Effectiveness of treatment initiation for secondary fracture prevention in the older population: Japanese Bone-fracture Osteoporosis in Late-stage population Database study (J-BOLD) – emulation of a randomized target trial

Abstract

Summary

Initiating osteoporosis medication within 3 months after fracture reduces secondary fractures, particularly hip fractures, in individuals aged ≥ 75 years. This finding highlights the importance of early and sustained treatment in older populations.

Purpose

To evaluate the efficacy of initiating osteoporosis medication within 3 months after a fracture and continuing it for at least 6 months in preventing secondary fractures among individuals aged ≥ 75 years.

Methods

This study used a targeted trial design, emulating a randomized controlled trial with Japanese administrative claims data from 2014–2022. Among 203,534 individuals with recent osteoporotic fractures, 40,063 initiated osteoporosis medication within 3 months (exposed), while 163,471 did not (controls). High-dimensional propensity score matching identified 53,436 individuals (26,718 exposed and 26,718 controls) for analysis. Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for secondary fractures at any and specific sites.

Results

The study population had a mean age of 83.7 years and included 77.9% women. After ≥ 6 months of treatment, HRs for any fracture were 0.71 (95% CI: 0.60–0.86) in men and 0.78 (95% CI: 0.71–0.88) in women. For hip fractures, HRs were 0.56 (95% CI: 0.36–0.80) in men and 0.60 (95% CI 0.49–0.72) in women. After ≥ 12 months of treatment, HRs for any fracture were 0.65 (95% CI: 0.48–0.82) in men and 0.74 (95% CI: 0.68–0.85) in women. For hip fractures, HRs were 0.59 (95% CI: 0.19–0.84) in men and 0.55 (95% CI: 0.44–0.69) in women.

Conclusion

Early initiation and sustained use of osteoporosis medication significantly reduced the risk of secondary fractures, particularly hip fractures, in men and women aged ≥ 75 years.

Supplementary Information

The online version contains supplementary material available at 10.1007/s00198-025-07687-8.

Introduction

Global osteoporosis prevalence is 18.3% and is projected to increase [1, 2]. Osteoporosis induces a yearly estimated 9.0 million fractures worldwide and represents a significant cause of decreased quality of life, future disability, morbidity and mortality, and economic burden [3–7]. The older population (aged ≥ 65 years) continues to grow worldwide. Japan has the highest proportion at 28.6%, followed by Italy (23.4%) and Germany (22.0%), of which approximately half are ≥ 75 years old [8]. Patients ≥ 80 years are in a more serious condition after a fracture, possibly requiring nursing care and becoming bedridden, increasing the burden for patients, their families, and society.

Osteoporosis treatment reduced subsequent fracture risk in placebo-controlled clinical studies in women. A recent review of 23 randomized controlled trials (RCTs) demonstrated that anti-osteoporotic medication reduced fracture risk among those above and below 70 years of age [9]. However, most RCTs enrolled women aged < 80 years, and the efficacy of medication in the older population remains uncertain. Although clinical trials focusing on specific medications exist, there is a lack of studies investigating the efficacy of newly initiated osteoporosis treatment in older populations, particularly in the highest age brackets. While the efficacy of osteoporosis treatment in preventing fractures in women is well established, evidence for men is lacking [10]. One observational study demonstrated that osteoporosis treatment prevents hip fracture similarly in both sexes [11].

Fracture risk increases with prior fracture [12]. A recent fracture, especially within the last 2 years, is a greater risk factor for subsequent fractures than older fractures [13]. The risk of imminent fractures is high not only for major osteoporotic fractures but also for fractures at other sites [13–18]. Globally, guidelines indicate the low rates of osteoporosis treatment after fracture and emphasize the importance of secondary fracture prevention and prompt treatment after a fracture, especially in the older population [19–26]. However, evidence regarding secondary fracture prevention during periods of imminent fracture risk is still limited.

Studies using real-world data have demonstrated that starting medication after a fracture reduces subsequent fractures in the elderly population [27–31]. However, the effects of medication were not examined separately by sex. Moreover, the duration from fracture to medication administration varies widely, with criteria such as within 6 months post-fracture [31], within 12 months post-fracture [29], and at any time after discharge [27, 28].

We aimed to investigate the effects of early initiation of new medication immediately after a fracture and its continuation in preventing imminent fractures in older men and women in a real-world setting. Specifically, using a target trial emulation framework, we hypothesized that initiating osteoporosis medication immediately after a fracture and continuing it for at least 6 months would be effective in reducing the risk of subsequent fractures in this population.

Materials and methods

Data sources

In the Japanese healthcare system, citizens are enrolled in one of three main insurance schemes: National Health Insurance, Social Health Insurance, or the Medical Care System for the Elderly (≥ 75 years), including 17.2 million people [32]. The DeSC database includes data for approximately 3 million insured individuals from all types of insurance [32], including International Classification of Diseases, Tenth Revision (ICD-10) codes covering all medical and dental diagnoses, prescribed medications, health check-up results, procedures, surgery, and medical expenditures. Mortality data were missing in less than 10% of the cases.

Target trial specification

A comprehensive protocol was established to evaluate the efficacy of osteoporosis medications in preventing secondary fractures. This protocol served as the basis for the study design describing the assumed clinical study and the present study emulated the real-world setting (Supplementary Table S1).

Data were collected between April 1, 2014, and June 30, 2022. The cohort entry date (CED, day 0) was defined as the date of the first osteoporotic fracture within this period. Determination of the fracture date and criteria relied on linking the diagnosis name to medical practice dates.

For the exposure assessment window (EAW, day 0–90), individuals were categorized as exposed when osteoporosis medication was started and when the exposure occurred within 90 days from day 0; otherwise, they were classified as controls.

Eligibility criteria were individuals aged ≥ 75 years with hip, vertebral, radius, humerus, or other fractures, with data in the database for 365 days before day 0. Hip and vertebral fractures were defined as cases involving any related surgery, procedure, or hospitalization in the same or following month with the diagnosis “fracture”; radius, humerus, and other fractures were defined similarly, excluding hospitalization (Supplementary Table S2). Excluded from the study were individuals meeting the following conditions during the period (Days [−365 to −1]): 1) those with exposure occurrence and 2) those with fracture diagnosis codes (excluding suspected diagnoses); the determination was based on linking diagnosis codes and medical procedures to specific dates.

The censoring date was determined based on the earliest occurrence of the initial fracture, end of data period, death, insurance withdrawal, or end of the observation period. The exposed group was censored if there was no prescription of any of the exposed medications for ≥ 90 days from the date of the last prescription, plus the number of prescriptions multiplied by the number of effective days per prescription. The controls were censored upon prescription of an exposed medication. Osteoporotic medications prescribed within 90 days of day 0 included bisphosphonates, human anti-RANKL monoclonal antibodies, parathyroid hormone analogs, selective estrogen receptor modulators, and humanized anti-sclerostin monoclonal antibodies (Supplementary Table S3). Treatment initiation was defined as the prescription and administration of any medication within the first 90 days following day 0. Treatment continuation was defined as the ongoing administration of any of these medications, even if the specific drug was switched to another drug within the same list.

Outcomes

The primary outcome was a composite measure of the secondary fracture sites, identified as fractures with a different disease code in the ICD-10 category from that of the index fracture after day 0 (Supplementary Table S4). If a secondary fracture with the same code as the initial fracture (index fracture) occurred, an outcome was determined after 180 days or more, as the initial diagnosis name could sometimes remain. Secondary outcomes included individual site-specific fracture incidences and their respective hazard ratios (HRs). For each site (hip, humerus, and other relevant sites), we calculated the HR and 95% confidence interval (CI) to quantify the relative risk reduction associated with the intervention. Additionally, we analyzed the time-to-event for each secondary fracture site to understand the temporal patterns of fracture risk.

Covariates

Covariates included sex, age, and initial fracture sites (hip, vertebral, radius, humerus, and others) determined on day 0. The following covariates were assessed during the covariate assessment window (CAW), used to evaluate baseline (−365 days to day 0): comorbidity (Charlson Comorbidity Index [CCI]) [33, 34] (Supplementary Table S5), concomitant oral medications (prednisolone, anxiolytics [Anatomical Therapeutic Chemical classification: N05B; hypnotics: N05C), polypharmacy (oral drugs with more than seven generic names prescribed over 14 days from different facilities in the same month in the CAW), and medication adherence for all oral drugs as determined by the modified medication possession ratio (MPRm) [35]. The time of acquisition for each covariate is depicted in Supplementary Figure S1.

Statistical analysis

We used high-dimensional propensity score matching (hdPSM), which ensures statistical robustness by adjusting for covariates related to diagnoses, treatments, and medications for both outpatient and inpatient populations [36]. hdPSM considered covariate variables such as sex, age, index fracture site, comorbidities, diagnosed osteoporosis in CAW, concomitant oral medications, and MPRm in CAW. We performed propensity score matching using logistic regression with the nearest neighbor method and evaluated the balance of covariates using standardized mean differences (SMD). Demographic information, including hdPSM, was described using the SMD before and after matching.

In the analysis of primary and secondary outcomes, we performed survival analysis using the Kaplan–Meier method to estimate the risk of secondary fractures over time. Survival curves were compared using the log-rank test to determine significant differences between exposed and control participants. Cox regression analysis was used to estimate HRs and 95% CIs. To evaluate individuals who were exposed to osteoporosis medication for a longer duration, we analyzed three cohorts by follow-up window: Day 0 Cohort (initiated treatment within 90 days after the fracture and continued treatment, regardless of the duration), Day 270 Cohort (exposed to medication for at least 180 days from the end of the 90 days exposure period), and Day 455 Cohort (exposed for at least 365 days from the end of the exposure period) (Fig. 1).

Fig. 1.

Schema of each cohort. → : Treatment duration for each patient, CED: Cohort Entry Date (onset of fracture), EAW: Exposure Assessment Window. The Day 0 Cohort was defined as the initiation of medication during the EAW, regardless of the duration of treatment. The Day 270 Cohort was defined as individuals who continued medication for at least 180 days from the end of the EAW. The Day 455 Cohort was defined as individuals who continued medication for at least 365 days from the end of the EAW

To address the immortal time bias until the end of the exposure period (day 90), we employed cloning methods, created period-comparable groups through hdPSM, and adjusted for bias using inverse probability of censoring weighting [37–39] to the comparability of exposed and control participants throughout the observation period (Supplementary Figure S2). During the follow-up period, the as-treated method was used to assess continued medication and no treatment. A cross-table was created to investigate the site at which patients with an index fracture had a secondary fracture. All statistical analyses were performed using R 4.3.3 (Supplementary Table S6).

Results

Patient characteristics

In the study period, 203,534 individuals met the eligibility criteria; 40,063 were exposed, and 163,471 were considered controls. After hdPSM, 53,436 (26,718 exposed, 26,718 controls) were analyzed (Tables 1 and 2, Fig. 2). Participants characteristics before hdPSM are shown in Supplementary Table S7.

Table 1.

Participant characteristics after high-dimensional propensity score matching

	Overall		Men		Women
	53,436	(100.0%)	11,810	(22.1%)	41,626	(77.9%)
Age, mean (SD)	83.7	(5.4)	83.4	(5.0)	83.8	(5.5)
Initial fracture site
Hip	11,144	(20.9%)	2,053	(17.4%)	9,091	(21.8%)
Vertebral	29,954	(56.1%)	8,037	(68.1%)	21,917	(52.7%)
Radius	4,731	(8.9%)	348	(2.9%)	4,383	(10.5%)
Humerus	1,540	(2.9%)	180	(1.5%)	1,360	(3.3%)
Other	8,312	(15.6%)	1,498	(12.7%)	6,814	(16.4%)
Number of diseases of Charlson Comorbidity Index, mean (SD)	2.2	(1.7)	2.8	(1.9)	2.0	(1.6)
Concomitant medications (only oral)
Prednisolone	2,321	(4.3%)	745	(6.3%)	1,576	(3.8%)
Sleep-inducing drugs	15,856	(29.7%)	3,344	(28.3%)	12,512	(30.1%)
Anti-anxiety drugs	8,591	(16.1%)	1,366	(11.6%)	7,225	(17.4%)
Polypharmacy (prescribed ≥ 7 different oral medications in a month)	11,474	(21.5%)	3,194	(27.0%)	8,280	(19.9%)
MPRm (adherence), median (IQR)	95.6%	(15.2%)	95.9%	(14.2%)	95.5%	(15.5%)

Values are numbers (percentages) unless otherwise stated. SD standard deviation. MPRm modified medication possession ratio. IQR interquartile range

Table 2.

Characteristics of exposure and control groups after high-dimensional propensity score matching

		Exposure		Control		SMD
		n = 26,718	(100.0%)	n = 26,718	(100.0%)
Age, mean (SD)		83.7	(5.3)	83.7	(5.5)	< 0.01
Sex (Women)		20,597	(77.1%)	21,029	(78.7%)	0.04
Initial fracture site
Hip		5,472	(20.5%)	5,672	(21.2%)	0.02
Vertebral		15,056	(56.4%)	14,898	(55.8%)	0.01
Radius		2,361	(8.8%)	2,370	(8.9%)	< 0.01
Humerus		752	(2.8%)	788	(2.9%)	0.01
Other		4,162	(15.6%)	4,150	(15.5%)	< 0.01
Number of diseases of Charlson's Comorbidity Index, mean (SD)		2.2	(1.7)	2.2	(1.7)	< 0.01
AIDS/HIV		3	(0.0%)	2	(0.0%)	< 0.01
Any malignancy		3,976	(14.9%)	3,923	(14.7%)	0.01
Cerebrovascular disease		8,270	(31.0%)	8,193	(30.7%)	0.01
Chronic pulmonary disease		6,698	(25.1%)	6,686	(25.0%)	< 0.01
Congestive heart failure		9,151	(34.3%)	9,195	(34.4%)	< 0.01
Dementia		5,999	(22.5%)	6,011	(22.5%)	< 0.01
Diabetes with chronic complications		2,109	(7.9%)	2,089	(7.8%)	< 0.01
Diabetes without chronic complications		2,203	(8.2%)	2,252	(8.4%)	0.01
Hemiplegia or paraplegia		403	(1.5%)	412	(1.5%)	< 0.01
Mild liver disease		5,085	(19.0%)	5,109	(19.1%)	< 0.01
Moderate or severe liver disease		158	(0.6%)	150	(0.6%)	< 0.01
Metastatic solid tumor		418	(1.6%)	415	(1.6%)	< 0.01
Myocardial infarction		921	(3.4%)	926	(3.5%)	< 0.01
Peptic ulcer disease		5,852	(21.9%)	5,866	(22.0%)	< 0.01
Peripheral vascular disease		4,432	(16.6%)	4,404	(16.5%)	< 0.01
Renal disease		1,865	(7.0%)	1,885	(7.1%)	< 0.01
Rheumatic disease		1,188	(4.4%)	1,278	(4.8%)	0.02
Osteoporosis medications
Bisphosphonate		14,251	(53.3%)	-	-
Human Anti-RANKL monoclonal Antibody		2,090	(7.8%)	-	-
Parathyroid hormone analogues		7,633	(28.6%)	-	-
Selective estrogen receptor modulators [SERM]		1,373	(5.1%)	-	-
Humanized anti-sclerostin monoclonal antibody		1,403	(5.3%)	-	-
Concomitant medications (only oral medications)
Prednisolone		1,181	(4.4%)	1,140	(4.3%)	0.01
Sleep-inducing drugs		7,881	(29.5%)	7,975	(29.8%)	0.01
Anti-anxiety drugs		4,259	(15.9%)	4,332	(16.2%)	0.01
Polypharmacy (prescribed ≥ 7 different oral medications in a month)		5,711	(21.4%)	5,763	(21.6%)	< 0.01
MPRm (adherence), median (IQR)		95.5%	(15.1%)	95.6%	(15.3%)	< 0.01

The values are numbers (percentages) unless otherwise stated. SMD: standardized mean difference. SD: standard deviation. AIDS/HIV Acquired Immunodeficiency Syndrome/Human Immunodeficiency Virus. MPRm modified medication possession ratio. IQR interquartile range

Fig. 2.

Inclusion flowchart of the emulated trial

The target population consisted of 22.1% men and 77.9% women, with a mean age of 83.7 years. The distribution of index fractures, which overlapped multiple counts for individuals with more than one site of fracture on the same day, was 11,144 (20.9%) hip, 29,954 (56.1%) vertebral, 4,731 (8.9%) radius, 1,540 (2.9%) humerus, and 8,312 (15.6%) other. Vertebral fractures represented ≥ 50% of all fractures. Details of the combinations of the index and secondary fractures are shown in Supplementary Table S8. The breakdown of osteoporosis medications used in the exposure group was bisphosphonate (53.3%), human anti-RANKL monoclonal antibody (7.8%), parathyroid hormone analogs (28.6%), selective estrogen receptor modulators (SERM; 5.1%), and humanized anti-sclerostin monoclonal antibody (5.3%) (Table 2).

Comparative validity was maintained up to the end of the exposure period (day 90), and the SMD of all variables was < 0.1 (Supplementary Figure S3).

Primary outcome

Overall, the results showed an HR for any fracture of 0.91 (95% CI: 0.89–0.94), indicating a significant decrease in secondary fractures with osteoporosis medication use (Fig. 3). The HR was 0.94 (95% CI: 0.90–1.00) for men and 0.90 (95% CI: 0.88–0.94) for women, indicating similar suppression. For the Day 270 Cohort, the HR was 0.78 (95% CI: 0.70–0.84) overall, 0.71 (95% CI: 0.60–0.86) in men and 0.78 (95% CI: 0.71–0.88) in women. For the Day 455 Cohort, the HR was 0.74 (95% CI: 0.65–0.83) overall, 0.65 (95% CI: 0.48–0.82) for men and 0.74 (95% CI: 0.68–0.85) for women. Increased treatment duration significantly reduced secondary fracture risk in both sexes. Kaplan–Meier curves for any fracture showed that the exposed exhibited a significantly lower event rate than the controls (Fig. 4).

Fig. 3.

Cox proportional hazards analyses for the composite outcome and each component in the emulated trial population by sex from days 0, 270, and 455. Effect of new use of osteoporosis medication (Exposed) compared with no treatment (Control). Cl, confidence interval. The Day 0 Cohort was defined as individuals who initiated treatment within 90 days after the fracture and continued treatment, regardless of the duration. The Day 270 Cohort was defined as individuals who were exposed to the medication for at least 180 days from the end of the exposure period (Day 90) (Day 90 plus 180 days), and the Day 455 Cohort was defined as individuals who were exposed for at least 365 days from the end of the exposure period (Day 90 plus 365 days). Smaller squares indicate more precise estimates

Fig. 4.

Kaplan–Meier analysis showing event rates in the control group (blue line) and the exposure group (yellow line). A Overall, B men, and C women

Secondary outcomes

Fractures at each site are shown in Fig. 3. The overall hip fracture HR was 0.77 (95% CI: 0.71–0.81); 0.81 (95% CI: 0.71–0.94) for men, and 0.76 (95% CI: 0.71–0.81) for women. In the Day 270 Cohort, the overall hip fracture HR was 0.60 (95% CI: 0.53–0.66); 0.56 (95% CI: 0.36–0.80) in men and 0.60 (95% CI: 0.49–0.72) in women, both showing a significant reduction. In the Day 455 Cohort, the hip fracture HRs were 0.59 (95% CI: 0.19–0.84) in men and 0.55 (95% CI: 0.44–0.69) in women, indicating similar medication efficacy. Survival analysis revealed a statistically significant difference between the exposed and control groups at each time point from day 0.

Exploratory analysis

Among those with an index hip fracture, 8.5% experienced a secondary hip fracture, whereas 11.4% experienced another fracture site (Supplementary Table S8). Among men, 7.1% with an index hip fracture experienced a secondary hip fracture; 8.9% of women with an index hip fracture experienced a secondary hip fracture.

Discussion

In an older population (average age ≥ 80 years), the initiation and continued use of a new osteoporosis drug within 3 months after a fracture prevented secondary fractures for at least 6 months after drug initiation. An effect on hip fracture prevention was observed in both sexes.

Ample evidence supports that osteoporosis medication reduces the subsequent fracture risk in placebo-controlled clinical studies in women. However, reports focusing on imminent fracture prevention are limited to RCTs [40–42] and real-world studies. Results from the National Registry in Sweden demonstrated that osteoporosis medication is effective in women ≥ 80 years who started treatment within 6 months after fracture; the magnitude of the effect was similar to that in RCTs [31]. The STORM cohort based on Sweden’s largest healthcare data demonstrated that anti-resorptive treatment significantly reduced hip fracture incidence and all-cause mortality in adults ≥ 75 years, though effects on any fracture were not significant [29]. A retrospective cohort study using Medicare fee-for-service also showed that osteoporosis medication continuance > 90 days decreased subsequent fractures in frail and non-frail older populations (average: 82 years), although not significantly [28]. By mimicking real clinical trials, our study demonstrates the importance of early initiation and continued use of pharmacotherapy to increase effectiveness in adults ≥ 75 years.

The influence of age on the efficacy of pharmacologic treatments for fracture risk reduction was summarized by the FNIH-ASBMR-SABRE project examining 23 RCTs in women [9], indicating that bisphosphonates reduced hip fractures with an HR of 0.47 in those aged < 70 years and 0.79 in those > 70 years; the odds ratios for vertebral fractures were 0.47–0.51 for both groups. Our results showed a similar or greater effectiveness on hip fracture with an HR of 0.60 among individuals aged > 75 years.

A significantly lower fracture risk in the medication group was observed for any fracture; however, site-specific analysis revealed a statistically significant effect only for hip fractures. Although a decreasing trend in the risk of vertebral, radial, and humeral fractures was noted, statistical significance was not consistently observed across all subgroups stratified by follow-up duration and sex. There are several potential interpretations of the differences in results. First, in the case of vertebral fracture, there was selection bias due to different diagnosis frequencies; the control group consisted of individuals who had never visited a medical facility or were untreated for fractures during the follow-up period. Morphological fractures diagnosed by spinal radiography may have been overlooked. Although we concluded that medication exposure had an effect, our results may have been underestimated because individuals in the treatment group regularly visited medical facilities where physicians conducted radiography and other tests, which increased the likelihood of detecting asymptomatic vertebral fractures. The control group, which did not visit healthcare facilities regularly, may have a higher likelihood of fractures that were overlooked. Second, for radius and humerus fractures, the number of incident cases was smaller compared to hip fractures. Therefore, the lack of statistical significance in the stratified subgroup analyses may be attributable to limited statistical power. Third, the length of the follow-up period may have influenced this finding. Patients in the Day 0 Cohort may have experienced a fracture before the effect of drug therapy was seen; it may have been difficult to find a difference before then, since the Day 270 or Day 455 Cohorts showed a decreasing trend, and the effect of drug exposure was more pronounced. In addition, no significant differences were observed up to 1 year (455 days) after medication initiation, but differences started to emerge after that period, suggesting that the full benefit of treatment may require sustained use for at least a year.

Osteoporosis medication can prevent fractures in women; however, real-world and RCT data on men are lacking. A recent observational study in a large integrated healthcare system compared hip fracture reduction by osteoporosis treatment between sexes [11]. The hip fracture odds ratio versus not treated was 0.26 for women and 0.21 for men (men: women = 0.81 [95% CI: 0.47 − 1.37]), indicating no significant sex effect. In the present study`s Day 0 Cohort, indicating patients who started osteoporosis treatment and continued regardless of treatment period, the HR for any fracture was 0.90 (95% CI: 0.88 − 0.94) for women, and 0.94 (95% CI: 0.90 − 1.00) for men; that for hip fracture was 0.76 (95% CI: 0.71 − 0.81) for women, and 0.81 (95% CI: 0.71 to 0.94) for men. Our results demonstrated that initiating medication within 90 days after fracture was almost equally effective in both sexes. The observed sex-neutral effect may be largely driven by hip fracture reduction. This finding is consistent with previous reports and suggest treatment efficacy is more strongly influenced by bone response than by sex [11].

In 2020, a multi-stakeholder coalition assembled by the American Society for Bone and Mineral Research recommended that the oral bisphosphonates alendronate and risedronate be first-line treatments to prevent secondary fractures among those aged ≥ 65 years with a hip or vertebral fracture [20]. Intravenous zoledronic acid and subcutaneous denosumab may be therapeutic options, and anabolic agents may be beneficial for selected patients at high risk; however, these are expensive. In our study, bisphosphonates, including a nonoral one, were used in 53.3% of patients initiating osteoporosis treatment within 90 days after fracture, teriparatide in 28.6%, denosumab in 7.8%, anti-sclerostin antibody in 5.3%, and SERM in 5.1%.

Prompt treatment is required to prevent imminent fractures. A review demonstrated a significant reduction of fracture risk after > 1 year of osteoporosis treatment for vertebral or hip fracture, while a significant reduction in the risk of non-vertebral fracture was observed after 6 months using zoledronate and denosumab in RCTs [43]. The present study found that fracture prevention is efficient at least 6 months post medication initiation. Additionally, few previous studies outside clinical trials have examined longitudinal causal relationships, but the present study demonstrated the beneficial effects of continuous medication (HR: 0.91 for Day 0 Cohort, 0.78 for Day 270 Cohort, and 0.74 for Day 455 Cohort).

We adapted the RCT design to real-world data using target trial emulation and minimized bias using cloning. Unlike previous database studies, we employed analytical methods to overcome the immortal-time bias and improve the comparability between the exposed and control participants during the observation period. Although this was not a real clinical trial, the results were devised to enhance comparative validity. However, this study had several limitations. First, the generalizability and transportability of the findings should be considered. It was difficult to distinguish detailed characteristics of the population, their living environments, and whether they were bedridden. Under the universal health insurance system in Japan, there are few disparities due to the cost of healthcare; hence, population differences do not arise in whether people receive treatment. However, these results may differ in populations in countries without universal health insurance or in situations where there are disparities in the burden of healthcare costs. Second, confounding by indication remains a potential concern. Treatment decisions are influenced by (1) unmeasured patient characteristics (e.g., disease severity), (2) physician prescribing preferences, and (3) institutional or socioeconomic factors. These factors may not be fully adjusted for, although their impact likely biases result toward the null, as more severe patients are more likely to receive treatment and experience fractures. However, selection bias could widen differences if severely ill patients avoid treatment due to personal or medical reasons. Third, the database had several limitations regarding the accurate assessment of osteoporosis and fracture outcomes. It lacked essential data such as bone mineral density, related laboratory values, unrecorded prior fractures, and information on living environments or care statuses. Additionally, the index fracture was defined as the initial fracture occurring in individuals ≥ 75 years, but prior fractures were not captured, which could affect both study groups. Claims data were used to define fracture outcomes, but this approach has inherent limitations, potentially leading to misclassification, especially for imminent fractures occurring within 180 days. To minimize such misclassification, only fractures associated with medical procedures that continued for 180 days post-fracture were considered, meaning imminent fractures within this period may have been underreported. Similarly, fractures may have been overestimated as affecting the same site due to lingering diagnoses in the medical records. Although the descriptive number of second fracture sites was a new finding in Japan, it is essential to note that caution is required when interpreting the results, given our limitations.

Additionally, differences in follow-up duration between the exposed and non-exposed groups may have influenced fracture incidence. If the exposed group had a shorter follow-up due to mortality or loss to follow-up, their fracture risk could have been underestimated. However, we adjusted for baseline imbalances, and this limitation likely led to a conservative bias. In addition, we excluded activated vitamin D (aVD) from the list of osteoporosis medications evaluated in this study, although aVD is widely used in Japan, especially among elderly patients. This decision was made to align with major international guidelines, which do not consider aVD a standard therapeutic agent for secondary fracture prevention. However, this exclusion may limit the generalizability of our findings within the Japanese clinical context. Finally, although all osteoporosis drugs were used in the same manner, each drug has a different efficacy and safety profile, and a detailed analysis of treatment patterns was not performed. The present findings reflect the preventive effects of all osteoporosis medications combined. Among the medications initiated after the initial fracture, bisphosphonates accounted for 53.3%, human anti-RANKL monoclonal antibody for 7.8%, humanized anti-sclerostin monoclonal antibody for 5.3%, SERM for 5.1%, and parathyroid hormone analogs for 28.6%. Thus, the findings of this study are likely to have been predominantly influenced by bisphosphonates. It should be noted that these results cannot be applied to evaluate the overall or site-specific effects of individual osteoporosis medications on secondary fracture.

Detailed investigations of the therapeutic efficacy and safety profile of each drug are needed. Considering the above limitations, the interpretation of the results, their applicability, and reliability must be carefully evaluated.

Conclusions

This study provides robust evidence that the initiation of new osteoporosis medications within 90 days of fracture and their continued use reduces the risk of secondary fractures in both older men and women. These findings are consistent with those of clinical trials and provide a new perspective that is expected to help optimize the pharmacological treatment of osteoporosis and improve quality of life in older populations.

Supplementary Information

Below is the link to the electronic supplementary material.

Funding

This study was funded by Asahi Kasei Pharma Corporation.

Data availability

The data that support the findings of this study are from DeSC Healthcare, Inc. and were used under license for the current study; therefore, restrictions apply, and the data are not publicly available. For any inquiries regarding access to the data set used in this study, please contact DeSC Healthcare, Inc. (https://desc-hc.co.jp/en).

Declarations

Human and animal rights

The study complied with the principles of the Declaration of Helsinki and its amendments. Although informed consent was not obtained, the study used an anonymized dataset and was reviewed and approved by the Institutional Review Board of Asai Dermatology [approval number 2023022001]. The research plan was registered in the University Hospital Medical Information Network (UMIN) Clinical Trials Registry [UMIN000054784].

Conflict of interest

MT has received payments for lectures, including speakers’ bureau fees, from Asahi Kasei Pharma Corporation. MT has received consulting fees from Zimmer Biomet G.K.

TH has received lecture fees from Asahi Kasei Pharma Corporation, Amgen K. K., Daiichi-Sankyo Healthcare Co., Ltd., Mochida Pharmaceutical Co., Ltd., and Teijin Pharma Ltd.

NO received payments for lectures, including speakers’ bureau fees, from Asahi Kasei Pharma Corporation, Amgen K. K., Daiichi-Sankyo Healthcare Co., Ltd., and Teijin Pharma Ltd.

YS is an employee of Datack Inc.

SF has received lecture fees from Asahi Kasei Pharma Corporation, Teijin Parma LTD, UCB Japan Co., Ltd., Amgen K.K. and GE Healthcare Japan, and supervision fees from Medical Data Card, Inc.