Heart Failure is an Independent Risk Factor for Incident Hip, Proximal Humerus, and Wrist Fractures in a High-Risk Older Population.

INTRODUCTION

Heart failure (HF) is a growing public health problem among older adults. Beyond cardiovascular, mortality, and quality of life consequences, studies suggest that HF increases osteoporosis independent of shared risk factors such as older age, menopause, smoking, and diabetes. 1 – 3 Adults with HF may have excess risk of hip and humerus fractures, 2 – 4 with higher associated mortality. 5 While adults with recent-onset HF may have lower bone mineral density than those without HF, bone density differences, osteoporosis risk factors, and some comorbidities do not fully explain the increased risk for osteoporotic fractures, which may be multifactorial. 1

In this study, we examined the association of HF and incident hip, proximal humerus, and wrist fractures in a high-risk population of adults who initiated osteoporosis therapy with bisphosphonate drugs.

METHODS

This retrospective study included Kaiser Permanente Northern California members aged 65–84 years who initiated oral bisphosphonate therapy in 2010–2019 (index date). 6 Those treated with other osteoporosis drugs and those with multiple myeloma, secondary metastatic cancer, selected bone disorders, or receipt of kidney dialysis/transplant were excluded. Prevalent HF was ascertained using ≥ 1 hospital diagnosis or ≥ 3 outpatient diagnoses within five years before index. Incident hip fracture (hospital diagnosis) and proximal humerus and distal radius/ulna (wrist) fractures (hospital/outpatient diagnosis) were ascertained during three years of follow-up using International Classification of Diseases (ICD-9/10-CM) diagnosis codes (excluding fractures in the first year if a same-site fracture diagnosis occurred before index and within one year of the incident fracture diagnosis). Baseline covariates included age, self-reported race, ethnicity, smoking, diabetes, rheumatoid arthritis, prior fracture, and body mass index (Table 1 ). Continued bisphosphonate therapy was based on ≥ 80% adherence (≥ 50–90% in sensitivity analysis) for each 3-month interval of follow-up.

Fracture incidence was compared by HF status using the log-rank test. The association of HF and incident fracture was examined using Cox proportional hazards regression, adjusting for baseline covariates, continued osteoporosis therapy, and an interaction term for baseline HF status and sex. These analyses were repeated with Fine-Gray regression models, accounting for death as a competing risk. Adjusted hazard ratios (aHR) are reported with 95% confidence intervals (CI).

RESULTS

Among 60,892 adults (82.5% women, 65.7% non-Hispanic White, 18.1% Asian/Pacific Islander, 11.8% Hispanic, and 3.0% Black) who initiated bisphosphonate therapy, one-third had prior fracture (34.9%). Men were more likely to be age ≥ 75 years (69.6% versus 38.6%) and have diabetes (26.3% vs 20.4%), and less likely to have obesity (17.3% versus 21.1%) than women (Table 1 ), but current smoking prevalence was similar (7.7% vs 8.0%).

During up to three years follow-up, the unadjusted incidence (per 1000 person-years, 95% CI) of hip, proximal humerus, and wrist fractures was 6.0 (5.6–6.4), 4.4 (4.1–4.8), and 7.1 (6.6–7.5) for women and 8.4 (7.4–9.5), 2.7 (2.2–3.4), and 3.0 (2.4–3.7) for men, respectively. For each skeletal site, cumulative fracture incidence was higher among those with versus without HF (p < 0.001).

In multivariable analyses adjusting for potential confounders, HF was independently associated with increased risk of hip (aHR 1.48 [1.20–1.83]), proximal humerus (aHR 1.46 [1.10–1.92]), and wrist fracture (aHR 1.37 [1.07–1.76]), with no significant interaction by sex (Fig. 1 ). Results were unchanged in sensitivity analyses, using ≥ 50% adherence criteria for bisphosphonate continuation.

DISCUSSION

In a diverse, contemporary population of older adults who initiated osteoporosis therapy, adults with HF had 40–50% higher risk of several types of non-vertebral osteoporotic fracture than those without HF. Building on earlier studies of European and North American populations unselected for osteoporosis, 1 – 5 our findings demonstrate that HF remains an independent risk factor for fracture even among higher risk populations who initiate osteoporosis therapy. Our cohort had large representation of US Asian and Hispanic adults, populations that were previously understudied.

Key limitations include lack of data on HF subtype, severity, and pharmacotherapy, frailty/functional status, kidney function, other osteoporosis risk factors, and bone density. Our analyses may have underestimated total osteoporotic burden. Nonetheless, our findings draw attention to HF as an important risk factor for fracture among older adults initiating osteoporosis therapy. In addition to pharmacologic treatment, falls prevention, nutrition, smoking cessation and lifestyle interventions, 7 identifying modifiable, HF-specific mechanisms contributing to excess fracture risk may support more optimal management of adults with HF. This may be especially important as the US population ages and there is greater intersection of skeletal and cardiovascular health.

Acknowledgements

The authors would like to thank Robert Adler, MD, for review and input on this manuscript and the Calculator for Length of Use of Bisphosphonates (CLUB) Study Team for support of this work.

Author Contributions

All authors contributed to study conception and/or development of study approach and methods; Malini Chandra abstracted the data and conducted the data analyses; all authors provided input on the interpretation of data; Amanda Chang and Joan Lo drafted the initial manuscript, and all authors provided input and manuscript edits for important intellectual content. All authors approved the final manuscript for publication.

Funding

This study was supported by a grant from the National Institute on Aging (NIA) and the Office of the Director (OD) at the National Institutes of Health ( AG079118 ). The sponsor had no role in the study concept and design, acquisition of data, analyses, and interpretation of data, and writing of the manuscript. This work, submitted by the authors, also does not represent the official viewpoints of the National Institutes of Health or Kaiser Permanente.

Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request. Due to privacy and ethical considerations, access to the data may be restricted and subject to approval by the appropriate institutional review boards.

Declarations

Human Ethics and Consent to Participate

The study was approved by Kaiser Permanente Northern California Institutional Review Board (IRB) with a waiver of informed consent and subsequently ceded to Health Partners Institute’s IRB as the single IRB of record.

Conflict of interest

Malini Chandra, Laura Carbone, Howard Fink, Susan Ott, and Joan Lo received funding from the National Institute on Aging related to this work but have no other conflicts of interest to report. Alan Go reports research funding to his institution from Bristol-Myer Squibb, Novartis, and Edwards Life Sciences and the National Institutes of Health outside of this work. Amanda Chang has no conflicts of interest to report.

Footnotes

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

REFERENCES

1. Majumdar SR, Ezekowitz JA, Lix LM, Leslie WD. Heart failure is a clinically and densitometrically independent risk factor for osteoporotic fractures: population-based cohort study of 45,509 subjects. J Clin Endocrinol Metab. 2012;97(4):1179-86. 10.1210/jc.2011-3055.

2. Ge G, Li J, Wang Q. Heart failure and fracture risk: a meta-analysis. Osteoporos Int. 2019;30(10):1903–09. 10.1007/s00198-019-05042-2.

3. van Diepen S, Majumdar SR, Bakal JA, McAlister FA, Ezekowitz JA. Heart failure is a risk factor for orthopedic fracture: a population-based analysis of 16,294 patients. Circulation. 2008;118(19):1946–52. 10.1161/CIRCULATIONAHA.108.784009.

4. Gerber Y, Melton LJ, 3rd, Weston SA, Roger VL. Osteoporotic fractures and heart failure in the community. Am J Med. 2011;124(5):418-25. 10.1016/j.amjmed.2010.11.029.

5. Carbone L, Buzkova P, Fink HA, et al. Hip fractures and heart failure: findings from the Cardiovascular Health Study. Eur Heart J . Jan 2010;31(1):77-84. 10.1093/eurheartj/ehp483

6. Lo JC, Chandra M, Khan MM, et al. Changing trends in bisphosphonate therapy: a twenty-five-year surveillance in a single US integrated healthcare system. Osteoporos Int. 2025;10.1007/s00198-024-07372-2

7. LeBoff MS, Greenspan SL, Insogna KL, et al. The clinician's guide to prevention and treatment of osteoporosis. Osteoporos Int. 2022;33(10):2049-2102. 10.1007/s00198-021-05900-y.

Associated Data

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request. Due to privacy and ethical considerations, access to the data may be restricted and subject to approval by the appropriate institutional review boards.