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Abstract

Introduction

Bisphosphonate medications reduce the risk of osteoporotic fragility fractures; however, prolonged use increases the risk of atypical femur fractures (AFF). As the population ages and the burden of osteoporosis rises, the relative incidence of AFFs is expected to grow. Current expert guidelines recommend discontinuing bisphosphonates and initiating alternative anti-fracture therapies (AFT), such as denosumab, teriparatide, or raloxifene, following an AFF to support skeletal health and reduce future fracture risk. However, it is unclear which patients receive these medications after an AFF. This study aims to identify demographics associated with the initiation of alternate osteoporosis therapies following an AFF.

Methods

We conducted a retrospective cohort study using data from the TriNetX Registry to identify patients who were on bisphosphonate therapy that had an AFF. The primary outcome was initiation of teriparatide, denosumab, or raloxifene within one year after AFF. We compared patient demographics and baseline characteristics between those initiated on AFT after an AFF and those who were not. Pairwise comparisons of proportions were performed between the groups using two-proportion Z-tests with Bonferroni correction to account for multiple comparisons.

Results

We identified 784 patients with AFFs following bisphosphonate use. 71 patients (9.5%) were initiated on AFT following the index fracture. Teriparatide (83.1%) was the most commonly prescribed AFT, followed by denosumab (21.9%), then raloxifene (≤14.1%). Patients initiated on AFT were more likely to have a previous fragility fracture (66.2% vs 45.2%, P < 0.001). Other patient demographics assessed did not show any significant differences.

Discussion and Conclusion

Despite expert recommendations, AFT was initiated in only a small percentage of patients following AFFs. These findings highlight a significant care gap in secondary fracture prevention and underscore the need for a multidisciplinary approach, including coordination between endocrinology, orthopaedics, and primary care, to improve adherence to post-fracture osteoporosis management guidelines.

Keywords

fragility fractures geriatric trauma metabolic bone disorders osteoporosis pharmacology

Introduction

The aging population in the United States is rapidly expanding with the proportion of adults over 65 years old tripling over the last century.¹ As the patient population continues to age, the rates of osteoporosis and osteoporosis related fragility fractures are increasing.^2,3 There are currently over ten million Americans with osteoporosis affecting an estimated 11.5% percent of Americans age fifty or over.^4,5 In addition, more than forty three million people in the United States have decreased bone density, putting them at risk of future development of osteoporosis.⁶ Osteoporosis increases the risk of fracture and it is projected that by 2025, there will be more than three million osteoporosis related fractures each year in the United States.^7-9 These fractures lead to decreased quality of life, disability, and increased mortality.^10-13 Treatment of osteoporotic fractures also impose a high cost to the healthcare system with an estimated cost of 25.3 billion dollars annually in 2025.¹⁴ Pharmacologic prevention of osteoporosis decreases rates of future fracture and is cost effective.^15,16 Given the high burden of osteoporotic fragility fractures on both patients and the healthcare system, prevention is imperative.

Bisphosphonates are the most common class of pharmacologic therapy used for the treatment of osteoporosis and have been shown to decrease rates of osteoporotic fragility fracture.^17,18 However, long-term use of bisphosphonates has been linked atypical femur fractures (AFFs).^19,20 These fractures, while uncommon, are associated with high rates of mortality and disability similar to other femur fractures.^21-23 Expert guidelines recommend discontinuing bisphosphonate therapy after an AFF, due to the possibility of delayed union or nonunion, increased surgical complications, or contributing to development of an AFF on the contralateral side.^24-26 In their place, alternative anti-fracture therapies (AFT), such as teriparatide, denosumab, or raloxifene, are recommended to reduce future fracture risk in high risk patients.^24,26

Despite these recommendations, it is unclear how often patients are transitioned to alternative therapies following an AFF and which clinical factors influence these prescribing decisions. The purpose of this study was to evaluate the use of AFT after bisphosphonate-associated AFFs in a large, multi-institutional cohort, and to identify demographic and clinical factors associated with their initiation.

Materials and Methods

The TriNetX Registry, a multicenter, multinational registry of deidentified medical records was queried and deidentified patient data from 108 health care organizations was obtained from the national database on September 15th, 2025.²⁷ This cohort was then evaluated using descriptive statistics and study specific cohorts were delineated. Institutional Review Board Approval was not required given the strict use of deidentified patient records with no individually identifiable data.

Cohort Selection

Patients who had an atypical femur fracture from the years 2005 to 2025 were identified using International Classification of Diseases, 10th Revision (ICD-10) code M84.75 (Atypical Femur Fracture). Atypical femur fractures can occur in patients without prior bisphosphonate exposure.^28,29 Therefore, patients without documented bisphosphonate use were excluded to ensure accurate cohort classification. Patients were then excluded if they had a history of hypercalcemia or neoplasm. Alternative anti-fracture therapy (AFT) was defined as teriparatide, denosumab, or raloxifene. To be included in the AFT group, patients must have been prescribed any of the above drugs within one year following AFF. We chose one year as the time frame for AFT initiation because previous studies have evaluated osteoporosis medication initiation within one to two years following a fragility fracture.^30-32 Given the mortality risk associated with femur fractures, we chose the shorter one year interval to more accurately capture treatment decisions after an AFF. We excluded patients who died within one year after their AFF. Patients without at least one year of follow-up after their AFF were also excluded. This process is summarized in Figure 1.

Figure 1.

Flowchart demonstrating cohort selection

Statistical Analysis

Alternative Anti-fracture Therapy Initiation Comparison

Pairwise comparisons of proportions for demographics and previous fragility fracture were performed between patients who had AFT prescribed after AFF and patients who were not prescribed AFT after AFF. Specific demographics assessed included age at time of AFF, gender, race, and ethnicity. We also compared previous medical conditions including prior osteoporotic fragility fracture and BMI. We used two-proportion Z-tests with Bonferroni correction to account for multiple comparisons. A P-value of less than 0.05 was set for statistical significance. A power analysis was not performed because this was a retrospective observational study that was intended to describe prescribing patterns following AFFs rather than test a predefined hypothesis. Figures were created using Microsoft Excel (Microsoft Corporation, Redmond, WA) and Microsoft Visio (Microsoft Corporation, Redmond, WA). All statistical analyses were performed using the built-in analysis tools available within the TriNetX platform (TriNetX, LLC, Cambridge, MA).

Results

Baseline Demographics of Patients Who are Prescribed AFT vs Not After AFF

There were a total of 1696 patients with AFFs identified. Of these patients, 930 (54.8%) were excluded from analysis due to no documented history of prior bisphosphonate usage. This left a total of 766 (45.2%) patients with bisphosphonate associated AFF and 748 patients were included in analysis after excluding patients who died within one year after their AFF. The recorded one year mortality rate was 2.3% overall (18/766), occurring in 4.2% of patients prescribed AFT (3/74) and 2.2% of those not prescribed AFT (15/692). There was no significant difference between mortality rates in patients who were or were not prescribed AFT after AFF (4.2% vs 2.2%, P = 0.309).

Most patients with an AFF were elderly with an average age of 76, white, female, and not Hispanic or Latino. There were 71 (9.5%) patients who were prescribed AFT within one year after AFF and 677 (90.5%) patients who were not prescribed AFT. Patients who were prescribed AFT after an AFF were more likely to have a diagnosis of a previous osteoporotic fragility fracture vs patients who were not prescribed AFT (66.2% vs 45.2%, P < 0.001). There were no statistically significant differences in demographic characteristics assessed between groups that were vs were not prescribed AFT after an AFF (P > 0.01). (Table 1).

Table 1.

Difference in Baseline Characteristics Between Atypical Femur Fractures With and Without Alternative Antifracture Therapy

Variables	BAT	No BAT	Adjusted P-value (P-value < 0.05 is significant)
Previous osteoporotic fragility fracture	66.2%	45.2%	<0.001
Female	98.6%	91.0%	0.162
White	70.4%	76.5%	5.412
Not Hispanic or Latino	87.3%	76.5%	0.228
BMI	26.8 ± 5.9	26.9 ± 6.0	5.052
Age	76.7 ± 7.0	76.5 ± 9.5	5.280

Types of AFT Prescribed

Teriparatide was the most commonly prescribed AFT after an AFF with 59 out of 71 (83.1%) patients having received a prescription. Denosumab was the second most common, prescribed to 17 out of 71 (23.9%) patients. Raloxifene was prescribed least often, prescribed to 10 or less patients out of 71 patients (14.1%).

Discussion

In our retrospective multicenter study, we found the rate of patients started on AFT after an AFF was low at 9.5%, despite current guideline recommendations. Our study showed a strong predominance of female patients, which aligns with the known epidemiology of osteoporosis, where older women make up the majority of those diagnosed and treated for osteoporosis.⁵ This finding is consistent with prior literature showing that treatment initiation rates after fragility fractures are generally low. For example, Ross et al³⁰ reported that rates of osteoporosis management and secondary preventative treatment after primary fragility fractures remain suboptimal, with many patients not receiving pharmacologic therapy despite clear indications. While some analyses suggest that factors such as age, sex, and other demographics may influence fracture risk, results across studies vary.⁶ In our cohort, we did not observe any clear differences in AFT initiation based on demographic factors.⁶ This study highlights a disconnect between current guidelines and actual practice patterns.

In our cohort, 54.8% of patients with an AFF did not have a documented history of bisphosphonate use. This aligns with previously reported rates of AFF in patients not taking bisphosphonates of 22 to 60%.^28,29 Patients who were initiated on AFT after an AFF were significantly more likely to have a previous diagnosis of a previous osteoporotic fragility fracture. A prior osteoporotic fragility fracture is one of the strongest predictors of subsequent future fractures, with the highest risk occurring in the first 24 months after the initial event.³³ Similarly, fragility fractures tend to cluster in time, highlighting a critical window to intervene after a first fracture to help prevent subsequent events.³⁴ In patients with previous osteoporotic fragility fractures, quick initiation of AFT after AFF may be especially important. Failing to treat patients during this period may increase future fracture risk. One limitation is we were unable to differentiate between the specific number or types of previous osteoporotic fragility fractures in our patient cohorts. Determining whether the number of previous fragility fractures or type of fragility fractures type are more strongly associated with AFT initiation requires further research.

In our study, the observed one-year mortality rate following an AFF was 2.3%, which is notably lower than the approximate 10% one-year mortality rate reported in a meta-analysis by Charoenngam et al³⁵ (95% CI, 5 - 16%). Like many other large databases, TriNetX is unable to record deaths which occur outside of the included healthcare systems, potentially showing an artificially lowered death rate.^27,36 Patients who die after discharge or who seek care in a different healthcare system may not be recorded, leading to an underestimation of true mortality.

Most patients who were prescribed AFT after AFF were started on teriparatide. While this study is unable to comment on the effectiveness of this medication in preventing repeat fracture, there is limited evidence that teriparatide, a recombinant parathyroid hormone 1-34, may improve fracture healing and be beneficial after AFF.²⁴ Teriparatide’s anabolic mechanism, through intermittent PTH stimulation, increases osteoblast activity and promotes new bone formation.²⁴ This provides a biologically plausible rationale for supporting fracture healing in patients with AFF. However, randomized controlled trials specifically evaluating AFF are scarce, and current recommendations to prescribe teriparatide to improve bone healing after AFF remain cautious, usually individualized based on fracture pattern, comorbidities, and prior antiresorptive therapy.²⁴

Alternative osteoporosis treatments vary in their effectiveness and safety profiles. Bisphosphonates and denosumab both reduce common osteoporotic fractures in trials and clinical practice, but the evidence around AFF is more nuanced.^3,18 Prolonged bisphosphonate use has the strongest association with AFF, though the overall risk remains low compared with their benefits for high-risk patients.^18,19 Denosumab has also been linked to AFF in some reports, but the population-level evidence for a causal association is less consistent than for long-term bisphosphonates and remains debated.²⁰ Current guidelines emphasize individualized treatment decisions that take into account prior fractures, current fracture risk, previous therapies, and patient-specific goals to optimize outcomes.

Our study has several limitations. This includes the retrospective, observational nature of our study, which only allows inferences of association, and not causation. No power analysis was performed, limiting our ability to assess whether the study was adequately powered to detect meaningful differences. We were unable to assess for subsequent fracture risk following the index AFF, limiting our ability to evaluate the clinical impact of AFT initiation. It was also not possible for this study to account for individual medical decision making and possible contraindications for some patients to receive AFT. We did not include other osteoporosis therapies such as abaloparatide, romosozumab, calcium, or vitamin D supplementation. This may limit the completeness of our assessment of pharmacologic treatment patterns following AFF. Additionally, we were unable to evaluate exact timelines of when AFT was started after AFF, which may have important implications for treatment effectiveness. We were also unable to assess socioeconomic status or insurance type, which may influence both prescribing patterns and access to care.^30,37 The true mortality rate was likely underreported, given the limitations of the ability of the database to record out of hospital deaths. If there are ten or fewer patients with a given set of criteria, TriNetX will round the number to ten to protect patient confidentiality.²⁷ This occurred in our analysis of patients who were prescribed raloxifene, likely overestimating the true rate of raloxifene prescription after AFF. While we attempted to include patients initiated on AFT if they had an active prescription within 1 year after their index AFF, we were unable to determine whether patients were compliant with their medication, the dose of medication prescribed, or medication adherence.

Conclusion

Despite guideline recommendations, initiation of AFT following bisphosphonate associated AFF remains low. Teriparatide is the most commonly prescribed alternative therapy, but overall use is limited, highlighting a significant care gap in secondary fracture prevention. Our study provides important insights into real-world patterns of AFT use following bisphosphonate associated AFFs. These findings emphasize the importance of a multidisciplinary approach, including coordination with endocrinology, orthopaedics, and primary care, to optimize post fracture management and ensure appropriate initiation of AFT. Future studies to assess the outcomes of AFT on secondary fracture risks are needed.

Footnotes

ORCID iDs

Andrew Ni

Dean Slocum

Ethical Considerations

This review was exempt from the University of Texas Health San Antonio Institutional Review Board approval given its retrospective nature and lack of patient-identifiable information.

Author Contributions

Andrew Ni, MD contributed to conceptualization, data curation, formal analysis, investigation, methodology, project administration, resources, software, visualization, writing – original draft, and writing - review & editing, Azophi Moffat contributed to formal analysis, writing – original draft, and writing – review and editing, Jordan Robbins MD contributed to methodology, data analysis, writing – original draft, writing – review & editing, Dean Slocum MD contributed to conceptualization, writing – review and editing, Abhi Rashiwala MD contributed to conceptualization, writing– review & editing, Katerina Papanikolaou MD contributed to methodology, writing– review & editing, Ravi, Karia MD contributed to methodology, supervision, project administration, and writing– review & editing.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

References

Anderson

Goodman

Holtzman

Posner

Northridge

. Aging in the United States: opportunities and challenges for public health. Am J Publ Health. 2012;102(3):393-395. doi:10.2105/AJPH.2011.300617

Naso

Lin

Song

Xue

. Time trend analysis of osteoporosis prevalence among adults 50 years of age and older in the USA, 2005–2018. Osteoporos Int. 2025;36(3):547-554. doi:10.1007/s00198-025-07395-3

Adami

Fassio

Gatti

, et al. Osteoporosis in 10 years time: a glimpse into the future of osteoporosis. Ther Adv Musculoskelet Dis. 2022;14:1759720X221083541. doi:10.1177/1759720X221083541

Sarafrazi

Wambogo

Shepherd

. Osteoporosis or Low Bone Mass in Older Adults: United States, 2017–2018. NCHS Data Brief. 2021;405:1-8. doi:10.15620/cdc:103477.

Salari

Darvishi

Bartina

, et al. Global prevalence of osteoporosis among the world older adults: a comprehensive systematic review and meta-analysis. J Orthop Surg Res. 2021;16:669. doi:10.1186/s13018-021-02821-8

Wright

Looker

Saag

, et al. The recent prevalence of osteoporosis and low bone mass in the United States based on bone mineral density at the femoral neck or lumbar spine. J Bone Miner Res. 2014;29(11):2520-2526. doi:10.1002/jbmr.2269

Riggs

Melton

. The worldwide problem of osteoporosis: insights afforded by epidemiology. Bone. 1995;17(5 Suppl):505S-511S. doi:10.1016/8756-3282(95)00258-4

NIH consensus development Panel on osteoporosis prevention D and therapy. Osteoporosis prevention, diagnosis, and therapy. JAMA. 2001;285(6):785-795. doi:10.1001/jama.285.6.785

Burge

Dawson-Hughes

Solomon

Wong

King

Tosteson

. Incidence and economic burden of osteoporosis-related fractures in the United States, 2005-2025. J Bone Miner Res. 2007;22(3):465-475. doi:10.1359/jbmr.061113

10.

Hallberg

Rosenqvist

Kartous

Löfman

Wahlström

Toss

. Health-related quality of life after osteoporotic fractures. Osteoporos Int. 2004;15(10):834-841. doi:10.1007/s00198-004-1622-5

11.

Johnell

Kanis

Odén

, et al. Mortality after osteoporotic fractures. Osteoporos Int. 2004;15(1):38-42. doi:10.1007/s00198-003-1490-4

12.

Fink

Ensrud

Nelson

, et al. Disability after clinical fracture in postmenopausal women with low bone density: the fracture intervention trial (FIT). Osteoporos Int. 2003;14(1):69-76. doi:10.1007/s00198-002-1314-y

13.

Guzon-Illescas

Perez Fernandez

Crespí Villarias

, et al. Mortality after osteoporotic hip fracture: incidence, trends, and associated factors. J Orthop Surg Res. 2019;14(1):203. doi:10.1186/s13018-019-1226-6

14.

Rashki

Rezapour

Jahangiri

Nikjoo

Farabi

Soleimanpour

. Economic burden of osteoporosis in the world: a systematic review. Med J Islam Repub Iran. 2020;34:154. doi:10.34171/mjiri.34.154

15.

Beaudart

Cauley

, et al. Cost effectiveness analyses of interventions for osteoporosis in men: a systematic literature review. Pharmacoeconomics. 2023;41(4):363-391. doi:10.1007/s40273-022-01239-2

16.

Svedbom

Hadji

Hernlund

, et al. Cost-effectiveness of pharmacological fracture prevention for osteoporosis as prescribed in clinical practice in France, Germany, Italy, Spain, and the United Kingdom. Osteoporos Int. 2019;30(9):1745-1754. doi:10.1007/s00198-019-05064-w

17.

Tan

Robinson

Jödicke

, et al. Drug utilization analysis of osteoporosis medications in seven European electronic health databases. Osteoporos Int. 2023;34(10):1771-1781. doi:10.1007/s00198-023-06837-0

18.

Byun

Jang

Lee

, et al. The efficacy of bisphosphonates for prevention of osteoporotic fracture: an update meta-analysis. J Bone Metab. 2017;24(1):37-49. doi:10.11005/jbm.2017.24.1.37

19.

Black

Geiger

Eastell

, et al. Atypical Femur fracture risk versus fragility fracture prevention with bisphosphonates. N Engl J Med. 2020;383(8):743-753. doi:10.1056/NEJMoa1916525

20.

Bauer

Black

Dell

, et al. Bisphosphonate use and risk of atypical femoral fractures: a Danish case-cohort Study with blinded radiographic review. J Clin Endocrinol Metab. 2024;109(11):e2141-e2150. doi:10.1210/clinem/dgae023

21.

Gibbons

Merrell

Ganta

Rivero

Konda

Egol

. Atypical versus typical subtrochanteric femoral fractures: disparate patient profiles, similar outcomes. J Bone Joint Surg Am. 2024;106(3):190-197. doi:10.2106/JBJS.23.00583

22.

Kharazmi

Hallberg

Schilcher

Aspenberg

Michaëlsson

. Mortality after atypical femoral fractures: a cohort study. J Bone Miner Res. 2016;31(3):491-497. doi:10.1002/jbmr.2767

23.

Davenport

Duncan

Dick

Bansal

Edwards

. Outcomes for elderly patients with atypical femoral fractures compared to typical femoral fractures for length of stay, discharge destination, and 30-Day mortality rate. Geriatr Orthop Surg Rehabil. 2018;9:2151459318820222. doi:10.1177/2151459318820222

24.

van de Laarschot

McKenna

Abrahamsen

, et al. Medical management of patients after atypical femur fractures: a systematic review and recommendations from the european calcified tissue society. J Clin Endocrinol Metab. 2020;105(5):1682-1699. doi:10.1210/clinem/dgz295

25.

Yue

Tang

Joseph

Richardson

. Delayed healing of lower limb fractures with bisphosphonate therapy. Ann R Coll Surg Engl. 2015;97(5):333-338. doi:10.1308/003588415X14181254789321

26.

Shane

Burr

Abrahamsen

, et al. Atypical subtrochanteric and diaphyseal femoral fractures: second report of a task force of the American society for bone and mineral research. J Bone Miner Res. 2014;29(1):1-23. doi:10.1002/jbmr.1998

27.

Real-world data for the life sciences and healthcare. TriNetX. Accessed September 13, 2025.https://trinetx.com/

28.

Giusti

Hamdy

NAT

Dekkers

Ramautar

Dijkstra

Papapoulos

. Atypical fractures and bisphosphonate therapy: a cohort study of patients with femoral fracture with radiographic adjudication of fracture site and features. Bone. 2011;48(5):966-971. doi:10.1016/j.bone.2010.12.033

29.

Schilcher

Michaëlsson

Aspenberg

. Bisphosphonate use and atypical fractures of the femoral shaft. N Engl J Med. 2011;364(18):1728-1737. doi:10.1056/NEJMoa1010650

30.

Ross

Lee

Harris

Dowd

Savoie

Sherman

. Rates of osteoporosis management and secondary preventative treatment after primary fragility fractures. JB JS Open Access. 2021;6(2):e20. doi:10.2106/JBJS.OA.20.00142

31.

Malik

Gordon

Awan

Khan

Goyal

. Declining trend in anti-osteoporotic treatment, despite a rise in DEXA screening following “sentinel” distal radius fractures. Hand. 2024;19(6):978-985. doi:10.1177/15589447231153176

32.

Viprey

Caillet

Canat

, et al. Low osteoporosis treatment initiation rate in women after distal forearm or proximal humerus fracture: a healthcare database nested cohort study. PLoS One. 2015;10(12):e0143842. doi:10.1371/journal.pone.0143842

33.

Söreskog

Ström

Spångéus

, et al. Risk of major osteoporotic fracture after first, second and third fracture in Swedish women aged 50 years and older. Bone. 2020;134:115286. doi:10.1016/j.bone.2020.115286

34.

van Geel

TACM

Huntjens

KMB

van den Bergh

JPW

Dinant

Geusens

. Timing of subsequent fractures after an initial fracture. Curr Osteoporos Rep. 2010;8(3):118-122. doi:10.1007/s11914-010-0023-2

35.

Charoenngam

Rittiphairoj

Jaroenlapnopparat

, et al. Mortality risk after atypical femoral fracture: a systematic review and meta-analysis. Endocr Pract. 2022;28(10):1072-1077. doi:10.1016/j.eprac.2022.08.005

36.

Aylin

Bottle

Majeed

. Use of administrative data or clinical databases as predictors of risk of death in hospital: comparison of models. Br Med J. 2007;334(7602):1044. doi:10.1136/bmj.39168.496366.55

37.

Viswanathan

Ward

, et al. Patterns of osteoporosis treatment change and treatment discontinuation among commercial and medicare advantage prescription drug members in a national health plan. J Eval Clin Pract. 2013;19(1):50-59. doi:10.1111/j.1365-2753.2011.01766.x

Alternative Osteoporosis Therapies After Bisphosphonate Associated Atypical Femur Fractures: A Retrospective Analysis

Abstract

Introduction

Methods

Results

Discussion and Conclusion

Keywords

Introduction

Materials and Methods

Cohort Selection

Statistical Analysis

Alternative Anti-fracture Therapy Initiation Comparison

Results

Baseline Demographics of Patients Who are Prescribed AFT vs Not After AFF

Types of AFT Prescribed

Discussion

Conclusion

Footnotes

ORCID iDs

Ethical Considerations

Author Contributions

Funding

Declaration of Conflicting Interests

References