Learning objectives
- •
Glucocorticoids induce bone loss, lead to osteoporosis, and increase the patient’s fracture risk.
- •
Glucocorticoid-induced bone loss and increased fracture risk can be reduced.
The case study
Reason for seeking medical help
- •
Mrs. GOI, 57 years old, has been diagnosed with giant cell arteritis about 4 weeks ago. She responded only to very high doses of corticosteroid therapy and is referred because of concerns about her bone health: the plan is to continue with high doses of prednisone: 60–120 mg daily for at least 6, probably 12 months.
Past medical and surgical history
- •
No relevant past medical history except for a bout of giant cell arteritis (GCA) about 3 years ago which was successfully treated with very large doses of prednisone.
- •
Mrs. GOI always enjoyed good health and led a physically active lifestyle.
- •
Menarche at age 13 years, regular menstrual periods.
- •
Natural menopause at age 46 years, no hormonal replacement therapy.
- •
Three children aged 39, 37, and 32 years, all in good health.
Lifestyle
- •
Mentally good and physically independent, drives her own car.
- •
Lives on her own since the death of her husband about 4 years ago.
- •
Retired dietitian works on a part-time basis 3 days a week in the local hospital and as a volunteer in the town visitors’ center during weekends.
- •
Good appetite, well-balanced, nutritious diet. No weight loss.
- •
No cigarette smoking, no alcohol intake, no caffeine intake, no excessive sodium intake.
Medication(s)
- •
Prednisone 80 mg daily, this is the lowest dose that controlled the giant cell arteritis.
- •
Vitamin D3 1000 units daily.
- •
Multivitamins 1 tablet daily.
Family history
- •
Negative for osteoporosis.
Clinical examination
Weight 115 pounds, steady; height 65″, no height loss.
Fading clinical evidence of giant cell arteritis.
Sitting BP 126/78, no postural drop, no orthostasis. No cushingoid features. Mild osteoarthritic changes in knees and hands, not interfering with daily activities. No clinical evidence of heart failure, good peripheral circulation, no significant clinical signs.
Laboratory results
She recently had the following laboratory tests done as part of her annual physical examination: comprehensive metabolic profile, complete blood count, serum TSH, and serum vitamin D. All were within the normal range. Erythrocyte sedimentation rate: 38 mm in first hour was much higher when the GCA was active.
DXA and radiologic results
T-scores: −1.0 in the upper four lumbar vertebrae; −0.8 and −0.6 in the right and left femoral necks, respectively; and −0.9 in the distal nondominant one-third radius. FRAX scores 1.2% and 9% for the 10-year risk of hip and major osteoporotic fractures, respectively.
Multiple choice questions
- 1.
In Mrs. GOI’s case, the following is/are correct:
- A.
The diagnosis is osteopenia.
- B.
The fracture risk is not increased.
- C.
There is no need for any medication for her bone health.
- D.
All of the above.
- E.
None of the above.
Correct answer: E
Comment:
The lowest T-score is −1.0, which is within the normal range. There is therefore densitometric evidence of neither osteopenia nor osteoporosis. Glucocorticoids, however, per se, increase the risk of fracture through a variety of mechanisms that are discussed later. Therefore, even though the bone density is within the normal range, Mrs. GOI is at an increased risk of fractures because of the glucocorticoids she has been prescribed, especially in large doses and the need to continue with this therapy.
She therefore should be aggressively treated to maintain her bone mass. There is some urgency in the pharmacological management of Mrs. GOI because she is on a high dose of glucocorticoids, which she needs to treat her giant cell arteritis. This is discussed further later.
- A.
- 2.
Bone loss associated with glucocorticoids:
- A.
Is accentuated during the first 3 months of therapy.
- B.
Peaks at about 6 months of therapy, then continues to increase, but at a slower rate.
- C.
Increased fracture risk is related to the daily and cumulative dose of glucocorticoids.
- D.
A and B.
- E.
A, B, and C.
Correct answer: E
Comment:
Glucocorticoid-induced osteoporosis is the most frequent type of secondary osteoporosis. Bone loss is accentuated during the first 3 months of therapy, peaks at about 6 months of continuous use, and then continues at a slower rate but remains elevated for the duration of glucocorticoid therapy. During the first year of therapy, 6%–12% of the BMD may be lost; the annual rate of decrease thereafter is about 3%. Although both cortical and cancellous bones are affected, the latter is more severely affected. High daily doses and high cumulative doses increase the risk of fractures. The rate of bone loss declines once glucocorticoid therapy is discontinued, but it is not clear whether it reverts to the baseline preglucocorticoid therapy level.
Glucocorticoids are frequently prescribed to older people for a variety of reasons. More than 10% of patients on long-term glucocorticoid therapy sustain a clinical fracture and 30%–40% have evidence of morphometric vertebral compression fractures.
The increased fracture risk parallels the decrease in BMD, is seen as early as the first 3 months of therapy, and is also modulated by other effects of glucocorticoids, including osteoblastic inhibition and apoptosis (therefore decreased bone formation), osteoclastic stimulation leading to an increased expression of Receptor Activator of Nuclear Factor Kappa-ß (RANK-L) ligand (therefore increased bone resorption), and a decreased osteoprotegrin expression and reduced osteoclastic apoptosis. Glucocorticoids also impair osteocyte function and increase their apoptosis.
A number of guidelines and algorithms are available to help clinicians decide when and how to treat patients on long-term glucocorticoid therapy including the FRAX and NOGG (National Osteoporosis Guideline Group), the International Osteoporosis Foundation, and the European Calcified Tissue Society algorithms and the American College of Rheumatology.
In addition, glucocorticoids reduce gastrointestinal calcium absorption, increase renal calcium excretion, and reduce gonadal hormones, which induce myopathy and muscle atrophy leading to impaired neuromuscular functions and thus an increased risk of sustaining repeated falls and fracture(s). Alternate day regimens, intermittent therapy, and inhaled glucocorticoids are also associated with nefarious skeletal effects.
- A.
- 3.
Assessing fracture risk in patients on glucocorticoids:
- A.
The FRAX tool overestimates the risk of fractures in patients on ≤2.5 mg prednisone daily.
- B.
The FRAX tool underestimates the risk of fractures in patients on ≥7.5 mg prednisone daily.
- C.
A number of algorithms are available to assess the patient’s fracture risk.
- D.
A and B.
- E.
A, B, and C.
Correct answer: E
Comment:
A number of algorithms are available to assess the fracture risk of patients on glucocorticoid therapy. The FRAX algorithm, however, is of limited use in patients on glucocorticoids because it considers neither the daily dose, nor the cumulative dose, nor the duration of treatment. Adjustments, nevertheless, can be made to the FRAX algorithm to better reflect the fracture risk in patients on glucocorticoid therapy. Because fracture risk is modulated by the dose of glucocorticoids, many algorithms classify the patient population on daily glucocorticoid therapy into those on high doses, i.e., those on 7.5 mg or more of prednisone or equivalent and those on smaller doses: 2.5 mg daily or less. It is possible, however, that even this classification underestimates the fracture risk in patients on very high-dose glucocorticoids as is the case in patients with giant cell arteritis, dermatomyositis, lupus, and vasculitis. Patients on high doses, i.e., exceeding 30 mg/day, even in those receiving that dose intermittently, are particularly at risk of sustaining hip and vertebral fractures.
Glucocorticoid-induced osteoporosis is potentially reversible: once glucocorticoids are discontinued the BMD gradually increases and the increased fracture risk gradually declines.
- A.
- 4.
The initial assessment of patients on glucocorticoid therapy includes:
- A.
An assessment of the fracture risk.
- B.
An assessment of the risk of falling.
- C.
A review of the glucocorticoid daily dose, frequency, and cumulative dose.
- D.
A, B, and C.
- E.
A and C.
Correct answer: D
Comment:
The initial fracture risk assessment should be made as soon as possible after initiating long-term glucocorticoid therapy. It should include an assessment of the fracture risk. If the FRAX tool is to be utilized, it first should be corrected for the intake of glucocorticoids. As the FRAX does not include the risk of falling and as fractures are usually preceded by falls it is important to also determine the patient’s risk of falling as this may alter the overall management strategy.
A thorough review of the patient’s medication should be done with particular emphasis on medication that can affect cognitive functions and increase the risk of falling. As much as possible sedatives, tranquilizers and hypnotics should be avoided. The daily dose, frequency, and cumulative dose of glucocorticoids are also important as they affect the fracture risk.
- A.
- 5.
Direct effects of glucocorticoids on bone cells and bone turnover include:
- A.
Increase bone resorption.
- B.
Decrease bone formation.
- C.
Induce osteocytes apoptosis.
- D.
A and C.
- E.
A, B, and C.
Correct answer: E
Comment:
Glucocorticoids increase the rate of bone resorption through a variety of mechanisms including :
- •
Effect on osteoclasts:
- ○
Stimulating the synthesis and release of RANK-L, thus increasing the recruitment and activation of osteoclasts.
- ○
Decreasing osteoprotegerin expression by osteoblasts, thus increasing the impact of RANK-L on preosteoclasts and their precursors.
- ○
Decreasing osteoclast apoptosis, thus further enhancing bone resorption.
- ○
- •
Effect on osteoblasts:
- ○
Suppress osteoblast differentiation.
- ○
Induce osteoblast apoptosis, thus reducing the rate of bone formation. Decreases in the serum levels of markers of bone formation have been documented almost immediately after the initiation of glucocorticoid therapy. Stimulate bone marrow stromal cells to differentiate into adipocytes rather than osteoblasts, thus reducing the number of functional osteoblasts and rate of bone formation.
- ○
- •
Effect on osteocytes:
- ○
Induce apoptosis of osteocytes, thus reducing their number.
- ○
Impair the osteocyte ability to increase local bone remodeling.
- ○
- A.
- 6.
Glucocorticoid-induced changes in BMD and bone architecture include:
- A.
Lower total, cortical, and trabecular volumetric BMD.
- B.
Increased trabecular separation and reduced trabecular number.
- C.
Lower trabecular bone score.
- D.
A and C.
- E.
A, B, and C.
Correct answer: E
Comment:
In addition to loss of bone mass, glucocorticoids induce profound changes in bone microarchitecture and strength which increase the fracture risk. Trabecular bone is affected more than cortical bone. This explains the high prevalence of vertebral compression fractures, most of which are asymptomatic because of the antiinflammatory effect of glucocorticoids. The risk of vertebral fractures is increased even in patients on very small doses of glucocorticoids such as 2.5 mg daily. The glucocorticoid increased risk of vertebral compression fractures is independent of the observed decreases in BMD.
- A.
- 7.
Glucocorticoids also induce bone demineralization by:
- A.
Reducing intestinal calcium absorption.
- B.
Increasing renal calcium loss.
- C.
Reducing gonadal hormone.
- D.
A and B.
- E.
A, B, and C.
Correct answer: E
Comment:
Glucocorticoids increase bone loss through a number of factors, in addition to the direct effect on osteocytes, osteoblasts, and osteoclasts. These include:
- ○
Reducing the intestinal calcium absorption by inhibiting vitamin D action and down-regulating the expression of calcium receptors in the duodenum. Increasing the renal calcium loss by down-regulating the expression of tubular calcium receptors in the kidneys.
- ○
Increasing the release of parathyroid hormone as a result of the tendency for the serum calcium level to fall secondary to the low intestinal absorption of calcium and increased renal calcium loss.
- ○
Decreased production of growth hormone, insulin-like growth factor 1 (IGF1), and IGF1 binding protein.
- ○
Interfering with the hypothalamus-pituitary-adrenal-gonadal axis reducing the synthesis and release of gonadotropin-releasing hormone, luteinizing hormone, and follicle-stimulating hormone in the hypothalamus and inducing hypogonadism.
- ○
Glucocorticoids also increase the risk of falls and subsequent fractures by inducing a myopathy due to:
- ○
Increased muscle proteolysis.
- ○
Reduced protein synthesis.
- ○
The production of myostatin which inhibits myogenesis.
Other extrinsic factors leading to bone demineralization include reduced physical activity and the underlying disease state for which glucocorticoids are prescribed.
- A.
- 8.
Other adverse effects of glucocorticoid therapy include:
- A.
Hypertension, hyperlipidemia, and hyperglycemia.
- B.
Cataracts and glaucoma.
- C.
Easy bruisability.
- D.
A and C.
- E.
A, B, and C.
Correct answer: E
Comment:
Glucocorticoid therapy is associated with a number of adverse events in addition to the listed one, including weight gain, fluid retention, increased susceptibility to infections, hypokalemia, depression, neuropsychiatric disorders, and osteonecrosis. Notwithstanding, in some patients the risk/benefit ratio is such that glucocorticoids, sometimes in large doses, have to be prescribed for prolonged periods as in cases of giant cell arteritis, other vasculitis, status asthmaticus, and inflammatory bowel diseases. In these instances, it behooves the prescribing clinician to ensure the patient is informed and that adequate measures are taken to minimize the associated risks and that patients are adequately followed up.
- A.
- 9.
Nonpharmacologic management of patients on glucocorticoids ≥2.5 mg/day for 3 or more months includes:
- A.
A daily calcium intake of 1000–1200 mg.
- B.
A daily vitamin D intake of 600–800 IU.
- C.
Lifestyle modification, including weight-bearing exercises.
- D.
A and B.
- E.
A, B, and C.
Correct answer: E
Comment:
Nonpharmacologic management of patients on glucocorticoids ≥2.5 mg/day for 3 or more months includes an adequate daily calcium and vitamin D intake, preferably from food sources, but failing this from supplements. Patients who have laboratory evidence of vitamin D deficiency may need larger doses of vitamin D. Vitamin D supplementation is discussed in another chapter.
Lifestyle modification is an integral part of the management of all patients at risk of fractures and includes balanced diet, weight-bearing exercises, limited alcohol intake, and smoking cessation.
- A.
- 10.
Pharmacologic management of glucocorticoid-induced osteoporosis includes:
- A.
Oral or iv bisphosphonates.
- B.
Teriparatide or abaloparatide.
- C.
Denosumab.
- D.
Raloxifene.
- E.
A, B, C, or D.
Correct answer: E
Comment:
A number of guidelines are available to help clinicians develop a treatment strategy geared to the particular needs and circumstances of the patient in question. Oral bisphosphonates are frequently recommended as a first-line treatment and prevention of glucocorticoid-induced osteoporosis in patients on 2.5 mg or more prednisone daily for 3 or more months. If the patient cannot tolerate them or cannot adhere to the intake of oral bisphosphonates, all the previously listed medications are effective at increasing BMD and reducing fracture risk. It is also important to emphasize the importance of a well-balanced diet, adequate calcium, vitamin D intake, and lifestyle changes to maximize the impact of the medication prescribed.
- A.
References
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