Endocrinology and Metabolism Clinics of North America
Glucocorticoid-Induced Osteoporosis and Osteonecrosis
Introduction
“A marked osteoporosis of the skeleton was found, it being easily possible to cut the vertebral bodies with a knife, the spongy part of the bone having largely disappeared.” Cushing1 described these adverse effects of long-term endogenous hypercortisolism on bone in his 1932 presentation to the Johns Hopkins Medical Society. Eighteen years later, only 1 year after the introduction of cortisone for the treatment of rheumatoid arthritis, clinicians became aware of the rapidly injurious skeletal effects of glucocorticoid administration.2, 3 At first, it was uncertain whether the hip fractures that had occurred were the result of falls caused by steroid myopathy or merely coincidental with cortisone therapy because vertebral fractures and radiographic osteoporosis had not yet been observed. However, within just a few more years, osteoporosis and fractures were clearly recognized as skeletal complications of treatment with cortisone, prednisolone, and prednisone.4 Collapse of the femoral and humeral heads after high-dose therapy was described shortly thereafter.5, 6 Today, glucocorticoid administration is the most common cause of secondary osteoporosis and the leading cause of nontraumatic osteonecrosis. In patients receiving long-term therapy, glucocorticoids induce fractures in 30% to 50% and osteonecrosis in 9% to 40%.7, 8 Patients are seldom warned about these side effects and, as a result, adverse skeletal events are the most common glucocorticoid-related complications associated with successful litigation.9
Section snippets
Risk Factors
Bone loss in glucocorticoid-induced osteoporosis (GIO) is biphasic, with a rapid reduction in bone mineral density (BMD) of 6% to 12% within the first year, followed by a slower annual loss of about 3% for as long as the glucocorticoids are administered.10 However, the relative risk of fracture escalates by as much as 75% within the first 3 months after initiation of glucocorticoid therapy and this often occurs before a significant decline in BMD.11 There is also a decrease in the risk of
Glucocorticoid-induced osteonecrosis
Aseptic, avascular or ischemic necrosis, and bone infarctions are other terms for osteonecrosis. The most common joint involved is the hip and the most common cause of the disorder is trauma. Glucocorticoids are the second most common cause.8 There are many other causes in adults including alcohol, sickle cell disease, ionizing radiation, Gaucher disease, Caisson disease or decompression sickness, and idiopathic causes. However, before concluding that any case of osteonecrosis is idiopathic, a
Areas of uncertainty
Precise prediction of the risk of fracture is currently not possible in GIO and efforts to alert physicians prescribing glucocorticoids to their responsibilities to prevent bone complications have met with limited success. More data are needed to establish precise clinical thresholds for intervention and develop strategies to convey this information to physicians and patients. In addition, more research is required to ascertain the optimal duration of protective therapy, best treatment of
Summary
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Glucocorticoid administration is the most common cause of secondary osteoporosis and the leading cause of nontraumatic osteonecrosis.
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Patients are seldom warned about these side effects and, as a result, adverse skeletal events are the most common glucocorticoid-related complications associated with successful litigation.
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Disparity between bone quantity and quality in GIO makes ultrasound or BMD measurements inadequate for identifying patients at risk of glucocorticoid-induced fractures.
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Acknowledgments
The author thanks Drs Stavros C. Manolagas, Robert L. Jilka, Maria Almeida, and Charles A. O’Brien for their advice and helpful discussions, and Drs Stavros C. Manolagas, Robert L. Jilka, Maria Almeida, Fred H. Faas, and Irina Lendel for reviewing the manuscript.
References (63)
- et al.
Bone loss in response to long-term glucocorticoid therapy
Bone Miner
(1990) - et al.
High prevalence of asymptomatic vertebral fractures in post-menopausal women receiving chronic glucocorticoid therapy: a cross-sectional outpatient study
Bone
(2006) - et al.
Glucocorticoids and tumor necrosis factor (TNF) α increase oxidative stress and suppress WNT signaling in osteoblasts via mechanisms involving pkcβ/P66SHC/JNK and AKT/FOXO
J Biol Chem
(2011) - et al.
Glucocorticoid enhances the expression of dickkopf-1 in human osteoblasts: novel mechanism of glucocorticoid-induced osteoporosis
Biochem Biophys Res Commun
(2004) - et al.
Zoledronic acid and risedronate in the prevention and treatment of glucocorticoid-induced osteoporosis (HORIZON): a multicenter, double-blind, double-dummy, randomized controlled trial
Lancet
(2009) - et al.
Treatment of early stage osteonecrosis of the femoral head with autologous implantation of bone marrow-deprived and cultures mesenchymal stem cells
Bone
(2012) The basophil adenomas of the pituitary body and their clinical manifestations (pituitary basophilism)
Bull Johns Hopkins Hosp
(1932)- et al.
Management of rheumatoid arthritis with smaller (maintenance) doses of cortisone acetate
JAMA
(1950) - et al.
Problems of prolonged cortisone treatment for rheumatoid arthritis
JAMA
(1951) - et al.
Major undesirable side-effects resulting from prednisolone and prednisone
JAMA
(1955)
Avascular necrosis of the femoral and humeral heads after high-dosage corticosteroid therapy
N Engl J Med
Osteopathia da prolungato trattmento cortisonico
Ortop Tramatol
Clinical practice: glucocorticoid-induced bone disease
N Engl J Med
Glucocorticoid-induced osteonecrosis
Endocrine
Medical malpractice and corticosteroid use
Otolaryngol Head Neck Surg
Bone density threshold and other predictors of vertebral fracture in patients receiving oral glucocorticoid therapy
Arthritis Rheum
Is long-term glucocorticoid therapy associated with a high prevalence of asymptomatic vertebral fractures in postmenopausal women?
Nat Clin Pract Endocrinol Metab
Oral glucocorticoid use is associated with an increased risk of fracture
Osteoporos Int
Fracture risk with intermittent high-dose oral glucocorticoid therapy
Arthritis Rheum
Longitudinal patterns in the prevention of osteoporosis in glucocorticoid-treated patients
Arthritis Rheum
Not all postmenopausal women on chronic steroids and estrogen treatment are osteoporotic: predictors of bone mineral density
Calcif Tissue Int
Age dependence of early symptomatic vertebral fracture with high-dose glucocorticoid treatment for collagen vascular diseases
J Clin Endocrinol Metab
Use of inhaled glucocorticoids and risk of fractures
J Bone Miner Res
Two polymorphisms in the glucocorticoid receptor gene directly affect glucocorticoid-regulated gene expression
J Clin Endocrinol Metab
Osteoblastic 11β-hydroxysteroid dehydrogenase type 1 activity increases with age and glucocorticoid exposure
J Bone Miner Res
Inhibition of osteoblastogenesis and promotion of apoptosis of osteoblasts and osteocytes by glucocorticoids: potential mechanisms of the deleterious effects on bone
J Clin Invest
Glucocorticoids act directly on osteoblasts and osteocytes to induce their apoptosis and reduce bone formation and strength
Endocrinol
Endogenous glucocorticoids decrease vascularity and increase skeletal fragility in aged mice
Aging Cell
Bone quality-the material and structural basis of bone strength and fragility
N Engl J Med
Glucocorticoids act directly on osteoclasts to increase their lifespan and reduce bone density
Endocrinol
The skeletal effects of glucocorticoid excess override those of orchidectomy in mice
Endocrinol
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Support: This material is based on work supported by a VA Merit Review Grant from the Office of Research and Development, Department of Veterans Affairs and the National Institutes of Health (P01-AG13918). The author has no potential conflicts of interest relevant to this article.