Prevention and Treatment of Glucocorticoid-Induced Osteoporosis

Prevention and Treatment of Glucocorticoid-Induced Osteoporosis* A Pathogenetic Perspective Cesar R. Libanati, M.D.; and David J Baylink, M.D.

Since the discovery of cortisol and the synthesis of related compounds, these potent pharmacologic agents have been progressively more widely utilized in allergic, pulmonary, and rheumatologic conditions. Organ transplantation represents a new group of patients added to the already large pool of subjects receiving g1ucocorticoids. However, g1ucocorticoids cause major side effects involving several organ systems, including the cardiovascular, endocrine, gastrointestinal, ophthalmologic, and musculoskeletal systems. Among the most dramatic side effects is the development of glucocorticoid-induced osteoporosis. Glucocorticoid use

in the treatment of chronic obstructive pulmonary disease accounts for the majority of male patients with osteoporosis seen in our mineral metabolism clinic. This article focuses on glucocorticoid-induced osteoporosis in the adult with an emphasis on the clinical aspects of this condition. It is intended not as an extensive review on the subject but as a practical guide to help clinicians prevent and treat this condition iD adult patients. (Chat 1992; 102:1426-35)

gl originally described the clinical effects of C ushin hypercortisolemia. In the skeletal system, in-

steroid-induced osteoporosis is unknown but studies suggest that as many as 50 percent of patients with Cushing syndrome or patients receiving exogenous glucocorticoids will suffer atraumatic fractures because of significant bone loss.5,6

creased cortisol results in osteopenia from accelerated bone loss that leads to spontaneous fractures. Similarly, prolonged administration of pharmacologic doses of synthetic glucocorticoids results in clinically significant bone loss. Bone loss secondary to glucocorticoids is more severe in trabecular bone than in corticol bone and as a result, the most frequent atraumatic fractures complicating glucocorticoid therapy are those of the vertebral bodies and ribs," These fractures eventually result in skeletal deformities (ie, dorsal kyphosis) that may complicate the patient's primary condition (ie, chronic obstructive pulmonary disease) as well as cause severe pain. Indeed, in our clinic, the most severe skeletal symptoms are seen in patients with chronic obstructive pulmonary disease treated with prednisone. It is generally accepted that the larger the prednisone daily dose (above 7.5 mg/day) or cumulative dose (over 10 g) and the longer the treatment, the greater the bone loss.3,4 Additionally, subjects with high bone remodeling rates are at higher risk of developing severe bone loss when steroid therapy is added. Thus children, perimenopausal women, and patients with other forms of high-turnover osteoporosis (ie, immobilization-induced osteoporosis) are more adversely affected by concomitant steroid use. The incidence of

*From the Department of Medicine, Lorna Linda University and Jerry L. Pettis Memorial VA Hospital, Lorna Linda, Calif. Supported in part by the Veterans Administration and grant AR 40614 from the National Institutes of Health, Bethesda, Md. Manuscript received September 16, 1991; revision accepted March 11. 1426

=

15 OH-D, 15-hydroxycholecalciferol; IRMA radiometric assay; PTH parathyroid hormone

=

=immuno-

PATHOGENESIS

The biochemical mechanisms of glucocorticoidinduced bone loss is thought to involve a combination of effects on several organs. Suggested mechanisms of glucocorticoid-induced bone loss include direct effects on bone cells, alterations in calcium absorption and renal handling of calcium, and abnormalities in the secretion of sex hormones. In this article, we propose a pathogenetic model as a basis for a rational approach to the prevention and treatment of glucocorticoidinduced osteoporosis. Figure 1 details the proposed pathogenetic model responsible for bone loss even with glucocorticoid treatment. Bone loss is rapid in response to glucocorticoid therapy since both arms of bone volume regulation may be negatively affected (ie, bone. resorption is increased and bone formation is decreased'), The enhanced bone resorption probably results from at least two mechanisms. First and most importantly, glucocorticoids result in secondary hyperparathyroidism." The measurable rise in immunoreactive serum parathyroid hormone (PTH) is presumably the consequence of (1) decreased net intestinal calcium absorption" and (2) increased urinary calcium excretion," both of which tend to lower serum calcium levels and thus increase PTH. Glucocorticoids may also directly stimulate PTH release. II Whatever the causes of the increased PTH, it can be suppressed by calcium infusion," and parathyroidectomy in animals Pnw8ntion and Treatment of Glucocorticoid-induced Osteoporosis (Ubanati, Bay/ink)

GWCOCORTICOID

t

~ MUSCLE STRENGTH

I t BONE

t SERUM PI'H

t

RESORPTION

~

I

BONE FORMATION

I ~

BONE VOWME

abolishes the excessive bone resorption induced by glueocorticoids," emphasizing the importance of PTH in the enhanced bone resorption seen with glucocorticoid treatment. It is also possible that glucocorticoidinduced reduction of circulating levels of estrone" may contribute to increased bone resorption. The effect of glucocorticoids to decrease bone formation appears to be more complex and can be attributed to at least three major mechanisms. First, glucocorticoids directly inhibit collagen production by bone cells. This may be a consequence of reduced bone cell production of insulin-like growth factors. IS Second, glucocorticoids may have a systemic action to reduce bone formation by reducing serum levels of testosterone, a potent bone anabolic agent, in both male and female patients. 16 Third, decreased physical activity due to glucocorticoid-induced myopathy may further depress bone formation. 17 To summarize, glucocorticoid-induced osteoporosis is the result ofboth increased resorption and decreased formation and, as shown in Figure 1, we can identify the major underlying mechanisms that are, most likely, responsible for these adverse skeletal changes. From this perspective, we can provide a rational approach to prevention and treatment of this problem. MANAGEMENT

Because there is a paucity of controlled, prospective studies on the ability of any therapeutic regimen to prevent or treat glucocorticoid-induced osteoporosis,

FIGURE 1. Model of mechanisms of bone loss in glucocorticoid-induced osteoporosis.

no guidelines are available for the management of this condition despite the widespread use of glucocorticoids. Noone would argue that we can afford to continue to administer glucocorticoids to patients and witness osteoporosis develop without at least attempting to prevent the bone loss. Until therapeutic modalities are validated by prospective clinical trials, we must attempt to prevent this complication of glucocorticoid treatment in a safe and logical manner. Accordingly, our recommendations are a logical extension of our understanding of the described pathogenetic model. Interventional algorithms along with corresponding diagnostic approaches are described below and outlined in Figures 2 and 3. General Recommendations When Prescribing Glucocorticoids

Ideally, all patients should receive the lowest possible glucocorticoid dose and glucocorticoid supplementation should be limited to the shortest possible time. In practice, however, a large number of patients require chronic steroid supplementation. In the past, glucocorticoid therapy was almost exclusively administered to patients suffering from pulmonary ailments such as chronic obstructive pulmonary disease and asthma or to patients suffering from rheumatologic conditions such as rheumatoid arthritis and systemic lupus erythematosus. Currently there is, in addition, a large population at risk for severe glucocorticoidinduced osteoporosis as a result of organ transplantaCHEST I 102 I 5 I NOVEMBER, 1992

1427

GLUCOCORTICOID TREATMENT and OSTEOPENIAQ or BONE LOSS GREATER THAN ZERO (as determined by serial bone density)

<-===-=-z=====a

EXERCISE~, REASSESS EVERY 12 MONTHS

>

NO CORRECTIVE REGIMEN SAME AS PREVENTIVE REGIMEN PLUS FLUORIDE, OR ANABOLIC AGENT/ANDROGEN (See text)

PREVENTIVE

(See Figure 3)

lions. 18 Although recommended to decrease many deleterious systemic side effects of glueocorticoids, alternateday scheduling will not prevent bone loss.19 Whenever possible, the use of inhaled glucocorticoids should be favored over oral glucocorticoids. However, inhaled glucocorticoids, particularly when used in high doses, may affect bone turnover negatively and result in bone IOSS.20.21 To our knowledge, there are no data on the long-term effects of high-dose inhaled glucocorticoids on bone mass. The development of corticosteroids with bone-sparing effects such as deflazacorr" is promising; however, such compounds are not routinely available in the United States. In summary, (1) avoid glucocorticoids if possible, (2) whenever possible use inhaled instead of systemic glucocorticoids, (3) if systemic glucocorticoids are needed, use the lowest effective dose and limit the cumulative prednisone dose to less than 10 g, and (4) use glucocorticoids for the least amount of time possible. Approach to the Patient Receiving Glucocorticoid Therapy

Approximately 50 percent of patients receiving glucocorticoids will experience bone loss and develop osteoporosis. We cannot, however, predict accurately which patients will suffer clinically significant bone loss. Thus, one may either apply preventive measures to all patients receiving long-term glucocorticoid therapy or attempt to assess the risk for each patient. We recommend measurement of baseline bone density in all patients receiving glucocorticoids. Bone density is the pivotal diagnostic parameter because bone 1428

REGIMEN

FIGURE 2. Proposed diagnostic and therapeutic algorithms for glucocorticoid-induced osteoporosis. (0) We recommend that bone density be performed in all patients receiving glucocorticoid therapy If obtaining a bone density measurement in all patients is not possible, then at least those patients considered at greater risk for glucocorticoid-induced osteoporosis as described in the text should undergo bone mass determination. (P) In addition to exercise, patients may receive calcium supplements once the presence ofhypercalciuria has been excluded.

MEASURE SERUM 25 OH VITAMIN D, (if low or low normal administer VITAMIN D 50,000 unite daily for one month)

IS THERE HYPERCALCIURIA? (urine calcium > than 180mq/day on a low calcium diet)

....---> I..._~_-

CLOSELY MONITOR FOR HYPERCALCEMIA AND HYPERCALCIURIA

BONE RESORPTION REMAINS INCREASED? (urine OH-proline or OH-proline/creatinine ratio above noraal)

ESTROGENQ OR CALCITONIN OR DIPHOSPHONATES

EXERCISE PROGRAM, REASSESS EVERY 6 MONTHS

FIGURE 3. Preventive regimen. (0) Estrogen should be considered for all perimenopausal women without contraindications. (P) Ideally these patients may also receive ca1citriol. However, we caution against the use of thiazides and calcitriol in combination because severe hypercalcemia may develop (see text for details).

Prevention and Treatment of Glucocorticoid-induced Osteoporosis (Ub.natJ, Bayllnk)

Table I-Factors Auociated with Increaaed Rillefor DevelopingClinictJlly Significant Bone Loa Secondary to GlucocorticoidAdminiltration in Adulta Factors Large glucocorticoid dose (greater than 7.5 mg of prednisone daily) Prolonged glucocorticoid therapy (cumulative dose greater than 10 g of prednisone) Preexisting osteopenia (as detennined by bone mass measured at the spine or at the hip) Age greater than 50 years old Perimenopausal status Family history of osteoporosis Presence of established risk factors for osteoporosis

strength is largely determined by the bone density. 23,24 Either dual-energy roentgenographic absorptiometry or quantitative computed tomography may be used to quantitate bone density.2,2:5 We favor quantitative computed tomography because it measures vertebral trabecular bone density and provides an estimate of fracture risk24 and, as we mentioned earlier, glucocorticoids induce trabecular bone loss preferentially. On the other hand, dual-energy roentgenographic absorptiometry has the advantage of measuring bone density at the hip, an area of clinical importance. If a baseline bone density measurement cannot be obtained in all glucocorticoid-treated patients, bone density measurements should be considered at least for patients at high risk for developing clinically significant bone loss when treated with glucocorticoids (Table 1). Once the bone density measurement is obtained, further therapeutic recommendations are as follows. Patients with normal bone density are encouraged to maintain a regular exercise program and are reexamined at yearly intervals. Patients with osteopenia (bone density less than that expected for age but above the putative absolute density level below which fragility fractures are likely to occur) should receive preventive therapy Patients with osteoporosis (presence of fragility fractures or bone density below the putative absolute density level below which fragility fractures are likely to occur) should receive corrective therapy In summary, assess the bone density in patients receiving glucocorticoid therapy to determine if osteopenia is present and institute a preventive or corrective therapeutic regimen, respectively. Both preventive and corrective therapies are described below Preventive Regimen

We propose that the prevention of glucocorticoidinduced bone loss should focus on correcting the enhanced bone resorption. This proposal is based on the following two factors. First, one can infer that in glucocorticoid-induced osteoporosis, the increase in bone resorption is probably a quantitatively more important determinant of net bone loss than the

decrease in bone formation. Accordingly, in glucocorticoid-induced osteoporosis, despite a decrease in bone formation (which would tend to increase the serum calcium level), the serum PTH level is elevated because of a slight decrease in the serum calcium and the net result is a state of secondary hyperparathyroidism. Thus, the increase in bone resorption may be greater than the decrease in bone formation. Second, we have available today many more drug therapies to reduce bone resorption than we have available to stimulate bone formation. The goal of our preventive regimen is to halt bone loss by preventing the increase in bone resorption. We accomplish this objective by approaching the patient via defined algorithms (Fig 3). These algorithms help determine and correct the prevailing pathogenetic mechanism of enhanced bone resorption secondary to glucocorticoid therapy Serum 25-hydroxycholecalciferol (25 OH-D3) , urine and serum calcium, serum PTH, and urine hydroxyproline are obtained serially to make rational therapeutic decisions as described below These biochemical assays allow us to effectively and safely tailor our therapeutic recommendations to the patient. Correcting Any Vitamin D Deficiency: Vitamin D deficiency results from decreased vitamin D 2 intake or from decreased exposure to sunlight. Thus, those patients at risk for vitamin D deficiency include elderly patients and patients living in northern latitudes. Mild vitamin D de6ciency causes osteoporosis, whereas severe vitamin D deficiency causes osteomalacia. Serum 25 OH-D3 is a measure of vitamin D status. We always evaluate and correct for vitamin D de6ciency as a first step. This must be done 6rst because vitamin D de6ciency will influence the subsequent evaluations described below including urine calcium determinations and urine calcium absorption. Glucocorticoid therapy does not increase the risk of vitamin D deficiency; rather, this is a routine approach for all osteoporoses prevention programs. If the serum 25 OU-D3 level is low or low normal, we administer ergocalciferol 50,000 international units daily for one month. This replacement therapy will replenish the vitamin D body stores and correct any possible calcium malabsorption due to vitamin D de6ciency. Once any vitamin D deficiency has been recognized and treated adequately, we proceed to diagnose and treat the major pathogenetic effects of glucocorticoid therapy (ie, the effect of glucocorticoids on urinary calcium excretion and on intestinal calcium absorption). First we evaluate the effect of glucocorticoid on urinary calcium excretion. Evaluating for Hypercalciuria: We evaluate for hypercalciuria before attempting any other therapeutic manipulations in patients receiving glucocorticoids because administration of calcium supplements or of CHEST I 102 I 5 I NOVEMBER, 1992

1429

calcitriol to patients with hypercalciuria could result in greater urinary calcium levels and increased risk for nephrolithiasis. We determine if glucocorticoidinduced hypercalciuria is present by measuring 24-h urine calcium levels while the patient is placed on a "low" calcium diet (ie, a diet without dairy products or added calcium). This baseline urine calcium measurement is aimed at identifying urine calcium leak as a major pathogenetic mechanism for glucocorticoidinduced bone loss. The 24-h urine calcium excretion should be less than 180 mg/day in either sex on such a diet. 26 If hype rcalciuria is detected, it can be corrected by means of thiazide administration. Thiazides are effective in lowering the urine calcium level because they stimulate calcium reabsorption in the distal tubule." The administration of 25 mg of hydrochlorothiazide daily usually suffices to correct the urinary calcium leak. Occasionally higher doses (50 or 75 mg) may be needed. Longitudinal studies have shown that thiazide users have diminished rates of bone 10ss28 and recent epidemiologic evidence suggests that thiazide can reduce the rates of osteoporotic fractures. 29 ,30 These data may be of clinical relevance to glucocorticoidtreated patients. Indeed, it is possible that if one did nothing more than add a low dose of thiazide, it might be possible to have a positive impact on glucocorticoidinduced osteoporosis. Administration of calcium supplements before a urinary calcium leak is corrected should be avoided because it can worsen the hypercalciuria. Patients without hypercalciuria can be given calcium supplements safely. In such patients, we admin-

ister calcium to achieve a total calcium intake of at least 1,500 mg/day. Unfortunately, there are no available means of quantifying calcium absorption in clinical practice, making it very difficult to make precise recommendations regarding optimal calcium intake or calcium preparations. A discussion of the potential benefits of a particular form of calcium is beyond the scope of this article. As a general rule, we favor calcium preparations that readily dissolve when placed in water or vinegar and encourage our patients to try that simple "home test" of solubility. Optimizing Calcium Absorption: The next step is to measure serum PTH levels. We measure the serum PTH because, based on our pathogenetic model, once any urinary calcium leak has been corrected, an elevated PTH level reflects inadequate intestinal calcium absorption. For measurement of serum PTH levels, the IRMA method is preferable because it measures intact PTH and therefore reflects biologically active PTH. Most serum PTH levels will fall within nonnallimits and elevations of PTH are rare in patients receiving 7.5 mg of prednisone or less daily. A "normal" PTH 1430

level, however, does not assure the euparathyroid state for a given individual. Thus, it is possible that in some patients, PTH will be increased above the basal level but still be within the normal range. Thus, a diagnosis of secondary hyperparathyroidism could be missed if it were based solely on a serum PTH level elevated above the upper normal limit. A serum PTH drawn before prescribing glucocorticoids or measured during a period free of glucocorticoid supplementation provides a useful baseline for interpretation of repeated serum PTH measurements. If the PTH is elevated above the normal range or above the baseline value, therapeutic interventions are initiated in order to prevent the PTH-dependent increase in bone resorption. These interventions depend on whether a particular patient had shown prior hypercalciuria. Therapeutic recommendations for (1) patients who have a high PTH level and who do not have preexisting hypercalciuria, and (2) patients who have a high PTH level and who are taking a thiazide for correction of preexisting hypercalciuria are described in the next two paragraphs. For patients who have an elevated PTH level, did not have preexisting hypercaliuria, and are not taking a thiazide diuretic, we recommend calcitriol to increase calcium absorption. This rationale assumes that calcium absorption has remained inadequate despite a total calcium intake of at least 1,500 mg/day and takes advantage of the fact that calcitriol is highly effective in enhancing intestinal calcium absorption. Glucocorticoid therapy does not decrease serum calcitriol but instead diminishes calcitriol's action to stimulate intestinal calcium absorption. For this rea-

son, calcitriol supplementation can correct this untoward effect of glucocorticoid therapy There is no known way of establishing an optimum dosage of calcitriol since there is no routine test for calcium absorption. A reasonable approach is to start with the lowest available dose (0.25 fJ-g/day). Serum PTH levels may be followed and calcitriol doses adjusted in order to document a reduction of PTH level to normal. The administration of calcitriol can be hazardous since a significant number of patients may develop hypercalcemia and/or hypercalciuria while receiving calcitriol. Toavoid such untoward effects, we monitor serum and urine calcium levels routinely in our patients at frequent intervals (ie, every two to three months). (These urine calcium measurements aim at identifying patients at risk for nephrolithiasis as a side effect of our therapy and should be performed without changing the diet or amount of calcium supplementation the patient is receiving. Urine calcium should be maintained below 300 mg/day in men and below 250 mg! day in women, since these values represent the upper normal limits for urine calcium excretion in patients without nephrolithiasis. Values above those levels Prevention andTreatment of Glucocorticoid-induced Osteoporosis (Ubanatl, Say/Ink)

require adjustment of the above-mentioned medications.) For patients who have an elevated PTH level and who are taking thiazides for correction of preexisting hypercalciuria, we administer calcium supplements sequentially to increase the 24-h urine calcium excretion to a value that approaches, but does not exceed, 300 mg/day in men and 250 mg/day in women. On a nonrestricted diet, urine calcium excretion above those limits results in increased risk for nephrolithiasis.31,32 This approach is based on past studies showing that the greater the calcium intake (and the greater the amount of calcium absorbed), the more calcium will be spilled through the kidneys.26,33 Increased oral calcium intake will result in a greater amount of calcium absorbed. This will decrease the serum PTH level and, consequently; a greater amount of calcium will be excreted in the urine. We increase the amount of calcium supplementation and monitor the calcium excretion to prevent urinary calcium spillage above the mentioned limits. Our goal is to correct the secondary hyperparathyroid state by enhancing the amount of calcium absorbed in the gut while maintaining the urine calcium below the level at which nephrolithiasis may develop. Accordingly these patients need follow-up of their serum PTH level as well as their serum and urine calcium. (See parenthetical information at the end of the previous paragraph.) Alternatively one may argue that similar results could be achieved by administering calcitriol to this patient group. However, we caution against the use of both drugs (calcitriol and thiazides) in combination. The combination of thiazide and calcitriol is potentially dangerous because calcitriol will maximize calcium absorption through the gut and the thiazide will prevent any excessive calcium from being cleared through the urine. As a result of those effects, the serum calcium level may increase to hypercalcemic levels. In addition to close monitoring, if a patient does receive both calcitriol and a thiazide, we recommend using a five days on/two days off schedule for the thiazide to allow for a cc safety period" during which any increased filtered load of calcium may be excreted effectively through the kidney This may help prevent the development of hypercalcemia. Assessing the Need for Other Antimsorbers: At this point, the patient should have a normal serum PTH level. Bone resorption may remain increased despite instituting the above-mentioned therapeutic recommendations and despite achieving a normal PTH level. Indeed, our pathogenetic model shows that in glucocorticoid-treated patients, mechanisms other than increased PrH levels, such as sexual hormone deficiencies, may further contribute to increased bone resorption. In order to assess the need for other antiresorbers, we need to quantitate bone resorption.

This can be done by measuring urine hydroxyproline levels. Hydroxyproline is an amino acid found almost exclusively in collagen and, during collagen turnover, it is released into the serum and cleared from the body in the urine. Urine hydroxyproline is an accepted marker for bone resorption. A 24-h urine hydroxyproline concentration expressed per unit of creatinine provides a useful index of the bone resorption rate. 34 Because dietary hydroxyproline is rapidly absorbed in the intestine and excreted into the urine, patients should be placed on a diet free of collagen-containing foods for the day before and the day of the urine collection. Alternatively adequate information without dietary restrictions can be obtained by measuring urine hydroxyproline/creatinine ratio in a second AM void sample (the first AM void eliminates all dietary hydroxyproline contribution, thus obviating the need for dietary restrictions). If the urine hydroxyproline! creatinine ratio remains elevated for age and sex, additional therapeutic measures may be considered; for example, estrogen (conjugated estrogens 0.625 mg to 0.9 mg daily), calcitonin (50 to 100 IU SC or 1M every other day), diphosphonates (etidronate disodium 400 mg daily for two weeks followed by 12 weeks ofl), or anabolic hormones (see below). Estrogen supplementation is encouraged in all perimenopausal women without contraindications not only because of its effect on bone but also because of the proven beneficial effects on cardiovascular risk. 35 In summary, by means of a stepwise approach, the preventive regimen aims at the following: (1) replenishing vitamin D body stores if needed; (2) evaluating and correcting glucocorticoid-induced hypercalciuria to prevent consequent increase in PTH level; (3) optimizing intestinal calcium absorption if PrH level remains elevated; and (4) utilizing additional antiresorbers once PrH level is normalized if bone resorption remains increased as assessed by urine hydroxyproline/creatinine ratio. Patients are reexamined every six months (or at shorter intervals in subjects at risk for hypercalcemia or hypercalciuria). Bone densities should be repeated at regular intervals (ie, every 12 months). Ifbone loss is documented from serial bone density measurements, therapeutic manipulations are reassessed. Additionally, as a general preventive measure, in every osteoporosis program, we encourage a regular exercise program. Walking at least a mile a day and upper body exercises such as lifting weights with each hand over the head while standing erect are examples of safe and effective exercises. Caution should be taken to avoid upper body exercises that involve flexion of the spine in osteopenic patients inasmuch as this may place excessive strain on the anterior vertebral axis and result in spine fractures. The expertise and CHEST /102 / 5 / NOVEMBER, 1992

1431

assistance of a qualified physical therapy program is of great value. We emphasized earlier that to our knowledge, there are no controlled studies that show that the above regimens will prevent glucocorticoid-induced bone loss. However, there is no reason to believe they may not be effective. With careful monitoring, our recommended approach is safe. Therefore, we believe our preventive protocol has an acceptable risklbenefit ratio. Consequently, we should no longer accept the morbid skeletal side effects seen with glucocorticoid therapy as a necessary price to pay for the use of a lifesaving drug. Corrective Therapy In patients with established osteoporosis, we need not only suppress the elevated PTH and normalize bone resorption, but we must also employ agents that stimulate bone formation. Ifwe sought only to prevent further bone loss, the most we could expect would be to maintain the current bone density level which, by definition in the osteoporotic patient, is insufficient to withstand the mechanical stresses of daily activities. To prevent atraumatic fractures associated with osteoporosis, it is necessary to increase bone density and this can be achieved only through a significant increase in the rate of bone formation. There are currently only two types of pharmacologic agents available that can increase bone density satisfactorily; these are the fluorides and the anabolic steroids. The following sections offer guidelines for the use of those two agents. It seems possible that both of these agents act to increase bone formation despite the effects of glucocorticoid therap~36.37 Corrective Therapy Using Fluoride: (A) Patient Selection: We treat all patients with glucocorticoidinduced osteoporosis with fluoride despite conflicting reports in the literature and despite a recent study that failed to demonstrate a decrease in the vertebral fracture rate in response to fluoride therapy" Our data show that patients who are responders to fluoride (ie, the bone density increases significantly) have a statistically significant lower vertebral fracture rate than those who are poor responders or nonresponders,39 and that large increments in bone density can be achieved in glucocorticoid-induced osteoporosis despite concomitant glucocorticoid use.P' Although fluoride is still considered an experimental drug in the United States, the use of fluoride for the treatment of osteoporosis has been approved in Austria, Belgium, France, Germany, Luxembourg, Norway, Switzerland, and the Netherlands. Thus, at this time, our position is that fluoride is an effective agent in the treatment of glucocorticoid-induced osteoporosis and that it should be administered to patients with glucocorticoid-induced osteoporosis unless contraindicated. 1432

Contraindications to fluoride use include severe renal Insufficiency, osteomalacia, active peptic or duodenal ulcer, and pregnancy (8) Fluoride Dose: Patients with glucocorticoidinduced osteoporosis should receive fluoride at a dose of 15 to 30 mg of elemental fluoride Per day in divided doses. This fluoride dose will provide a morning fasting serum fluoride level of 0.20 mgIL which has been shown effective for increasing bone formation..f() Patients with decreased renal function require lower fluoride doses to achieve that serum fluoride level. Because the side effects of fluoride are dose related (see below), we recommend starting with a low fluoride dose and increasing the dose of fluoride as tolerated. Fluoride is commercially available as sodium fluoride for oral administration as a dietary supplement for the prevention of dental caries in children. Tablets containing 2.2 mg of sodium fluoride are generically available (2.2 mg of sodium fluoride contain 1 mg of elemental fluoride). A convenient preparation (Florical) contains 8.3 mg of sodium fluoride (approximately 3.7 mg of elemental fluoride) and 364 mg of calcium carbonate. (C) Monitoring the Effect of Fluoride on Bone: Fluoride is believed to increase bone density by acting directly on osteoblasts, the cells responsible for bone formation, to promote proliferation and differentiation." We rely on serum alkaline phosphatase measurements and on bone density measurements to evaluate the skeletal response to Iluortde." Serum alkaline phosphatase activity significantly correlates with the rate of bone formation in the absence of liver dysfunction. 43 •44 An increase in the serum alkaline phosphatase value precedes the measurable increase in bone density seen in responders to fluoride therapy. Because, in fluoride-treated patients, the level of alkaline phosphatase and the degree of osteomalacia correlate; it has been recommended that fluoride and calcium doses be adjusted so that the increase in alkaline phosphatase does not exceed 50 percent of the baseline value. Increases larger than 50 percent should caution about the possibility of too much fluoride or too little calcium being administered. Using this approach, we have been able to increase trabecular bone density to normal levels in some patients with glucocorticoid-induced osteoporosis. 36 In addition to serum alkaline phosphatase, osteocalcin has the potential to be used to monitor the effects of therapies on bone formation. Osteocalcin is a noncollagenous protein specific to bone tissue. It is produced by osteoblasts and its serum level is a sensitive marker of bone turnover. 45 •46 Serum osteocalcin is depressed during glucocorticoid therapy" and may be measured to assess the response to therapeutic agents." At present, there is limited experience with serial osteocalcium determinations in response to fluoride therPnMntion and Treatment of Glucocorticoid-induced Osteoporosis (Ubanati, Bay/ink)

ap)'. Additionally, we monitor bone density at yearly intervals. (D) Duration of Fluoride Therapy: The duration of fluoride therapy depends both on the severity of the osteoporosis at the start of treatment and on the rate of increase in bone density. The goal of the therapy is to return bone density to a value above the absolute putative fracture threshold level (ie, lumbar trabecular bone density of 100 mg/cu em in women as measured by quantitative computed tomography). Four to five years of fluoride therapy are required to accomplish that goal in the average osteoporotic patient whose pretreatment vertebral trabecular bone density measured by quantitative computed tomography is approximately 60 mg/cu em. The average rate of increase in trabecular bone density in response to fluoride therapy is 10 mg/cu em/year, Because of the large interpatient variation in the response to fluoride, the duration of therapy may vary. As a general rule, the greater the bone density deficit, the longer the period of therapy needed to correct it. According to the literature, almost 20 percent of aU osteoporotic patients treated with fluoride do not respond with an increase in bone density In our experience, the percentage of nonresponders to fluoride in glucocorticoid-induced osteoporotic patients is less than 10 percent and, the rate of bone density increase with fluoride therapy may also be increased in glucocorticoid-induced osteoporosis. (E) Fluoride Side Effects: Side effects of fluoride therapy are mainly gastrointestinal irritation and osteoarticular lower extremity pain. Both side effects appear to be dose related. Gastrointestinal irritation is common with plain sodium fluoride but can frequently be overcome by giving fluoride after meals or by using a combination of sodium fluoride and calcium carbonate. Enteric-coated or slow-release preparations produce less gastrointestinal side effects but are not generally available. In patients receiving nonsteroidal anti-inflammatory drugs, fluoride should be used with caution as the two drugs in combination may contribute to peptic ulceration. Transient osteoarticular pain involving the knees, ankles, or feet occurs in 20 to 40 percent of patients treated with fluoride and is easily reversed by temporary discontinuation of fluoride therapy or a reduction of the fluoride dose. Another concern is the possibility that fluoride increases the risk for appendicular stress fractures. 49 To date, no statistical difference has been observed in hip fracture incidence between fluoride-treated patients and control subjects in large longitudinal studies. 38 •50 Corrective Therapy Using Anabolic Steroids: Both male and female patients become androgen deficient

in response to glucocortieoids." Androgens and anabolic steroids have been shown to increase bone mass in other osteoporoses,51 probably by decreasing bone resorption and increasing bone formation. Thus, the use of these agents should be considered in both sexes for the treatment of glucocorticoid-induced osteoporosis.

(A) lbtient Selection: Female patients with glucocorticoid-induced osteoporosis who are unable to receive fluoride therapy should be considered for anabolic steroid therapy and male patients with concurrent androgen deficiency who are unable to receive fluoride therapy should be considered for testosterone cypionate (Depo-Testosterone) therapy. Lipid changes are always a concern in patients receiving androgens, particularly if other cardiac risk factors are present. Contraindications to the use of androgens or anabolic steroids include severe cardiac or hepatic disease, hyperlipidemias, prostate cancer, and pregnancy. (8) Pharmacologic Form and Dose: Unfortunately, to our knowledge, there are no clinical studies addressing an appropriate or effective dose. In male patients we use depot preparations of testosterone and aim at obtaining preinjection serum testosterone levels that are near the lower normal limit and postinjection serum levels that remain within the normal range. In order to accomplish this, testosterone cyplomate at a dose of 50 to 100 mg needs to be injected every two to three weeks. Few patients require 200 mg of testosterone cyplomate. In female patients, we favor nandrolone phenpropionate because this agent tends to cause less virilization and less liver dysfunction than the other anabolic agents and thus is better tolerated. A dose of 50 mg given intramuscularly every three weeks has proven effective in increasing bone mass at the radius in osteoporotic women.P

(C) Side Effects ofAnabolic Steroids: Male patients receiving androgens should be closely monitored for the development of carcinoma of the prostate. This is of major concern and we recommend pretreatment and yearly urologic evaluations as well as serum acid phosphatase and prostatic specific antigen determinations every six months in male patients receiving testosterone. Female patients prescribed anabolic steroids should be advised about the potential cosmetic side effects such as acne, facial hirsutism, and lowering of the voice. Metabolic side effects such as a negatively altered lipid profile (increased total cholesterol) and liver enzyme elevation may force discontinuation of therapy In summary, patients with established osteoporosis should receive therapy aimed at correcting the bone mineral deficit. These therapies are at present limited to fluoride or anabolic steroids and ideally should be administered in osteoporosis centers. CHEST I 102 I 5 I NOVEMBER, 1992

1433

Management of lbin from an Osteoporotic Fracture

We see a large number of patients who developed acute back pain from an osteoporotic fracture while receiving glucocorticoids in consultation. In these patients, in addition to the above-mentioned protocols, we use calcitonin injections for up to six months as this agent has analgesic properties53 as well as antiresorptive action. After skin testing for allergy, calcitonin is injected intramuscularly at a dosage of 100 IU every day. In some patients, calcitonin-induced nausea may require that lower doses be used initially: CONCLUSIONS AND PERSPECTIVES

Until other forms of therapy become available to treat chronic pulmonary, allergic, and rheumatologic conditions, or until bone-sparing glucocorticoids are available, up to 50 percent of patients will develop osteoporotic fractures from glucocorticoid therapy: The prevention and treatment programs described herein should help prevent the dramatic skeletal side effects of long-term glucocorticoid therapy: Although both bone formation and bone resorption are negatively affected by glucocorticoids, both classes of effects may be corrected through therapeutic interventions. For those patients who fail the described regimens, referral to a mineral metabolism or osteoporosis clinic may be beneficial. ACKNOWLEDGMENTS: We thank Drs. Philip Gold, John Farley, and John Jennings for their lcind review of the manuscript and their multiple valuable suggestions. REFERENCES

1 Cushing H. The basophile adenomas of the pituitary body and their clinical manifestations. Bull Johns Hoplcins Hosp 1932; 50:131-95 2 Seeman E, Wagner H~ Offord K~ Kumar R, Johnson WJ, Riggs BL. Differential effects of endocrine dysfunction on the axial and appendicular skeleton. J Clio Invest 1982; 69: 1302-09 3 Dykman TR, Gluck OS, Murphy WA, Hahn 1}, Hahn BH. Evaluation of factors associated with glucocorticoid induced osteopenia in patients with rheumatic diseases. Arthritis Rheum 1985; 28:361-68 4 Nagant de Deuxchaisnes C, Devogelaer J~ Esselincb ~ Bouchez B, Depresseux G, Rombouts-Lindemans C, et al.The effect of low dosage glucocorticoids on bone mass in rheumatoid arthritis: a cross-sectional and a longitudinal study using single photon absorptiometry Adv Exp Med Bioi 1984; 171:209-39 5 Ross EJ, Linch DC. Cushings syndrome-killing disease: discriminatory value of signs and symptoms aiding early diagnosis. Lancet 1982; 2:646-49 6 Adinoff AD, Hollister JR. Steroid induced fractures and bone loss in patients with asthma. N Engl J Med 1983; 309:265-68 1 Bressot C, Meunier PJ, Chapuy MC, Lejeune E, Edouard C, Darby AJ. Histomorpbometric profile, pathophysiology and reversibility of corticosteroid-induced osteoporosis. Metab Bone Dis Relat Res 1919; 1:303-11 8 Fucik RF, Kukreja SC, Hargis GK, Bowser EN, Henderson WJ, Williams GA. Effect of glucocorticoids on function of the parathyroid gland. J Clio Endocrinol Metab 1915; 40:152-55 9 Klein RG, Arnaud SB, Gallagher JC, DeLuca HF, Riggs BL. Intestinal calcium absorption in exogenous hypercortisonism:

1434

role of 25-hydroxyvitamin D and corticosteroid dose. J Clin Invest 1977; 60:253-59 10 Suzuki Y, Ichikawa Y, Saito E, Homma M. Importance of increased urinary calcium excretion in the development of secondary hyperparathyroidism of patients under glucocorticoid the~ Metabolism 1983; 32:151-56 11 Au WY. Cortisol stimulation of parathyroid hormone secretion by rat parathyroid glands in organ culture. Science 1916; 193:1015-11 12 Lukert B~ Adams JS. Calcium and phosphorus homeostasis in man: effect of corticosteroids. Arch Intern Med 1916; 136:124953

13 Jee WSS, Pack HZ, Roberts WE, Kenner GH. Corticosteroid and bone. Am K Anat 1910; 129:477-99 14 Crilly RG, Cawwod M, Marsba1l DH, Nordin BE. Hormonal status in normal, osteoporotic and corticosteroid-treated postmenopausal women. J R Soc Med 1918; 71:133-36 15 McCarthy TL, Centrella M, Canalis E. Cortisol inhibits the synthesis of insulin-like growth factor I in skeletal cells. Endocrinology 1990; 126:1569-15 16 MacAdams MR, White RU, Chipps BE. Beduction of serum testosterone levels during chronic glucocorticoid the~ Ann Intern Med 1986; 104:648-51 11 Asbri A, Vignos PJ Jr, Moskowitz RW Steroid myopathy in connective tissue disease. Am J Med 1916; 61:485-92 18 Julian B, Laskow D, Dubovsky J, Dubovsky E, Curtis J, Quarles LD. Rapid loss of vertebral mineral density after renal transplantation. N Engl J Med 1991; 325:544-50 19 Gluck OS, Murphy WA, Hahn T], Hahn B. Bone loss in adults receiving alternate day glucocorticoid therapy: a comparison with daily the~ Arthritis Rheum 1981; 24:892-98 20 Ali NJ, Capewell S, Ward MJ. Bone turnover during high dose inhaled corticosteroid treatment. Thorax 1991; 46:160-64 21 Reid OM, Nicoll JJ, Smith MA, Higgins B, Tothill ~ Nuki G. Corticosteroids and bone mass in asthma; comparisons with rheumatoid arthritis and polymyalgia rheumatica. BMJ 1986; 293:1463-66 22 Gennari C, Imbimbo B, Montagnani M, Bernini M, Nardi ~ Avioli L~ EfJects of prednisone and deflazacort on mineral metabolism and parathyroid activity in humans. Calcif TISsue Int 1984; 36:245-52 23 Hoi SL, Slemenda C~ Johnston CC Jr. Baseline measurements of bone mass predicts fracture in white women. Ann Intern Med 1989; 111:355-61 24 Odvina Wergedal JE, Libanati CR, Schulz EE, Baylink DJ. Relationship between trabecular vertebral body density and fractures: a quantitative definition of spinal osteoporosis. Metabolism 1988; 31:221-28 25 Schaadt 0, Bohr H. Loss ofbone mineral in axial and peripheral skeleton in aging, prednisone treatment and osteoporosis. In: Dequeker ~ Johnston CC, eds. Non-invasive bone measurements: methodological problems. Oxford: IRL Press, 1982; 2(1114 26 Pack CYC, Data M, Lawrence EC, Snyder W The hypercalciurias: causes, parathyroid function and diagnostic criteria. J Coo Invest 1974; 54:381-400 27 Costanzo LS. Localization of diuretic action in microperfused rat distal tubules: Ca and Na transport. Am J Physiol 1985; 248:F527-35 28 Wasnich R, Davis J, Ross ~ \bgel J. Effect of thiazide on rates of bone mineral loss: a longitudinal stud~ BMJ 1990; 301:130305 29 Felson OT, Sloutskis D, Anderson JJ, Anthony JM, Kiel DJ! Thiazide diuretics and the risk of hip fracture: results from the Framingham Stud~ JAMA 1991; 265:370-13 30 LaCroix AZ, Wienpahl J, White LR, Wallace RB, Scherr PA, George LK, et ale Thiazide diuretic agents and the incidence of

cv

Pnwention and 1htatmentof Glucocorticoid-in 08te0p0r08is (UbanatJ. Baylink)

hip fracture. N Eng) J Moo 1990; 322:286-90 31 Hodgkinson A, Pyrah LN. The urinary excretion of calcium and inorganic phosphate in 344 patients with calcium stones of renal origin. Br J Surg 1958; 46:10-8 32 Coe FL, Davalach AG. Hypercalciuria and hyperuricosuria in patients with calcium nephrolithiasis. N Eng) J Med 1974; 291:1344-50 33 Broadus AE, Dominguez M, Bartter FC. Pathophysiological studies in idiopathic hypercalciuria: use of an oral calcium tolerance test to characterize distinctive hypercalciuria subgroups. J Clin Endocrinol Metab 1978; 47:751-60 34 Hodgkinson A, Thompson T. Measurement of the fasting urinary hydroxyproline: creatinine ratio in nonnal adults and its variation with age and sex. J Clin Pathol 1982; 35:807-11 35 Bush TL, Barrett-Connor E, Cowan LD, Criqui MH, Wallace RB, Suchindran CM, et ale Cardiovascular mortality and noncontraceptive use of estrogen in women: results from the lipid research clinics program follow-up stud}'. Circulation 1987; 75:1102-09 36 Odvina cv Wergedal JE, Baylinlc DJ. Glucocorticoid-induced osteoporosis. In: Uthoff HR, Jaworski ZFG, OOs. Current concepts of bone fragilit}'- Berlin: Springer-Verlag, 1986: 295-309 37 Albright F, Reifenstein EC. Metabolic bone disease: osteoporosis. In: The parathyroid glands and metabolic bone disease selected studies. Baltimore: Williams & Willdns Co, 1948: 16581 38 Riggs BL, Hodgson SF, O'Fallon M, Chao EYS, Wahner H~ Muhs JM, et ale Effect ofOuoride treatment on the fracture rate in postmenopausal women with osteoporosis. New Eng) J Moo 1990; 322:802-09 39 Farley SM, Wergedal JE, Farley JR, Javier GN, Schulz EE, Ubanati CR, et ale Fluoride decreases spinal fracture rate: a study of over 500 patients. In: Overgaard K, Christiansen C, eds. Osteoporosis 1990. Denmark: Handelstryldceriet Aalborg ApS, 1990; 3:1330-34 40 Van Kesteren RG, Duursma SA, Visser WJ, van der Sluys ~ Backer Dirks o. Fluoride in serum and bone during treatment of osteoporosis with sodium 8uoride, calcium, and vitamin D. Metab Bone Dis Rei Res 1982; 4:31-7 41 Farley JR, Wergedal JE, Baylink DJ. Fluoride directly stimulates proliferation and alkaline phosphatase activity of bone fonning

cells. Science 1983; 222:330-32 42 Farley SMG, Wergedal J, Smith ic, Lundy M~ Farley JR, Baylink DJ. Fluoride therapy for osteoporosis: characterization of the skeletal response by serial measurements of serum alkaline phosphatase activit}'- Metabolism 1987; 36:211-18 43 Lauffenburger T, Olah AJ, Dambacher J, Guncaga J, Lentner C, Haas HG. Bone remodeling and calcium metabolism: a correlated histomorphometric, calcium kinetic, and biochemical study in patients with osteoporosis and Paget's disease. Metabolism 1977; 26:589-606 44 Clark 1£, Beck E. Serum alkaline phosphatase and growth in adolescent children. J Pediatr 1950; 36:335-41 45 Brown J~ Delmas PD, Malaval L, Eduaord C, Chapuy MC, Meunier PJ. Serum bone Gia-protein: a speciRc marker for bone formation in postmenopausal osteoporosis. Lancet 1984; 1:1091-

93 46 Uan JB, Gundberg CM. Osteocalcin: biochemical considerations and clinical applications. Clin Orthop 1988; 226:267-91 47 Hodsman A, Toogood J, Jennings B, Fraher L, Baskerville J. Differential etrects of inhaled budesonide and oral prednisolone on serum osteocalcin. J Clin Endocrinol Metab 1991; 72:530-40 48 Deftos LJ, Parthemore JG, Price PA. Changes in plasma bone Gia protein during treatment of bone disease. CalcifTissue Int 1982; 34:121-24 49 Hedlund LR, Gallagher JC. Increased incidence of hip fracture in osteoporotic women treated with sodium fluoride. J Bone Miner Res 1989; 4:223-25 50 Mamelle N, Meunier PJ, Dusan R, Guillaume M, Martin JL, Gaucher A, et ale Risk-benefit ratio of sodium 8uoride treatment in primary vertebral osteoporosis. Lancet 1988; 2:361-65 51 Need AG. Corticosteroids and osteoporosis. Aust N Z J Med 1987; 17:267-72 52 Gennari C, AgnusDei D, Gonnelli S, Nardi ~ Effects of nandrolone decanoate therapy on bone mass and calcium metabolism in women with established postmenopausal osteoporosis: a double-blind placebo-controlled study. Maturitas 1989; 11:187-97 53 Pecile A, Ferris S, Braga PC, Olgiati VR. Effects ofintracerebroventricular calcitonin in the concious rabbit. Experientia 1975; 31:332-33

CHEST I 102 I 5 I NOVEMBER. 1992

1435