Osteoporosis
Which Bone Agent Is Best in High-risk Osteoporosis?
By Eric S. Schned, MD
Abstract
Background: Bisphosphonate therapy is the current standard of care for the prevention and treatment of glucocorticoid-induced osteoporosis (GIO). Studies of anabolic therapy in patients who are receiving long-term glucocorticoids (GCs) and are at high risk for fracture are lacking.
Methods: In an 18-month randomized, double-blind, controlled trial, we compared teriparatide with alendronate in 428 women and men with osteoporosis (ages 22 to 89) who had received GCs for at least three months (prednisone equivalent, 5 mg daily or more). A total of 214 patients received 20 μg of teriparatide once daily, and 214 received 10 mg of alendronate once daily. The primary outcome was the change in bone mineral density at the lumbar spine (LS). Secondary outcomes included changes in bone mineral density at the total hip and in markers of bone turnover, the time to changes in bone mineral density, the incidence of fractures, and safety.
Results: At the last measurement, the mean (±SE) bone mineral density at the LS had increased more in the teriparatide group than in the alendronate group (7.2±0.7% versus 3.4±0.7%, p<0.001). A significant difference between the groups was reached by six months (p<0.001). At 12 months, bone mineral density at the total hip had increased more in the teriparatide group. Fewer new vertebral fractures occurred in the teriparatide group than in the alendronate group (0.6% versus 6.1%, p=0.004); the incidence of nonvertebral fractures was similar in the two groups (5.6% versus 3.7%, p=0.36). Significantly more patients in the teriparatide group had at least one elevated measure of serum calcium.
Conclusions: Among patients with osteoporosis who were at high risk for fracture, bone mineral density increased more in patients receiving teriparatide than in those receiving alendronate.
Commentary
Rheumatologists know intimately the hazards of long-term GC therapy. GIO and resultant fractures are especially vexing problems since some patients in whom we use GCs are already at high risk for these complications. These patients include postmenopausal women with long-standing RA or lupus and elderly patients with polymyalgia rheumatica (PMR) and giant cell arteritis (GCA).
Bisphosphonate therapy is the current standard of care for patients who already have—or are at risk for developing—GIO.1 Bisphosphonates act primarily on bone resorption, however, while teriparatide directly stimulates osteogenesis and inhibits osteoblast apoptosis, two key mechanisms in bone affected by GCs.2 These actions make teriparatide a good candidate for treating or preventing GIO.
Saag and colleagues undertook trial comparing teriparatide and alendronate in patients with GIO. All patients also received 1000 mg of calcium carbonate and 800 IU of vitamin D. The primary outcome was change in bone density at the LS.
Patients had a history of sustained GC therapy and a T-score at the LS or total hip of either -2.0 or less or -1.0 or less plus at least one fragility fracture while receiving GCs.
Four hundred twenty-eight patients were randomized, and 75% were being treated for rheumatologic disorders (almost half with RA). The median daily prednisone dose was 7.6 mg and the median duration of therapy was 1.3 years. Almost 70% had prevalent fragility fractures and the mean baseline LS T-score was -2.5.
At 18 months, patients in the teriparatide group had a significantly greater increase in mean bone mineral density (BMD) at the LS than those in the alendronate group. Similarly, at the total hip, the teriparatide group’s increase in BMD from baseline (3.8±0.6%) was significantly greater than the alendronate group (2.4±0.6%, p=0.005).
Ten patients in the alendronate group (n=165) had new radiographic vertebral fractures while only one in the teriparatide group (n=171) did (p=0.004). Markers of bone formation and resorption both showed increases in the teriparatide group and decreases in the alendronate group.
There were no significant differences in the overall incidence of adverse events between the two groups, although more patients treated with teriparatide had one or more serum calcium values greater than 10.5; there were no instances of sustained elevation.
I think this paper should encourage rheumatologists to be more aggressive in evaluating patients on sustained GCs and considering the various therapeutic options. For many individuals on GCs who are at relatively low risk for immediate GIO or fracture—such as younger individuals starting GCs, individuals with only mildly or moderately low BMD, or those with relatively mild osteoporosis—I’ll undoubtedly continue to use oral bisphosphonates.
However, this study’s patient population, which clearly was at high risk for fracture (over two-thirds had prevalent GC-induced fractures at baseline), benefited significantly from teriparatide compared with alendronate. Less than 5% of the patients in this study had PMR and the mean age of the patients was 57. It seems likely that for patient populations which are enriched in PMR, GCA, and other diseases in older individuals, benefits of teriparatide might be even more striking.
At least two practical issues could limit the use of teriparatide: daily injections and cost. In particular, when Fosamax becomes available generically in 2008 and cost is reduced, resistance from payers to use of teriparitide can be expected. Cost-effectiveness analyses may be necessary to demonstrate the magnitude of fracture risk needed to justify teriparatide use. In the meantime, this study should reinforce the value of performing routine fracture assessments on postmenopausal women and men over age 60 who are on chronic GCs in order to help identify patients at particularly high risk.
References
- ACR Ad Hoc Committee on Glucocorticoid-Induced Osteoporosis. Recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis: 2001 update. Arthritis Rheum. 2001;44:1496-1503.
- Jilka RL, Weinstein RS, Bellido T, et al. Increased bone formation by prevention of osteoblast apoptosis with parathyroid hormone. J Clin Invest. 1999;104:439-446.
In Brief
Trauma and Fractures
By Daniel H, Solomon, MD, MPH
Abstract
Context: It is widely believed that fractures resulting from high trauma are not osteoporotic; however, this assumption has not been studied prospectively.
Objective: To examine the association between BMD and high-trauma fracture and between high-trauma fracture and subsequent fracture in older women and men.
Design, setting, and participants: Two prospective U.S. cohort studies in community-dwelling adults 65 or older from geographically diverse sites. The Study of Osteoporotic Fractures followed up 8,022 women for 9.1 years (1988–2006). The Osteoporotic Fractures in Men Study followed up 5,995 men for 5.1 years (2000–2007).
Main outcome measures: Hip and spine BMD were assessed by dual-energy X-ray absorptiometry. Incident nonspine fractures were confirmed by radiographic report. Fractures were classified, without knowledge of BMD, as high trauma (due to motor vehicle crashes and falls from greater than standing height) or as low trauma (due to falls from standing height and less severe trauma).
Results: Overall, 264 women and 94 men sustained an initial high-trauma fracture and 3,211 women and 346 men sustained an initial low-trauma fracture. For women, each 1-SD reduction in total hip BMD was similarly associated with an increased risk of high-trauma fracture (multivariate relative hazard [RH], 1.45; 95% confidence interval [CI], 1.23–1.72) and low-trauma fracture (RH, 1.49; 95% CI, 1.42–1.57). Results were consistent in men (high-trauma fracture RH, 1.54; 95% CI, 1.20–1.96; low-trauma fracture RH, 1.69; 95% CI, 1.49–1.91). Risk of subsequent fracture was 34% (95% CI, 7%–67%) greater among women with an initial high-trauma fracture and 31% (95% CI, 20%–43%) greater among women with an initial low-trauma fracture, compared with women having no high- or low-trauma fracture, respectively. Risk of subsequent fracture was not modeled for men.
Conclusions: Similar to low-trauma nonspine fractures, high-trauma nonspine fractures are associated with low BMD and increased risk of subsequent fracture in older adults. High-trauma nonspine fractures should be included as outcomes in osteoporosis trials and observational studies.
Commentary
Many clinicians have long suspected that even fractures occurring after high trauma (such as in a motor vehicle accident) might be related to osteoporosis in a given individual. Mackey and colleagues used data from several large prospective cohorts to prove that this is the case. They found that high-trauma fractures had a similar relationship with bone mineral density as did low-trauma fractures and that high-trauma fractures predicted future fractures equally as well as their low-trauma counterparts. These findings should spur physicians to consider any prior fracture (low- or high-trauma) as a marker of patients that need vigorous screening and possible treatment for osteoporosis.
CORRECTION
In the article “Difficult Gout” (July 2007 issue, p. 1), regarding statements that oxypurinol does not effectively inhibit the oxidized form of xanthine oxidase, the statements should read as follows:
Oxypurinol can slowly dissociate from the enzyme. Moreover, oxypurinol can fail to completely inhibit the oxidized form of xanthine oxidase in certain biologic milieus (as opposed to enzyme inhibition in simple solution), as shown by the recent work of Kelley et al (Kelley EE, Trostchansky A, Rubbo H, et al. Binding of xanthine oxidase to glycosaminoglycans limits inhibition by oxypurinol. J Biol Chem. 2004;279:37231-37234).
Please visit www.The-Rheumatologist.org to download a corrected version of the July issue under the “Download Issues” tab.
