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Keywords:

  • aging;
  • clinical trials;
  • menopause;
  • osteoporosis;
  • bisphosphonates

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials And Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References

Zoledronic acid reduces the risk of death by 28% after hip fracture, but the mechanisms are not known. This exploratory analysis sought to identify potential pathways for the reduction in mortality with zoledronic acid after hip fracture. This was a retrospective analysis of a randomized, controlled trial. Patients with recent hip fracture (n = 2111) were treated with zoledronic acid or placebo infusion yearly, as well as calcium and vitamin D supplementation. Causes of death were adjudicated by a blinded central review committee. Baseline comorbidities, events occurring during the study period, including subsequent fracture, change in bone density, infections, cardiovascular events, arrhythmias, and falls, were included in multivariable analyses. In a model adjusted for baseline risk factors, zoledronic acid reduced the risk of death by 25% [95% confidence interval (CI) 0.58–0.97). The effect was consistent across most subgroups. Subsequent fractures were significantly associated with death (hazard ratio 1.72, 95% CI 1.17–2.51) but explained only 8% of the zoledronic acid effect. Adjusting for acute events occurring during follow-up eliminated the death benefit, and zoledronic acid–treated subjects were less likely to die from pneumonia (interaction p = .04) and arrhythmias (interaction p = .02) than placebo-treated subjects. Only 8% of zoledronic acid's death benefit is due to a reduction in secondary fractures. Zoledronic acid may have an effect on cardiovascular events and pneumonia. Further studies of zoledronic acid in other acute illnesses may be warranted. Copyright © 2010 American Society for Bone and Mineral Research


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials And Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References

Hip fractures are associated with substantial excess mortality in older adults.1 The risk of death in the first 6 months after hip fracture, adjusted for multiple risk factors, is up to 7-fold greater for women and 40-fold greater for men compared with those without fracture.2 In many,2, 3 but not all studies,1 an increased risk of mortality persists for at least 5 years after the hip fracture. With the aging population, the risk of death owing to hip fractures is expected to increase.4 These data highlight the urgent need to identify strategies to reduce the risk of mortality following hip fractures.

The intravenous bisphosphonate zoledronic acid given as an annual 5 mg infusion after hip fracture reduced the risk of clinical fracture by 35% and the risk of death by 28% compared with placebo.5 Although osteoporotic fractures (including vertebral fractures) have been shown to be associated with increased mortality,6 this significant mortality reduction was unexpected in a trial powered to show a reduction in clinical fractures, and this was the first trial to demonstrate that an osteoporosis therapy can reduce mortality significantly. This mortality benefit was manifested after the first year of treatment and persisted after adjustment for demographic and baseline variables. However, the pathway(s) or underlying mechanism(s) producing the benefit remain unknown.

Previous research has suggested several potential physiologic mechanisms for bisphosphonates to affect mortality after hip fracture. A hip fracture is associated with substantial increases in proinflammatory cytokines such as interleukin 6 (IL-6), IL-8, IL-10, C-reactive protein, tumor necrosis factor-α (TNF-α), and vascular endothelial growth factor (VEGF).7–13 These increases can be measured in bone, in plasma, and in cerebrospinal fluid and may persist for months in some patients. Persistently elevated proinflammatory markers are associated with perioperative complications and worse long-term functional outcomes8–10 and are hypothesized to explain the excess infections and cardiovascular events observed in the 1 to 2 years after hip fracture. Intravenous bisphosphonates have immunomodulatory effects, affecting both dendritic cells and γδ T cells,14 with variable changes in proinflammatory cytokines, TNF-α, and VEGF.15 Clinically, this effect is likely responsible for the acute-phase reaction of fever and myalgia, as well as the transient lymphocytopenia and increased C-reactive protein seen in patients receiving intravenous bisphosphonates.16 With long-term administration, an anti-inflammatory effect has been observed in animal models of arthritis and colitis and in case series of patients with rheumatoid arthritis.15 In cancer patients treated with intravenous pamidronate, a significant decrease in angiogenic factors such as VEGF also has been documented.17 Therefore, by modifying the inflammatory, angiogenic, and immunologic effects of hip fracture, intravenous bisphosphonates potentially could mediate a mortality benefit through decreased cardiovascular disease, infections, or malignancies.

A better understanding of the patient and disease factors that influence the reduction in mortality of zoledronic acid may inform both clinical practice and future research. Therefore, the purpose of this retrospective analysis was to determine how much of the mortality effect could be explained by the reduction in fracture incidence and how much was due to other bisphosphonate effects or other medical conditions. Specifically, we hypothesized that the reduction in mortality risk could be related to secondary fracture reduction, reduction in cardiovascular disease, or reduction in infections.

Materials And Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials And Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References

The design of the HORIZON Recurrent Fracture Trial has been reported elsewhere.5 This was a randomized, double-blind, placebo-controlled trial of intravenous zoledronic acid 5 mg administered annually beginning within 90 days of low-trauma hip fracture repair. Prespecified key outcomes were time to clinical fracture and death.

Subjects and randomization

Participants were 50 years of age or older, ambulatory prior to the hip fracture, and unwilling or unable to take an oral bisphosphonate. Participants were excluded for recent bisphosphonate, strontium, or parathyroid hormone use. Additional exclusion criteria included an active malignancy, calculated creatinine clearance less than 0.5 mL/s (30 mL/min), hyper- or hypocalcaemia, metabolic bone disease other than osteoporosis, and life expectancy of less than 1 year as judged by the investigator. Randomization was blocked by site and performed centrally using an interactive voice-response system.

Interventions and follow-up

All subjects either had a documented 25,OH-vitamin D level >15 ng/mL or received a loading dose of 50,000 to 125,000 IU vitamin D2 or D3 two weeks prior to study drug infusion. All subjects received oral daily calcium (1000 to 1500 mg/d) and vitamin D (800 to 1000 IU/d). Concomitant therapy with calcitonin, hormone-replacement therapy, or selective estrogen receptor modulators was allowed. Subjects were seen annually and were contacted by telephone every 3 months for a mean follow-up period of approximately 2 years. All study procedures were approved by the local ethics or institutional review board. Clinical trial registration number is NET00046254.

Death ascertainment and adjudication

Adverse events and serious adverse events were recorded by the site investigator at each contact and were coded in the trial database using the Medical Dictionary for Regulatory Activities (MedDRA) preferred term. The site investigator indicated the primary cause for all deaths. In addition, a blinded central adjudication committee consisting of 2 geriatricians and 3 cardiologists examined source documents submitted by the investigator (including clinical notes, death certificates, and accounts from family members) and coded the death as “cardiovascular,” “cerebrovascular,” “other,” or “unknown.” The “other” category was broken down further to include infection, malignancy, respiratory (e.g., chronic lung disease), and other vascular deaths.

Analysis

This analysis includes the 2111 participants who received at least one dose of study drug. To adjust for potential confounders at baseline that may have been maldistributed by chance despite the randomization process, stepwise Cox proportional hazards regression analysis was performed, including the following variables: gender, race, age, geographic region, body mass index (BMI), baseline Short Portable Mental Status Questionnaire (SPMSQ) score (an indicator of cognitive impairment), femoral neck T-score, type of qualifying hip fracture (e.g., femoral neck, intertrochanteric, subcapital, subtrochanteric), place of residence prior to hip fracture (e.g., private residence, assisted living, nursing home), discharge destination after hip fracture, previous history of fracture, previous bisphosphonate use, hypertension, diabetes, stroke, hypercholesterolemia, coronary artery disease, congestive heart failure, tachyarrhythmia, bradyarrhythmia, history of atrial fibrillation, valvular heart disease, and hyperthyroidism.

To explore whether postrandomization events (time-dependent covariates) were associated with subsequent mortality, a Cox regression model with time-dependent covariates was used to adjust for the percentage change in bone mineral density at the end of the study relative to baseline, falls occurring during the study, subsequent fractures, pneumonia, acute-phase reactions, and cardiac arrhythmias, whereas stepwise model selection was used to chose additional baseline risk factors. Although some of these variables are discrete events (e.g., falls, pneumonia), the model did not assume return to baseline state because such events are associated with a persistently elevated risk for functional decline and death in older adults. The distribution of the causes of death, as adjudicated by the blinded central committee, was similar to those reported by the investigator. Since only 50% of death cases could be adjudicated based on available documents, the investigator-reported deaths are used in these analyses. To explore whether these baseline and time-dependent covariates were potential mediators of zoledronic acid's mortality benefit, treatment by covariate interaction terms was added to the selected Cox regression model along with the risk factor (if not included in the chosen model) to determine if the risk of death was influenced by the presence of specific baseline and postbaseline risk factors and the treatment received.

To explore whether zoledronic acid affected immune function as a mediator of its death benefit, the presence of acute-phase reaction during the first infusion (defined as fever, myalgia, arthralgia, headache, or influenza-like illness within 72 hours of study drug administration) was added to the model as a marker of greater zoledronic acid immunomodulatory effect.

Role of the funding source

The study was sponsored by Novartis Pharmaceuticals Corporation and Novartis Pharma AG. The study sponsor participated in the study design, analysis, interpretation of the data, and authoring of the first draft. Independent steering committee members had full access to the data. An independent statistical replication of the main study results, including the mortality benefit, was conducted at the University of California San Francisco. Study sponsor contracted BioScience Communications of New York, NY, to provide additional editorial support in preparation of this article.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials And Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References

Baseline characteristics, including risk factors for mortality, were similar in the zoledronic acid and placebo groups (Table 1). The cumulative mortality rates were 9.6% in the zoledronic acid group and 13.3% in the placebo group [hazard ratio (HR) 0.72; 95% confidence interval (CI) 0.56–0.93; P = .01]. The mortality curves did not separate until approximately 16 months after the first infusion (Fig. 1), which was approximately 12 months after the first separation in clinical fracture incidence rates (approximately month 4).

Table 1. Baseline Characteristics for Zoledronic Acid and Placebo-Treated Subjects
 Zoledronic acid, N = 1054Placebo, N = 1057P valuea
  • a

    P value based on Fisher's exact test/chi-square test as applicable.

Female (%)810 (76.8)796 (75.3)0.41
Age (%)  0.25
 <65172 (16.3)191 (18.1) 
 65–74305 (28.9)268 (25.3) 
 75–84440 (41.7)447 (42.3) 
 ≥85137 (13.0)151 (14.3) 
Race (%)  0.76
 Caucasian962 (91.3)960 (90.8) 
 Other92 (8.7)97 (9.2) 
Geographic region (%)  0.90
 North America297 (28.2)313 (29.6) 
 Latin America132 (12.5)131 (12.4) 
 Western Europe356 (33.8)353 (33.4) 
 Eastern Europe269 (25.5)260 (24.6) 
BMI (kg/m2)  0.90
 <1979 (7.5)72 (6.8) 
 19–25502 (47.6)506 (47.9) 
 >25441 (41.8)450 (42.6) 
SPMSQ Score (%)  0.78
 0524 (49.7)523 (49.5) 
 >0–2283 (26.9)285 (27.0) 
 >2168 (15.9)180 (17.0) 
 Missing79 (7.5)69 (6.5) 
Femoral neck T-score  0.94
 −2.5 or less448 (42.5)437 (41.3) 
 Greater than −2.5 to −1.5360 (34.2)374 (35.4) 
 Greater than −1.5122 (11.6)121 (11.4) 
 Missing124 (11.8)125 (11.8) 
Hip fracture type (%)  0.78
 Intertrochanteric335 (31.8)342 (32.4) 
 Subtrochanteric48 (4.5)57 (5.4) 
 Subcapital221 (21.0)211 (20.0) 
 Femoral neck354 (33.6)373 (35.3) 
 Other76 (7.2)74 (7.0) 
Prior residence (%)  0.35
 Private home945 (89.7)928 (87.8) 
 Assisted living60 (5.7)61 (5.8) 
 Skilled nursing facility31 (2.9)44 (4.2) 
 Other18 (1.7)24 (2.3) 
Hypertension (%)543 (51.5)567 (53.6)0.34
Diabetes (%)173 (16.4)160 (15.1)0.44
Stroke (%)181 (17.2)190 (18.0)0.65
Coronary artery disease (%)209 (19.8)224 (21.2)0.45
Tachyarrhythmia (%)61 (5.8)79 (7.5)0.14
thumbnail image

Figure 1. Cumulative mortality incidence in zoledronic acid and placebo groups.

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The investigator-reported primary causes of death are listed in Table 2. There was a trend toward more cardiac and respiratory failure–related deaths in the placebo group (Fig. 2, top panel). The blinded central adjudication committees further classified arrhythmias that led to hospitalization and cardiac death based on available source documentation. However, 58 of 88 (65.9%) deaths coded by the site investigator as cardiac could not be classified by the adjudication committee owing to inadequate source documents; e.g., deaths occurring at home frequently lacked evaluable medical records. For the cardiac events that could be adjudicated (n = 29), 11 for zoledronic acid and 18 for placebo), 3 of 29 (10.3%) were due to sudden cardiac death, 10 of 29 (34.5)% were due to pump failure, 11 of 29 (37.9%) were due to fatal myocardial infarctions, 2 of 29 (6.9%) were due to fatal arrhythmias, 1 of 29 (3.5%) was due to other cardiac deaths, and 7 of 29 (24.1%) were due unspecified cardiac causes. Note that it was possible for deaths to be attributed to more than one cardiac factor. Other illnesses, such as pneumonia, were confirmed but not further classified by the blinded adjudication committee.

Table 2. Causes of Death in Placebo- and Zoledronic Acid–Treated Patients
 Zoledronic acid, N = 1054Placebo, N = 1057P valuea
  • a

    P value based on Fisher's exact test.

All causes (%)101 (9.6)141 (13.3)0.01
Cardiac36 (3.4)52 (4.9)0.10
Infectious18 (1.7)14 (1.3)0.48
Respiratory13 (1.2)22 (2.1)0.17
Neoplasms7 (0.7)13 (1.2)0.26
Cerebrovascular10 (1.0)11 (1.0)1.00
Gastrointestinal2 (0.2)4 (0.4)0.69
Cachexia/failure to thrive1 (0.1)1 (0.1)1.00
Renal1 (0.1)3 (0.3)0.62
Other vascular3 (0.3)3 (0.3)1.00
thumbnail image

Figure 2. Incidence of common conditions in the zoledronic acid (ZOL) and placebo groups (top panel) and the risk of dying from a given condition among subjects who experienced that condition (bottom panel).

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The magnitude and direction of the mortality benefit were consistent across most subgroups (Table 3). Males experienced a greater absolute mortality benefit than females (6.4% versus 2.8%) but had a similar reduction in the risk of death. Subjects living in a nursing facility prior to their hip fracture and subjects with baseline SPMSQ scores greater than 2 (indicating greater cognitive impairment) had a similar risk of death regardless of treatment arm.

Table 3. Relative Risk of Death in Zoledronic Acid–Treated Subjects Compared With Placebo-Treated Subjects by Subgroup
SubgroupCumulative death rates, zoledronic acid, N = 1054 (%)Cumulative death rates, placebo, N = 1057 (%)Hazard ratio (95% CI)
Gender   
 Male32/244 (22.0)51/261 (25.5)0.71 (0.46, 1.31)
 Female69/810 (11.9)90/796 (15.6)0.74 (0.54, 1.02)
Race   
 Caucasian93/962 (14.6)128/960 (18.2)0.73 (0.56, 0.95)
 Other8/92 (10.2)13/97 (16.7)0.63 (0.26, 1.51)
Age   
 <75 years23/477 (5.1)31/460 (9.8)0.75 (0.44, 1.28)
 75–84 years44/440 (16.7)64/447 (20.4)0.71 (0.49, 1.05)
 ≥85 years34/137 (31.7)46/150 (36.7)0.72 (0.46, 1.12)
Region   
 North America54/297 (22.0)74/313 (25.4)0.76 (0.53, 1.07)
 Latin America9/132 (7.8)17/131 (20.2)0.54 (0.24, 1.21)
 Western Europe23/356 (9.9)32/353 (13.4)0.71 (0.42, 1.21)
 Eastern Europe15/269 (6.3)18/260 (8.4)0.81 (0.41, 1.61)
BMI (kg/m2)   
 <1911/79 (19.0)23/72 (42.8)0.43 (0.21, 0.89)
 19–2554/502 (17.2)66/506 (15.7)0.82 (0.58, 1.18)
 >2528/441 (6.6)47/450 (17.4)0.59 (0.37, 0.95)
SPMSQ score   
 024/524 (5.7)37/523 (10.8)0.65 (0.39, 1.09)
 >0–225/283 (13.4)49/285 (24.8)0.47 (0.29, 0.77)
 >240/168 (35.1)47/180 (31.6)0.96 (0.63, 1.46)
Femoral neck T-score−2.5 or less   
 Greater than −2.5 to −1.552/448 (16.3)76/437 (22.6)0.70 (0.49, 0.99)
 or less19/360 (9.4)28/374 (9.9)0.71 (0.40, 1.27)
 Greater than −1.53/122 (4.1)12/121 (13.5)0.22 (0.06, 0.77)
Residence prior to hip fracture   
 Private home73/945 (11.9)103/928 (14.9)0.70 (0.52, 0.95)
 Assisted living11/60 (25.6)17/61 (41.0)0.71 (0.33, 1.51)
 Skilled nursing facility14/31 (55.6)18/44 (51.0)1.02 (0.51, 2.05)

In a model adjusting for multiple baseline risk factors (e.g., time to dosing following hip fracture repair, age, sex, private residence before hip fracture, private residence after hip fracture, cognitive impairment, BMI, diabetes, coronary artery disease, congestive heart failure, hypercholesterolemia, and baseline femoral neck T-score), zoledronic acid significantly reduced the risk of death relative to placebo (HR 0.75, 95% CI 0.58–0.97, p = .03; Table 4).

Table 4. Comparison of Models for Mortality
 Hazard ratio96% CI
Unadjusted0.720.56–0.93
Adjusting for baseline risk0.750.58–0.97
Adjusting for baseline risk and new clinical fractures0.770.59–0.99
Adjusting for baseline and competing risk including acute phase reaction0.970.74–1.28

Subsequent postrandomization fractures were significantly associated with higher risk of death (HR 1.62, 95% CI 1.09–2.40) independent of treatment. Including this factor in the model reduced the risk reduction of zoledronic acid slightly (HR = 0.77, 95% CI 0.59–0.99), suggesting that 0.02 of the 0.25 risk reduction or approximately 8% of zoledronic acid's death benefit is mediated through its reduction of fracture rates. A treatment-by-fracture interaction term was not significant, indicating that subjects who fractured had a similar risk of mortality regardless of treatment group.

To explore whether zoledronic acid might affect death through an immunomodulatory effect, subjects with acute-phase reactions occurring during the first infusion were compared with subjects without such a reaction. Although subjects with acute-phase reaction were only half as likely to die as subjects without acute-phase reactions (5.2% versus 11.9%, p = .02), this variable was not significant when adjusting for the other risk factors in the multivariate models.

Including other competing risks for death that occurred after first-study drug infusion (change in bone mineral density, falls, pneumonia, other infection, acute-phase reaction, cardiovascular disease, and cardiac arrhythmia) and further performing stepwise model selection on baseline risks to the model eliminated the mortality benefit (see Table 4). This suggests that either these events occurred more often in placebo-treated participants by chance or that zoledronic acid's death benefit is mediated through one or more of those pathways. Most notably, cardiac arrhythmias (HR 14.3, 95% CI 10.4–19.8) and pneumonia (HR 3.46, 95% CI 2.40–4.98) were highly associated with mortality. Significant interactions for zoledronic acid treatment by pneumonia (p = .04) and zoledronic acid by arrhythmia (p = .02) were observed. The parameter estimates indicate a greater reduction in death for patients who received zoledronic acid and experienced these events than those who received placebo and experienced these events (see Fig. 2, bottom panel) despite a similar incidence of pneumonia and arrhythmia in the groups (see Fig. 2, top panel). No other notable treatment-by-factor interactions were observed, although there was a nonsignificant trend toward decreased risk of dying from other cardiac deaths, respiratory failure, and neoplasia despite overall similar incidence of these conditions in the study arms (see Fig. 2).

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials And Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References

These analyses attempt to disentangle the mechanism(s) for zoledronic acid's (Aclasta/Reclast, Novartis Pharma AG) impact on mortality. While a definitive explanation cannot be obtained from a retrospective analysis of clinical trial data, the insights from this study will help to guide further basic research and epidemiologic inquiries.

Zoledronic acid's benefit was similar across a wide range of subgroups and disease states. Even the oldest age group (>85 years) derived a death benefit, although there is a suggestion that subjects with characteristics associated with greater frailty, such as prior nursing home residence or high degrees of cognitive impairment, do not receive as large a death benefit. While making treatment decisions based on post hoc subgroup analyses is inadvisable, clinicians should give consideration to zoledronic acid's death benefit, which manifests in the second year of treatment, to their patients' remaining life expectancy and competing risks of mortality.

In contrast, the statistically significant fracture benefit of zoledronic acid is seen as early as 12 months, and previous studies have shown a strong association between fractures and mortality. Acute and subacute fracture complications such as myocardial ischemia, venous thromboembolism, and fat embolism and the hazards associated hospitalization and delirium may explain some of this excess risk.18 However, after adjusting for secondary fractures and other baseline risk factors, the risk of mortality was still 23% lower in zoledronic acid–treated participants, suggesting that other pathways also may be involved.

One of our a priori hypotheses was that zoledronic acid might affect cardiovascular mortality. There is a clear epidemiologic association between osteoporosis and cardiovascular disease,19 with suppression of monocyte-macrophages,20 alteration in cytokines, and vascular calcium deposition suggested as common pathophysiologic mechanisms. A meta-analysis of subjects enrolled in clinical trials testing the oral bisphosphonate risedronate showed a trend toward lower cardiovascular mortality driven primarily by a reduction in strokes.21 Given the 29% prevalence of elevated markers of myocardial injury in hip fracture patients and its association with subsequent mortality,22 any impact of bisphosphonates on cardiovascular disease may be particularly important in hip fracture patients. We found a trend toward decreased arrhythmias and cardiovascular deaths in zoledronic acid–treated patients and a significant treatment by postrandomization arrhythmia interaction. This contrasts with the previous report of increased atrial fibrillation serious adverse events with zoledronic acid in postmenopausal women.23 Bisphosphonates affect ion channels in several cell lines, including cardiac myocytes24, 25; thus a true bisphosphonate impact on arrhythmia is physiologically plausible. Alternatively, since many arrhythmias in older adults are precipitated by myocardial ischemia, the reduction in arrhythmia incidence and death rates may reflect an impact on cardiovascular disease rather than on the conduction system. Further studies are needed to disentangle this controversy.26

Another possible pathway is through a bisphosphonate effect on the immune system. In addition to the changes in cytokines and the monocyte-macrophage system noted earlier, there is epidemiologic evidence to support this hypothesis. A greater than 10-fold increased relative risk of infectious death, particularly septicemia and pneumonia, was seen in a cohort of hip fracture patients relative to the general population over 2 years.27 We found a treatment by postrandomization pneumonia interaction that suggested that zoledronic acid–treated patients were less likely to die from a pneumonia event than placebo-treated patients even though the overall incidence of pneumonia was similar between treatment groups (5.5% versus 5.6%).

A third hypothesis is that rather than influencing one particular organ system, zoledronic acid influences physiologic reserve more generally and thus the ability to “recover” from acute illnesses. Hormetic effects, where low-level or intermittent exposure to a substance produces enhanced ability to withstand stressors, while high-level or chronic exposure is toxic, have been noted in osteoblasts.28 A hormetic effect could explain the mortality pattern we observed: a lower risk of death from a variety of illnesses despite a similar overall incidence of these illnesses. Although direct evidence is lacking, zoledronic acid might produce a hormetic response directly or through impact on inflammatory cytokines or other mediators. The lower death rate in participants who experienced an acute-phase reaction is intriguing and consistent with a hormetic response. However, this finding also could be due to preexisting inflammatory or malignant conditions that decrease the risk of experiencing an acute-phase reaction and are also associated with higher subsequent mortality. Persistently elevated inflammatory cytokines such as IL-6 after hip fracture have been associated with adverse clinical outcomes in older patients, such as reduced lower extremity function29 and cognitive decline.30, 31 Little is known about the long-term effects of zoledronic acid on the immune system, and further studies exploring the link between changes in inflammatory markers with zoledronic acid and mortality may be warranted.

This analysis has several limitations. First, the subjects enrolled in this clinical trial were likely healthier than the general population of hip fracture patients; this could affect the rate and types of deaths we observed. However, the distribution of the causes of mortality in the HORIZON Recurrent Fracture Trial was similar to that reported in previous cohort studies. Second, the primary cause of death could not be adjudicated in a high proportion of subjects owing to unwitnessed events, missing source documentation, or multiorgan system disease with an unclear precipitant. Since a common cause of unwitnessed sudden death is cardiovascular events, the distribution of the missing data is likely not random. Finally, we relied on investigator-reported adverse events and baseline comorbidities for our models, and the accuracy and completeness of their reporting are not known.

In summary, our analysis suggests that zoledronic acid's impact on mortality is mediated only to a small extent through its fracture-reduction benefit. Subjects treated with zoledronic acid were less likely to die from cardiac arrhythmias and pneumonia than placebo-treated subjects. The mechanism for this finding is currently unknown and warrants further prospective studies.

Disclosures

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials And Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References

Cathleen Colón-Emeric, Kenneth Lyles, Jay Magaziner, Carl Pieper, and Steven Boonen have received research funding and are consultants for Novartis. Peter Mesenbrink is an employee of Novartis Pharmaceuticals Corporation and a shareholder in the company. Erik Eriksen was an employee of Novartis Pharma AG at the time of the development of this article and is now a consultant for the company. Dr. Colón-Emeric is supported by Paul A. Beeson Award K23 AG024787. Dr. Boonen is senior clinical investigator of the Fund for Scientific Research-Flanders, Belgium (F.W.O.-Vlaanderen) and holder of the Leuven University Chair in Metabolic Bone Diseases. Dr. Lyles holds patent “Methods for preventing or reducing secondary fractures after hip fracture” (US Patent Application 20050272707) and is Provisional Patent Application Inventor of “Medication Kits and Formulations for Preventing, Treating or Reducing Secondary Fractures after Previous Fracture.” Dr. Magaziner's effort was supported, in part, by grants from the National Institute on Aging (NIA) and the Claude D. Pepper Older Americans Independence Center P30-AG028747, R37 AG009901, R01 AG029315, and R01 AG018668.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials And Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References

The HORIZON Recurrent Fracture Trial was funded by Novartis Pharmaceuticals. The authors wish to thank BioScience Communications for editorial support in preparation of this manuscript.

Cathleen S. Colon-Emeric participated in the planning of the study, the collecting of data, the supervision of analyses, the interpretation of results, authoring of the first draft of this article, and final responsibility for the decision to submit it for publication. Peter Mesenbrink participated in planning the study, performing the statistical analyses, interpreting the results, and authoring of the first draft of this article. Kenneth W. Lyles participated in the planning of the study, the collection of data, the supervision of analyses, and the interpretation of results. Carl F. Pieper participated in the planning of the study, the collection of data, and the interpretation of results. Steven Boonen participated in the planning of the study, the collection of data, and the interpretation of results. Pierre Delmas participated in the planning of the study, the collection of data, and the interpretation of results. Erik F. Eriksen participated in the planning of the study, the collection of data, and the interpretation of results. Jay Magaziner participated in the planning of the study, the collection of data, and the interpretation of results. All authors were involved in planning the article, critical review of the first draft, and subsequent revisions to the paper. All have seen and approved the final version, excepting Pierre Delmas, who passed away before it was completed.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials And Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References