Although there are many treatments currently used in medical practice that can cause bone loss, this section will focus on two; these include glucocorticoid- and immunosuppressant-induced bone loss.
Treatment-induced bone loss can result from systemic glucocorticoid use in chronic conditions as well as from immunosuppressant therapy. Fractures resulting from bone loss are the most incapacitating sequelae of steroid therapy.1
Studies suggest that a loss of skeletal mass may occur early in the course of glucocorticoid therapy and appears to be related to the cumulative steroid dose. 2 For example, an average loss of 8% of trabecular bone density and 2% of cortical bone density has been seen in the lumbar spine over a 20-week period in people treated with a mean prednisone dose of 7.5 mg/day. 3
Glucocorticoids used to prevent organ transplantation rejection are usually given in high doses (particularly after solid organ transplants) and thus can lead to early and rapid bone loss—particularly trabecular bone loss. 4-6 Information about the contributions of nonglucocorticoid immunosuppressive agents to bone loss is limited, but such agents appear to have an analogous effect when used independently or in combination with glucocorticoids. Cyclosporine A and tacrolimus, two agents commonly used in transplant patients, inhibit osteoclastic bone resorption and suppress T-cell activation (producing a release of cytokines). 5,6
Experts at the National Center for Health Services Research estimate that more than 60,000 kidneys have been transplanted in the world in the past two decades. Nearly 27,000 people in the United States received an organ transplant in 2004,7 and substantial effort is being expended to increase that yearly figure. Current treatment guidelines include high-dose immunosuppressant medications followed by lifelong maintenance therapy. The overall success of transplants will depend in part on the ability to manage side effects such as bone loss in the short and long term.
Prevalence and Impact
The prevalence of glucocorticoid-induced osteoporosis is often difficult to determine due to the confounding effects of comorbidities and polypharmacy. A study of general practice patients in Iceland showed that 26% of those treated with oral glucocorticoids for more than 3 months were diagnosed with osteoporosis, and 20% had a history of fragility fractures.8
More than 30 million Americans may be affected by diseases that are treated with glucocorticoids, including rheumatoid arthritis, asthma, and some allergic conditions, according to the American College of Rheumatology. In as little as 3 months, chronic steroid use (greater than or equal to 7.5 mg/day of prednisone or equivalent) can cause significant bone loss in 30% to 50% of patients.1 Up to 50% of patients on chronic glucocorticoid therapy will experience osteoporotic fractures, the majority of which are vertebral fractures.1
Osteopenia is a nearly ubiquitous sequelae in the 2 years following an organ transplant, and high rates of trabecular bone fracture are seen after solid organ transplantation (kidney, liver, heart, lung, and pancreas).6 Such fractures clearly affect survival, post-transplant rehabilitation, and the cost of recovery.5,9
Current Treatments and Guidelines
Recent guidelines published by the American College of Rheumatology recommend that all patients beginning glucocorticoid therapy at a daily prednisone dosage equivalent to at least 5 mg in whom treatment is planned to last at least 3 months should be offered supplementation with calcium and vitamin D at a dosage of 800 IU/day or an activated form of vitamin D (eg, alfacalcidiol at 1 microgram/day or calcitriol at 0.5 micrograms/day) to restore normal calcium balance.10 Patients receiving long-term glucocorticoid therapy who are hypogonadal should also be offered hormone replacement therapy.
Published guidelines state that organ transplant patients should be monitored for rapid loss of bone mass post-transplant. National Kidney Foundation guidelines, for example, suggest that “patients should be monitored for changes in their bone mass on a regular basis following kidney transplantation” and “if osteoporosis is identified by changes in BMD, therapy should be initiated.” 9
Treatment with a bisphosphonate (alendroate or risedronate) is recommended to prevent bone loss in all men and postmenopausal women in whom long-term glucocorticoid treatment of at least 5 mg/day is being initiated, as well as in men and postmenopausal women receiving long-term glucocorticoids in whom the bone mineral density (BMD) T-score at either the lumbar spine or the hip is below normal (ie, T-score below –1). Because premenopausal women may also lose bone mass if they are being treated with glucocorticoids, the guidelines suggest that prevention of bone loss with antiresorptive agents should be considered in this population. 10
Current guidelines also recommend weight-bearing exercise, reduction of alcohol intake if excessive, and smoking cessation or avoidance. For patients taking long-term glucocorticoid treatment, annual or biannual bone mineral density (BMD) scans are encouraged. 10
Role of RANKL in Glucocorticoid-induced Osteoporosis
Glucocorticoid-induced osteoporosis is characterized by increased bone resorption and decreased bone formation. 11 Prolonged exposure to glucocorticoids enhances receptor activator of nuclear factor kappa B ligand (RANKL) expression and inhibits osteoprotegerin (OPG) production by osteoblasts and other cells in vitro. 12 Thus, excess RANKL activity promotes bone destruction via increased osteoclast activation and bone resorption. 3
In a rat model of glucocorticoid-induced osteoporosis, RANKL inhibition decreased bone resorption and reduced osteoclast numbers to subphysiologic levels. 13 These effects, which translated into an increase in BMD, suggest that RANKL inhibition is a potential new avenue of therapeutic intervention in glucocorticoid-induced osteoporosis.
A separate preclinical model confirmed that glucocorticoids promote osteoclastogenesis by inhibiting OPG and concurrently stimulating RANKL production by osteoblastic lineage cells, thereby enhancing bone resorption. 12 These findings suggest that strategies aimed at inhibiting excess RANKL activity during the systemic use of glucocorticoids may be useful in preventing glucocorticoid-induced osteoporosis. 12
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