Treatment and Prevention of Glucocorticoid-Induced Osteoporosis

Low bone mineral density^a

Advanced age^a

Female sex^a

Prior history of fragility (low-trauma) fracture^a

Glucocorticoid use^a,b

Low body mass index^a

Parental history of hip fracture^a

Cigarette smoking^a,b

Excess alcohol consumption^a,b

Medical comorbidities^a,c

Caucasian or Asian ethnicity

Calcium or vitamin D deficiency

Reduced mobility or fall history

Dementia

Frailty or poor health

Medications including antiandrogen drugs

^aIncluded in the World Health Organization’s Fracture Risk Assessment Tool (FRAX equation)

^bThe FRAX equation does not account for dose or duration of exposure

^cIncluding rheumatoid arthritis, inflammatory bowel disease, celiac disease, cystic fibrosis, hyperthyroidism, diabetes, and renal disease

Bone mineral density is expressed as a “T-score,” the standard deviation difference between the patient’s score and that of a reference population of young adults. Those with T-scores < −2.5 have osteoporosis and are at greatest risk of fracture. Those with T-scores between −1.0 and −2.5 have osteopenia and are at an increased, though somewhat lower, risk of fracture than those with osteoporosis. There are more patients with osteopenia than osteoporosis, and more fragility fractures occur in that group as a result. Overall, most fragility fractures occur in patients with T-scores greater than −2.5 [26]. For this reason, strategies for identifying patients at risk of fracture must be comprehensive and should not rely solely on measurement of bone mineral density.

To help determine which patients are at risk, the World Health Organization developed a Fracture Risk Assessment Tool (FRAX) to predict the probability of hip and major osteoporotic fracture (including hip, spine, proximal humerus, and forearm) over a 10-year period for untreated patients between ages 50 and 90. To estimate this risk, the FRAX equation uses the aforementioned clinical risk factors and the femoral neck bone mineral density, as measured by dual-energy x-ray absorptiometry (DXA). The calculation is based on data from large prospective studies and has been validated in 11 independent cohorts.

The FRAX is a useful screening and clinical assessment tool, but due to several limitations, it may under- or overestimate the risk of fracture in some patients. Some of these limitations, which include failure of the FRAX tool to take into consideration the dose and duration of glucocorticoid exposure, are listed in a position statement by the International Society for Clinical Densitometry [27]. While the FRAX tool can be used to help identify patients with an elevated risk of fracture, it provides only general guidance; treatment decisions should be made on an individual basis, incorporating the full range of unique risk factors for a specific patient.

63.5 Candidates for Pharmacologic Osteoporosis Therapy

Those at highest risk of fracture are most likely to benefit from pharmacologic therapy. Cost-effectiveness modeling has been performed in various populations to determine the 10-year fracture probability threshold at which treatment becomes cost-effective [28–31]. Such models consider the morbidity and cost associated with osteoporotic fracture treatment and prevention and use generally accepted cost per quality-adjusted life year (QALY) thresholds. Treatment recommendations by the American College of Rheumatology (reviewed below) and other organizations are based on this type of modeling and are summarized in Fig. 63.1.

Fig. 63.1

Recommendations for fracture prevention in postmenopausal women and men over age 50 initiating glucocorticoid therapy

63.5.1 Established Osteoporosis

Patients with bone mineral density T-scores < −2.5 or a history of previous fragility fracture at the time of initial assessment have osteoporosis and are at high risk of repeat fracture. Such patients should be treated with bisphosphonates whether or not they are exposed to glucocorticoids.

63.5.2 Prevention of Osteoporosis

Postmenopausal women and men >50 years of age at high risk of fracture should also receive prescription osteoporosis therapy regardless of glucocorticoid use, according to American College of Rheumatology and National Osteoporosis Foundation Guidelines [32]. These high-risk patients are those with T-scores between −1.0 and −2.5 or calculated FRAX scores estimating the 10-year probability of hip or combined major osteoporotic fracture at >3 % and 20 %, respectively. According to US-specific cost-effectiveness analysis, a 3 % 10-year risk of hip fracture, with its high morbidity and cost, is the threshold at which treatment of osteoporosis becomes cost-effective (less than $60,000 per quality-adjusted life year gained) [28].

Postmenopausal women and men >50 years of age who do not meet this threshold are at low or intermediate risk of fracture. They should receive pharmacologic therapy if taking >7.5 mg of prednisone or its equivalent daily for three or more months.

Guidelines for premenopausal women and men younger than age 50 are less well defined. The FRAX tool was not developed for use in these populations, and there is limited evidence related to glucocorticoid-induced osteoporosis and fracture risk in these groups. Clinical trials involving premenopausal women and younger men showed low fracture rates in both glucocorticoid-treated and control groups [33]. Furthermore, the long-term safety of bisphosphonates and other medications used to treat glucocorticoid-induced osteoporosis and the effect of these medications on a developing fetus are not well defined. For these reasons, the American College of Rheumatology recommends pharmacologic therapy only for patients with a history of fragility fracture who are clearly at high risk of additional fractures and taking 7.5 mg of prednisone or its equivalent for 3 months or longer [32]. Patients without a history of fragility fracture who have evidence of accelerated bone loss should also be considered for therapy. In the absence of definitive data in these groups, the decision to initiate pharmacologic osteoporosis therapy should be individualized and should weigh potential risks and benefits.

63.5.3 Bisphosphonates

For men and postmenopausal women, bisphosphonates are the agents of choice for the treatment and prevention of glucocorticoid-induced osteoporosis. A large amount of data support their use, showing efficacy in randomized, controlled trials for improving bone mineral density and reducing fracture risk. A meta-analysis of 13 randomized trials with a total of 842 patients on chronic glucocorticoid therapy showed a significant improvement in lumbar and femoral neck bone mineral density of 4.3 and 2.1 %, respectively, among those taking bisphosphonates as compared to placebo groups. The odds of spinal fracture were reduced by 24 %, though this result was not statistically significant [OR 0.76 (95 % CI 0.37, 1.53) [34]. Clinical trials have shown bisphosphonates to be superior to calcium alone as well as to vitamin D and active vitamin D metabolites [24]. For women of childbearing potential, bisphosphonates remain an option in select patients despite the concerns noted above.

Mechanistically, bisphosphonates are thought to promote osteoclast apoptosis and, in general, prolong osteoblast survival, opposing the effects of glucocorticoids [35, 36]. However, the effects of bisphosphonates on osteoblast gene expression and survival appear to be quite complex, varying with the specific bisphosphonate and its concentration [37].

Of the several bisphosphonates—alendronate (Fosamax), risedronate (Actonel), zoledronic acid (Reclast), ibandronate (Boniva), pamidronate (Aredia), etidronate (Didronel), and clodronate (Bonefos)—alendronate, risedronate, and zoledronic acid are best supported by the available data and most widely used in clinical practice (Table 63.2). Randomized trials of 5 mg daily, 10 mg daily, and 70 mg weekly alendronate showed improvements in bone mineral density and a decrease in vertebral fractures among patients receiving glucocorticoids, benefits which were maintained for 2 years [33]. Trials of risedronate 5 mg daily or 35 mg weekly similarly showed efficacy for the treatment and prevention of osteoporosis in patients taking glucocorticoids [38]. These patients maintained or increased their bone mineral density and reduced their vertebral fracture risk by 70 % compared with control patients [39]. For patients who cannot take oral medications or for whom adherence is a concern, intravenous zoledronic acid at a dose of 5 mg every 12 months is an alternative. It too has shown efficacy in increasing bone mineral density in patients taking glucocorticoids chronically [40].

Table 63.2

Recommended therapies for the prevention and treatment of glucocorticoid-induced osteoporosis

Intervention	Dosing regimen
Calcium and vitamin D	1,200 mg calcium and 800 IU vitamin D by mouth daily^a
Alendronate	5 or 10 mg once daily or 70 mg once weekly by mouth
Risedronate	5 mg once daily or 35 mg once weekly by mouth
Zoledronic acid	5 mg once yearly injected intravenously
Teriparatide	20 ug once daily injected subcutaneously

^aMay be obtained through diet or supplementation

Ibandronate, pamidronate, etidronate, and clodronate all have demonstrated efficacy for preserving bone mineral density in patients exposed to glucocorticoids. However, clodronate and oral pamidronate are not available in the United States. Etidronate and intravenous pamidronate are uncommonly used; in clinical practice alendronate and risedronate are favored over the former, while zoledronic acid is favored over the latter. Ibandronate is more commonly used, but there are fewer data concerning the use of its oral formulation than its intravenous formulation for the prevention and treatment of glucocorticoid-induced osteoporosis.

Where available, these agents are likely to be acceptable alternatives to alendronate, risedronate, and zoledronic acid, but overall, there are fewer data to support their use in this patient population. The American College of Rheumatology has stated that it considers the amount and quality of data concerning ibandronate and etidronate specifically to be insufficient to recommend their use [32]. Studies comparing bisphosphonates directly to one another have only rarely been performed, but in one trial comparing zoledronic acid to risedronate, bone mineral density improved to a greater extent among those who received zoledronic acid [40].

63.5.3.1 Bisphosphonate Prescribing Guidelines, Side Effects, and Controversies

The bioavailability of oral bisphosphonates is <1 %. To aid absorption, patients should be instructed to take the medication on an empty stomach, first thing in the morning and at least half an hour before breakfast. If not dosed in this manner, bisphosphonates may lose some efficacy [41].

There have been rare reports of renal impairment and acute renal failure following zoledronic acid infusion, though usually this complication has occurred in the setting of multiple myeloma. As a precaution, bisphosphonates are not recommended in patients with creatinine clearance below 30 mL/min.

Bisphosphonates may cause symptomatic reflux, esophagitis, or esophageal ulcers. To help prevent these symptoms, patients are advised to take bisphosphonates with a glass of water and remain upright for at least 30 min after dosing. When following these recommendations, the incidence of adverse events is very low. Clinical trials have not shown any excess risk of upper GI symptoms in patients taking bisphosphonates compared to those taking placebo [42]. Whether bisphosphonates increase the risk of esophageal cancer is controversial. One large case-cohort study involving 46,000 bisphosphonate users found no increased incidence of esophageal or gastric cancer over 4.5 years [43]. Conversely, a case-control study involving 2,954 patients with esophageal cancer showed a relative risk of 1.30 (95 % CI 1.02–1.66) among those taking bisphosphonates over an average of 7.5 years of observation [44]. At present, it is not clear whether bisphosphonates increase esophageal cancer risk, but they are not recommended for use in patients with active upper gastrointestinal disease such as those with Barrett’s esophagus.

Osteonecrosis of the jaw, characterized by pain, exposed bone, and pathologic jaw fracture, has been described in the setting of chronic bisphosphonate therapy. The risk of osteonecrosis of the jaw is roughly 1 in 10,000 to 1 in 100,000 in those taking oral bisphosphonates for osteoporosis [45]. Factors such as multiple myeloma, high-dose intravenous bisphosphonates, long duration of bisphosphonate therapy, dental disease, dental procedures, and smoking increase that risk. Since the risk of osteonecrosis is quite small for most patients taking bisphosphonates for osteoporosis, there are no special recommendations for dental examination prior to starting therapy. There are also no data to support stopping bisphosphonates prior to dental surgery. However, the American Association of Oral and Maxillofacial Surgeons does recommend stopping bisphosphonates 3 months prior to dental surgery if the duration of therapy has been longer than 3 years. Because bisphosphonates bind to bone, however, their effects may linger for years, and it is not known whether cessation of therapy truly decreases the risk of complications.

Individual cases of atypical femur fractures, such as subtrochanteric fractures manifest by new onset pain in the mid-thigh or groin, have been reported in patients taking bisphosphonates. Bisphosphonates prevent osteoporotic fractures in part by decreasing bone resorption. In so doing, they may also prevent normal bone turnover, theoretically increasing bone fragility [46]. Population-based studies suggest the risk of atypical fractures in patients taking bisphosphonates is quite low and is not significantly increased with duration of therapy less than 5 years. With the use of a bisphosphonate for longer than 5 years, the risk of atypical fracture increases to roughly 0.13–0.22 % over 2 years. Conversely, the risk of typical osteoporotic fractures decreases with longer bisphosphonate use [47]. While long-term bisphosphonate therapy increases the risk of atypical fractures, the absolute risk is low with uncertain clinical significance.

For this reason, the recommended duration of bisphosphonate therapy is controversial. Bisphosphonates have demonstrated efficacy and safety in studies lasting as long as 10 years [48]. Pooled data on patients receiving bisphosphonates for 6 years or longer show maintenance of bone mineral density but no clear and consistent fracture prevention advantage compared to patients who switch to placebo. While these analyses are limited by statistical power and sample size, they suggest bisphosphonates may be safely discontinued in some patients without sacrificing therapeutic gains. Given the potential safety concerns associated with long-term bisphosphonate use, there is new urgency to determine which patients are more likely to benefit from bisphosphonate therapy beyond 3–5 years and which are not [49]. Stopping bisphosphonate therapy after 5 years with continued bone mineral density and risk factor monitoring may be appropriate for patients at low risk of fracture, whereas those at high risk should likely continue. Ultimately, the risk of major complications associated with bisphosphonate use is very low compared with their proven benefit [50].

63.5.4 Parathyroid Hormone

Parathyroid hormone (teriparatide) is another drug with proven efficacy for the treatment and prevention of glucocorticoid-induced osteoporosis [51]. Intermittent administration of parathyroid hormone produces anabolic skeletal effects and stimulates bone formation [52]. In a head-to-head randomized trial of alendronate versus teriparatide 20 mcg injected subcutaneously daily, teriparatide-treated patients experienced a greater increase in bone mineral density than their counterparts taking alendronate, though both groups experienced statistically significant increases [53]. Compared to alendronate, those taking teriparatide also experienced significantly fewer vertebral fractures [54]. Despite these impressive results, teriparatide is not used as a first-line drug for most patients because of its cost, route of administration, and potential dose-dependent risk of osteosarcoma, for which it has a black box warning from the Food and Drug Administration in the United States.

In a meta-analysis to determine the comparative effectiveness of different pharmacologic agents in reducing fragility fractures, teriparatide was most efficacious for fracture risk reduction. However, differences between bisphosphonates, teriparatide, and denosumab were small and not statistically significant [55]. Bisphosphonates thus remain the first-line treatment option for the majority of glucocorticoid-treated patients with increased fracture risk [56]. Patients at particularly high risk of fracture, such as those who have failed bisphosphonate therapy, those who are unable to tolerate bisphosphonates, and high-risk premenopausal women, are potential candidates for therapy with teriparatide. As with the other pharmacologic option, potential benefits should outweigh potential risks.

63.5.5 Calcitonin

Subcutaneous injection or intranasal inhalation of calcitonin does not consistently prevent bone loss in patients starting glucocorticoid therapy compared with calcium and vitamin D alone [57]. Calcitonin does increase lumbar spine bone mineral density, but trials have not shown the same benefit for bone of the femoral neck, nor have they shown any reduction of fracture risk [58]. The pooled relative risk from five studies was 0.71 (95 % CI 0.26–1.89) [59]. For this reason, calcitonin is second line for the treatment and prevention of glucocorticoid-induced osteoporosis [60]. It may be used in patients for whom bisphosphonates and teriparatide are contraindicated or are poorly tolerated, and it may also be useful for fracture pain reduction.

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