The Impact of Targeted Therapies on the Bone-Vascular Axis in Psoriasis: A Narrative Review

Introduction

Psoriasis is increasingly recognized as a systemic immune-mediated inflammatory disorder, contributing to a range of comorbidities, including psoriatic arthritis (PsA), metabolic dysfunction, impaired skeletal health, and cardiovascular disease (CVD), which cannot be fully explained by traditional risk factors.^1–4 Studies show that 40–60% of psoriasis patients have reduced bone mineral density (BMD), and many also experience vascular calcification, particularly those with CVD. Ogdie et al found that PsA patients have a higher incidence of cardiovascular events, including myocardial infarction and stroke, compared to the general population.³ This review focuses on the role of biologic agents and small-molecule inhibitors in managing these comorbidities, particularly their effects on bone and vascular health.

A key issue is that even with controlled skin activity, residual systemic inflammation can still lead to bone loss and vascular calcification. This suggests a shared, inflammation-driven pathobiology rather than coincidental comorbidities. Moreover, vascular calcification progression is linked to reduced BMD in psoriasis.⁵

Psoriasis is driven by the IL-23/IL-17 axis, where Th17 responses amplify cytokines like IL-17A, IL-17F, and IL-22, contributing to skin pathology and systemic effects.^5–8 In moderate-to-severe disease, psoriasis acts as an “inflammatory pump,” releasing TNF-α, IL-6, and IL-1β, which disrupt bone remodeling and impair vascular homeostasis.^1,9 We explore the molecular basis of the bone-vascular axis in psoriasis, summarize evidence linking targeted therapies to skeletal and cardiovascular outcomes, and propose a management strategy that goes beyond skin clearance.

Literature Search Criteria and Terms

We conducted a comprehensive narrative review to synthesize current evidence on the inflammation-driven bone–vascular axis in psoriasis. We searched PubMed, MEDLINE, and Embase for English-language publications up to January 2026 using combinations of keywords and MeSH/Emtree terms related to psoriasis, psoriatic arthritis, IL-23/IL-17, bone metabolism, osteoporosis, RANKL/OPG, vascular calcification, atherosclerosis, cardiovascular events, FDG-PET/CT, GlycA, and targeted therapies (TNF inhibitors, IL-17/IL-23 inhibitors, JAK inhibitors, TYK2 inhibitors).

Inclusion criteria focused on peer-reviewed randomized controlled trials (RCTs), systematic reviews, large cohort studies, and mechanistic studies directly addressing the bone–vascular axis in psoriatic disease; whereas case reports, small-scale pilot studies, and non-English publications were generally excluded. We additionally screened ClinicalTrials.gov and major conference proceedings for pivotal Phase II/III trials and long-term extension data to ensure the integration of the most recent clinical evidence. Priority was given to high-quality RCTs and meta-analyses directly relevant to the skeletal and cardiovascular outcomes of targeted therapies. References of key reviews and landmark studies were hand-searched to identify additional eligible reports. As this is a narrative review intended for conceptual synthesis and thematic integration rather than a systematic meta-analysis, a formal risk-of-bias (RoB) assessment for each included study was not performed, representing a limitation in methodological secondary analysis.

Molecular Mechanisms of the Bone-Vascular Axis: Deciphering the Calcification Paradox

In psoriasis, a “calcification paradox” is observed, where reduced bone mineral density (BMD) occurs alongside vascular calcification (VC). As shown in Figure 1, this paradox can be explained by the dysregulation of the bone-vascular axis, driven by sustained cytokine exposure and oxidative stress, which promotes osteoclast activity and osteogenic reprogramming of vascular smooth muscle cells (VSMCs).

Figure 1 Schematic representation of the bone–vascular axis in psoriasis and therapeutic interception points. (A) Psoriasis-driven activation of the IL-23/IL-17 pathway leads to systemic cytokine spillover. (B) Within the skeletal compartment, elevated levels of IL-17A and TNF-α increase RANKL expression while reducing OPG levels, thereby enhancing osteoclast activity and promoting bone loss; concurrently, entheseal microenvironments may develop pathological osteoproliferation. (C) Simultaneously, within the vasculature, inflammatory and metabolic stress induces osteogenic reprogramming of vascular smooth muscle cells (VSMCs), evidenced by upregulation of Runx2, promoting vascular calcification. (D) Therapeutic interception points shown include blockade of the IL-23/IL-17 axis, TYK2 inhibition, and adjunct cardiometabolic therapies (eg., GLP-1RA). Symbols: α, alpha; ↑, increased expression or upregulation. Abbreviations: GLP-1RA, glucagon-like peptide-1 receptor agonist; IL, interleukin; OPG, osteoprotegerin; RANKL, receptor activator of nuclear factor kappa-B ligand; Runx2, runt-related transcription factor 2; TNF, tumor necrosis factor; TYK2, tyrosine kinase 2; VSMC, vascular smooth muscle cell.

Biological Drivers of Vascular Calcification

VC is now recognized as an actively regulated process rather than passive mineral deposition. In inflammatory milieus, vascular smooth muscle cells (VSMCs) can undergo osteogenic transdifferentiation, downregulating contractile markers and upregulating osteogenic mediators such as Runx2, BMP-2 (preclinical evidence), and alkaline phosphatase.^10–13 Pro-inflammatory cytokines and oxidative stress activate NF-κB, STAT3, and Wnt/β-catenin signaling (preclinical), lowering the threshold for calcific remodeling.^12,13 Inflammasome activation (eg., NLRP3) and cell death pathways can further promote release of calcification-competent matrix vesicles that serve as nucleation sites.¹² IL-17A may amplify these processes via oxidative stress and osteogenic gene transcription, plausibly contributing to both medial calcification and plaque-associated microcalcification phenotypes.¹³

Clinical takeaway: In psoriatic disease, VC should be viewed as an inflammation-modulated, cell-programming phenomenon, supporting therapeutic strategies that reduce systemic inflammatory burden and cardiometabolic stress rather than focusing solely on traditional lipid-centric paradigms.

Bone Metabolic Disorders and Inflammation-Mediated Osteoclast Activity

On the skeletal side, systemic inflammation primarily leads to bone loss via the RANK/RANKL/OPG system. Pro-inflammatory cytokines TNF-α and IL-17 can significantly induce the release of RANKL from osteoblasts and immune cells (translational/clinical data). RANKL binds to the RANK receptor on osteoclast precursors, activating multiple signaling pathways (eg., NF-κB and MAPK) to promote osteoclast maturation and function.^11,14 It is noteworthy that psoriasis and its associated PsA exhibit unique skeletal manifestations, often presenting with pathological new bone formation at entheseal sites alongside systemic bone loss. This dynamic imbalance between bone resorption and formation results from the differential effects of the IL-23/IL-17 axis in distinct microenvironments. Within the joint microenvironment, IL-17A has been shown to promote the differentiation of mesenchymal progenitor cells into osteoblasts (preclinical/clinical), particularly at damaged entheseal sites, leading to joint stiffness and structural damage^14,15(Table 1).

Table 1 Key Pathogenic Processes in the Psoriasis-Related Bone-Vascular Axis and Their Effects on Skeletal and Cardiovascular Systems

Intervention of Biologic Agents on Skeletal Integrity and Structural Protection

The advent of biologic agents has profoundly transformed the treatment landscape for psoriasis and psoriatic arthritis (PsA). By precisely blocking upstream regulators or downstream effectors, these agents not only improve clinical symptoms but also demonstrate potential for modulating bone metabolism.

IL-23 Inhibitors: Upstream Control and Structural Outcomes

IL-23 inhibitors (eg., guselkumab, risankizumab) suppress Th17 pathway maintenance, offering upstream inflammatory control. In PsA, radiographic progression is a clinically meaningful endpoint. In the APEX study, guselkumab demonstrated significantly less radiographic progression compared to placebo at Week 24, with a mean change in the PsA-modified vdH-S score of 0.55 versus 1.35 (P = 0.002), an effect that was sustained through longer follow-up.¹⁶ Furthermore, long-term follow-up from the DISCOVER-2 study substantiated the efficacy of guselkumab in structural protection, specifically manifested as significant reductions in the incidence of joint space narrowing and bone erosion.¹⁷

IL-17 Inhibitors: A Novel Paradigm of Dual Blockade

Bimekizumab, currently the only agent capable of simultaneously inhibiting both IL-17A and IL-17F, has garnered significant attention for its performance in bone protection. Given that IL-17F is more abundant than IL-17A in psoriatic synovium and skin lesions, and the two exhibit synergistic effects in inducing pro-inflammatory gene expression, dual blockade is believed to provide deeper inflammatory control.¹⁶ In the BE OPTIMAL study for PsA, bimekizumab demonstrated potent inhibition of radiographic progression over 52 weeks, with over 87% of patients showing no significant progression (defined as ΔvdH-S ≤0.5).¹⁸ Long-term follow-up data from studies such as BE MOBILE 2 further confirmed the excellent performance of bimekizumab in maintaining minimal disease activity and clearing swollen joints, which clinically translates into long-term protection of joint function and skeletal integrity¹⁹ (Table 2).

Table 2 Clinical Trials of Biologic Agents in Psoriatic Arthritis: Follow-Up Duration, Key Skeletal Metrics, and Clinical Significance

Systemic Bone Mineral Density: A Less Consistent Signal

While biologics convincingly prevent erosive joint damage, evidence for improvement in systemic BMD is mixed. Anti-TNF therapy has been associated with increases in lumbar spine BMD in some cohorts, whereas other longitudinal studies report no significant change.^20,21 This discrepancy likely reflects a temporal and mechanistic dissociation: osteoclast-driven resorption may normalize rapidly after inflammatory suppression, but restoration of osteoblast function, bone formation, and mineralization is slower and influenced by vitamin D status, physical activity, and metabolic factors.

Section takeaway: Current evidence supports biologics as disease-modifying for structural joint outcomes in PsA; however, systemic BMD improvement is variable and likely requires adjunctive lifestyle and metabolic optimization.

Targeted Therapies and Cardiovascular Risk: Imaging Manifestations and Real-World Evidence

Psoriasis confers elevated cardiovascular risk that is not fully captured by traditional risk factors, with biological hallmarks including accelerated subclinical atherosclerosis, endothelial dysfunction, and altered plaque biology.^22–24 To quantify therapeutic effects, studies increasingly rely on surrogate imaging endpoints such as ¹⁸F-FDG PET/CT, where aortic target-to-background ratio (TBR) reflects vascular inflammatory activity.^25,26 Reductions in vascular FDG uptake have been reported after systemic therapy in some cohorts, suggesting improvement in vascular inflammation concordant with reduced systemic inflammatory burden.^26,27

Importantly, changes in vascular inflammation or biomarkers should be interpreted as surrogate signals, not definitive proof of reduced cardiovascular events. Long-term RCTs powered for MACE in psoriasis remain scarce, and vascular remodeling may lag behind skin clearance. For example, despite strong dermatologic efficacy, adalimumab did not consistently improve vascular inflammation over 12–52 weeks in randomized settings, underscoring potential dissociation between cutaneous response and vascular endpoints and/or counterbalancing metabolic effects.²⁷ Emerging biomarkers such as GlycA may capture systemic inflammatory burden and partially mediate relationships between psoriasis severity and coronary plaque burden, offering promise for risk stratification and monitoring.^28,29 Section takeaway: Current data support beneficial effects of some systemic therapies on vascular inflammation surrogates, but definitive evidence for MACE reduction is limited; integrated cardiometabolic management remains essential.

Safety Profile of Small-Molecule Inhibitors: JAK versus TYK2

Regulatory concern regarding JAK inhibitors has been shaped largely by high-risk RA populations (eg., ORAL Surveillance). In PsA, available network meta-analyses suggest MACE and thromboembolic risks for tofacitinib and upadacitinib may be comparable to TNF inhibitors, with relatively low event rates (eg., IR ≈ 0.25/100 person-years).^30,31 Notably, integrated analysis of clinical trials for upadacitinib has demonstrated a consistent safety profile over up to 5 years of treatment across various spondyloarthritis phenotypes.³² However, lower baseline risk and selection effects likely contribute to these estimates. Accordingly, cardiovascular risk stratification remains critical before initiating JAK inhibitors, particularly in individuals aged ≥65 years, smokers, or those with established cardiovascular disease.^33,34

Deucravacitinib, an allosteric TYK2 inhibitor, does not inhibit JAK1/2/3 catalytic activity and therefore may have a distinct safety profile. Long-term extension datasets report low and stable exposure-adjusted MACE rates and no clinically meaningful adverse lipid or blood pressure signals over multi-year follow-up.^35–38However, while these signals are encouraging, it is important to note that large-scale, hard endpoint-driven cardiovascular outcome trials (CVOTs) are still awaited to confirm the definitive long-term cardiovascular protection of TYK2 inhibition in this population.

Section takeaway: JAK inhibitors require careful risk stratification; while TYK2 inhibition shows favorable safety signals in long-term extension data to date, continued real-world validation and dedicated cardiovascular outcome trials are warranted (Table 3).

Table 3 Long-Term Safety Comparison Between Conventional JAK Inhibitors and TYK2 Inhibitors in Psoriatic Arthritis Treatment

Risk Tools & Pathway

Traditional risk calculators often underperform in psoriatic disease because they incompletely capture inflammation-driven risk. QRISK3 incorporates chronic inflammatory disease and glucocorticoid exposure, improving discrimination in some cohorts but potentially overestimating risk depending on population calibration.^39–41 SCORE2, developed in the modern prevention era, may demonstrate better calibration in European populations, although performance varies across regions and disease phenotypes.⁴² A pragmatic approach may combine QRISK3’s discriminatory capacity with SCORE2’s calibration characteristics, complemented by targeted imaging in intermediate-risk patients.

Guidelines (AAD-NPF/EULAR) have historically suggested multiplying calculated risk by 1.5 for severe psoriasis or systemic-therapy candidates, yet the need for a universal multiplier may be reduced when using risk tools that already embed inflammatory variables (eg., QRISK3).^43,44 To reduce screening gaps, structured pathways recommend baseline assessment of glucose, lipids, blood pressure, and central adiposity, with CAC scoring or carotid ultrasound to detect subclinical atherosclerosis in intermediate-risk individuals.^4,44 Early statin initiation may yield dual lipid-lowering and anti-inflammatory benefits and may mitigate lipid changes seen with some immunomodulators.⁴⁵ GLP-1 receptor agonists are promising adjuncts for cardiometabolic optimization; however, evidence specifically attributing MACE reduction in psoriasis to GLP-1RA use should be interpreted in light of study design and confounding until more robust endpoint data are available.⁴⁶

Section takeaway: Risk estimation in psoriasis should be tool-aware and population-calibrated, augmented by subclinical imaging when appropriate, and embedded within an interdisciplinary cardiometabolic management pathway.

Conclusions and Recommendations for Further Research

Psoriasis is a systemic inflammatory disease in which dysregulation of a bone–vascular axis may drive concurrent skeletal fragility and vascular calcification. Mechanistic evidence implicates IL-23/IL-17–centered inflammation in both RANKL/OPG imbalance–mediated bone resorption and osteogenic programming of the vascular wall. Clinically, biologics targeting IL-23 and IL-17A/F show consistent benefit in structural outcomes in PsA, whereas effects on systemic BMD remain heterogeneous and likely require longer time horizons and adjunctive metabolic and lifestyle interventions. For cardiovascular comorbidity, improvements in surrogate measures of vascular inflammation and inflammatory biomarkers are encouraging, but definitive evidence for MACE reduction remains limited by the scarcity of long-term endpoint-driven trials.

While IL-23/IL-17 inhibition has shown significant efficacy in managing bone and cardiovascular comorbidities in psoriasis, additional inflammatory pathways, such as IL-6 and TNF, likely contribute to the observed disease comorbidities. Future longitudinal studies, particularly those assessing fracture risk and major cardiovascular events, are essential to further elucidate the long-term benefits and safety of these therapeutic interventions.

Future studies should prioritize (i) validated translational biomarkers that predict skeletal and cardiovascular trajectories beyond skin response, (ii) early-intervention designs testing whether high-efficacy therapy alters progression from psoriasis to PsA and downstream bone–vascular outcomes, and (iii) pragmatic real-world comparative effectiveness and safety studies—particularly for oral targeted agents—integrating cardiometabolic co-therapies to optimize long-term outcomes.