Supplements Fracture Prevention in Osteoporosis
Importance of Early Diagnosis and Treatment of Osteoporosis to Prevent Fractures
Accumulating evidence from a variety of clinical studies suggests that there is no specific BMD threshold that renders an individual patient "safe" from fracture. The largest study of postmenopausal osteoporosis in the United States, the National Osteoporosis Risk Assessment (NORA) study, which included 200 160 ambulatory postmenopausal women, mean age, 64.5 years, without known osteoporosis, found that almost half the participants displayed low BMD (39.6% osteopenia and 7.2% osteoporosis).17 Among the participants with follow-up information (163 979 subjects), osteoporosis was linked to a 4-fold increase in fracture rate; yet, even the presence of osteopenia was associated with almost a 2-fold increase in the risk of fractures. A separate analysis of the NORA database that included 149 524 white, postmenopausal women revealed that 82% of the 2259 participants with fractures had Tscore >-2.5, suggesting that individuals may experience significant fracture risk with bone density scores that are not in the osteoporotic range (Figure 2).18
In women, bone loss begins insidiously in young adulthood, proceeds in a linear fashion thereafter and, as bone mass progressively declines, fracture risk increases exponentially.19,20
Results from the Study of Osteoporotic Fracture (SOF) suggest that in white women over the age of 65 years, a combination of low BMD and other risk factors, such as a previous fracture of any type, treatment with long-acting benzodiazepines or anticonvulsants, previous hyperthyroidism, ingestion of high amounts of caffeine or physical inactivity, yielded a particularly high risk for hip fracture, the risk increasing as the number of risk factors increased.21 Other investigators have shown that neuromuscular and visual impairments in elderly women (over the age of 75 years), as well as low BMD, are independent risk factors for fracture.22 These findings highlight the importance of considering other risk factors, such as advanced age and prior fracture, in addition to low BMD, when evaluating an individual's risk for osteoporosis-related fracture. A recent WHO initiative to determine absolute fracture risk or 10-year probability of sustaining a fracture based on key risk factors such as age, prior fracture history, and bone density is under review.
Additionally, the results of numerous clinical studies in osteoporosis suggest that although low BMD is of value in predicting future fractures, increases in BMD in response to intervention do not directly correlate with vertebral fracture risk reduction. Indeed, reduction in fracture risk secondary to antiresorptive therapy occurs early when there is a significant decrease in bone turnover and before a large increase in BMD is evident.23-29
Although stable or increased BMD measurements and decreases in bone turnover are important surrogate markers, the clinically important endpoint is reduction in fracture. Indeed, in clinical trials of alendronate, raloxifene, or risedronate, increases in lumbar spine BMD accounted for only a small portion (<20%) of the reduction in risk for vertebral fracture.30-32 Antiresorptive agents may reduce the risk of fracture through a variety of interrelated mechanisms, including improvements in bone turnover, density, architecture, and mineralization.
Antiresorptive therapies that yield greater improvements in more than 1 of these mechanisms–greater decreases in bone turnover in conjunction with greater increases in BMD–are associated with a reduction in hip and other nonvertebral fractures.33
Together, these findings suggest that, in the treatment of osteoporosis, increased BMD alone is not a clinically meaningful endpoint; reduction in fracture rate remains the desired outcome.
Therapeutic Interventions to Reduce Fracture Risk in Osteoporosis
Over the past several decades major advances have been made in the treatment of osteoporosis based on accumulating evidence from randomized controlled trials. Nonetheless, many women who have had fractures remain untreated. In a retrospective chart review of fracture clinic visits, Hajcsar and colleagues identified 228 patients with fragility fractures, 56% of whom were contacted and agreed to participate in an interview 1 year from the date of fracture.34 For these mostly female (85%), postmenopausal (77%) patients, follow-up treatment was far less than adequate: 18.5% had received a diagnosis of osteoporosis, 32.4% were prescribed calcium supplementation, 13% were prescribed vitamin D supplementation, and 7.4% were taking bisphosphonates.
General Prevention Strategies. Universal treatment strategies in the management of osteoporosis include counseling all patients on lifestyle management, and emphasizing the importance of adequate daily intake of calcium (1200 mg/day) and vitamin D (400 to 800 IU/day). Calcium and vitamin D favorably modulate age-related increases in parathyroid hormone levels and bone resorption, increase spine and femoral BMD, and reduce vertebral and nonvertebral fracture risk.6,35 In addition, at-risk patients should be advised to engage in weight-bearing and muscle-strengthening exercises not only to maintain optimal bone maintenance but also to reduce the risk for falls. Patients at risk for osteoporosis should also be advised to avoid tobacco use and excessive alcohol intake, since these activities can accelerate bone loss.36
Pharmacotherapy. The National Osteoporosis Foundation advocates initiating pharmacotherapy to reduce fracture risk in women ≥65 years of age with the following characteristics1:
- BMD T-scores <-2.0 by hip DXA with no risk factors
- BMD T-scores <-1.5 by hip DXA with 1 or more risk factors
- A prior vertebral or hip fracture
The current FDA-approved pharmacologic classes for the management of osteoporosis include bisphosphonates, calcitonin, hormone therapy, parathyroid hormone, and selective estrogen receptor modulators.
Bisphosphonates. The bisphosphonates–alendronate, risedronate, and ibandronate–are antiresorptive agents that bind to hydroxyapatite, especially at sites where bone is formed and resorbed, thus attenuating bone turnover and, in turn, bone loss.37
Alendronate: In the Fracture Intervention Trial, 3 years of alendronate treatment significantly reduced the risk of vertebral fractures in women with and without baseline vertebral fractures.28,29 Although not a primary endpoint, alendronate reduced the risk of hip fractures by 51% in women with prevalent vertebral fractures at baseline. The reduction in hip fracture was seen as early as 18 months (Figure 3).28 In posthoc analysis, patients with T-scores <-2.5 or a prevalent vertebral fracture, alendronate reduced the risk of clinical vertebral fractures by 59% after 1 year of treatment. Alendronate has also demonstrated a sustained effect on BMD for up to 10 years but the reduction in fractures was not assessed.38
Risedronate: In the Vertebral Efficacy with Risedronate Therapy (VERT)-North America study, risedronate significantly reduced the 3-year risk of vertebral and nonvertebral fractures by 41% and 39%, respectively.26 Vertebral fracture risk reduction was maintained at 5 years, and results after 7 years of risedronate therapy demonstrate a continued low incidence of fracture.39 Risedronate has also demonstrated a rapid onset of action. At 1 year, vertebral fracture risk was significantly reduced by up to 65%.26,27 In addition, a pooled analysis of the VERT data and data from other studies indicate a reduction in clinical vertebral, as well as nonvertebral fractures risk as early as 6 months after initiation of risedronate therapy (Figure 4).40,41
The Hip Intervention Program (HIP) was designed to prospectively evaluate the effect of risedronate on hip fracture risk. After 3 years, risedronate reduced hip fracture risk by 40% in women aged 70 to 79 years with osteoporosis (T-score <-2.5) and by 60% in women with osteoporosis and baseline vertebral fracture.42 There was a nonsignificant reduction in hip fractures in the older group of subjects in whom osteoporosis was not documented by densitometry measurements. The reduction in hip fracture with risedronate was demonstrated within 6 to 18 months after initiation of treatment (Figure 5).43
Ibandronate: In a 3-year, randomized, placebo-controlled study that included 2946 postmenopausal women (55 to 80 years of age) with T-scores <-2.5 and >-5.0 with at least 1 previous vertebral fracture, ibandronate, 2.5 mg daily dosing or intermittent dosing with 20 mg every other day for 12 doses every 3 months, reduced the risk for vertebral fractures by 62% and 50% for the daily and intermittent regimens, respectively, when compared with placebo.44
No significant differences, however, were detected between ibandronate and placebo in terms of nonvertebral fracture rates. In a noninferiority study, monthly ibandronate, 100 mg and 150 mg, was found to be noninferior in the increases in BMD at spine and hip to daily 2.5-mg dosing.45 Subsequent analysis showed superiority of the 150-mg monthly regimen to the daily 2.5-mg regimen.
Calcitonin: An antiresorptive agent, calcitonin is indicated for the treatment of postmenopausal osteoporosis in women at least 5 years postmenopausal with low bone mass.46 The results of a 5-year, double-blind trial found that salmon calcitonin nasal spray (200 IU/day) reduced the risk for vertebral fractures by about a third, but no significant reductions were detected in the risk for nonvertebral fractures.47
Raloxifene: A second-generation selective estrogen receptor modulator and antiresorptive agent, raloxifene, 60 mg daily for 3 years in women with osteoporosis, has been shown to increase lumbar spine bone density by 2.5%.48 In addition, in women with osteoporosis or prevalent fractures, raloxifene 60-mg treatment for 3 years decreased the relative risk of vertebral fractures by 30% to 50%, when compared with placebo, but had no statistically discernible effect on nonvertebral fracture risk.24
Teriparatide (1-34 PTH): As a recombinant parathyroid hormone, teriparatide contains the same amino acid sequence as the biologically active portion of endogenous parathyroid hormone and, thus, exerts an anabolic action, building new bone.49 After 19 months of therapy, once-daily, subcutaneously administered teriparatide (20 Âµg or 40 Âµg) reduced the risk for new vertebral fractures by 65% in postmenopausal women with prevalent fractures when compared with placebo (placebo 14% vs teriparatide 5% fracture rate).50 Moreover, teriparatide treatment resulted in a 50% reduction in at least 1 new nonvertebral fracture over 19 months (placebo 6% vs teriparatide 3%).