Fracture Risk
As discussed previously, the pathophysiology of osteoporotic fragility fractures during GC treatment is multifactorial, as it includes bone- and fall-related factors and is also strongly related to baseline risk. Identifying patients with increased fracture risk solely using bone mass measurements has several disadvantages and shortcomings, such as its age dependency and its inaccuracy in measuring bone quality. Therefore, it has been recommended that fracture risk should be assessed using models that calculate the absolute fracture risk for the individual patient. The disadvantage of using the absolute fracture risk is the lack of consensus regarding when exactly treatment should be initiated. Therefore, any cutoff point will be arbitrary. Several algorithms are presently available to determine how to prevent GIOP and fractures, most based on the daily dosage of prednisone and on the T-score of BMD measurements of the hip and spine. First, the General Practice Research Database, also known as FIGS (Fracture in GIOP Score), has been developed [
9]. This model calculates the 5- and 10-year risk of an osteoporotic fracture of the hip, vertebrae, and wrist. The use of this model is somewhat complicated, but this scoring method has the advantage that the underlying disease, the GC dosage, and the fall risk are taken into account. Another frequently used model is the Fracture Risk Assessment (FRAX) tool as proposed by the World Health Organization [
36]. This model is unique in that it takes into account the family history and the BMD but excludes the evaluation of the risk factors of falls and the presence or absence of prevalent vertebral deformities, although they are recognized as a risk factor for fractures. Furthermore, GC usage, but not dosage, is recorded in this model. The 10-year fracture risk can be calculated easily on the Internet. Besides being useful in treatment decisions, the assessment of fracture risk may also be useful in improving a patient’s treatment adherence, as it gives the patient a better insight into his or her future fracture risk and into the degree of risk reduction once treatment with anti-osteoporotic drugs is initiated.
Medication
Bisphosphonates have been shown to be effective in preventing GC-induced bone loss in several randomized controlled trials (Table
1) [
5,
6,
37‐
41]. Alendronate improved lumbar spine BMD in patients on long-term GCs after 1 year, while the BMD decreased in patients receiving placebo [
39]. After 2 years, this difference was sustained [
5]. Interestingly, the greatest increase in BMD occurred within the first year. Two trials addressed the efficacy of risedronate in preventing GC-induced bone loss [
6,
38]. One study included patients starting with GCs and found that risedronate prevented bone loss. The other study included patients on long-term GC treatment and showed that risedronate increased the BMD. The average difference in percentage of BMD change among patients using bisphosphonates was plus 4.6% compared with patients using placebo/calcium [
37]. Adding vitamin D supplementation to bisphosphonate treatment further enhanced the beneficial effect to an estimated difference of plus 6%.
Table 1
Treatment effects on BMD and incident vertebral fractures in GIOP
| Placebo | 224 | Prevention | 1 year | -2.8 | +0.6a
| -3.1 | +0.8a
| 9/52 (17.3%) | 3/53 (5.7%) |
| Placebo | 290 | Treatment | 1 year | +0.4 | +2.9a
| -0.3 | +1.8b
| 9/60 (15%) | 3/60 (5%) |
| Placebo | 518 | Both | 1 year | -1.0 | +1.9a
| -1.5 | +1.3a
| 18/111 (16.2%) | 6/111 (5.4%)b
|
| Placebo | 477 | Treatment | 1 year | -0.4 | +2.9a
| -1.2 | +1.0a
| 8/135 (5.9%) | 8/268 (2.9%) |
| Placebo | 477 | Treatment | 2 years | -0.8 | +3.9a
| -2.9 | +0.6b
| 4/59 (6.8%) | 1/143 (0.7%)d
|
| Placebo | 173 | Treatment | 1 year | -0.6 | +2.5a
| +0.1 | +0.4 | – | – |
| Risedronate | 545 | Treatment | 1 year | +2.7 | +4.1e
| +1.5 | +0.4a
| 5/833 (0.6%) | 3/833 (0.4%) |
| | 288 | Prevention | | +2.0 | +2.6e
| +1.3 | -0.03a
| | |
| Placebo | 58 | Prevention | 1 year | -25 | 0a
| -23 | 0a
| (53%) | (13%)d
|
Strontium ranelate | No data | – | – | – | – | – | – | – | – | – |
| Alendronate | 428 | Treatment | 18 months | +3.4 | +7.2a
| – | – | 10/165 (6%) | 1/171 (0.6%)f
|
| Alendronate | 428 | Treatment | 36 months | +5.3 | +11.0a
| +3.4 | +6.3a
| 13/169 (7.7%) | 3/173 (1.7%)g
|
PTH (1-84) | No data | – | – | – | – | – | – | – | – | – |
Furthermore, for both alendronate and risedronate, a reduction in vertebral fractures has been observed in randomized controlled trials involving patients treated with GCs [
5,
41]. Alendronate reduced vertebral fracture risk compared with placebo after 2 years of follow-up: the incidence of morphometric vertebral fractures in patients treated with alendronate was 0.7%, compared with 6.8% in placebo-treated patients (
P = 0.026) [
5]. No reduction in nonvertebral fractures was observed (incidental fractures, 9.8% vs 5.4% [placebo vs alendronate]). Similarly, a 70% reduction in vertebral fracture risk was found for risedronate as compared with placebo [
41]. Again, no significant difference was noted in the incidence of nonvertebral fractures. Recently, zoledronic acid, given yearly by intravenous infusion, was shown to prevent GIOP [
7••]. In this randomized controlled trial, zoledronic acid was not compared with placebo, but rather with an active comparator: daily risedronate. Zoledronic acid was found to be more effective than risedronate in both the treatment (zoledronic acid, +4.06% spine BMD vs risedronate, +2.71% spine BMD) and prevention subgroups (zoledronic acid, +2.6% spine BMD vs risedronate, +0.64% spine BMD) after 12 months of treatment. In this trial, no statistically significant difference in fracture rate was observed. Obviously, this is related to the fact that in this trial, a comparison with an anti-osteoporotic drug, not placebo, was performed. The larger increase in BMD in the zoledronate group is difficult to interpret because it is not known whether the larger increase in BMD is also reflected in a larger increase in bone strength and/or a larger reduction in fracture rate. Zoledronic acid should be given by intravenous infusion, which may have some practical considerations and an impact on hospital budget (depending on the health system of each specific country). In addition, the risk of renal damage is higher in patients with compromised kidney function (eg, in older adult patients with moderate kidney function and a superimposed infection), leading to dehydration. The effects of ibandronate were recently studied in men after cardiac transplantation. All men received GCs directly after transplantation, and the mean cumulative dose of cortisone was 17 g after 1 year. Men were randomly assigned to ibandronate or placebo, and after 1 year, spine BMD remained unchanged in the men treated with ibandronate, compared with a decline in spine BMD (-25%) in patients treated with placebo. Furthermore, there was a significant difference in number of morphometric vertebral fractures (ibandronate, 13% vs placebo, 53%) [
42]. Thus, ibandronate prevents bone loss and vertebral fractures in cardiac transplantation patients on immunosuppressive therapy, including GCs. No data are available on the effects of strontium ranelate and parathyroid hormone (PTH) 1-84 with respect to the prevention of GIOP.
Because the effect of GCs is dominated by their inhibiting effect on bone formation, it is theoretically more or less unexpected that antiresorptive drugs (eg, bisphosphonates) will be useful in GC-treated patients. Recently, the mechanism of bone loss prevention by bisphosphonates has become more clear. Experimental studies demonstrated that bisphosphonates lower the expression of genes that inhibit the mineralization, thereby increasing trabecular bone volume [
43]. Theoretically, anabolic agents should be the first choice in GC-treated patients, based on the pathogenesis of GIOP. Clinical studies show that PTH 1-34 (teriparatide) is more effective in preventing GIOP than bisphosphonates. Recently, the anabolic agent teriparatide was compared with the active comparator alendronate in 428 women and men with osteoporosis who received GCs (>5 mg/d) for at least 3 months [
44]. After 18 months, the BMD in the lumbar spine increased significantly more in patients receiving teriparatide than in patients receiving alendronate (7.2% vs 3.4%). Remarkably, a difference in the number of patients with new vertebral fractures was observed as well: 0.6% in the teriparatide group versus 6.1% in the alendronate group (
P = 0.004). In line with other studies, no difference was found in nonvertebral fracture rate. This finding was confirmed in the follow-up study during another 18 months of treatment [
45••]. Interestingly, treatment with teriparatide not only reduced fracture rate but was also shown to reduce back pain and to improve quality of life [
46]. No data are available for PTH 1-84 in GC-treated patients. Intervention with PTH 1-34 restored trabecular bone volume, increased bone formation, and increased bone strength in an animal model [
43,
47]. PTH treatment counteracts the negative effects of GCs on osteoblast and osteocyte apoptosis. These effects were recently demonstrated to be exerted by increasing the expression of Wnt signaling agonists [
43,
47]. Thus far, no clear guidelines exist regarding which GC-treated patients should be offered teriparatide as a first-line drug. Because of the relatively high cost of teriparatide, introduction of teriparatide may have an impact on several budgets. In addition, the inconvenience of injecting teriparatide may limit its use. Nevertheless, teriparatide is attractive not only because of its working mechanism but also because it has been proven to be superior to bisphosphonates in GC-treated patients. Thus, it may be attractive to prescribe teriparatide in patients with a very high risk of fractures (eg, 10-year absolute fracture risk > 20%).
Recent studies on the molecular pathways underlying bone metabolism have identified potential novel therapeutic targets for the management of osteoporosis. For the future, it can be expected that new drugs interfering with the Wnt signaling or RANKL/OPG pathways may prove more effective than current treatment options (eg, bisphosphonates) in reducing GIOP. It is obvious that new anti-osteoporotic drugs for GIOP (eg, denosumab, cathepsin K inhibitors, and monoclonal antibody against sclerostin) should be tested against an active comparator for ethical reasons.
Very recently, the American College of Rheumatology recommendations for the prevention and treatment of GIOP were updated, including renewed recommendations for counseling and monitoring GIOP and updated pharmacotherapeutic interventions [
48••]. This update was necessary because of new insights into the value of BMD measurements in identifying patients at risk and because new diagnostic tools and data on therapies were available. These recommendations provide an up-to-date guideline for the management of GIOP for two patient groups: postmenopausal women and men older than 50 years of age, and premenopausal women and men younger than 50 years of age initiating or receiving GC therapy. The subdivision of patients into fracture risk categories (low [<10%], medium [10%–20%], and high [>20%]) results in clear recommendations that are easy to work with in clinical practice. These risk categories were established using the FRAX tool. The FRAX tool is based on a large database, but as mentioned earlier, it unfortunately does not include some important risk factors for fractures, such as daily dose of prednisolone, the presence or absence of prevalent vertebral fractures, and risk of falling. Furthermore, the risk categories were defined by an expert panel rather than based on evidence.
Adherence
Adherence to therapy is also a well-known and important problem in GIOP. A large, retrospective database study recently showed that after 1 year, less than 40% of patients were adherent to treatment [
49•]. This low percentage may be explained in several ways. First, anti-osteoporotic drugs are prescribed for prevention of future fractures. In comparable circumstances (eg, patients on blood pressure–lowering drugs), nonadherence is an important issue, whereas in patients with arthritis, adherence is usually better because anti-inflammatory drugs induce relief of pain and inflammation. Second, patients starting on GCs are usually ill and are being informed about their underlying disease, including several possible side effects of GCs, such as hypertension, diabetes, glaucoma, infections, and osteoporosis. Thus, osteoporosis is just one item on the long list of possible side effects, for which it might be necessary to take two or three types of additional drugs. Third, monitoring the effects of anti-osteoporotic drugs is not optimal. The value of BMD testing to monitor therapy and the interval of BMD testing are controversial. Changes in bone markers occur by 2 to 3 months after initiation of treatment with anti-osteoporotic drugs, but measurement of bone marker values is limited in daily clinical practice because of a relatively high analytical variation, circadian rhythm, and costs. It is only possible in some centers that have focused their research on biomarkers and osteoporosis. Finally, (mild) gastrointestinal side effects may occur in 20% to 30% of patients, and 2 to 3 days of fever and flu-like symptoms occur in nearly all patients treated with high-dose bisphosphonates, causing patients to be nonadherent. Furthermore, general factors not directly related to bisphosphonates may come into play. For example, an increased number of prescribed drugs increases an individual’s risk of nonadherence; anti-osteoporotic drugs are usually prescribed in older adults, in whom adherence may be limited due to (early) dementia; and some patients have a general negative opinion against drugs.
Several measures to improve adherence in GIOP have been suggested, such as the model of “shared decision making” [
50] and a specialized “GIOP outpatient clinic” [
51]. In the model of shared decision making, the patient and physician discuss the pros and cons of starting anti-osteoporotic drugs. It is important to realize that the arguments used may differ between patients and physicians. Moreover, “patients’ health-believe” is a major factor in therapeutic compliance. Using the absolute fracture risk may be very useful, as it gives patients better insight into their future fracture risk and the degree of risk reduction when treatment with anti-osteoporotic drugs is initiated.
An organized program of care called a
glucocorticoid-induced osteoporosis program, in which high fracture risk patients were identified, educated, and intensively monitored, proved to be effective in the treatment of patients on chronic GCs [
51]. Patients’ knowledge, lifestyle, and serum vitamin D levels all significantly improved, while adherence to therapy was 91%. The challenge for the future will be the development of implementation strategies to translate these care programs from highly specialized clinics to routine daily clinical care.