise. Moreover, in the multivariate analysis, they found a lower occurrence of 3 or more enthesophytes in patients who exercised.

Ramiro et al. [21] concluded that patients with high mSASSS are mainly men, blue-collar workers and smokers. They suggested that blue-collar jobs amplified the effect of disease activity on radiographic damage in comparison with white-collar jobs.

Zhou et al. [20], analysing 307 patients with longstanding PsA, found a direct association between damage to the peripheral joints and prolonged repetitive hand movements and a high level of finger dexterity. No correlation was found between mSASSS and occupation-related mechanical factors.

Ward et al. [19] found that occupational activities, such as bending, twisting, reaching and stretching, and exposure to whole-body vibration are associated with greater radiographic damage in axial joints.