Psoriasis and osteoporosis: a literature review

Abstract Psoriasis is a chronic inflammatory skin disease with complex comorbidities. Recent evidence has revealed how the inflammatory nature of psoriasis affects bone mineral density and may lead to osteoporosis. This review outlines the current understanding and advances on the association between psoriasis and osteoporosis. The current literature suggests an increased risk of osteopenia and osteoporosis in patients with extensive and chronic psoriasis, compounded by other lifestyle and genetic factors. It suggests that prophylactic measures such as vitamin D supplementation and increasing weight‐bearing exercises can help, but in patients with extensive psoriasis, prolonged systemic inflammation may require long‐term management. Although there have been many short‐term RCTs on the efficacy and safety of biologics in psoriasis, clinical studies looking at the long‐term effects of biologics, such as whether they might improve bone mineral density in these patients with psoriasis are yet to be conducted.


Introduction
Over the past decade, evidence has linked psoriasis and psoriatic arthritis with cardiovascular disease and metabolic syndrome. Studies associate psoriatic arthritis with osteoporosis; however, there is limited literature on an association between psoriasis and osteoporosis. We aimed to determine if a relationship exists, through assessing the prevalence of osteopenia and osteoporosis in patients with psoriasis, and focusing on patients with severe psoriasis receiving treatment with monoclonal antibodies (biologics).

Psoriasis
Psoriasis is an immune-mediated chronic inflammatory skin disease affecting 2% of white populations, with its visibility causing social stigmatization, pain, discomfort and psychological distress, leading to reduced quality of life (QoL). 1,2 In psoriasis, cytokine overactivity leads to keratinocyte hyperproliferation, creating thickened inflamed plaques with silvery scale. [3][4][5] Patients with visible psoriatic plaques often cover their skin and avoid sport, contributing to osteopenia. 6 Metabolic syndrome occurs with extensive psoriasis. 7 In the past two decades, severe psoriasis has been managed with biologics. [8][9][10] Osteopenia and osteoporosis Osteopenia is characterized by low bone mineral density (BMD), and can progress to osteoporosis, the systemic diminished bone mass and deterioration of microarchitectural bone tissue, increasing the risk of bone fragility and fractures. 10 Osteoporosis affects > 200 million people worldwide, approximately 20% of men and 50% of women, with a higher prevalence among postmenopausal women. 11 Dual-energy X-ray absorptiometry measures BMD using T scores, 12 measured at the lumbar or proximal femur, with scores of À2.5 to À1 SD defined as osteopenia, and scores below À2.5 SD defined as osteoporosis. 13 Early osteoporosis diagnosis and intervention can prevent fractures. 14 Patients are recommended adequate calcium and vitamin D intake, weight-bearing exercises and pharmacological therapy. 14

Psoriasis pathophysiology and osteoporosis
In psoriasis, systemic T-cell activation plays a key role in the development of a T-helper 1 type cytokine pattern with predominant secretion of interleukin (IL)-2, IL-6, interferon (IFN)-c and tumour necrosis factor (TNF)-a. These cytokines induce abnormal proliferation and differentiation of keratinocytes, leading to psoriatic plaques 15 (Fig. 1). IL-6, IFN-b and TNF-a are involved in bone metabolism regulation and the pathogenesis of osteoporosis. 11 TNF-a and IL-6 increase the production of both receptor activator of receptor activator of nuclear factor-jB ligand and osteoprotegerin, which stimulate osteoclastogenesis. 16 Effects of antipsoriatic treatments on bone mineral density Antipsoriatic drugs such as methotrexate and ciclosporin interfere with bone metabolism, 17 and systemic corticosteroids reduce collagen genesis. [17][18][19] Ultraviolet light therapy increases vitamin D and improves BMD. 14,17

Prevalence of osteoporosis and osteopenia in patients with psoriasis
The first case-control study was conducted in Israel in 2009 by Dreiher et al., 20 enrolled 22 771 patients aged 51-90 years with a psoriasis duration of 5 AE 3 years, and 14 835 matched controls. Male patients with psoriasis had a higher prevalence of osteoporosis compared with controls (3.1% vs. 1.7%, OR = 1.86, P < 0.001).
In 2011, Pedreira et al. 21 performed a cross-sectional study of 52 patients in Brazil, and reported a higher incidence of fractures and metabolic diseases in patients with psoriasis and patients with psoriatic arthritis.
Balato et al. 22 conducted a prospective cohort study in 2012 in Italy on 102 patients with psoriasis, and identified an association between osteoporosis and psoriasis, with 5% prevalence.
A population-based case-control study by Keller et al. 3 in Taiwan enrolled 79 680 patients with psoriasis and 52 521 controls, and found a higher osteoporosis prevalence in patients with psoriasis (1.5% vs. 0.87%, OR = 1.65, P < 0.001) compared with controls (n = 52 521).
There was a proposal from D'Epiro et al. 16 that the higher risk of developing osteopenia and osteoporosis was linked with increased duration of psoriasis. A 2014 prospective cohort study of 43 patients in Italy by D'Epiro et al. 16 found a longer duration of psoriasis in patients with osteopenia or osteoporosis than in patients with psoriasis with a normal T score (17 years vs. 8.8 years). 16 Among patients with moderate to severe psoriasis, 66% had osteopenia and 18% has osteoporosis of the lumbar spine (L1-L4) and/or femoral neck. 16 In 2015, Kincse et al. 23 published a cross-sectional study from Hungary of 185 patients with a shorter duration of psoriasis (12 AE 6 years) and found a reduced BMD in patients with mild psoriasis compared with matched controls. 23 This study also recruited patients with moderate to severe psoriasis requiring systemic treatments, and found an inverse relationship between vitamin D and both body mass index and severity of skin involvement. 23 Nearly two-thirds (63%) of patients with psoriasis had vitamin D deficiency and BMD loss, and BMD was higher in patients with psoriatic arthritis than in patients with psoriasis alone. 23 A 2016 Norwegian study by Modalsli et al. 24 found no clear association in 48 194 patients between psoriasis and either BMD T score or osteoporosis prevalence. In 2017, a population-based crosssectional study in the USA by Kathuria et al. 18 assessed 183 725 patients with psoriasis (mean age: 54.4 AE 1 years) and ascertained the prevalence of osteoporosis to be 3.3%. This large sample size contributed to the general association not only between osteoporosis and psoriasis, 3,21 but also between osteoporosis and other comorbidities such as psoriatic arthritis and fractures. 18 In 2017, Lajevardi et al. 25 reported 64 patients aged 44 AE 17 years with chronic psoriasis (duration 27 AE 5 years in a cross-sectional study in Iran, and found that BMD levels were lower in males, 25 similar to the results from the previous study by Dreiher et al. 20 The prevalence of osteopenia (43.8%) and osteoporosis (12.5%) showed that BMD reduction was associated with psoriasis, 23,26 smoking and lack of physical activity. 25 Freier et al. 27,28 conducted two prospective cohort studies in Germany, investigating women aged around 60 with mild to severe psoriasis, over a period of 2 years. The prevalence of osteopenia and osteoporosis in patients with psoriasis was similar to the normal population, which contrast with the existing evidence at the time, and the authors suggest that further investigation was needed. 27,28 The study included only women and mild cases, potentially skewing the data.
A South Korean case-control study in 2021 by Lee et al. 29 analysed 79 212 control-matched patients with psoriasis with a mean age of 40 years. Osteoporosis was higher in patients with psoriasis compared  with controls (5.1% vs. 4.1%, OR = 1.21) and the increased risk of osteoporosis among patients with psoriasis aged ≥ 40 years was similar in both sexes. 29 In light of the current literature, there is an increased risk of osteopenia and osteoporosis in patients with extensive psoriasis who have had psoriasis for a long time, compounded by other lifestyle and genetic factors. It suggests that prophylactic measures such as vitamin D supplementation and increasing weight-bearing exercises can help but patients with extensive psoriasis and prolonged systemic inflammation may require long-term management.

Limitations of the study
The review showed that there are inconsistencies in the association of psoriasis and osteoporosis. Small sample sizes 16,21,23,25,27 affect the reliability and generalizability of the results, and missing patient information can further bias results 3,18,22,23,29 (Table 1). Lee et al. 29 did not provide details on psoriasis type, severity or duration. 24,26 Patients with psoriasis are more likely to have concurrent diagnoses such as osteoporosis, but they are also more likely to have increased exposure to medical professionals, thus there is a risk of surveillance bias. 3

Conclusion
The limited studies conducted on the association between psoriasis and osteoporosis have not assessed the prevalence of BMD in patients with psoriasis on biologics. Further studies are required to determine how chronic psoriasis may affect BMD and lead to generalized bone loss. This will also help assess the effects of psoriasis on BMD and report the levels of vitamin D in patients on biologics, assisting clinicians to consider whether to incorporate bone health into everyday management of patients with psoriasis.

Learning points
• Psoriasis is a chronic inflammatory skin disease that has been linked to multiple complex comorbidities, including osteoporosis.
• Cytokines (IL-6, IFN-c and TNF-a) involved in the pathogenesis of psoriasis have also shown to be present in the bone metabolism process of osteoporosis.
• The use of monoclonal antibodies (i.e. biologics) could have a role in the co-management of patients with psoriasis with low BMD compared with nonbiologic systemic treatments. • Limited studies have demonstrated an association between psoriasis and osteoporosis; in this review, 13 studies were critically appraised. • There is reasonable evidence in the literature to support the association between psoriasis and osteoporosis. • However, various limitations exist, and larger multicentre studies need to be conducted to validate the relationship between these two entities.