Recommendations for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis

Glucocorticoids are widely used in the treatment of patients with chronic noninfectious inflammatory diseases, especially asthma, chronic lung disease, rheumatoid arthritis and other connective tissue diseases, inflammatory bowel disease, and in organ transplantation. Although the beneficial antiinflammatory and immunosuppressive effects of glucocorticoids necessitate their use, adverse side effects are frequent. Osteoporosis and related fractures are one of the most serious adverse effects; indeed, glucocorticoids are the most common cause of drug-related osteoporosis. While our knowledge of this condition is not complete, many comprehensive reviews of this topic have appeared during this decade, some of which include recommendations for prevention and treatment (1-16). In this article, we briefly review the clinical significance and pathophysiology of glucocorticoid-induced osteoporosis and provide recommendations for the prevention and treatment of this disorder.

Clinical significance

It is generally accepted that moderate-to-high-dose glucocorticoid therapy is associated with loss of bone and increased risk of fracture. Skeletal wasting is most rapid during the first 6 months of therapy; trabecular bone is affected to a greater degree than cortical bone. The skeletal effects of glucocorticoids appear to be both dose and duration dependent, with daily prednisone doses of [lte]7.5 mg often resulting in significant bone loss and increased fracture risk (17-24). The cumulative dose also affects the severity of bone loss. It is not known whether there is a threshold dose of glucocorticoid below which osteopenia does not occur; alternate-day glucocorticoid regimens, however, have not been shown to produce less bone loss than daily regimens (25,26). Even inhaled steroids have been shown to increase bone loss (27-29).

The magnitude of this problem has been demonstrated by cross-sectional studies, which suggest that the majority of patients receiving long-term glucocorticoid therapy have low bone mineral density, and that over one-fourth sustain osteoporotic fractures. The prevalence of vertebral fractures in asthma patients receiving steroid therapy for at least 1 year is 11% (17), and steroid-treated patients with rheumatoid arthritis have an increased incidence of fractures of the hip, rib, spine, leg, ankle, and foot (20-22). Thus, glucocorticoid-induced osteoporosis is an important clinical problem which commands the physician's attention to both prevention and treatment.

Pathogenesis

Glucocorticoid-induced osteoporosis occurs as a result of increased osteoclast-mediated bone resorption and decreased osteoblast-mediated bone formation. Specific mechanisms include 1) effects on calcium homeostasis, 2) effects on sex hormones, and 3) inhibition of bone formation, as well as other effects. These mechanisms are briefly summarized below.

Effects on calcium homeostasis. Glucocorticoids cause a decrease in intestinal absorption of both calcium and phosphate. The mechanisms of this action are poorly understood, but are thought to be mediated by factors independent of vitamin D (30,31). Urinary calcium excretion is increased in glucocorticoid-treated patients, possibly due to a direct effect on tubular reabsorption of calcium (32,33). Decreased gastrointestinal absorption and increased renal excretion of calcium can lead to secondary hyperparathyroidism with elevated serum levels of parathyroid hormone (PTH) (31,32). Persistently elevated PTH levels can increase bone resorption. Of note, no consistent abnormalities in vitamin D, PTH, or calcitonin levels have been found in glucocorticoid-treated patients (31,34).

Effects on sex hormones. Glucocorticoids cause a reduction in sex hormone production both indirectly, by reducing endogenous pituitary hormone levels and adrenal androgen production, and directly, through effects on gonadal hormone release (35-37). Secretion of luteinizing hormone from the pituitary is decreased, with a resultant decrease in estrogen and testosterone production by the ovaries and testes, respectively. Circulating levels of estradiol, estrone, dehydroepiandrosterone sulfate, androstenedione, and progesterone are lowered in both men and women. Deficiencies of these anabolic hormones likely play a significant role in the pathogenesis of glucocorticoid-induced osteoporosis.

Inhibition of bone formation. Long-term exposure to glucocorticoids inhibits osteoblast proliferation, attachment of osteoblasts to matrix, and synthesis of both type I collagen and noncollagenous proteins by osteoblasts (38,39). This is reflected in a dose-related reduction in the circulating levels of osteocalcin, and is likely mediated by effects on the expression of oncogenes (40), prostaglandin E production (41), and synthesis of insulin-like growth factors (42) and transforming growth factor [gb] (43).

Other effects. Glucocorticoid-induced myopathy and muscle weakness may also contribute to bone loss by removing the normal forces on bone that are produced by muscle contraction. Finally, the underlying inflammatory disease (e.g., rheumatoid arthritis), or concomitant drug therapy (e.g., cyclosporine), may also contribute to osteoporosis in the patient being treated with glucocorticoids.

Evaluation of the patient

Advances in the measurement of bone mineral density, especially the development of dual-energy x-ray absorptiometry (DXA), make it possible to precisely and rapidly quantify the amount of bone in the lumbar spine, proximal femur, forearm, and entire body with minimum radiation exposure (44). The bone mineral density (BMD) in a patient is expressed as a T score (the difference in standard deviation [SD] compared with peak bone mass in a young adult of the same race and sex) or a Z score (the difference in SD compared with healthy age-matched controls of the same race and sex); persons with a BMD [lt]1 SD below the mean in young adults (i.e., T score [lt][minus]1) are considered to have low BMD, while those with a BMD [lt]2.5 SD below the mean in young adults (i.e., T score [lt][minus]2.5) are considered to have osteoporosis (45). Current indications for bone densitometry delineated by the Scientific Advisory Board of the National Osteoporosis Foundation include glucocorticoid treatment (46).

Because trabecular or cancellous bone and the cortical rim of the vertebrae are lost more rapidly than cortical bone from the long bones, the earliest changes of glucocorticoid-induced bone loss can be detected in the lumbar spine using the techniques of quantitative computed tomography (QCT) or DXA. QCT provides information only on trabecular bone, while DXA measures a combination of both cortical and trabecular bone. Because most medical practices do not have access to QCT and because QCT requires a larger radiation exposure, the Task Force recommends that physicians obtain an anteroposterior (AP) DXA measurement of both the lumbar spine and femoral neck. If only one site can be obtained, we recommend the lumbar spine in men and women below age 60 and the femoral neck in men and women age 60 and above, since measurements of the lumbar spine in the elderly may be unreliable because of osteophyte formation at the vertebral bodies and facet joints (47). DXA of the lumbar spine in the lateral position may be a more sensitive indicator of glucocorticoid-induced bone loss than in the AP position; however, preliminary data from the Study of Osteoporotic Fractures failed to demonstrate that lateral spine DXA measurements were better predictors of vertebral fracture than AP spine DXA measurements (Black D: personal communication). Ideally, baseline bone mineral densitometry should be performed before long-term (i.e., [lte]6 months) corticosteroid therapy is initiated, or very soon thereafter.

Prevention and treatment

Glucocorticoid-induced bone loss can be both prevented and treated. Evidence from studies of patients cured of Cushing's syndrome indicates that bone density increases following the restoration of normal glucocorticoid levels (48). Optimal management strategies to prevent bone loss should include the use of the lowest effective dose of glucocorticoid that is possible. As noted above, use of alternate-day dosing does not offer protection against glucocorticoid-induced bone loss. Topical and inhaled preparations should be used whenever possible. In addition, all patients should be encouraged to modify their lifestyles to include smoking cessation, limitation of alcohol consumption, and participation in a weight-bearing exercise program for 30-60 minutes/day.

The Task Force's recommendations will be divided into the following groups: 1) approach to the patient receiving long-term glucocorticoid treatment who has an osteoporotic fracture; 2) approach to the patient receiving long-term glucocorticoid treatment who does not have an osteoporotic fracture; and 3) approach to the patient who is beginning long-term glucocorticoid treatment. We have also included specific comments for 3 treatment groups: postmenopausal women, premenopausal women, and men aged 18 years and older. Finally, we have included a separate section on recommendations for the prevention and treatment of glucocorticoid-induced bone loss in children.

Evidence of the effectiveness of therapy for glucocorticoid-induced bone loss

Numerous therapeutic approaches have been used for glucocorticoid-induced bone loss. The evidence supporting the use of these pharmacologic therapies is summarized below.

Calcium. Since glucocorticoid-induced bone loss results in part from decreased calcium absorption from the gastrointestinal tract and increased calcium loss in the urine, an attempt to normalize calcium balance may limit the extent of bone loss. Indeed, in one study of patients taking steroids, calcium supplementation alone inhibited bone resorption and decreased bone loss (49). The Task Force recommends that all patients maintain an adequate calcium intake of |mf1,500 mg/day, through either diet or supplements, unless contraindicated.

Vitamin D. Vitamin D is of benefit in both the treatment and prevention of glucocorticoid-induced bone loss. Hahn and colleagues showed that, in rheumatic disease patients taking corticosteroids, the addition of vitamin D (50,000 units 3 times per week) or 25-hydroxyvitamin D (40 [gm]g/day) with 500 mg of elemental calcium had beneficial effects on bone density measured in the radius (31,50). Neither of these studies, however, was randomized or measured BMD in the lumbar spine or hip. In a recent primary prevention study, patients beginning prednisone therapy were randomized to received either vitamin D (50,000 units per week) and calcium (1,000 mg/day) or double placebo (51). Although there was a slightly smaller decline in lumbar spine BMD at 12 months in the treated group (2.6% versus 4.1%), the changes in lumbar spine BMD measured at 36 months were not significantly different between the groups. Thus, this regimen did not appear to be of benefit in primary prevention.

In another primary prevention study, patients were randomized to 1 of 3 groups: 1) a combination of 1,25-dihydroxyvitamin D (calcitriol; 0.5-1.0 [gm]g/day), salmon calcitonin nasal spray (400 IU/day), and calcium (1,000 mg/day); 2) calcitriol (0.5-1.0 [gm]g/day) and calcium (1,000 mg/day) with placebo nasal spray; or 3) calcium (1,000 mg/day) alone with placebo calcitriol and placebo nasal spray (52). The patients who took calcitriol, with or without intranasal calcitonin, were shown to lose significantly less bone from the lumbar spine than those who took calcium alone during the first year of corticosteroid therapy. Bone loss at the radius and femoral neck did not significantly differ between the 3 groups. Unfortunately, about one-fourth of patients taking calcitriol developed hypercalcemia, and most showed worsening of their hypercalciuria. This illustrates the narrow margin of safety of calcitriol and emphasizes the need to closely monitor serum calcium levels in patients receiving this therapy. Concern about these side effects led us to recommend that vitamin D (either 800 IU/day or 50,000 IU 3 times per week) or calcitriol (0.5 [gm]g/day) be used in the management of glucocorticoid-induced osteoporosis. If either high-dose vitamin D or calcitriol is used, then careful followup of both serum and urine calcium levels is essential.

Thiazide diuretics. Sodium restriction and thiazide diuretics have been shown to improve gastrointestinal absorption and decrease urinary excretion of calcium (53). These effects can ameliorate the hypercalciuria that is associated with glucocorticoid therapy and would be expected to improve calcium balance. Glucocorticoid-treated patients who, while consuming a normal diet, excrete [lt]300 mg of calcium in their urine over a 24-hour period may benefit from the addition of a low-dose thiazide diuretic (e.g., hydrochlorothiazide 25 mg/day), with potassium supplements as needed. Although the effects of thiazide diuretics on bone density have not been adequately assessed in glucocorticoid-treated patients, in the absence of glucocorticoid treatment, thiazide use is associated with higher bone density and a modest reduction in fracture risk (54-56). Serum calcium levels must be monitored carefully in patients receiving both vitamin D, especially calcitriol, and thiazides because these patients are more prone to hypercalcemia than those receiving either vitamin D or thiazides alone.

Hormone replacement therapy (HRT). Glucocorticoid-induced hypogonadism should be corrected if possible. One small study of 15 women with asthma who were receiving glucocorticoid therapy showed that a combination of estrogen and progesterone therapy was associated with increased lumbar spine BMD after 1 year (57). In a trial of women with rheumatoid arthritis who were taking prednisone and were randomized to receive HRT or placebo, those who received HRT had a significant increase in their lumbar spine BMD compared with controls (58). There was no significant change in femoral neck BMD in either group. Based on the results of these 2 studies, postmenopausal women taking glucocorticoids should receive HRT if there are no contraindications. Premenopausal women who experience menstrual irregularities (i.e., oligo- or amenorrhea) while taking steroids should be offered therapy with oral contraceptives if contraindications are not present. Although no studies have been performed in glucocorticoid-treated premenopausal women, observational epidemiologic studies and studies in premenopausal athletic women with menstrual irregularities suggest that women who received oral contraceptives had higher adjusted BMD than did women who did not take oral contraceptives (59).

A recent randomized crossover trial demonstrated the effectiveness of testosterone therapy in 15 men with glucocorticoid-treated asthma (60). All men had low serum testosterone levels prior to therapy. Lumbar spine BMD, but not hip BMD, was significantly increased after 12 months of monthly testosterone injections. Associated with this change in BMD, there was a significant decrease in the percentage of body fat and a significant increase in lean body mass. Thus, if serum testosterone levels are low in men who are taking glucocorticoids, they may benefit from testosterone replacement, since testosterone deficiency is a recognized cause of osteoporosis in men. Guidelines for the use of androgens in men have been published recently (61).

Bisphosphonates. Bisphosphonates are pyrophosphate analogs that bind to hydroxyapatite at sites of active bone remodeling. There, they inhibit bone resorption by directly inhibiting the action of osteoclasts, and have a sustained effect because of their long half-life in bone (62). There are currently 3 bisphosphonates available in the United States: etidronate, pamidronate, and alendronate. Etidronate has been shown to be effective in the primary prevention, and both etidronate and pamidronate have been shown to be effective in the secondary prevention of glucocorticoid-induced osteoporosis. Trials of alendronate in secondary prevention are currently in progress.

Mulder and Struys studied 20 postmenopausal women with temporal arteritis who were beginning glucocorticoid therapy (63). The women were alternately assigned to receive either etidronate 400 mg/day for 2 weeks every 13 weeks or no therapy in addition to their prednisone. The change in lumbar spine BMD from baseline was significantly different between treated and control patients (+1.4% versus [minus]5.0%, respectively). Diamond and colleagues studied 15 postmenopausal women with rheumatoid arthritis, polymyalgia rheumatica, or asthma who were beginning prednisone therapy and who received cyclical etidronate 400 mg/day for 4 weeks of the first 3-month cycle followed by 400 mg/day for 2 weeks of every other 3-month cycle for 2 years (64). Data from these patients were compared with data from 11 female historical control subjects who received only calcium supplements. At 12 months, the etidronate-treated patients had significant increases in lumbar spine and femoral neck BMD compared with controls. At 24 months, the change in lumbar spine BMD was sustained while that at the femoral neck increased.

Two additional studies have demonstrated the effectiveness of etidronate in secondary prevention of glucocorticoid-induced osteoporosis (65,66). Adachi and colleagues compared 35 glucocorticoid-treated patients who received cyclical etidronate to 33 control patients who received calcium supplements alone (65). There was a significant increase in lumbar spine BMD in the etidronate-treated patients compared with a reduction in those who received calcium alone; no changes were noted in femoral neck BMD. Struys and colleagues studied 39 patients receiving glucocorticoids for a variety of conditions; 19 received open-label cyclical etidronate and 20 received calcium supplements alone (66). Both lumbar spine and femoral neck BMD were significantly increased in the etidronate-treated patients at 6 and 12 months. In a randomized controlled trial of 40 patients with chronic lung disease, oral pamidronate (150 mg/day) and calcium (1,000 mg/day) produced a significant increase in lumbar spine BMD after 12 months in patients taking long-term steroids (67). Two-year followup data in 13 of these patients showed that lumbar spine BMD was maintained in the pamidronate-treated group but further declined in the controls (68). Because of the long skeletal retention of bisphosphonates, caution should be exercised in treating young patients with long-term bisphosphonates.

Calcitonin. Calcitonin, which is approved by the Food and Drug Administration for the treatment of osteoporosis, inhibits bone resorption through a direct effect on osteoclasts. Given subcutaneously (100 IU/day or every other day) or intranasally (200 IU/day), it is effective in the prevention of bone loss and fractures in established osteoporosis, and it also prevents bone loss caused by glucocorticoids (52,69-71). Ringe and Welzel found that salmon calcitonin injections led to an increase in forearm BMD in glucocorticoid-treated patients with chronic lung diseases (69). Montemurro and colleagues studied 68 patients with sarcoidosis at the beginning of prednisone therapy and found that treatment with salmon calcitonin, either by injection or intranasally, prevented bone loss at the lumbar spine (70). In a recent randomized, 2-year, placebo-controlled study of patients with temporal arteritis and polymyalgia rheumatica, Healey and colleagues found that the lumbar spine BMD of patients who received injections of salmon calcitonin remained stable but did not increase (71). Thus, calcitonin appears to be effective for both the primary and secondary prevention of glucocorticoid-induced bone loss. A multicenter trial of intranasal salmon calcitonin in the treatment of glucocorticoid-induced osteoporosis has recently been completed; results are pending.

Anabolic steroids. Adami and Rossini performed an 18-month controlled trial in 35 postmenopausal women receiving long-term glucocorticoid therapy (72). Patients who received nandrolone decanoate (50 mg intramuscularly every 3 weeks) had a rapid increase in forearm BMD at 6 months, which was sustained, while controls had a decline in BMD. The authors suggested that anabolic steroids could be used for the treatment of glucocorticoid-induced osteoporosis. The Task Force believes that further controlled trials of the efficacy of anabolic steroids in patients with glucocorticoid-induced osteoporosis need to be conducted before these agents can be recommended for therapy.

Fluoride. Greenwald and colleagues administered a slow-release enteric-coated preparation of sodium fluoride, 20-30 mg/day, to 10 patients who had glucocorticoid-induced osteoporosis (73). Patients had a mean annual increase of 18.7% in lumbar spine BMD despite the continued use of corticosteroids; there was no significant change in BMD at the femoral neck. None of the patients reported adverse effects from the sodium fluoride treatment; one patient sustained a vertebral compression fracture after 14 months of therapy. The authors suggested that controlled trials of the efficacy of sodium fluoride should be conducted in patients with glucocorticoid-induced osteoporosis. The Task Force agrees and further recommends that such trials utilize low-dose slow-release preparations of sodium fluoride.

Approach to the patient receiving long-term glucocorticoid treatment who has an osteoporotic fracture

The initial visit for a patient who has been treated long term with glucocorticoids and has sustained an osteoporotic fracture should include a history and physical examination that documents potentially modifiable risk factors for osteoporosis, including dietary calcium and vitamin D intake, smoking history, alcohol consumption, medication use, and menstrual history in women and, in men, any history of infertility or impotence (Table 1). In addition, the history should include a survey of potentially modifiable risk factors for falls and fractures. Physical examination should include a measure of height and weight, tests of lower extremity muscle strength and balance (e.g., arising from a seated position to a standing position [chair stands], and attempts to stand with the feet next to one another [tandem stands]), and tests of visual acuity and depth perception (74,75). Laboratory tests should focus on identifying secondary causes of osteoporosis and assessing urinary calcium excretion. The tests should include a complete blood cell count, erythrocyte sedimentation rate, serum electrolytes, calcium, phosphorus, alkaline phosphatase, creatinine, and 25-hydroxyvitamin D, among others, and a 24-hour urine collection to quantify urinary calcium excretion; men should also have a serum testosterone level determined. As part of the initial evaluation, DXA of the hip and/or spine should be done to measure BMD.

After the history, physical examination, and laboratory tests have been obtained, treatment should be initiated. First, the patient may require analgesia for the recent fracture. Simple analgesics including acetaminophen or nonsteroidal antiinflammatory drugs may be tried; if found to be insufficient, short-acting narcotic analgesics or intranasal or subcutaneous calcitonin can be prescribed. The analgesic effects of calcitonin have been documented with both the subcutaneous and intranasal preparations (69,76). Treatment with calcitonin is recommended until the pain is controlled, then the medication can be tapered over the next 4-6 weeks.

At the initial visit, the patient should also be given educational materials about glucocorticoid-induced bone loss and instructed in lifestyle modifications. Since glucocorticoids reduce muscle mass, patients should be educated by the physician or a physical therapist regarding exercises they can perform to maintain or increase muscle strength. Also, patients who have sustained an osteoporotic fracture should receive a balance and gait evaluation. All patients who have osteoporosis should receive posture training, back extension exercises, assistive devices, and kypho-orthoses as needed, as well as nonpharmacologic strategies to control acute and chronic pain (77). Patients with a vertebral compression fracture need to avoid bending and lifting, because these movements may increase the biomechanical forces in the vertebrae and lead to additional fractures. Furthermore, exercises which involve back flexion, including sit-ups and toe-touches, should be avoided as well.

Recommendations for pharmacologic therapy will depend on the results of laboratory tests and the DXA measurement (Figure 1). These should be given to the patient at a followup visit within 2 weeks of the initial visit. Depending on the BMD measurement, a number of different treatment options are available to the physician and patient. In general, calcium and vitamin D supplementation and patient education and physical therapy are recommended for all patients.

Patients who are receiving long-term steroid therapy who sustain an osteoporotic fracture and have a normal BMD and normal laboratory values should have a further evaluation as to the cause of their fracture. Patients taking long-term steroids who have abnormal laboratory values, irrespective of the BMD results, should undergo further evaluation (Table 3). The most common causes of osteoporosis in the setting of abnormal laboratory findings unrelated to steroids include hyperparathyroidism, osteomalacia, thyroid disease or over-supplementation with thyroid medication, renal osteodystrophy syndromes, and multiple myeloma. Appropriate laboratory tests should be ordered for further evaluation of these diseases.

A followup visit should be scheduled in 6-12 months. At that time, a repeat BMD measurement should be obtained to determine the efficacy of the therapeutic interventions. In general, if the BMD is increased, has remained stable, or declined less than 5%, it is reasonable to continue the present therapy. If the BMD loss over the 12-month period is more than 5%, either alternative or additional therapy may be required. If the patient had been receiving HRT, consideration should be given to either the addition or substitution of either a bisphosphonate or calcitonin to the regimen.

Approach to the patient receiving long-term glucocorticoid treatment who does not have a fracture

The evaluation is similar to that outlined above. At the initial evaluation a detailed history and physical examination is performed, laboratory tests obtained and a DXA measurement for BMD is recommended. All patients should be given patient education, a referral for a physical therapy appointment, calcium and vitamin D supplementation, as well as HRT in postmenopausal women. If the BMD measurement is normal, no further therapy is indicated other than a return visit at 1 month to adjust the calcium supplementation or for the addition of a thiazide diuretic if hypercalciuria is detected. Although no studies have been performed of the role of exercise in patients with glucocorticoid-induced osteoporosis, several studies have documented the effectiveness of weight-bearing and resistive exercise in postmenopausal women with low BMD (78,79). For patients on long-term steroids with an abnormal BMD and/or abnormal laboratory tests, all recommendations remain the same as those for patients with an osteoporotic fracture.

Approach to the patient who is beginning long-term glucocorticoid treatment

Given that bone is lost most rapidly during the first 6 months of steroid use, primary prevention measures should begin as soon as steroids are prescribed. Importantly, attempts to preserve bone should not be delayed until the underlying disease process is quiescent. On the initial visit when the patient is about to initiate long-term steroid therapy, a complete history should be obtained with a special emphasis on modifiable risk factors for osteoporosis (Figure 2). The history should include a review of medications that increase the risk of osteoporosis, including thyroid hormone replacement, diphenylhydantoin, long-term coumadin or heparin, cyclosporin A, and antigonadotropins, including gonadotropin-releasing hormone agonists. The physical examination should include a measurement of height (in bare feet) and weight, and evaluation of balance and muscle strength.

As part of this evaluation, a BMD measurement of the spine and hip should be obtained; this measurement can determine the patient's risk of osteoporosis independent of glucocorticoid therapy, and provides a baseline measurement for monitoring changes in bone mass. The results of this measurement may help patient compliance with the therapy (80). After the BMD measurement, the patient should be educated about glucocorticoid-induced bone loss and lifestyle modifications they can make to prevent bone loss. Since steroids alter muscle mass, patients should be educated by the physician or a physical therapist about exercises they can perform to maintain muscle strength while taking steroids. Also, for elderly patients or patients who have problems with their balance, education on fall prevention should be provided. For all patients starting steroids, calcium and vitamin D supplementation should be initiated. Further therapy depends on the results of the DXA measurement. Patients who have an abnormal BMD value (i.e., T score [lt][minus]1) for their lumbar spine or hip should initiate HRT. If there are contraindications to HRT, a bisphosphonate or calcitonin should be started. If the BMD of the lumbar spine and hip is normal, calcium and vitamin D supplementation should be started, and postmenopausal women should be encouraged to initiate HRT for general health reasons, unless contraindicated, while taking steroids.

Approximately 1 month after starting therapy, the patient should return and a 24-hour urine should be obtained to measure calcium excretion. If the urinary calcium is [lt]300 mg/day and the patient is not taking calcitriol, a thiazide diuretic with or without potassium supplementation should be added. If the urine calcium is [lt]300 mg/day and the patient is taking calcitriol, the dosage of either the calcium supplement or calcitriol should be adjusted. Six or 12 months after the initiation of steroids, a repeat BMD measurement should be done to determine the efficacy of the therapeutic interventions. If the BMD has decreased more than 5% from baseline, the medication can be changed or another one added. If the BMD measurement has increased, remained stable, or declined less than 5% from baseline, no change in therapy is required.

Prevention and treatment of glucocorticoid-induced bone loss in children

Glucocorticoid-induced osteoporosis and associated fractures are a common complication in children and adolescents, for several reasons. First, childhood and adolescence are a time of high bone turnover, with very high rates of bone formation being required to maintain adequate mineralization of the rapidly growing skeleton. Second, the use of glucocorticoids during adolescence may prevent the patient from reaching his/her peak bone mass (81), since glucocorticoids are potent inhibitors of bone formation. Finally, a number of pediatric disorders for which glucocorticoids are prescribed are independently associated with osteoporosis (82).

Methods of monitoring bone mineralization in children and adolescents are similar to those in adults. DXA has been shown to be reliable and safe, and normal values for BMD have been established for healthy children and adolescents (83). Treatment issues, however, differ between children and adults. Only a few, small, open, short-term studies of pharmacologic approaches to increasing BMD in children have been published. Although these results are promising, larger controlled studies of longer duration will be required before these agents can be broadly recommended for use in children. Fortunately, significant improvement in BMD can often be achieved with oral administration of calcium and vitamin D (84).

In a crossover study of children with rheumatic diseases receiving glucocorticoid therapy, significant improvement in BMD was demonstrated after 6 months of treatment with a combination of 1,000 mg/day of calcium and 400 IU/day of vitamin D. At this time, the most prudent approach to minimizing the negative effect of glucocorticoids on BMD is by ensuring that patients consistently ingest, through either diet or supplements, the following daily calcium intake: 800 mg/day at ages 1-5 years, 1,200 mg/day at ages 6-10 years, and 1,500 mg/day at ages 11-24 years (85). In addition, all children should receive at least 400 IU/day of vitamin D. Currently, a number of studies are being performed that will hopefully address the role of other forms of interventions for glucocorticoid-induced osteoporosis in children and adolescents.

Future therapeutic possibilities

Much work remains to be done to improve our management of glucocorticoid-induced osteoporosis. Future possibilities for treatment include attempts to stimulate growth factors in bone that are altered by glucocorticoids, such as insulin-like growth factor 1 and transforming growth factor [gb]. Therapies that stimulate the osteoblast include intermittent PTH, and recombinant human growth hormone (hGH). In glucocorticoid-treated children, hGH has been shown to improve protein balance and to stimulate collagen synthesis and linear growth (86). Another area under investigation is the use of biochemical markers of bone turnover to assess the effects of treatment on glucocorticoid-induced changes in bone formation and resorption. Markers of bone formation include serum levels of osteocalcin and bone-specific alkaline phosphatase; markers of bone resorption include urinary excretion of deoxypyridinoline and n-telopeptide crosslinks of collagen (87). These markers have been used extensively in studies of antiresorptive agents in postmenopausal women and are just beginning to be used to evaluate bone metabolism in glucocorticoid-treated patients. In the future, they may prove useful in monitoring response to therapy in glucocorticoid-treated patients.

Conclusions

Glucocorticoid therapy at doses of 7.5 mg/day of prednisone or above for 6 months or more often results in a rapid loss of trabecular bone in the spine, hip, and forearm. Corticosteroids act through multiple mechanisms to promote skeletal loss, and preventive measures include selecting the lowest possible steroid dose. It is reasonable to measure BMD in all individuals who appear likely to be taking corticosteroids long term, and to begin preventive therapies as soon as the clinical situation permits. Calcium and vitamin D supplements, sex hormone replacement, and a weight-bearing exercise program that maintains muscle mass are suitable first-line therapies. Thiazide diuretics and sodium restriction are useful in reducing the hypercalciuria associated with glucocorticoid use. In patients who 1) are unable to take sex hormone replacement, 2) have established osteoporosis, or 3) are showing deterioration in BMD despite these interventions, other agents, including bisphosphonates or calcitonin, are indicated. In the future, the availability of agents that stimulate bone formation in the presence of glucocorticoids may make the prevention and treatment of this condition much more straightforward. These recommendations will be updated as new therapies for preventing and treating this condition become available.

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Members of the Task Force on Osteoporosis Guidelines are as follows. Marc C. Hochberg, MD, MPH (co-chair): University of Maryland, Baltimore; Mark J. Prashker, MD, MPH (co-chair): Edith Nourse Rogers Memorial Veterans Hospital, Bedford, MA; Maria Greenwald, MD: Rancho Mirage, CA; Marian T. Hannan, DSc, MPH: Boston University School of Medicine, Boston, MA; Nancy E. Lane, MD: University of California at San Francisco; Stephen M. Lindsey, MD: Ochsner Clinic, Baton Rouge, LA; Daniel J. Lovell, MD, MPH: Children's Hospital Medical Center, Cincinnati, OH; Elizabeth A. Tindall, MD: Portland, OR.

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Submitted for publication July 16, 1996; accepted in revised form September 3, 1996.