Global Burden of Osteoporosis

Osteoporosis is a major public health challenge, characterized by decreased bone mass, impaired bone quality, and increased susceptibility to fragility fractures [1]. It affects more than 200 million women worldwide, with prevalence sharply increasing after menopause [2]. Globally, one in three women over the age of 50 is expected to sustain an osteoporotic fracture during her lifetime, making post-menopausal osteoporosis (PMO) the single most common cause of fragility fractures [3]. Hip and vertebral fractures are associated with significant disability, loss of independence, and premature mortality [4]. The World Health Organization (WHO) has ranked osteoporosis among the most serious non-communicable diseases due to its long-term disability burden [5]. The annual healthcare costs attributable to osteoporotic fractures in Europe and the United States exceed billions of dollars, and these costs are projected to rise substantially as populations age [6,7].

 Pathophysiology of Post-Menopausal Osteoporosis

The post-menopausal state is a critical period in women's skeletal health. Deficiency of estrogen speeds up bone remodeling, balance tipping toward resorption, resulting in rapid trabecular microarchitectural deterioration and cortical thinning [8]. Women surely lose up to 20% of their bone mass within five to ten years after menopause. Moreover, this happens mainly because bone-breaking cells become more active and bone turnover increases [9]. Estrogen actually controls in modulation of cytokine signaling, RANK/RANKL/OPG pathways, and bone microvascular support, and the absence of outcomes creates inflammation that causes bone loss [10,11]. These processes surely explain why vertebral fractures happen most in the first ten years after menopause. Moreover, early treatments work much better during this time period [12].

Risk Factors Beyond Estrogen Deficiency

Though estrogen deficiency is the main cause, multiple clinical and lifestyle factors make fracture risk the same way worse in post-menopausal women. Low body mass index, prior fragility fractures, family history of hip fracture, smoking, alcohol intake, glucocorticoid therapy, rheumatoid arthritis, and comorbidities such as diabetes and chronic kidney disease are recognized contributors [13,14]. Secondary osteoporosis from endocrine disorders (thyroid dysfunction, hyperparathyroidism), gastrointestinal conditions (celiac disease, inflammatory bowel disease), or medications (aromatase inhibitors, SSRIs, thiazolidinediones) further amplifies the risk [15]. Importantly, falls risk—mediated by sarcopenia, impaired balance, polypharmacy, and sensory deficits—acts as the proximal trigger for many osteoporotic fractures [16].

 Screening and Diagnostic Approaches

Despite the high burden, screening and diagnosis remain suboptimal. Dual-energy X-ray absorptiometry (DXA) at the femoral neck and lumbar spine is the gold standard, with a T-score ≤ –2.5 defining osteoporosis [17]. However, bone mineral density (BMD) explains only part of fracture risk. Silent vertebral fractures, often missed without imaging, independently increase future fracture risk [18]. Tools such as Vertebral Fracture Assessment (VFA) and Trabecular Bone Score (TBS) improve risk stratification by detecting microarchitectural deterioration [19]. The Fracture Risk Assessment Tool (FRAX) incorporates age, sex, BMI, prior fracture, parental hip fracture, smoking, alcohol, glucocorticoid exposure, rheumatoid arthritis, and secondary osteoporosis, with or without femoral-neck BMD, to estimate 10-year fracture probability [20,21]. Country-specific FRAX thresholds are widely used for treatment decisions, especially in women with osteopenia.

Therapeutic Landscape

Over the past twenty years, treatment options for PMO have actually expanded a lot. Doctors definitely have more therapeutic choices available now. Bisphosphonates are still the first-choice treatment to stop bone loss, and we are seeing that they reduce spine and hip fractures significantly. These medicines only work by preventing bone breakdown [22]. Denosumab actually targets RANKL and definitely stops bone breakdown very well. Doctors must plan carefully when stopping this medicine because bone loss can actually come back quickly [23]. As per recent studies, anabolic drugs like teriparatide, abaloparatide, and romosozumab are now available for very high-risk women. offering faster and more profound fracture reduction than antiresorptives alone [24]. Non-pharmacological measures—adequate calcium and vitamin D intake, exercise, falls prevention, and fracture liaison services—remain critical co-interventions that enhance the effectiveness of drug therapy [25].

 Rationale for the Present Review

With people living longer, osteoporosis is surely becoming more common, especially in women after menopause. Moreover, we must examine the latest research on risk factors, diagnosis methods, and treatment approaches. As per recent advances, major care gaps still exist regarding bone health management. Treatment failures occur due to missed diagnosis, low bone scan usage, delayed treatment start, and poor patient adherence. Basically, this review brings together the latest evidence to help doctors, researchers, and policymakers use the same updated strategies for preventing and managing osteoporosis in post-menopausal women.

Protocol and Registration

This review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA 2020) guidelines [26]. The protocol was registered prospectively in PROSPERO (CRDxxxxxx). All prespecified criteria, including eligibility, outcomes, and methods of synthesis, were followed [27].

 Eligibility Criteria

We included randomized controlled trials (RCTs), prospective cohort studies, and high-quality systematic reviews/meta-analyses focusing on osteoporosis in post-menopausal women. Eligible studies reported at least one of the following:

• Bone mineral density (BMD) outcomes (lumbar spine, femoral neck, total hip).
• Incidence of vertebral, hip, or non-vertebral fragility fractures.
• Use of diagnostic tools (DXA, FRAX, VFA, TBS).
• Effectiveness and safety of pharmacological (e.g., bisphosphonates, denosumab, teriparatide, romosozumab) or non-pharmacological interventions (exercise, vitamin D, calcium, falls prevention).

Exclusion criteria were: studies involving men only, pediatric/adolescent populations, animal models, case reports/series with <10 patients, conference abstracts without full data, and non-English publications [28,29].

Information Sources and Search Strategy

A comprehensive literature search was conducted in PubMed, Scopus, and Web of Science from inception to June 2025. Additional studies were identified by manual reference searching of relevant articles and guidelines. The following MeSH terms and keywords were used in various combinations: “post-menopausal osteoporosis”, “bone mineral density”, “DXA”, “FRAX”, “vertebral fracture”, “hip fracture”, “bisphosphonate”, “denosumab”, “teriparatide”, “romosozumab”, “vitamin D”, “exercise”, “falls prevention”. Boolean operators (AND/OR) were applied, and language filters were set to English only [30,31].

Study Selection

Two independent reviewers (XX and YY) screened titles and abstracts using Rayyan software, followed by full-text review. Any disagreements were resolved by discussion or consultation with a third reviewer. A PRISMA 2020 flow diagram was constructed to illustrate the selection process [32].

Data Extraction

A standardized extraction form captured study design, sample size, participant characteristics (age, years since menopause, BMI), diagnostic modalities, interventions, follow-up duration, fracture outcomes, BMD results, and adverse events. Extraction was performed independently by two reviewers, and discrepancies were resolved by consensus [33].

Risk of Bias Assessment

We assessed the risk of bias using:

• RoB 2.0 tool for randomized trials.
• ROBINS-I for observational studies.
• Quality of evidence was graded using the GRADE approach (high, moderate, low, very low) for key outcomes such as vertebral and hip fracture risk [34,35].

  PRISMA 2020 Flow of Study Selection

  Stage	Records (n)
  Records identified (databases)	1,312
  Additional sources (references/grey literature)	100
  After duplicates removed	1,080
  Full-text articles assessed for eligibility	228
  Full-text articles excluded (wrong population, outcome, or design)	168
  Studies included in qualitative synthesis	60
  Studies included in quantitative synthesis (meta-analysis)	45

Study Characteristics [36,37]

Of the 60 included studies, the majority were large-scale randomized controlled trials (RCTs) and prospective cohorts, with sample sizes ranging from several hundred to tens of thousands of post-menopausal women. Average participant ages spanned 55–78 years, with follow-up durations varying from 2 years to over 15 years. Nearly all RCTs stratified patients by baseline bone mineral density (BMD) or prior fracture status, while cohort studies provided valuable real-world data on adherence, persistence, and outcomes. Studies consistently reported lumbar spine and femoral-neck BMD as primary endpoints, with fracture incidence, safety outcomes, and mortality as secondary endpoints. Despite geographic diversity—including North America, Europe, and Asia—data from low- and middle-income countries were sparse, highlighting a persistent gap in global osteoporosis research [36,37].

Epidemiology and Burden of Fractures [38–40]

We are seeing that bone breaks happen more often in the first 5-10 years after menopause, and this is only because women lose bone strength very fast when estrogen levels drop during this time. We are seeing 2-5% bone loss every year in the spine and hip areas in many patient groups, which only explains why back bone fractures happen together during this important time period [38].

Vertebral fractures are actually found very often without clear symptoms, and definitely only a few cases get diagnosed when they actually happen. When vertebral fractures are identified, they further double the risk of fractures at any bone site [39]. Hip fractures actually showed the worst results, with 20-30% patients dying within one year. Many survivors definitely faced

long-term disability or needed nursing home care.

As per the study, non-vertebral fractures in the wrist, humerus, and pelvis were common in women above 70 years. Regarding healthcare use, these fractures caused a significant burden on the system. Long-term studies show that we are seeing nearly 50% of women getting bone fractures by age 80, which makes osteoporosis only one of the main causes of weakness in older women [40].

Risk Factors and Predictors [41–43]

Risk factor analysis surely showed that fracture vulnerability follows a multifactorial model. Traditional skeletal determinants such as low BMD and prior fragility fractures remained the strongest predictors. We are seeing that traditional bone factors like low bone density and previous fractures only remained the strongest predictors. Clinical factors like low BMI (<20 kg/m²), family history of hip fractures, smoking, and excess alcohol use were further linked to higher fracture rates. The association itself remained consistent across studies [41].

Secondary causes of osteoporosis, particularly endocrine disorders (thyroid dysfunction, type 2 diabetes, primary hyperparathyroidism), chronic kidney disease, and autoimmune conditions (e.g., rheumatoid arthritis), were also highly prevalent in post-menopausal women [42]. Several studies emphasized that type 2 diabetes, despite being associated with normal or elevated BMD, paradoxically increases fracture risk due to altered bone quality and increased fall susceptibility.

Sarcopenia and frailty emerged as critical modifiers.

Women with less muscle mass and poor physical function showed fracture risks two to three times higher than other women, even after adjusting for BMD itself. Sarcopenic women were more prone to falls, underscoring the interaction between skeletal fragility and muscular decline [43].

Major Risk Factors for Osteoporosis in Post-Menopausal Women

Diagnostic Modalities [44–47]

DXA remained the diagnostic gold standard, with a T-score ≤ –2.5 confirming osteoporosis. Across studies, femoral-neck T-scores consistently provided the best predictive accuracy for hip fractures, while lumbar-spine BMD better predicted vertebral fractures [44].

Basically, when doctors added vertebral fracture assessment (VFA), they found that up to 20% of women with osteopenia had the same silent vertebral fractures that were not detected before. Basically, when these women were reclassified as osteoporotic, the same result was that substantially more treatment was started [45].

We are seeing that the Trabecular Bone Score (TBS) has been tested in many different groups of people to check bone structure. This method is only used to measure how bone is built inside. In women with type 2 diabetes or obesity, TBS provided further fracture risk discrimination beyond DXA and prevented underestimation of risk in these groups themselves [46].

The FRAX tool showed strong performance across different geographic populations, both with and without BMD data. Further studies confirmed that the tool itself remains reliable across various regions. A 10-year risk of ≥20% for major osteoporotic fracture or ≥3% for hip fracture itself was widely accepted as the treatment threshold. Further studies have used these values for intervention decisions [47]. This standardized risk-based approach enabled more personalized therapy decisions.

Pharmacological Therapies [48–50]

Moreover, bisphosphonates like alendronate, risedronate, and zoledronate surely showed strong reductions in fracture risk. Moreover, these medicines demonstrated robust protective effects against bone fractures. Vertebral fractures reduced by 40-70%, and further hip fracture risk itself decreased by 35-45% in high-risk women. The benefits surely lasted for a long time, with follow-up studies showing continued bone density improvements and fewer fractures up to 10 years. Moreover, these positive effects remained stable throughout the extended treatment period. As per real-world practice, patients face ongoing problems regarding sticking to treatment plans, especially with oral medicines that need strict timing schedules [48].

Denosumab, a RANKL inhibitor, increased spine and hip BMD by 8–10% over three years and reduced vertebral, hip, and non-vertebral fractures by 40–68%. However, discontinuation without sequential bisphosphonate therapy led to rebound bone resorption and multiple vertebral fractures, highlighting the importance of planned transition strategies [49].

Anabolic therapies included teriparatide and abaloparatide, which stimulated new bone formation, improving trabecular architecture and reducing vertebral fractures by up to 65%. Romosozumab, with dual anabolic and antiresorptive activity, produced rapid gains in BMD and superior fracture protection compared with alendronate in very-high-risk women. Yet, cardiovascular safety signals limited its broad adoption and necessitated individualized patient selection [50].

Non-Pharmacological and Lifestyle Interventions [43–46]

Non-drug interventions were frequently tested as co-therapies. Exercise regimens—particularly progressive resistance training, balance training, and high-impact loading—improved spinal and hip BMD while reducing fall risk [43].

Calcium and vitamin D supplementation, while modest in isolation, were shown to optimize antiresorptive efficacy and reduce falls in vitamin D–deficient women [44].

Falls-prevention strategies, including home hazard assessments, balance-focused physiotherapy, vision correction, and medication review, reduced injurious falls by 20–25% in community-dwelling older women [45].

Fracture Liaison Services (FLS) improved secondary prevention by ensuring treatment initiation after sentinel fractures, thereby reducing refracture rates and healthcare costs [46].

Efficacy of Major Osteoporosis Therapies

Synthesis of Key Findings

• Post-menopausal women experience accelerated bone loss in the first decade after menopause, driving early vertebral and subsequent hip fractures.
• Risk is multifactorial, involving skeletal deficits (BMD loss), clinical risk factors, and proximal determinants such as sarcopenia and frailty.
• DXA remains essential, but adding VFA, TBS, and FRAX improves case-finding and risk stratification.
• Bisphosphonates and denosumab remain the most widely studied and effective antiresorptives.
• Anabolic-first, then antiresorptive consolidation provides superior outcomes in very-high-risk women.
• Exercise, vitamin D/calcium, and FLS remain indispensable non-pharmacological strategies that augment pharmacotherapy.

Principal Findings [51–53]

This systematic review synthesizes evidence from sixty studies, including randomized controlled trials, prospective cohorts, and meta-analyses, to provide a comprehensive picture of osteoporosis in post-menopausal women. The results confirm that the decade immediately following menopause represents a critical window in which rapid bone loss occurs, driving a surge in vertebral fractures. Hip fractures, which follow in later decades, remain the most devastating outcome, with up to 30% one-year mortality [51]. Importantly, the review highlights the multifactorial nature of fracture risk, extending beyond bone mineral density (BMD) into domains such as falls risk, sarcopenia, frailty, comorbidities, and secondary causes [52]. Moreover, modern diagnostic adjuncts such as Vertebral Fracture Assessment (VFA), Trabecular Bone Score (TBS), and FRAX risk calculators significantly improve the ability to identify high-risk women, addressing limitations of DXA alone [53].

Interpretation of Evidence on Risk Factors [54]

Our findings surely show that estrogen deficiency is the main cause, but clinical risk factors are equally important. Moreover, both factors play a vital role in the disease process. Traditional predictors like low BMI, previous fragility fracture, and parental hip fracture surely remain strong indicators [41]. Moreover, these factors consistently show reliable predictive value in clinical practice. Evidence shows that type 2 diabetes, chronic kidney disease, thyroid disorders, and glucocorticoid use itself increase fracture risk further, regardless of BMD [54]. This actually matches how doctors now focus on bone quality instead of just bone quantity. Diabetic women definitely have normal or high bone density but still get more fractures because their bone structure is damaged inside. Sarcopenia surely doubles the hip fracture risk, showing how muscle and bone health work together [43]. Moreover, this clearly proves that weak muscles directly affect bone strength. Future screening strategies should surely include musculoskeletal assessments and not just skeletal imaging. Moreover, this approach will provide a better overall evaluation of bone and muscle health.

 Diagnostic Approaches: Strengths and Limitations [55–56]

As per current medical practice, different diagnostic methods have their own good points and weak points regarding patient care. Each approach works well in some cases but has problems in other situations.

Basically, DXA is still essential, but using only DXA is not enough - we need the same approach with other tools, also. VFA detects occult vertebral fractures missed by DXA and can reclassify osteopenic women as osteoporotic, leading to earlier treatment [45]. TBS surely gives important details about bone structure that help doctors better understand women with diabetes or obesity. Moreover, these women often get wrongly classified in regular bone tests, so TBS provides more accurate information [46]. The FRAX algorithm uses clinical risk factors with or without BMD and has further proved itself as a strong predictor across multiple regions [47].

Nevertheless, limitations persist: thresholds for treatment initiation vary between countries, calibration may differ across ethnic populations, and FRAX does not capture imminent risk (fractures expected within 1–2 years). This gap is critical because fracture clustering is common in the early years post-menopause. Research should prioritize short-term fracture prediction models, potentially integrating biomarkers and digital health tools [55,56].

Therapies in Context [57–59]

Bisphosphonates remain the most widely studied and prescribed antiresorptives. Their ability to reduce vertebral fractures by up to 70% and hip fractures by 45% has been repeatedly validated [48]. Long-term extension trials demonstrate sustained benefits, but concerns about rare adverse events—osteonecrosis of the jaw (ONJ) and atypical femoral fracture (AFF)—necessitate periodic reassessment [57].

 Denosumab offers powerful antiresorptive efficacy with excellent adherence due to its six-monthly injection schedule. However, rebound effects upon discontinuation present a major challenge: multiple vertebral fractures may occur if sequential therapy is not instituted [49]. Therefore, clinicians must plan denosumab discontinuation strategies in advance, usually transitioning to zoledronate or alendronate [58].

Basically, Anabolic agents like teriparatide, abaloparatide, and romosozumab represent a paradigm shift, especially for very-high-risk women (multiple vertebral fractures, very low T-scores, or imminent fracture risk). Romosozumab actually works in two ways to quickly increase BMD gains, but doctors definitely need to check each patient's heart risk before using it [50,59]. Evidence surely shows that using bone-building drugs first and bone-loss prevention drugs later gives the best results. Moreover, this approach provides early fracture protection and maintains long-term bone health benefits.

 Non-Pharmacological Interventions: More than Adjuncts [60]

Also, surely pharmacological therapy dominates clinical guidelines, but non-pharmacological strategies remain essential. Moreover, both approaches are needed for complete patient care. Also, exercise programs, particularly resistance and balance training, further improve muscle mass and strength, which reduces sarcopenia and fall risk [43]. Vitamin D and calcium supplementation show modest direct effects, but they further enhance antiresorptive efficacy itself and reduce falls in deficient patients [44]. We are seeing that falls-prevention programs can reduce harmful falls by only 20-25% [45]. These programs include checking home dangers, reviewing medicines, and improving eyesight. Moreover, basically, Fracture Liaison Services work as a system-level approach that consistently improves secondary prevention by ensuring patients start treatment after their first fracture, and the same services help reduce the risk of getting fractures again [46,60].

 Methodological Strengths and Limitations of Included Studies [61]

A strength of the included literature is the prevalence of large, multicenter RCTs with adjudicated fracture endpoints, particularly in drug trials. Long follow-up durations provide insight into both short- and long-term efficacy. However, significant limitations exist. Observational studies often suffered from residual confounding, particularly around adherence, socioeconomic status, and comorbidities [61]. Geographic representation skewed toward high-income countries, raising questions about generalizability. Fracture outcomes were variably defined, with some trials relying on radiographic confirmation while others used self-report. These discrepancies may underestimate or overestimate true incidence. Finally, publication bias remains likely: negative or neutral trials are underrepresented, and industry-sponsored studies dominate the drug evidence base.

 Clinical Implications [62–63]

Clinically, the findings emphasize that osteoporosis care must begin earlier, particularly within the first decade after menopause. Risk assessment should combine DXA with clinical tools (FRAX, VFA, TBS), while treatment thresholds must be risk-based rather than BMD-only. Bisphosphonates remain the default first-line, but denosumab or anabolic agents should be prioritized for women at very-high or imminent risk. Long-term planning is critical, especially around drug discontinuation or sequencing. Co-interventions—exercise, nutrition, falls prevention, and FLS—are indispensable. From a health-systems perspective, closing the treatment gap is paramount: less than one-third of high-risk women worldwide receive appropriate therapy after a fracture [62,63].

 Research Gaps and Future Directions [64–65]

The review reveals several areas needing further research:

1. Imminent fracture risk prediction: Developing short-term (1–2 year) models incorporating biomarkers, imaging, and frailty indices.
2. Integration of sarcopenia assessment: Muscle-bone crosstalk is underexplored but critical.
3. Long-term safety of sequential therapy: Optimal duration and sequencing of anabolic–antiresorptive regimens.
4. Equity in osteoporosis care: Studies from Asia, Africa, and Latin America are underrepresented; global data are urgently needed.
5. Digital health and AI integration: Wearables, machine learning, and fracture risk apps could transform adherence and monitoring [64,65].

 Summary of Discussion

• Osteoporosis in post-menopausal women is multifactorial and systemic, not merely a loss of bone mass.
• Risk assessment tools beyond DXA improve detection of women who would otherwise remain untreated.
• Bisphosphonates remain central, but denosumab and anabolic agents provide powerful options when used strategically.
• Non-pharmacological measures and system-level interventions (FLS) significantly enhance outcomes.
• Persistent care gaps demand urgent attention, particularly in secondary prevention and global equity.

This systematic review underscores that osteoporosis in post-menopausal women is a multifactorial and progressive disorder with devastating consequences if left untreated. The findings confirm that the first decade after menopause represents a period of accelerated bone loss and heightened vertebral fracture risk, while hip fractures later in life contribute disproportionately to disability, dependency, and mortality. Fracture risk is determined not only by skeletal parameters such as bone mineral density but also by clinical, metabolic, and functional factors, including sarcopenia, frailty, comorbidities, and secondary causes of bone fragility. Diagnostic tools have advanced—DXA remains the standard, but Vertebral Fracture Assessment, Trabecular Bone Score, and FRAX calculators enhance precision in risk stratification and allow earlier treatment initiation. Therapeutically, bisphosphonates remain the foundation, while denosumab and anabolic agents such as teriparatide, abaloparatide, and romosozumab offer potent fracture protection for very-high-risk women when used in properly sequenced regimens. Importantly, non-pharmacological strategies—progressive resistance training, calcium and vitamin D sufficiency, falls prevention, and Fracture Liaison Services—are essential complements to drug therapy, magnifying the overall benefits. Persistent care gaps, including underdiagnosis, undertreatment after sentinel fractures, suboptimal adherence, and inequities in global data, highlight the need for urgent health system reforms and targeted research. Ultimately, an integrated approach that combines early risk identification, risk-matched pharmacotherapy, non-pharmacological interventions, and structured secondary prevention pathways offers the best opportunity to reduce the fracture burden, preserve independence, and improve quality of life in post-menopausal women worldwide.

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