Glucocorticoid induced osteoporosis

Are You Sure the Patient Has Glucocorticoid Induced Osteoporosis (GIOP)?

Symptoms: fracture, none

It is estimated that nearly 50% of patients treated with long-term glucocorticoids will fracture. Bone changes begin quickly after the initiation of glucocorticoids, even before changes will be seen on any imaging studies or by Dual-energy X-ray Absorptiometry (DXA). Therefore, GIOP needs to be considered at the time of glucocorticoid initiation.

Signs: Fracture, loss of bone mineral density (BMD), none

Fracture risk increases quickly after the initiation of glucocorticoids, especially fractures of the vertebrae and hip. This fracture risk is seen even with relatively low doses of glucocorticoids, i.e. 3-10 mg of prednisone or higher-dose inhaled glucocorticoids.

Fracture risk increases with duration and dose of glucocorticoid, regardless of changes in bone mineral density. However, lower BMD or loss of BMD may both be indicative of a higher risk of fracture.

Osteoporosis, in general, is a silent disease. Therefore, most patients will not “feel” any changes happening prior to a feared fracture.

Key Laboratory Findings: None, Reduced BMD

Laboratory studies are typically not useful in diagnosing GIOP. The underlying cause of GIOP is largely due to changes in reduced bone formation coupled with persistent bone destruction and increased osteocyte and osteoblast apoptosis. The latter may influence the early bone fragility seen after the initiation of glucocorticoids. Thus, BMD measurement will frequently not be able to detect microarchitectural changes in bone quality.

What Else Could the Patient Have?

• Postmenopausal osteoporosis

• Other secondary causes of Osteoporosis (hypogonadism, Cushing Disease, thyroid disease, parathyroid disease, etc.)

• Chronic kidney disease

Other secondary causes of osteoporosis should be evaluated and/or corrected if present. However, if chronic glucocorticoid treatment is present, GIOP should be monitored and appropriate preventative or treatment recommendations made.

Key Laboratory and Imaging Tests

An initial laboratory evaluation of renal function, serum calcium, and alkaline phosphatase levels is the first step in evaluating a person treated with glucocorticoids for possible osteoporosis treatment. Serum 25(OH) vitamin D should be assessed; if not feasible, empirical anti-osteoporosis treatment could be offered.

Measurement of height routinely during clinic visits is important in order to document any height loss. Most vertebral fractures are asymptomatic and will be missed if a patient is not monitored. Additional imaging is recommended if height loss is noted or there is a new onset of back pain. The occurrence or presence of an occult vertebral fracture will impact treatment decisions, as the risk of further fracture is significantly greater in someone with a history of prior fracture.

Since glucocorticoid therapy raises the risk of vertebral fracture greater than the risk at other fracture sites, assessment of the vertebral bodies, either by plain films or vertebral fracture assessment (VFA), should be considered.

A dual x-ray absorptiometry (DXA) scan provides further information regarding fracture risk and allows for long-term monitoring. However, the inability to obtain a DXA scan should not hinder management.

Other Tests That May Prove Helpful Diagnostically

In addition to the basic laboratory mentioned above, other labs can be beneficial in looking for or monitoring other causes of bone loss or fracture risk. These include:

• Testosterone profile to evaluate for possible underlying hypogonadism

• Thyroid function studies if a patient has signs or symptoms of hyper- or hypothyroidism or is currently on thyroid medications

• Complete Blood Count (CBC) to rule out other hematologic diseases

• Liver function studies to rule out underlying liver disease

• Serum protein electrophoresis

• 25(OH) Vitamin D, if not previously completed

Management and Treatment of the Disease

Overall treatment: All patients receiving glucocorticoid treatment should receive counseling on smoking avoidance, limiting alcohol intake, increasing weight-bearing exercise, and appropriate calcium and vitamin D supplementation. The Institute of Medicine published recommendations for calcium and vitamin D supplementation in 2009 (Table 1).

Table 1.

Further pharmacologic treatment for GIOP is dependent on multiple determinants, most specifically other clinical risk factors for fracture and expected dose and duration of glucocorticoid. The use of the FRAX tool, which calculated a 10-year absolute fracture risk, has been advocated by the American College of Rheumatology (2010) to help stratify risk (http://www.shef.ac.uk/FRAX/). FRAX scores take into consideration age, gender, race/ethnicity, height, weight, family history of fracture, glucocorticoid use, prior history of fracture, alcohol use, tobacco use, presence of rheumatoid arthritis, and other secondary causes of osteoporosis (such as Type 1 Diabetes Mellitus, osteogenesis imperfecta, untreated hyperthyroidism, hypogonadism or premature ovarian failure, chronic malnutrition, chronic malabsorption, chronic liver disease, cystic fibrosis, polymyalgia rheumatica, inflammatory bowel disease, chronic pulmonary disease, organ transplantation, etc). Please see Table 2 (2a and 2b).

Table 2.

Clinical Risk Factors

Bone Mineral Density: Fractures are possible, even in patients with normal bone density or no change in bone mass, especially when treated with glucocorticoids. However, if a patient’s T-score is ≤-2.5 and they are over the age of 50, his/her fracture risk is higher than others and a pharmacologic osteoporosis treatment should be initiated. Patients with T-scores >-2.5 should have other clinical risk factors assessed prior to determining treatment.

Race/Ethnicity: Fracture risk is higher among Caucasians than African-Americans. Thus, it is recommended that Caucasian women and men be started on pharmacologic osteoporosis treatment at an earlier age and better BMD than African-American men and women. In the general population, people of Hispanic and Asian descent have fracture risk slightly lower than their Caucasian counterparts but higher than African-Americans.

Age: Fracture risk increases with age, regardless of glucocorticoid use. Therefore, greater consideration for pharmacologic osteoporosis treatment should be given to older individuals. Following the initiation of glucocorticoids, fracture risk rises faster in older persons than in younger persons. It is recommended that all Caucasian women 80 years and older started on chronic glucocorticoids also start a pharmacologic osteoporosis treatment. However, ALL patients treated with glucocorticoids are at risk of fracture.

Low body mass index: Body mass is an important predictor of fracture risk. People with lower body mass are at significantly higher risk of fracture.

Parental history of hip fracture: Fracture risk has a strong genetic component. As hip fracture is one of the most common osteoporotic fractures, a history of this type of fracture is a good indicator of osteoporosis in primary family members.

Current Smoking: Smoking has been found to increase a patient’s risk of fracture by approximately 25%. Past smoking, too, increases one’s fracture risk but not to the same degree as current smoking. Thus, all patients should be counseled on smoking cessation.

Alcohol use: Alcohol intake appears to have a varying relationship with fracture risk, depending on the amount consumed. However, it is accepted that excessive alcohol intake, defined by many as ≥3 alcoholic beverages per day, increases patients fracture risk. If patients consume alcohol, they should be counseled to limit their intake to a maximum of 3 drinks daily.

Glucocorticoid dose: The dose of glucocorticoid will impact fracture risk, with direct relationship: the higher the dose the greater the fracture risk. This relationship also holds true for cumulative dose, i.e. the higher and greater duration the glucocorticoid use, the higher the risk of fracture. However, even lower doses of oral glucocorticoids, alternate-day therapy, and inhaled glucocorticoids increase the risk of fracture. See Table 3.

Table 3.

Special Circumstances

Glucocorticoid replacement for Adrenal Insufficiency: There does not appear to be an increased risk of osteoporosis if patients with adrenal insufficiency are treated with appropriate replacement doses (current recommendations are hydrocortisone doses of 10-12 mg/m2/day). However, due to the difficulty in calculating precise replacement doses for those with adrenal insufficiency, bone health should be monitored with DXA imaging as these patient age, and preventative treatment with calcium, vitamin D, and resistance exercise is advisable.

Recommended Treatment Regimens in order of Preference

Teriparatide: If fracture risk is high (i.e. prior fracture, loss of BMD, older person with low BMD), Teriparatide should be considered as a first-line treatment option. It has been shown to be superior to alendronate in reducing vertebral fracture risk and its mechanism of action opposes the changes in osteocyte and osteoblast number and action. Cost, daily injections, and the potential for transient hypercalcemia can be issues with teriparatide.

Risedronate: There are no head-to-head trials of risedronate and the other oral bisphosphonate option, alendronate. However, the available data showing reduced vertebral fractures with risedronate therapy and improved BMD in GIOP make it a good oral bisphosphonate option for treatment of GIOP in patients with low to moderate fracture risk.

Zoledronate: In a head-to-head trial with risedronate, zoledronate increased BMD to a greater degree. In addition, it is dosed intravenously, which is important due to the common side effect of nausea or gastroesophageal reflux with oral bisphosphonates and the physician-controlled compliance. Oral bisphosphonates have poor absorption, even when taken as prescribed (on an empty stomach with water, nothing else to eat or drink for 30-60 minutes), and must be taken consistently to be effective in reducing fracture risk. Frequently, patients have difficulty remembering to take a monthly or weekly medication or do not take them per the dosing instructions. If this is the case, full benefit will not be gained.

Alendronate: Alendronate has been shown to increase BMD in patients with GIOP. It is available as an oral, weekly preparation in a generic form. Therefore, it is frequently the most affordable medication. There are no placebo-controlled trials that show that fracture risk is significantly reduced in GIOP treated with alendronate, although a systematic review suggests fracture risk reduction is similar to postmenopausal osteoporosis.

Combination Teriparatide and Zoledronate: This combination of teriparatide and a bisphosphonate has not been studied in GIOP. When used in combination in postmenopausal women, there was an additive affect with a greater increase in hip and spine BMD with the combination than with either treatment alone. No fracture data are available. Thus, it may be considered in someone with very high fracture risk.

Other Medications Used for Osteoporosis

Ibandronate: Ibandronate (Boniva®) is approved for use in postmenopausal osteoporosis. It is not currently approved for use in GIOP. In postmenopausal women, ibandronate, either orally or intravenously, has been shown to improve lumbar spine BMD and reduce the risk of vertebral fractures. When compared to alfacalcidol in a group of chronic glucocorticoid users, ibandronate treatment also led to significantly greater gain of BMD at the lumbar spine and femoral neck after 3 years.

Denosumab: Denosumab is approved for use in postmenopausal osteoporosis but it is not currently approved for use in GIOP. It has been studied in patients with Rheumatoid Arthritis treated with methotrexate, and denosumab treatment led to similar gains in BMD in those on and off concurrent glucocorticoid treatment. Denosumab may have the added benefits of being dosed subcutaneously (potentially in a doctor’s office), having a dosing interval of every 6 months, and having limited long-term effects after discontinuation.

Concurrent secondary causes of bone loss or increased fracture risk

Hypogonadism: The current (2010) American College of Rheumatology guidelines for GIOP no longer recommend estrogen replacement for treatment or prevention of GIOP. This is largely based on concerns regarding estrogen replacement, as described in the Women’s Health Initiative (some groups of women being at increased risk of cardiovascular disease, breast cancer, stroke and pulmonary thromboembolus). However, estrogen replacement reduces bone mineral density losses in women treated concurrently with glucocorticoids. Therefore, if a female patient is otherwise unable to take an osteoporosis-specific prescription treatment, hormone replacement therapy could be considered.

Similarly, in men, testosterone replacement in those with hypogonadism has been shown to improve bone mineral density. Although it is not recommended as first line for fracture risk reduction in men taking glucocorticoids, testosterone therapy could be considered as an adjunct to other osteoporosis treatments or as sole treatment if other treatments are contraindicated or not tolerated in a hypogonadal male.

Chronic Kidney Disease: Patients with chronic kidney disease require thoughtful consideration when determining the diagnosis of and treatment for fractures and osteoporosis. In a study of osteoporotic women with varying degrees of renal insufficiency, no significant differences in side effects or renal outcomes were seen between women with mild (creatinine clearance {CrCl} 50-79 mL/min), moderate (CrCl 30-49 mL/min), or severe (CrCl <30 mL/min) renal impairment when treated with daily risedronate. Zoledronic acid has been associated with a few cases of renal impairment when used in patients with multiple myeloma or bone metastases.

Based on this evidence, it appears safe to treat patients with mild renal impairment with FDA-prescribed doses of bisphosphonates. Product labeling does not recommend the use of a bisphosphonate in persons with a calculated CrCl of less than 30-35 mL/minute. Denosumab can be used in patients with a calculated CrCl of <30 mL/minute, although this medication is not approved for use in GIOP. Due to the risk of adynamic bone disease and osteomalacia in persons with stage 5 CKD (e.g. dialysis dependent), bone biopsy is recommended before the initiation of any anti-osteoporosis therapy to rule out adynamic or osteomalacic bone.

Vitamin D Deficiency or Insufficiency: The optimal level of serum 25 hydroxyvitamin (OH) vitamin D (25(OH)D) remains unclear. Most agree that vitamin D deficiency can be defined as a 25(OH)D level of less than 20 ng/mL. Because a 25(OH)D level below 30 ng/mL is sometimes associated with PTH elevation, a serum 25(OH)D level of 30 ng/mL has been recommended by others. Vitamin D intoxication, leading to hypercalcemia, generally does not occur until 25(OH)D levels reach 150 ng/mL or higher, except in patients with primary hyperparathyroidism. Due to the risk of further bone loss associated with secondary hyperparathyroidism as a result of vitamin D deficiency, replacement of vitamin D to a goal 25(OH)D level of 20-30ng/mL is recommended. A common method of doing so involves using Ergocalciferol 50,000units twice weekly for 6-12 weeks, depending on the degree of deficiency.

When to Switch and What to Consider Switching To

There are two main reasons to consider switching anti-osteoporosis treatments: (1) intolerance, and (2) heightened fracture risk.

Intolerance: If a patient is intolerant to an oral bisphosphonate, zoledronate should be considered since it is dosed intravenously, bypassing the gastrointestinal tract. There is a risk of an acute phase reaction associated with zoledronate. This reaction is lessened if a patient has ever been exposed to a bisphosphonate in the past and/or is treated with acetaminophen prior to the infusion.

If a patient is intolerant to teriparatide, possibly due to transient hypercalcemia or myelopathy, zoledronate may also be an alternate option. Typically, patients selected for treatment with teriparatide are at higher risk of fracture. Use of zoledronate would ensure appropriate dosing without concern regarding compliance. Risedronate or alendronate could be also be an option.

Heightened fracture risk: If a patient’s fracture risk increases while on a treatment, modifying his/her therapy should be considered. Examples of heightened fracture risk include loss of BMD while on treatment or fracture while on treatment. If this occurs and the patient is already treated with a bisphosphonate, changing to teriparatide should be considered. If a patient had been on teriparatide, adding zolendronate could be considered.

How long should patient stay on an Osteoporosis treatment?

Bisphosphonates

In most cases, patients should be continued on treatment as long as they are continued on glucocorticoids. Although many clinicians are recommending “drug holidays” for postmenopausal osteoporosis treatment, there is even less data on which to make this decision for chronic glucocorticoid users. There is evidence showing an increased loss of bone mineral density when patients stop bisphosphonate treatment but continue on glucocorticoids. It is possible that persons using chronic glucocorticoids may be at heightened risk of oversuppression of bone.

There are recent concerns regarding the long-term risks associated with bisphosphonate treatment, including atypical fractures (subtrochanteric fractures) and osteonecrosis of the jaw (ONJ). However, the absolute risk of these events is small and a clear causative effect has not been found. Bisphosphonates accumulate in bone and the duration of their presence is not fully known.

Teriparatide

Currently, it is recommended that patients remain on teriparatide for 2 years. In postmenopausal women or in men over the age of 50, an anti-resorptive treatment (bisphosphonate or denosumab) should be initiated after discontinuing teriparatide to maximize the benefits gained from that treatment. In premenopausal women or younger men, teriparatide treatment may not need to be followed by anti-resorptive treatment if the glucocorticoids are not continued and if there is no evidence of hypogonadism.

What’s the Evidence?/References

Hansen, K.E.. “Uncertainties in the prevention and treatment of glucocorticoid-induced osteoporosis”. J Bone Miner Res. vol. 26. 2011. pp. 1989-96. (This manuscript reviews the most recent changes to the American College of Rheumatology guidelines for the treatment of GIOP, comparing the 2010 guidelines to the 2001 guidelines. The authors also present potential patient scenarios and discuss their recommendations for treatment.)

Grossman, J.M.. “American College of Rheumatology 2010 recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis”. Arthritis Care Res (Hoboken). vol. 62. 2010. pp. 1515-26. (These guidelines go into depth regarding the 2010 American College of Rheumatology GIOP guidelines, basis for the recommendations, and the strength of the recommendations.)

Adler, R.A.. “Glucocorticoid-induced osteoporosis: management update”. Curr Osteoporos Rep. vol. 8. 2010. pp. 10-4. (This review discusses the currently available treatment options for GIOP. The mechanisms of action, risks and benefits for the available prescription drugs are discussed.)

Weinstein, R.S.. “Clinical practice. Glucocorticoid-induced bone disease”. N Engl J Med. vol. 365. 2011. pp. 62-70. (This review discusses the underlying pathogenesis of GIOP, the evaluation and management of GIOP in correlation with a clinical vignette.)

Reid, D.M.. “Zoledronic acid and risedronate in the prevention and treatment of glucocorticoid-induced osteoporosis (HORIZON): a multicentre, double-blind, double-dummy, randomised controlled trial”. Lancet. vol. 373. 2009. pp. 1253-63. (This manuscript describes the findings of a head-to-head trial of zolendronate and risedronate for the prevention and treatment of GIOP. The findings showed that zolendronate was non-inferior to risedronate in regards to lumbar spine BMD. There were more adverse events in the zolendronate group, mainly related to symptoms of an acute phase reaction in the days following the infusion.)

Adachi, J.D.. “Two-year effects of alendronate on bone mineral density and vertebral fracture in patients receiving glucocorticoids: a randomized, double-blind, placebo-controlled extension trial”. Arthritis Rheum. vol. 44. 2001. pp. 202-11. (This manuscript describes the extension of an initial trial evaluating alendronate vs. placebo for the prevention and treatment of GIOP. The findings suggest that alendronate leads to continued benefit in the 2nd year of treatment in regards to improved BMD and bone turnover markers in patients treated with glucocorticoids.)

Reid, D.M.. “Efficacy and safety of daily risedronate in the treatment of corticosteroid-induced osteoporosis in men and women: a randomized trial. European Corticosteroid-Induced Osteoporosis Treatment Study”. J Bone Miner Res. vol. 15. 2000. pp. 1006-13. (This paper presents the findings of a placebo-controlled trial of risedronate vs. placebo in patients treated with chronic glucocorticoids. Risedronate therapy resulted in gain of BMD vs. no gain in the placebo group. The study was not powered to analyze fractures but there did appear to be fewer vertebral fractures in the treatment groups than in the placebo group.)

Emkey, R.. “Changes in bone mineral density following discontinuation or continuation of alendronate therapy in glucocorticoid-treated patients: a retrospective, observational study”. Arthritis Rheum. vol. 48. 2003. pp. 1102-8. (This manuscript reports the results of a retrospective study looking at the effect of alendronate discontinuation in people taking chronic glucocorticoids. The results showed that the men and women that remained on alendronate did not lose BMD, whereas those that discontinued alendronate but continued on glucocorticoids lost BMD in the subsequent 3-5 years.)

Saag, K.G.. “Teriparatide or alendronate in glucocorticoid-induced osteoporosis”. N Engl J Med. vol. 357. 2007. pp. 2028-39. (This paper describes a head-to-head, double-blind, controlled trial of teriparatide vs alendronate in men and women treated with chronic glucocorticoids with a high risk of fracture. Following 18 months of treatment, there was a significantly greater gain of BMD in the teriparatide group and significantly fewer vertebral fractures in the teriparatide group, when compared to the alendronate group.)

Dore, R.K.. “Effects of denosumab on bone mineral density and bone turnover in patients with rheumatoid arthritis receiving concurrent glucocorticoids or bisphosphonates”. Ann Rheum Dis. vol. 69. 2010. pp. 872-5. (This paper describes the BMD changes seen in patients with Rheumatoid Arthritis treated with denosumab vs. placebo. The results showed that BMD increased more significantly in the denosumab treatment groups than in the placebo group, regardless of concomitant glucocorticoid use.)

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