Unveiling the Elevated Risk of Osteoporosis and Fractures in Idiopathic Inflammatory Myopathies: Emphasizing Awareness of Modifiable Risk Factors

Abstract

Comorbid conditions such as cardiovascular diseases, mood disorders, and renal impairment can be observed in patients with autoimmune inflammatory rheumatic diseases. One of the most important comorbidities relates to bone health [1]. Osteoporosis and fragility fractures are more common in patients with idiopathic inflammatory myopathies (IIMs) compared to healthy population [2, 3]. Lee et al. reported increased osteoporosis risk in dermatomyositis or polymyositis independent of the treatments [4]. The current article aimed to (i) review the literature on bone health in IIMs and (ii) discuss the predictors of impaired bone health emphasizing awareness of modifiable risk factors.

The results of the previous studies revealed that 13%–32.7% of myositis population had osteoporosis [5-9] (Table 1). Fracture rate is also more common in patients with IIMs than in healthy subjects (17.9% vs. 5.1%) [3]. Patients with previous vertebral fractures accrue fractures at a rate of 26.2 per 100 patient years [10]. Moreover, almost half of the patients with inflammatory myositis have asymptomatic vertebral fractures [8]. The diversity in osteoporosis frequency may partly be related to the interpretation of dual energy X-ray absorptiometry (DXA) reports [5-9]. The Adult Official Positions of the International Society for Clinical Densitometry recommends BMD testing in all adults with a disease/condition causing low bone mass/bone loss or those taking medications related to low bone mass/bone loss. Measuring BMD at both the posteanterior spine and hip is recommended. Forearm BMD should be tested if hip and/or spine cannot be measured or interpreted, or if hyperparathyroidism exists, or the patient is above DXA weight limit [11]. According to the Adult Official Positions of the International Society for Clinical Densitometry, osteoporosis may be diagnosed in postmenopausal women and men aged ≥ 50 if the T-score of the lumbar spine, total hip, or femoral neck is ≤ −2.5. Other hip areas (e.g., Ward's area) should not be utilized to diagnose. In certain cases, the 33% radius may be used. On the other hand, in females prior to menopause and in males < 50 years of age, Z-scores are preferred instead of not T-scores. Z-scores ≤ −2.0 are defined as “below the expected range for age”. The diagnosis of osteoporosis cannot be made solely based upon BMD in men < 50 years of age. Women in the menopausal transition may be diagnosed using the World Health Organization criteria [11].

The risk factors of osteoporosis and fractures in IIMs can be categorized into three as (i) non-modifiable factors, (ii) potentially modifiable factors, and (iii) modifiable factors. Non-modifiable risk factors include advanced age [2, 3, 8, 12], female gender [6], disease duration [13], genetic background (race, family history), menopause [3], and low peak bone mass. Nevertheless, low peak bone mass may potentially be modified through appropriate education on bone health in younger ages. Although longer disease duration is a risk factor for osteoporosis in IIM patients, Gupta et al. showed that half of the fractures occurred in subjects with disease duration of less than 5 years [8]. While this finding might be attributed to the potential role of ongoing inflammation-that is to say disease itself-in bone impairment, current evidence in IIMs has several limitations. Only a limited number of studies considered bone mineral density testing at the early phase of IIMs. The mechanism of impaired bone health secondary to systemic inflammation in IIMs should be evaluated in studies with larger sample sizes. Moreover, the effects of glucocorticoid use should be controlled/excluded in analyses before concluding that inflammation itself is primarily responsible for the observed bone impairment in IIMs.

Disease-related variables including inflammatory status (disease activity), muscle weakness, glucocorticoid therapy, impaired balance, and frailty can be regarded as potentially modifiable risk factors. The impact of inflammation on bone health relates to the increased secretion of pro-inflammatory cytokines such as interleukin (IL)-6, tumor necrosis factor-α (TNF-α), and IL-1; and the decrease in protective cytokines like IL-2 and IL-10. Such an imbalance induces osteoclastogenesis [14]. TNF-α and IL-1 can directly induce the expression of osteoclast-associated receptor, which is a costimulatory molecule in osteoclastogenesis. They can also increase the expression of receptor activator of nuclear factor-kappa B ligand [1]. There is limited data regarding the potential association of autoantibody profile with bone health in IIMs. Valle et al. showed that elevated rate of osteoporosis was independent of anti-Sjögren's-Syndrome-related antigen A (anti-SSa)/SSb or anti-Ro52 status [5]. It is possible to reduce the risk of osteoporosis/fractures through appropriate management of the disease. On the other hand, steroid therapy can lead to glucocorticoid-induced osteoporosis. In their study, Kalluru et al. showed that 85% of the IIMs experienced osteopenia or osteoporosis as a steroid-related complication [15]. This point underscores the importance of routine follow-ups in patients with IIMs, those on steroid therapy in particular.

Modifiable factors include aspects such as hypovitaminosis D, smoking and alcohol consumption, nutritional deficiencies, and a sedentary lifestyle. Being aware of the modifiable risk factors and targeting them is essential in preventing bone loss in IIMs. Such an approach can also help reduce fracture risk and fracture-related morbidities and mortality. Vincze et al. showed that the number of prevalent fractures was correlated with reduced physical function and poorer health status in patients with myositis group [12]. Exercise therapy can improve bone health through several mechanisms in patients with IIMs. Exercise can enhance capillary density, thereby improving microcirculation in muscles. Additionally, mitochondrial biogenesis and enzyme activity can be increased particularly by endurance exercises [16, 17]. Improved protein synthesis and cytoskeletal restructuring can increase muscle strength/function, which is required for proper bone health. A large cohort study revealed that patients who achieve or exceed recommendations for physical activity present with better muscle function and lower organ damage assessed by the Myositis Damage Index compared to individuals who were physically inactive [18]. Exercise has anti-inflammatory effects as well. Reprogramming of immune and inflammatory pathways and reduction in endoplasmic reticulum stress can decrease muscle fibrosis. This effect not only decreases inflammation-related bone loss, but also further improves muscular strength and function [16]. Increased muscle activity and mechanical loading can enhance osteblastogenesis. Moreover, improved muscular performance can reduce the risk of falls and fractures. Thus, contrary to the earlier belief that exercise should be avoided in IIM, it is now considered a crucial and safe non-pharmacological supportive treatment in all stages of the disease [19].

Patients with IIMs-particularly those on glucocorticoids-should be evaluated regularly in terms of osteoporosis risk. According to the 2022 American College of Rheumatology Guideline for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis, fracture risk assessment should be performed in adults starting/continuing glucocorticoids for over 3 months. Pharmacologic treatment is recommended for those at medium to very high fracture risk, with oral or intravenous bisphosphonates, denosumab, or parathyroid hormone analogs. Anabolic agents are conditionally recommended as initial therapy for high−/very high-risk cases [20].

When managing patients with IIMs, it is crucial to carefully consider modifiable risk factors for osteoporosis. A few practical ways to address the modifiable risk factors are proper nutrition and consumption of essential vitamins/minerals, quitting smoking, avoidance of excessive alcohol intake, management of hypovitaminosis D, and tailoring individualized exercise regimens [1]. Modifiable risk factors can significantly impact the patient's condition, and because they can be adjusted, they present an important opportunity for intervention.

Conception and design of study: I.C.B., H.A., L.G. Interpretation of literature data: I.C.B., H.A., L.G. Drafting the article: I.C.B. Revising the article critically for important intellectual content: I.C.B., H.A., L.G. Final approval of the version to be submitted: I.C.B., H.A., L.G. All co-authors take full responsibility for the integrity and accuracy of all aspects of the research. All authors approve the submitted version of the manuscript.

The authors declare no conflicts of interest.