Osteoporosis in Rheumatology

Abstract

Introduction

Osteoporosis is a common diagnosis and comorbidity observed in patients with rheumatic diseases. It is frequently associated with conditions such as rheumatoid arthritis, spondyloarthropathy, systemic lupus erythematosus, and other autoimmune rheumatic diseases.

Conclusion

The incidence of osteoporosis is influenced by factors such as uncontrolled disease, prolonged and higher doses of steroid use, immobility, advanced age, and postmenopausal status. Achieving good control of the underlying disease, minimizing or avoiding the use of steroids for extended periods, and ensuring adequate supplementation of vitamin D and calcium are crucial in reducing the incidence of osteoporosis. Regular screening and appropriate management of osteoporosis can significantly decrease the associated morbidity and mortality.

Introduction

Advances in the management of autoimmune rheumatic diseases (AIRDs) have contributed to improved survival rates and maintenance of mobility. Cardiovascular diseases contribute to increased mortality among patients with AIRDs, while deteriorating bone health leads to reduced quality of life and certain morbidities. Osteoporosis is one of the major comorbidities that vary among different AIRDs and is often ignored by the treating physician and rheumatologist. Osteoporosis in rheumatology practice can be encountered in two different circumstances. Patients with symptomatic osteoporosis, experiencing vague pain and ache symptoms, may present initially to a rheumatology clinic and their primary concern could be osteoporosis requiring direct management. Osteoporosis is often referred to as a ‘silent thief,’ as it typically manifests with pain only in cases with fractures. Often patients suffer from bone pain due to enhanced nociceptive and neuropathic pain [1].

Patients with osteoporosis develop back pain and often have an increased likelihood of having secondary bone fractures. However, it is important to note that the pain can occur without vertebral fracture and can be distinguished clinically by patients reporting higher pain intensity and specific characteristics such as worsening during the daytime and upon body movement [2]. Pain associated with osteoporosis requires a specialized approach for pain reduction, alongside the management of the underlying osteoporosis. Additionally, there is another scenario in which osteoporosis acts as an additional comorbidity. This can arise as a direct consequence of the disease itself or as a result of drug administration including the use of glucocorticosteroids in the management of autoimmune inflammatory rheumatic diseases (AIRDs) [3]. The steroid-induced osteoporosis is one of the common causes of osteoporosis and has been discussed in the related chapters. The current chapter focuses on the relevant aspects of glucocorticoid-induced osteoporosis (GIOP) and associated rheumatic diseases. The chapter also focuses on other drugs used in rheumatology that can contribute to the development of osteoporosis and other bone disorders, along with the impact of disease activity itself.

Autoimmune Rheumatic Diseases and Osteoporosis

Inflammation and immobility are the primary pathogenic mechanisms that lead to bone loss in AIRDs. Cytokines, the key mediators of inflammation, play a crucial role in increasing bone turnover, impairing blastogenesis, and ultimately causing osteoporosis. These cytokines alter metabolic processes as well the function of osteoclast or osteoblast through different signals and mechanisms. Specifically, they act on secondary regulators of bone remodelling such as activator of the nuclear factor kappa-B ligand (NFkB), receptor activator of nuclear factor-κB ligand (RANKL)/osteoprotegerin (OPG) and Wnt pathways.

The role of drugs in the development of osteoporosis in AIRDs is controversial. Osteoporosis has been observed in patients with active diseases, even without any drug exposure. There are reports suggesting that certain drugs, including corticosteroids, may provide an initial protective benefit by reducing inflammation and inflammatory cytokine. However, corticosteroids when used at higher doses for longer periods, their metabolic effects can lead to subsequent reduction in bone density (Fig. 1).

Fig. 1.

The mechanism of osteoporosis in AIRDs. Red lines with blunt ends indicate inhibition and the arrows show activation of steps

Osteoporosis in Common AIRDs

Rheumatoid Arthritis

It is a common AIRDs with a prevalence ranging from 0.6 to 1.3% in the population. Although the outcomes of rheumatoid arthritis (RA) have significantly improved, the associated comorbidities often have a negative impact on the life-expectancy and quality of life of affected subjects. Osteoporosis is one of the most common comorbidities that remains inadequately diagnosed and managed both in speciality care as well as in primary care. However, the level of management and diagnosis tends to be slightly better in specialty care as opposed to primary care. Osteoporosis is often asymptomatic and reduced mobility may be the only clue in most cases. Immobility, age, post-menopause, prolonged use of steroids, persisting high disease activity are the major predisposing factors for the development of osteoporosis. Studies indicate that both local and systemic osteoporosis can develop at the initial phases of the disease. The maximum accumulation occurs during the initial stage of disease, followed by a study state of bone loss. Even the use of steroids for controlling inflammation can paradoxically reduce bone loss. Patients with active disease experience significant decline in bone mass compared to those managed with moderate- to low-dose steroids. The prolonged use of steroids, especially in higher doses, increases bone loss, irrespective of the disease activity.

The reported incidence of osteoporosis differs across countries, ranging from 22% to more than 50% among RA patients. However, there is a limited number of studies addressing the problems in India. The studies that have evaluated the incidence of related comorbidities in India have collected the data retrospectively, and the reported prevalence of osteoporosis is < 10%. However, prospective studies have reported the prevalence as between 20 and 30%, respectively [3, 4]. The incidence of osteoporosis reported in Western literature is higher than in Indian literature. One possible reason for the lower incidence in Indian RA patients could be that Indian subjects tend to be younger than their Western counterparts [5]. However, studies have emphasized the fact that osteoporosis as a comorbidity can significantly impact both quality of life and mortality [6]. Hence, several recommendations suggest proactive screening for osteoporosis, especially in high-risk patients (Table 1).

Table 1.

Indications for osteoporosis screening in AIRDs

1. Long-standing AIRDs

2. Post-menopausal status

3. Use of high-dose steroids with cumulative use of > 6 months

4. Prolonged high disease activity

5. Immobility

6. Presence of other risk factors of osteoporosis such as smoking and sedentary life

7. Vague pain and aches, especially in the pelvic and low back regions

8. Fractures, especially pathological fracture or cases where trauma and fracture are mismatching

A protocol for screening osteoporosis is a step forward to reduce the incidence of osteoporosis and its related complications like vertebral and hip fractures. However, there are no specific guidelines, especially with reference to the Indian population. The agreement and usefulness of the Fracture Risk Assessment Tool (FRAX) without bone mineral density (BMD) is still a matter of debate, particularly in the presence of diseases like RA. However, the treatment decisions regarding the initiation of the treatment did not have significant differences [7]. Therefore, in resource-limited settings with limited availability of BMD, using the FRAX score can help to identify patients with osteoporosis. However, it would be ideal to use the dual-energy X-ray (DEXA) scan in such scenarios. The role of bone turnover markers is still debatable and the available literature is very limited. However, they can assist in choosing appropriate interventions and measuring the disease progression.

Recommendations from various organizations, including American College of Rheumatology, advocate early initiation of disease-modifying anti-rheumatic drugs (DMARDs), the minimal or low-dose use of steroids for the shortest possible duration, screening with DEXA or quantitative ultrasound (QUS) for early identification of osteoporosis in high-risk patients, and vitamin D and calcium supplementation. The management of osteoporosis may involve the use of bisphosphonates, denosumab, and parathyroid hormone (PTH) analogs when indicated [8].

Spondyloarthropathy Including Ankylosing Spondylitis

Spondyloarthropathy (SpA) differs from RA by increased new bone formation, characterized by syndesmophytes and sclerosis across synovitis [9]. The use of steroids is also relatively less in patients with SpA, as the response to steroids is not very encouraging in these patients. However, the literature indicates that osteoporosis and pathological fracture are the most common comorbidities reported in SpA. The reported prevalence varies from 3 to 50% [10]. The bone density of patients with axial SpA is significantly lower than the age-matched control [10]. The traditional DEXA measurement by anteroposterior may not be very effective and may often underreport the bone density due to overlying calcified tendons and the ligament. The lateral DEXA, instead of anteroposterior, may improve the assessment [11]. Recent methods like trabecular bone score (TBS) and high-resolution peripheral quantitative computed tomography (HR-pQCT) are more useful tools to assess fracture risk in patients with ankylosing spondylitis (AS) and other related SpA [12]. Due to sclerosis of the ligament, though core bone mass as well as trabecular bone loss occurs, it may not be reflected in BMD measured by conventional DEXA. The hip bone density may often reduce, whereas, with the advancing time in axial SpA, the spine bone density may apparently increase. This paradox is often due to measurement error rather than the actual process.

Vertebral fracture is a common complication observed in long-standing AS and has often led to severe disability. Bisphosphonates have been shown to play a critical role in the prevention of this complication. Low BMD is often observed in younger males suffering from AS, with 51–54% experiencing decreased BMD, and 13–16% having osteoporosis [13]. There are no specific guidelines available with reference to osteoporosis screening in AS and SpA. It is important to consider the possibility, even in younger male patients with a disease duration of > 10 years.

Since there are no guidelines or recommendations available with reference to the therapy of osteoporosis in SpA, general guidelines for osteoporosis can be used as a reference [14]. Since osteoporosis is more common in young males, it is recommended to evaluate any secondary causes for osteoporosis and manage them if present. Attaining good control of inflammation and disease, either using disease-modifying antirheumatic drugs (DMARDs) or biologics like Tumour Necrosis Factor-alpha (TNF-alpha) or Interleukin 17 (IL17), can preserve or even improve BMD. Currently recommended therapy in patients with moderate to severe osteoporosis is either oral or IV bisphosphonates [15]. The role of denosumab in the management of osteoporosis in SpA is debatable. Though receptor activator of NF-kappaB (RANK) pathways are speculated to be one of the primary reasons for the development of osteoporosis in SpA, there are not enough studies to validate the same. Neridronate, an intravenous N-bisphosphonate with high skeletal affinity, and pamidronate, an intravenous bisphosphonate, have been shown to be useful in reducing the disease activity and improving the BMD comparable to anti-TNF biologics [16, 17].

Osteoporosis in the context of SpA is underdiagnosed and poorly managed. Clinical suspicion should be raised, particularly in young adult males with a long-standing disease. Supplement with vitamin D and calcium may help in reducing the incidence of osteoporosis.

Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a multi-system autoimmune rheumatic disease that primarily occurs in younger females and is commonly managed with steroids. The use of steroids often poses a significant risk factor for developing osteoporosis. In addition, persisting inflammation associated with SLE is also responsible for the development of osteoporosis. Although studies available from Indian settings are limited, they have reported higher prevalence of osteopenia in the country compared to their Western counterparts [18]. The corresponding prevalence rates of osteoporosis and osteopenia reported by recent studies range between 5 to 10% and 40% to 50%, respectively. The differences in prevalence can be attributed to patient selection, disease activity, steroid usage, ethnicity, and other factors [19].

Osteoporosis screening is recommended, even in younger subjects, especially when other possible indications are present (Table 1). FRAX score may not be useful in this specific population and the BMD may need careful interpretation, considering the age-specific data of younger patients, which may differ from the WHO guidelines for osteoporosis [20]. Prevention is the key in the management of osteoporosis. Better management of SLE, minimal use of steroids, promoting mobility, and supplementing with vitamin D and calcium help reduce the incidence of osteoporosis. Drugs like bisphosphonate, teriparatide, and denosumab are useful in the management of osteoporosis.

Other Connective Tissue Diseases

Inflammatory myositis, vasculitis, and other connective tissue diseases have an increased incidence of osteoporosis, independent of steroid use. It is paramount to evaluate for osteoporosis in these conditions and implement effective management strategies.

Conclusion

Osteoporosis can complicate AIRDs and other rheumatic diseases, potentially increasing the associated morbidity and mortality. These complications can further impact the quality of life and overall well-being of patients. Therefore, it is essential to prioritize comprehensive evaluation and management of osteoporosis in this population.

Funding

None.

Declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical standard statement

This article does not contain any studies with human or animal subjects performed by the any of the authors.

Informed consent

For this type of study informed consent is not required.