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Anti-Osteoporotic Treatment after Hip Fracture
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.
2. Adherence to 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 .
4. Second Fracture
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.
The entry is from 10.3390/jpm11050341
- Åkesson, K.; IOF Fracture Working Group; Marsh, D.; Mitchell, P.J.; McLellan, A.R.; Stenmark, J.; Pierroz, D.D.; Kyer, C.; Cooper, C. Capture the Fracture: A best practice framework and global campaign to break the fragility fracture cycle. Osteoporos. Int. 2013, 24, 2135–2152.
- Kanis, J.A.; Johansson, H.; Odén, A.; Harvey, N.C.; Gudnason, V.; Sanders, K.M.; Sigurdsson, G.; Siggeirsdottir, K.; Fitzpatrick, L.A.; Borgström, F.; et al. Characteristics of recurrent fractures. Osteoporos. Int. 2018, 29, 1747–1757.
- Johnell, O.; Kanis, J.A.; Odén, A.; Sernbo, I.; Redlund-Johnell, I.; Petterson, C.; De Laet, C.; Jönsson, B. Fracture risk following an osteoporotic fracture. Osteoporos. Int. 2004, 15, 175–179.
- Johansson, H.; Siggeirsdóttir, K.; Harvey, N.C.; Odén, A.; Gudnason, V.; McCloskey, E.; Sigurdsson, G.; A Kanis, J. Imminent risk of fracture after fracture. Osteoporos. Int. 2017, 28, 775–780.
- Haleem, S.; Lutchman, L.; Mayahi, R.; Grice, J.; Parker, M. Mortality following hip fracture: Trends and geographical variations over the last 40 years. Injury 2008, 39, 1157–1163.
- Farahmand, B.Y.; Michaëlsson, K.; Ahlbom, A.; Ljunghall, S.; Baron, J.A.; Swedish Hip Fracture Study Group. Survival after hip fracture. Osteoporos. Int. 2005, 16, 1583–1590.
- Haentjens, P.; Magaziner, J.; Colón-Emeric, C.S.; Vanderschueren, D.; Milisen, K.; Velkeniers, B.; Boonen, S. Meta-analysis: Excess mortality after hip fracture among older women and men. Ann. Intern. Med. 2010, 152, 380–390.
- Boudou, L.; Gerbay, B.; Chopin, F.; Ollagnier, E.; Collet, P.; Thomas, T. Management of osteoporosis in fracture liaison service associated with long-term adherence to treatment. Osteoporos. Int. 2011, 22, 2099–2106.
- Kanis, J.A.; Svedbom, A.; Harvey, N.; McCloskey, E.V. The osteoporosis treatment gap. J. Bone Miner. Res. 2014, 29, 1926–1928.
- McLellan, A.R.; Wolowacz, S.E.; Zimovetz, E.A.; Beard, S.M.; Lock, S.; McCrink, L.; Adekunle, F.; Roberts, D. Fracture liaison services for the evaluation and management of patients with osteoporotic fracture: A cost-effectiveness evaluation based on data collected over 8 years of service provision. Osteoporos. Int. 2011, 22, 2083–2098.
- Benjamin, B.; Benjamin, M.A.; Swe, M.; Sugathan, S. Review on the comparison of effectiveness between denosumab and bisphosphonates in post-menopausal osteoporosis. Osteoporos. Sarcopenia 2016, 2, 77–81.
- Saito, T.; Sterbenz, J.M.; Malay, S.; Zhong, L.; MacEachern, M.P.; Chung, K.C. Effectiveness of anti-osteoporotic drugs to prevent secondary fragility fractures: Systematic review and meta-analysis. Osteoporos. Int. 2017, 28, 3289–3300.
- Goessl, C.; Katz, L.; Dougall, W.C.; Kostenuik, P.J.; Zoog, H.B.; Braun, A.; Dansey, R.; Wagman, R.B. The development of denosumab for the treatment of diseases of bone loss and cancer-induced bone destruction. Ann. N. Y. Acad. Sci. 2012, 1263, 29–40.
- Palacios, S.; Kalouche-Khalil, L.; Rizzoli, R.; Zapalowski, C.; Resch, H.; Adachi, J.D.; Gallagher, J.C.; Feldman, R.G.; Kendler, D.L.; Wang, A.; et al. Treatment with denosumab reduces secondary fracture risk in women with postmenopausal osteoporosis. Climacteric 2015, 18, 805–812.
- Austin, M.; Yang, Y.; Vittinghoff, E.; Adami, S.; Boonen, S.; Bauer, D.C.; Bianchi, G.; A Bolognese, M.; Christiansen, C.; Eastell, R.; et al. FREEDOM Trial. Relationship between bone mineral density changes with denosumab treatment and risk reduction for vertebral and nonvertebral fractures. J. Bone Miner. Res. 2012, 27, 687–693.
- Fahrleitner-Pammer, A.; Papaioannou, N.; Gielen, E.; Tepie, M.F.; Toffis, C.; Frieling, I.; Geusens, P.; Makras, P.; Boschitsch, E.; Callens, J.; et al. Factors associated with high 24-month persistence with denosumab: Results of a real-world, non-interventional study of women with postmenopausal osteoporosis in Germany, Austria, Greece, and Belgium. Arch. Osteoporos. 2017, 12, 1–13.
- Hadji, P.; Papaioannou, N.; Gielen, E.; Tepie, M.F.; Zhang, E.; Frieling, I.; Geusens, P.; Makras, P.; Resch, H.; Moller, G.L.; et al. Persistence, adherence, and medication-taking behavior in women with postmenopausal osteoporosis receiving denosumab in routine practice in Germany, Austria, Greece, and Belgium: 12-month results from a European non-interventional study. Osteoporos. Int. 2015, 26, 2479–2489.
- Shah, A.; The REFRESH Study Team. Prieto-Alhambra, D.; Hawley, S.; Delmestri, A.; Lippett, J.; Cooper, C.; Judge, A.; Javaid, M.K. Geographic variation in secondary fracture prevention after a hip fracture during 1999–2013: A UK study. Osteoporos. Int. 2017, 28, 169–178.
- Brozek, W.; Reichardt, B.; Zwerina, J.; Dimai, H.P.; Klaushofer, K.; Zwettler, E. Antiresorptive therapy and risk of mortality and refracture in osteoporosis-related hip fracture: A nationwide study. Osteoporos. Int. 2016, 27, 387–396.
- Suzuki, T.; Yoshida, H. Low bone mineral density at femoral neck is a predictor of increased mortality in elderly Japanese women. Osteoporos. Int. 2009, 21, 71–79.
- Nguyen, N.D.; Center, J.R.; Eisman, J.A.; Nguyen, T.V. Bone loss, weight loss, and weight fluctuation predict mortality risk in elderly men and women. J. Bone Miner. Res. 2007, 22, 1147–1154.
- Qu, X.; Huang, X.; Jin, F.; Wang, H.; Hao, Y.; Tang, T.; Dai, K. Bone mineral density and all-cause, cardiovascular and stroke mortality: A meta-analysis of prospective cohort studies. Int. J. Cardiol. 2013, 166, 385–393.
- Ahmadi, N.; Mao, S.S.; Hajsadeghi, F.; Arnold, B.; Kiramijyan, S.; Gao, Y.; Flores, F.; Azen, S.; Budoff, M. The relation of low levels of bone mineral density with coronary artery calcium and mortality. Osteoporos. Int. 2018, 29, 1609–1616.
- Sambrook, P.N.; Cameron, I.D.; Chen, J.S.; March, L.M.; Simpson, J.M.; Cumming, R.G.; Seibel, M.J. Oral bisphosphonates are associated with reduced mortality in frail older people: A prospective five-year study. Osteoporos. Int. 2011, 22, 2551–2556.
- Center, J.R.; Bliuc, D.; Nguyen, N.D.; Nguyen, T.V.; Eisman, J.A. Osteoporosis medication and reduced mortality risk in elderly women and men. J. Clin. Endocrinol. Metab. 2011, 96, 1006–1014.
- Cummings, S.R.; Lui, L.-Y.; Eastell, R.; Allen, I.E. Association between drug treatments for patients with osteoporosis and overall mortality rates. JAMA Intern. Med. 2019, 179, 1491–1500.
- Abtahi, S.; Burden, A.M.; Geusens, P.; van den Bergh, J.P.; Van Staa, T.; De Vries, F. The association of oral bisphosphonate use with mortality risk following a major osteoporotic fracture in the United Kingdom: Population-based cohort study. J. Am. Med. Dir. Assoc. 2020, 21, 811–816.
- Lyles, K.W.; Colón-Emeric, C.S.; Magaziner, J.S.; Adachi, J.D.; Pieper, C.F.; Mautalen, C.; Hyldstrup, L.; Recknor, C.; Nordsletten, L.; Moore, K.A.; et al. HORIZON recurrent fracture trial. Zoledronic acid and clinical fractures and mortality after hip fracture. N. Engl. J. Med. 2007, 357, 1799–1809.
- Boonen, S.; Orwoll, E.; Magaziner, J.; Colón-Emeric, C.S.; Adachi, J.D.; Bucci-Rechtweg, C.; Haentjens, P.; Kaufman, J.-M.; Rizzoli, R.; Vanderschueren, D.; et al. HORIZON recurrent fracture trial. Once-yearly zoledronic acid in older men compared with women with recent hip fracture. J. Am. Geriatr. Soc. 2011, 59, 2084–2090.
- Prieto-Alhambra, D.; Judge, A.; Arden, N.K.; Cooper, C.; Lyles, K.W.; Javaid, M.K. Fracture prevention in patients with cognitive impairment presenting with a hip fracture: Secondary analysis of data from the HORIZON Recurrent Fracture Trial. Osteoporos. Int. 2013, 25, 77–83.
- Reid, I.R.; Horne, A.M.; Mihov, B.; Stewart, A.; Bastin, S.; Gamble, G.D. Effect of zoledronate on lower respiratory infections in older women: Secondary analysis of a randomized controlled trial. Calcif. Tissue Int. 2021, 1–5.
- Sing, C.; Kiel, D.P.; Hubbard, R.B.; Lau, W.C.; Li, G.H.; Kung, A.W.; Wong, I.C.; Cheung, C. Nitrogen-containing bisphosphonates are associated with reduced risk of pneumonia in patients with hip fracture. J. Bone Miner. Res. 2020, 35, 1676–1684.
- Han, S.; Wen, S.-M.; Zhao, Q.-P.; Huang, H.; Wang, H.; Cong, Y.-X.; Shang, K.; Ke, C.; Zhuang, Y.; Zhang, B.-F. The efficacy of teriparatide in improving fracture healing in hip fractures: A systematic review and meta-analysis. BioMed Res. Int. 2020, 2020, 591450.
- Behanova, M.; Reichardt, B.; Stamm, T.A.; Zwerina, J.; Klaushofer, K.; Kocijan, R. treatment effects of bisphosphonates and denosumab on survival and refracture from real-world data of hip-fractured patients. Calcif. Tissue Int. 2019, 105, 630–641.
- Sambrook, P.N.; Chen, C.J.; March, L.; Cameron, I.D.; Cumming, R.G.; Lord, S.R.; Simpson, J.M.; Seibel, M.J. High bone turnover is an independent predictor of mortality in the frail elderly. J. Bone Miner. Res. 2006, 21, 549–555.
- Santini, D.; Martini, F.; Fratto, M.E.; Galluzzo, S.; Vincenzi, B.; Agrati, C.; Turchi, F.; Piacentini, P.; Rocci, L.; Manavalan, J.S.; et al. In vivo effects of zoledronic acid on peripheral γδ T lymphocytes in early breast cancer patients. Cancer Immunol. Immunother. 2008, 58, 31–38.
- Carbone, L.D.; Warrington, K.J.; Barrow, K.D.; Pugazhenthi, M.; Watsky, M.A.; Somes, G.; Ingels, J.; Postlethwaite, A.E. Pamidronate infusion in patients with systemic sclerosis results in changes in blood mononuclear cell cytokine profiles. Clin. Exp. Immunol. 2006, 146, 371–380.
- Sawalha, S.; Parker, M.J. Characteristics and outcome in patients sustaining a second contralateral fracture of the hip. J. Bone Jt. Surg. Br. Vol. 2012, 94, 102–106.
- Van Geel, T.A.C.M.; Bliuc, D.; Geusens, P.P.M.; Center, J.R.; Dinant, G.-J.; Tran, T.; van den Bergh, J.P.W.; McLellan, A.R.; Eisman, J.A. Reduced mortality and subsequent fracture risk associated with oral bisphosphonate recommendation in a fracture liaison service setting: A prospective cohort study. PLoS ONE 2018, 13, e0198006.
- González-Quevedo, D.; Bautista-Enrique, D.; Pérez-Del-Río, V.; Bravo-Bardají, M.; García-De-Quevedo, D.; Tamimi, I. Fracture liaison service and mortality in elderly hip fracture patients: A prospective cohort study. Osteoporos. Int. 2019, 31, 77–84.
- Makras, P.; Babis, G.C.; Chronopoulos, E.; Karachalios, T.; Kazakos, K.; Paridis, D.; Potoupnis, M.; Tzavellas, A.-N.; Valkanis, C.; Kosmidis, C. Experience gained from the implementation of the fracture liaison service in Greece. Arch. Osteoporos. 2020, 15, 12.
- Chen, Y.; Kung, P.; Chou, W.; Tsai, W. Alendronate medication possession ratio and the risk of second hip fracture: An 11-year population-based cohort study in Taiwan. Osteoporos. Int. 2020, 31, 1555–1563.
- Kanis, J.; Oden, A.; Johnell, O.; De Laet, C.; Jonsson, B.; Oglesby, A. The components of excess mortality after hip fracture. Bone 2003, 32, 468–473.
- Senohradski, K.; Markovic-Denic, L.; Lešić, A.; Bumbasirevic, V.; Bumbasirevic, M. Trends in the incidence of hip fractures. Osteoporos. Int. 2013, 24, 1759–1763.