INFO - Preventing steroid-induced osteoporosis

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Preventing glucocorticoid-induced osteoporosis

Sep 15, 2002

Patient Care

Bone loss from glucocorticoid therapy is immediate and occurs at the

highest rate during the first 6 months. Judicious use of calcium, vitamin D,

hormone replacement therapy, and bisphosphonates at the onset of long-term

treatment can improve bone density.

Exogenous glucocorticoids are the treatment of choice for many medical

conditions, and their beneficial effects can be quite dramatic. Yet this

class of drugs is potentially one of the most toxic, with side effects

ranging from less serious medical conditions such as truncal obesity,

striae, and cataracts, to more serious ones such as hypertension, diabetes

mellitus, osteonecrosis, and osteoporosis. Glucocorticoids have been a known

risk factor for osteoporosis since the 1930s, when their association with

skeletal changes and endocrine tumors was first reported.1

By the 1950s, exogenous glucocorticoid therapy became widespread, and

the severity of glucocorticoid-induced osteoporosis (GIO) was more fully

appreciated. Recent data suggest that osteoporosis will develop in

approximately 50% of patients who undergo long-term glucocorticoid therapy,

thereby increasing their risk of sustaining spontaneous fractures.2

Long-term therapy with 7.5 mg/d of prednisone is associated with an average

of 3% bone loss annually. Despite its prevalence and significant morbidity,

this common iatrogenic disease is often underrecognized and inadequately

treated. This article will review the problem and suggest solutions.

HOW GLUCOCORTICOIDS CAUSE BONE LOSS

Bone is actively remodeled throughout adult life. Even in the absence

of glucocorticoid exposure, 25% of trabecular bone and 3% of cortical bone

are remodeled annually.

Osteoblasts and osteoclasts are the cell types largely responsible for

bone turnover. Osteoblasts are cuboidal cells found in clusters at the bone

surface. They produce a layer of osteoid, which matures over a period of 10

days by a process of calcification that, over the course of several months,

results in new bone. Osteoclasts are multinucleated giant cells responsible

for bone resorption. They attach to bone matrix via integrin receptors,

which help to create pockets of extracellular space bordered by folds of

ruffled osteoclast membrane. This process creates secondary lysosomes

characterized by a low pH and an enzyme-rich environment in which bone

matrix degradation occurs. When glucocorticoids cause bone resorption to

occur at a faster rate than bone formation, osteoporosis results.

Corticosteroid receptors are partitioned into two types:

mineralocorticoid (found in CNS and renal tissue) and glucocorticoid

(present in virtually all cells of the body). Glucocorticoid receptors

mediate both the anti-inflammatory and metabolic effects of corticosteroids.

When glucocorticoids bind to the cellular receptors, the resulting complex

migrates to the nucleus where gene expression is induced. Consequently, all

levels of the inflammatory cascade are inhibited. Glucocorticoids are most

effective at suppressing T lymphocytes and natural killer cells, but they

tend to be less effective at inhibiting mature B cells. Corticosteroids also

suppress proinflammatory cytokines such as tumor necrosis factor-alpha and

interleukin-1. They have inhibitory effects on inflammatory mediators such

as gamma interferon, prostaglandin E2, and leukotrienes. The overall result

appears to be preferential suppression of cellular immunity rather than

humoral immunity.

GIO occurs as a consequence of multiple direct and indirect effects of

glucocorticoids on bone formation and resorption, the metabolism of calcium

and vitamin D, and the modulation of sex hormones. Glucocorticoids directly

inhibit osteoblast proliferation and matrix synthesis and cause a decline in

circulating levels of osteocalcin. They have also been implicated in

osteoblast apoptosis. Since bone formation is linked to body mass and muscle

strength, the catabolic effects of corticosteroids on muscle may indirectly

reduce bone formation. Hence, glucocorticoids weaken bone formation by way

of a glucocorticoid-induced myopathy with its associated loss of the trophic

effect of muscle stress on bone.

Corticosteroids also reduce sex hormone levels. They specifically

suppress estrogen, luteinizing hormone, and follicle-stimulating hormone in

women, which normally act to inhibit bone resorption. Moreover, a loss of

estrogen is associated with a net increase in numbers of osteoclasts. The

resultant hypogonadism favors osteoclastic over osteoblastic activity.

In addition, glucocorticoids may indirectly accelerate bone resorption

by causing excessive calciuria. The reduced availability of substrate for

bone formation that results is worsened by impaired renal tubular

reabsorption of calcium caused by glucocorticoids as well as reduced serum

levels of 1,25-dihydroxyvitamin D. This net loss in calcium causes a

secondary hyperparathyroidism, leading to further resorption of bone.3

Furthermore, glucocorticoids also decrease trabecular bone mass by

interfering with bone-active cytokines such as insulinlike growth factors.

GIO becomes detectable by sensitive radiologic methods as early as 1

month into systemic glucocorticoid therapy. Dual-energy x-ray absorptiometry

(DXA) and quantitative CT are radiologic methods available for detecting low

bone mass. Of these techniques, DXA is less expensive and more widely

available. T-scores, which are used in clinical decision-making, represent

the number of standard deviations below or above the peak bone mass in a

young adult reference population of the same sex. According to the World

Health Organization, a T-score above -1 reflects normal bone density,

between -1 and -2.5 is osteopenia, and below -2.5 signifies osteoporosis.3 A

T-score below -2.5 in addition to a personal history of fractures indicates

severe osteoporosis.

Individuals at greatest risk for GIO are those experiencing high bone

turnover or those with a preexisting imbalance between resorption and

formation, including children aged 15 and younger, adults older than 50,

postmenopausal women, and immobilized patients. Bone loss occurs mostly in

areas of high turnover, such as trabecular bone of the vertebra, and

resulting spontaneous fractures commonly involve the vertebrae or ribs.4,5

In one study, current corticosteroid users were 2.7 times more likely to

sustain a hip fracture compared with nonusers.6

Significant metabolic bone disease due to glucocorticoid therapy

occurs in a short amount of time. Even low-dose, 6-week corticosteroid

treatment is associated with adverse effects on bone metabolism.7 In one

study, 10 mg/d of prednisone over a 2-month period adversely affected

calcium and bone metabolism by uncoupling bone formation and resorption.7

Another study found that 20 weeks of treatment with low-dose prednisone

induced a mean trabecular bone mineral density decline of 8.2% in patients

with rheumatoid arthritis.8 Susceptibility to fracture is dependent on

dosage, and the overall risk of fracture is increased during oral

corticosteroid therapy, becoming apparent within the first 3 months of

treatment.9 Therefore, preventive therapy for osteoporosis should commence

when glucocorticoids are first prescribed.2

PROPHYLAXIS AGAINST GIO

Early strategies for the prevention and treatment of GIO blunted the

adverse impact of steroids on bone but did not consistently improve bone

strength, as has been seen with the more recently released class of agents

known as bisphosphonates. Among those strategies were sodium restriction

with concurrent thiazide diuretic therapy and treatment with sodium fluoride

or calcitonin. In particular, the use of thiazide diuretics with salt

restriction remains of unproved benefit, while treatment with vitamin D

carries a risk of hypercalciuria and urinary stone formation. Sodium

fluoride stimulates bone formation but remains controversial because of the

resultant abnormal bone quality noted during such therapy.10

Over the past decade, however, some notable inroads toward the

reduction of corticosteroid-induced bone mineral loss were made.11-15 Most

notably, these include gonadal hormone supplementation and bisphosphonates,

both of which have antiresorptive properties and may maintain or increase

bone density in some persons taking corticosteroids. Calcitonin can be

effective in some cases and may be considered when bisphosphonates are not a

viable option.

In addition to using those therapies, the American College of

Rheumatology (ACR) recommends treating confounding comorbid conditions such

as hyperthyroidism.2 Lifestyle alterations that may improve bone health

include exercise, reduction of alcohol use, and avoidance of cigarettes.

Although the best preventive measure is to discontinue use of

glucocorticoids, in many situations this course of action is not feasible.

Glucocorticoids should be prescribed at the minimum effective dose. Topical

or inhaled agents are preferred over systemic corticosteroids, if practical.

Because bone loss is most rapid during the first 6 months of glucocorticoid

therapy, the ACR advises physicians to start all patients on calcium plus

vitamin D at the onset of treatment.

Calcitonin and vitamin D metabolites

Providing adequate substrate for bone formation includes

supplementation with calcium in addition to vitamin D. A daily intake of

1500 mg of elemental calcium, either through diet or supplements, reduces

bone turnover. In most patients, cholecalciferol, 400 to 800 IU/d, is

sufficient to maintain serum levels in a proper range. If high-dose

cholecalciferol is used, carefully check both serum and urine calcium levels

periodically.

Intranasal salmon calcitonin administered in dosages up to 400 IU/d

was shown in several studies to blunt the loss of bone mineral content.10

One study comparing prophylactic use of calcium, calcitriol, and calcitonin

found that only treatment with calcium and calcitriol (with or without

calcitonin) prevented or reduced bone loss from the lumbar spine.15 A

significant side effect of treatment was hypercalcemia. Variable dosing of

corticosteroid therapy and the lack of a placebo control group, however, may

limit interpretation of results of this particular study. Expert

consultation should be obtained before prescribing calcitriol.

Hormone replacement therapy

Corticosteroids reduce levels of sex hormones, thereby indirectly

facilitating osteoclastic bone resorption. Therefore, patients taking

glucocorticoids may benefit from hormone replacement therapy (HRT), a

strategy that is still being investigated. One study using gonadal hormone

replacement for patients receiving chronic glucocorticoid therapy

demonstrated either stability or improvement of bone mineral density in both

men and women.16

Bisphosphonates

Synthetic pyrophosphates that resist chemical

degradation-bisphosphonates-have recently become key players in treating and

preventing GIO. A study assessing the benefit of alendronate for patients on

long-term corticosteroid therapy found that those taking alendronate showed

increased bone mineral density in the lumbar spine, hips, and overall

compared to patients taking placebo.12 In addition, fewer new vertebral

fractures were observed in the alendronate group. The evidence suggests that

prophylaxis with alendronate, 5 mg/d, may be warranted in patients receiving

long-term glucocorticoids. More recently, a third-generation oral

bisphosphonate was shown to prevent bone loss in patients initiating

corticosteroid treatment. Risedronate, 5 mg/d, resulted in significant

positive treatment effects in both men and women after 12 months of

intervention.13 Other bisphosphonates that may help treat or prevent GIO

include IV pamidronate and the cyclical administration of etidronate.

Anabolic therapy

Recently, anabolic therapy, with parathyroid hormone in particular,

has shown promise in the treatment of GIO.17 Early studies, however, do not

reveal consistent improvement throughout the skeleton, and primary

prevention studies are yet to be completed.

EVIDENCE OF UNDERTREATMENT

Despite recent guidelines published by the ACR and numerous studies

establishing the efficacy of preventive therapy against GIO, growing

evidence suggests widespread underutilization of these measures. A telephone

survey of patients on long-term glucocorticoids reported that 29% were

taking calcium supplements and 45% were receiving vitamin D. Of the

postmenopausal women surveyed, 40% were receiving HRT, 14% were receiving

bisphosphonates, and 29% had undergone a DXA scan.18 In another study,

charts of 215 clinic patients on glucocorticoid therapy for more than 1

month were reviewed. Prophylaxis against GIO was prescribed for 58% of the

patients.10

The rheumatology staff at The Washington University Medical

Center, Washington, DC, performed a similar retrospective chart review. In

this unpublished study, only 29% of the patients surveyed were given

preventive therapy, and only 16% were assessed via DXA scan. All of the

patients evaluated and given prophylaxis were women, most of whom were in

their 40s. Preventive therapy was typically initiated after the patient had

taken glucocorticoids for more than 2 years and at dosages equivalent to

more than 10 mg/d of prednisone. The results showed that even

university-based rheumatologists who commonly confront the adverse effects

of excess exogenous glucocorticoids infrequently evaluate for, or provide

prophylaxis against, GIO.

A history of a DXA scan correlated with a higher rate of preventive

therapy by increasing the likelihood of diagnosing GIO. Therefore,

increasing physician awareness concerning issues surrounding GIO may be of

significant importance in detecting and treating patients with metabolic

bone disease. These studies show the need to initiate a better approach to

educate patients and physicians regarding the importance of GIO prevention.

A checklist addressing issues pertinent to patients taking

glucocorticoids, such as adverse effects of corticosteroids, risk factors

for osteoporosis, previous DXA scan results, and preventive therapy

selected, may be a useful tool for physicians (see " Monitoring patients on

glucocorticoids " ). This type of document can be placed in the charts of all

patients when initiating glucocorticoid therapy to serve as a reminder of

the increased risk of osteoporosis and the need for prophylaxis.

EDITED BY STACY DILORETO

REFERENCES

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supplementation prevents bone loss in the spine secondary to low-dose

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15. Sambrook P, Birmingham J, P, et al. Prevention of

corticosteroid osteoporosis: a comparison of calcium, calcitrol, and

calcitonin. N Engl J Med. 1993;328:1747-1752.

16. Lukert BP, BE, RG. Estrogen and progesterone

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17. Lane NE, S, Genant HK, et al. Short-term increases in bone

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osteoporosis. Osteoporos Int. 2000;11:434-442.

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ARTICLE CONTRIBUTORS

DEBORAH T. ZAREK, MD, Internal Medicine Resident, Christiana Care

Health System-Christiana Hospital, Newark, Del.

JAMES D. KATZ, MD, Assistant Professor of Medicine, Division of

Rheumatology, The Washington University Medical Center, Washington,

DC.

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