Glucocorticoids are a very common treatment option for various inflammatory conditions, and in many cases, patients may receive long-term glucocorticoid treatment. However, a major adverse effect of this pharmacologic treatment is significant bone loss, which is most pronounced in the first 3 to 6 months of use and has been reported with daily doses as low as 2.5 to 7.5 mg of prednisone or its equivalent.1,2
Glucocorticoid-induced osteoporosis is the most common cause of secondary osteoporosis and the risk for fracture can be significant.3 Several international societies have provided recommendations for the management of glucocorticoid-induced osteoporosis.2,4,5
The effects of glucocorticoids on bone are direct and indirect, including a receptor activator of nuclear factor-κB ligand (RANKL)-induced increase in osteoclasts, osteocyte apoptosis, and decreased recruitment and accelerated apoptosis of osteoblasts.3 Furthermore, glucocorticoids increase the risk for falls because of reduced muscle mass and a decrease in calcium resorption.6,7 On the other hand, the fracture risk rapidly decreases after glucocorticoid discontinuation.8
Fracture Risk Categories
According to the 2017 guidelines by the American College of Rheumatology,2 glucocorticoid-treated patients can be classified into the following fracture risk categories:
- High fracture risk
- All adults with prior osteoporotic fracture
- Men aged ≥50 years and postmenopausal women with hip or spine bone mineral density T-score ≤-2.5
- Adults aged ≥40 years with a glucocorticoid-adjusted Fracture Risk Assessment Tool (FRAX) 10-year risk for major osteoporotic fracture or hip fracture of ≥20% or ≥3%, respectively
- Moderate fracture risk
- Adults aged ≥40 years with a glucocorticoid-adjusted FRAX 10-year risk for major osteoporotic fracture of 10% to 19% or risk for hip fracture of >1% to <3%
- Adults aged <40 years with a hip or spine bone mineral density z score of <-3 or rapid bone loss of ≥10% at the hip or spine over 1 year and glucocorticoid treatment at ≥7.5 mg/d for ≥6 months
- Low fracture risk
- Adults aged ≥40 years with a glucocorticoid-adjusted FRAX 10-year risk for major osteoporotic fracture of <10% and risk for hip fracture of ≤1%
- Adults aged <40 years with none of the above risk factors other than glucocorticoid treatment
Most strategies to prevent and treat glucocorticoid-induced osteoporosis are similar to those used to manage other causes of osteoporosis. It is strongly recommended to prescribe glucocorticoids in the lowest possible dose and to stop the treatment as soon as possible given the rapid effects of the medication on bone loss.3 Furthermore, lifestyle measures have an important role, including avoiding or stopping smoking, limiting alcohol intake, maintaining normal body weight, and participating in routine weight-bearing physical activities.3
Calcium and vitamin D supplementations are recommended for the management of glucocorticoid-induced osteoporosis, as these may aid in preserving bone mass. The American College of Rheumatology guidelines support a total calcium intake of 1000 to 1200 mg/d and vitamin D intake of 600 to 800 U/d through diet and/or supplements.2
Pharmacologic therapy for glucocorticoid-induced osteoporosis is based on fracture risk; patients with the highest risk for fracture are those who are most likely to benefit from this treatment modality.
The 2017 American College of Rheumatology guidelines2 recommend drug therapy in any patient with a previous osteoporotic fracture who is receiving glucocorticoids (prednisone dose >2.5 mg/d or its equivalent). Treatment is also recommended for glucocorticoid-treated men ≥50 years of age and for postmenopausal women with a bone mineral density T-score of ≤-2.5 at the spine or the femoral neck. Among adults ≥40 years of age who do not meet these criteria, drug therapy is recommended if their 10-year risk for major osteoporotic fracture is ≥10% or if their risk for hip fracture is >1% according to the glucocorticoid-adjusted FRAX tool (increasing the risk value by 1.15 [15%] and 1.2 [20%], respectively, for a prednisone dose >7.5 mg/d).2
Women ≥40 years of age who are not of childbearing potential and men ≥40 years of age who are at moderate (conditional recommendation) or high risk (strong recommendation) for fracture should be treated with an oral bisphosphonate. If treatment with oral bisphosphonates is not appropriate (due to comorbidities, patient preference, or adherence issues), intravenous bisphosphonates should be used. The next line of treatment, according to the guidelines, is teriparatide, and in cases in which neither bisphosphonates nor teriparatide is appropriate, denosumab should be used. Raloxifene should be used in postmenopausal women in whom all of these medications are not appropriate.2
For women <40 years of age who are not of childbearing potential and men <40 years of age who are at moderate or high risk for fracture, an oral bisphosphonate is recommended as the first-line drug therapy. If this option is not appropriate, the same alternative medications, listed previously for older adults, other than raloxifene, are recommended.
As for young women who are of childbearing potential at moderate or high risk for fractures, oral bisphosphonates can be considered if the patient is not actively planning to become pregnant during the period of osteoporosis therapy. Teriparatide can be considered if oral bisphosphonate therapy is not appropriate, but the use of densoumab or intravenous bisphosphonates should be limited because of the lack of safety data and potential fetal harm.
In cases of a fracture occurring ≥18 months after initiation of oral bisphosphonate therapy or significant bone loss (≥10%/y) after 12 months of therapy, it is recommended to treat with an intravenous bisphosphonate (if absorption or adherence problems are suspected) or another class of osteoporosis medication (teriparatide, denosumab).2
For patients who have completed 5 years of oral bisphosphonate therapy and are expected to continue glucocorticoid treatment, further treatment for osteoporosis is recommended and may include continuing oral bisphosphonate for 7 to 10 years or switching to a different class of osteoporosis medication.2
When glucocorticoid therapy is discontinued, fracture risk should be reassessed. If the fracture risk is deemed to be low, it is recommenced to withhold osteoporosis therapy. Otherwise, treatment should be continued.2
1. van Staa TP, Leufkens HGM, Cooper C. The epidemiology of corticosteroid-induced osteoporosis: a meta-analysis. Osteoporos Int. 2002;13:777-787.
2. Buckley L, Guyatt G, Fink HA, et al. 2017 American College of Rheumatology guideline for the prevention and treatment of glucocorticoid-induced osteoporosis. Arthritis Rheumatol. 2017;69(8):1521-1537.
3. Raterman HG, Bultink IEM, Lems WF. Current treatments and new developments in the management of glucocorticoid‑induced osteoporosis. Drugs. 2019;79(10):1065-1087.
4. Lekamwasam S, Adachi JD, Agnusdei D, et al. A framework for the development of guidelines for the management of glucocorticoid-induced osteoporosis. Osteoporos Int. 2012;23:2257-2276.
5. Hoes JN, Jacobs JWG, Boers M, et al. EULAR evidence-based recommendations on the management of systemic glucocorticoid therapy in rheumatic diseases. Ann Rheum Dis. 2007;66(1):1560-1567.
6. Panday K, Gona A, Humphrey MB. Medication-induced osteoporosis: screening and treatment strategies. Ther Adv Musculoskelet Dis Rev. 2014;6(5):185-202.
7. Compston J. Glucocorticoid-induced osteoporosis: an update. Endocrine. 2018;61:7-16.
8. Buckley L, Humphrey MB. Glucocorticoid-induced osteoporosis. N Engl J Med. 2018;379(26):2547-2556.