Management of glucocorticoid-induced osteoporosis in rheumatic diseases

Abstract

Glucocorticoid-induced osteoporosis (GIOP) and its attendant fractures are a major concern for patients with rheumatic diseases. This 2025 review highlights preventive and treatment strategies for GIOP. An overview of the epidemiology and pathogenesis of GIOP is discussed. Key questions considered are.

(1) What are the optimum risk factor assessment strategies to identify patients with GIOP at fracture risk, including the role of clinical risk factors, imaging modalities and fracture risk calculators?

(2). What are the preventive strategies for GIOP incorporating information on steroid-sparing agents for the treatment of rheumatic diseases, the role of calcium and vitamin D intake, and exercise ?

(3). What are treatment strategies for GIOP with a focus on clinical trial data for FDA-approved therapies that have been studied in patients with rheumatic diseases?

Clinical practice guidelines are discussed. Future directions for the prevention and treatment of GIOP in persons with rheumatic diseases are considered.

1. Epidemiology of glucocorticoid induced osteoporosis (GIOP)

Long-term Glucocorticoid (GC) use is the leading cause of secondary osteoporosis and confers increased fracture risk [1]. In patients with rheumatic diseases, the use of oral GCs for more than three months has continually increased over the last 20 years, despite the advent and increasing availability of steroid-sparing therapies [2].

Loss of bone mineral density (BMD) occurs soon after administration of GCs. BMD loss begins within three months of GC administration and mainly affects trabecular-rich skeletal sites, such as the lumbar spine, although cortical bone is also affected [3,4]. BMD loss is dose and duration-dependent, with higher doses of GCs causing greater losses [5]. Longer duration of GC exposure, defined as greater than ninety days, is associated with increased fracture risk and further loss of BMD [6]. Changes in bone microarchitecture from GCs are also dose dependent and can be seen within as little as three months of administration [7]. The thoracic/lumbar vertebral column is the most common site of osteoporotic fracture in long-term users of GCs [8]. Sites with predominantly cortical bone, such as the distal forearm, are less common sites of fracture in the setting of GC exposure [9,10].

Studies investigating loss of BMD following GC administration have largely focused on oral therapy. Data on the effects of short-term, high-dose intravenous (IV) GCs on BMD and fracture risk in rheumatic diseases is limited. In a cohort of patients with rheumatoid arthritis (RA) given IV GC pulse therapy, BMD at the lumbar spine, femoral neck, and total body was not significantly reduced compared to baseline values. In contrast, BMD was significantly decreased in all areas examined in patients treated with oral methylprednisolone [11]. However, in patients with Graves’ orbitopathy treated with IV GC pulse therapy, even a single dose of IV GC therapy, decreased bone formation and resorption markers [12].

Studies evaluating epidural GC administration, used for back pain, have historically reported inconsistent effects on BMD [13,14]. More recent data, however, suggests that the frequency and total number of epidural steroid injections (ESIs) negatively affect BMD [15,16]. A study in persons receiving ESI for radicular back pain observed a 39% higher fracture rate among those who received ESI compared to those who did not. Rates of spine fractures, an area particularly vulnerable to the effects of GCs, were 54% higher compared to the non-ESI group [17]. In terms of intra-articular GC administration, suppression of bone formation has been reported [18], but there are no studies that report changes in BMD or fracture risk.

Time since last exposure to GCs is an important consideration for fracture risk, but recovery of loss in BMD from GCs is gradual and often incomplete [19]. Cumulative exposure to GCs predicts fracture risk following GC discontinuation. One study reported that fracture risk returned to baseline levels after 6 months of GC discontinuation in those with <1 g of cumulative GC dose, whereas those with ≥1 g did not return to baseline levels until 15 months later. [20]. There is also a genetic contribution to BMD loss and fracture risk from GCs [21–23]. As such, it may be appropriate to consider, even in patients who are at a low fracture risk following GC discontinuation, continued fracture prevention therapies beyond GC discontinuation for a finite time (e.g., 6-12 months) [24].

2. Pathogenesis of glucocorticoid-induced osteoporosis

This section reviews the mechanisms by which GCs lead to osteoporosis, recognizing that their effects on the bone are often difficult to distinguish from the effects of the underlying inflammatory conditions(s) for which GC therapy is prescribed.

The section is divided into four parts: a description of the GC receptor (GCR); the impact of GCs on cells involved in bone formation and degradation; the impact of GCs on extra-osseous mechanisms influencing bone health; and histologic bone changes associated with chronic GC use.

2.1. The glucocorticoid receptor (GCR)

The GCR resides in the cytosol of most cells, complexed with a variety of proteins, including heat shock proteins [1]. When the glucocorticoid hormone cortisol diffuses through the cell membrane into the cytoplasm, it binds to the GCR, resulting in the release of heat shock proteins. Activated GCR is then transported via active processes into the nucleus, where it either directly attaches to DNA and stimulates gene expression or it complexes with other transcription factors, preventing them from binding to their target genes. The latter effect suppresses the expression of genes associated with inflammation that are normally upregulated by NF-κB or the activator protein-1 (AP-1) [25].

2.2. Osseous effects of glucocorticoid therapy

The major effect of GCs on the skeleton is impairment of bone formation. GCs inhibit the proliferation and differentiation of osteoblasts and enhance the apoptosis of osteoblasts and osteocytes.

2.3. Extra-osseous effects of glucocorticoid therapy on bone

2.3.1. Calcium and phosphorus

GCs decrease calcium-binding-protein in the intestine, thereby lowering calcium absorption and bone mineralization [26]. Increased bone resorption from GCs may also lead to excessive calcium excretion in the urine, triggering secondary hyperparathyroidism [27].

2.3.2. Hormones

GCs, when given in high doses, reduce not only levels of Adrenocorticotropic Hormone (ACTH) but also levels of Luteinizing Hormone (LH) and Follicular Stimulating Hormone (FSH), thereby lowering estradiol, estrone, Dehydroepiandrosterone Sulfate (DHEAS), and testosterone [28]. Likewise, growth hormone, Insulin-like Growth Factor (IGF)-1 and Insulin-like Growth Factor-Binding Protein (IGFBP) levels are reduced by prolonged GC use [29,30]. GCs increase IGFBP transcription [6] which decreases IGF2 levels, a local regulator of osteoblast function [31].

2.3.3. Muscle

High doses of GCs lead to decreased protein synthesis and loss of muscle mass [32].

2.3.4. Genetics

Polymorphisms in the glucocorticoid receptor have been linked to varying responses to GCs and to risk of fracture [33]. Differences in genetics may help to explain the differences in effects that GCs can have on bone health in individuals.

2.4. Histopathology of bone after glucocorticoid use

Bone remodeling is initially activated by GCs, leading to high bone resorption. Over time, resorption parameters decrease, and bone becomes quiescent [34]. Bone biopsies from patients on GC therapy for more than 12 months show increased bone resorption, decreased bone formation, and decreased trabecular volume. GC-induced osteoporosis differs from post-menopausal osteoporosis. In GC osteoporosis, the number of trabeculae and their surface area are thin but still connected. In post-menopausal osteoporosis, trabeculae are perforated by resorption, with a loss of continuity [35].The preservation of thinned trabeculae in GC-induced osteoporosis may provide the foundation for new bone formation.

3. Prevention of glucocorticoid-induced osteoporosis

Overview.

There are a number of nonpharmacological and pharmacological measures available to prevent GIOP. The first step in decision-making is to determine the individual patient’s risk for fracture. A fracture risk assessment should include: (1) Consideration of dose and duration of GCs; (2) identification of patient-level fracture risk factors, including the contribution of the underlying rheumatic disease to fracture risk; (3) workup of secondary causes of osteoporosis; (4) measurement of Bone Mineral Density (BMD) (and potentially Trabecular Bone Scores (TBS) and radiographic imaging for vertebral fractures); and (5) utilization of fracture risk calculators that incorporate information on GC use.

3.1. Fracture risk and dose and duration of GCs

Fracture risk increases in a dose- and duration-dependent manner with GCs, with elevated risk observed even at low daily doses and within the first few months of GC treatment [36]. Doses of prednisone equivalents ≥7.5 mg/day confer a substantially higher risk for fracture, with up to a fivefold increase for vertebral fractures [37–42].

Duration of GC therapy is also an important determinant of fracture risk, as BMD loss progresses most rapidly during the first three to six months of GC initiation. Fracture risk increases by approximately 75% in the first three months of GC initiation and continues to rise with ongoing treatment [38,40]. Even short-term daily doses of ≥5 mg prednisone equivalents for thirty to fifty-nine days elevate vertebral and hip fracture risk, and doses ≥1 and < 2.5 mg prednisone equivalents daily for ninety days significantly increase vertebral and hip fracture risk [43].

3.2. Patient-level risk factors for fracture independent of GC use

3.2.1. Non- modifiable and modifiable fracture risk factors

A critical step in fracture risk assessment is identifying patient-specific risk factors. These include age, menopausal status, history of prior fragility fractures, body mass index (BMI), and frailty status [44]. Nonmodifiable risk factors for fragility fractures include older age [44], female sex, post-menopausal status [45–47], premature menopause (before age 40) [46,47], family history of fragility fractures [48] and previous fractures (particularly hip, vertebral, or minimal trauma fractures)^45–47. Age-adjusted hip fracture incidence rates are highest in White women, followed by Asian, Hispanic, and Black women [49]. Despite having lower BMD on average than White women, Asian women have a lower fracture risk [47–49].

Potentially modifiable fracture risk factors include current smoking [50,51], excessive alcohol intake [52,53], and low body weight (<57.6 kg). These fracture risk factors are independent determinants of bone loss and, as such, are incorporated into major fracture-risk assessment tools, including the Fracture Risk Assessment Tool (FRAX) and QFracture [37,47,53,54]. Other modifiable fracture risk factors include low calcium [46,55,56], vitamin D [56], and low protein intake [57], frequent falls [58,59], certain medications, and low levels of physical activity [58].

3.2.2. Contribution of rheumatic diseases to fracture risk

The risk of vertebral and nonvertebral fractures varies across rheumatic diseases. Risk is higher in patients with RA across all fracture sites. Patients with RA have a 1.5- to 3-fold increased risk of vertebral and nonvertebral fractures, with a comparable elevation in both sexes [60]. A 2025 meta-analysis including twenty-nine prospective cohorts reported that RA was associated with a hazard ratio (HR) of 1.49 (95% CI 1.35-1.65) for any clinical fracture and a HR of 2.23, (95% CI 1.85-2.69) for hip fracture, independent of sex, BMD, and GC exposure [61].

Patients with ankylosing spondylitis are at increased risk for vertebral fractures [62]. However, clinicians caring for patients with ankylosing spondylitis face unique challenges in fracture risk assessment as it is difficult to accurately assess the BMD of the lumbar spine by Dual energy X-ray absorptiometry (DXA) in these patients [63,64]. BMD is decreased in the hip (as shown by DXA) but not in the lumbar spine (by DXA) [65–68] later in the course of the disease. These paradoxical findings are due to the occurrence of bridging syndesmophytes and ligamentous ossification that artificially increase BMD by DXA [69–72]. Trabecular bone score (TBS) is a gray-level textural measurement derived from standard lumbar spine DXA images(L1-L4). Higher TBS values correlate with skeletal microstructure. Lower values indicate weaker bone texture. [73–76]. Low TBS (<1.23) is associated with a 5.3-fold increased risk of vertebral fractures ((OR 5.3, (95% CI 2.0–14.1)), and the presence of syndesmophytes independently increases the risk of vertebral fractures ((OR 5.5, (95% CI 2.2–13.5)) [77,78]. Therefore, femoral neck BMD and TBS are more accurate predictors of fracture risk than the lumbar spine by DXA in patients with ankylosing spondylitis [78].

Patients with Systemic Lupus Erythematosus (SLE) have an elevated fracture risk across several skeletal locations (RR 1.97(95 % CI 1.20-3.25)), particularly for hip (RR 1.99 (95 % CI 1.55-2.57)) and vertebral fractures (RR 2.97(95 % CI 1.71-5.16)) [79]. The risk of fragility fractures and osteoporosis is higher in patients with SLE who have lupus nephritis [80,81].

Despite inconsistent findings for osteoporosis and osteopenia, patients with psoriatic arthritis and psoriasis have a higher risk of fractures compared to controls [82–84].

The contribution of the disease states of polymyalgia rheumatica and giant cell arteritis (GCA) to fracture risk is difficult to dissociate from GC use, as GCs are first-line therapy for both conditions. In a Swiss population-based study, osteoporosis was almost three times higher in patients with GCA compared to the general population [85].

Similar to GCA, in all forms of systemic vasculitides (SV), GCs are a cornerstone of treatment, with high doses of IV GCs often initially required. A meta-analysis including forty studies with SV reported a pooled osteoporosis prevalence of 14.6% (95% CI 12.2–18.9) and fragility fracture prevalence of 17.1% (95% CI 11.4–24.8). Compared to healthy controls, the odds ratio for osteoporosis in SV patients was 2.92 (95% CI 1.72–4.98) and for fragility fractures was 2.39 (95% CI 1.34–4.26). Cumulative GC exposure was a significant predictor of osteoporosis risk [86].

3.3. Secondary causes of osteoporosis

3.3.1. Identification of secondary causes of osteoporosis

Screening to identify secondary causes of osteoporosis is needed for all patients at risk for fracture, including those receiving GCs. Up to 30% of postmenopausal women, more than 50% of premenopausal women, and between 50% and 80% of men have a secondary cause of osteoporosis [87]. Secondary causes of osteoporosis include endocrine, neuromuscular, or gastrointestinal diseases, chronic inflammatory conditions, chronic kidney disease (CKD), nutritional impairments, organ transplantation, HIV, malignancy, and genetic conditions [87]. The response to anti-osteoporosis treatments may be suboptimal if the underlying condition remains unrecognized and untreated [88,89].

Laboratory studies to consider in a workup for secondary causes of osteoporosis include serum calcium (corrected for albumin) or ionized calcium, phosphate, creatinine (with estimated glomerular filtration rate), alkaline phosphatase, liver function tests, 25-hydroxyvitamin D, a complete blood count, a serum protein electrophoresis in older individuals, and testosterone in men [79,90]. A 24-h urine calcium collection should be obtained to assess the adequacy of calcium intake and absorption. Urinary creatinine in the same collection helps confirm completeness. A spot urine calcium/creatinine does not accurately detect hypercalciuria [91].Urinary sodium may be useful when hypercalciuria is suspected, given that high sodium intake can increase urinary calcium losses [92].

Secondary causes of osteoporosis, including vitamin D deficiency and CKD can also disrupt calcium and phosphate homeostasis, leading to increased bone resorption and impaired bone formation [93]. Vitamin D deficiency impairs calcium absorption and bone mineralization. Advanced CKD patients have up to an 8-fold higher fracture risk when compared to the general population [94]. The fracture incidence per 1000 person-years progressively increases by 15.0, 20.5, 24.2, 31.2, and 46.3 for CKD stages 1 to 2, 3a, 3b, and 4, respectively [95].

3.3.2. Effects of medications on fracture risk

Medications prescribed to treat rheumatic diseases or therapies for reproductive health in women can influence bone metabolism, either increasing or decreasing fracture risk.

Standard low-dose methotrexate (<25 mg/week), as used in rheumatology practice, has not been associated with BMD loss in large cohort and cross-sectional studies of patients with RA and other inflammatory diseases [96]. Therapy for RA with methotrexate, sulfasalazine, or hydroxychloroquine alone or in combination is not associated with incident fractures in postmenopausal women with RA [97].

Opioids may have a limited and carefully circumscribed role in rheumatology practice, for short-term use, as there is no improvement in function or pain control with their long-term use in people with rheumatic diseases [98]. There is an increased risk for fracture with opioids, with risk highest in the early stages of use and with higher doses, with adjusted odds ratios for fracture ranging from 1.5 to 2.7 [99,100].

Antidepressants may also be used by rheumatologists, primarily to manage comorbid depression, sleep disturbances, fatigue, and certain chronic pain syndromes, in particular fibromyalgia. A significant reduction in BMD at multiple skeletal sites is reported, and a 2.5-fold increased risk of hip fracture among antidepressant users compared to non-users has been reported. [101]. However, there are no studies that suggest that duloxetine, a serotonin-norepinephrine reuptake inhibitor (SNRI) commonly used by rheumatologists for the treatment of fibromyalgia, has any effects on skeletal health.

Mechanistic reviews highlight that gabapentinoids can interfere with calcium channel function in bone and muscle, potentially affecting calcium-mediated signaling important for skeletal health [102]. The anticonvulsant pregabalin is FDA-approved for the treatment of neuropathic pain and fibromyalgia. Clinical studies do not show significant differences in lumbar or femoral neck BMD or bone turnover markers between pregabalin users and controls, though there may be a trend toward lower lumbar spine BMD in men and in those treated for less than 24 months [103].

Calcineurin inhibitors (CNIs), primarily tacrolimus and the newer agent voclosporin, are used in rheumatology practice largely for treatment of SLE, particularly lupus nephritis. Calcineurin is a phosphatase critical for osteoblast differentiation and bone formation [104] . Tacrolimus is used in the management of lupus nephritis, idiopathic inflammatory myopathies (IIM), and skin fibrosis in systemic sclerosis. [105–108]. Tacrolimus is linked to increased bone resorption and lower BMD, with higher blood concentrations correlating with greater bone loss. The risk is dose-dependent and more pronounced with prolonged use [109].

No studies have specifically evaluated the effects of voclosporin on bone metabolism or fracture risk in patients treated with GCs. The clinical trials Urinary Protein Reduction in Active Lupus with Voclosporin (AURA-LV) and Renal Response in Active Lupus with Voclosporin (AURORA 1) used rapidly tapered GC regimens but did not report bone-specific outcomes [107,110].

3.3.3. Medications used for reproductive health in patients with rheumatic diseases

Leuprolide and depot medroxyprogesterone acetate (DMPA) are used as part of reproductive health management in patients with autoimmune diseases. Leuprolide induces hypogonadism, leading to decreased BMD and increased risk of osteoporosis and fractures. BMD loss of 4–6% at the lumbar spine can occur after 6 months of treatment, with partial recovery after discontinuation [111].

DMPA suppresses estrogen production, resulting in a BMD loss of 0.5 -3.5% at the hip and spine after one year, and up to 5–7% after two years. The FDA includes a boxed warning for significant, potentially irreversible bone loss with prolonged use, especially in adolescents and young women. BMD may recover after discontinuation, but recovery is incomplete, particularly with longer duration of use [112].

3.4. Radiographic assessment: bone mineral density, Trabecular Bone Scores, and vertebral fracture assessment

Measurement of BMD using DXA, with vertebral fracture assessment (VFA), if possible, should be initiated as soon as possible after starting prednisone doses of >/ = 2.5 mg/day or equivalents [44]. BMD with VFA testing or spinal x-rays are also advised in patients younger than age forty [44]. BMD measurements by DXA frequently underestimate fracture risk in GIOP because GCs disproportionately impair bone quality and microarchitecture, especially at trabecular-rich sites, without always causing marked reductions in BMD. [89] Patients on long-term GCs can sustain fragility fractures even with BMD values above the conventional osteoporosis threshold (T-score > −2.5) [89]. Height loss is an important clinical indicator of possible VFs [113].

Assessment of bone microarchitecture using TBS may be useful, particularly in patients with osteoporotic fractures and in men. TBS is more sensitive than areal BMD for fracture detection in GIOP [114]. Adding TBS to BMD substantially improves fracture-risk stratification [115]. TBS is most useful in GIOP as an adjunct to DXA, particularly in patients whose BMD is normal or only mildly reduced but who carry significant clinical risks for fracture [75].

3.5. Fracture risk assessment calculators

Fracture risk calculators offer additional information than BMD alone for fracture risk stratification in patients on GC therapy. In clinical practice for adults aged forty and older, the most commonly used fracture prediction tool, which incorporates GC use as a risk factor, is the Fracture Risk Assessment Tool (FRAX). Moderate doses of GCs (2.5 - 7.5 mg prednisolone daily or equivalent) are the assumed exposure in the FRAX calculator [116]. FRAX can be adjusted for the dose of prednisone [39]. For high doses of GCs (>7.5 mg of prednisone equivalents daily), one would multiply the 10-year risk of Major Osteoporotic fracture (MOF) by 1.15 and the hip fracture risk by 1.2 [44]. However, FRAX does not account for the cumulative dose of GCs and may underestimate fracture risk in some patients. More recently, the FRAX plus tool, which allows for imputation of GC doses, has become available, but requires a fee to use. In adults younger than forty, FRAX cannot be used, and risk assessment is mainly based on BMD and previous history of fracture, with VFA testing where appropriate. QFracture is another risk calculator that estimates fracture risk over one to ten years and includes GC as an individual risk, but does not specifically adjust for GC dose [89,117].

3.6. Non-pharmacological preventive strategies for GIOP

3.6.1. Overview

Once the fracture risk assessment evaluation is completed, consideration for nonpharmacological therapies, as discussed below, or pharmacological therapies as reviewed in the upcoming section, should be considered.

3.6.2. Glucocorticoid minimization and steroid-sparing agents in rheumatic diseases

The American College of Rheumatology (ACR) recommends that clinicians prioritize strategies to reduce GC burden, including tapering and switching to steroid-sparing regimens when disease control allows, as these steps are fundamental to lowering fracture risk and improving long-term bone health [44,89]. The European Calcified Tissue Society also stresses that fracture risk is highest early in the course of GC therapy, and that optimal management of the underlying disease, often through steroid-sparing agents, can further reduce the need for prolonged or high-dose GC use [88,118].

3.6.2.1. Systemic Lupus Erythematosus.

The 2025 ACR guideline for SLE management emphasizes hydroxychloroquine use, limitation of GC exposure, and early introduction of immunosuppressive therapies to achieve remission or low disease activity while minimizing medication toxicity. For stable patients on >5 mg/day prednisone, tapering to ≤5 mg/day and ideally discontinuing GCs within six months are recommended. [119,120]. For lupus nephritis, the latest evidence emphasizes early combination therapy with immunosuppressive agents such as mycophenolate mofetil, cyclophosphamide, and CNIs to allow GC tapering [121]. The use of short-term pulse-dose IV methylprednisolone for severe organ involvement allows for more rapid oral GC reduction, and the cumulative dose from pulse therapy is not considered equivalent to chronic high-dose oral GC exposure in terms of osteoporosis risk [121–124]. In proliferative lupus nephritis (class III/IV), standard induction involves pulse IV GCs plus either mycophenolate or cyclophosphamide, followed by maintenance therapy, with a target of tapering oral prednisone to ≤7.5 mg/day by 3–6 months [125].

3.6.2.2. Giant cell arteritis (GCA).

In the treatment of GCA, the combination of IV methylprednisolone (125–500 mg/day for three days) plus methotrexate with lower-dose oral prednisone (≤30 mg/day) achieves similar rates of remission and relapse as standard high-dose oral prednisone (40–60 mg/day), but with a substantially lower cumulative GC dose, much faster taper to prednisone ≤5 mg/day (mean 13.8 vs 56.5 weeks), and a significantly lower risk of GC related adverse effects [126]. In the Giant Cell Arteritis Actemra (GiACTA) trial, a sustained remission at week 52 was achieved in 56% of patients receiving weekly tocilizumab (Actemra) plus a 26-week prednisone taper, compared to only 14 -18% in the placebo group with the standard prednisone taper [127,128]. Tocilizumab also reduced the median cumulative prednisone dose over 52 weeks by nearly half [129,130]. In a Randomized Clinical Trial (RCT) of upadacitinib 15 mg once daily, for GCA, upadacitinib use significantly reduced cumulative glucocorticoid exposure over one year [131].

3.6.2.3. Polymyalgia rheumatica (PMR).

Sarilumab is FDA-approved for treating patients with PMR who have had an inadequate response to GCs or who cannot tolerate a GC taper [132]. Sarilumab plus a 14-week prednisone taper resulted in significantly higher sustained remission rates and lower cumulative GC doses compared to placebo [132–134].

3.6.2.4. Anti- neutrophil cytoplasmic antibody (ANCA) mediated vasculitis.

Reduced-dose GC regimens and early introduction of steroid-sparing agents such as rituximab, cyclophosphamide, and avacopan should be considered in ANCA-associated vasculitis. The Plasma Exchange and Glucocorticoid in Severe Anti-Neutrophil Cytoplasm Antibody Associated Vasculitis (PEXIVAS) and Avacopan in Disease Vasculitis Outcomes Clinical Assessment Trial Evaluation (ADVOCATE) trials established treatment approaches with lower doses of GCs as the standard of care [135]. Avacopan was noninferior to prednisone for remission at 26 weeks and superior for sustained remission at 52 weeks, with significantly lower GC toxicity scores and fewer serious adverse events. Subgroup analyses show the greatest benefit in patients at high risk for GC toxicity (e.g., older age, diabetes, osteoporosis, infection risk) [136–138].

The PEXIVAS trial reported that a reduced-dose GC regimen (approximately 50% lower cumulative exposure over six months) was noninferior to standard-dose regimens. The reduced-dose regimen resulted in a significantly lower risk of GC-related adverse events, without adversely this is supposed to be affecting remission rates or survival [135,139,140]..

3.6.3. Nonpharmacological treatments for GIOP

3.6.3.1. Calcium and vitamin D supplementation.

The majority of studies examining the effects of calcium and/or vitamin D supplementation have been done in community-dwelling persons, and not specifically in persons treated with GCs [141]. A large meta-analyses concluded that increases in calcium intake, whether through diet or supplements, resulted in a benefit of about 1% on BMD in the treated groups at the end of the first year of use, which did not increase further with continued supplementation. These effects were independent of whether or not vitamin D was given, and were not related to baseline calcium intakes or doses of calcium used [142].

Most studies do not show a relationship between calcium intake and fracture risk [143]. A meta-analysis reported that monotherapy with calcium tended to increase hip fracture risk (RR, 1.53; 95% confidence interval, 0.97, 2.42)), and that, when combined with vitamin D, it had no effect [144]. The addition of calcium supplements to anti-resorptive drugs used to treat osteoporosis has not been shown to substantially impact fracture risk [141]. Calcium supplementation is best given through dietary means, as diet does not lead to constipation, renal stones [145] and potentially cardiovascular disease [146].

Vitamin D supplementation may prevent BMD loss in persons who are vitamin D deficient [145]. Moreover, correction of vitamin D deficiency (<25 nmol/L) is necessary before use of anti-resorptive drugs used to treat osteoporosis to avoid hypocalcemia [141]. Although there is some controversy as to optimum serum levels of 25-hydroxyvitamin D, most recommendations are for a minimum target of 30 ng/ml [147].

In the one meta-analysis that did include patients treated with GCs, there was significant prevention of BMD loss at the lumbar spine and forearm with vitamin D and calcium supplementation [148]. However, there is no data to suggest that calcium and/or vitamin D prevent fractures in persons taking GCs.

The ACR recommends that all patients taking GCs also take at least 1500 mg of calcium and 800 IU of vitamin D every day [44]. This is likely best given through diet to the extent possible.

3.6.3.2. Protein intake.

It is suggested that older adults with chronic illnesses should consume a protein-rich diet (≥1.2 – 1.5 g/kg/day) to support bone and muscle health [149]. A systematic review concluded that dietary protein intake above 0.8 g/kg/day (the recommended daily allowance) was associated with reduced hip fracture risk in older adults and found positive trends in total hip and femoral neck BMD; however this was not studied in GIOP [150].

3.6.3.3. Exercise and fall prevention.

Data are limited as to the effects of exercise for the prevention of GIOP. A systematic review and meta-analysis that included three trials (one of which included patients with RA) with a duration of >6 months reported that there was a significant positive effect of exercise on BMD at the lumbar spine but not the hip [151]. Falls increase rapidly after initiation of GC therapy, and rates return to baseline values fairly rapidly after discontinuation [152]. GC treatment also increases the risk of developing cataracts, which might impair visual acuity and increase the likelihood of falls [153]. However, no studies have directly examined whether fall prevention can reduce fragility fractures in patients receiving GCs [89].

3.6.3.4. Other considerations.

Lifestyle measures other than diet and exercise, including eliminating smoking or excessive alcohol use, are important measures to consider in persons with GIOP [118]. A novel therapy for skeletal health recently FDA-approved, although not assessed in patients with GIOP, is low-intensity vibration therapy, specifically Osteoboost devices, which is emerging as an adjunct for bone health. Clinical trials report improvements in lumbar and hip BMD, muscle strength, and potential synergistic effects when combined with pharmacologic therapy [154]. Standardization of protocols and long-term efficacy data are still evolving, and as indicated, there is no data for GIOP.

4. Treatment of glucocorticoid-induced osteoporosis

Table 1 summarizes mechanisms of action on bone turnover and safety considerations for pharmacological therapies that may be used for GIOP. Information on clinical trials for FDA-approved therapies for GIOP is shown in Table 2. We also included Romosozumab (ROMO), in Tables 1 and 2, which is not FDA-approved for the treatment of GIOP but is recommended by several professional society guidelines for use in GIOP in select patients [44,155].

Table 1.

Pharmacologic options for glucocorticoid-induced osteoporosis.

Medication	Class	Use in GIOP	Mechanism	Side Effects/Precautionsa	References
aAlendronate	Oral bisphosphonate	First-line for moderate–high fracture risk	Antiresorptive	GI irritation; avoid in severe CKD	[44,88,171]
aRisedronate	Oral bisphosphonate	Alternative first-line option	Antiresorptive	GI upset; avoid in severe CKD	[44,88,171]
aZoledronic acid	IV bisphosphonate	Use when oral agents not tolerated	Antiresorptive	Acute phase reaction; renal toxicity; hypocalcemia	[44,88,171]
Teriparatide	PTH analog	Very high-risk or vertebral fractures	Anabolic	Hypercalcemia;	[44,88]
aDenosumab	RANKL inhibitor	Alternative when bisphosphonates unsuitable	Antiresorptive	Rebound fractures if stopped; hypocalcemia	[88,172]
aRomosozumab	Sclerostin inhibitor	Consider for very high-risk patients when other agents are inadequate or contraindicated.	Anabolic and Antiresorptive	FDA black box warning for ↑ cardiovascular risk; requires transition therapy after 12 months.	[44,88,172, 173]

^aAtypical Femoral Fractures [174], [175]: and Medication Related Osteonecrosis of the Jaw [176] may be Late Sequelae.

Table 2.

Trials of pharmacological therapies for prevention or treatment of GIOP.

No/Author (year) PMIDRef	Age (years)	Sex (M/F with%)	Race/Ethnicity	Prevention vs Treatment	Rheumatic Diseases	GC Dose/Duration	Cal/Vit D	Intervention (Dose/duration)	BMD Outcomes	Fracture Outcome
Mok (2024) 39387335 [164]	62.6 ± 9.1	96%F	NA	Prevention	SLE (51%), RA (29%), inflammatory myopathies (9%), and others (11%)	Median prednisolone dose 5.0 mg/day; duration of therapy 10.7 ± 7.4 years	Ca (1500 mg bid); Vit D3 (cholecalciferol 1000 IU/day)	Romo (n = 35) vs DEN (n = 35) for 12 months	LS ROMO > DEN (p < 0.001) TH ROMO = DEN	NA
Iseri (2018) 29543887 [165]	Median 66	44% F (PM)	NOS	Treatment	RA, ANCA vasculitis, Lupus Nephritis, NonRheumatic disease	Min 5 mg Prednisone for a minimum 3 mo	All patients received at least 0.25 μg/day of calcitriol throughout the study.	ALN 35 mg PO QW (n = 16) vs DEN 60 mg SubQ once every 6 months (n = 16)	12 mo: LS DEN > ALN (p < 0.05)	NA
Saag (2016) 27111239 [167]	≥21	80% F	White	Treatment	NOS	Median 7.5 mg/day prednisone equivalent for ≥90 days	Ca (1000 mg/day) and Vit D (800 IU/day)	ALN 10 mg/day (n = 214) TPTD 20 μg/day (n = 214) for 36 mo	LS TPTD > ALN (p < 0.001)	NA
Mok (2015) 25761434 [166]	54.7 ± 12.9	100% F (PM)	NOS	Treatment	NOS	prednisolone (≥2.5 mg/day for ≥1 year)	NOS	Continued oral bisphosphonates (n = 21) vs. switching to DEN (n = 21) 60 mg SubQ every 6 mo over 12 mo period	LS gain DEN (p = 0.03), > BP (p = 0.12) at 12 mo	NA
Roux (2012) 21975559 [168]	18–85	NOS	NOS	Both	Both Rheumatic and non-rheumatic diseases	Prednisone does NA. Exposure groups: <3 mo or >3 mo	NOS	ZOL 5 mg IV once yearly (n = 416) Risedronate 5 mg orally daily (n = 417) Duration: 12 mo	LS TH ZOL > RIS (P < 0.05)	NA
Stoch (2009) 19487264 [156]	NOS	61% F	NOS	Both	NOS	Minimum 7.5 mg/day prednisone or equivalent ≥3 mo prior to study	Ca 1000 mg/day and Vit D 400 IU/day	ALN: 70 mg PO QW (n = 114) vs. placebo (59) for 12 mo	LS, Trochanter, TH, total body ALN > placebo	NA
Katayama (2008) 18266400 [169]	50-79	79% F	NOS	Both	RA	2–15 mg/day for at least 1 year	NOS	ALN 5 mg/day (n = 80) or RIS 2.5 mg/day (n = 58)		Incident Fracture vertebral/non-vertebral RIS > ALN (p = 0.0386)
Saag (2007) 18003959 [170]	22-89	80% F	NOS	Treatment	Rheumatic and non-rheumatic disease NOS	Prednisone 5 mg daily or more for 3 mo	All patients received Ca and Vit D supplements	20 μg of TPTD once daily (n = 214), 10 mg of ALN once daily (n = 214) each for 18 mo	LS TPTD > ALN 6 and 12 mo (p < 0.001) TH TPTD > ALN 18 mo (P = 0.005)	Incident vertebral fractures TPTD < ALN (p = 0.004)
Mok (2007) 18038273 [177]	42.8 ± 14.3	64 % F	NOS	Prevention	Not restricted to rheumatic disease	Prednisolone (>0.5 mg/kg/day)	Ca: 1000 mg/day to all participants	Risedronate 5 mg/day (n = 60) vs placebo (n = 60) for 6 mo	LS RIS > placebo (p = 0.006) Hip ↓ both but RIS < Placebo (<0.05)	NA
Emkey (2003) 12687554 [178]	NOS	70% F	NOS	Treatment	NOS	> =7.5 mg prednisone or equivalent	NOS	ALN 5 (n = 90) or 10 mg daily (n = 93) for 1 year, 1 year f/u ALN:	[ALN <90 days]: LS (CI −11.1, 1.0), FN (CI −15.6, −2.8),	NA
						<90 days (n = 11), >90 (n = 8) > 300 days (n = 31) For additional 3–4.6 years			TH (CI −14.0, 0.7) ↑ [ALN >300 days]: LS (CI −2.0, 2.3), FN (CI −3.2, 1.4), TH (CI −0.5, 4.2)]
Giannini (2001) 11697808 [157]	44.2 ± 11.6	33% F	NOS	Treatment	Not rheumatic disease – renal transplant patients	Steroid exposure in all groups, dose NA	Baseline Calcitriol: 0.50 μg/day Ca carbonate: 500 mg/day	ALN 10 mg/day (n = 20) vs no treatment (n = 20)	BTM ↓ALN LS, FN, total femur ↑ ALN	NA
Yilmaz (2001) 11269535 [161]	NOS; (PM)	100% F	NOS	Prevention and treatment	RA	prednisolone (7.5 mg/day) for 6 mo	Ca: 1000 mg/day in all groups	ALN 10 mg/day (n = 25) vs no treatment (n = 25)	LS ALN > Placebo (<0.05)	NA
Reid (2001) 11730260 [162]	NOS	100% M	NOS	Both	NOS	Prevention arm: Started corticosteroids ≥7.5 mg prednisone/day Treatment arm: On chronic steroids ≥7.5 mg prednisone/day 1 year	Calcium: 500–1000 mg daily for 1 year	Risedronate: 2.5 mg/day vs 5 mg/day orally for 12 mo (n = 120) vs Placebo (n = 64)	RIS: LS, FN, trochanter 5 mg (p < 0.01) > 2.5 mg	Vertebral fracture RIS < placebo (p = 0.008)
Estell (2000) 10928223 [163]	NOS	100% F (PM)	UK and Belgium	Prevention	RA	Chronic GC therapy: >2.5 mg/day prednisolone – about 2 years	NOS	Daily risedronate: 2.5 mg/day orally (n = 40), Cyclical risedronate: 15 mg/day for 2 out of every 12 weeks (n = 40), Placebo group (n = 40)	LS (p = 0.009)/Trochanter (p = 0.02) RIS 2.5 mg > placebo at 97 weeks FN nonsignificant Cyclical ~ daily (P < 0.05)	NA
Lane (2000) 10804025 [179]	mean 63	100% F (PM), history of HRT	NOS	Treatment	RA, SLE, Vasculitis, Polymyalgia, Nonrheumatic diseases	Avg daily prednisone dose equivalent 5 to 20 mg/day	Ca carbonate 1000 mg/day; Vit D 800 IU/day)	12 mo of PTH 1–34 (n = 19) and 12 mo off treatment (n = 19)	PTH: LS (p < 0.001), Hip and FN p (<0.01) ↑ 24 mo ↑ >150% in 6 mo	NA
Compston (1999) 10375295 [158]	17-83	71% F	NOS	Both	Both rheumatic and nonrheumatic disease	>7.5 mg prednisone Exposure Groups: <4 mo, 4 – 12 mo or > 12 mo	Ca, 800–1000 mg/day, and Vit D, 250–500 IU/day.	ALN 5 mg/day (n = 161) vs 10 mg/day (n = 157), vs a matching placebo (n = 159) for 48 weeks	LS, FN, trochanter ALN 5/10 mg > placebo (p < 0.001) Fracture risk ALN 5/10 ~ Placebo	NA
Saag (1998) 9682041 [159]	17-83	76% F	NOS	Both prevention and treatment	NOS	All on steroids, dose NA	Each patient received 800 to 1000 mg of elemental calcium and 250 to 500 IU of vit D daily.	ALN 5 mg (n = 161) vs 10 mg daily (n = 157) vs Placebo (n = 159) for 48 weeks.	LS (p < 0.001)/FN (p < 0.1) ALN > placebo	Incident vertebral fractures ALN < placebo (RR 0.6)
Gonnelli (1997) 9351879 [160]	NOS	60% F (PM)	Siena	Prevention	Sarcoid	Mean cumulative prednisone 4945 ± 1956 mg treatment 5110 ± 2013 mg Placebo	NOS	ALN 5 mg/day (n = 15) vs placebo (n = 15) for 12 mo.	↓ ALN < placebo (p < 0.01)	NA

Key: F/u: Follow-up,↑: increase; ↓: decrease; PO: Oral; GIOP: GC-Induced Osteoporosis; RTC: Randomized Controlled Trial; GIO: GC-Induced Osteoporosis; BMD: Bone Mineral Density; LS: Lumbar Spine; ALN: Alendronate; DEN: Denosumab; TPTD: Teriparatide; DXA: Dual energy Xray Absorptiometry; QCT: Quantitative Computed Tomography; PTH: Parathyroid Hormone; ROMO: Romosozumab; SLE: Systemic Lupus Erythematosus; RA: Rheumatoid Arthritis; ANCA: Anti-Neutrophil Cytoplasmic Antibody; SubQ: Subcutaneous; Ca: Calcium; Vit: Vitamin; HRT: Hormone Replacement Therapy; GC: Glucocorticoid; GCs: Glucocorticoids IU: International Units; bid: Twice daily; QW: Once Weekly; mo: Months; mg: Milligrams; g: Grams; mcg: Micrograms; IV: Intravenous; RIS: Risedronate; ZOL: Zoledronic Acid; FN: Femoral Neck; TH: Total Hip; PM: Postmenopausal; MF: Male/Female; F (PM); postmenopausal female; BTMs: Bone Turnover Markers; TBS: Trabecular Bone Score; RR: Relative Risk; NOS: Not Otherwise Specified; VS: Versus; NA:Not Available.

Most trials investigated the use of bisphosphonates. The most common therapy used was alendronate (ALN) followed by risedronate (RIS), zoledronic acid (ZOL), teriparatide (TPTD), denosumab (DEN) then ROMO. There were substantial differences in the design of these trials, including demographics and comorbidities of the study populations; whether or not calcium and/or vitamin D supplementation was used and if so, at what dose; whether or not rheumatic diseases were included, and if so, which ones; the severity of the rheumatic condition and the average prednisone dose equivalents used and for what duration. Finally, trial duration and outcomes assessed also varied among these trials (Table 2). Some trials focused on rheumatic diseases (RA, SLE, or several rheumatic conditions) while others included non-rheumatic conditions.

4.1. Placebo controlled trials

Placebo-controlled trials were included among the early RCTs for GIOP but would not be considered ethical today. These trials reported improvements in BMD and/or fracture reduction with the active drug. For example, trials that compared ALN to placebo showed significant BMD increases in multiple sites, including the lumbar spine and femoral neck, with ALN [156–159] Saag (1998) reported a reduction in new vertebral fractures with ALN [159]. Gonnelli reported that ALN decreased GC-related bone loss although without absolute BMD gains [160]. Yilmaz 2001 showed lumbar spine BMD increased significantly with ALN compared with no treatment [161]. For studies that included RIS, Reid (2001) showed that RIS significantly improved BMD at the lumbar spine, femoral neck, and trochanter and reduced incident vertebral fractures [162]. Eastell 2000 reported a significant difference in BMD with daily risedronate use compared to the placebo at the lumbar spine (1.4% in the treatment group versus −1.6% in the placebo) and the trochanter (−0.4% in the treatment group versus −4% in the placebo) [163] These studies also showed that across trials, ALN consistently suppressed bone turnover markers (BTMs). Stoch 2009 and Saag 1998 showed significant reductions in BTM [156,159]. Giannini 2001 similarly demonstrated decreased BTMs compared to placebo [157].

4.2. Active comparator trials

Across active comparator GIOP trials, significant differences in reports of changes in BMD, BTM, and fractures were observed among different drug classes. ROMO was associated with higher LS BMD gains compared to DEN [164]. DEN, on the other hand, demonstrated superior LS BMD improvement compared with ALN [165]. Mok 2015 showed that switching to DEN provided higher LS BMD gains and stronger BTM suppression than continuing oral bisphosphonates in patients on BP therapy [166]. Among anabolic agents, TPTD consistently outperformed ALN in lumbar spine and hip BMD, as well as showed a reduction in vertebral fractures. Saag reported that the increase in BMD at the lumbar spine was greater with TPTD treatment compared to ALN (TPTD +10.3% versus ALN +5.5%) [167]. Among bisphosphonates, ZOL had a stronger antiresorptive effect and greater LS and hip BMD gains compared to RIS [168]. In another study, ALN was associated with fewer fractures than RIS [169].

In summary, the literature indicates that current FDA-approved drugs for osteoporosis have shown efficacy in preventing and treating GIOP, although few report vertebral fracture data and none have reported hip or nonvertebral fracture reduction. All FDA-approved therapies demonstrate benefit over placebo in regard to BMD changes and, in some cases, reduce vertebral fracture risk. Active competitor trials have reported differences in efficacy among different therapies. However, due to the variabilities in treatment groups as well as significant variations between the studies, it is impossible to confidently ascertain superiority across all classes of drugs. In general, the literature supports that anabolic agents produce larger gains in BMD in GIOP; in populations that are at high risk, anabolic agents should be prioritized over antiresorptived [170].

5. Clinical practice guidelines for GIOP

Multiple international bodies have published guidelines to standardize prevention, diagnosis, and treatment strategies for GIOP. Below, we summarize recommendations from recent guidelines and consensus statements. We include Fig. 1 as a summary guideline from several societies.

Fig. 1.

Approach to Fracture Risk Assessment and Therapies

*Clinical risk factors include G dose, duration, pattern of use, alcohol intake, smoking, hypogonadism, prior fractures, low body weight, significant weight loss, parental hip fracture, falls, thyroid disease, hyperparathyroidism, rheumatoid arthritis, malabsorption, chronic liver disease, and inflammatory bowel disease, height loss, and advanced age.

**Low fracture risk (≥40 years): GC < 7.5 mg/day AND FRAX major osteoporotic fracture <10%, hip fracture <1%, BMD T score > −1.5.

***Moderate fracture risk (≥40 years): FRAX GC adjusted 10–19% or hip > or equal to 1%, less than 3%, OR BMD T score between −1 and −2.4.

***High fracture risk (≥40 years): T-score ≤ equal to −2.5 but > −3.5, or FRAX-GC adjusted ≥20% but <30% (major) or ≥3% but <4.5% (hip).

***Very high fracture risk: prior OP fracture OR BMD T score > −3.5 OR FRAX GC Adjusted MOF > −30% or hip ≥4.5% OR High GC ≥ 30 mg/day for >30 days or cumulative dose≥5 g/year.

(derived from clinical guideline)s; Humphrey et al. 2022, Yoshiya et al. 2023, Julien et al. 2024 [44,88,183].

5.1. Risk assessment

All major guidelines emphasize that early and accurate fracture risk assessment is the cornerstone of managing GIOP [44,88]. It is recommended that patients receiving ≥3 months of systemic GCs should undergo fracture risk assessment at the initiation of therapy, with ongoing reassessment during treatment [44,88]. The ACR recommends the use of the FRAX tool adjusted for GC dose, validated in adults older than 40 years, combined with BMD measurement for risk stratification [44]. Japanese guidelines similarly advocate integrating clinical risk factors—including age, sex, prior fractures, fall risk, serum calcium, vitamin D levels, and GC dose—with BMD-based decision-making [172]. The European Calcified Tissue Society (ECTS) also supports the combined assessment of clinical risk factors and BMD for optimal risk assessment [88]. Colombian and European/Belgian frameworks emphasize individualized risk assessment that accounts for comorbidities and local resource availability [88,180].

High-risk-patients, such as those with a FRAX-derived Major Osteoporotic Fracture (MOF) risk ≥10% or prior fragility fracture, require pharmacologic therapy [44,171], while low-risk individuals may benefit primarily from non-pharmacologic strategies [171, 172]. This structured approach ensures timely fracture prevention and optimized treatment allocation [44,88].

5.2. Monitoring of BMD in GIOP

Regular BMD monitoring every 1–2 years is recommended by the ACR, ECTS, and United Kingdom (UK) guidelines [44,88,171]. Treatment duration should align with the dose and duration of GC exposure, with reassessment when GCs are tapered or discontinued [44,172]. Japanese and European guidelines also highlight the need for vigilance about rebound bone loss after stopping denosumab [88,172].

5.3. Non-pharmacologic measures

Recommendations across guidelines include adequate calcium intake (1000–1200 mg/day) and vitamin D supplementation (800–1000 IU/day) [44,171]. Weight-bearing exercise, fall-prevention strategies, and lifestyle modification are also important to consider.

5.4. Approach to pharmacologic management of glucocorticoid-induced osteoporosis

Evidence-based guidelines from the ACR, ECTS, Japanese, UK, Colombian, and Latin American societies consistently recommend early fracture risk stratification and timely initiation of pharmacologic therapy in adults receiving ≥3 months of systemic GCs [44,88, 171–173,180,181]. Pharmacologic treatment is strongly indicated for individuals at moderate or high fracture risk, including those with prior fragility fractures, T-scores ≤ −2.5, or elevated FRAX estimates adjusted for GC dose [44,88,171]. The ACR identifies high cumulative exposure (>5 g/year of prednisone equivalents), particularly when combined with very high daily doses (≥30 mg/day prednisone equivalents), as a threshold warranting pharmacologic intervention [37,182].

Oral bisphosphonates (e.g., alendronate, risedronate) are generally considered first-line therapy for GIOP due to efficacy, safety, and cost-effectiveness [44,88,171]. An IV bisphosphonate, zoledronic acid, is recommended when oral agents are contraindicated or poorly tolerated [44,88]. Teriparatide is preferred in patients with a very high risk, rapid bone loss, or vertebral fractures [44,88]. Denosumab is accepted as an alternative when bisphosphonates are unsuitable, though guidelines caution about rebound bone loss on discontinuation, requiring transition therapy [88,172]. Treatment choice should consider fracture risk category, GC dose, comorbidities, renal function, and patient preference [44,88,171–173,180,181].

6. Conclusions

GIOP, with its attendant fracture risk, is a serious concern for patients on long-term GC therapy for rheumatic diseases. Dose and duration of GCs are major determinants of fracture risk. Prevention of GIOP should ideally begin within 3 months of initiating oral GCs. Baseline fracture assessment - including patient-level risks with consideration for the underlying rheumatic disease, and ascertainment of risk from BMD and TBS measurements, vertebral imaging, and fracture risk calculators - is an important first step in the management of patients on GCs. The lowest possible dose of GCs to treat the underlying condition should be used, and one should consider steroid-sparing therapies, when possible, for treatment of the underlying rheumatic disorder. Preventive strategies for GIOP, including lifestyle measures, calcium and vitamin D intake, and exercise, should be considered based on the fracture risk assessment. Consensus among guidelines exists for pharmacological therapies in persons at risk for fractures from GIOP. Anabolic therapy with teriparatide appears to confer greater benefit for GIOP than antiresorptive therapies and should be considered in the appropriate setting.

Practice Points.

• All adults receiving ≥3 months of systemic GCs should undergo early fracture risk assessment

• Patients on long-term GCs can sustain fragility fractures even with BMD values above the conventional osteoporosis threshold (T-score > −2.5) as BMD may underestimate fracture risk in patients on GCs

• Early consideration for the use of steroid-sparing agents for the treatment of rheumatic diseases is important.

• Among current FDA-approved pharmacological therapies for GIOP, teriparatide has the strongest data for BMD increases and VF reduction

Research Agenda.

• RCTs should be done to compare the efficacy of BPs, denosumab, and anabolic agents, including newer anabolic therapies (Abaloparatide, Romosozumab) for fracture prevention in GIOP in persons with rheumatic diseases.

• Observational studies using a targeted trial emulation approach are needed to understand the comparative efficacy and safety of sequential therapies for GIOP