The role of anti-osteoporotic treatment as part of the secondary prevention after hip fracture in terms of mortality and re-fracture risk has been studied, and the results are promising. Lower mortality after hip fracture is associated with anti-osteoporotic treatment.
Anti-osteoporotic treatment plays an important role both in the primary and secondary prevention of fragility fractures. Bisphosphonates (BPs) are used as a first-line therapy and are widely recognized as efficient and safe . BPs prevent fractures by increasing bone mineral density (by suppressing bone turnover rates) and are associated with a 40–70% reduction in vertebral and hip fracture rates . Another anti-resorptive agent used is denosumab, a human monoclonal antibody to RANKL, first approved for use in 2010 . Like the BP treatment, denosumab was also proven to effectively prevent osteoporotic fractures, with a significant reduction in vertebral and non-vertebral fragility fractures . In Europe, adherence to denosumab is higher compared to that to the BP treatment , which is probably explained by the administration mode—denosumab requires only a subcutaneous dose at six months compared to a weekly/monthly administration of oral BP . The authors showed a 24-month persistence with denosumab of 75.1% to 86% with adherence of 62.9% and 70.1%, with lower durability in patients who had at least one fall in the last 12 months and subjects with more comorbidities .
A low bone mass density (BMD) with or without a rapid loss of bone mass was associated with increased mortality risk . However, the mechanisms are uncertain considering that, to date, no bone-related factor vital for bone catabolism was demonstrated to affect survival or, inversely, a bone factor that lowers mortality risk independent of fracture risk reduction. An association between a low BMD and a significant risk of cardiovascular mortality and all-cause mortality risk was analyzed . An increased coronary artery calcification seems to correlate with a lower BMD. Both factors are independently associated with the severity of artery calcification on the coronaries with the power to predict mortality .
Encouraging news about the anti-osteoporotic treatment being associated with lower mortality rates in osteoporotic patients has been published, and the authors showed increased survival in treated patients . A meta-analysis of 61 randomized controlled trials showed a lower risk of cardiovascular mortality (RR = 0.81, 0.64–1.02, in 10 studies) and a significant reduction in all-cause mortality (RR = 0.90, 0.84–0.98 in 48 studies) with BP treatment .
At the same time, a recent comprehensive meta-analysis of randomized placebo-controlled clinical trials published in 2019  suggested that anti-osteoporotic treatment and bisphosphonates particularly were not associated with lower mortality rates. The majority of the included studies in the meta-analysis reported only osteoporotic patients without a fragility fracture .
The most significant number of patients covered was 163,273 (all major osteoporotic fractures) in the study of Abtahi et al., recently published in 2020. It showed a 28% lower mortality after hip fracture in current BP-treated patients and, interestingly, a 42% lower mortality after hip fracture in patients with past BP exposure (>1 year)  using Cox proportional hazard models.
The HORIZON Zoledronic Acid Once-Yearly Recurrent Fracture Trial One was one of the first studies demonstrating a lower mortality rate after hip fracture associated with anti-osteoporotic treatment . It investigated zoledronic acid , with findings that led to the European Union’s approval of zoledronic acid treatment in osteoporosis. Other studies published in 2011  and 2014  performed secondary analyses using the patients database from the HORIZON study. The first study mentioned  showed lower mortality after 5 mg of zoledronic (HR 0.71, 0.46–1.31 in men and HR 0.74, 0.54–1.02 in women), but with a short median follow-up of 1.9 years. In the second study , the authors analyzed zoledronic acid’s effect in a subgroup of cognitively impaired patients. A minor difference in mortality rate between the two groups in cognitively impaired patients (23.2% compared to 26.9%) was observed, as well as lower mortality rates in the treatment arm (6.2% compared to 10.5% in the placebo arm, p < 0.001). Another secondary analysis of the HORIZON study  showed a lower relative risk of pneumonia or a lower respiratory infection associated with bisphosphonate therapy, although not statistically significant (p > 0.05). Risk and mortality after pneumonia were significantly lower in bisphosphonate-treated patients compared to naive patients but also when compared to other anti-osteoporosis treatments .
Teriparatide was the pro-osteogenic agent investigated. Most of the studies regarding teriparatide and hip fracture are related to secondary outcomes such as accelerated fracture healing and union, with less data regarding mortality or subsequent fractures . The meta-analysis regarding the effect of teriparatide included in the review showed data from two clinical trials and three retrospective cohort studies , with a total of 607 patients. The model showed no significant effect on mortality or subsequent fracture risks . The most important limitation is the lower heterogeneity between included studies, related to the inconsistencies between treatment doses and duration .
It is well known that a prevalent fragility fracture almost doubles the risk of a second fracture . The high mortality associated with hip fracture is even higher in patients who suffer recurrent fractures . A link between the lower mortality after hip fracture in patients with anti-osteoporotic treatment and subsequent lower risk of re-fracture was searched and investigated.
After eight years of follow-up, a prospective cohort study found a lower risk for subsequent fractures (HR 0.60, 0.49–0.73) in treated patients included in Fracture Liaison Services (FLS). Other medical interventions included in addition to anti-osteoporotic treatment can explain in part this association . The FLS implementation was not correlated with a decreased risk of second fractures . All new fractures were recorded in patients not treated in a group multicenter prospective study that investigated the results of implementing FLS in Greece .
Another population-based cohort study  that included 88,320 hip fracture patients found a statistically significant correlation between re-fracture rate and alendronate treatment, also related to the medication possession ratio (MPR).
Although new data showed that anti-osteoporotic treatment does not have an effect on mortality in osteoporotic patients , data regarding only hip fracture patients are still scarce and insufficient. The excess mortality in hip fracture patients  compared to osteoporotic individuals without fracture is an important argument to continue the research for possible beneficial effects for this category. The increased trends of hip fracture incidence worldwide  and the relatively unchanged mortality rates in the last few decades  in hip fracture patients further necessitate the search for possible treatment benefits.