Suggested Rationale for Prevention and Treatment of Glucocorticoid-Induced Bone Loss in Dermatologic Patients FREE

We recommend that patients who are receiving a long-term regimen of corticosteroids be managed with a 3-pronged approach: (1) Risk assessment should include bone mineral density testing of the spine and the proximal femur using dual-energy x-ray absorptiometry (DXA) at the beginning of treatment, and in addition, lateral spine radiography in patients over the age of 60 years. (2) Primary prevention measures should include adoption of a healthy lifestyle, calcium and vitamin D (cholecalciferol) supplementation, possible hormone replacement therapy for postmenopausal women, and treatment with bisphosphonates or calcitonin therapy. Prevention measures should start when corticosteroid therapy begins. (3) Treatment intervention should be based on bone mineral density measurements, with joint management by an endocrinologist.

Systemic glucocorticoids are the mainstay of immunosuppressive therapy for immunobullous diseases and collagen vascular diseases in dermatology. Prolonged administration of corticosteroids is often needed to control diseases such as pemphigus, bullous pemphigoid, lupus erythematosus, and dermatomyositis. In pemphigus vulgaris, high doses of corticosteroids (1-2 mg/kg daily) are widely used to control disease activity, with some regimens recommending up to 200 to 400 mg/d of prednisolone for severe disease.^1- 2 Unfortunately, the use of systemic corticosteroids is associated with numerous adverse effects that are related to both the corticosteroid dose and the duration of treatment.³ The most predictable and debilitating complication is osteoporosis—it has been shown that osteoporotic fractures occur in one third or more of individuals taking corticosteroids for 5 to 10 years.⁴ A recent study has shown that glucocorticoid users have a significantly higher risk of hip fractures compared with nonusers (odds ratio, 2.1).⁵ Although osteoporotic fractures occurring in the spine and the forearm are associated with notable morbidity, the most serious consequences occur in patients who incur hip fractures, which are associated with a marked increase in mortality in the first year after fracture (12%-35%),^5- 6 particularly in elderly individuals. The variation in mortality is related to differences in the age of the patients, their premorbid health status, and the length of follow-up. An analysis of patients who sustained osteoporotic hip fractures in Singapore demonstrated a mortality rate of 26% in the first year; of the survivors, 9% were bedridden and 24% were wheelchair bound.⁷ In bullous pemphigoid, a disease of the elderly commonly managed by dermatologists, the prolonged use of corticosteroids constitutes an additional risk factor in patients who are already elderly or postmenopausal.

Patients with osteoporosis may remain asymptomatic for many years, in contrast to other visible signs of aging, such as thinning of the skin with increased ecchymoses, proximal muscle wasting, truncal obesity, loss of truncal height, and round upper back. Vertebral crush fractures may develop with no warning or with minimal or no trauma.^8- 10 It is therefore important to prevent osteoporosis and treat steroid-dependent patients early. There have been significant developments in the field of osteoporosis, with substantial evidence that it can be tempered by agents that in turn decrease the risk of fracture.^8- 9,11 With the wider availability of diagnostic aids and safe treatments for osteoporosis plus increased public awareness, there is a growing need for management strategies for dermatologists who manage patients who require prolonged corticosteroid therapy.

Interestingly, most studies on the effect of corticosteroids on bone density and the efficacy of treatment regimens for preventing bone loss have been in patients with asthma and rheumatologic disease, such as rheumatoid arthritis and systemic lupus erythematosus; in both, osteoporosis can be a part of the disease process itself. At this time, there are no published studies on patients with bullous diseases who have no other systemic risk factors for osteoporosis and who require large doses of glucocorticoids.

This review aims to raise awareness in the dermatologic community of the recent developments in assessing, preventing, and treating osteoporosis. It is likely that practice guidelines will vary in different treatment centers, depending on local expertise and health economics.¹²

The predominant effect of glucocorticoids on the skeleton is a loss of trabecular bone induced by several mechanisms^9- 11: First, glucocorticoids affect bone by decreasing osteoblast proliferation and matrix synthesis as well as by decreasing the life span of these cells. This effect may be mediated in part by a reduction in the production of local growth factors, such as insulin-like growth factor 1.¹³ Second, glucocorticosteroids affect calcium homeostasis by reducing intestinal absorption of calcium and phosphate and increasing urinary excretion of calcium, leading to secondary hyperparathyroidism, which in turn leads to increased bone resorption. Third, glucocorticoids affect mineral metabolism indirectly by reducing levels of sex hormones.

Bone loss occurs most rapidly in the first 6 to 12 months of glucocorticoid therapy, but accelerated loss appears to continue as long as therapy is continued.⁹ Young men receiving glucocorticoids lose bone more rapidly than older men, and perimenopausal women and postmenopausal women have greater bone loss and are more prone to develop fractures.^10- 11

In general, the extent of bone loss is dose and duration dependent. Alternating days of treatment or pulse therapy has not been shown to prevent bone loss.^9,14 Recent studies have shown that even low doses of prednisone (5-10 mg/d) can cause substantial bone loss in a matter of few months.^15- 16 Prolonged use of high-potency topical glucocorticoids can also cause osteoporosis.¹⁷

The most common osteoporotic fractures occur in the distal radius, the vertebrae, and the upper femur. Assessment of bone mineral density in the lumbar spine, proximal femur, and distal forearm is an accurate marker for osteoporosis and helps to identify risk of fracture.

The World Health Organization classification of bone densitometry results categorizes a normal value for bone mineral content as being within 1 SD of the mean value for young adults of the same age and sex (T-score, –1 to 0). Osteopenia or low bone mass is defined as a mean bone mineral density value 1 to 2.5 SDs lower than the mean value for sex-matched healthy young adults (T-score, − 1 to − 2.5). Osteoporosis is diagnosed when the T-score is −2.5 or lower.¹⁸

Advances in bone densitometry enable us to accurately calculate the normal range of bone mineral density. Several techniques are available for measuring bone mineral density in the axial and appendicular skeleton. Large prospective studies have demonstrated that bone density measurements of the distal and proximal radius, os calcis, proximal femur, or spine can predict the development of the major types of osteoporotic fractures, including hip fractures.^8- 11 The 2 major techniques are quantitative computed tomography of the spine and DXA of the lumbar spine. These techniques differ greatly in their sensitivity and reproducibility, radiation exposure, examination time, and cost. Currently, DXA is the method of choice for measuring bone mineral density, but is not as sensitive as quantitative computed tomography for detecting early trabecular bone loss. However, its far greater precision, low radiation dose, rapid examination time, and lower cost make DXA the preferable technique.^8,19- 20 Potential artifacts that may interfere with DXA analysis, such as vertebral compressed fracture or osteoarthritic spurs, may appear as sites with normal bone density. A site of previous operation on the spine may have increased or decreased bone density values. Recent studies have demonstrated that DXA of the proximal femur is a better indication of risk of fracture and status of bone mass, and therefore both sites should be tested.^9,11

Radiographs of the thoracic and lumbar spine continue to be of some value in the assessment of osteoporosis, especially in elderly patients. However, in the absence of fractures, radiographs are insensitive indicators of bone loss because a substantial reduction in bone mass is required before it becomes visible on radiographs. Radiographs show loss of trabecular bone in the vertebral bodies, and the vertebral end plates appear to be accentuated. The normal contrast between the radiodensity of the spinal column and the adjacent soft tissues also may be lost. Vertebral deformity may take the form of collapse (reduction in both anterior and posterior height), anterior wedging (reduction in anterior height), or the so-called codfish deformity (due to weakening of the subchondral plates and expansion of the intervertebral discs). Protrusion of the intervertebral discs in the vertebral bodies produces Schmorl nodules. Abundant pseudocallus formation at the site of stress fracture is considered a distinctive feature of glucocorticoid-induced bone loss.^20- 21 Laboratory tests are also important to measure blood calcium levels and urinary excretion of calcium in order to rule out disorders of calcium metabolism and to prevent giving calcium supplements to hyperkalemic patients or patients with nephrolithiasis.

Glucocorticoid-induced bone loss can be prevented and treated. Because of the fact that bone loss is rapid during the first 6 months of glucocorticoid therapy, preventive measures, including medications, should begin as soon as glucocorticoids are prescribed.^9- 11 Inaction leads to rapid bone loss. It is important to instruct the patient to engage in both weight-bearing and non–weight-bearing exercises, which appear to have beneficial effects on bone mass. For most patients, exercises to strengthen the abdominal, back, and limb muscles are recommended to counteract the negative effects of glucocorticoids on muscle tissue^22- 23; however, there are currently no published studies on the beneficial effect of exercise on glucocorticoid bone loss. In our experience, a referral to a physical therapist with expertise in treating osteoporotic patients is often helpful. It is also important to advise the patient to refrain from smoking and excessive alcohol consumption.^8,11,22 In elderly patients, precautions to prevent falls should be taken. Dermatologists should be instructed to prescribe the lowest doses of glucocorticoids necessary to control the underlying disease.

Pharmacologic therapy includes calcium supplements, vitamin D supplements, and antiresorptive therapies such as estrogens in perimenopausal women, calcitonin, and bisphosphonates, which are the most effective.

It is reasonable to assume that daily calcium and vitamin D supplementation may help prevent bone loss since glucocorticoids induce a negative calcium balance. Therefore, calcium and vitamin D supplementation has been used to prevent bone loss in patients starting glucocorticoid therapy.^10- 11,24 However, recent studies in whites have not demonstrated a significant effect on bone loss.^25- 26 Since calcium intake is low in Asians²⁷ and glucocorticoids reduce calcium absorption, we believe that our patients receiving glucocorticoid therapy should regularly take calcium and vitamin D supplements.

Calcium therapy appears to be more effective in early and late menopausal women. The recommended dosages according to most experts are 1000 to 1500 mg of calcium and 800 IU of vitamin D daily. All patients can receive this medication except patients with hypercalcemia, hypercalciuria, or nephrolithiasis. It has been suggested that patients with significant hypercalciuria (>300 mg of calcium over a 24-hour period) might benefit from the addition of a low-dose thiazide diuretic,¹¹ which would decrease urinary excretion of calcium and improve gastrointestinal absorption. However there are no long-term studies of the effect of thiazides on bone loss in glucocorticoid-treated patients.

Estrogen replacement therapy inhibits osteoclastic bone resorption in women and prevents bone loss in both early and late menopause. Studies have shown that it reduces the risk of forearm, vertebral, pelvic, and hip fractures.²⁸ Since glucocorticoids reduce levels of estrogen, they can be used as a supplement for early and late menopausal women as well as premenopausal women who become amenorrheic. The efficacy of these drugs in preventing glucocorticoid osteoporosis has rarely been studied.

A study in rheumatoid arthritis patients taking prednisone who were randomized to receive hormone replacement therapy vs placebo showed a marked 2% to 3% increase in lumbar spine bone mineral density compared with placebo.²⁹

The recommended dosage is 0.625 mg of conjugated estrogen daily⁸; an unanswered question is how long women should take estrogen replacement therapy. The relationship between estrogen replacement therapy and endometrial and breast cancer has limited its use; most experts add a progestin to estrogen therapy to lower the risk of endometrial cancer.³⁰ Several transdermal delivery systems that continuously release estradiol with and without progesterone have been used and have been effective in prevention of bone loss in postmenopausal women. This treatment bypasses the liver, and therefore patients may be more compliant with this route of administration.^31- 32 The recommended dosage of transdermal estradiol is 50 µg daily. Estrogen replacement therapy is contraindicated in patients with breast and endometrial cancer.³⁰ It might be contraindicated in systemic lupus erythematosus patients receiving glucocorticoid therapy.

Raloxifene hydrochloride, which belongs to the new generation of estrogen receptor modulators, may be a good alternative to estrogen for preventing postmenopausal osteoporosis, especially for women who are more concerned about the risk of breast cancer or vaginal bleeding. It has an agonist effect on bone and antagonist (anti-estrogen) activity in the uterus and breasts.³³

Raloxifene has been evaluated for the prevention of osteoporosis in postmenopausal women in large controlled studies and was found to increase bone mineral density in the lumbar spine and the entire hip.^34- 35 The efficacy of raloxifene in preventing corticosteroid-induced osteoporosis remains to be established. Glucocorticoids suppress serum testosterone, which leads to low bone mass. One study demonstrated the effectiveness of testosterone therapy in increasing bone density in 15 men with glucocorticoid-treated asthma.³⁶ Based on this study, it has been suggested that testosterone replacement therapy should be considered in men with low testosterone levels who are taking glucocorticoids.²²

Bisphosphonates are considered the agents of choice for both treatment and prevention of glucocorticoid-induced osteoporosis. They are analogues of pyrophosphates that inhibit osteoclastic-mediated bone resorption. At low doses they bind to hydroxyapatite, inhibit bone resorption, and are retained for months and years. Several types of bisphosphonates are available: cyclic etidronate therapy was the initial treatment regimen approved by the Food and Drug Administration (FDA) and is given at a dosage of 400 mg/d for 2 weeks in a 13-week cycle.⁸ It is important not to administer it continuously since it impairs bone mineralization. Several studies have demonstrated that cyclic etidronate is effective in reversing the progressive loss of lumbar spine bone density due to corticosteroid therapy.^37- 40

Alendronate sodium, a bisphosphonate recently approved by the FDA for patients receiving prolonged glucocorticoid therapy, is considered a more effective treatment. It is 200 to 1000 times more potent than etidronate in inhibiting bone resorption and is given at a dosage of 10 mg daily on a continuing basis for treatment and 5 mg daily for prevention. A recent large placebo-controlled study with alendronate showed that it increased bone density in patients receiving glucocorticoid therapy by 2.9% in the lumbar spine and 1% in the femoral neck.⁴¹ A newer type of bisphosphonate has been recently launched—risedronate sodium—that has been said to have a potent effect in reducing the incidence of vertebral fracture.^42- 43 A recent double-blind placebo-controlled study with risedronate in patients receiving long-term corticosteroid treatment demonstrated that bone mineral density increased markedly in comparison with placebo, by 3.8% in the lumbar spine and by 4.1% in the femoral neck.⁴⁴

A meta-analysis study of all controlled trials with bisphosphonates demonstrated that they were effective at preventing and treating corticosteroid bone loss in the lumbar spine and less effective in preventing osteoporosis in the femoral neck.⁴⁵

Bisphosphonates are generally well tolerated when orally administered. Currently, there are no data available on the effect of long-term treatment of bisphosphonates on the immature skeleton, and, therefore, in children and young patients with pemphigus receiving long-term corticosteroid therapy, calcitonin may be the treatment of choice.

Calcitonin inhibits osteoclastic bone resorption and may prevent spinal bone loss in late menopausal women. It has been demonstrated recently that salmon calcitonin is effective in preventing the early resorptive phase of bone loss seen during the initial weeks of corticosteroid treatment.⁴⁶ However, calcitonin does not seem to increase bone mass.

An additional advantage of calcitonin is its central analgesic effect, which is useful in the management of pain in acute vertebral fracture.^47- 48

It has been approved by the FDA for treating postmenopausal osteoporosis at a recommended dose of 200 IU/d intranasally, in addition to calcium and vitamin D supplementation.⁴⁹ Subcutaneous injections of calcitonin are used less often because of nausea, flushing, and local inflammatory reactions, which occur in 15% of patients.⁵⁰ Combination therapies with calcium supplements are generally recommended.^8,11 Estrogens with bisphosphonates may be effective for women, although currently there are no studies confirming this. Combination therapies with bisphosphonates and calcitonin have not been initiated.

Dermatologic patients receiving prolonged corticosteroid therapy should be monitored for osteoporosis and provided with intervention strategies to prevent further bone loss to decrease fracture risk. Since bone loss occurs early during the first months of treatment, it is best to start preventive measures as soon as possible. This should also take into consideration the cost-effectiveness of bone mineral density measurements (value as a case-finding strategy vs the cost of prophylactic treatment). There is a need to conduct long-term studies of the impact of prolonged corticosteroid treatment in dermatologic patients to justify the rationale for prophylactic treatment of glucocorticoid-induced osteoporosis.

For those receiving high-dose and long-term glucocorticosteroid therapy, the following guidelines should be considered:

Risk Assessment:

Prevention:

Treatment

Follow-up

Accepted for publication September 28, 2000.

Corresponding author and reprints: Gil Yosipovitch, MD, National Skin Center, 1 Mandalay Rd, Singapore 308205 (e-mail: gil@nsc.gov.sg).