Osteoporosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]; Associate Editor(s)-in-Chief: Eiman Ghaffarpasand, M.D. [3] Anum Ijaz M.B.B.S., M.D.[4]

Synonyms and keywords: Bone loss, bone density loss, decreased bone density, porous bones, osteoporotic bones

Overview

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [5] Associate Editor(s)-in-Chief: Ibrahim Elkhayat, M.B.B.Ch.[6]

Definition

Osteoporosis is a systemic skeletal disease characterized by low bone mass and deterioration of bone microarchitecture, resulting in reduced bone strength and increased susceptibility to fragility fractures.

A fragility fracture is a fracture caused by trauma that would be insufficient to fracture normal bone, conventionally a fall from standing height or less.

Bone strength depends on both bone mineral density (BMD) and bone quality. Osteoporosis is commonly identified by a fragility fracture or a densitometric diagnosis based on dual-energy X-ray absorptiometry (DXA). Fracture-risk assessment also identifies patients who may benefit from treatment despite BMD values above the osteoporotic range. Diagnostic criteria and treatment thresholds are discussed in Classification and Other diagnostic studies.

Clinical significance

Osteoporosis is frequently asymptomatic until a fragility fracture occurs. Fractures, particularly those involving the hip or vertebrae, are associated with substantial morbidity, disability, loss of independence, and increased mortality. A previous fragility fracture also identifies patients at increased risk of subsequent fractures.

Hip fractures are particularly consequential because recovery may be incomplete and long-term independence may be compromised. Vertebral fractures may cause persistent pain, height loss, spinal deformity, and functional impairment.

Osteoporosis affects both women and men, particularly with advancing age. Despite the availability of effective interventions, osteoporosis remains underdiagnosed and undertreated, including after fragility fractures. Fracture liaison services provide a coordinated approach to post-fracture evaluation, treatment initiation, and secondary fracture prevention.

Summary of diagnosis and management

Diagnosis

Evaluation integrates clinical assessment, fracture history, BMD measurement, and estimation of fracture risk.

• Clinical assessment: Identify previous fragility fractures, relevant clinical risk factors, and features suggesting secondary osteoporosis.
• Bone mineral density: Central DXA is the standard method for measuring BMD and applying densitometric diagnostic criteria.
• Fracture-risk assessment: Tools such as the Fracture Risk Assessment Tool (FRAX) combine clinical risk factors, with femoral-neck BMD when available, to estimate absolute fracture probability.
• Evaluation for secondary causes: Investigate potentially reversible underlying conditions when clinically indicated, particularly in patients with atypical presentations or suspected secondary osteoporosis.

Although DXA-measured BMD is central to assessment, most fragility fractures occur in people whose T-scores are above the osteoporotic threshold. Combining BMD with clinical risk assessment therefore helps identify patients whose fracture risk may warrant intervention.

Detailed screening recommendations, diagnostic thresholds, FRAX interpretation, and evaluation of secondary causes are covered in Screening, Laboratory findings, and Other diagnostic studies.

Management

The primary goal of osteoporosis management is to prevent fragility fractures and preserve mobility and independence. Treatment intensity is determined by fracture risk, fracture history, comorbidities, contraindications, and patient preferences.

• Lifestyle and supportive measures: Ensure adequate calcium and vitamin D intake, encourage appropriate weight-bearing and resistance exercise, address fall risk, and recommend smoking cessation and moderation of alcohol intake.
• Low fracture risk: Emphasize appropriate nutrition, physical activity, fall prevention, and reassessment of fracture risk when indicated.
• High fracture risk: Pharmacologic treatment commonly includes an antiresorptive agent, selected according to the patient's clinical circumstances.
• Very high fracture risk: Anabolic therapy (e.g., teriparatide, abaloparatide, or romosozumab) is preferred as initial treatment in selected patients, followed by antiresorptive therapy to maintain treatment gains.
• Secondary fracture prevention: Following a fragility fracture, promptly assess the need for osteoporosis treatment and implement measures to prevent recurrent fractures. Fracture liaison services can improve systematic identification, evaluation, and treatment of affected patients.

Detailed drug selection, treatment sequencing, monitoring, and duration are addressed in Medical therapy. Strategies to prevent first and subsequent fractures are covered in Primary prevention and Secondary prevention.

Historical Perspective

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [7] Associate Editor(s)-in-Chief: Ibrahim Elkhayat, M.B.B.Ch.[8]

Early Recognition of Osteoporosis

The recognition of osteoporosis evolved from descriptions of fragile, porous bones to a measurable skeletal disorder associated with fracture risk. In 1822, Astley Cooper described age-related changes in bone and their relationship to fracture. In 1835, Jean Lobstein introduced the term osteoporosis; its early use was not entirely consistent with the modern clinical definition.

A major conceptual advance came from Fuller Albright and colleagues in the early 1940s. They recognized the association between postmenopausal estrogen deficiency and osteoporosis, linking vertebral fractures and bone loss to menopause and bilateral oophorectomy. Albright's work helped establish osteoporosis as a disorder involving inadequate bone formation relative to resorption, rather than simply an inevitable consequence of aging. This historical distinction contributed to the later understanding of osteoporosis as a disorder of bone remodeling.

Development of Bone Densitometry

For much of its early history, osteoporosis was recognized primarily through fractures, skeletal deformity, and radiographic evidence of bone loss. The development of quantitative bone densitometry made it possible to measure bone mineral density (BMD) and identify low bone mass before a fracture occurred.

Cameron and Sorensen introduced single-photon absorptiometry (SPA) in 1963, enabling quantitative assessment of peripheral skeletal sites. Dual-photon absorptiometry (DPA), developed during the 1970s, expanded measurement to axial skeletal sites, including the spine and hip. Dual-energy X-ray absorptiometry (DXA) was first described by Mazess and colleagues in 1981 and entered clinical use in the late 1980s. DXA subsequently became the standard method for measuring areal BMD because of its precision, relatively low radiation exposure, and ability to assess clinically important fracture sites.

The availability of standardized BMD measurements transformed osteoporosis from a predominantly radiographic diagnosis into an operationally defined condition. However, BMD measures only one component of bone strength and cannot fully capture bone architecture, material properties, or all determinants of fracture risk.

The WHO Definition and Operational BMD Classification

In 1993, an international consensus development conference described osteoporosis as a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration, resulting in increased bone fragility and susceptibility to fracture. This definition established the conceptual basis for understanding osteoporosis as a disorder of both bone quantity and bone structure.

In 1994, the WHO Study Group introduced an operational classification based on BMD T-scores. The original classification was developed for postmenopausal White women and compared an individual's BMD with the mean BMD of a young-adult reference population:

• Normal BMD: T-score within 1 standard deviation of the young-adult reference mean.
• Low bone mass (osteopenia): T-score more than 1 but less than 2.5 standard deviations below the young-adult reference mean.
• Osteoporosis: T-score at least 2.5 standard deviations below the young-adult reference mean.
• Severe (established) osteoporosis: T-score more than 2.5 standard deviations below the young-adult reference mean in the presence of one or more fragility fractures.

The T-score classification provided a common language for epidemiology, research, and clinical practice. However, the reference population and use of a single numerical threshold subsequently raised questions about its application to men, younger individuals, and different populations.

Importantly, the relationship between BMD and fracture risk is continuous, with no threshold at which risk abruptly begins. The WHO cutoff is therefore an operational classification device rather than a biological boundary. Consistent with this, most fragility fractures occur in people whose BMD is above the osteoporotic threshold (T-score > −2.5). In the Dubbo Osteoporosis Epidemiology Study, approximately half of fragility fractures occurred in individuals without BMD in the osteoporotic range.

From Bone Mineral Density to Bone Strength

The 2000 NIH Consensus Development Conference, published in 2001, broadened the conceptual framework by defining osteoporosis as a skeletal disorder characterized by compromised bone strength, predisposing an individual to an increased risk of fracture. Bone strength was understood to reflect both bone density and bone quality, including aspects of architecture, turnover, accumulated microdamage, and mineralization. This framework emphasized that BMD is an important predictor of fracture risk but is not a complete measure of bone strength.

Albright's observations concerning postmenopausal bone loss helped establish the importance of estrogen deficiency in osteoporosis research. Subsequent work expanded this framework to include age-related changes in bone remodeling and the contribution of multiple determinants of bone strength.

Extension of BMD Classification Beyond Postmenopausal Women

The original WHO T-score classification was developed for postmenopausal White women. Subsequent positions from the International Society for Clinical Densitometry (ISCD) extended the use of T-score-based classification to additional populations, including men aged 50 years and older and postmenopausal women. The historical expansion of densitometric classification also established a distinction between T-score-based classification and age-matched assessment in younger individuals.

Interpretation of BMD in premenopausal women, men younger than 50 years, and children requires population-appropriate assessment and should not rely on the postmenopausal T-score framework alone. Detailed interpretation of T-scores and Z-scores belongs in the classification and diagnostic chapters.

Development of FRAX and Fracture-Risk Assessment

The limitations of a BMD-only approach became increasingly apparent because fracture risk depends on age and other clinical factors in addition to BMD. The observation that many fragility fractures occur in people whose BMD is above the osteoporotic threshold provided an important rationale for incorporating clinical risk factors into fracture prediction.

The WHO Collaborating Centre for Metabolic Bone Diseases at the University of Sheffield developed the Fracture Risk Assessment Tool (FRAX), which was released in 2008. FRAX estimates the 10-year probability of a major osteoporotic fracture (hip, clinical spine, distal forearm, or proximal humerus) and hip fracture. Its model incorporates age, sex, body mass index, and clinical risk factors, with femoral-neck BMD available as an optional input. The development and validation of FRAX represented a shift from classifying low BMD alone toward estimating absolute fracture probability.

By 2016, FRAX had been incorporated into approximately 120 guidelines worldwide and embedded in DXA software following US FDA approval, as well as electronic health record clinical decision-support systems, reflecting its broad adoption in fracture-risk assessment. Two broad intervention-threshold approaches emerged. The United States adopted a fixed-threshold approach, whereas the United Kingdom's National Osteoporosis Guideline Group (NOGG) adopted an age-dependent approach in which FRAX is applied initially without BMD and densitometry is reserved for individuals whose estimated risk falls into an intermediate range. The detailed mechanics of these approaches belong in the diagnostic and management chapters.

Expansion of the Clinical Concept of Osteoporosis

The historical definition of osteoporosis initially became closely associated with low BMD, particularly the WHO T-score threshold. Over time, the limitations of relying on BMD alone became more apparent, because fragility fractures may occur in individuals whose BMD does not meet the densitometric definition of osteoporosis. Clinical fracture-risk assessment consequently became an important complement to densitometric classification.

Contemporary discussions have considered whether the clinical diagnosis of osteoporosis should also encompass selected fragility fractures or elevated fracture risk despite a T-score above −2.5. However, definitions used for diagnosis, densitometric classification, and decisions to initiate intervention are related but distinct concepts. The precise diagnostic criteria and their application to individual patients are addressed in the diagnostic chapter.

Historical Lessons

The evolution of osteoporosis reflects several major conceptual changes:

• The disease became recognized as more than an inevitable consequence of aging, with estrogen deficiency identified as an important contributor to postmenopausal bone loss.
• Quantitative densitometry, particularly DXA, made BMD measurement reproducible and clinically useful.
• The 1994 WHO classification established an operational BMD-based definition that facilitated communication and research but did not create a biological boundary between normal and abnormal fracture risk.
• The bone-strength framework emphasized that BMD does not fully capture bone quality or all determinants of fracture.
• FRAX extended assessment beyond BMD by incorporating clinical risk factors and estimating absolute fracture probability.
• Modern practice distinguishes densitometric classification from overall clinical fracture risk and from thresholds used to guide intervention.

Classification

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [9] Associate Editor(s)-in-Chief: Ibrahim Elkhayat, M.B.B.Ch.[10] Osteoporosis is classified along two complementary axes: etiologic classification, which distinguishes primary from secondary osteoporosis, and densitometric classification, which categorizes bone mineral density (BMD) using T-scores or, in younger populations, Z-scores. These systems address different clinical questions: etiology identifies the underlying cause, whereas densitometry describes BMD relative to a reference population. Both should be considered when characterizing an individual patient.

Etiologic Classification

Osteoporosis is traditionally divided into primary and secondary forms. Primary osteoporosis is associated principally with aging and sex-hormone decline, whereas secondary osteoporosis occurs in association with an identifiable disease, medication, or other contributing condition.

Primary Osteoporosis

Primary osteoporosis is traditionally subdivided into two types:

• Type I (postmenopausal osteoporosis): Classically associated with estrogen deficiency after menopause. It is characterized by increased bone turnover, with bone resorption exceeding formation and relatively rapid loss of trabecular bone. Vertebral and distal radius fractures are characteristic fracture patterns.
• Type II (senile osteoporosis): Classically associated with aging in both sexes, particularly after age 70. It is traditionally described as gradual loss of both cortical and trabecular bone, with hip and vertebral fractures among the characteristic manifestations.

The type I/type II distinction is a traditional teaching framework rather than a rigid separation of disease mechanisms. Age-related bone loss, estrogen deficiency, and secondary contributors may coexist in the same patient. The underlying remodeling mechanisms are discussed in the Pathophysiology chapter.

Secondary Osteoporosis

Secondary osteoporosis is associated with one or more identifiable contributing diseases, medications, or clinical conditions. Major categories include endocrine disorders, gastrointestinal or malabsorptive conditions, chronic kidney disease–mineral and bone disorder, rheumatologic diseases, and medication-associated bone loss.

The specific etiologies, their mechanisms, and potentially reversible causes are covered in the Causes/Etiology chapter.

Densitometric Classification by T-Score

The 1994 World Health Organization (WHO) operational classification categorizes BMD using the T-score, which expresses the number of standard deviations (SD) above or below the mean BMD of a young-adult reference population. In adults for whom T-score classification is appropriate, central dual-energy X-ray absorptiometry (DXA) is used to assess the lumbar spine, total hip, and femoral neck. Classification generally uses the lowest valid T-score at the recommended diagnostic sites; the 33% radius may be used in specified circumstances.

Category	T-score
Normal BMD	≥ −1.0
Low bone mass (osteopenia)	< −1.0 and > −2.5
Osteoporosis	≤ −2.5
Severe (established) osteoporosis	≤ −2.5 with one or more fragility fractures

The WHO densitometric classification was originally developed for postmenopausal women. Contemporary DXA positions apply T-score-based diagnostic classification to postmenopausal women and men aged 50 years and older.

Densitometric classification does not capture all individuals who will experience fragility fractures. Approximately 70% of osteoporotic fractures occur in people whose BMD is above the T-score threshold of −2.5. This limitation underscores why BMD categories should be considered alongside fracture history and clinical fracture-risk assessment.

A fragility fracture, particularly of the hip or vertebra, may establish a clinical diagnosis of osteoporosis independently of the T-score. Detailed diagnostic criteria and the integration of fracture history, DXA, and fracture-risk assessment are addressed in the Other Diagnostic Studies chapter.

T-Score Versus Z-Score in Younger Individuals

In children and adolescents, premenopausal women, and men younger than 50 years, Z-scores are generally used to compare BMD with an age- and sex-matched reference population. Ethnicity-specific reference databases should be used where appropriate and available.

According to the International Society for Clinical Densitometry (ISCD), a Z-score of −2.0 or lower is described as below the expected range for age. In these populations, BMD alone should not automatically be used to assign the diagnosis of osteoporosis. Clinical context, fracture history, and potential secondary causes must be considered.

In children and adolescents, T-scores must not be used before age 20. Pediatric osteoporosis is diagnosed in the presence of either:

• One or more vertebral compression fractures, in the absence of high-energy trauma or local disease affecting the vertebrae; or
• A clinically significant fracture history together with a BMD Z-score of −2.0 or lower. A clinically significant fracture history is defined as two or more long-bone fractures by age 10 years, or three or more long-bone fractures at any age up to 19 years.

There is explicit guideline disagreement regarding the diagnosis of osteoporosis in younger adults. The ISCD recommends reporting Z-scores and cautions against applying the terms osteopenia and osteoporosis on the basis of BMD alone in these groups. In contrast, the International Osteoporosis Foundation (IOF) and European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) retain a role for a T-score of −2.5 or lower in premenopausal women and men younger than 50 years when skeletal fragility is present, such as a fragility fracture or an underlying chronic disease affecting bone metabolism. These positions should be recognized when interpreting studies and applying recommendations to individual patients.

Clinical Application and Common Pitfalls

• Describe both axes: When applicable, document the likely etiology (primary or secondary) and the densitometric category.
• Use the appropriate reference score: T-scores are used for densitometric classification in postmenopausal women and men aged 50 years and older; Z-scores are generally used in younger adults and children.
• Use valid diagnostic sites: Classification generally relies on the lowest valid T-score from the recommended central DXA sites. The 33% radius is reserved for specified circumstances.
• Do not equate BMD with the entire diagnosis: Many fragility fractures occur in people whose BMD is above the osteoporotic threshold. Fracture history and clinical fracture-risk assessment remain important.
• Evaluate secondary causes when indicated: Primary osteoporosis should not be assigned without considering secondary contributors, particularly in men and younger adults.
• Interpret younger patients carefully: A low Z-score indicates BMD below the expected range for age; it is not, by itself, sufficient to establish osteoporosis in every clinical context.
• Retain the diagnosis after treatment-related improvement: A previously established diagnosis of osteoporosis should not automatically be removed solely because treatment subsequently raises the T-score above −2.5; the patient's fracture history and overall clinical context remain relevant.

Pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [11] Associate Editor(s)-in-Chief: Ibrahim Elkhayat, M.B.B.Ch.[12] Osteoporosis develops when bone strength is compromised by reduced bone mass, deterioration of bone microarchitecture, or both. Its pathophysiology reflects an imbalance between osteoclastic bone resorption and osteoblastic bone formation, together with the failure to attain optimal peak bone mass. Estrogen deficiency and aging are major drivers, although their relative contributions and effects on bone remodeling differ. These changes weaken the skeleton and increase susceptibility to fragility fractures.

This chapter focuses on mechanisms. The classification of osteoporosis is discussed in Classification, specific underlying diseases and medication-related causes in Causes/Etiology, clinical risk factors in Risk factors, and pharmacologic management in Medical therapy.

Normal Bone Remodeling

Bone remodeling is the continuous replacement of old or microdamaged bone with newly formed bone. It differs from bone modeling, which changes bone size and shape, particularly during skeletal growth. In adults, remodeling occurs in spatially organized basic multicellular units and proceeds through activation, resorption, reversal, formation, and termination or quiescence.

Three principal cell types coordinate remodeling:

• Osteoclasts are multinucleated cells derived from the hematopoietic monocyte–macrophage lineage. They resorb bone by acidifying the resorption compartment and releasing proteolytic enzymes, including cathepsin K.
• Osteoblasts arise from mesenchymal progenitor cells and synthesize osteoid, which subsequently mineralizes. They also regulate osteoclast differentiation through signaling molecules such as receptor activator of nuclear factor kappa-B ligand (RANKL) and osteoprotegerin (OPG).
• Osteocytes are terminally differentiated osteoblasts embedded within the bone matrix. Their interconnected network senses mechanical strain and microdamage and regulates remodeling, including through the production of RANKL and sclerostin.

Trabecular (cancellous) bone is abundant in the vertebrae and other metabolically active skeletal regions, whereas cortical bone forms much of the outer shell and the shafts of long bones. Both compartments contribute to skeletal strength, but their structure and remodeling patterns differ.

During growth, bone formation exceeds resorption, allowing bone mass to accumulate. After skeletal maturity, remodeling is approximately balanced under favorable conditions. When resorption persistently exceeds formation, each remodeling cycle leaves a net deficit, progressively reducing bone mass and compromising structural integrity.

RANK/RANKL/OPG Signaling: Regulation of Bone Resorption

The RANK/RANKL/OPG pathway is a central regulator of osteoclast differentiation and activity.

• RANKL (receptor activator of nuclear factor kappa-B ligand) is expressed by osteoblast-lineage cells, osteocytes, and certain activated immune cells. It binds RANK on osteoclast precursors and promotes their differentiation, fusion, activation, and survival. Macrophage colony-stimulating factor (M-CSF) supports osteoclast precursor survival and differentiation.
• RANK is the receptor for RANKL on osteoclast precursors and osteoclasts. RANK activation recruits intracellular signaling machinery, including TRAF6, and activates pathways such as NF-κB and mitogen-activated protein kinases. These signals converge on transcription factors, including c-Fos and NFATc1, that regulate osteoclastogenesis.
• Osteoprotegerin (OPG) is a soluble decoy receptor produced by osteoblast-lineage cells. By binding RANKL, OPG prevents RANK activation and limits osteoclast formation and activity.

The balance between RANKL and OPG is therefore a major determinant of osteoclast-mediated resorption. Experimental disruption confirms the pathway's importance: OPG overexpression causes osteoclast-deficient osteopetrosis, whereas OPG deficiency produces osteoporosis through excessive osteoclast formation and activity.

Inflammatory mediators, including tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and interleukin-17 (IL-17), can amplify osteoclastogenesis and bone resorption. Their effects may involve increased RANKL signaling and additional pathways, linking immune activation and chronic inflammation to skeletal loss.

Wnt/β-Catenin and Sclerostin Signaling: Regulation of Bone Formation

Canonical Wnt/β-catenin signaling is essential for osteoblast differentiation and bone formation. Wnt ligands bind Frizzled receptors and the low-density lipoprotein receptor-related proteins LRP5 and LRP6. This signaling stabilizes β-catenin, allowing it to enter the nucleus and regulate genes involved in osteoblast differentiation, including those associated with RUNX2 and Osterix.

Sclerostin, encoded by the SOST gene, is produced predominantly by osteocytes. It inhibits Wnt signaling by binding LRP5/6, an interaction facilitated by the co-receptor LRP4, thereby suppressing osteoblast differentiation and bone formation. Sclerostin may also favor resorption by influencing the RANKL/OPG balance, linking reduced formation with increased osteoclast activity.

Human genetic disorders provide evidence for the importance of this pathway. Loss-of-function variants in LRP5 can cause osteoporosis-pseudoglioma syndrome, whereas gain-of-function variants are associated with high bone mass. Loss of SOST function causes high-bone-mass disorders, including sclerosteosis and van Buchem disease. These findings have informed the development of therapies targeting sclerostin; treatment mechanisms are discussed in Medical therapy.

Peak Bone Mass and Age-Related Bone Loss

Peak bone mass (PBM) is the maximum amount of bone accumulated by an individual. It is attained during young adulthood, with the timing varying by skeletal site and individual characteristics. Genetic factors account for up to approximately 80% of the variance in peak bone mass; estimates for the heritability of bone mineral density (BMD) overall range approximately from 50% to 85%. Fracture heritability is substantially lower, estimated at approximately 25%–35%, because fractures also depend on bone structure, falls, and other factors.

Nutrition, particularly adequate calcium and protein intake, weight-bearing physical activity, and hormonal factors influence the acquisition of peak bone mass. A lower peak bone mass reduces the amount of skeletal reserve available to withstand subsequent age-related loss. Osteoporosis in later life can therefore reflect a low peak bone mass, excessive subsequent bone loss, or both.

After peak bone mass is attained, gradual bone loss occurs with aging, and the pattern differs by sex. In women, aging is associated with increased remodeling and a negative remodeling balance, producing high-turnover loss with trabecular thinning and loss of trabeculae, together with endocortical and intracortical loss. In men, age-related loss is more predominantly associated with reduced bone formation and low bone turnover. A structural correlate accompanies this difference: aging men lose trabecular bone chiefly through trabecular thinning while largely preserving trabecular connectivity, whereas women lose trabecular number and connectivity, contributing to their higher fragility-fracture risk. These patterns overlap in individual patients and change with age.

Age-related skeletal changes also involve reduced osteoblast and osteoprogenitor supply relative to remodeling demand, osteocyte and progenitor senescence, and a shift of mesenchymal progenitor differentiation toward adipogenesis. These changes can reduce bone formation and impair the repair of microdamage. Other age-associated contributors include changes in calcium and vitamin D physiology, reduced mechanical loading, and alterations in hormonal and inflammatory signaling.

Cortical bone becomes increasingly vulnerable to porosity with aging. Endocortical and intracortical remodeling can thin the cortex and create resorption spaces, weakening the structural shell of bone. These changes contribute to skeletal fragility even when areal BMD does not fully reflect the deterioration in bone structure.

Estrogen Deficiency and Postmenopausal Bone Loss

Estrogen restrains bone remodeling and helps maintain the balance between resorption and formation. The decline in estrogen around menopause increases remodeling activity and creates a high-turnover state in which bone resorption exceeds formation. This imbalance is a major mechanism of postmenopausal bone loss.

Important mechanisms include:

• Altered RANKL/OPG signaling: Estrogen restrains resorption by lowering RANKL and M-CSF, maintaining OPG, and suppressing sclerostin. Estrogen deficiency reverses this balance, raising the RANKL:OPG ratio and prolonging osteoclast survival, thereby increasing resorption.
• Changes in bone-cell survival: Estrogen deficiency decreases osteoclast apoptosis and can increase apoptosis of osteoblasts and osteocytes. This prolongs resorptive activity while compromising bone formation and maintenance.
• Increased sclerostin signaling: Increased sclerostin activity inhibits Wnt-mediated osteoblast differentiation and reduces bone formation.
• Immune and inflammatory signaling: Estrogen loss can increase inflammatory signaling, including TNF-α, IL-1, IL-6, and IL-17, which amplifies osteoclastogenesis and resorption.

Beyond direct effects on bone cells, estrogen deficiency drives an immune-mediated component: expansion of TNF-producing T cells and Th17 cells amplifies RANKL-driven osteoclastogenesis, while reduced regulatory T-cell suppression further favors resorption. A gut-microbiome-dependent trafficking mechanism involving intestinal TNF-producing T cells and Th17 cells has been demonstrated in animal models; its precise contribution to human postmenopausal osteoporosis remains uncertain.

Increased remodeling activation produces more resorption sites and can deepen resorption cavities. When trabecular plates are perforated or trabecular connections are lost, the resulting structural damage may not be fully restored by subsequent bone formation. Loss of trabecular connectivity therefore contributes to the persistent reduction in bone strength after estrogen deficiency.

Microarchitectural Deterioration and Bone Fragility

Bone strength depends on more than BMD. It also reflects bone geometry, trabecular and cortical microarchitecture, material properties, and the distribution of bone within the skeleton. Osteoporosis is associated with trabecular thinning, reduced trabecular number and connectivity, cortical thinning, and increased cortical porosity.

Areal BMD measured by dual-energy X-ray absorptiometry (DXA) is clinically useful but does not capture every determinant of bone strength. Fractures can occur in people whose BMD does not meet the densitometric threshold for osteoporosis because microarchitecture, bone material properties, fall exposure, and other clinical factors also influence fracture risk.

High-resolution peripheral quantitative computed tomography (HR-pQCT) can characterize trabecular and cortical microarchitecture and estimate mechanical properties. Prospective cohort studies have found that microarchitectural measures predict incident fractures independently of DXA BMD and FRAX. HR-pQCT remains primarily a specialized and research technique rather than a routine diagnostic test.

Changes in the mineral–collagen interface and impaired bone material properties can further reduce the capacity of bone to absorb energy before failure. A fragility fracture occurs when the load applied to the skeleton exceeds the strength of the affected bone, often following a fall from standing height or less.

Clinical Relevance of the Pathophysiology

• Resorption and formation are distinct therapeutic targets. Antiresorptive drugs act on osteoclast activity or signaling, whereas anabolic therapies promote bone formation through different pathways. Their selection, sequencing, and safety considerations are discussed in Medical therapy.
• Estrogen deficiency and aging are related but distinct mechanisms. Estrogen deficiency is strongly associated with high-turnover, resorption-dominant loss, whereas aging can involve reduced osteoblast activity and formation, with increasing cortical porosity. Both mechanisms may coexist.
• BMD alone does not describe all skeletal fragility. Bone microarchitecture and material properties contribute to strength and fracture risk beyond measured BMD; clinical assessment must also account for prior fractures and fall risk.
• Peak bone mass influences later skeletal reserve. Bone mass acquired during growth and young adulthood affects the amount of bone available before age-related and menopause-associated losses occur.

Areas of Uncertainty

• The relative contributions of direct estrogen effects on bone cells and immune-mediated pathways to postmenopausal bone loss remain under investigation, although both mechanisms are supported.
• The contribution of gut-microbiome-dependent immune-cell trafficking to human postmenopausal osteoporosis is not established to the same degree as the findings in animal models.
• Although HR-pQCT-derived microarchitectural measures predict fracture in research cohorts, the optimal role of these measurements in routine clinical risk assessment remains unsettled.
• Genetic studies have identified numerous determinants of BMD, but their ability to predict an individual's peak bone mass or fracture risk remains limited.

Causes

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [13] Associate Editor(s)-in-Chief: Ibrahim Elkhayat, M.B.B.Ch.[14] Osteoporosis may be primary or secondary. Secondary osteoporosis results from an underlying disease, endocrine or metabolic disturbance, nutritional deficiency, or medication exposure that impairs bone strength or increases fracture risk. An identifiable secondary contributor has been reported in up to approximately 30% of postmenopausal women, more than 50% of premenopausal women, and 50–80% of men with osteoporosis. The index of suspicion should therefore be particularly high in men and younger patients. Identifying the cause is important because some contributing conditions are reversible or modifiable. The mechanisms of normal bone remodeling are discussed in Pathophysiology, while the evaluation for secondary causes is covered in Laboratory findings.

Endocrine and metabolic causes

Hyperparathyroidism

Primary hyperparathyroidism causes excess parathyroid hormone (PTH) secretion, usually from a parathyroid adenoma or hyperplasia. Sustained PTH excess increases bone turnover and can preferentially affect cortical bone, contributing to reduced bone strength and fractures. Secondary hyperparathyroidism may develop in vitamin D deficiency, calcium malabsorption, or chronic kidney disease (CKD). In CKD, secondary hyperparathyroidism is part of chronic kidney disease–mineral and bone disorder (CKD-MBD), which may involve high-turnover disease, low-turnover disease, or impaired mineralization.

Hyperthyroidism and thyroid hormone excess

Overt hyperthyroidism accelerates bone turnover, with resorption exceeding formation and resulting in bone loss. Prolonged exposure to excessive thyroid hormone, including levothyroxine over-replacement with suppressed thyroid-stimulating hormone (TSH), may also increase bone loss and fracture risk, particularly in older adults and postmenopausal women.

Hypogonadism and sex-hormone deficiency

Estrogen and testosterone deficiency contribute to bone loss in both sexes.

• Women: Menopause causes a decline in estrogen, increasing bone resorption and accelerating bone loss. Premature ovarian insufficiency and prolonged amenorrhea can lead to reduced bone mineral density (BMD).
• Men: Primary or secondary hypogonadism reduces testosterone and may also reduce estrogen produced through aromatization. Causes include testicular failure, hypothalamic or pituitary disease, and treatments that suppress androgen production.

The associated bone loss may improve when the underlying hormonal deficiency is corrected, although recovery depends on its duration, severity, and other contributing factors.

Cushing syndrome and glucocorticoid excess

Endogenous hypercortisolism, as in Cushing syndrome, contributes to osteoporosis through suppression of osteoblast function, impaired bone formation, reduced calcium absorption, and effects on gonadal function and muscle strength. Excess glucocorticoids also increase bone resorption early in exposure and increase fracture risk through skeletal and extra-skeletal effects.

Diabetes mellitus

Both type 1 and type 2 diabetes are associated with increased fracture risk, although the relationship with BMD differs.

• Type 1 diabetes mellitus: Insulin deficiency and impaired bone acquisition contribute to lower BMD and increased fracture risk.
• Type 2 diabetes mellitus: Fracture risk may be elevated despite normal or relatively high BMD. Altered bone material properties, advanced glycation, falls, complications, and disease duration contribute to the mismatch between BMD and fracture risk. Conventional BMD and FRAX estimates may underestimate risk, particularly with longer disease duration, including 10 years or more.

When estimating fracture risk in type 2 diabetes, proposed alternative FRAX adjustments include lowering the femoral-neck T-score input by 0.5 standard deviations, substituting rheumatoid arthritis for diabetes, increasing the patient's age by 10 years, or incorporating trabecular bone score (TBS). These are alternative approaches and should not all be applied simultaneously.

Gastrointestinal and malabsorptive causes

Celiac disease

Celiac disease may cause low BMD and increased fracture risk through calcium and vitamin D malabsorption, secondary hyperparathyroidism, nutritional deficiencies, and systemic inflammation. Skeletal effects may occur even without prominent gastrointestinal symptoms. BMD may improve after institution of a strict gluten-free diet and correction of nutritional deficiencies, although recovery is variable and may be incomplete.

Inflammatory bowel disease

Crohn disease and ulcerative colitis may contribute to osteoporosis through chronic inflammation, malnutrition, reduced calcium and vitamin D absorption, low body weight, hypogonadism, and glucocorticoid exposure. In Crohn disease, small-bowel involvement or resection can further impair nutrient absorption.

Bariatric surgery and other malabsorptive states

Bariatric procedures, particularly those with a malabsorptive component, can reduce calcium and vitamin D absorption and contribute to secondary hyperparathyroidism and metabolic bone disease. Other causes include pancreatic insufficiency, short-bowel syndrome, and conditions associated with chronic malnutrition. The degree of skeletal impact depends on the underlying condition, procedure, nutritional status, and adequacy of supplementation.

Renal causes

Chronic kidney disease–mineral and bone disorder

CKD can cause skeletal disease through phosphate retention, altered vitamin D metabolism, secondary hyperparathyroidism, and changes in bone turnover and mineralization. The resulting spectrum of CKD-MBD includes high-turnover bone disease, adynamic or other low-turnover disease, and osteomalacia. Low BMD in CKD should therefore not automatically be interpreted as conventional osteoporosis.

Renal impairment also affects the safety of some osteoporosis medications. Renal restrictions are agent-specific: risedronate and ibandronate are generally not recommended below a creatinine clearance of 30 mL/min, whereas alendronate and zoledronic acid are generally not recommended below 35 mL/min, according to product labeling. Denosumab is not renally cleared but carries an increased risk of severe hypocalcemia in advanced CKD. Specific drug selection and monitoring are discussed in Medical therapy.

Rheumatologic and inflammatory diseases

Chronic inflammatory conditions, including rheumatoid arthritis and other systemic inflammatory diseases, are associated with bone loss through inflammatory signaling, reduced physical activity, disability, and glucocorticoid exposure. The relative contribution of inflammation, immobility, comorbidities, and medication exposure varies by disease and patient.

Medication-induced osteoporosis

Medication exposure is an important and potentially modifiable cause of secondary osteoporosis. The magnitude of risk depends on the medication, dose, duration, underlying disease, and patient characteristics.

Glucocorticoids

Systemic glucocorticoids are a major cause of medication-induced osteoporosis. They suppress osteoblast differentiation and function, promote osteoblast and osteocyte apoptosis, alter calcium balance, and contribute to muscle weakness and falls. Bone loss is often fastest during the first 3–6 months of exposure, and clinically important fracture risk may develop with prolonged treatment, including courses lasting 3 months or longer.

In population data from the UK General Practice Research Database, the dose-dependent relative risk of hip fracture was approximately 1.0 at daily prednisolone-equivalent doses of ≤2.5 mg, 1.77 at 2.5–7.5 mg/day, and 2.27 at ≥7.5 mg/day. At doses below 2.5 mg/day, the increased fracture risk is more evident for vertebral fractures, with a relative risk of approximately 1.55. These are population-level estimates, not individual predictions. The commonly cited 7.5 mg/day threshold is a convention rather than a safety floor; fracture risk can increase at lower doses and depends on dose, duration, underlying disease, and patient characteristics.

Inhaled, topical, and epidural glucocorticoids may also contribute to skeletal risk, generally to a lesser extent than systemic oral exposure. High-dose inhaled glucocorticoid exposure (at least 1000 µg/day of fluticasone-equivalent) for more than 4 years was associated with a modest increase in fracture risk in a population-based study (relative risk 1.10, 95% confidence interval 1.02–1.19).

Cancer endocrine therapy

Aromatase inhibitors used in hormone receptor-positive breast cancer reduce estrogen concentrations and accelerate bone loss. Risk is further increased when an aromatase inhibitor is combined with ovarian suppression in premenopausal patients. Androgen-deprivation therapy for prostate cancer reduces sex-hormone signaling and increases fracture risk. Other cancer treatments may affect bone health through gonadal failure, reduced mobility, nutritional impairment, or direct skeletal effects. Cancer-related bone disease and the effects of endocrine therapy should be distinguished from metastatic bone disease.

Antiepileptic medications

Some antiepileptic medications are associated with lower BMD and increased fracture risk. Enzyme-inducing agents may increase vitamin D catabolism, contributing to vitamin D deficiency and secondary hyperparathyroidism. Other mechanisms, including effects on bone metabolism and the risk of falls, may also contribute.

Other medications

Other medications associated with bone loss or fracture risk include:

• Depot medroxyprogesterone acetate (DMPA): Associated with BMD loss during use, with greater loss as duration increases. The FDA boxed warning states that bone loss may not be completely reversible. Label data show partial BMD recovery by 2 years after discontinuation in adults and incomplete recovery at the hip and femoral neck at 5 years in adolescents treated for more than 2 years. The FDA label accordingly states that DMPA is not recommended as long-term (longer than 2 years) contraception unless other methods are inadequate. In contrast, the American College of Obstetricians and Gynecologists (ACOG), citing substantial BMD recovery after discontinuation, does not advise limiting duration of use or routine BMD monitoring and recommends shared decision-making. This guideline discrepancy should be made explicit during counseling.
• Proton pump inhibitors (PPIs): Observational studies and meta-analyses report a modest association with fracture (hip relative risk approximately 1.26, spine relative risk approximately 1.58, and any-site relative risk approximately 1.33). However, a consistent effect on BMD and a confirmed mechanism have not been demonstrated, and causality is not established. Routine BMD monitoring solely because a patient uses a PPI is not advised.
• Selective serotonin reuptake inhibitors (SSRIs): Associated with a modestly increased fracture risk in observational studies and meta-analyses (pooled relative risk approximately 1.6). The association persists in some analyses after adjustment for BMD and depression but is driven largely by specific agents, including citalopram and sertraline, and attenuates with confounder adjustment. Causality remains uncertain and may partly reflect underlying illness and falls.
• Heparin: Prolonged exposure, particularly to unfractionated heparin, can contribute to bone loss.
• Thiazolidinediones: Pioglitazone and rosiglitazone are associated with accelerated bone loss and roughly doubled fracture risk in women (odds ratio approximately 1.9), with no significant increase in men in the cited evidence. The association has been reported across menopausal status.
• Sodium-glucose cotransporter 2 (SGLT2) inhibitors: A fracture signal reported with canagliflozin in the CANVAS trial was not replicated in CANVAS-R or in trials of empagliflozin (EMPA-REG) and dapagliflozin (DECLARE-TIMI 58). Pooled meta-analyses have not demonstrated a statistically significant class-wide increase in fracture risk (for example, relative risk 1.21, 95% confidence interval 0.95–1.54). The class is generally regarded as bone-neutral; the isolated canagliflozin finding may reflect chance or fall-related mechanisms.
• Other cancer therapies, immunosuppressants, and selected anticoagulants: Skeletal effects vary by agent, exposure, and indication.

Medication associations should be interpreted in the context of indication, duration, dose, and baseline fracture risk. Detailed medication-specific prevention and treatment are addressed in Medical therapy.

Other systemic and inherited causes

Additional causes of secondary osteoporosis or skeletal fragility include:

• Hematologic disease and malignancy: Multiple myeloma and other malignancies can cause bone destruction or fragility. Bone metastases represent a separate mechanism of skeletal disease.
• Organ transplantation: Bone loss may result from the underlying disease, glucocorticoids, immunosuppressants, and changes in mobility or nutrition.
• HIV infection and antiretroviral therapy: Both the infection-associated inflammatory state and some treatment exposures may contribute to reduced BMD.
• Systemic mastocytosis: Mast-cell mediators can increase bone resorption and contribute to osteoporosis.
• Inherited disorders: Osteogenesis imperfecta and selected connective-tissue disorders, including Ehlers-Danlos syndrome and Marfan syndrome, may cause skeletal fragility. These conditions are discussed further in Differential diagnosis.
• Other metabolic or systemic disorders: Thalassemia, Gaucher disease, hemophilia, renal tubular acidosis, hypercalciuria, and prolonged immobilization may contribute to bone loss or impaired skeletal strength.

Reversibility and clinical implications

Some secondary causes improve when the underlying condition is treated or the causative exposure is modified. Examples include correction of hyperthyroidism or thyroid hormone over-replacement, treatment of vitamin D deficiency and malabsorption, management of celiac disease, and correction of reversible hypogonadism. Recovery of BMD and fracture risk is variable and may be incomplete, particularly after prolonged exposure or established skeletal damage.

Patients with osteoporosis or fragility fractures should be assessed for potentially reversible secondary causes. The diagnostic laboratory evaluation is covered in Laboratory findings. If osteomalacia or another mineralization disorder is suspected, distinguish it from osteoporosis before proceeding with osteoporosis-specific treatment; see Differential diagnosis. Decisions about osteoporosis medication selection, monitoring, and prevention during high-risk drug exposure are covered in Medical therapy.

Differentiating Osteoporosis from Other Diseases

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [15] Associate Editor(s)-in-Chief: Ibrahim Elkhayat, M.B.B.Ch.[16] Osteoporosis should be distinguished from other disorders that cause low bone mineral density (BMD), skeletal fragility, or atraumatic fractures but require different investigations and management. Important mimics include osteomalacia, primary hyperparathyroidism, multiple myeloma and metastatic bone disease, Paget disease, chronic kidney disease–mineral and bone disorder (CKD-MBD), osteogenesis imperfecta, and hypophosphatasia. The most useful discriminators are the biochemical profile, clinical presentation, fracture pattern, and characteristic imaging findings. Dual-energy X-ray absorptiometry (DXA) measures BMD but cannot independently distinguish osteoporosis from these disorders.

In uncomplicated primary osteoporosis, routine serum calcium, phosphate, and alkaline phosphatase (ALP) are generally normal. Abnormal biochemical findings, disproportionate skeletal symptoms, unusual fracture patterns, or systemic features should prompt evaluation for an alternative or coexisting diagnosis. These conditions are not mutually exclusive with osteoporosis: osteomalacia and CKD-MBD, for example, may coexist with osteoporosis, and DXA alone cannot distinguish their contributions to skeletal fragility.

The diagnostic approach should branch toward alternative diagnoses when the clinical or biochemical findings are inconsistent with uncomplicated primary osteoporosis. The laboratory evaluation and imaging techniques are described in their respective microchapters; this chapter emphasizes the features that distinguish the major mimics.

At-a-glance comparison

Disease	Key biochemical findings	Distinguishing clinical or imaging features
Primary osteoporosis	Calcium, phosphate, and ALP are generally normal.	Often asymptomatic until fracture. Low BMD and fragility fractures, including vertebral compression fractures, may occur. DXA does not exclude alternative diagnoses.
Osteomalacia	May include low or low-normal calcium, low phosphate, elevated ALP, low 25-hydroxyvitamin D, and elevated PTH when secondary hyperparathyroidism is present.	Diffuse bone pain, proximal muscle weakness, and Looser zones (pseudofractures); vertebral biconcavity may occur.
Primary hyperparathyroidism	Elevated calcium with elevated or inappropriately non-suppressed PTH; phosphate may be low or low-normal.	Preferential cortical bone loss, particularly at the distal one-third radius, although trabecular bone and vertebral fracture risk may also be affected.
Multiple myeloma or metastatic bone disease	Possible anemia, hypercalcemia, renal impairment, monoclonal protein, or abnormal serum free light chains.	Lytic lesions, pathologic fractures, marrow replacement, or soft-tissue masses. DXA is not diagnostic of myeloma bone disease.
Paget disease of bone	Total ALP may be elevated, with calcium, phosphate, and PTH often normal.	Focal bone pain or deformity; radiographs may show bone expansion, cortical thickening, osteolysis, and coarse trabeculae.
CKD-MBD / renal osteodystrophy	Abnormalities of calcium, phosphate, PTH, vitamin D metabolism, and renal function; findings depend on disease subtype.	May involve high-, low-, or mixed-turnover bone disease and impaired mineralization. DXA cannot determine the specific turnover state.
Osteogenesis imperfecta	Calcium, phosphate, PTH, and ALP are often normal.	Recurrent or childhood-onset fractures, blue or gray sclerae, dentinogenesis imperfecta, hearing loss, short stature, or family history.
Hypophosphatasia	Persistently low ALP is the key biochemical clue.	Recurrent fractures, bone pain, poor fracture healing, premature loss of primary teeth, or atypical femoral fractures. Antiresorptive exposure may be harmful.

Osteomalacia

Osteomalacia is a defect in bone mineralization, whereas osteoporosis primarily involves reduced bone mass and deterioration of bone microarchitecture. Both conditions may lower DXA-measured BMD and may coexist, so BMD alone cannot distinguish them.

Features favoring osteomalacia include:

• Biochemistry: Low or low-normal calcium, low phosphate, elevated ALP, low 25-hydroxyvitamin D, and secondary hyperparathyroidism may be present. The pattern depends on the underlying cause.
• Clinical presentation: Diffuse bone pain, bone tenderness, and proximal muscle weakness are more suggestive of osteomalacia than uncomplicated osteoporosis.
• Radiographs: Looser zones, also called pseudofractures, are characteristic and appear as transverse lucent bands perpendicular to the cortex. Vertebral biconcavity may also occur.
• Confirmation: A compatible clinical presentation, biochemical abnormalities, and imaging findings often establish the diagnosis. Bone biopsy with tetracycline labeling may be considered when diagnostic uncertainty persists but is rarely required in routine practice.

When osteomalacia is suspected, identify and address the underlying mineralization defect before initiating osteoporosis-specific treatment. Antiresorptive treatment may worsen hypocalcemia in susceptible patients.

Primary hyperparathyroidism

Primary hyperparathyroidism is characterized by elevated serum calcium with an elevated or inappropriately non-suppressed PTH concentration. This biochemical pattern distinguishes it from uncomplicated primary osteoporosis, in which calcium and PTH are generally normal. Phosphate may be low or low-normal, and urinary calcium assessment may help in the appropriate diagnostic context.

Skeletal findings may include preferential cortical bone loss, particularly at the distal one-third radius, with relative preservation of lumbar-spine BMD in the classic densitometric pattern. However, this does not mean that trabecular bone is spared: high-resolution peripheral quantitative computed tomography (HR-pQCT), trabecular bone score (TBS), and vertebral fracture assessment demonstrate that trabecular bone and the spine may also be affected, with increased fracture risk at both cortical and trabecular sites.

Nephrolithiasis is a supportive clinical clue. Severe skeletal manifestations, such as osteitis fibrosa cystica, subperiosteal bone resorption, and brown tumors, are now uncommon in many settings. When primary hyperparathyroidism is suspected, assess serum calcium and PTH together and pursue further evaluation according to the biochemical findings.

Normocalcemic primary hyperparathyroidism requires careful evaluation to exclude secondary causes of elevated PTH; its skeletal implications and diagnostic boundaries remain areas of ongoing study.

Multiple myeloma and metastatic bone disease

Consider multiple myeloma or metastatic bone disease in patients with vertebral fractures or low BMD accompanied by unexplained anemia, hypercalcemia, renal impairment, persistent focal bone pain, a known malignancy, or other concerning systemic findings. Depending on the presentation, investigations may include serum and urine protein electrophoresis, immunofixation, serum free light chains, and appropriate imaging.

Under International Myeloma Working Group criteria, one or more osteolytic lesions of at least 5 mm on CT, including low-dose whole-body CT, or PET-CT can establish myeloma-related bone disease in the appropriate diagnostic context. Osteoporosis or vertebral compression fractures alone, without qualifying lytic lesions or other myeloma-defining events, are not sufficient to establish myeloma bone disease. DXA is not a diagnostic test for myeloma-related skeletal involvement.

MRI may help distinguish benign osteoporotic from malignant vertebral fractures. Features favoring malignancy include diffuse or focal marrow replacement, posterior-element or pedicle involvement, posterior cortical convexity, and an associated paravertebral or epidural soft-tissue mass. Preserved marrow fat and an intravertebral fluid cleft may favor a benign fracture, but no single MRI feature is definitive. Findings must be interpreted in the clinical context; equivocal lesions may require further imaging, follow-up, or biopsy.

Paget disease of bone

Paget disease is a focal disorder of abnormal bone remodeling and should be distinguished from the generalized reduction in bone mass characteristic of osteoporosis. Many patients are asymptomatic, while others develop focal bone pain, deformity, long-bone bowing, skull enlargement, or hearing impairment.

The characteristic biochemical clue is an elevated total ALP with otherwise often-normal calcium, phosphate, and PTH. An elevated ALP is not specific to Paget disease; hepatic sources and other causes of increased bone turnover must be considered.

Plain radiographs of the affected bone may demonstrate osteolysis, coarse trabeculae, bone expansion, and cortical thickening. Radionuclide bone scanning can help determine the extent of disease. Correlate ALP with liver tests and the clinical and imaging findings before attributing the elevation to Paget disease.

CKD-MBD and renal osteodystrophy

Chronic kidney disease can cause CKD-MBD, a systemic disorder involving abnormalities in mineral metabolism, PTH signaling, vitamin D metabolism, bone turnover, and mineralization. Renal osteodystrophy includes high-turnover disease, low-turnover or adynamic bone disease, and mixed patterns. These disorders may coexist with osteoporosis, and their biochemical profiles vary with disease severity and subtype.

DXA can help estimate fracture risk in people with CKD, but it cannot determine the underlying bone-turnover state or reliably distinguish the different forms of renal osteodystrophy. When defining the bone phenotype would materially change treatment, bone biopsy with turnover, mineralization, and volume assessment may be considered. Biopsy is not required routinely in every patient with CKD and low BMD.

Avoid assuming that all low BMD in CKD represents conventional osteoporosis. Interpretation should integrate renal function, trends in calcium, phosphate, PTH and ALP, fracture history, and the clinical context. Decisions about osteoporosis treatment in advanced CKD require individualized assessment of potential benefits and risks.

Osteogenesis imperfecta and hypophosphatasia

Osteogenesis imperfecta

Osteogenesis imperfecta (OI) should be considered in patients with recurrent fractures beginning in childhood, disproportionate skeletal fragility, or features of a heritable connective-tissue disorder. Clues include blue or gray sclerae, dentinogenesis imperfecta, hearing loss, short stature, ligamentous laxity, Wormian bones, and a family history of fractures. Milder forms may be recognized in adulthood and initially labeled as unexplained or early-onset osteoporosis.

Calcium, phosphate, PTH, and ALP are often normal in OI. DXA may demonstrate low BMD but is not diagnostic. When the clinical history or examination suggests inherited bone fragility, genetic evaluation may begin with COL1A1 and COL1A2 and expand according to the phenotype and testing strategy.

Recognizing OI is important because patients may require evaluation for associated hearing impairment, scoliosis, respiratory complications, and other extraskeletal manifestations. In children with fractures, OI must be distinguished from non-accidental trauma, while recognizing that the two can coexist.

Hypophosphatasia

Hypophosphatasia is an inherited disorder of tissue-nonspecific alkaline phosphatase activity that can cause defective skeletal mineralization and increased fracture risk. Consider it when ALP is persistently low, particularly in a patient with recurrent fractures, bone pain, poor fracture healing, premature loss of primary teeth, or atypical femoral fractures. A low ALP should not be interpreted as evidence against a metabolic bone disorder.

Recognition is clinically important because bisphosphonates and other antiresorptive therapies may be inappropriate in hypophosphatasia and have been associated with atypical femoral fractures in affected patients. Diagnosis is based on the clinical and biochemical picture and may be supported by ALPL genetic testing. Genetic assessment should be tailored to the suspected disorder rather than routinely combining ALPL testing with COL1A1/COL1A2 testing in every patient.

Clinically actionable approach

• Review the clinical pattern and discriminating biochemistry. Calcium, ALP, and PTH are particularly useful when interpreting possible hyperparathyroidism or other metabolic bone disorders. Interpret abnormalities in context rather than assuming that a single abnormal result establishes a diagnosis.
• Investigate possible myeloma or malignancy when fractures or low BMD coexist with anemia, hypercalcemia, renal impairment, unexplained focal pain, or other suspicious findings. Select protein studies and imaging according to the presentation.
• Evaluate elevated calcium with PTH. Elevated calcium with a non-suppressed PTH suggests primary hyperparathyroidism and warrants further evaluation.
• Investigate an isolated ALP elevation. Consider Paget disease when the elevation is consistent with a bone source and imaging or symptoms support the diagnosis. Persistently low ALP should raise the possibility of hypophosphatasia.
• Use targeted imaging for atypical fractures. MRI can help characterize an indeterminate vertebral fracture and assess for malignancy or other pathology, but imaging features must be interpreted together rather than in isolation.
• Consider genetic evaluation when fragility is disproportionate to age, fractures began early in life, extraskeletal features are present, or the family history suggests inherited bone disease.
• Avoid premature osteoporosis treatment when a mineralization disorder is suspected. Identify and address osteomalacia or another relevant metabolic abnormality before selecting treatment.

The detailed laboratory workup is covered in Laboratory findings, and the acquisition and interpretation of DXA and other diagnostic studies are addressed in the relevant diagnostic chapters.

Epidemiology and demographics

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [17] Associate Editor(s)-in-Chief: Ibrahim Elkhayat, M.B.B.Ch.[18] Osteoporosis is a common skeletal disorder characterized by reduced bone strength and increased susceptibility to fragility fractures. Its population burden rises with age, particularly among postmenopausal women, but osteoporosis and associated fractures also affect men and diverse racial and ethnic populations. The burden extends beyond fracture incidence to premature mortality, disability, loss of independence, and substantial healthcare expenditure.

Prevalence and incidence

In the United States, data from the National Health and Nutrition Examination Survey (NHANES) 2017–2018 indicate that osteoporosis, defined by bone mineral density (BMD) criteria at the femoral neck or lumbar spine, affects approximately 12.6% of adults aged 50 years or older. Prevalence is higher among women than men: approximately 19.6% in women and 4.4% in men. Among adults aged 65 years or older, prevalence is approximately 27.1% in women and 5.7% in men. These estimates depend on the skeletal sites and diagnostic definitions used and do not capture every individual who will experience a fragility fracture.

Fractures attributable to osteoporosis constitute a substantial and growing public health burden. Estimates of annual fracture counts vary according to the population, fracture sites, case definitions, and data source. The 2025 US Preventive Services Task Force review reported approximately 1.8 million Medicare beneficiaries with a new fracture in 2016; this is a population-specific estimate and should not be interpreted as the total number of osteoporotic fractures among all US adults.

In Europe, approximately 3.5 million new fragility fractures were estimated to occur annually, including hip, vertebral, forearm, and other fractures. Population aging is expected to increase the absolute number of fractures even where age-specific incidence rates remain stable or decline.

Importantly, approximately 70% of osteoporotic fractures occur in individuals who do not meet the densitometric definition of osteoporosis (T-score ≤ −2.5). Therefore, the population burden of fragility fractures is substantially broader than the population classified as having osteoporosis by BMD alone.

Age and sex distribution

Osteoporosis prevalence and fracture incidence increase with age. Bone loss and age-related changes in bone strength contribute to the rising risk of fragility fractures in older adults. Hip-fracture incidence increases steeply in later life, with rates roughly doubling every 5 to 6 years in older populations.

Women have a higher prevalence of osteoporosis and sustain the majority of osteoporotic fractures, particularly after menopause. Men have a lower incidence of hip fracture but remain an important affected population. Hip-fracture incidence in men is projected to increase substantially, with estimates suggesting an approximately 51% rise between 2010 and 2030, while the number in women was projected to decline modestly. These projections emphasize the growing and often under-recognized burden among men.

The estimated remaining lifetime probability of hip fracture from age 50 is approximately 23% in women and 11% in men. This is the lifetime risk of hip fracture specifically and should not be confused with the higher lifetime probability of experiencing any osteoporotic fracture.

Racial and ethnic variation

Osteoporosis prevalence and fracture incidence differ among racial and ethnic populations. In the United States, Black adults have, on average, higher BMD and lower prevalence of BMD-defined osteoporosis than White adults. However, lower prevalence does not imply absence of clinically important fracture risk. Differences in fracture incidence, age distribution, access to preventive care, diagnosis, and treatment contribute to variation in observed outcomes.

Published US estimates have reported lower hip-fracture incidence among Asian, Black, and Hispanic women than among White women, although rates vary by study, population, and period. These estimates should not be generalized to all individuals within a racial or ethnic group or across different countries. Race and ethnicity are population descriptors rather than substitutes for individual clinical assessment.

Mortality, disability, and functional outcomes

Hip fractures are associated with substantial mortality, particularly in older adults and those with greater comorbidity. Contemporary reviews report approximately 21% to 30% mortality within one year after hip fracture in many studied populations, although estimates differ by setting, age, sex, health status, and study methodology. US estimates for 2008–2017 were approximately 26.9% in men and 18.5% in women, illustrating the higher post-fracture mortality observed among men in that cohort.

Vertebral fractures, the most common osteoporotic fracture, are also associated with increased mortality, and many are asymptomatic and do not initially come to clinical attention.

The consequences of hip fracture extend beyond mortality. Approximately 20% of patients may require long-term nursing-facility care after hip fracture. Functional recovery is frequently incomplete: only approximately 42% to 71% of patients regain their prefracture level of basic activities of daily living by six months. These outcomes highlight the effects of osteoporosis on mobility, independence, and long-term care needs.

Population burden of recurrent fractures

A previous fragility fracture identifies a population at increased risk of subsequent fracture. A systematic review and meta-analysis estimated that approximately 7.6% of patients experienced a subsequent fracture within one year and 11.6% within two years after an initial fracture. Estimates vary with the index fracture, population, follow-up period, and ascertainment method.

The natural history of recurrent fractures and the clinical implications of an initial fracture are discussed in the osteoporosis natural-history chapter. Post-fracture evaluation and secondary prevention are addressed in the relevant management chapter.

Economic burden

Osteoporotic fractures impose substantial healthcare and societal costs. Contemporary estimates place the annual US healthcare cost of osteoporotic, predominantly postmenopausal, fractures at approximately $57 billion in 2018, with total costs projected to exceed $95 billion by 2040. Direct medical costs alone are projected to exceed $81 billion by 2040. These are estimates and projections, not measurements of actual US expenditure in 2026.

Earlier estimates of approximately $17 billion in annual US fracture-related costs in 2005, with a projection of $25.3 billion by 2025, are historical figures and should not be interpreted as current expenditure. In Europe, the annual economic burden of fragility fractures was estimated at approximately €37 billion, with most costs attributable to fracture care and long-term consequences rather than pharmacological treatment alone.

Epidemiologic implications

Osteoporosis is a major cause of fragility fractures, disability, loss of independence, and healthcare expenditure in aging populations. Women experience a greater overall burden, but men also face substantial fracture-related mortality and a projected increase in hip-fracture incidence. Racial and ethnic differences in BMD and fracture outcomes underscore the importance of interpreting population estimates in context. Because many fractures occur in individuals whose BMD does not reach the densitometric threshold for osteoporosis, BMD-defined prevalence alone does not fully represent the population burden of fracture.

Risk factors

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [19] Associate Editor(s)-in-Chief: Ibrahim Elkhayat, M.B.B.Ch.[20] Osteoporosis-related fracture risk reflects a combination of bone strength, clinical risk factors, and the likelihood of falling. Risk factors help identify individuals who may benefit from further assessment, but they do not independently establish a diagnosis. Approximately 70% of osteoporotic fractures occur in people whose bone mineral density (BMD) T-score is above −2.5; therefore, fracture risk should not be assessed using BMD alone.

The evaluation and interpretation of BMD and fracture-risk tools are discussed in Osteoporosis Other diagnostic studies. Population prevalence and incidence are discussed in Osteoporosis Epidemiology and demographics.

Low bone mineral density

Low BMD is a central risk factor for fragility fracture. Central dual-energy X-ray absorptiometry (DXA) BMD predicts major osteoporotic fracture (MOF) with areas under the receiver operating characteristic curve (AUCs) of approximately 0.60–0.80 and hip fracture with AUCs of approximately 0.64–0.86 across cohorts.

Many fragility fractures occur in people whose T-scores do not meet the densitometric definition of osteoporosis. BMD should therefore be interpreted alongside age, previous fracture, falls, medication exposures, and other clinical risk factors.

Non-modifiable risk factors

Age

Age is one of the strongest determinants of fracture probability. Analyses of the FRAX algorithm identified age and femoral-neck T-score as the strongest contributors to hip-fracture probability. The USPSTF notes that advancing age is a stronger determinant of fracture than BMD; older adults have higher fracture rates than younger adults with the same BMD because of declining bone quality and an increasing risk of falling.

Previous fracture

A previous fragility fracture is an important predictor of subsequent fracture, including when BMD is not in the osteoporosis range. A meta-analysis of 64 cohorts involving approximately 2.1 million participants found that a previous fracture was associated with increased risk of any clinical fracture (hazard ratio [HR] 1.88; 95% confidence interval [CI] 1.72–2.07), hip fracture (HR 1.82), and MOF (HR 1.83). Associations did not differ materially between men and women. Low BMD explained only a minority of the excess risk: approximately 14% for any clinical fracture, 17% for osteoporotic fracture, and 33% for hip fracture.

The recency, site, and number of previous fractures also matter. Among 377,500 Medicare women aged 65 years or older with a first clinical fracture, subsequent-fracture risk was approximately 10% during the next year and 18% over 2 years. Short-term risk was highest after vertebral and pelvic fractures and lowest after ankle fractures, although the 1-year risk after ankle fracture remained just below 5%. Approximately half of subsequent fractures occur within 2 years of the index fracture.

Multiple prior fractures confer greater risk than a single fracture. Proposed adjustments to conventional FRAX estimates based on the number or recency of fractures are described in Osteoporosis Other diagnostic studies.

Fractures that occurred many years earlier remain clinically relevant. In a Manitoba cohort, FRAX underestimated MOF risk after non-recent vertebral fractures (observed-to-predicted ratio 1.32) and multiple fractures (1.34). Fractures in early adulthood are also associated with subsequent fracture risk, with reported adjusted HRs of 1.51–2.12.

Family history

A parental history of hip fracture is associated with increased fracture risk. A 2025 meta-analysis reported an HR of 1.37 (95% CI 1.23–1.52) for hip fracture and 1.19 (95% CI 1.12–1.27) for MOF in people with a parental history of hip fracture. Parental non-hip fractures showed similar associations in more limited data. The association was not shown to vary materially according to which parent was affected or the offspring's age.

Female sex, menopause, and estrogen deficiency

Estrogen deficiency is strongly associated with fragility fracture. It occurs after natural menopause and may also occur with premature ovarian insufficiency, surgical menopause, and male hypogonadism. Premature menopause before age 45 years and hypogonadism are included among the conditions represented by the FRAX secondary-osteoporosis input.

An estimated one in three women and one in five men older than 50 years will sustain an osteoporotic fracture during their lifetime. An older estimate from the UK General Practice Research Database placed lifetime risk from age 50 years at approximately one in two for women and one in five for men.

Men generally sustain fragility fractures approximately 10 years later than women. The female-to-male hip-fracture ratio narrows with age, from approximately 4.5 at ages 60–69 years to 1.9 at age 80 years or older. Male sex should not be used to exclude an individual from fracture-risk assessment.

Body weight and body composition

Low body mass index

Low body mass index (BMI), particularly BMI below 18.5 kg/m², is associated with increased hip-fracture risk. In a meta-analysis of 63 cohorts involving approximately 1.67 million participants, the association persisted after adjustment for BMD. Compared with normal BMI, the HR for hip fracture among underweight participants was 1.69 in women and 1.46 in men after BMD adjustment.

Obesity and weight loss

Obesity should not be assumed to be protective against fracture. The relationship varies by fracture site, sex, and degree of obesity. In a meta-analysis, class II obesity (BMI ≥35 kg/m²) appeared protective in models without BMD (hip-fracture HR versus normal BMI: 0.66 in women and 0.91 in men). After adjustment for femoral-neck BMD, the direction reversed in men (HR 1.70; 95% CI 1.06–2.75); the estimate in women was smaller and imprecise (HR 1.24; 95% CI 0.97–1.58).

Weight loss is also associated with hip fracture. A meta-analysis reported a pooled odds ratio (OR) of 1.88 (95% CI 1.32–2.68). In a prospective study of 6,785 White women aged 65 years or older, weight loss of at least 5% was associated with a 79% higher hip-fracture risk after adjustment for baseline weight, BMD, and clinical risk factors.

Modifiable lifestyle risk factors

Smoking

Current smoking is associated with increased hip-fracture risk. A systematic review and meta-analysis reported an OR of approximately 1.50 (95% CI 1.22–1.85). Smoking status should be considered as part of the overall fracture-risk assessment.

Alcohol

High alcohol consumption is associated with increased fracture risk. A meta-analysis of eight cohorts involving 240,871 individuals reported hip-fracture relative risks of 1.33 (95% CI 1.04–1.69) for three standard drinks daily and 1.59 (95% CI 1.23–2.05) for four standard drinks daily, compared with no alcohol. Conventional FRAX uses alcohol consumption equivalent to at least three units daily as a risk-factor threshold. Definitions of a standard drink or alcohol unit vary across studies, and observational associations should be interpreted accordingly.

Physical inactivity

Physical inactivity is associated with increased hip-fracture risk. A meta-analysis reported a pooled OR of 2.14 (95% CI 1.21–3.77), although the certainty and consistency of evidence vary across studies.

Falls and fall-promoting medications

Falls are an important risk factor for fragility fractures and contribute risk independently of BMD. An individual-participant meta-analysis of 46 cohorts involving approximately 906,000 participants found that a history of falls was associated with increased risk of any clinical fracture in women (HR 1.42) and men (HR 1.53). The association was stronger in men than women and weakened with increasing age in women; the association was not explained by BMD.

For hip fracture specifically, the HR was 1.36 (95% CI 1.23–1.50) in women and 1.59 (95% CI 1.38–1.84) in men. Risk increases with recurrent falls. In a registry-based cohort, the HR for MOF was approximately 1.49 after one fall, 1.74 after two falls, and 2.62 after three or more falls; three or more falls were associated with an HR of 3.41 for hip fracture.

A recent fall can signal imminent fracture risk. In the Study of Osteoporotic Fractures and the Osteoporotic Fractures in Men study, a fall within the previous 4 months was associated with an 8.1% 1-year risk of non-spine fracture in women, approximately 2.5 times the risk in women without a recent fall.

The American Geriatrics Society/British Geriatrics Society guideline recommends annual fall-risk assessment for adults aged 65 years or older and following an acute fall. Conventional FRAX does not directly include falls; fall history and fall-promoting medications should therefore be considered during clinical assessment, even when a calculated FRAX probability appears modest. Some alternative or supplemental risk tools incorporate falls. Detailed tool comparison belongs in Osteoporosis Other diagnostic studies.

Medications that may increase fall risk include sedatives and other agents associated with impaired alertness, balance, or postural blood pressure. Examples include benzodiazepines, opioids, selective serotonin reuptake inhibitors (SSRIs), and antihypertensive medications when they contribute to postural hypotension. Medication review should consider the individual's symptoms, comorbidities, and overall treatment regimen. In a meta-analysis of 38 observational studies involving approximately 1.24 million participants, antidepressants (OR 2.07), antipsychotics (OR 2.0), benzodiazepines (OR 1.84), systemic corticosteroids (OR 1.65), proton pump inhibitors (OR 1.41), and thyroid hormone (OR 1.29) were associated with fragility hip fracture; these associations are subject to confounding by indication.

Frailty and sarcopenia

Frailty is associated with fracture risk independent of BMD. In the UK Biobank, a frailty index was associated with any fracture (HR 1.53), vertebral fracture (HR 2.33), and hip fracture (HR 1.74).

In a cohort of women aged 75 years, frailty predicted fracture independently of BMD and was associated with imminent risk, including a 2-year hip-fracture subdistribution HR of 3.16 (95% CI 1.34–7.47).

Sarcopenia has also been associated with hip fracture after BMD adjustment in older adults, although estimates vary according to the definition used. Frailty and sarcopenia may increase fracture risk through impaired balance, reduced muscle strength, falls, and reduced physical function. Conventional FRAX does not directly include frailty.

Vitamin D status

Severe vitamin D deficiency has adverse skeletal effects. In a prospective cohort of adults aged 66 years or older, serum 25-hydroxyvitamin D below 30 nmol/L was associated with incident hip fracture. After adjustment for volumetric BMD and physical function, the association persisted in women (HR 1.7; 95% CI 1.1–2.4) but not in men.

This is an observational association and does not establish that supplementation prevents fractures. In the VITAL randomized trial (25,871 adults; median follow-up 5.3 years), vitamin D3 2000 IU/day did not reduce total fractures (HR 0.98; 95% CI 0.89–1.08), nonvertebral fractures, or hip fractures (HR 1.01) among adults not selected for vitamin D deficiency, low bone mass, or osteoporosis. Few participants had severe deficiency, and these findings may not apply to people with very low 25-hydroxyvitamin D levels, malabsorption, or osteoporosis. Supplementation and nutritional interventions are discussed in Osteoporosis Primary prevention.

Glucocorticoid exposure

Oral glucocorticoid exposure is an important risk factor for osteoporosis and fracture. Conventional FRAX records glucocorticoid exposure using a defined input, generally corresponding to current or previous oral exposure to prednisone-equivalent doses of at least 5 mg/day for more than 3 months. Conventional FRAX assumes an average prednisolone-equivalent dose of 2.5–7.5 mg/day and does not directly account for treatment duration or cumulative dose. Clinical risk depends on dose, duration, cumulative exposure, underlying disease, and other patient factors.

At prednisolone doses of 2.5–7.5 mg/day, clinical vertebral-fracture risk is approximately doubled and hip-fracture risk increases by approximately 50%. Fractures have been reported at doses as low as 2.5 mg/day. Vertebral-fracture risk can rise within 3 months of treatment and may peak at approximately 12 months. Bone loss is particularly rapid during the first 3–6 months of exposure.

Very high exposure confers the greatest risk. Among adults receiving prednisolone 30 mg/day with cumulative doses of at least 5 g, vertebral-fracture risk was approximately 14-fold higher and hip-fracture risk approximately 3-fold higher. Intermittent high-dose courses with cumulative doses of 1 g or less had less effect. The ACR includes very-high-dose exposure in its very-high-risk category.

High-dose inhaled glucocorticoids (≥1000 μg fluticasone-equivalent daily for more than 4 years) were associated with a small increase in fracture risk (RR 1.10; 95% CI 1.02–1.19) in one analysis. An increased risk of hip fracture has not consistently been observed with high-dose inhaled therapy, and confounding by concurrent oral glucocorticoids and underlying disease limits interpretation.

Fracture risk generally declines rapidly after glucocorticoids are discontinued, although it may not return to baseline.

The ACR recommends fracture-risk assessment as soon as possible, and within 6 months, for adults beginning or continuing glucocorticoid therapy at doses of at least 2.5 mg/day for more than 3 months. Doses of at least 2.5 mg/day increase both spine and hip fracture risk, whereas doses below 2.5 mg/day are associated with increased spinal-fracture risk. This is a strong recommendation based on low-certainty evidence. Assessment should include previous fractures, including asymptomatic vertebral fractures when relevant. The ACR defines very high fracture risk as any prior osteoporotic fracture; a T-score of −3.5 or lower; glucocorticoid-adjusted FRAX MOF probability of at least 30% or hip-fracture probability of at least 4.5%; or a mean prednisone-equivalent dose of at least 30 mg/day for at least 30 days or cumulative dose of at least 5 g over 1 year.

For prednisone-equivalent doses above 7.5 mg/day, the ACR guideline describes adjusting FRAX probabilities upward by multiplying MOF probability by 1.15 and hip-fracture probability by 1.20. Detailed calculation and interpretation of these adjustments belong in Osteoporosis Other diagnostic studies.

Diabetes mellitus

Type 2 diabetes mellitus

Type 2 diabetes mellitus (T2D) is associated with increased fracture risk despite BMD values that are often 5–10% higher than those of people without diabetes. Impaired bone quality and microarchitecture, diabetes duration, complications, hypoglycemia, and falls may contribute to this discordance between BMD and fracture risk. The American Diabetes Association notes that some recent findings suggest fracture risk may be similar at a given femoral-neck T-score in people with and without diabetes; therefore, the magnitude of underestimation and the best adjustment method remain uncertain.

Hip-fracture risk is increased approximately 1.79-fold in the evidence summarized by the ADA. Each 1% higher HbA1c has been associated with an 8% higher fracture risk (RR 1.08; 95% CI 1.03–1.14), and hypoglycemia with an RR of 1.52 (95% CI 1.23–1.88). Microvascular complications, cardiovascular disease, poor physical function, and frequent falls are additional risk markers. Insulin use and diabetes duration exceeding 10 years are also associated with greater risk.

Conventional FRAX does not include T2D as a separate input. The ADA states that multiple large cohort studies and meta-analyses show that FRAX systematically underestimates fracture risk in T2D across diverse ethnic groups, with underestimation increasing with diabetes duration and most pronounced for hip fracture and in older adults. Proposed adjustments include entering rheumatoid arthritis as a surrogate input, lowering the femoral-neck T-score input by 0.5 SD, increasing the age input by 10 years, incorporating trabecular bone score, and using supplemental tools; no single adjustment completely resolves the limitations of fracture-risk prediction in T2D. Detailed calculator adjustments are discussed in Osteoporosis Other diagnostic studies.

The ADA recommends routine fracture-risk assessment in older adults with diabetes (Grade A). It also recommends avoiding thiazolidinediones and sulfonylureas in people at elevated fracture risk (Grade B) and prioritizing glucose-lowering agents with a low risk of hypoglycemia to reduce falls (Grade B).

Type 1 diabetes mellitus

Type 1 diabetes mellitus is associated with increased fracture risk and is represented in conventional FRAX under the secondary-osteoporosis input. FRAX may underestimate absolute fracture risk in people with type 1 diabetes; the secondary-osteoporosis input is inactivated when BMD is entered. The underlying mechanisms and clinical evaluation are discussed in Osteoporosis Causes.

Other medication exposures

Endocrine cancer therapies, including aromatase inhibitors, androgen-deprivation therapy (ADT), gonadotropin-releasing hormone agonists, and chemotherapy-induced ovarian failure, may add to baseline fracture risk. The American Society of Clinical Oncology recommends accounting for these exposures in fracture-risk assessment, based on moderate-strength recommendations and moderate-quality evidence. In postmenopausal women with estrogen receptor-positive early breast cancer, 5-year fracture risk was 8.2% with an aromatase inhibitor versus 5.5% with tamoxifen. This estimate derives from a patient-level meta-analysis of 31,920 women; real-world cohorts have reported 5-year fracture incidence as high as 20% with aromatase inhibitors. ASCO notes that existing fracture-risk tools, including FRAX, have not been validated in patients with cancer and that clinical judgment is necessary when interpreting their results (moderate-strength recommendation).

ADT for prostate cancer is associated with increased fracture risk. A meta-analysis reported an OR of 2.83 (95% CI 2.52–3.17). The National Comprehensive Cancer Network recommends fracture-risk assessment for all patients initiating ADT of any duration and advises entering luteinizing hormone-releasing hormone analogue ADT as secondary osteoporosis in FRAX; bone-loss risk is greater with more potent androgen suppression, longer therapy or delayed testosterone recovery, and concurrent prednisone.

Other medication exposures associated with bone loss, falls, or fracture include proton pump inhibitors, levothyroxine, loop diuretics, thiazolidinediones, and sulfonylureas. The magnitude of risk may vary with the indication, dose, duration, and characteristics of the individual. These are clinical risk categories rather than equivalent or uniformly causal effects; mechanisms are discussed in Osteoporosis Causes.

Secondary osteoporosis and chronic kidney disease

Several disorders can contribute to secondary osteoporosis or increased fracture risk. Conventional FRAX includes a secondary-osteoporosis input for selected conditions, including type 1 diabetes, osteogenesis imperfecta, untreated long-standing hyperthyroidism, hypogonadism or premature menopause before age 45, chronic malnutrition or malabsorption, and chronic liver disease. Rheumatoid arthritis is represented as a separate input. The secondary-osteoporosis input is inactivated when BMD is entered. The full evaluation of secondary causes is discussed in Osteoporosis Causes.

Chronic kidney disease (CKD) complicates fracture-risk assessment because renal disease may affect bone strength and mineral metabolism. In a Manitoba registry cohort, FRAX predicted MOF and hip fracture across non-dialysis estimated glomerular filtration rate (eGFR) strata, including eGFR below 30 mL/min/1.73 m², although it modestly underestimated risk in the lowest eGFR stratum. In hemodialysis populations, FRAX without BMD discriminated major fractures with an AUC of 0.76, but may underestimate absolute risk. A lower intervention threshold (FRAX >5%) has been proposed in a single-country hemodialysis cohort and should not be generalized without validation.

KDIGO suggests BMD testing to assess fracture risk in people with CKD stages G3a–G5D who have evidence of CKD-mineral and bone disorder and/or osteoporosis risk factors, when the result will affect treatment decisions (grade 2B). Evidence specific to dialysis populations remains limited. Detailed evaluation and management of CKD-related bone disease belong in the relevant diagnostic and treatment chapters.

FRAX and other fracture-risk tools

FRAX estimates 10-year probability of hip fracture and MOF. Its clinical inputs include age, sex, weight, height, previous fracture, parental hip fracture, current smoking, glucocorticoid exposure, rheumatoid arthritis, secondary osteoporosis, and alcohol consumption equivalent to at least three units daily. Femoral-neck BMD can be entered when available. The previous-fracture input includes a previous osteoporotic fracture in adult life, including morphometric vertebral fracture; the FRAX definition excludes certain sites, including hands, feet, and craniofacial bones.

Conventional FRAX has important limitations: it does not directly account for falls, the number or recency of previous fractures, T2D, glucocorticoid dose, lumbar-spine BMD, or frailty. It may underestimate risk at very high glucocorticoid doses and is not validated for adults younger than 40 years or for patients with cancer. These limitations may lead to underestimation of risk in some clinical settings; clinical judgment is needed when relevant factors are not adequately represented. Full calculation, interpretation, and comparison with other tools belong in Osteoporosis Other diagnostic studies.

FRAX discrimination is modest; AUCs for MOF in women are approximately 0.65–0.71, and are lower in women younger than 65 years when BMD is not included. Detailed performance data are presented in Osteoporosis Other diagnostic studies.

FRAXplus allows adjustments for selected factors not directly captured in conventional FRAX, including fracture recency, high-dose oral glucocorticoids, T2D duration, lumbar-spine BMD, trabecular bone score, falls during the previous year, and hip axis length. These adjustments may improve risk classification, but should be interpreted using the applicable tool and its supporting evidence. Detailed tool-specific methods belong in Osteoporosis Other diagnostic studies.

Controversies and limitations in risk prediction

Race and ethnicity in fracture-risk prediction

The use of race and ethnicity in fracture-risk calculators remains controversial. US FRAX has separate versions for Hispanic, non-Hispanic Asian, non-Hispanic Black, and non-Hispanic White persons; for otherwise identical inputs, the race-specific calculator estimates lower risk for Asian, Black, and Hispanic persons than for White persons.

An American Society for Bone and Mineral Research (ASBMR) task force recommended population-based models without race or ethnicity adjustment. The International Osteoporosis Foundation disagreed, arguing that omitting race could reduce FRAX performance and expose individuals to unnecessary treatment.

Calibration findings conflict. Among 67,169 Women's Health Initiative (WHI) participants aged 50–64 years, FRAX without BMD was well calibrated for MOF in Asian, Hispanic, and White women but underestimated risk among high-risk Black women.

In a separate WHI analysis of 27,512 women aged 50–79 years, FRAX with BMD overestimated fracture risk by 82% in African American women and 48% in Hispanic women. The authors subsequently acknowledged differential censoring and sparse subgroup events as limitations.

In a clinical cohort with diabetes or hypertension, FRAX without BMD underestimated MOF in Black (observed-to-predicted ratio 1.3–2.3) and Hispanic (1.8–2.4) patients. A hypothetical race-neutral FRAX improved overall calibration but overestimated risk in Black women (observed-to-predicted ratio 0.7–0.8) and only partly corrected underestimation in Hispanic patients (1.2–1.6). The clinical implications and performance across populations remain under investigation.

Race should not be treated as a biological substitute for individual assessment. The competing recommendations and inconsistent calibration findings remain important limitations of fracture-risk prediction.

Clinical application

• Assess the number of falls in the previous year and any fall in the previous few months; recurrent or recent falls add risk beyond BMD and conventional FRAX.
• Record the site, number, and timing of prior fractures, including asymptomatic vertebral fractures when relevant, rather than treating prior fracture as a simple binary input.
• Perform fracture-risk assessment within 6 months for adults starting or continuing glucocorticoids at doses of at least 2.5 mg/day for more than 3 months, consistent with the ACR recommendation.
• Assess fracture risk when starting aromatase inhibitors or androgen-deprivation therapy.
• In T2D, interpret normal or high BMD cautiously, particularly with long disease duration, insulin use, hypoglycemia, or complications; account for the uncertainty in diabetes-specific risk adjustments.
• Consider frailty, sarcopenia, and vitamin D deficiency in the overall clinical assessment when relevant.
• Do not regard obesity or a T-score above −2.5 as reassuring in isolation.
• Interpret FRAX as one component of clinical assessment, particularly when falls, recent or multiple fractures, diabetes, glucocorticoid dose, or frailty may not be fully captured.

Screening

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [21] Associate Editor(s)-in-Chief: Ibrahim Elkhayat, M.B.B.Ch.[22] Osteoporosis is usually asymptomatic until a fragility fracture occurs. Screening aims to identify asymptomatic adults at increased fracture risk before their first fracture, allowing appropriate diagnostic evaluation and preventive treatment. The 2025 US Preventive Services Task Force (USPSTF) recommends screening women aged 65 years or older and postmenopausal women younger than 65 years who are at increased fracture risk. Evidence is insufficient to determine the balance of benefits and harms of screening in men.

This chapter addresses screening eligibility, pre-screening risk assessment, screening modalities, guideline recommendations, and repeat-testing intervals. Detailed dual-energy X-ray absorptiometry (DXA) interpretation, FRAX calculation, and diagnostic criteria are covered in Osteoporosis other diagnostic studies.

Evidence that screening prevents fractures

Three pragmatic randomized controlled trials (SCOOP, ROSE, and the Dutch SOS trial, also reported as SALT), involving 42,009 participants, compared screening strategies with usual care. All enrolled older European women, with median ages of 71–76 years.

• SCOOP and ROSE used a two-step strategy: FRAX without BMD was calculated first, followed by DXA in women exceeding a prespecified threshold (age-based 10-year hip fracture risk in SCOOP; 10-year major osteoporotic fracture risk ≥15% in ROSE).
• SOS enrolled women with at least one clinical risk factor and performed DXA, vertebral fracture assessment (VFA), laboratory testing, falls-risk assessment, and FRAX.
• In all three trials, results and treatment recommendations were shared with the primary care clinician, who made the final treatment decision.
• Baseline 10-year FRAX-estimated hip fracture risk was 8.5% in SCOOP, 6.7% in ROSE, and 11.6% in SOS.

Pooled results from the USPSTF evidence review showed the following outcomes over approximately 3.7–5 years:

Outcome	Relative risk (95% CI)	Absolute effect
Hip fracture	0.83 (0.73–0.93)	5 fewer per 1,000 screened (95% CI 7 to 2 fewer)
Major osteoporotic fracture	0.94 (0.88–0.99)	6 fewer per 1,000 screened (95% CI 12 to 1 fewer)

Pooled estimates for all fractures and all osteoporotic fractures had similar absolute risk differences but were not statistically significant. No significant association was observed for all-cause mortality (pooled RR 0.99, 95% CI 0.95–1.04; 3 trials; 57,633 participants; approximately 1 fewer death per 1,000 screened, 95% CI 5 fewer to 4 more).

The evidence has important limitations. Two trials did not report race or ethnicity; participation and adherence were incomplete, and control groups were contaminated by receipt of screening-related care. The trial populations had relatively high baseline fracture risk and were studied in European health systems, limiting certainty about the magnitude of benefit in lower-risk populations and other health systems. No trial directly evaluated screening with DXA alone.

Harms of screening

Only one of the three screening trials (SCOOP) reported harms of screening. Anxiety, measured with the State-Trait Anxiety Inventory at repeated intervals over 5 years, did not differ between screened participants (including those classified as high risk and invited for DXA) and controls (P = .52). One systematic review estimated, from SCOOP and SOS data, that 11.8% to 24.1% of participants were overdiagnosed. In placebo-controlled treatment trials included in the review, bisphosphonates and denosumab were not associated with statistically significant increases in discontinuations due to adverse events, serious adverse events, or gastrointestinal adverse events. Evidence was insufficient to evaluate rare harms such as osteonecrosis of the jaw, atypical femoral fracture, rebound vertebral fractures after denosumab discontinuation, or harms of prolonged treatment; observational cohorts cited by the USPSTF reported an increased risk of atypical femoral fracture with bisphosphonate use, although residual confounding was possible.

Who should be screened?

Women

• Women aged 65 years or older: The USPSTF recommends screening with central DXA, with or without fracture-risk assessment (Grade B; moderate certainty of moderate net benefit).
• Postmenopausal women younger than 65 years: The USPSTF recommends screening women at increased fracture risk based on clinical risk assessment (Grade B). Assess clinical risk factors first and use an appropriate risk-assessment tool when indicated.
• Premenopausal women: DXA is not recommended for routine screening in healthy premenopausal women. It may be considered in patients with a significant history of fragility fracture or a specific risk factor for bone loss, such as long-term glucocorticoid therapy.

The 2025 statement differs from 2018 in two ways: the target for younger women changed from increased risk of osteoporosis determined by a formal risk-assessment tool to increased risk of osteoporotic fracture estimated by clinical risk assessment, and the screening test is specified as central (hip or lumbar spine) DXA rather than bone measurement testing generally.

In younger postmenopausal women, ordering DXA solely to establish a baseline is not a strong indication when fracture risk is low. Screening decisions should reflect clinical risk and whether the result is likely to alter management.

Men

The USPSTF considers the evidence insufficient to determine the balance of benefits and harms of screening men (I statement). This reflects the absence of adequate direct evidence rather than evidence that screening is ineffective. The USPSTF advises clinicians to use clinical judgment regarding screening in men.

Other professional organizations recommend age-based or risk-based testing:

• The Bone Health and Osteoporosis Foundation (BHOF) recommends BMD testing in all men aged 70 years or older and in men aged 50–69 years with risk factors; the International Society for Clinical Densitometry (ISCD) recommends testing in all men aged 70 years or older and in younger men with risk factors for low bone mass. The American College of Radiology practice parameter likewise lists men aged 70 years or older as a screening indication.
• The Endocrine Society (2012) recommends testing in men aged 70 years or older and in men aged 50–69 years with significant risk factors or a fracture after age 50.
• Commonly cited risk factors in younger men include prior adult fracture, low body weight, hypogonadism, prolonged glucocorticoid exposure, and androgen-deprivation therapy.
• The Canadian Task Force on Preventive Health Care takes a more conservative approach to routine screening in community-dwelling adults; its recommendations and applicability are summarized below.

A 2025 cluster randomized trial evaluated a centralized, nurse-led remote bone-health service in 3,112 male veterans aged 65–85 years with at least one fracture risk factor and no prior fracture or osteoporosis medication; when more than 100 men per team were eligible, the 100 with the lowest Osteoporosis Self-Assessment Tool scores were enrolled, restricting the sample to the highest-risk tertile (32.5% of eligible men). Overall, 41% were Black. DXA completion increased to approximately 50% with the intervention versus 2% with usual care. Among men meeting treatment criteria, 84% initiated treatment. The trial was not powered to determine whether the intervention reduced fractures.

Patients with a previous fragility fracture

A previous fragility fracture changes the clinical scenario from screening to diagnostic evaluation and secondary fracture prevention. Hip or vertebral fragility fractures may establish a clinical diagnosis of osteoporosis regardless of BMD. Other fracture sites, including the forearm, humerus, and pelvis, may also support the diagnosis depending on the clinical context and applicable guideline. See Osteoporosis secondary prevention.

Screening tests and pre-screening risk assessment

Central DXA

Central DXA of the hip and lumbar spine is the reference-standard method for measuring BMD in osteoporosis screening. It was used to select participants in most osteoporosis pharmacotherapy trials.

Peripheral quantitative ultrasound, peripheral DXA, and quantitative CT may provide information about fracture risk or bone density in selected settings but should not replace central DXA for establishing the standard densitometric diagnosis of osteoporosis. See Osteoporosis CT, Osteoporosis ultrasound, and Osteoporosis other diagnostic studies.

Risk assessment in postmenopausal women younger than 65 years

The USPSTF recommends a two-step approach:

1. Identify clinical risk factors, such as low body weight, smoking, parental hip fracture, excessive alcohol consumption, or a condition associated with secondary osteoporosis.
2. In women with one or more risk factors, apply a validated clinical risk-assessment tool that does not require BMD to help determine whether DXA is warranted.

The Osteoporosis Self-Assessment Tool (OST) and Osteoporosis Risk Assessment Instrument (ORAI) are options for pre-screening risk assessment.

Tool	Inputs	Threshold supporting further assessment	Important limitation
Osteoporosis Self-Assessment Tool (OST)	Age and weight: 0.2 × (weight in kg − age in years), truncated to an integer	Score <2	Identifies women more likely to have osteoporosis; does not establish the diagnosis
Osteoporosis Risk Assessment Instrument (ORAI)	Age, weight, and current estrogen use	Score ≥9	Identifies women more likely to have low BMD; does not establish the diagnosis
FRAX without BMD	Clinical fracture-risk factors	No specific USPSTF 2025 threshold for ordering DXA in women younger than 65 years	Does not reliably identify osteoporosis in this population when used as a screening gatekeeper

OST is a simple pre-screening tool. In women aged 50–64 years, OST with a threshold below 2 is preferred among the formal tools because it performs as well as or better than FRAX, ORAI, OSIRIS, and SCORE for identifying women with a T-score of −2.5 or lower.

Among 62,492 women aged 50–64 years in the Women's Health Initiative, an OST score below 2 had a sensitivity of 79%, specificity of 70%, and area under the receiver operating characteristic curve (AUC) of 0.75 for femoral-neck osteoporosis.

The USPSTF 2025 recommendation does not define a FRAX threshold for screening. For context only, it notes that a 65-year-old White woman with a body mass index of 25 and no risk factors has an estimated 10-year FRAX risk without BMD of 1.3% for hip fracture and 9.3% for major osteoporotic fracture. These figures are not intended as mechanistic thresholds for ordering DXA, and fixed FRAX cutoffs from the 2018 recommendation should not be applied as current USPSTF screening criteria.

At the previously recommended FRAX major osteoporotic fracture thresholds of 9.3% (2011) and 8.4% (2018), FRAX without BMD had a sensitivity of 5% to 49%, specificity of 63% to 96%, and AUC of 0.55 to 0.62 for identifying osteoporosis in younger postmenopausal women.

Guideline recommendations

Recommendations differ across countries because of differences in evidence interpretation, screening strategies, and health-system priorities.

Organization	Women aged 65 years or older	Younger women	Men
USPSTF (2025)	Screen; Grade B	Screen postmenopausal women younger than 65 years who are at increased fracture risk by clinical assessment; Grade B	Insufficient evidence to assess benefits and harms; I statement
ACOG (2021)	BMD screening recommended (strong recommendation, high-quality evidence)	BMD screening in postmenopausal women younger than 65 years at increased risk as determined by a formal clinical risk assessment tool (strong recommendation, high-quality evidence); ACOG adopted the USPSTF 2018 threshold of FRAX MOF >8.4%, which the USPSTF 2025 statement no longer specifies	Not addressed
AACE/ACE (2020)	BMD testing recommended	Evaluate all women aged 50 years or older for osteoporosis risk; test postmenopausal women with a fracture without major trauma, radiographic osteopenia, or systemic glucocorticoid therapy for ≥3 months; consider testing other perimenopausal or postmenopausal women with risk factors if willing to consider pharmacologic intervention	Guidance principally addresses postmenopausal osteoporosis
BHOF	BMD testing recommended	Test postmenopausal women aged 50–64 years with risk factors and adults with a fracture after age 50	Test all men aged 70 years or older and men aged 50–69 years with risk factors
ISCD	BMD testing recommended	Test women with risk factors, including selected women in the menopausal transition	Test men aged 70 years or older and younger men with risk factors
ACR–SPR–SSR (2024)	DXA screening in all women aged 65 years or older	Postmenopausal women younger than 65 years with risk factors (prior low-trauma wrist, hip, spine, or proximal humerus fracture; family history of osteoporotic fracture; body mass <57.6 kg [127 lb]; current smoking; excessive alcohol use; height loss or thoracic kyphosis); also medication-related, endocrine, and other secondary-cause indications; routine BMD not recommended for proton pump inhibitor use alone	DXA screening in all men aged 70 years or older; men younger than 70 years with the same risk factors or secondary-cause indications
Canadian Task Force on Preventive Health Care (2023)	Risk assessment first using Canadian FRAX without BMD and shared decision-making; femoral-neck DXA if pharmacotherapy is being considered (conditional recommendation, low-certainty evidence)	Recommends against screening women aged 40–64 years (strong recommendation, very-low-certainty evidence)	Recommends against screening men aged 40 years or older (strong recommendation, very-low-certainty evidence)
Osteoporosis Canada (2023)	Fracture-risk assessment	Targeted screening according to fracture risk in postmenopausal women aged 65 years or younger; supporting evidence is limited	Targeted screening according to fracture risk in men aged 50 years or older; supporting evidence is limited
NOGG (2024 guideline, published 2025)	Case finding, not population screening: FRAX without BMD in postmenopausal women with a clinical risk factor; add BMD when FRAX-estimated risk is intermediate	Same case-finding approach (no age-based screening)	FRAX without BMD in men aged 50 years or older with a clinical risk factor; add BMD when FRAX-estimated risk is intermediate
NICE (UK, CG146; 2012, updated 2017)	Fracture-risk assessment in all women aged 65 years or older	Fracture-risk assessment in women younger than 65 years with risk factors	Fracture-risk assessment in all men aged 75 years or older and in younger men with risk factors

The Canadian Task Force recommendations apply to community-dwelling adults not receiving preventive pharmacotherapy and should not be generalized to patients with established osteoporosis, prior fragility fractures, or other indications for diagnostic testing.

Rescreening intervals

The optimal interval for repeat DXA is uncertain; no randomized trials have informed the value or timing of repeat BMD testing. Because of measurement error, rates of bone loss are difficult to estimate accurately over intervals shorter than about 5 years, and large apparent short-term decreases are often followed by smaller changes (regression to the mean). Intervals should therefore be based primarily on baseline BMD and age, with adjustment for changes in clinical risk factors.

In 4,957 women aged 67 years or older without osteoporosis at baseline, followed for up to 15 years in the Study of Osteoporotic Fractures, the covariate-adjusted time for 10% to transition to osteoporosis (before a hip or clinical vertebral fracture and before osteoporosis treatment) varied by baseline hip T-score:

Baseline T-score category	Adjusted time for 10% to develop osteoporosis
Normal (≥ −1.00)	16.8 years
Mild osteopenia (−1.01 to −1.49)	17.3 years
Moderate osteopenia (−1.50 to −1.99)	4.7 years
Advanced osteopenia (−2.00 to −2.49)	1.1 years

The 16.8-year estimate for normal BMD was conservatively calculated at the lowest BMD in the normal range. Within a T-score category, transition was faster with older age; in moderate osteopenia, the estimated interval was approximately 5 years at age 70 versus approximately 3 years at age 85. In postmenopausal women aged 50–64 years with baseline T-scores above −1.50, transition is slow enough that deferring the next DXA to age 65 may be considered. These estimates apply to untreated women without prior fracture or secondary causes of osteoporosis and are not mandatory intervals.

Guideline considerations

• USPSTF (2025): No specific rescreening interval is recommended. Cohort studies suggest that repeating BMD testing at an interval of 4 to 8 years does not add accuracy in predicting fractures; transition to osteoporosis occurs over shorter intervals with lower baseline T-scores and older age.
• ACOG (2021): Repeat screening may be considered when the initial BMD is near a treatment threshold or risk factors change significantly. For most patients, repeat BMD testing should occur no sooner than 2 years after initial screening (conditional recommendation, low-quality evidence). The North American Menopause Society considers repeat testing before 2–5 years unnecessary in untreated individuals.
• American College of Radiology: A 2-year monitoring interval is recommended for patients with fracture risk factors or low BMD; 1-year follow-up is recommended for patients at risk of substantial short-term bone loss, such as those receiving glucocorticoid therapy, as summarized in ACOG guidance.

In the Women's Health Initiative Bone Density Substudy, repeating DXA approximately 3 years after baseline did not improve discrimination of hip or major osteoporotic fracture beyond baseline BMD, and the authors concluded that routine 3-year repeat testing should not be performed. Similar findings were reported with approximately 4-year repeat testing in the Framingham Osteoporosis Study and with repeat testing a mean of 8 years after baseline in 4,124 women aged 65 years or older in the Study of Osteoporotic Fractures.

Patients with major causes of accelerated bone loss fall outside average-risk screening schedules. The 2022 American College of Rheumatology guideline strongly recommends that all adults initiating or continuing glucocorticoids at ≥2.5 mg/day for more than 3 months undergo initial fracture risk assessment as soon as possible within 6 months of initiation, including fracture history, BMD with vertebral fracture assessment or spine radiography, and FRAX in those aged 40 years or older (strong recommendation based on good clinical practice, low-certainty evidence). In adults younger than 40 years, BMD is recommended when one or more additional osteoporosis risk factors are present. DXA is also indicated in adults beginning or receiving long-term therapy with medications that adversely affect BMD (e.g., androgen-deprivation therapy, aromatase inhibitors, anticonvulsants, or chronic heparin), in hypogonadal men after surgical or chemotherapeutic castration, and in endocrine disorders such as hyperparathyroidism, hyperthyroidism, or Cushing syndrome. Routine BMD testing is not recommended for proton pump inhibitor use alone in the absence of other risk factors. See Osteoporosis causes and Osteoporosis other diagnostic studies.

Clinical recommendations

1. Offer central DXA to women aged 65 years or older who have no established osteoporosis or prior fragility fracture (USPSTF Grade B; ACOG strong recommendation).
2. In postmenopausal women younger than 65 years, assess clinical risk factors first and, in those with one or more risk factors, use a validated pre-screening tool. Commonly used thresholds include OST <2 and ORAI ≥9. FRAX without BMD has no defined USPSTF screening threshold.
3. Do not use the USPSTF 2025 FRAX context example of 9.3% major osteoporotic fracture risk, or the 2018 threshold of 8.4%, as a screening cutoff.
4. In men, the USPSTF finds the evidence insufficient (I statement); individualize decisions. Specialty societies support DXA in men aged 70 years or older and in men aged 50–69 years with significant risk factors.
5. In adults starting or continuing glucocorticoids at ≥2.5 mg/day for more than 3 months, perform initial clinical fracture risk assessment as soon as possible and within 6 months of initiation; in adults aged 40 years or older, include BMD with vertebral fracture assessment or spine radiography and FRAX, and in adults younger than 40 years, obtain BMD when one or more additional osteoporosis risk factors are present.
6. Adults with a prior fragility fracture require diagnostic evaluation and consideration of secondary fracture prevention rather than routine screening alone.
7. Individualize repeat DXA according to baseline BMD, age, and changes in clinical risk. Avoid routine short-interval testing in stable, low-risk patients.
8. Ensure that screening results lead to appropriate clinical assessment and intervention when indicated.

Evidence limitations and areas of disagreement

• Screening in men: The USPSTF considers evidence insufficient, whereas several specialty organizations recommend age-based or risk-based testing. Direct randomized evidence for fracture reduction remains limited.
• Women aged 50–64 years: The USPSTF and ACOG support risk-based screening in postmenopausal women, whereas the Canadian Task Force recommends against routine screening in women aged 40–64 years who are not receiving preventive pharmacotherapy.
• DXA-first versus risk-assessment-first strategies: The USPSTF recommends central DXA with or without fracture-risk assessment. The Canadian Task Force and NOGG use risk-assessment-first approaches. No trial has directly established the superiority of DXA-alone screening over risk-first screening.
• Rescreening intervals: Observational estimates and guideline recommendations vary. Evidence does not establish one interval that is appropriate for all patients.
• Race and ethnicity: Screening trials have limited representation or reporting across racial and ethnic groups, limiting certainty about generalizability.
• Magnitude of benefit: Screening reduced hip and major osteoporotic fractures in older women, but the absolute benefit was modest. A mortality benefit has not been established.
• Harms: Data on screening-related harms come from a single trial (SCOOP), which found no increase in anxiety; estimated overdiagnosis ranged from 11.8% to 24.1% in a systematic review of SCOOP and SOS data. Evidence on rare and long-term treatment harms is insufficient.

Natural History, Complications and Prognosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [23] Associate Editor(s)-in-Chief: Ibrahim Elkhayat, M.B.B.Ch.[24]

Overview

Osteoporosis is clinically silent until a fragility fracture occurs. A first fracture marks a period of imminent risk, greatest in the first 1–2 years, during which approximately 10% of women aged 65 years or older with a clinical fracture sustain another fracture within 1 year and 18% within 2 years (US Medicare data). Hip and clinically recognized vertebral fractures carry the greatest excess mortality and loss of independence. Much of the excess mortality reflects underlying frailty and comorbidity, and randomized evidence that osteoporosis treatment lowers mortality is inconsistent.

Natural history

Osteoporosis is generally asymptomatic until a fragility fracture occurs. Its clinical course reflects progressive skeletal deterioration, followed in some patients by a cascade of fractures, functional decline, loss of independence, and excess mortality. A prior fragility fracture is a strong predictor of subsequent fracture, particularly during the first 1–2 years after the index event.

Progression before the first fracture

In women, bone loss accelerates across the menopause transition. In the multiethnic SWAN cohort, BMD loss began about 1 year before the final menstrual period and was greatest from 1 year before through 2 years after it; of a cumulative 10-year lumbar spine loss of 10.6%, 7.38% occurred during this transmenopausal window (femoral neck: 9.1% and 5.8%). Higher body mass index was associated with slower loss. In glucocorticoid-treated patients, bone loss is most rapid in the first 3–6 months and vertebral fracture risk rises within 3 months, peaking at about 12 months; risk declines after discontinuation (see Osteoporosis causes).

The rate at which an individual progresses from low bone mineral density (BMD) to densitometric osteoporosis depends substantially on baseline BMD and age. In the Study of Osteoporotic Fractures, 4,957 untreated women aged 67 years or older without osteoporosis at baseline were followed to estimate the time for 10% of each baseline BMD group to reach densitometric osteoporosis.

Baseline T-score category (femoral neck and total hip)	Estimated time for 10% to develop osteoporosis
Normal (≥ −1.00)	16.8 years
Mild osteopenia (−1.01 to −1.49)	17.3 years
Moderate osteopenia (−1.50 to −1.99)	4.7 years
Advanced osteopenia (−2.00 to −2.49)	1.1 years

Transition was defined as reaching densitometric osteoporosis (T-score ≤ −2.5 at the femoral neck or total hip) before a hip or clinical vertebral fracture and before osteoporosis treatment. More than 99% of participants were White.

Among women with moderate osteopenia, the estimated interval was approximately 5 years at age 70 and 3 years at age 85. Current estrogen use was associated with a longer interval. In the same cohort, 2.4% experienced a hip or clinical vertebral fracture before reaching densitometric osteoporosis.

Each standard-deviation decrease in T-score below 0 is associated with an approximately twofold to threefold increase in fracture risk; AACE/ACE cites a 1.6- to 2.6-fold increase per SD decrease in age-adjusted BMD. A 50-year-old White woman has an estimated 50% lifetime risk of any osteoporotic fracture and a 15%–20% lifetime risk of hip fracture. In men, lifetime risk of an osteoporotic fracture from age 50 years is approximately 1 in 5. Men account for 29% of osteoporotic fractures in the United States but have higher fracture-related morbidity and mortality; about 1 in 3 men with a hip fracture die within a year. Across cohorts, the proportion of fragility fractures occurring above the densitometric osteoporosis threshold ranges from approximately half (Dubbo Osteoporosis Epidemiology Study) to about 70%–80%; one prospective cohort found that more than 70% of women with fractures had osteopenia or normal BMD.

Fracture cascade and imminent fracture risk

A first fragility fracture is a sentinel event that identifies a patient at substantially increased risk of subsequent fractures. The relative risk is greatest in the first months after the index fracture, remains elevated for approximately 2 years, and subsequently declines but remains above baseline. This early period is termed imminent fracture risk.

Risk of subsequent fracture

Population or study	Principal findings
Medicare women aged ≥65 years with a clinical fracture (n = 377,561)	Cumulative subsequent fracture risk (counted from 30 days after the index fracture, with death as a competing risk) was 10% at 1 year, 18% at 2 years, and 31% at 5 years. Short-term risk was highest after vertebral and pelvic fractures and lowest after ankle fractures, although ankle fractures still carried a 1-year risk just below 5% and a 2-year risk of almost 10%.
Worldwide meta-analysis of 19 observational studies in adults aged ≥50 years	Pooled imminent fracture incidence was 7.58% at 1 year and 11.58% at 2 years. In studies with more than 5 years of follow-up, a pooled 47% (95% CI 26%–68%) of refractures occurred within the first 2 years.
Swedish registry of women aged ≥50 years (n = 231,769)	Five-year cumulative incidence of subsequent major osteoporotic fracture was 20.7% after one fracture versus 12.3% in controls, and 32.0% after two fractures versus 15.3% in controls.
US commercial/Medicare Advantage women aged ≥50 years, 2012–2021 (n = 467,721)	24-month cumulative risk of subsequent fracture (occurring ≥90 days after the index fracture) was 19.4% overall, 27.8% after a spine fracture, and 24.2% after a pelvic fracture.
Patients after hip fracture	A JAMA review reported that approximately 25.5% of adults with hip fracture experience another fracture within the subsequent year; this broader subsequent-fracture estimate is not directly comparable with Medicare estimates for all index fracture sites. The pooled incidence of a second hip fracture is 10.63% (higher in women). In a Danish national cohort from 1977–2001, cumulative incidence of a second hip fracture was 9% at 1 year and 20% at 5 years, with relative risk not normalizing until about 15 years. These estimates are higher than those in a contemporary Valencia cohort (2008–2015), where recurrent hip fracture incidence was 2.5% in women and 2.3% in men at 1 year (8.3% and 6.6% at 5 years). Differences in study periods, populations, and outcome definitions limit direct comparison.

Independent predictors of imminent fracture include a recent fracture, age over 80 years, densitometric osteoporosis or low total hip BMD, a central index fracture, comorbidities, and a history of falls. In the FRISBEE prospective cohort, a recent fracture was associated with an odds ratio of 3.7 for imminent fracture. Older age increases absolute risk, whereas younger age at the index fracture, a vertebral index fracture, and two or more prior fractures are associated with the greatest relative risk. Relative risk after a sentinel fracture declines with age and is higher after hip and vertebral fractures than after humeral, forearm, or minor fractures. Sex differences are inconsistent: relative risk was higher in men in the Reykjavik cohort, whereas a 64-cohort international meta-analysis (HR 1.88 for any clinical fracture) found no significant difference between men and women; low BMD explained only a minority (14%) of the risk conferred by prior fracture.

Complications and prognosis by fracture site

Vertebral fractures

Vertebral compression fractures are common osteoporotic fractures and may remain clinically silent. They can present with acute back pain, progressive height loss, or thoracic kyphosis. Vertebral fractures account for an estimated 700,000 of the 1.5 million osteoporotic fractures occurring annually in the United States; only one-fourth to one-third of incident radiographic vertebral fractures are clinically diagnosed.

Complications include:

• Chronic back pain and persistent functional limitation.
• Progressive height loss and thoracic kyphosis.
• Rib–pelvis approximation and abdominal distension from pressure on the viscera.
• Delayed healing, vertebral deformity, and subsequent fractures.
• Impaired balance and gait, falls, and possible restrictive pulmonary impairment with severe kyphosis (supporting evidence is limited).
• Loss of independence and increased need for residential care.

One study cited in a 2025 review reported that only 39% of patients were living in their original home 2 years after a vertebral fracture.

Mortality after vertebral fracture is influenced by fracture severity, the number of vertebral fractures, age, sex, and underlying comorbidity. In a Korean nationwide cohort of 291,203 patients, a first osteoporotic vertebral compression fracture was associated with an adjusted HR for death of 1.22 versus matched controls; earlier US Medicare data, as cited by Son et al., reported approximately twofold mortality, higher in men. In a Korean national registry, 1-year mortality was 14.6% in men versus 7.16% in women, with the standardized mortality ratio highest in the first 3 months. In a Spanish cohort of hospitalized adults older than 65 years, 5-year survival after vertebral compression fracture was approximately 59%.

Clinical recognition matters: in a Manitoba population cohort of patients undergoing densitometric vertebral fracture assessment, clinically recognized vertebral fractures were associated with increased mortality (adjusted HR 1.70) persisting for up to 10 years, whereas previously unrecognized fractures detected on vertebral fracture assessment were not significantly associated with mortality after adjustment for comorbidity (HR 1.18; 95% CI 0.95–1.45). Much of the excess mortality after vertebral fracture is attributed to underlying frailty.

The association between vertebral fracture and mortality is not uniform across studies. In the population-based Tromsø Study, the presence of any vertebral fracture detected by DXA was not significantly associated with mortality after full adjustment. However, three or more vertebral fractures were associated with a hazard ratio (HR) of 2.43, and at least one severe vertebral fracture with an HR of 1.65.

Vertebral fractures are important sentinel events, including when found incidentally on imaging. In a Manitoba cohort of 9,972 patients undergoing densitometric vertebral fracture assessment, a definite prevalent vertebral fracture was associated with incident hip (HR 1.95), nonvertebral (HR 1.99), and clinical vertebral fracture (HR 2.68) after adjustment for BMD and FRAX risk factors. Risk increases with the number and grade of vertebral fractures. Hip fractures accounted for 73.3% of extremity fractures after an index vertebral fracture, with most subsequent fractures occurring within 1–3 years.

Hyperkyphosis is not synonymous with vertebral fracture: in older men, only about one-third of those with the most severe kyphosis had underlying vertebral fractures, and degenerative disc disease contributed to progression. In a Framingham convenience sample (193 women, 82 men), greater kyphosis severity predicted steeper FEV1 decline over 16 years in women but not in men. A systematic review found that the broader evidence linking osteoporotic kyphosis to reduced vital capacity rests on a few small case-control studies. In older men in MrOS, greater kyphosis was associated with higher mortality independent of prior vertebral fractures, incident clinical fractures, and physical function.

Hip fractures

Hip fractures are associated with substantial early mortality, prolonged disability, and loss of independence. The reported outcomes vary by age, comorbidity, health system, and study population.

Outcome	Reported estimate
30-day mortality	6.7% (UK National Hip Fracture Database, 2016)
Median 1-year mortality across worldwide studies from 2005–2018	22%
1-year mortality in US data from 2008–2017	26.9% in men; 18.5% in women
Long-term nursing facility care	Approximately 20.1%
Regained prefracture basic activities of daily living by 6 months (3 US/Canadian cohorts)	42%–71%
Recovery of prefracture mobility among survivors	40%–60%; fewer than half regain instrumental activities of daily living
Among patients independent in activities of daily living before fracture (US Health and Retirement Study)	36% returned to ADL independence, 27% survived with ADL dependence, and 37% died
Institutionalization after hip fracture	10%–20% in Western nations; 10%–60% of survivors unable to return to their previous residence (estimates vary by setting)

In an Australian registry of 4,912 patients aged 65 years or older with an isolated hip fracture, 28% had died, 46% had moderate-to-severe disability, and only 26% were living independently at 12 months. Outcomes vary internationally: among high-income settings, 1-year mortality after hip fracture ranges from 10.8% in Singapore to 23.8% in New Zealand, and fewer than one in three older adults return to their premorbid level of function.

The most common causes of death after hip fracture include pneumonia, sepsis, myocardial infarction, pulmonary embolism, and cancer. Mortality is highest during the immediate post-fracture period. In UK Biobank, adjusted mortality HRs versus matched controls were 23.67 during days 0–30 (95% CI 12.17–46.01) and 15.24 during days 31–90; excess mortality remained detectable at 10 years (HR 2.15; 95% CI 1.15–4.00). Controls were matched on age, sex, and frailty status; the any-fracture cohort had a mean age of 58.3 years. The cohort has healthy-volunteer selection bias and is predominantly White British. In the CHANCES consortium, the HR was 2.78 in the first year and 1.79 at 8 or more years. In a meta-analysis of prospective cohorts, the relative hazard for all-cause mortality in the first 3 months after hip fracture was 5.75 (95% CI 4.94–6.67) in women and 7.95 (95% CI 6.13–10.30) in men; relative hazards declined but did not return to those of age- and sex-matched controls, and excess annual mortality at any given age was higher in men. The duration of excess mortality varies by age and sex: in a Swedish 22-year cohort, excess mortality persisted up to 10 years in women younger than 80, for 5 years in women older than 80, and throughout follow-up in men younger than 80, with cardiovascular disease and pneumonia the predominant causes of death. Fewer than half of deaths after hip fracture are considered attributable to the fracture itself. In the Study of Osteoporotic Fractures, only 14% of deaths after hip or pelvic fracture were judged to have been caused or hastened by the fracture, highlighting the contribution of underlying frailty and comorbidity.

Perioperative complications are common. In a meta-analysis of 95 studies, 30-day prevalence was 7.01% for urinary tract infection, 4.08% for lower respiratory tract infection, 2.15% for venous thromboembolism, and 1.98% for myocardial infarction. In a prospective cohort aged over 70 years, 16% developed delirium, with 30-day mortality of 16% versus 6% without delirium. Among US long-term nursing-home residents, 36% had died by 180 days, and only about 1 in 5 of those with baseline locomotor independence both survived and regained that level of locomotor independence.

Outcomes are particularly poor in older adults with frailty, substantial comorbidity, malnutrition, delayed surgery, or failure to regain mobility. In a single-center Japanese cohort (n = 355; mean age 84 years), delayed surgery, higher Charlson Comorbidity Index, and low Geriatric Nutritional Risk Index independently predicted mortality; failure to regain ambulation by 3 months predicted new nursing-home admission. In the Victorian registry, 12-month mortality was higher without surgery than with internal fixation (aHR 1.65), with injury in a residential institution (aHR 2.63), with ICU admission (aHR 1.68), and in the most socioeconomically disadvantaged areas (aHR 1.25); treatment selection and underlying illness may confound the nonoperative association. Approximately 6.6% of patients become newly eligible for Medicaid or a Medicare Part D low-income subsidy after hip fracture.

Other fragility fractures

Fractures involving the pelvis, proximal humerus, and forearm are important markers of skeletal fragility and future fracture risk. Fragility fractures at these sites can establish a clinical diagnosis of osteoporosis even when the T-score is above −2.5; site-specific criteria are addressed in Osteoporosis other diagnostic studies.

Pelvic fractures are associated with particularly high imminent refracture risk. In the Manitoba Bone Density Program, 10-year recurrent fracture rates after a primary wrist fracture were lower than after hip, spine, or humerus fractures but higher than in women without a prior fracture.

Nonhip, nonvertebral fractures account for a substantial proportion of fragility fractures and are associated with excess mortality. In the Dubbo cohort, they were associated with approximately 20% excess mortality over 5 years, with about half attributable to subsequent fractures. In the population-based Tromsø Study of adults aged 50 years and older, proximal nonhip, nonvertebral fractures (including pelvis, humerus, rib, and proximal tibia) were associated with increased mortality (HR 1.49 in women and 1.81 in men), whereas distal fractures were not; a subsequent fracture independently increased mortality (HR 1.89 in women and 1.77 in men). In a separate Dubbo analysis, age-adjusted standardized mortality ratios were 2.43 (women) and 3.51 (men) after hip fracture, 1.82 and 2.12 after vertebral fracture, and 1.42 and 1.33 after minor fractures (increased only above age 75 years); excess mortality persisted for 5 years for all fractures and up to 10 years for hip fracture, and subsequent fracture increased mortality (HR 1.91 in women and 2.99 in men). In the Dubbo cohort, subsequent-fracture risk was at least twofold across normal, osteopenic, and osteoporotic BMD categories. Findings from additional cohorts also link fractures at many sites with adverse outcomes.

Prognostic modifiers

Patient-related factors

The prognosis after a fragility fracture is influenced by:

• Age and frailty: Increasing age and frailty are associated with poorer functional recovery and greater mortality.
• Sex: Men have higher reported mortality after hip fracture than women in multiple cohorts. In UK Biobank, mortality after hip fracture was 22.03 versus 15.83 deaths per 1,000 person-years in men and women, respectively. After a second hip fracture, 1-year mortality was 27% in men versus 9% in the male background population, and 21% in women versus 10% in the female background population. The Victorian registry reported lower mortality among women than men (aHR 0.56). Higher mortality after vertebral fracture has also been reported in men.
• Cognitive impairment: Among older adults independent in ADLs before hip fracture, only 8% with dementia returned to ADL independence, versus 39% without dementia; recovery was also lower at age ≥85 years (26% vs 44%) and with Charlson comorbidity score >2 (23% vs 44%).
• Comorbidity: Greater comorbidity burden is associated with poorer recovery and higher mortality after hip fracture.
• Nutrition and mobility: Malnutrition, delayed surgery, and failure to regain ambulation are associated with mortality and new institutionalization (see Hip fractures above).
• Socioeconomic disadvantage: In an Australian registry, residence in the most disadvantaged areas was associated with higher 12-month mortality after hip fracture (aHR 1.25).
• Race and ethnicity: US data are inconsistent. Among long-term nursing-home residents with hip fracture, White race was associated with lower survival, whereas Black residents had a slightly higher risk of death or new total locomotion dependence.

Treatment and the post-fracture treatment gap

Appropriate osteoporosis treatment after a fragility fracture reduces subsequent fracture risk. Evidence that treatment independently reduces mortality is less consistent.

In the HORIZON Recurrent Fracture Trial, annual zoledronic acid initiated within 90 days after hip-fracture repair reduced new clinical fractures by 35% (HR 0.65) and all-cause mortality by 28% (HR 0.72) over a median follow-up of 1.9 years. In a post hoc analysis, fracture prevention explained only about 8% of the observed mortality reduction, and the Endocrine Society notes that a mortality reduction has not been shown in other zoledronic acid trials. Meta-analyses of randomized placebo-controlled trials have reached differing conclusions. In 38 trials, osteoporosis drugs as a group (RR 0.98; 95% CI 0.91–1.05) and bisphosphonates (RR 0.95; 95% CI 0.86–1.04) did not reduce overall mortality, and zoledronate results were heterogeneous (RR 0.88; 95% CI 0.68–1.13; I² 48.2%). A 2025 meta-analysis of 47 bisphosphonate trials likewise found no reduction (RR 0.95; 95% CI 0.88–1.03). By contrast, an earlier meta-analysis restricted to 8 trials of agents with proven vertebral and nonvertebral fracture efficacy found an 11% mortality reduction (RR 0.89; 95% CI 0.80–0.99), greatest in populations with higher mortality.

Observational studies have also associated post-fracture treatment with lower mortality; in a Taiwanese nationwide cohort, bisphosphonate use after major fracture was associated with an HR of 0.90 overall and 0.77 for zoledronic acid. These findings should be interpreted cautiously. The 25%–60% mortality reductions reported in observational studies are too large to be explained by fracture prevention alone; the healthy-adherer effect and residual confounding are plausible explanations.

The post-fracture treatment gap remains substantial. Among postmenopausal US women with an incident fracture, only 17.5% initiated osteoporosis treatment by 24 months. Further detail on treatment patterns and fracture liaison services is addressed in Osteoporosis secondary prevention. A recent fragility fracture should therefore trigger prompt assessment of fracture risk, consideration of pharmacotherapy, and measures to reduce falls and recurrent fractures. Drug selection and the organization of secondary-prevention programs are addressed in Osteoporosis medical therapy and Osteoporosis secondary prevention.

Denosumab discontinuation

Stopping denosumab is followed by rebound bone turnover and an increased risk of vertebral fractures, a disproportionate share of which are multiple. In the phase 3 trial, 6% of women who discontinued denosumab and remained in the study developed new vertebral fractures and 3% developed multiple vertebral fractures, with mean onset of multiple vertebral fractures at 17 months (range 7–43) after the last injection; prior vertebral fracture predicted multiple fractures. The overall vertebral fracture rate after discontinuation (7.1 per 100 participant-years) was similar to that after placebo discontinuation (8.5). Risk is higher after more than 3 years of treatment. Management is addressed in Osteoporosis medical therapy.

Clinically actionable recommendations

1. Treat a recent fragility fracture as a high-risk event requiring prompt fracture-risk assessment and secondary prevention. Hip and vertebral fractures in particular warrant urgent attention; pelvic, proximal humeral, and forearm fractures also identify clinically important skeletal fragility.
2. Prioritize rapid fracture-risk reduction after a recent hip, vertebral, or pelvic fracture, because the risk of a subsequent fracture is greatest during the first 1–2 years.
3. Ensure that a recent hip or vertebral fracture prompts timely evaluation and coordinated secondary prevention; details of treatment timing and fracture liaison services are addressed in Osteoporosis medical therapy and Osteoporosis secondary prevention. The supporting multistakeholder consensus was not GRADE-rated.
4. Recurrent fractures or continued bone loss should prompt reassessment for secondary causes and adherence (see Osteoporosis laboratory findings and Osteoporosis differentiating osteoporosis from other diseases).

Areas of uncertainty

• Fracture-related mortality: The degree to which vertebral fractures independently cause excess mortality, rather than marking underlying frailty and comorbidity, remains uncertain. Studies differ according to fracture ascertainment, severity, and adjustment for confounding.
• Duration of excess mortality after hip fracture: UK Biobank and CHANCES showed excess mortality persisting for 8–10 years or more, whereas in the Cardiovascular Health Study excess risk lasted up to 4 years in women and 6 months in men, and in the Study of Osteoporotic Fractures only 1 year in women. Differences in age, comorbidity, study design, and population limit direct comparisons.
• Mortality benefit of osteoporosis treatment: HORIZON-RFT showed a mortality reduction with zoledronic acid after hip-fracture repair; meta-analyses disagree, with the largest recent analyses showing no overall reduction and an earlier analysis of agents with proven fracture efficacy showing an 11% reduction concentrated in higher-mortality populations.
• Site-specific prognosis: Fractures at nonhip, nonvertebral sites are also associated with excess mortality, but the magnitude varies by fracture site, subsequent fracture occurrence, and underlying comorbidity.
• Generalizability of estimates: Many quantitative estimates come from older adults in North America or Europe and may not apply directly to younger populations or other health systems.

High-yield pearls

• A first fragility fracture is a sentinel event; subsequent fracture risk is greatest during the first 1–2 years.
• Hip fractures carry substantial early mortality and long-term risk of disability and loss of independence. Clinically recognized vertebral fractures also predict adverse outcomes.
• A vertebral fracture identified incidentally on imaging is clinically important even if asymptomatic.
• Denosumab should not be stopped without a plan for subsequent antiresorptive treatment.

Common pitfalls

• Do not equate absence of a T-score ≤ −2.5 with absence of clinically important fracture risk; most fragility fractures occur in women with BMD above the densitometric osteoporosis threshold.
• Do not assume that all vertebral fractures or all degrees of kyphosis confer the same mortality risk; findings vary with fracture severity, number, ascertainment, and adjustment for comorbidity.
• Do not interpret observational associations between osteoporosis treatment and lower mortality as proof of a causal mortality benefit.
• Do not interpret denosumab discontinuation risk from the overall vertebral-fracture rate alone; multiple vertebral fractures make up a greater proportion of fractures after discontinuation.

Updates vs older teaching

• Fracture risk after an index fracture is concentrated in the first 1–2 years, but risk can remain elevated for years; the Danish cohort found that relative risk of a second hip fracture did not return to baseline until approximately 15 years.
• The evidence for a mortality benefit from osteoporosis medication is mixed: randomized trials and meta-analyses do not consistently demonstrate an overall mortality reduction.
• Denosumab discontinuation is associated with rebound bone turnover, rapid BMD loss, and risk of multiple vertebral fractures; the FDA label states that patients should be transitioned to an alternative antiresorptive.

Diagnosis

History and Symptoms | Physical Examination | Laboratory Findings | Electrocardiogram | Chest X Ray | CT | MRI | Echocardiography or Ultrasound | Other Imaging Findings | Other Diagnostic Studies

Treatment

Life style Modification | Medical Therapy | Surgery | Primary Prevention | Secondary Prevention | Cost-Effectiveness of Therapy | Future or Investigational Therapies

Case Studies

Case #1

Related Chapters

• Bone healing
• Back pain
• bone mineral density
• Dental x-ray
• Osteopetrosis, the opposite of osteoporosis
• Osteoimmunology

External links

• Diet, Nutrition and the prevention of chronic diseases (including osteoporosis) by a Joint WHO/FAO Expert consultation (2003)

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