Glucocorticoid-induced osteoporosis (GIOP) is one of the most common and serious adverse effects associated with glucocorticoid use. This article highlights GIOP pathophysiology, epidemiologic associations, effective treatment, and lifestyle modifications that can reduce fracture risk for long-term glucocorticoid users and additionally emphasizes the importance of early intervention.
Key points
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Glucocorticoid-induced osteoporosis (GIOP) is one of the most common and serious adverse effects associated with glucocorticoid use.
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GIOP is associated with significant morbidity secondary to resultant fractures, and despite GIOP being a well-characterized problem, it remains undertreated, and prevention strategies are underused.
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This article highlights GIOP pathophysiology, epidemiologic associations, effective treatment, and lifestyle modifications that can reduce fracture risk for long-term glucocorticoid users and additionally emphasizes the importance of early intervention.
Introduction
Glucocorticoid-induced osteoporosis (GIOP) is one of the most common and serious adverse effects associated with glucocorticoid use. GIOP, the most common secondary form of osteoporosis, is associated with significant morbidity secondary to resultant fractures. Despite GIOP being a well-characterized problem that can occur rapidly, within the first few months of glucocorticoid use, it remains undertreated, and prevention strategies are underused. This article highlights GIOP pathophysiology, epidemiologic associations, effective treatment, and lifestyle modifications that can reduce fracture risk for long-term glucocorticoid users and additionally emphasizes the importance of early intervention.
Introduction
Glucocorticoid-induced osteoporosis (GIOP) is one of the most common and serious adverse effects associated with glucocorticoid use. GIOP, the most common secondary form of osteoporosis, is associated with significant morbidity secondary to resultant fractures. Despite GIOP being a well-characterized problem that can occur rapidly, within the first few months of glucocorticoid use, it remains undertreated, and prevention strategies are underused. This article highlights GIOP pathophysiology, epidemiologic associations, effective treatment, and lifestyle modifications that can reduce fracture risk for long-term glucocorticoid users and additionally emphasizes the importance of early intervention.
Glucocorticoid effects on bone
Glucocorticoids lead to decreased bone formation and increased bone resorption ( Fig. 1 ). The effects on osteoblasts, which are essential for bone formation, include decreased differentiation and maturation leading to their decreased number and function. In addition, excess glucocorticoid results in osteoblast apoptosis, further contributing to reduced bone formation. Osteocytes also undergo apoptosis and, because they are involved in repair of microdamage to bone, this leads to a decrease in bone quality. Glucocorticoids increase the expression of cytokines, including receptor of activator of NF-kappa β ligand (RANKL), that are involved in differentiation of osteoclasts and conversely decrease those involved in inhibition of osteoclasts, with the net effect of increased bone resorption. Indirect effects of glucocorticoids contribute to bone loss as well, such as decreases in calcium resorption, suppression of sex hormones and growth hormones, and alteration of parathyroid hormone pulsatility. However, subclinical secondary hyperparathyroidism leading to bone resorption is considered a more minor pathway for bone loss in GIOP. Areas of exploration include determining whether there are genetic factors that may make an individual more susceptible to adverse effects from glucocorticoids. A polymorphism in the glucocorticoid receptor gene has been identified that is associated with increased sensitivity to glucocorticoids with regard to cortisol suppression and insulin response, and although lower bone mineral density (BMD) in the spine was also found compared with controls, this did not reach statistical significance. To date, genetic testing has not found a role in risk stratification for GIOP.
Epidemiology
Up to 40% of persons receiving glucocorticoids develop bone loss over time. Bone loss secondary to glucocorticoids occurs early in their course of use; most significantly in the first 6 months. The initial rate of bone loss is rapid at up to 12% in the first year and then averages 2% to 3% a year. It is trabecular bone that is first affected, leading to an increased risk for fractures, particularly of the vertebrae. Later effects on cortical bone include the femoral neck of the hip. Among patients at risk for GIOP, age plays a major role, with postmenopausal women and older men at greatest fracture risk. Other risk factors that independently increase the risk for glucocorticoid-induced fractures are the same as those associated with traditional osteoporosis, except for glucocorticoid dose and mechanism of administration. Dose and duration of glucocorticoid use have a significant impact on fracture risk. The average daily dose of glucocorticoids seems more predictive of fracture than the cumulative dose. Doses as low as 2.5 mg of prednisone oral daily are associated with increased fracture risk, but at doses greater than 7.5 mg (the approximate physiologic amount of glucocorticoid produced endogenously) this risk increases 5-fold. This increase leads to the debate of whether there is a threshold dose that would confer a greater risk of fracture. A meta-analysis suggests that using more than 5 mg of prednisolone or equivalent daily leads to a decrease in BMD and increase in fracture risk. Cessation of glucocorticoid use results in decline in fracture risk, although not back to baseline. Supporting the premise that there is likely not a completely safe dose, it seems that even inhaled corticosteroids and intra-articular steroids can increase risk, therefore no route of administration and perhaps no dose is completely innocuous. In addition to the use of glucocorticoids themselves, many of the diseases that they are used to treat, such as rheumatoid arthritis (RA) and chronic obstructive pulmonary disease, are associated with bone loss, independent of glucocorticoid use. Proinflammatory cytokines involved in the pathophysiology of these conditions affect changes in bone formation and bone resorption. As an example, in RA several cytokines, such as tumor necrosis alpha and interleukin (IL)-1, IL-6, IL-11, and IL-17, increase expression of RANKL leading to increased bone resorption. Based on an understanding of this pathophysiology, there has been debate about whether low-dose glucocorticoids could be protective to bone in RA. Randomized trials of lower dose prednisone in RA have failed to consistently show an increased fracture risk. However, these studies are of insufficient size or duration to identify fracture signals adequately.
Diagnosis/identifying patients at risk
Bone Mineral Density Measurement
BMD measurement does not have the same utility in glucocorticoid-exposed patients as it does in postmenopausal osteoporosis. Comparison of fractures between these two groups at similar BMD measurements shows higher fracture risk in the glucocorticoid users. Thus, fracture risk for GIOP is partially independent of BMD and may relate to the direct toxic effect of glucocorticoids on osteoblasts and osteocytes. Despite these limitations, BMD measurement can still be used as a tool to help risk stratify patients with GIOP for treatment decisions and to follow patients over time, particularly in response to bone-specific therapies.
FRAX
The FRAX tool ( https://www.Shef.ac.uk/FRAX/ ) developed by the World Health Organization provides the 10-year probabilities of hip fracture and a major osteoporotic fracture (fractures of the hip, spine, forearm, and humerus). It incorporates numerous osteoporosis risk factors, including the use of glucocorticoids. In assessing glucocorticoid users, there are some restrictions associated with FRAX. This tool does not input specific glucocorticoid doses or duration but relies on an average dose of 7.5 mg of prednisolone per day. In addition, only the femoral neck BMD is incorporated into the calculation and patients with GIOP may lose bone mass in the spine or the hip trochanter earlier, thereby underestimating risk. There is an adjustment for FRAX that can be applied and takes into account the dose of glucocorticoids ( Table 1 ).
| Fracture Site and Dose | Glucocorticoid Dose (Prednisolone Equivalent mg/dL) | Average Percentage Adjustment for All Ages |
|---|---|---|
| Hip Fracture | ||
| Low | <2.5 | −35 |
| Medium | 2.5–7.5 | No adjustment |
| High | ≥7.5 | +20 |
| Major Osteoporotic | ||
| Low | <2.5 | −20 |
| Medium | 2.5–7.5 | No adjustment |
| High | ≥7.5 | +15 |
Other Testing Strategies
Patients on glucocorticoids who present with low bone mass or fractures should also be initially evaluated for other secondary causes of bone loss. Hyperparathyroidism, osteomalacia (most commonly caused by vitamin D deficiency or relative insufficiency), and more rarely other metabolic bone disorders may coincidentally be detected and require alternate therapeutic approaches. Beyond routine blood chemistries and a complete blood count, selective biochemical tests, including a 25-hydroxy (OH) vitamin D, parathyroid hormone, serum phosphorus, and occasionally a serum immunoelectrophoresis (looking for a paraproteinemia), may be prudent. For patients who have an intermediate risk based on dual-energy x-ray absorptiometry (DXA) or FRAX, lateral vertebral imaging by conventional radiography or using the DXA machine to obtain a vertebral fracture assessment is appropriate to exclude vertebral compression fractures. The trabecular bone score (TBS) is an additional technique that may be used to assess bone as an adjunct to DXA. It has the benefit of analyzing skeletal microarchitecture, and can be extrapolated from data obtained from a DXA scan. The higher the TBS, the better the bone microarchitecture. TBS has been shown in primary osteoporosis to predict current and future fragility fractures and has been used to assess treatment effect. TBS may be decreased in patients on glucocorticoids compared with normal controls, even when there is no significant change in BMD. Larger studies are needed to ascertain whether TBS provides added value in this clinical setting, but TBS could prove to be another tool to aid in the prevention and treatment of GIOP.
Prevention and treatment
Lifestyle Measures and Assessment
Despite most of the evidence being consensus opinion extrapolated from data in other forms of osteoporosis, these measures should not be minimized and patients should be educated on how to make these modifications ( Box 1 ). Regrettably, lifestyle modifications are difficult for most patients to implement and the overall magnitude of their benefit is limited.
Assessments
Fall risk assessment
Baseline dual x-ray absorptiometry
Serum 25-hydroxyvitamin vitamin D level
Baseline height
Assessment of prevalent fragility fractures
Consider radiographic imaging of the spine or vertebral fracture assessment for patients initiating or currently receiving prednisone greater than or equal to 5 mg/d or its equivalent
Recommendations
Weight-bearing activities
Smoking cessation
Avoidance of excessive alcohol intake (>2 drinks per day)
Nutritional counseling on calcium and vitamin D intake
Calcium intake (supplement plus oral intake) 1200–1500 mg/d
Vitamin D supplementation
Calcium and Vitamin D
Calcium and vitamin D combined are effective in decreasing bone loss among glucocorticoid users compared with calcium or placebo. A meta-analysis focused on lumbar spine BMD outcome revealed a 3.2% positive difference in the percentage change in BMD in those patients taking calcium plus vitamin D. Despite calcium’s benefits as an essential bone building block and the role of vitamin D in maximizing calcium absorption and minimizing its losses, calcium and vitamin D have not been shown to independently reduce fracture risk in GIOP. Thus, for most persons on chronic glucocorticoids, calcium and vitamin D are necessary but not sufficient. International guidelines for the treatment of GIOP all recognize the need for adequate calcium and vitamin D supplementation, although they vary slightly in dosing and target groups. Consistent with the Institute of Medicine recommendations, we recommend at least 1200 mg of elemental calcium per day, acquired preferentially from diet rather than supplements. Calcium is best consumed with food to promote an acid environment and older adults on proton pump inhibitors may absorb more calcium citrate than other forms of calcium. Vitamin D can be administered through daily multivitamins or through calcium supplements to achieve at least 600 IU of vitamin D per day. For patients who have 25-OH vitamin D levels less than 20 ng/mL a short course (typically 50,000 IUs 2 times per week for 2 months) of ergocalciferol (vitamin D 2 ) is appropriate to replete the fat-soluble vitamin D stores. There is growing concern that too much calcium and too much vitamin D are neither necessary nor perhaps safe. Hypercalcemia, nephrolithiasis, and potentially a heightened risk of cardiovascular adverse events have been associated with overzealous use of calcium supplements and/or vitamin D in some, but not in all, studies.
Bisphosphonates
Bisphosphonates constitute the first-line therapy for the treatment of GIOP. They inhibit osteoclast activity and therefore result in decreased bone resorption. At present, alendronate, risedronate, and zoledronic acid are approved by the US Food and Drug Administration (FDA) for the treatment of GIOP. Risedronate and zoledronic acid are also approved for prevention. Off-label use of ibandronate, pamidronate, and etidronate is supported by some clinical trial data showing efficacy on BMD end points as well as an open-label study that showed lower fracture risk on ibandronate. All bisphosphonates are poorly absorbed orally. They should be taken on an empty stomach with a full 240-mL (8 ounce) glass of water and nothing eaten for at least 30 minutes afterward to maximize their absorption. It is also necessary to remain upright afterward for at least 30 minutes after ingestion. Dyspepsia and, less commonly, esophagitis are the most frequently reported adverse events. Arthralgias can occur and can often be distinguished from other causes with a dechallenge-rechallenge strategy. A particular issue with all bisphosphonates in GIOP is that some of the potential recipients are premenopausal women of childbearing potential. There is no compelling evidence of concerns to the fetus after prolonged use of a bisphosphonate by the mother, albeit based on very limited data. There is no clear evidence of serious risk to the unborn child (as long as the drug is not actively onboard at the time of delivery, when fetal hypocalcemia might be expected). It is still best to avoid these drugs in young women and in children, except among those at greatest risk and those who have already experienced fragility fractures associated with their glucocorticoid use.
There are also concerns regarding longer term safety of bisphosphonates in GIOP. Because a low-turnover bone state follows prolonged use of glucocorticoids, bisphosphonates may be limited in their long-term effectiveness and theoretically could contribute to an oversuppression of bone turnover, which likely represents the mechanism for the very rare side effects of osteonecrosis of the jaw and atypical femoral fractures. Despite these theoretic concerns, some expert groups, such as the UK National Osteoporosis Guidelines Group, recommend continued bisphosphonate use as long as supraphysiologic glucocorticoids are still being used. Counseling on proper use and potential side effects should be performed for every patient to ensure a full understanding of benefits and risks and to maximize compliance, which is low long term.
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Alendronate
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In a randomized, double-blind, placebo-controlled study by Saag and colleagues and its extension study by Adachi and colleagues, alendronate significantly increased BMD at the spine and trochanter, while maintaining BMD at the femoral neck in patients receiving glucocorticoids. There was also a significant reduction in vertebral fractures in the extension study. A meta-analysis of oral bisphosphonates overall showed similar vertebral fracture risk reduction to that seen in postmenopausal osteoporosis.
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Recommended dose for treatment: 10 mg daily or 70 mg weekly orally in postmenopausal women and men with osteoporosis and 35 mg weekly in premenopausal women.
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Risedronate
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Prevents bone loss in the lumbar spine, femoral neck, and trochanter in patients taking glucocorticoids as shown in randomized trials by both Cohen and colleagues for new users and Reid and colleagues for prevalent users. Significant risk reduction by 70% of new vertebral fractures was also observed in a post hoc analysis that combined these two studies.
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Recommended dose for prevention or treatment: 5 mg daily or 35 mg weekly orally.
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Zoledronic acid
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A randomized controlled, noninferiority trial of zoledronic acid versus risedronate for prevention and treatment of GIOP showed that zoledronic acid was noninferior and was more efficacious in increasing BMD than risedronate. Despite this being the largest bisphosphonate GIOP study to date, BMD was not a part of the inclusion criteria and patients on average had lower fracture risk than in other studies. There was no significant fracture risk reduction seen comparing zoledronic acid with risedronate. Zoledronic acid can cause an acute phase reaction leading to arthralgias/myalgias, low-grade fevers, and less commonly flulike symptoms in about 10% of patients given an intravenous infusion.
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Recommended dose for prevention or treatment: 5 mg once a year intravenously in persons with adequate renal function (glomerular filtration rate >35 mL/min).
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Teriparatide
A bone anabolic agent, teriparatide is a recombinant human parathyroid hormone. Because the pathogenesis of GIOP includes decreased osteoblast differentiation and maturation leading to decreased bone formation, anabolic agents such as teriparatide might counteract this by direct effects on osteoblasts that include increasing the number of osteoblast precursors, promoting differentiation into mature cells, and increasing survival with the combined effect of increasing bone formation. In a study comparing teriparatide with alendronate for GIOP, there were greater increases in BMD in the spine and hip with teriparatide. The study was not statistically powered for fracture risk reduction, but even so there were also fewer morphometrically assessed vertebral fractures in the teriparatide group compared with alendronate, although no significant difference was found for nonvertebral fractures. Teriparatide is FDA approved for GIOP and is given as 20 μg subcutaneously daily. The main side effect of teriparatide is a mild hypercalcemia (on average 1 mg/dL). In the initial development of teriparatide a Fisher rat model developed osteosarcoma. A black-box warning in the product circular cautions about this finding, although to date the postmarket rate of this outcome has mirrored the background rate of osteosarcoma in general populations. It is recommended that teriparatide not be given to children or young adults with open epiphyses or those who have received past radiation therapy. Patients with bone malignancy are likely also not good teriparatide candidates. A finite anabolic window further limits therapy to a 24-month maximum. Teriparatide may be cost-effective compared with alendronate in glucocorticoid users with incident vertebral fractures.
Denosumab
Denosumab is a fully human monoclonal antibody against RANKL. After binding to RANKL, it prevents RANKL from binding to receptor of activator of NF-kappa β, which is necessary for the formation and function of osteoclasts, and therefore inhibits osteoclast activity and thereby bone resorption. Denosumab has been shown to decrease the risk of vertebral, nonvertebral, and hip fracture in postmenopausal women with osteoporosis and is approved by the FDA for treatment in this group. It has not yet been approved for GIOP and is currently undergoing phase III clinical trials comparing its effect on BMD with risedronate. During a study testing its efficacy in RA, some of the patients receiving it were on glucocorticoids. The relative improvement in bone mass seen with denosumab (particularly at the standard dose of 60 mg every 6 months) compared with placebo seemed to be qualitatively similar between patients receiving and not receiving glucocorticoids.
Raloxifene
Raloxifene is a selective estrogen receptor modulator, shown in postmenopausal osteoporosis to reduce vertebral fracture risk. A small randomized controlled trial showed preservation to slight gain of bone mass at the spine with raloxifene compared with placebo. Although it is not approved for GIOP, it may represent another therapeutic option for women who are not at heightened risk for venous thromboembolic disease.
Percutaneous Vertebroplasty
As discussed earlier, there is considerable evidence in support of medical management to prevent vertebral fractures in patients with GIOP. Some studies suggest that percutaneous vertebroplasty (PVP) and percutaneous kyphoplasty (PKP) may address pain and improve postfracture mobility in postmenopausal women. Case reports not controlled for underlying vertebral fracture risk suggest that patients with GIOP were at increased risk for vertebral refracture (at time of initial PVP) at vertebral sites above and below the vertebral level treated, compared with those with primary osteoporosis. A cluster phenomenon of multiple vertebral refractures occurred within a short time of the initial procedure, requiring additional procedures. PVP and PKP should therefore be used with caution in patients with GIOP until their safety and comparative effectiveness are better delineated in this patient population.
International Guidelines for Glucocorticoid-induced Osteoporosis
Postmenopausal women and men greater than or equal to 50 years of age
There are numerous international guidelines for the management of GIOP. In general, it is agreed that lifestyle modifications, as noted previously, should be implemented and attempts should be made to minimize exposure to glucocorticoids whether by reducing the dose or initiating a steroid-sparing agent whenever possible. The threshold for intervention with bone-specific pharmacologic agents varies between countries and is related to cost and access. Table 2 provides a comparison of the guidelines between the American College of Rheumatology (ACR) and the International Osteoporosis Foundation and the European Calcified Tissue Society.
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