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Abstract

Background:

Cholecystectomy is a common surgical procedure for gallbladder diseases. Removal of the gallbladder alters bile flow and may affect the absorption of fat-soluble vitamins, especially vitamin D, which could influence bone metabolism. However, epidemiological studies have yielded inconsistent findings regarding its association with osteoporosis and fractures.

Objectives:

To systematically evaluate the association between cholecystectomy and the risks of osteoporosis and fractures, and to examine potential effect modification by age.

Design:

Systematic review and meta-analysis of cohort studies.

Methods:

Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, cohort studies published up to June 1, 2025, were identified through comprehensive searches of PubMed, Embase, and Web of Science. Eligible studies compared individuals who underwent cholecystectomy with non-surgical controls and reported outcomes of osteoporosis or fractures. Study quality was assessed using the Newcastle–Ottawa Scale. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using a random-effects model. Subgroup analyses were conducted according to age and adjustment for confounders.

Results:

Four high-quality cohort studies, including more than 1.5 million participants, were eligible. Meta-analysis demonstrated a modest but statistically significant increase in fracture risk after cholecystectomy (pooled HR = 1.07; 95% CI, 1.05–1.10; I² = 50%). The association was stronger among individuals younger than 50 years (pooled HR = 1.14; 95% CI, 1.12–1.16), while no significant association was found among those aged ⩾50 years. For osteoporosis, the pooled estimate was inconclusive due to substantial heterogeneity (I² = 97%) and limited data (HR = 1.09; 95% CI, 0.88–1.37).

Conclusion:

Cholecystectomy may be associated with a small increase in fracture risk, particularly among younger adults, although the absolute risk remains low. Evidence for osteoporosis is inconclusive due to high heterogeneity and limited studies. Further large-scale prospective studies are needed to clarify these associations and mechanisms.

Trial registration:

PROSPERO (CRD420251071872).

Plain language summary

Does gallbladder removal (cholecystectomy) affect the risk of osteoporosis or bone fractures? A review of current evidence

Gallbladder removal surgery, also known as cholecystectomy, is a common procedure performed to treat gallbladder problems such as gallstones. Some researchers have wondered whether having your gallbladder removed might affect bone health, possibly leading to a higher risk of osteoporosis (weaker bones) or bone fractures. To answer this question, we carefully reviewed and combined results from four large, high-quality studies, including more than 1.5 million people. We compared people who had their gallbladders removed with those who did not have the surgery. Our findings showed that people who had a cholecystectomy had a slightly higher chance of breaking a bone, especially if they were under 50 years old. However, the overall risk was still low, and for people aged 50 or older, there was no clear link between gallbladder removal and broken bones. When we looked at the risk of osteoporosis, the results were uncertain because the studies we found were very different from each other and there were not enough of them to draw a firm conclusion. Based on the current evidence, we do not recommend routine special screening or treatment for bone health just because someone has had their gallbladder removed. Standard healthy habits for bone health—like good nutrition, regular exercise, not smoking, and getting enough calcium and vitamin D—are still the best advice for everyone. More research is needed to better understand whether certain groups might need special attention to their bone health after gallbladder surgery.

Keywords

cholecystectomy fracture meta-analysis osteoporosis systematic review

Introduction

Cholecystectomy is currently the standard surgical approach for managing gallbladder disorders, such as gallstones and cholecystitis. With the widespread adoption of laparoscopic techniques and a globally aging population, the annual number of cholecystectomies worldwide has steadily increased.¹ Under physiological conditions, the gallbladder serves as a reservoir for bile, concentrating and periodically releasing it into the intestine in response to meals. Removal of the gallbladder disrupts this physiological pattern of bile secretion, potentially impairing the absorption and metabolism of fat-soluble vitamins—particularly vitamin D—and thereby raising concerns regarding adverse effects on bone metabolism.

Several observational studies have reported decreased serum concentrations of 25-hydroxyvitamin D and reductions in bone mineral density (BMD) following cholecystectomy.² Two mechanisms have been proposed: first, diminished intestinal vitamin D absorption due to altered bile secretion³; second, disruption of the bile acid–gut microbiota–immune–endocrine axis, which disturbs bone remodeling.⁴ Although several mechanistic studies support these hypotheses, epidemiological findings remain notably inconsistent. For instance, a prospective cohort analysis from the UK Biobank (n = 35,206) demonstrated a significant increase in osteoporosis risk following cholecystectomy (hazard ratio (HR), 1.23; 95% confidence interval (CI), 1.14–1.32).⁵ Conversely, a nationwide Danish registry-based study involving approximately 870,000 participants found no clinically meaningful difference in osteoporosis risk associated with cholecystectomy (incidence rate ratio (IRR) = 0.98; 95% CI, 0.96–1.00).⁶ Regarding fracture risk, several studies suggest a modest long-term increase after cholecystectomy; however, the reported effect sizes are small, and their clinical significance remains uncertain.⁷ Discrepancies among studies may partly result from differences in study populations, methodological designs, and the extent to which potential confounders were addressed.

To date, no systematic review or meta-analysis has comprehensively assessed and quantitatively synthesized the association between cholecystectomy and the risks of osteoporosis and fracture. To address this evidence gap, we performed a systematic review and meta-analysis employing rigorous methodological standards to (1) evaluate whether cholecystectomy increases osteoporosis risk; (2) quantify the association with fracture risk; and (3) explore potential effect modifiers, particularly age. The findings from this research may help inform long-term monitoring strategies and targeted interventions aimed at preserving bone health in patients who have undergone cholecystectomy, thus potentially guiding personalized risk assessment and clinical management.

Methods

This systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines⁸ (see Supplemental Material). The study protocol was prospectively registered with PROSPERO (CRD420251071872).

Search strategy

Two investigators independently searched PubMed, Embase, and Web of Science for cohort studies published up to June 1, 2025. The search combined Medical Subject Headings (MeSH) and free-text terms related to cholecystectomy, BMD, osteoporosis, and fracture risk. The PubMed search string was as follows: (“Cholecystectomy”[MeSH Terms] OR cholecystectomy OR gallbladder removal) AND ((“Bone Density”[MeSH Terms] OR “bone mineral density” OR BMD) OR (“Vitamin D”[MeSH Terms] OR “25-hydroxyvitamin D” OR “vitamin D status”) OR (“Fractures, Bone”[MeSH Terms] OR fracture OR “osteoporotic fracture” OR osteoporosis)). Reference lists of included studies were manually reviewed to identify additional relevant publications. This review imposed no language restrictions. Two reviewers independently screened titles and abstracts, then assessed full texts for eligibility. Although no date restrictions were imposed, priority was given to recent, high-quality studies.

Inclusion and exclusion criteria

Eligible studies were prospective or retrospective cohort studies evaluating the association between cholecystectomy and the risks of osteoporosis and/or fractures. Studies were included if they (1) compared individuals who underwent cholecystectomy with matched or general-population controls who did not undergo the procedure; (2) reported clearly defined and quantified outcomes of osteoporosis (based on clinical diagnosis or BMD criteria) or fracture, that reported effect estimates—HRs preferred when available—or relative risks (RRs) and IRRs; and (3) explicitly documented measurable outcomes during the follow-up period. We excluded cross-sectional, case–control, case-series, descriptive, animal, mechanistic, or otherwise irrelevant studies. When multiple reports originated from the same cohort, we retained the article with the most comprehensive data or the highest methodological quality.

Data extraction and quality assessment

Two reviewers independently extracted data using standardized forms. Extracted information included the following: (1) study identification details (first author, year, country); (2) study design and data source (cohort characteristics, databases, sample size); (3) participants’ baseline characteristics (age and sex distribution); (4) exposure and control definitions (methods used to ascertain cholecystectomy status and criteria for selecting controls); (5) follow-up information (duration, completeness of follow-up); (6) outcome definitions and ascertainment methods for osteoporosis and/or fractures; (7) adjusted effect estimates (preferably HRs or RRs, with IRRs accepted only if others were unavailable) and their corresponding 95% CIs; and (8) covariates adjusted for in analyses, including age, sex, body mass index (BMI), and history of chronic conditions. If multiple statistical models were presented, estimates from the most comprehensively adjusted model were extracted. When adjusted estimates were unavailable, crude estimates were used. The Newcastle–Ottawa Scale (NOS) was applied to assess study quality across three domains: selection of study groups, comparability between groups, and ascertainment of outcomes and follow-up adequacy. The NOS ranges from 0 to 9; studies scoring ⩾7 were considered high quality.⁹ Disagreements in data extraction or quality assessment were resolved through consensus or arbitration by a third reviewer.

Statistical analysis

HRs were the primary effect measure for quantifying the association between cholecystectomy and outcomes. Given the relatively rare occurrence of these outcomes, RRs and IRRs reported in studies were approximated as HRs; thus, RRs and IRRs were log-transformed and included as HR equivalents in the meta-analysis.¹⁰ Pooled HRs and their 95% CIs were calculated using the DerSimonian–Laird random-effects model. Heterogeneity was assessed with the Cochran Q test (significance, α = 0.10) and the I² statistic. I² values >50% were considered indicative of moderate to high heterogeneity. Given the limited number of included studies, subgroup analyses were restricted to two predefined factors of clinical and methodological relevance. First, based on the original age stratifications reported by studies, participants were grouped by age to examine effect modification between cholecystectomy and fracture risk, thereby identifying vulnerable subpopulations. Second, considering variations in confounder adjustments across studies, we separately pooled studies with comprehensive multivariable adjustment and those reporting crude or minimally adjusted estimates, thus assessing the potential influence of residual confounding. Due to the limited number of included studies, sensitivity analyses (e.g., leave-one-out analyses) and formal tests of publication bias (Egger’s or Begg’s tests) were not performed. This methodological limitation and its potential implications for interpreting the findings were addressed in detail within the discussion section.¹¹ Statistical analyses were conducted using RevMan 5.3 (The Cochrane Collaboration, London, UK), with two-tailed p-values reported throughout.

Results

Literature search

The initial database search yielded 602 records: 155 from PubMed, 203 from Embase, and 244 from Web of Science. After deduplication in EndNote, 357 unique articles remained. Title and abstract screening by two independent reviewers excluded 323 records that were irrelevant to the study question or clearly ineligible, leaving 34 articles for full-text assessment. Upon detailed review, 30 additional studies were excluded: 22 did not investigate cholecystectomy or bone-related outcomes, 1 duplicated data from an existing cohort publication,¹² and 7 used ineligible study designs (e.g., case-series or descriptive studies) or lacked extractable effect measures. Ultimately, four cohort studies met the inclusion criteria. The PRISMA flow diagram is presented in Figure 1.

Figure 1.

PRISMA flow diagram for literature search and study selection.

Study characteristics

All four included studies were published recently and demonstrated high methodological quality (Table 1). Nielsen et al.⁶ conducted a retrospective nationwide cohort study using the Danish National Health Register, including approximately 150,000 cholecystectomy patients and 720,000 matched controls. Cholecystectomy exposure was identified via hospital procedure codes, and osteoporosis and fracture outcomes were extracted based on ICD-10 diagnostic codes, with a mean follow-up of 9 years. Cheng et al.¹² used Taiwan’s National Health Insurance Research Database (NHIRD) to analyze 304,081 patients who underwent cholecystectomy, hepatectomy, or pancreatectomy from 2000 to 2012, matched 1:1 with nonsurgical controls. The mean follow-up was approximately 10 years, and subgroup analyses were performed to assess fracture risk by surgical type. Lee et al.⁷ analyzed data from the Korean National Health Insurance Service (NHIS), including 143,667 patients aged ⩾40 years who underwent cholecystectomy between 2010 and 2015, compared with 255,522 age- and sex-matched controls. Median follow-up was 2.6 years, with fracture outcomes identified via diagnostic and claims data. Yang et al.⁵ conducted a prospective cohort study using the UK Biobank, including 17,603 individuals with a history of cholecystectomy and 35,206 matched controls. Median follow-up was 13.6 years. Exposure was defined via self-report and hospital records, and osteoporosis outcomes were identified using ICD-10 codes. Across studies, the mean or median participant age ranged from 50 to 60 years, with the proportion of females ranging from 47% to 77% (Table 1). Three studies assessed fracture outcomes, with minor variations in definitions: Lee et al.⁷ reported separate outcomes for any fracture, vertebral fractures, and hip fractures; Cheng et al.¹² focused specifically on osteoporotic fractures. All studies targeted clinically meaningful fracture endpoints. Two studies^5,6 reported osteoporosis outcomes, based on clinical diagnoses or ICD-10 coding. All studies adjusted for age and sex in multivariable models; several further adjusted for BMI, chronic comorbidities (e.g., diabetes, hypertension), and lifestyle factors, such as smoking and alcohol consumption, to reduce residual confounding. Study quality was assessed using the NOS, with all four studies scoring between 8 and 9, indicating high quality (Table 2). All studies demonstrated rigorous participant selection and outcome ascertainment. Most controlled for key confounders through multivariable adjustment or propensity score matching. However, the Danish cohort lacked data on certain lifestyle factors (e.g., diet, physical activity), potentially resulting in residual confounding.

Table 1.

Overview of basic study characteristics.

First author, publication year	Country	Study design	Participants	Average age	Sample size	Percentage of females	Diagnosis of fractures	Acquisition of cholecystectomy history	Median follow-up	Risk estimate (95% CI)		Adjusted risk estimate (95% CI)		Adjusted variables
First author, publication year	Country	Study design	Participants	C/NC	C/NC	C/NC	Diagnosis of fractures	Acquisition of cholecystectomy history	Median follow-up	Osteoporosis	Fractures	Osteoporosis	Fractures	Adjusted variables
Nielsen, 2023	Denmark	Nationwide cohort	Danish Health Registers	50.1 ± 15.9/49.6 ± 15.7	149,968/727,456	71.1/70.9	ICD-10	Nordic surgical codes (KJKA2, KJKA21)	9 y	IRR 0.98 (0.96–1.00)	IRR 1.06 (1.05–1.07)	NA		Age, sex, and comorbidity index, but residual confounding is possible
Cheng, 2020	China, Taiwan	Retrospective cohort	Taiwan National Health Insurance Research Database	NA/57.0 ± 16.0	NA/304,081	NA/50.3	ICD-9	Procedure codes in NHIRD	10 y	NA	HR 1.09 (1.00–1.18)	NA	HR 1.10 (1.01–1.19)	Sex, age, comorbidities (hypertension, diabetes, hyperlipidemia, stroke, COPD, cirrhosis, CKD, cancer, folate deficiency, depression, thyroid disease, fibromyalgia, CAD, alcohol-related diseases, biliary stone, asthma, and hyperparathyroidism)
Lee, 2021	Korea	Nationwide cohort	Korean National Health Insurance Service	57.40 ± 10.92/57.92 ± 10.91	143,667/255,522	46.8/46.8	ICD-10	Procedure code Q7380	2.6 y	NA	HR 1.06 (1.026, 1.096)	NA	HR 1.095 (1.059, 1.132)	Age, sex, income, place of residence, diabetes mellitus, hypertension, dyslipidemia, smoking, alcohol drinking, and exercise, BMI
Yang, 2023	United Kingdom	Prospective cohort	UK Biobank	59.56 ± 7.13/59.56 ± 7.13	17,603/35,206	77/77	ICD-10	Self-report and OPCS procedure codes	13.6 y	HR 1.11 (1.04–1.20)	NA	HR 1.23 (1.14–1.32)	NA	Age, sex, ethnicity, smoking status, income, education, BMI, alcohol intake, hypertension, diabetes, total cholesterol, and vitamin D

BMI, body mass index; C, cholecystectomy; CAD, coronary artery disease; CKD, chronic kidney disease; CI, confidence interval; COPD, chronic obstructive pulmonary disease; HR, hazard ratio; IRR, incidence rate ratio; NA, not applicable; NC, non-cholecystectomy; NHIRD, National Health Insurance Research Database; OPCS, Office of Population Censuses and Surveys Classification of Surgical Operations and Procedures.

Table 2.

NOS assessment of included cohort studies.

Author	Year	Design	Selection				Comparability		Outcome			Total stars	Quality
Nielsen	2023	Cohort	★	★	★	★	★	✖	★	★	★	8	High
Chen	2020	Cohort	★	★	★	★	★	★	★	★	★	9	High
Lee	2021	Cohort	★	★	★	★	★	★	★	✖	★	8	High
Yang	2023	Cohort	✖	★	★	★	★	★	★	★	★	8	High

NOS, Newcastle–Ottawa Scale.

Cholecystectomy and fracture risk

Three studies evaluated the association between cholecystectomy and fracture risk, with consistent findings suggesting a modest increase. Specifically, Nielsen et al.⁶ reported an unadjusted IRR of 1.06 (95% CI, 1.05–1.07). The Korean NHIS cohort⁷ showed an adjusted HR of 1.10 (95% CI, 1.06–1.13). The Taiwanese NHIRD cohort¹² reported an adjusted HR of 1.10 (95% CI, 1.01–1.19) for osteoporotic fractures. These effect estimates were closely aligned across studies, suggesting a potential, modest increase in fracture risk following cholecystectomy, although the possibility of residual confounding cannot be excluded. The pooled HR using a DerSimonian–Laird random-effects model was 1.07 (95% CI, 1.05–1.10; p < 0.00001; Figure 2). While this corresponds to a RR increase of 7%, the absolute risk difference was small. For example, Lee et al.⁷ reported a fracture incidence of 14.689 per 1000 person-years in the cholecystectomy group versus 13.862 per 1000 person-years in controls, an absolute difference of 0.827 per 1000 person-years. Similarly, Nielsen et al.⁶ found a 9-year fracture prevalence of 22.2% in cholecystectomy patients and 20.9% in controls. Despite large sample sizes and precise estimates, moderate heterogeneity was observed (I² = 50%, Q test p = 0.14), indicating some variability across studies but within an acceptable range.¹¹

Figure 2.

Forest plot of meta-analysis on cholecystectomy and fracture risk: shows pooled relative risk and 95% CI, indicating a slightly increased fracture risk in the cholecystectomy group compared with controls.

Cholecystectomy and osteoporosis risk

Two studies assessed the association between cholecystectomy and osteoporosis, yielding divergent results. Nielsen et al.,⁶ using Danish registry data, reported comparable osteoporosis incidence in the cholecystectomy and control groups (3.5% vs 3.5%), with an IRR = 0.98 (95% CI, 0.96–1.00), suggesting no significant association. By contrast, Yang et al.,⁵ using UK Biobank data, found a significantly increased risk of osteoporosis following cholecystectomy, with an adjusted HR of 1.23 (95% CI, 1.14–1.32) after controlling for age, sex, BMI, and serum vitamin D levels. The pooled HR was 1.09 (95% CI, 0.88–1.37; p = 0.43) using a random-effects model (Figure 3), indicating no statistically significant overall association. However, substantial heterogeneity was present (I² = 97%), reflecting considerable inconsistency between studies and underscoring the need for cautious interpretation of the pooled estimate.

Figure 3.

Forest plot of meta-analysis on cholecystectomy and osteoporosis risk: the pooled estimate suggests no significant effect of cholecystectomy on osteoporosis diagnosis, though substantial heterogeneity exists between studies.

Subgroup analysis, sensitivity analysis, and publication bias

Due to data limitations, only two prespecified subgroup analyses—age and adjustment for confounding factors—were conducted to explore potential effect modifiers of the association between cholecystectomy and fracture risk (Figure 4). In the age-stratified analysis, participants were grouped into <50, 50–65, and >65 years, based on original study categories. An apparent age-related gradient was observed, with a stronger association between cholecystectomy and fracture risk among individuals younger than 50 years (HR = 1.14; 95% CI, 1.12–1.16), with no heterogeneity (I² = 0%). By contrast, no significant association was observed in those aged 50–65 years (HR = 1.03; 95% CI, 0.96–1.11; I² = 84%) or >65 years (HR = 1.04; 95% CI, 0.94–1.16; I² = 93%), both of which showed substantial heterogeneity. While the RR was elevated in younger participants, their low baseline fracture rates imply a limited absolute risk increase. Regarding adjustment for confounding, pooled estimates were similar for multivariable-adjusted studies (HR = 1.10; 95% CI, 1.06–1.13) and for crude or minimally adjusted studies (HR = 1.06; 95% CI, 1.05–1.07), with negligible heterogeneity (I² = 0%), suggesting that residual confounding may have had a limited impact on the overall findings. Due to the small number of included studies, sensitivity analyses (e.g., leave-one-out) and formal publication bias assessments (e.g., Egger’s or Begg’s tests) were not conducted. These methodological limitations are further discussed in the “Discussion” section.

Figure 4.

Subgroup analysis forest plot—cholecystectomy and fracture risk: fracture risk was significantly increased in individuals aged <50 years following cholecystectomy, with no significant difference observed in those aged ⩾50 years.

Discussion

This systematic review and meta-analysis represents the first comprehensive synthesis of available evidence on the association between cholecystectomy and the risks of osteoporosis and fracture. While our findings suggest a modest but statistically significant increase in fracture risk following cholecystectomy (approximately 7%), particularly among individuals younger than 50 years (≈14%), these results should be interpreted with caution, given the limited number of included studies and methodological heterogeneity. By contrast, current evidence regarding the association between cholecystectomy and osteoporosis risk is inconclusive, primarily due to substantial heterogeneity across studies. The observed discrepancy between an increased risk of fracture and the absence of a statistically significant association with osteoporosis may reflect underlying mechanisms not fully captured by BMD assessments or current diagnostic criteria.

Several plausible biological mechanisms may underlie this relationship. First, cholecystectomy alters bile dynamics, converting meal-stimulated, pulsatile bile secretion into a continuous low-concentration flow. This shift may reduce peak post-prandial bile concentrations and potentially impair the intestinal absorption of fat-soluble vitamins, particularly vitamin D.^13,14 Vitamin D deficiency can compromise calcium absorption and induce secondary hyperparathyroidism, thereby promoting bone resorption. It also plays a role in regulating trabecular mineralization and collagen maturation; thus, deficiency may degrade bone microarchitecture and mechanical integrity even before a measurable decrease in BMD occurs.¹⁵ Several prior studies have reported lower serum 25-hydroxyvitamin D levels and downward trends in BMD following cholecystectomy.^3,2,16,17 Moreover, vitamin D deficiency can impair muscle strength, proprioception, and balance, thereby increasing the risk of falls and fractures.^18,19 The current findings—an elevated incidence of fractures without a corresponding rise in osteoporosis diagnoses—may reflect subclinical deficits in bone quality and fall-related risk, sufficient to modestly increase fracture rates but not necessarily to decrease BMD below osteoporotic thresholds in the short-to-medium term. Future prospective studies should incorporate serial BMD measurements and bone turnover markers to investigate these potential effects over time. Alternative or complementary mechanisms may also contribute to this association. Cholecystectomy patients frequently present with metabolic or inflammatory comorbidities such as obesity, insulin resistance, or nonalcoholic fatty liver disease, all of which can alter bone turnover and microarchitecture through hormonal and cytokine-mediated pathways.^20,21 Gallstone disease itself—often preceding surgery—has been linked to systemic metabolic dysfunction, which may confound the postoperative risk signal. Notably, NHIRD data indicate that gallstone disease per se is associated with higher hip fracture risk irrespective of surgery,²² suggesting potential confounding by shared metabolic and inflammatory pathways and underscoring the need to differentiate disease—from surgery-specific effects. Furthermore, postoperative alterations in bile acid signaling can modulate endocrine receptors, such as FXR and TGR5, influencing glucose and lipid metabolism, energy expenditure, and inflammatory tone, which collectively may affect skeletal homeostasis. Changes in gut microbiota composition after cholecystectomy and low-grade chronic inflammation might also contribute to impaired bone remodeling or increased fall susceptibility. These overlapping metabolic and inflammatory mechanisms could therefore act synergistically with vitamin D malabsorption to modestly elevate fracture risk. Second, the bile acid–gut microbiota–immune axis may also play a role in post-cholecystectomy bone metabolism dysregulation. Chronic low-level bile acid exposure in the intestine has been shown to alter the composition of the gut microbiome,²³ and both animal and human studies suggest that dysbiosis may increase intestinal permeability, stimulate systemic inflammation, and disrupt short-chain fatty acid metabolism—factors that can promote osteoclast differentiation and accelerate bone resorption.^24,25 Bile acids also act as endocrine signaling molecules, activating the nuclear receptor FXR and the membrane receptor TGR5. FXR is involved in osteoblast differentiation and matrix mineralization, while TGR5 signaling may suppress osteoclast activity.²⁶ Interactions between microbial dysbiosis and bile acid signaling could therefore contribute to disrupted skeletal homeostasis. Collectively, these pathways—including malabsorption, hormonal imbalance, and immune-metabolic dysregulation—may contribute to the observed increase in fracture risk. Future large-scale cohort studies incorporating bile acid profiling, gut microbiome analyses, and bone metabolism biomarkers are needed to clarify the relative contributions of these mechanisms and to inform post-cholecystectomy monitoring strategies.

Subgroup analyses identified age as a significant effect modifier, with a stronger association between cholecystectomy and fracture risk observed in individuals younger than 50 years. However, the clinical relevance of this finding remains uncertain, as the absolute fracture risk in younger populations is low. Several factors may account for these age-related differences. Younger individuals typically have higher baseline BMD and greater vitamin D reserves, potentially rendering them more susceptible to subtle metabolic disturbances following cholecystectomy. By contrast, older adults already face an increased risk of osteoporosis and vitamin D deficiency, which may attenuate or mask any additional effect of cholecystectomy. Moreover, early-onset gallstone disease requiring cholecystectomy in younger patients may reflect underlying metabolic or genetic predispositions that also influence bone health. For instance, Nielsen et al.⁶ reported higher rates of both fractures and osteoporosis among cholecystectomy patients aged ⩽30 years, suggesting possible coexisting malabsorptive or inflammatory conditions in this subgroup. Conversely, in older adults, cholecystectomy is often associated with obesity and metabolic syndrome,^20,21 factors that may exert protective effects on bone through increased estrogen levels and mechanical loading,²⁷ thereby potentially offsetting the skeletal impact of surgery. This hypothesis is supported by Danish registry data, which show that the association between cholecystectomy and osteoporosis shifts from positive in younger individuals to neutral or slightly protective in older adults (HR = 0.98 (95% CI, 0.96–1.02) for ages 51–65; HR = 0.95 (95% CI, 0.92–0.99) for ages 66–80). These findings suggest that age modifies both the magnitude and the heterogeneity of risk, likely due to differences in baseline bone status and comorbidity profiles. Further research is needed to clarify these age-specific mechanisms and to inform individualized bone health management in patients undergoing cholecystectomy.

The analysis of osteoporosis outcomes revealed substantial heterogeneity (I² = 97%), which severely limits the interpretability of the pooled estimate. Several factors may have contributed to this variability: (1) differences in study populations—Nielsen’s Danish cohort⁶ included a broader general population with a younger age distribution and a higher proportion of male participants, while Yang’s UK Biobank study⁵ focused on older, healthier volunteers, predominantly female (≈77%), who may have been more likely to undergo osteoporosis screening; (2) disparities in confounder adjustment—Nielsen et al. did not account for key variables such as BMI or vitamin D status, whereas Yang et al. included extensive adjustments, revealing a significant association; (3) variations in follow-up duration and diagnostic definitions—UK Biobank had a longer follow-up (13.6 vs 9 years) and used both hospital records and self-reported diagnoses, potentially capturing more marginal cases. By contrast, the Danish registry relied solely on ICD-10 coding, which may have underestimated subclinical osteoporosis. These methodological differences limit the robustness of the pooled result and highlight the need for harmonized outcome definitions, longer follow-up, and standardized collection of key covariates in future studies.

From a clinical perspective, although the observed increase in fracture risk following cholecystectomy appears modest and the absolute risk remains low, the finding of a relatively higher risk among younger patients should be interpreted with caution, given the low baseline fracture rates and limited available evidence. Current data do not support routine or targeted bone health screening, monitoring, or preventive interventions specifically for patients undergoing cholecystectomy, regardless of age or other risk factors. Standard recommendations for bone health—such as maintaining adequate nutrition, regular weight-bearing exercise, avoiding tobacco use, moderating alcohol intake, and ensuring sufficient calcium and vitamin D—remain appropriate for all individuals, including those with a history of cholecystectomy. In older adults, fracture risk is primarily determined by age and established risk factors, rather than cholecystectomy status. Overall, clinical management should be individualized, and current evidence does not justify changes to existing bone health practices solely based on a history of cholecystectomy. Further research is needed to clarify whether any subgroups may benefit from targeted interventions.

This study has several important limitations. First, the number of included studies was small, and all were observational, leaving residual confounding and selection bias as concerns despite high NOS scores and preference for adjusted estimates. Key lifestyle variables—diet, sun exposure, calcium and vitamin D intake, and physical activity—were largely unreported. Second, inconsistencies in the definitions of fractures and osteoporosis across studies (e.g., inclusion of fragility fractures vs all fractures, variable diagnostic criteria) may have introduced misclassification bias and heightened heterogeneity. Third, small subgroup sample sizes and disparate age strata limited analytic precision. Fourth, generalizability is limited because all included studies were conducted in European or East Asian populations. Fifth, we were unable to assess dynamic changes in BMD or bone turnover markers, which would provide valuable mechanistic insights. In addition, the small number of included studies precluded formal sensitivity analyses and assessment of publication bias. Due to data limitations, subgroup analyses based on outcome definitions (e.g., any fracture vs osteoporotic fracture), follow-up duration (which varied widely across studies, from 2.6 to 13.6 years), fracture site, or sex could not be conducted. Therefore, the findings should be regarded as preliminary and hypothesis-generating. Future large-scale prospective cohort studies with robust covariate data and serial bone health monitoring are needed to confirm and extend these observations.

Conclusion

This meta-analysis suggests that cholecystectomy may be associated with a modestly increased risk of fracture, particularly among individuals younger than 50 years, although the absolute risk remains low. Evidence regarding osteoporosis risk is inconclusive due to substantial heterogeneity and limited data. Current findings do not support routine bone health screening or targeted interventions specifically for patients undergoing cholecystectomy. Standard recommendations for bone health remain appropriate for all individuals. Further large-scale prospective studies are needed to confirm these associations and clarify potential mechanisms.

Supplemental Material

sj-docx-1-tab-10.1177_1759720X251396750 – Supplemental material for Cholecystectomy and the risk of osteoporosis and fractures: a systematic review and meta-analysis

Supplemental material, sj-docx-1-tab-10.1177_1759720X251396750 for Cholecystectomy and the risk of osteoporosis and fractures: a systematic review and meta-analysis by Guoming Sun, Jianjun Shen, Hongying Tang, Jian Yao, Limin Huang, Yangri Duan and Zhaoxu Tian in Therapeutic Advances in Musculoskeletal Disease

Footnotes

Acknowledgements

None.

Declarations

ORCID iD

Zhaoxu Tian

Supplemental material

Supplemental material for this article is available online.

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