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Prevention and treatment of glucocorticoid-induced osteoporosis

Prevention and treatment of glucocorticoid-induced osteoporosis
Authors:
Harold N Rosen, MD
Kenneth G Saag, MD, MSc
Section Editor:
Clifford J Rosen, MD
Deputy Editor:
Katya Rubinow, MD
Literature review current through: Nov 2022. | This topic last updated: Aug 30, 2022.

INTRODUCTION — Glucocorticoid therapy is associated with an appreciable risk of bone loss, which is most pronounced in the first few months of use. In addition, glucocorticoids increase fracture risk, and fractures occur at higher bone mineral density (BMD) values than occur in postmenopausal osteoporosis. The increased risk of fracture has been reported with doses of prednisone or its equivalent as low as 2.5 to 7.5 mg daily [1]. Thus, glucocorticoid-induced bone loss should be treated aggressively, particularly in those already at high risk for fracture (older age, prior fragility fracture). In other individuals, clinical risk factor and bone density assessment may help guide therapy. The prevention and treatment of glucocorticoid-induced bone loss will be reviewed here. The clinical features are reviewed separately. (See "Clinical features and evaluation of glucocorticoid-induced osteoporosis".)

Many of the prevention and treatment strategies for glucocorticoid-induced bone loss are similar to those used to prevent and treat other causes of osteoporosis. (See "Overview of the management of osteoporosis in postmenopausal women" and "Treatment of osteoporosis in men" and "Evaluation and treatment of premenopausal osteoporosis".)

GENERAL MEASURES — In an attempt to minimize bone loss, certain general principles should be followed in all patients receiving any dose of glucocorticoids for a duration of ≥3 months [2-4].

The dose and the duration of glucocorticoid therapy should be as low as possible because even what are thought to be replacement doses or chronic inhaled glucocorticoids can cause bone loss [5]. Alternative therapy should be used whenever possible. (See "Major side effects of inhaled glucocorticoids", section on 'Osteoporosis and fracture risk in adults'.)

Topical therapy (such as inhaled glucocorticoids or glucocorticoid enemas for asthma or bowel disease, respectively) is preferred over enteral or parenteral glucocorticoids, whenever possible.

Patients should do weightbearing exercises to prevent both bone loss and muscle atrophy.

Patients should avoid smoking and excess alcohol.

Patients should take measures to prevent falls.

CALCIUM AND VITAMIN D

Calcium and vitamin D – We agree with the American College of Rheumatology (ACR) Task Force osteoporosis guidelines, which suggest that all patients taking glucocorticoids (any dose with an anticipated duration of ≥3 months) maintain a total calcium intake of 1000 to 1200 mg/day and vitamin D intake of 600 to 800 international units/day through either diet and/or supplements [3]. (See "Calcium and vitamin D supplementation in osteoporosis".)

Glucocorticoids induce negative calcium balance by decreasing intestinal calcium absorption and increasing urinary calcium excretion [6]. Therefore, calcium supplementation may attenuate bone loss in patients taking glucocorticoids. In a meta-analysis of five randomized trials comparing calcium and vitamin D (cholecalciferol or an active vitamin D metabolite) with calcium alone or placebo in patients taking glucocorticoids, there was significant improvement in lumbar spine and radial bone mineral density (BMD) in the calcium and vitamin D group (weighted mean difference between treatment and control groups 2.6 and 2.5 percent, respectively) [7]. The incidence of new, nontraumatic fractures was not significantly different (two trials, odds ratio [OR] 0.6, 95% CI 0.1-2.4).

In one of the larger studies included in the meta-analysis, 96 patients with rheumatoid arthritis receiving low-dose glucocorticoid therapy (mean prednisone dose 5.6 mg daily) were randomly assigned to calcium carbonate (1000 mg of elemental calcium daily) plus vitamin D3 (500 international units/day) or placebo [8]. The between-group difference in the annual rate of change in BMD was 2.65 percent (95% CI 0.73-4.57) and 2.08 percent (95% CI 0.43-3.73) for the spine and trochanter, respectively, favoring calcium and vitamin D supplementation.

Although calcium and vitamin D supplementation is necessary, it is generally not sufficient to prevent bone loss and fracture in patients taking high-dose glucocorticoids [9-12]. Pharmacologic therapy is often required. (See 'Candidates for pharmacologic therapy' below and 'Bisphosphonates' below.)

Active vitamin D metabolites – Vitamin D metabolites that are more active than vitamin D itself, such as calcitriol and alfacalcidol, have been evaluated for the prevention and treatment of glucocorticoid-induced bone loss [13]. Calcitriol (1,25-dihydroxyvitamin D, the most active metabolite of vitamin D) plus calcium protects against spine bone loss more than calcium alone in patients taking glucocorticoids [10,14]. A meta-analysis of five trials of active vitamin D metabolites in patients exposed to corticosteroids reported a beneficial effect of vitamin D metabolites on lumbar spine BMD [13]. There were insufficient data to address fracture prevention.

Active vitamin D metabolites are less commonly used, however, because of the risks of hypercalcemia and hypercalciuria in patients whose urinary calcium excretion is already increased and because more effective therapies are available [15]. The superior efficacy of bisphosphonates compared with an active vitamin D metabolite for preventing glucocorticoid-induced bone loss has been demonstrated in several randomized trials [16-21]. Although not statistically significant, one trial showed that compared with alfacalcidol, fewer patients randomly assigned to alendronate had new vertebral fractures (three versus eight patients) [17]. (See 'Bisphosphonates' below.)

CANDIDATES FOR PHARMACOLOGIC THERAPY — Our approach described below is largely in agreement with various guidelines, which collectively suggest pharmacologic therapy for patients based upon fracture risk. (See 'Guidelines' below.)

Fracture risk assessment — Patients with the highest risk for fracture are the ones most likely to benefit from drug therapy. Thus, selection of patients based upon fracture risk, as determined by a combination of bone mineral density (BMD) and clinical risk factors, is desirable. (See "Clinical features and evaluation of glucocorticoid-induced osteoporosis", section on 'Evaluation'.)

Patients with established osteoporosis (history of fragility fracture or BMD T-score ≤-2.5) are at the highest risk for fracture.

For patients without established osteoporosis, fracture risk can be assessed using a fracture risk calculator, such as the Fracture Risk Assessment Tool (FRAX).

FRAX estimates the 10-year probability of fracture for untreated patients between ages 40 and 90 years, using femoral neck BMD and clinical risk factors, including glucocorticoid exposure. FRAX does not account for glucocorticoid dose or duration, and therefore, FRAX risk estimates must be corrected according to the dose of glucocorticoid [22]. For patients taking prednisolone >7.5 mg/day or equivalent, the risk estimate should be increased by 15 percent for major osteoporotic fracture and by 20 percent for hip fracture [22]. (See "Osteoporotic fracture risk assessment", section on 'Fracture risk assessment tool'.)

In North America, reasonable glucocorticoid-corrected thresholds to indicate high, moderate, and low risk of fracture are as follows [3]:

High risk – A 10-year probability of hip or combined major osteoporotic fracture of ≥3 and 20 percent, respectively

Moderate risk – A 10-year probability of hip or combined major osteoporotic fracture between 1 to 3 percent and 10 to 19 percent, respectively

Low risk – A 10-year probability of hip or combined major osteoporotic fracture of ≤1 and <10 percent, respectively

Some patients receiving glucocorticoids are at high risk, even if they fail to meet the FRAX criteria for high risk. As an example, for patients with clinical risk factors for fracture, low lumbar spine BMD, but normal femoral neck BMD, FRAX is likely to underestimate fracture risk. This situation is especially likely in patients taking glucocorticoids, which are more likely to cause osteoporosis of the spine than of the hip. Thus, intervention guidelines with or without the use of FRAX provide only general clinical guidance. Treatment should remain individualized through shared decision-making between patient and clinician.

Fracture risk assessment, including the FRAX tool and its limitations, is reviewed in detail separately. (See "Osteoporotic fracture risk assessment", section on 'Clinical application of fracture risk assessment' and "Osteoporotic fracture risk assessment", section on 'Limitations'.)

Postmenopausal women and men >50 years — Pharmacologic therapy is indicated for postmenopausal women and men >50 years with moderate to high risk of fracture. (See 'Fracture risk assessment' above.)

For men ≥50 years and postmenopausal women (who are initiating or are chronically treated with any dose of glucocorticoids for any duration) who have osteoporosis (previous fragility fracture and/or a BMD T-score ≤-2.5) at initial assessment, we recommend pharmacologic therapy.

For high-risk men ≥50 years and postmenopausal women who are initiating or are chronically treated with any dose of glucocorticoids for any duration and have T-scores between -1.0 and -2.5, we suggest pharmacologic therapy. A reasonable threshold to indicate high risk in some settings is a glucocorticoid-corrected, FRAX-calculated, 10-year probability of hip or combined major osteoporotic fracture of ≥3 or 20 percent, respectively.

For postmenopausal women and men >50 years with T-scores between -1.0 and -2.5 who have a glucocorticoid-corrected, FRAX-calculated absolute risk below these thresholds, we suggest pharmacologic therapy if they are taking ≥7.5 mg/day of prednisone or its equivalent for an anticipated duration of ≥3 months.

These recommendations are based upon randomized trial data showing that pharmacologic therapy improves BMD in patients taking glucocorticoids [23,24] and additional randomized trial data showing that pharmacologic therapy reduces fracture in men and postmenopausal women with established osteoporosis [25]. (See 'Efficacy' below and "Overview of the management of osteoporosis in postmenopausal women" and "Bisphosphonate therapy for the treatment of osteoporosis" and "Treatment of osteoporosis in men".)

Premenopausal women and younger men — In the absence of definitive data, the decision to initiate pharmacologic therapy should be individualized in premenopausal women and younger men. The FRAX tool was not developed for use in men <40 years or premenopausal women. In premenopausal women and younger men included in clinical trials for glucocorticoid-induced osteoporosis, fractures were generally infrequent in both treated and control groups [12,26-28]. Fracture risk in these patients taking glucocorticoids is not clearly defined and may differ from reported fracture risk in other glucocorticoid-treated populations. In addition, the presence or absence of hypogonadism may influence fracture risk and decisions about nonhormonal pharmacologic therapy.

Hypogonadal patients — Glucocorticoids may increase bone resorption by decreasing secretion of androgens and estrogens, mediated primarily by inhibition of gonadotropin secretion [29]. Therefore, it is logical to replace these hormones in women or men with confirmed hypogonadism, as long as there are no contraindications. (See "Evaluation and management of secondary amenorrhea" and "Management of primary ovarian insufficiency (premature ovarian failure)" and "Testosterone treatment of male hypogonadism".)

Premenopausal women – For premenopausal women of childbearing potential who are taking or initiating glucocorticoids and who are hypogonadal, we suggest some form of estrogen/progestin replacement. We typically choose oral contraceptives (OCs) as women may resume ovulatory cycles when glucocorticoids are tapered and stopped. However, for women who are unable to take OCs (eg, migraine with aura, side effects), standard menopausal doses of estradiol and progesterone can be used. There is no reason to believe, however, that treatment with estrogens will benefit young women with normal ovarian function. (See "Functional hypothalamic amenorrhea: Evaluation and management", section on 'Estrogen replacement'.)

In a cross-sectional study of 119 perimenopausal women with asthma (65 receiving oral glucocorticoids), the asthmatic women who were not taking hormone replacement therapy had lower mean BMD than did non-asthmatics [30]. This observation plus the extensive literature supporting the value of estrogen in the prevention of postmenopausal osteoporosis makes it likely that estrogen therapy can help reduce or reverse bone loss in premenopausal hypoestrogenic women treated with glucocorticoids. (See "Menopausal hormone therapy in the prevention and treatment of osteoporosis", section on 'Efficacy of estrogen therapy'.)

Men – Bisphosphonates are first-line therapy for prevention and treatment of glucocorticoid-induced osteoporosis in men because they are known to reduce fracture risk. Men who develop symptomatic hypogonadism should also be treated with testosterone for its benefits on muscle, energy, and libido, as well as on bone [31,32]. A number of testosterone preparations are available for the treatment of testosterone deficiency. (See "Treatment of osteoporosis in men", section on 'Hypogonadism' and "Testosterone treatment of male hypogonadism", section on 'Choice of testosterone regimen'.)

Eugonadal patients — In the absence of definitive data, pharmacologic therapy should be individualized in eugonadal men and women. We generally treat such patients if they are at moderate to high risk for fracture. (See 'Fracture risk assessment' above.)

Potential short- and long-term risks, as well as potential effects on the fetus, should be considered as part of the decision to use bisphosphonates or teriparatide for the treatment of premenopausal osteoporosis. Effective contraception should be used. (See 'Choice of therapy' below and "Epidemiology and etiology of premenopausal osteoporosis" and "Evaluation and treatment of premenopausal osteoporosis".)

For premenopausal women who do not need estrogen replacement therapy because they have normal ovarian function and who have a fragility fracture while receiving glucocorticoids, we suggest pharmacologic therapy.

For similar women who do not have a fragility fracture but have accelerated bone loss (≥4 percent/year) or Z-score <-3 while receiving glucocorticoids (7.5 mg prednisone equivalent for ≥3 months), we also suggest pharmacologic therapy.

For men <50 years of age who have a fragility fracture while receiving glucocorticoids, we suggest pharmacologic therapy.

For similar men who do not have a fragility fracture but have accelerated bone loss (≥4 percent/year) or Z-score <-3 while receiving glucocorticoids (7.5 mg prednisone equivalent for ≥3 months), we also suggest pharmacologic therapy.

We also suggest pharmacologic therapy for men <50 years and premenopausal women taking prednisone >30 mg/day for >1 month.

CHOICE OF THERAPY

Men and postmenopausal women – For pharmacologic therapy for men and postmenopausal women, we favor bisphosphonates as first-line therapy. We prefer alendronate or risedronate because of clinical trial data demonstrating efficacy in men and women with glucocorticoid-induced osteoporosis. For such patients who cannot tolerate oral bisphosphonates or who have difficulty with the dosing requirements or adherence, intravenous (IV) zoledronic acid is an acceptable alternative. (See 'Bisphosphonates' below and "Bisphosphonate therapy for the treatment of osteoporosis", section on 'Oral regimen' and "Bisphosphonate therapy for the treatment of osteoporosis", section on 'IV regimen'.)

We typically reserve parathyroid hormone (teriparatide, PTH) for patients with severe osteoporosis (T-score of -3.5 or below even in the absence of fractures or a T-score of -2.5 or below plus a fragility fracture). In addition, teriparatide is an option for patients who are unable to tolerate any of the available bisphosphonates or who continue to fracture after one year of bisphosphonate therapy. (See 'Parathyroid hormone' below.)

Denosumab is also an alternate therapeutic option for those at high risk for fracture. However, due to the increased risk of vertebral fracture after discontinuation of denosumab, the need for a careful "exit strategy" if denosumab is stopped should be discussed with patients prior to its initiation. (See 'Other pharmacologic therapy' below.)

Premenopausal women – For premenopausal women with fractures or accelerated bone loss who do not need estrogen replacement therapy because they have normal ovarian function, bisphosphonates are generally the drugs of choice (see 'Bisphosphonates' below). Teriparatide is an alternative option for such women, as long as epiphyses are fully fused (see 'Parathyroid hormone' below). Potential short- and long-term risks, as well as potential effects on the fetus, should be considered as part of the decision to use bisphosphonates or teriparatide for the treatment of premenopausal osteoporosis. (See "Evaluation and treatment of premenopausal osteoporosis" and "Evaluation and treatment of premenopausal osteoporosis".)

We do not typically prescribe denosumab for the prevention or treatment of glucocorticoid-induced osteoporosis in premenopausal women. (See 'Other pharmacologic therapy' below.)

EFFICACY

Bisphosphonates — There are substantial data supporting the use of antiresorptive agents, such as the bisphosphonates, for the prevention and treatment of glucocorticoid-induced bone loss. In a meta-analysis of 27 randomized trials evaluating bisphosphonates (alone or in combination with calcium and vitamin D) versus calcium and vitamin D (alone or with placebo) for the prevention and treatment of glucocorticoid-induced osteoporosis, there was significant improvement in lumbar spine (absolute difference 3.5 percent) and femoral neck bone mineral density (BMD) (absolute difference 2.1 percent) in the bisphosphonate group [24]. There was a reduction in the risk of new vertebral fracture with bisphosphonates (44 versus 77 per 1000 persons in the bisphosphonate and no treatment groups, respectively, risk ratio [RR] 0.57, 95% CI 0.35-0.91). The reduction in risk of nonvertebral fracture did not reach statistical significance (42 versus 55 per 1000 persons, RR 0.79, 95% CI 0.47-1.33).

Few premenopausal women were included in the large clinical trials [24], and fractures were generally infrequent in both treated and control groups [12,26,27]. Two small clinical trials that included premenopausal women with corticosteroid-treated connective tissue diseases (CTD) used the less potent first-generation bisphosphonate, etidronate, as the antiresorptive agent and found successful maintenance of BMD in the women taking the drug [33,34].

The therapeutic efficacy of bisphosphonates in patients with glucocorticoid-induced osteoporosis has been thought to be related to their ability to promote osteoclast apoptosis (programmed cell death) [35]. However, glucocorticoids may negate the pro-apoptotic effect of bisphosphonates, suggesting that these drugs may prevent glucocorticoid-induced bone loss by prolonging the lifespan of osteoblasts [35,36].

Alendronate – The efficacy of alendronate in patients receiving glucocorticoid therapy was demonstrated in a study of 477 patients age 17 to 83 years who were randomly assigned to receive one of two doses of alendronate or placebo [12]. The mean BMD of the lumbar spine increased by 2.1 and 2.9 percent over 48 weeks in the patients receiving 5 and 10 mg of alendronate daily, respectively, while decreasing 0.4 percent in the placebo group. Femoral neck, trochanter, and total body BMD also increased significantly in the alendronate groups (figure 1). Those receiving alendronate had fewer new vertebral fractures compared with placebo (2.3 versus 3.7 percent), although fracture was not a primary outcome. These benefits were maintained for two years [37]. Once-weekly alendronate (70 mg) similarly improves BMD [38], and in a retrospective cohort study, alendronate was associated with a significantly lower risk of hip fracture in older patients taking oral prednisolone [39].

RisedronateRisedronate is also effective for the prevention and treatment of osteoporosis, including glucocorticoid-induced osteoporosis [11,40,41]. In a one-year study of risedronate versus placebo in 290 patients receiving glucocorticoids (prednisone ≥7.5 mg/day for six or more months), lumbar spine and femoral neck BMD increased by 2.7 and 1.8 percent, respectively, in the risedronate group, as compared with no change in the placebo group [40]. The relative risk of vertebral fracture (a secondary outcome) was reduced by 70 percent.

Zoledronic acid – The efficacy of zoledronic acid for the prevention and treatment of glucocorticoid-induced osteoporosis was demonstrated in a one-year, randomized trial of IV zoledronic acid (5 mg once) or daily oral risedronate (5 mg) in 288 patients who recently started glucocorticoids (prevention group) and 545 patients who had been taking them for more than three months (treatment group) [42]. In an analysis of patients who received the study drug and had baseline and follow-up BMD measurements, zoledronic acid and risedronate increased mean BMD of the lumbar spine in both the prevention (2.6 and 0.6 percent, respectively) and treatment (4.1 and 2.7 percent, respectively) groups. The study was not designed to evaluate fractures, which occurred in three and five subjects in the risedronate and zoledronic acid groups, respectively.

During the first three days, the occurrence of adverse events (predominantly arthralgias, fever, and flu-like symptoms) was greater in the zoledronic acid group. (See "Risks of bisphosphonate therapy in patients with osteoporosis", section on 'Risks specific to intravenous bisphosphonates'.)

Other bisphosphonates – Oral and IV pamidronate have been shown to prevent glucocorticoid-induced bone loss [9,43-45]. However, pamidronate is rarely used now that zoledronic acid is available.

There are few data evaluating the efficacy of oral ibandronate for the prevention and treatment of glucocorticoid-induced osteoporosis. However, IV ibandronate appears to preserve BMD. In an open-label, randomized trial of ibandronate (2 mg IV every three months for two years) versus alfacalcidol (1 mcg daily) in 104 patients with established glucocorticoid-induced osteoporosis, IV ibandronate resulted in superior improvements in spine, femoral neck, and calcaneal BMD compared with alfacalcidol (between-group differences of 9.7, 3.4, and 7.9 percent, respectively) [18]. These improvements were sustained in a third year of treatment, and there were fewer vertebral fractures (a secondary outcome) in the ibandronate group compared with the alfacalcidol group (8.6 versus 22.8 percent) [19].

Parathyroid hormone — Parathyroid hormone (teriparatide, PTH) is generally not used as a first-line drug for treatment or prevention of glucocorticoid-induced osteoporosis, because of its cost, subcutaneous route of administration, and the availability of other agents. However, PTH is an option for the treatment of glucocorticoid-induced osteoporosis in men or postmenopausal women who:

Have severe osteoporosis (T-score of -3.5 or below even in the absence of fractures; T-score of -2.5 or below plus a fragility fracture) before initiating glucocorticoids

Have osteoporosis (T-score below -2.5) who are unable to tolerate oral or IV bisphosphonates, or who have relative contraindications to bisphosphonates (achalasia, scleroderma esophagus, esophageal strictures)

Fail other osteoporosis therapies (fracture with loss of BMD in spite of compliance with therapy)

Teriparatide is also an option for premenopausal women, as long as epiphyses are fully fused, who have fragility fractures or accelerated bone loss (≥4 percent/year) while receiving glucocorticoids (7.5 mg prednisone equivalent for ≥3 months) and who do not need estrogen replacement therapy because they have normal menstrual function.

Due to the lack of proven efficacy beyond two years, a single course of teriparatide in most patients is limited to two years duration. Treatment with an antiresorptive agent (eg, bisphosphonates) after PTH preserves the gains in BMD achieved with PTH. Thus, for patients who receive teriparatide as initial treatment and who remain at high risk for fracture after discontinuation, a bisphosphonate should be started after PTH is discontinued. (See "Parathyroid hormone/parathyroid hormone-related protein analog therapy for osteoporosis".)

PTH stimulates bone formation as well as resorption, and intermittent administration stimulates formation more than resorption. Because the predominant effect of glucocorticoids on the skeleton is to reduce bone formation and bisphosphonates (antiresorptive agents) do not address this mechanism of bone loss, treatment with PTH is theoretically a more appealing approach [46].

In randomized trials, PTH is effective in improving BMD in patients treated with glucocorticoids [23,47-49]. As an example, in an 18-month, randomized trial of alendronate (10 mg orally daily) versus PTH 1-34 (teriparatide, 20 mcg subcutaneously daily) in 428 men and women who had taken glucocorticoids for ≥3 months (≥5 mg of prednisone equivalent daily), both treatments significantly increased BMD. However, teriparatide was associated with a greater increase in lumbar spine (8.2 versus 3.9 percent), total hip (3.8 versus 2.4 percent), and femoral neck (4.4 versus 2.8 percent) BMD [23]. There was no difference in the incidence of nonvertebral fractures, a secondary outcome (5.6 versus 3.7 percent), but there were fewer new radiographic vertebral fractures (1 versus 10) in subjects randomly assigned to teriparatide compared with alendronate. Thirty percent of subjects in each treatment group discontinued the study prior to completion. There was more nausea and insomnia in the teriparatide group and more rashes in the alendronate group.

The trial was designed to have an 18-month continuation phase, with prespecified secondary outcomes that included BMD, fractures, and adverse events at 36 months [47]. After 36 months (n = 241 subjects), increases in BMD from baseline remained significantly greater in the teriparatide group (11 versus 5.3, 5.2 versus 2.7, and 6.3 versus 3.4 percent for lumbar spine, total hip, and femoral neck, respectively). New vertebral fractures occurred significantly less often in patients receiving teriparatide (3 versus 13 in the alendronate group). The majority of vertebral fractures occurred in the first 18 months. There was no difference in the incidence of nonvertebral fractures.

Premenopausal women with glucocorticoid-induced osteoporosis also benefit from treatment with teriparatide [23]. In a secondary analysis of the randomized trial of teriparatide versus alendronate in patients with glucocorticoid-induced osteoporosis, the increase in lumbar spine BMD was significantly greater in the teriparatide group for both premenopausal (7.0 versus 0.7 percent) and postmenopausal (7.8 versus 3.7 percent) women [26]. In premenopausal women, fractures were infrequent in both treatment groups.

Abaloparatide, a synthetic analog of parathyroid hormone-related protein (PTHrP) has not been evaluated as a treatment for glucocorticoid-induced osteoporosis. Its use for osteoporosis of other etiologies is reviewed in detail elsewhere. (See "Parathyroid hormone/parathyroid hormone-related protein analog therapy for osteoporosis".)

Other pharmacologic therapy

Denosumab – We do not typically prescribe denosumab for the prevention or treatment of glucocorticoid-induced osteoporosis. Denosumab may be beneficial in some patients with glucocorticoid-induced osteoporosis [50-52]. However, emerging data have raised concern about increased risk of vertebral fracture after discontinuation of denosumab, and the need for a careful "exit strategy" if denosumab is stopped should be discussed with patients prior to its initiation. If denosumab is discontinued, administering an alternative therapy (typically a bisphosphonate) to prevent rapid bone loss and vertebral fracture is strongly advised. (See "Denosumab for osteoporosis", section on 'Increased vertebral fractures'.)

Denosumab is a monoclonal antibody to an osteoclast differentiating factor. It inhibits osteoclast formation, decreases bone resorption, increases BMD, and reduces the risk of fracture. It has been used in postmenopausal women and in men undergoing androgen deprivation therapy for prostate cancer. (See "Denosumab for osteoporosis" and "Side effects of androgen deprivation therapy", section on 'Denosumab'.)

In a noninferiority trial evaluating denosumab versus risedronate in 505 patients receiving glucocorticoids for ≥3 months and 290 patients who were initiating glucocorticoids (<3 months), the increase in lumbar spine BMD was greater with denosumab (4.4 versus 2.3 percent for glucocorticoid continuing and 3.8 versus 0.8 percent for glucocorticoid initiating) [50,51]. There was no difference in adverse events, including the incidence of fracture (osteoporosis-related fractures, 7 and 6 percent, respectively; new and worsening vertebral fractures in postmenopausal women, 5 percent in each group). Denosumab also increased BMD in a prospective, observational study of 36 patients treated with glucocorticoids for pulmonary disease [53].

Romosozumab – There are no data about the use of romosozumab, an anabolic based on an antibody to sclerostin, for the prevention or treatment of glucocorticoid osteoporosis. Its use for osteoporosis is reviewed in detail elsewhere. (See "Overview of the management of osteoporosis in postmenopausal women", section on 'Romosozumab'.)

Calcitonin – We do not use calcitonin for the treatment or prevention of glucocorticoid-induced osteoporosis, because more effective drugs (eg, bisphosphonates, teriparatide) are available for the prevention of bone loss and reduction of fracture risk. Another concern is that the long-term use of calcitonin for osteoporosis has been associated with an increase in cancer rates. (See "Calcitonin in the prevention and treatment of osteoporosis", section on 'Concerns about the use of calcitonin'.)

MONITORING — There are several published guidelines for monitoring the response to osteoporosis therapy. Although all recommend follow-up bone mineral density (BMD) testing, there is no consensus on the optimal frequency of monitoring and the preferred site to monitor. (See "Overview of the management of osteoporosis in postmenopausal women", section on 'Monitoring'.)

We typically measure BMD (dual-energy x-ray absorptiometry [DXA]) of the lumbar spine and hip at the initiation of glucocorticoid therapy and after one year.

BMD stable or improved – If BMD is stable or improved, we measure it less frequently (every two to three years) thereafter. If glucocorticoids are discontinued and BMD is stable, measurement at five-year intervals may be sufficient.

BMD decreased – The finding of a BMD decrease greater than the least significant change or a new fracture in a treated patient should trigger additional evaluation for contributing factors, which may include poor adherence to therapy, inadequate gastrointestinal absorption, inadequate intake of calcium and vitamin D, or the development of a disease or disorder with adverse skeletal effects. Switching from oral bisphosphonates to intravenous (IV) zoledronic acid may be effective in patients with poor absorption or poor compliance with the oral regimen. Alternative options for patients who fail oral bisphosphonate therapy are similar to those for patients with osteoporosis in general. (See "Overview of the management of osteoporosis in postmenopausal women", section on 'Bone mineral density decreased or fracture during therapy'.)

There may be a significant increase in bone density after discontinuation of exogenous glucocorticoid therapy or reversal of endogenous Cushing's syndrome [54,55]. One study, as an example, examined spine BMD after successful treatment for Cushing's disease in 20 patients, all of whom had marked osteoporosis of lumbar spine and femoral neck [54]. There was no change in BMD for six months, the time required for gradual reversal of increased osteoclastic activity, after which BMD increased. However, patients who have had a fracture may have permanent deformity.

GUIDELINES — The American College of Rheumatology (ACR) guidelines recommend intervention based upon risk of fracture (high, medium, low), guided in part by the Fracture Risk Assessment Tool (FRAX) [3,56]. FRAX is reviewed in detail elsewhere. (See "Osteoporotic fracture risk assessment", section on 'Fracture risk assessment tool' and "Treatment of osteoporosis in men", section on 'Candidates for therapy' and "Overview of the management of osteoporosis in postmenopausal women", section on 'Patient selection'.)

For adults ≥40 years, low, medium, and high risk are defined as follows [3,56]:

Low risk – 10-year risk of hip or a major osteoporotic fracture of ≤1 and <10 percent, respectively

Medium risk – 10-year risk of hip or a major osteoporotic fracture >1 to <3 percent and 10 to 19 percent, respectively

High risk – History of a fragility fracture, a lumbar spine or hip T-score below -2.5, or 10-year risk of hip or a major osteoporotic fracture ≥3 and 20 percent, respectively

For adults <40 years, low, medium, and high risk are defined as follows [3,56]:

Low risk – No medium- or high-risk factors other than glucocorticoid treatment

Medium risk – Hip or spine Z-score <-3, or rapid bone loss (≥10 percent over one year) and continuing glucocorticoid treatment at ≥7.5 mg/day for ≥6 months

High risk – History of a fragility fracture

In addition to lifestyle modification and calcium and vitamin D supplementation, the ACR guidelines recommend oral bisphosphonates for adults at medium or high risk of major fracture. If oral bisphosphonates contraindicated or not tolerated, options include intravenous (IV) bisphosphonates, teriparatide, denosumab, and raloxifene. For premenopausal women of childbearing potential, confirm there are no plans for pregnancy during the period of osteoporosis treatment and that effective contraception is utilized.

The patient should be followed yearly to determine if bone loss continues. An exercise program should also be initiated, although this may be limited by restrictions from the underlying illness. (See "Overview of the management of osteoporosis in postmenopausal women", section on 'Exercise'.)

Other published guidelines largely agree with the recommendations above, except for some minor differences:

The National Osteoporosis Guideline Group in the United Kingdom recommends using FRAX (adjusted for glucocorticoid dose) to determine assessment thresholds (fracture probabilities for bone mineral density [BMD] testing) and intervention thresholds (fracture probabilities for therapeutic intervention) [57,58]. In general, antiresorptive therapy should be initiated at the time of starting glucocorticoids in patients at highest risk for fracture (eg, ≥70 years of age, history of prior fragility fracture, or taking large doses of glucocorticoids [ie, ≥7.5 mg prednisolone/day]). Good nutrition, adequate dietary calcium intake, and a bisphosphonate are recommended as therapy. Alendronate or risedronate are the preferred bisphosphonates because of efficacy and low cost.

The International Osteoporosis Foundation and the European Calcified Tissue Society recommend osteoporosis therapy in postmenopausal women and men who are ≥70 years, have a previous fragility fracture, or a dose of prednisolone ≥7.5 mg daily (or its equivalent) for ≥3 months [59,60]. For those at highest risk, bone protective therapy should be started at the onset of glucocorticoid therapy. For patients who do not meet these criteria, fracture risk should be assessed using FRAX with intervention thresholds based upon country-specific population fracture risks and health economic assessments and corrected for glucocorticoid exposure. For premenopausal women and men <50 years of age who are taking glucocorticoids for ≥3 months, osteoporosis therapy is considered for those with a history of a fragility fracture. For all others, treatment decisions are individualized based upon patient characteristics and clinical judgement.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Osteoporosis".)

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Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Osteoporosis (The Basics)" and "Patient education: Calcium and vitamin D for bone health (The Basics)")

Beyond the Basics topics (see "Patient education: Osteoporosis prevention and treatment (Beyond the Basics)" and "Patient education: Calcium and vitamin D for bone health (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

In an attempt to minimize bone loss, glucocorticoid dose and the duration of therapy should be as low and as short as possible, respectively, because even replacement doses can cause bone loss. Patients should be encouraged to do weightbearing exercises for protection against both bone loss and muscle atrophy. Patients should avoid smoking and excess alcohol and take measures to prevent falls. (See 'General measures' above.)

For all patients receiving any dose of chronic glucocorticoid therapy or initiating glucocorticoids with an anticipated duration of ≥3 months, we suggest calcium and vitamin D supplementation (Grade 2B). Most individuals require 1200 mg of elemental calcium daily, total diet plus supplement, and 800 international units of vitamin D daily. (See 'Calcium and vitamin D' above.)

For men ≥50 years and postmenopausal women with established osteoporosis (T-score ≤-2.5 or fragility fracture) who are receiving or are about to initiate glucocorticoids (any dose for any duration), we recommend pharmacologic therapy (Grade 1B). (See 'Postmenopausal women and men >50 years' above.)

For high-risk men ≥50 years and postmenopausal women who are initiating or are treated with any dose of glucocorticoids for any duration and who have T-scores between -1.0 and -2.5, we suggest pharmacologic therapy (Grade 2B). A reasonable threshold to indicate high risk in some settings is a glucocorticoid-corrected, Fracture Risk Assessment Tool (FRAX)-calculated, 10-year probability of hip or combined major osteoporotic fracture of ≥3 or 20 percent, respectively. For postmenopausal women and men >50 years who have a FRAX-calculated absolute risk below these thresholds, we suggest pharmacologic therapy if they are taking ≥7.5 mg/day of prednisone or its equivalent for an anticipated duration of ≥3 months (Grade 2C). (See 'Postmenopausal women and men >50 years' above.)

In the absence of definitive data, the decision to initiate pharmacologic therapy should be individualized in premenopausal women and younger men through shared decision-making between patient and clinician. (See 'Premenopausal women and younger men' above and "Evaluation and treatment of premenopausal osteoporosis".)

Glucocorticoids may increase bone resorption by decreasing secretion of androgens and estrogens, mediated primarily by inhibition of gonadotropin secretion. Therefore, it is logical to replace these hormones (as long as there are no contraindications) in premenopausal women or men with confirmed hypogonadism. (See 'Hypogonadal patients' above.)

For premenopausal women who do not need estrogen replacement therapy because they have normal ovarian function and who have a fragility fracture while receiving glucocorticoids, we suggest pharmacologic therapy (Grade 2B). For similar women who do not have a fragility fracture but have accelerated bone loss (≥4 percent/year) or Z-score <-3 while receiving glucocorticoids (7.5 mg prednisone equivalent for ≥3 months), we also suggest pharmacologic therapy (Grade 2C). (See 'Premenopausal women and younger men' above.)

For men <50 years of age who have a fragility fracture while receiving glucocorticoids, we suggest pharmacologic therapy (Grade 2B). For similar men who do not have a fragility fracture but have accelerated bone loss (≥4 percent/year) or Z-score <-3, while receiving glucocorticoids (7.5 mg prednisone equivalent for ≥3 months), we also suggest pharmacologic therapy (Grade 2C). (See 'Premenopausal women and younger men' above.)

For men and postmenopausal women who are candidates for pharmacologic therapy, we suggest bisphosphonates over other available agents as first-line therapy (Grade 2B). We prefer weekly oral alendronate or risedronate over other oral bisphosphonates because of clinical trial data demonstrating efficacy in women and men with glucocorticoid-induced osteoporosis. Intravenous (IV) zoledronic acid is an option for patients unable to tolerate oral bisphosphonates or who have difficulty with the dosing requirements or adherence to oral therapy. (See 'Choice of therapy' above and 'Bisphosphonates' above.)

Parathyroid hormone (teriparatide, PTH) is generally not used as a first-line drug for treatment or prevention of glucocorticoid-induced osteoporosis, because of its cost, subcutaneous route of administration, and the availability of other agents. However, for the prevention or treatment of glucocorticoid-induced osteoporosis in men or postmenopausal women with osteoporosis (T-score below -2.5) who are unable to tolerate any of the available bisphosphonates, we suggest PTH over other available therapies (Grade 2B). Other candidates for PTH include patients with severe osteoporosis (T-score of -3.5 or below even in the absence of fractures or a T-score of -2.5 or below plus a fragility fracture) and patients who fail other osteoporosis therapies (fracture with loss of bone mineral density [BMD] in spite of compliance with therapy). Denosumab is also an alternate therapeutic option for those at high risk for fracture. However, due to the increased risk of vertebral fracture after discontinuation of denosumab, the need for a careful "exit strategy" if denosumab is stopped should be discussed with patients prior to its initiation. (See 'Choice of therapy' above and 'Parathyroid hormone' above and 'Other pharmacologic therapy' above.)

For premenopausal women of childbearing potential who are candidates for pharmacologic therapy, we suggest bisphosphonates as first-line therapy (Grade 2B). Teriparatide is an alternative option for such women, as long as epiphyses are fully fused. (See 'Bisphosphonates' above and 'Parathyroid hormone' above and "Evaluation and treatment of premenopausal osteoporosis".)

For premenopausal women of childbearing potential, confirm there are no plans for pregnancy during the period of osteoporosis treatment and that effective contraception is utilized. It is important to consider the potential for harm to the fetus in women who become pregnant and are currently receiving teriparatide or who are currently receiving or were recently treated with bisphosphonates. (See "Evaluation and treatment of premenopausal osteoporosis".)

We typically measure BMD at the initiation of glucocorticoid therapy and after one year. If BMD is stable or improved, we measure BMD less frequently (every two to three years) thereafter. (See 'Monitoring' above and "Overview of the management of osteoporosis in postmenopausal women", section on 'Monitoring'.)

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