According to the American College of Rheumatology (ACR), more than 30 million Americans may be affected by diseases commonly treated with glucocorticoids. Glucocorticoids are the primary therapy for many inflammatory and autoimmune diseases, such as asthma, rheumatoid arthritis, and inflammatory bowel disease. They are also used to treat many allergic conditions. While these agents are generally effective in treating such ailments, they are also the most common cause of drug-induced osteoporosis. This issue of NIH ORBD~NRC NEWS will provide an overview of the effects of glucocorticoids on bone and discuss strategies for the prevention and treatment of glucocorticoid-induced osteoporosis. While glucocorticoids are one of various types of steroids, the term “steroid” will be used interchangeably with “glucocorticoid.”
Glucocorticoids and Bone Remodeling
Glucocorticoids affect calcium and bone metabolism in many ways. Steroids decrease the amount of calcium absorbed by the intestine and increase calcium excretion through the kidneys. These two factors combine to produce a decline in the circulating ionized calcium concentration. This triggers the parathyroid glands to increase their secretion of parathyroid hormone (PTH), a condition known as secondary hyperparathyroidism. Elevated PTH levels result in increased bone resorption (breakdown), as the body attempts to rectify low circulating calcium levels by releasing calcium from the bones into the blood.
Glucocorticoids can also decrease the levels of sex hormones, important regulators of bone metabolism in both men and women. The resulting decreases in estrogen (in women) and testosterone (in men) are associated with increased bone loss. Glucocorticoids also cause muscle weakness, which may lead to inactivity and additional bone loss. A major effect of glucocorticoids is that they can impact bone directly by suppressing bone formation (osteoblastic) activity.
Patterns of Bone Loss in Glucocorticoid Use
There are two types of bone tissue: cortical and trabecular. Cortical bone forms the outer shell of bone and comprises 80 percent of the skeleton. Trabecular bone, the remaining 20 percent, is found inside the bone. Each bone in the skeleton contains both types of bone, but their proportions vary. Glucocorticoids primarily cause bone loss in those areas of the skeleton that are rich in trabecular bone, such as the spine. Bone loss occurs most rapidly in the first 6-12 months of therapy and is dose- and duration- dependent. The usual risk factors for osteoporosis, such as age, gender or underlying disease may have an additive effect on bone loss. For example, elderly men on steroids may experience even greater bone loss and risk for fracture than middle-aged men. ACR estimates that without prevention measures, an estimated 25 percent of individuals on long-term glucocorticoids will experience a fracture.
The dose of glucocorticoids is a strong predictor of fracture risk. While it is not clear whether there is a low-dose threshold below which bone loss does not occur, recent studies have found inhaled steroids to have little to no effect on bone density when administered in standard doses and apart from systemic steroids. A 20-month study on the effects of inhaled steroids in children found no damaging effects on bone mineral density. It appears that inhaled glucocorticoids may have little systemic activity and are safe in moderate doses, even when administered for extended periods.
Options in Management
Glucocorticoid-induced osteoporosis is both preventable and treatable. According to recommendations published by the American College of Rheumatology, individuals initiating glucocorticoid therapy should have a bone mineral density test performed. This test will provide a baseline measurement from which to monitor subsequent changes in bone mass. ACR also recommends a daily intake of 1500 milligrams of calcium and 400-800 International Units of vitamin D. Calcium and vitamin D can help maintain calcium balance and normal parathyroid hormone levels, and can even preserve bone mass in some patients on low-dose steroid therapy.
Risedronate (for prevention and treatment) and alendronate (for treatment) are approved by the Food and Drug Administration (FDA) for glucocorticoid-induced osteoporosis. In glucocorticoid users, both drugs deliver beneficial effects on the spine and hip bone mineral density and are associated with a decrease in spinal fractures. Estrogen and calcitonin may help preserve spinal bone mass in postmenopausal women on glucocorticoids, but neither is approved by the FDA for glucocorticoid-induced osteoporosis.
Lifestyle modifications, such as eliminating smoking and alcohol, are important in reducing the risk of steroid-induced osteoporosis. Physical activity and exercise can help to preserve bone and muscle mass, while increasing muscle strength and reducing the risk of falls. Fall prevention safety measures are of particular significance for elderly individuals and for those who have experienced steroid-induced muscle weakness.
Osteoporosis prevention measures should begin early, ideally at the onset of glucocorticoid therapy. Experts recommend using the lowest dose of steroid for the shortest period of time possible and, when feasible, inhaled or topical glucocorticoids should be utilized.