Secondary Prevention of Low-Trauma Fractures: In Search of an Effective Solution
Mortality Following Fragility Fractures
Perhaps the most concerning complication, however, is the excess mortality seen after fractures. Several studies have demonstrated excess mortality after vertebral fractures, especially in the year following the fracture [29–33], but the highest increase in mortality was observed following hip fractures. In fact, the 30-day mortality after a hip fracture approximates 7% [23] and the excess 1-year mortality is estimated at 8% to 36% [34,35]. While the highest risk of mortality is seen in the first year following the fracture, the increased risk persists for at least 5 to 6 years [36]. Malnutrition, decreased mobility, male sex, and the number of coexisting medical comorbidities further increase the risk of mortality [29,32,34,36,37].
Risk of Fracture Recurrence
In both men and women, a fragility fracture at any site increases the risk of subsequent fractures [38–41], and the risk increases with the number of prevalent fractures [42]. Gehlbach et al estimated an 80% increase in the risk of fracture recurrence after 1 fracture, a threefold increase after 2 fractures, and an almost fivefold increase after 3 fractures [42]. The increase in risk is even more pronounced following vertebral fractures specifically, doubling after the first fracture an increasing by up to ninefold after 3 fractures [42, 43]. This increase in risk is highest in the first year following the fracture but may persist for up to 10 years [39,43].
Fracture Impact on Society
Fractures are associated with a high financial burden to society, in terms of direct acute care costs and long-term rehabilitation [3,4,44–48]. In 2010, the direct cost from fractures in the EU was estimated at €24.6 billion [3]. In the US, this cost was around $14.0 billion in 2002 and $16.9 billion in 2005 [4,48], and in Canada it was $1.5 billion in 2011 [47]. These numbers increase substantially when costs associated with long-term post-fracture rehabilitation are included, with an additional estimated yearly cost of €10.7 billion in the EU and $1.03 billion in Canada [3,47].
While hip fractures account for only about 18% of all low-trauma fractures, they are associated with the highest cost burden, accounting for about 50% to 70% of the total fracture-associated expenditures [3,4,44]. This is likely due to the fact almost all hip fractures require hospitalization, most require surgical repair and rehabilitation, and because they lead to the highest rates of morbidity and mortality.
Can Fracture Recurrence After a Low-Trauma Fracture Be Prevented?
Many approaches to secondary fracture prevention have been proposed, including but not limited to fall prevention, exercise therapy, nutrition therapy, prevention and treatment of sarcopenia, vitamin D and calcium supplementation, and osteoporosis pharmacotherapy [49–53]. Of those, osteoporosis pharmacotherapy has the strongest and most compelling efficacy data and will be reviewed in the following sections.
Effect of Antiresorptive Therapy After a Fracture
In the Fracture Intervention Trial (FIT), alendronate decreased the risk of new vertebral fractures by about 47% and of hip fractures by about 50% in women with preexisting vertebral fractures [54,55]. Similar fracture protection benefits were demonstrated in the Hip Intervention Program (HIP), where risedronate decreased the risk of hip fractures by 60% in women with prior history of vertebral fractures [56].
The best data regarding secondary prevention of hip fractures however comes from the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) trial, where patients were randomized to zoledronic acid or placebo within 90 days of a hip fracture. Over a median duration of therapy of about 2 years, zoledronic acid decreased the risk of any new clinical fracture by 35%, of new vertebral fractures by 46%, and of recurrent hip fractures by 30% [57].
Effect of Anabolic Therapy After a Fracture
The Fracture Prevention Trial (FPT) compared the effect of teriparatide to placebo in women with at least 1 moderate or 2 mild atraumatic vertebral fractures and showed a 65% reduction in the risk of new vertebral fractures and a 53% reduction in the risk of new non-vertebral fractures [58]. Likewise, the Abaloparatide Comparator Trial In Vertebral Endpoints (ACTIVE) enrolled women with at least 2 mild vertebral fractures, 1 moderate vertebral fracture or history of a low trauma fracture of the forearm, humerus, sacrum, pelvis, hip, femur, or tibia. In this trial, abaloparatide decreased the risk of new vertebral fractures by 85% and of new non-vertebral fractures by 43% compared to placebo [59].
Will Anti-Osteoporosis Therapy After a Low-Trauma Fracture Impact Fracture Healing?
One major question regarding the use of anti-osteoporosis drugs in patients with a recent fracture is the effect that treatment might have on bone healing after fracture or fracture-repair surgery. With antiresorptive agents in particular, the main concern is whether suppression of bone turnover may lead to delayed bone healing, since healing requires callus remodeling. A small prospective study evaluated fracture healing in 196 patients treated for a distal radius fracture, 153 of whom were on a bisphosphonate at the time of the fracture. While bisphosphonate use was associated with a longer time to radiographic union, the time to union was only 6 days longer in the bisphosphonate group (55 days versus 49 days to union in the bisphosphonate and control groups, respectively), and has generally not been felt to be clinically significant [60]. The most reassuring data regarding this question however, comes from the HORIZON trial where 2127 men and women were randomized to zoledronic acid or placebo within 90 days of a hip fracture. No difference in healing between the 2 groups was seen, regardless of the time of initiation of zoledronic acid (within 2 weeks of fracture, between 2 and 4 weeks, between 4 and 6 weeks or after 6 weeks) [61].
