|Year : 2019 | Volume
| Issue : 5 | Page : 90-98
Glucocorticoids: A review of its adverse effects including bone loss
Amit Dua1, Parthajit Das2, Vinod Ravindran3
1 Dua's Clinic, Rheumatology and Arthritis Care, Bilaspur, Chhattisgarh, India
2 Department of Rheumatology, Apollo Gleneagles Hospital, Kolkata, West Bengal, India
3 Centre for Rheumatology, Kozhikode, Kerala, India
|Date of Web Publication||2-Dec-2019|
Dr. Vinod Ravindran
Centre for Rheumatology, Kozhikode - 673 009, Kerala
Source of Support: None, Conflict of Interest: None
Glucocorticoids (GCs) play a crucial role in the management of many inflammatory, immunological, and autoimmune diseases. Apart from symptomatic relief, they also act as disease-modifying agents as in arthritis and potent immunosuppressive agents as in vasculitides and systemic lupus erythematosus. However, they have been overused, misused, and abused because of their easy availability, low cost, and rapid action. On the other hand, they are also associated with a variety of adverse effects such as osteoporosis, increase risk of infections, cataract, glaucoma, myopathy, glucose intolerance, dyslipidemia, cardiovascular diseases, psychiatric disturbances, and adrenal suppression. GC-induced osteoporosis (GIOP) with increased fracture risk needs special mention, as it causes significant morbidity. In this review, we bring the readers up-to-date information with regard to the major adverse effects of systemic GCs with a special reference to prevention and management of GIOP.
Keywords: Denosumab, glucocorticoid-induced, glucocorticoid-induced osteoporosis, newer steroids, osteoporosis, steroids
|How to cite this article:|
Dua A, Das P, Ravindran V. Glucocorticoids: A review of its adverse effects including bone loss. Indian J Rheumatol 2019;14, Suppl S1:90-8
| Introduction|| |
Since their introduction about more than seven decades ago, glucocorticoids (GCs) remain one of the most popular classes of drugs in rheumatology. They have been the most commonly prescribed drugs in autoimmune and inflammatory diseases. Approximately 1% of all adults and 3% of adults older than 50 years of age receive GC for allergies, inflammatory conditions, or cancer. GC is known not only for their effectiveness but also for their unwanted outcomes. These adverse effects are a major concern for clinicians because improvement in patients seems to be achievable at the cost of substantial adverse effects that are often difficult to prevent or treat.
| Search Strategy|| |
To appraise the documented toxicities of GC therapy in systemic autoimmune rheumatic diseases, we searched the available literature by the screening of primary sources MEDLINE (1966 to date) and Old MEDLINE (1949–1965) using the PubMed interface, as well as secondary sources, the Embase and Cochrane library without any time limits. Appropriate combinations of search terms including “rheumatic” “autoimmune,” “corticosteroids,” “glucocorticoids,” “adverse effects,” “toxicities,” and the names of individuals known side effects of GCs were used with limits “(English, Human, Animal).” Relevant keyword variations for different databases were used. This was supplemented by a manual search of bibliographies of these articles and of previously published reviews and animal studies. However, the focus was on articles published since 1980, but commonly cited and highly regarded older publications were not excluded.
| Factors Affecting Adverse Effects of Glucocorticoids|| |
GC has a high potential for frequent adverse effects [Table 1]. Many retrospective reviews have shown that the risks of GC-associated adverse effects are both dose and duration dependent.,,, These adverse effects also depend on the nature and severity of the underlying disease being treated, comorbidities and the other medications being concurrently administered. Two patterns of GC associated adverse effects, namely “linear” and” threshold” have been described in a large retrospective analysis.
A “linear” pattern is one in which the incidence of adverse effects will increase with increasing dose of GC. This pattern was found for ecchymotic patches, pedal edema, shortness of breath, mycosis, parchment-like skin, cushingoid phenotype, and sleep disturbance. A “threshold pattern” is one in which events occur beyond a defined threshold. For example, there is an increased incidence of higher intraocular pressures (glaucoma), mood disorders such as depression, and hypertension, at dosages of over 7.5 mg/day. Daily dosages ≥5 mg were found to predispose towards epistaxis and gain in weight. A very low threshold was seen for cataract (<5 mg/day). One retrospective cohort study showed that even short-term GC use may be associated with serious adverse effects such as sepsis, venous thromboembolism (VTE), and fracture. Various randomized controlled trials (RCTs) and meta-analyses have proved clinical efficacy of GC in RA but concerns regarding its safety have led to doubts among clinicians. It is important to recognize that precise data on frequency and severity of adverse effects of GC and its method of assessment are lacking. A comprehensive review of four prospective RCTs on the safety of low-dose GC therapy and of the Combinatie therapie Bij Reumatoide Artritis study concluded that definitive association of low dose with adverse effects is weak. This meta-analysis has shown that medium to long-term GC therapy in RA is associated with limited toxicity compared to placebo.
Although this article is focused on the effects of GC on bone health, treating physicians should be aware of a few interesting facts about the serious adverse effects. GC is associated with around two-fold increased risk of a gastrointestinal adverse effect when used in combination with nonsteroidal anti-inflammatory drugs (NSAIDs) compared to NSAIDs alone. In a large population-based study, patients receiving GC doses ≥7.5 mg/day were more than 2.5 times likely to experience cardiovascular events such as myocardial infarction, in-hospital treatment for cardiac failure, and ischemic cerebrovascular events. Although controversial, moderate-to low-dose GCs have shown insignificant unfavorable effect on lipoprotein levels when other confounding risk factors were assessed.,, GCs have an impact on innate and acquired immunity resulting in higher risk of common bacterial, viral, and fungal pathogens. In patients with rheumatoid arthritis, GCs have demonstrated greater risk of infections when compared with TNF Blockers. The risk of infection involved with the inhaled and topical GC were insignificant. It is recommended to offer appropriate immunization schedule to the patients requiring extended GC therapy. Gurwitz et al. have reported incremental relative risk of development of hyperglycemia from 1.8 in patients treated with prednisolone <10 mg/day to 10.3 in those receiving more than 30 mg/day. However, the risk of development of de novo diabetes in patients with normal glucose tolerance is uncommon. Cautious GC withdrawal is advised in patients on prolonged therapy to avoid adrenaline insufficiency. Growth retardation is more pronounced in children receiving daily GC and inhaled GC as compared to alternate day regime. It is recommended to use lowest possible GC dosage during pregnancy to avoid complications such as premature rupture of membrane, intrauterine growth retardation, pregnancy-induced hypertension, gestational diabetes, and infection. Pregnant women receiving prednisolone >5 mg for more than 3 weeks within 6 months of delivery were at higher risk of suppression of HPA axis during the peripartum period.
| Mechanisms of Adverse Effects|| |
Direct and indirect genomic effects, as well as nongenomic mechanisms, have been recognized methods of GC actions. Genomic effects are mediated through cytosolic GC receptor (cGCR)-coupled gene expression. A direct genomic effect is due to either transcriptional activation or transactivation or transcriptional repression or transrepression. There is consensus that, transrepression leads to desired anti-inflammatory effects of GC and transactivation leads to many of the recognized side effects (such as diabetes glaucoma). Some actions are likely a result of transrepression (e.g., suppression of the hypothalamic–pituitary–adrenal axis). Indirect genomic action involves regulation of other GC-responsive genes including interactions between the cytosolic cGCRs complex and other transcription factors, such as nuclear factor-kappa B. Nongenomic actions are triggered at higher concentration of GC (such as when using pulse IV methylprednisolone) whose effects also include rapid, nonspecific interactions of GC with cellular membranes and specific interactions with membrane-bound cGCRs. A logical approach to decrease the side effect profile of GC is to develop some novel drugs which result in transrepression, however, cause little transactivation, thus diminishing the adverse effects of GC.
Selective GCs receptor agonists (A276575, its four enantiomers, and ZK216348) are analogs made in a way that leads to dissociation of transrepression from transactivation. Apart from this, novel drug delivery systems (liposomes containing GC) and combinations (e.g., nitrosteroids) are also being experimented. Liposomes containing GC (endothelial cell-specific drug delivery system) target sites of inflammation resulting in more local desirable effects. Nitrosteroids (combination of nitrous oxide and GC) have synergistic effects of GC and NO and hence has enhanced anti-inflammatory action with favorable effects on the bone. Combination of prednisolone and dipyridamole causes selective amplification of GC-mediated anti-inflammatory signaling. Other approaches include nonsteroidal GCR ligand (LGD-5552) (differential gene regulation resulting in a potent anti-inflammatory effect and safer bone and glycemic profile) and inhibition of pro-apoptotic BAX protein leading to prevention of any undesirable side effects of GC on bones. Many of the aforementioned approaches have been tested in animal models, but human studies are required.
| Glucocorticoid-Induced Osteoporosis|| |
[Table 1] lists some of the important adverse effects of GC. A special mention has to be made of GC-induced osteoporosis (GIOP). GIOP with increased fracture risk leads to significant morbidity. In India, it is assumed that more than 25 million people have osteoporosis.
Mechanism of bone loss
GC can have negative effect on calcium balance [Figure 1]. This may result from a dual mechanism of reducing absorption of calcium from the gut, as well as enhancing excretion of calcium in urine. Negative calcium balance leads to secondary hyperparathyroidism which increases osteoclast activity and accelerates bone resorption. In bone, GC can increase apoptosis of osteoblasts and may prevent apoptosis of osteoclasts. Oral GCs inhibit follicle-stimulating hormone-induced estrogen production in women and suppress testosterone levels in men. These negative effects on gonadal hormones contribute to increased bone resorption. GC can inhibit HPA axis and so can inhibit the production of adrenal androgens, decreasing their beneficial effect on bone formation [Figure 1]. GC at a dose of over 20 mg of prednisolone or equivalent can inhibit the production of gonadotropin-releasing hormone, which decreases the production of luteinizing hormone and therefore causing secondary hypogonadism. This secondary hypogonadism decreases testosterone production, further decreasing bone formation and increasing bone resorption. Apart from these, GC can cause muscle atrophy and weakness by reducing muscle protein synthesis. Muscle atrophy will lead to low bone mass and also increases susceptibility to physical falls.
|Figure 1: Schematic representation of mechanism of bone loss in patient with glucocorticoid-induced osteoporosis|
Click here to view
Following GC intake, the balance between bone formation and resorption is disturbed leading to osteoporosis. Although a decline in bone mineral density (BMD) correlate with fracture risk, analysis of placebo groups from randomized trials indicates that at a given BMD, the incidence of vertebral fractures (VFs) is higher in patients taking GC than others. This explains that apart from BMD, the GC-induced microarchitectural changes of collagen content and cross-linking are also important determinants of fracture risk. Chronic inflammatory conditions such as RA may themselves contribute to an increased fracture risk and bone loss. This is because of the pro-inflammatory cytokines leading to bone loss. Although GC reduces inflammation, the incidence of fractures is still higher in patients taking GC compared to those who are not using GC with similar underlying disease.
Clinical features and risk factors
There have been few studies that quantify the rate of fracture among GC users. In a study, 244,235 patients from the UK general practitioner research database on GC was compared with control revealed that, the relative risk of vertebral, hip, and forearm fractures for GC users was 2.6, 1.6, and 1.1, respectively. Postmenopausal women and elderly men are at a higher risk for developing GC-induced bone loss and fractures. An increased risk of fragility fracture may be seen even with short-term use, i.e., within the 1st month of starting treatment. The risk of bone loss is most rapid during the early few months of use, followed by slower and steady loss with continued use. It may happen in any patient and with any dose of steroids. Fracture risk is increased even at daily doses of prednisolone or its equivalent as low as 2.5–7.5. Although fracture risk rises soon after GC initiation, it also rapidly reverses back when treatment is stopped within a year following withdrawal. Initially, trabecular bone is affected thus increasing the risk of VFs, but later, on prolonged use, cortical bone is also involved (e.g., femoral neck).
Bone mineral density
Prevention of GC-induced fractures requires the identification of patients who would benefit from preventive treatment. Within 6 months of starting GC, fracture risk assessment should be done using clinical risk factors assessment and in selected cases, BMD.
The absolute risk of fracture can be calculated using a fracture prediction tool, such as Fracture Risk Assessment Tool (FRAX) (www.shef.ac.uk/frax/), which combines many risk factors for osteoporosis [Table 2] including GC use with the BMD and estimates 10-year risk of major osteoporotic fracture and hip fracture among patients of and above 40 years of age. The risk of fracture can be calculated even when the BMD T-score is not available. Still, BMD is recommended for patients who are above 40 years of age and are on GC, as it improves the accuracy of FRAX estimate. When GC use is considered as a risk factor in the FRAX tool, the fracture risk associated is with prednisone at a dose of 2.5–7.5 mg/day. The risk estimate must be corrected for GC exposure if the dose of prednisolone is above 7.5 mg/day or equivalent (increase by 15% for major osteoporotic fracture and by 20% for hip fracture).
Although there are several limitations of FRAX calculation including its inability to account for physical activity, Vitamin D levels, bone turnover markers, doses and duration of GC use, quantity of alcohol intake and smoking exposure, the difference of risk between single versus multiple fractures, overreliance on measurement of hip BMD input, and poor definition of secondary osteoporosis; it remains a useful assessment tool.
BMD measurement is not essential in all patients before starting steroids. However, in the following situations, it should be done before starting on GC; age more than 65 years, history of fragility fracture, premature menopause (<45 years), family history of fragility fracture, BMI <19 kg/m2, and prolonged immobilization.
Vertebral imaging is either performed with conventional radiography or with VF assessment (VFA), a component of the DXA instrument. VFA compares favorably with spine radiographs in detecting moderate and severe VFs but is less effective in the identification of mild VFs. It can detect moderate-to-severe spinal fracture but is poor in diagnosing mild VFs., VFs are the most common type of fragility fracture, yet approximately two-thirds of VFs are not clinically detected. VFs are a strong predictor of future fractures of all types and are an indication for pharmacologic therapy.
Trabecular bone score could be obtained from DXA images of the lumbar spine which has a predictive value for fracture independent of BMD.
Quantitative ultrasound (QUS) is a noninvasive means of quantitating skeletal bone mass. QUS provides information about bone structure, bone density, and associates independently with fracture risk. An Indian study revealed the potential utility of QUS to assess decreased bone mass in settings where more complex techniques like DEXA have limited availability. However, its correlation with fracture risk remains to be established and requires studies with greater sample size, as well as a longitudinal follow-up period.
Other imaging modalities
Advanced methods of measuring volumetric BMD, including high-resolution microcomputed tomography/micromagnetic resonance imaging, allow noninvasive, three-dimensional evaluation of bone architecture. They are used only for research and do not offer much help in the routine clinical evaluation of patients with GIOP.
These are not currently recommended to diagnose osteoporosis. Bone resorption markers such as N-telopeptide and C telopeptide of Type 1 collagen may have an adjunctive role alongside DEXA to identify patients with a greater fracture risk. Such markers of bone resorption require to be repeated annually.
Monitoring of therapy
DEXA (hip and lumbar spine L1–L4) should be repeated at 1–2 years intervals. Above-mentioned bone turnover markers (N-telopeptide and C-telopeptide of type I collagen) along with DXA can be used to monitor treatment response. Bone resorption markers can be repeated every year.
Management of glucocorticoid-induced osteoporosis
Minimizing GC use is the most important step to prevent fractures. Lifestyle recommendations include weight-bearing exercise, maintenance of normal weight, smoking cessation, limitation of alcohol consumption, and the assessment of fall risk and its prevention (such as walking aids and better footwear).
Calcium and Vitamin D
Most individuals in our country are Vitamin D and calcium deficient. Dark skin prevents adequate Vitamin D synthesis., Low dietary intake of calcium is also very common. GC depresses intestinal calcium absorption and promotes urinary calcium excretion. Adequate Calcium and Vitamin D supplementation to patients without any risk of bone loss, who are on lower doses of steroids for short duration (5 mg or less for <3 months) alone might be sufficient. Patients with associated risk factors, preexisting bone loss and who are on higher doses of steroids for longer duration may also need antiresorptive therapy in addition. Recommended calcium intake is 1000–1200 mg/day and Vitamin D intake 600–800 IU/day. Vitamin D in the dose of 2000 IU/day is recommended in the Indian context, as lower doses are usually insufficient to achieve adequate 25(OH)D levels <30 ng/mL). Sunlight exposure is recommended in the mornings for 10–30 min a day at least three times a week. There is a decrease in bone loss in patients on GC and receiving calcium and vitamin D together, although a reduction in fracture risk has not been demonstrated.
This is the standard therapy of GIOP management. Oral bisphosphonates are preferred in view of their cost, safety profile, and the lack of definitive evidence of superiority of other medical therapies for OP. Alendronate and risedronate are most commonly used. They result in about 3%–4% rise in BMD over placebo when prescribed along with calcium and Vitamin D for a period of 1 year. Alendronate (35–70 mg/week or of 5–10 mg/day, oral), risedronate (35 mg/week or 5 mg/day, oral), ibandronate 150 mg/month, oral or 3 mg IV once in 3 months, and zoledronic acid (5 mg intravenous [IV] infusion once a year) are used. Bisphosphonates are recommended as primary prevention in all patients on prednisolone >7.5 mg/day for more than 3 months, particularly in postmenopausal women and elderly men. Although ibandronate is approved for use in postmenopausal osteoporosis and not currently approved for use in GIOP when compared to alfacalcidol in a group of chronic GC users, ibandronate treatment also led to significantly greater gain of BMD at the lumbar spine and femoral neck after 3 years. In a 2016 Cochrane review of 12 RCTs, patients who received bisphosphonates had a 43% (95% confidence interval, 9–65) lower risk of new VFs than patients who received calcium, Vitamin D, or both.
Parathormone analogs (teriparatide and abaloparatide)
Teriparatide and abaloparatide both are anabolic and increase bone formation., It is the most physiological way of treating GIOP, as it results in normal bone formation. It can improve trabecular bone mass significantly and reduce the fracture risk. Its use is limited due to its cost and parenteral route of administration. It can cause hypercalcemia and hypercalciuria, hence regular monitoring is required during therapy. Teriparatide, when compared with alendronate in the treatment of GIOP, in a trial of 428 patients for 36 months resulted in greater increment in BMD at spine, total hip, and femoral neck as compared to those on alendronate (11% vs. 5.3%, for lumbar spine, 5.2% vs. 2.7% for total hip, and 6.3% vs. 3.4% for femoral neck) (P < 0.001 for all) and a lower rate of radiographic VFs (1.7% vs. 7.7%, P = 0.007); however, rates of non-VF in these two treatment groups were not significantly different. However, after teriparatide is discontinued, rate of bone loss and fractures increases. Hence, antiresorptive agents such as a bisphosphonate or denosumab should be initiated after discontinuation of teriparatide. Abaloparatide is a synthetic analog of parathyroid hormone-related protein and has not been evaluated for the treatment of GIOP.
Denosumab is a monoclonal antibody to an osteoclast differentiating factor. It binds to receptor activator of nuclear factor-kappa-B ligand and interferes with osteoclast development, decreases bone resorption, increases BMD, and thus reduces the risk of fracture. In a noninferiority trial evaluating denosumab versus risedronate where patients on GC, who also received these agents concluded that denosumab was superior with respect to increases in spinal BMD at one year and was noninferior with respect to rates of fracture. Some studies have shown a higher risk of infection with denosumab than with bisphosphonates., Denosumab is generally not recommended as the agent to be preferred for initial treatment of patients on multiple immunosuppressive drugs or a biologic treatment due to the lack of relevant safety data. After discontinuation of denosumab, VF rate increases rapidly, especially among patients with a previous VF, and hence, alternative antiresorptive agents are needed after discontinuation of denosumab.
Raloxifene (a selective estrogen-receptor modulator) in postmenopausal women and calcitonin, another antiresorptive agent should be reserved for patients, in whom other treatments are contraindicated or in whom other treatments have failed. How raloxifene may help patients with GIOP is not yet fully understood. In a clinical trial involving postmenopausal women on GC, raloxifene significantly increased absolute BMD at lumbar spine by 1.3% from the baseline, as compared with placebo, which decreased the absolute BMD. Raloxifene reduces the risk of estrogen-receptor-positive breast cancer. Its major adverse effects are hot flushes, leg cramps, VTE, and stroke. Cathepsin K inhibitors (e.g., odanacatib) and monoclonal antibodies to sclerostin (e.g., romosozumab) are newer options in the treatment of GIOP. The ARCH trial demonstrated that romosozumab treatment for 12 months followed by alendronate in a patient population of women who had attained menopause, and were at a high risk for fracture, resulted in a significantly reduction in fracture risk than alendronate alone. It must be cautioned that the potential beneficial effects and safety profile of newer agents in individuals with GIOP is not yet fully established.
| Guidelines on the Management of Glucocorticoid-Induced Osteoporosis|| |
The guidelines provided by the American College of Rheumatology (ACR) guidelines advise intervention based on risk of fracture (high, medium, and low). The FRAX score can be used to evaluate the predicted fracture risk in such patients.
For adults ≥40 years:
- Low risk – 10-year risk of hip fracture ≤1% or a major osteoporotic fracture <10%
- Medium risk – 10-year risk of hip fracture >1 to <3% or a major osteoporotic fracture 10%–19%
- High risk– History of a fragility fracture, a lumbar spine or hip T-score below −2.5, or 10-year risk of hip fracture ≥3% or a major osteoporotic fracture 20%.
- For adults <40 years:
- Low risk – No medium- or high-risk factors other than GC treatment
- Medium risk – Hip or spine Z-score <−3 or rapid bone loss (≥10% at hip or spine over 1 year) and continuing GC treatment at ≥7.5 mg/day for ≥ 6 months
- High risk – History of a osteoporotic fracture
ACR guidelines suggest lifestyle modifications and supplementation of calcium and vitamin D for all patients. Apart from it, oral bisphosphonate is recommended for adults at medium or high risk of major fracture. Other options include IV bisphosphonates, teriparatide, denosumab, and raloxifene if oral bisphosphonates are contraindicated or not tolerated. Effective contraception is recommended during osteoporotic treatment for premenopausal women of childbearing potential. The patient should be followed yearly to determine if bone loss continues.
The Indian Rheumatology Association (IRA) has published comprehensive guidelines for the management of GIOP which have also been endorsed by other major national societies, namely, the Endocrine Society of India and Indian Society for Bone and Mineral Research.
The chief points provided by these guidelines are as follows:
- There is no safe dose of GC with respect to bone health
- Clinicians should strive to use the minimum possible dose of GCs, that too for the shortest possible duration of time
- Every attempt should be made to initiate a steroid-sparing agent, such as mycophenolate, methotrexate, azathioprine, and others, so as to minimize the exposure to GCs
- It is preferable to use local routes of administration of GC, such as inhalational route for bronchial asthma, or in the form of suppositories/enemas in patients with inflammatory bowel disease, wherever possible
- Healthy lifestyle choices such as adequate intake of calcium, avoidance of smoking, and moderation of alcohol intake should be preferred
- Standardized tools, such as the FRAX, should be used to evaluate the risk of developing fracture
- In those patients at a high risk of fractures, such as elderly males, postmenopausal women, and those with a prior documented fragility fracture, one should consider initiating primary fracture prophylaxis
- With respect to the patients lacking high-risk factors, consider initiation of primary prophylaxis for fracture prevention, in those with a BMD less than – 1.5
- In such patients (point number 8) with a BMD more than –1.5, reassess the BMD after 1–2 years if such patients are continuing GCs.
- The Indian version of FRAX is now available and can be used in our population of patients.
| Treatment in Women of Childbearing Age|| |
The difference in steroid adverse effects in pregnancy depends on their propensity to cross the placenta. Primary prophylaxis for fracture prevention is not recommended in pregnant women. A review of case reports has suggested that the maternal use of bisphosphonates before or during pregnancy did not have significant adverse fetal or neonatal outcomes. However, in special situations, in patients with previous fracture or a high risk of fracture while receiving GCs, therapeutic agents with shorter half-life and lesser bone retention rates, e.g., risedronate and teriparatide are generally recommended. Administration of denosumab in pregnant women is debatable because of mild risk of teratogenicity in animal studies.
| Conclusion|| |
GC is commonly used to treat multiple medical conditions. Their use should be limited to minimum dose and duration to ameliorate unwanted adverse outcomes. GIOP is one of the most important adverse effects as it leads to increased fracture risk and hence morbidity. Timely commencement of bone protection strategies will be useful to prevent bone loss secondary to GC use. Efforts should be taken at a national and regional level to disseminate the concepts of appropriate GC use among the health professionals and patients. Novel agents targeting the key cellular pathways could be useful to combat GIOP in the future.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2]