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.^[1]

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.^[2]

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.^[1][2]

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.^[1][2]

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.^[1][3][4]

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.^[1][2][5]

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

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.^[2][6]
• 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.^[1][3][4]

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.

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.^[1]

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.^[2]

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.^[3][1]

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.

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.^[4]

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.^[4]

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.^[1][5]

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.^[6]

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.^[1]

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.

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.^[7][3][4]

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.^[3][4]

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.

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.

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.^[1]

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.^[3]

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.^[3][1]

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.^[1]

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

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.^[2]

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.^[2]

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.^[4]

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.^[4][5]

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.^[2][6]

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.^[2][6]

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.^[6][7]

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.^[2][8]

• 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.^[9]

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.

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.^[3]

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.^[1][3]

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.^[1]

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.^[4][5]

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.^[4]

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.^[6][7]

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.^[8][9]

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.^[10][11][12]

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.^[13][14]

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.^[15][16]

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.^[15][17]

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.^[18][19][20]

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.^[18][19]

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.^[21]

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.^[2][22]

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.^[7][4]
• 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.^[7][17]
• Increased sclerostin signaling: Increased sclerostin activity inhibits Wnt-mediated osteoblast differentiation and reduces bone formation.^[10][23]
• 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.^[7][24]

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.^[25][26]

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.^[18][27]

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.^[28][29]

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.^[28]

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.^[30][31]

Changes in the mineral–collagen interface and impaired bone material properties can further reduce the capacity of bone to absorb energy before failure.^[32] 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.

• 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.

• 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.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Cafer Zorkun, M.D., Ph.D. [2], Raviteja Guddeti,M.B.B.S.[3], Eiman Ghaffarpasand, M.D. [4]

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.^[1][2]

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.^[1][2]

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.^[1][2]

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.^[1][2]

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.^[3][4][2]

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.^[1][5]

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.^[1][2]

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.^[1][2]

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.^[1][2]

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.^[6][7]

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.^[8][2]

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.

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.^[2][9]

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.^[10]

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).^[11][9]

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.^[12]

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.^[1][2]

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.^{[13][14][15][16]}
• 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.^[17][18][19]
• 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.^[20][21]
• 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.^[22][23]
• 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.^[24][25][26]
• 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.^[27][28][2]

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.

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.^[1][2]

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.

Overview

Osteoporosis must be differentiated from other diseases that cause a decrease in the bone mineral density (BMD), such as idiopathic transient osteoporosis of hip, osteomalacia, scurvy, osteogenesis imperfecta, multiple myeloma, homocystinuria, and hypermetabolic resorptive osteoporosis.

Differentiating Osteoporosis from other Diseases

Osteoporosis must be differentiated from other diseases that cause a decrease in the bone mineral density (BMD), such as idiopathic transient osteoporosis of hip, osteomalacia, scurvy, osteogenesis imperfecta, multiple myeloma, homocystinuria, and hypermetabolic resorptive osteoporosis. The major similarities and differences among the diseases are discussed in the following table:

Diseases	History and Physical Examination					Imaging findings			Laboratory Findings				Other Findings
	Bone pain	Fatigue	Short stature	Scoliosis	Bone tenderness	BMD	Sub-chondral cortical loss	Bone fracture	Vitamin C	Ca	Vitamin D	ALKph
Osteoporosis	+	–	+	–	+	↓↓↓	–	+	↓	–	–	–
Idiopathic transient osteoporosis of hip	+	–	–	–	–	↓↓	+	–	–	–	–	↑	Mostly pregnant women Self-limiting
Osteomalacia	–	–	–	–	–	↓	–	+	–	↓	↓	–
Scurvy	+	+	–	–	–	–	–	+	–	–	–	–	Mucosal bleeding Bleeding gums
Osteogenesis imperfecta	–	–	+	+	–	↓	–	+	–	–	–	–	Tooth defect Hearing problems Blue sclera
Multiple myeloma	+	+	–	–	+	↓	–	+	–	–	–	↑	Bone lytic lesions
Homocystinuria	+	–	–	–	–	↓	–	+	–	–	–	–	Visual impairment Homocysteine in urine

Idiopathic transient osteoporosis of hip

• It was initially thought to be seen in women during the third trimester of pregnancy but it is seen also in middle-aged men.
• Acute hip pain is the main feature of the disease, usually self-limited and resolves after 6-8 months.
• Sometimes it may be explained as early or benign avascular necrosis (AVN).
• Subchondral cortical loss and diffuse osteopenia of the femoral head and neck are the pathognomonic features.
• Treatment includes joint protection, limited weight bearing, and NSAIDs.^[1]

Osteomalacia

• Osteomalacia is the inability to mineralize the newly formed bone matrix, caused by the deficiency of vitamin D in adults.

• It is due to low turn-over of bone in which osteoblasts are deficient.
• Diffuse bone pain, fatigue, and fractures are the most common symptoms.
• It can also progress to osteoporosis.^[2]

Scurvy

• Vitamin C deficiency causes defective collagen synthesis, leading to dysfunction of every collagen containing organ such as bones.
• New bone formation is disturbed and the old bone becomes brittle due to lack and poor quality of collagen.
• Treatment is vitamin C replacement.^[3]

Osteogenesis imperfecta

• Osteogenesis imperfecta is mainly induced by defect in the synthesis of collagen type I along with improper osteoblasts functioning.
• Short stature, scoliosis, tooth defects, hearing defects, blue sclera, and propensity for fractures are the main clinical features of the disease.^[4]

Multiple myeloma

• Multiple myeloma is a malignant proliferation of the plasma cells, mostly in bone marrow.
• It accounts for 40% of all bone tumors.
• Diffuse bone pain and tenderness are common.
• Radiologically, osteolytic lesions could be found in the bones.
• The prognosis is poor.
• Chemotherapy is the mainstay of treatment.^[5]

Homocystinuria

• Homocystinuria is an autosomal recessive disorder that affects the metabolism of the amino acid methionine.
• Clinical features include failure to thrive, visual and musculoskeletal problems.^[6]

References

1. ↑ Balakrishnan A, Schemitsch EH, Pearce D, McKee MD (2003). “Distinguishing transient osteoporosis of the hip from avascular necrosis”. Can J Surg. 46 (3): 187–92. PMC 3211740. PMID 12812240.CS1 maint: Multiple names: authors list (link)
2. ↑ Hiramatsu R, Ubara Y, Sawa N, Hasegawa E, Kawada M, Imafuku A; et al. (2016). “Bone Histology of Two Cases with Osteomalacia Related to Low-dose Adefovir”. Intern Med. 55 (20): 3013–3019. doi:10.2169/internalmedicine.55.6806. PMC 5109571. PMID 27746441.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
3. ↑ Chojkier M, Spanheimer R, Peterkofsky B (1983). “Specifically decreased collagen biosynthesis in scurvy dissociated from an effect on proline hydroxylation and correlated with body weight loss. In vitro studies in guinea pig calvarial bones”. J Clin Invest. 72 (3): 826–35. doi:10.1172/JCI111053. PMC 1129247. PMID 6309911.CS1 maint: Multiple names: authors list (link)
4. ↑ Van Dijk FS, Pals G, Van Rijn RR, Nikkels PG, Cobben JM (2010). “Classification of Osteogenesis Imperfecta revisited”. Eur J Med Genet. 53 (1): 1–5. doi:10.1016/j.ejmg.2009.10.007. PMID 19878741.
5. ↑ “Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group”. Br. J. Haematol. 121 (5): 749–57. 2003. PMID 12780789.
6. ↑ Grieco AJ (1977). “Homocystinuria: pathogenetic mechanisms”. Am. J. Med. Sci. 273 (2): 120–32. PMID 324277.

​ ​

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Eiman Ghaffarpasand, M.D. [2], Cafer Zorkun, M.D., Ph.D. [3], Raviteja Guddeti, M.B.B.S.[4]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Eiman Ghaffarpasand, M.D. [2]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Eiman Ghaffarpasand, M.D. [2]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Eiman Ghaffarpasand, M.D. [2]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Eiman Ghaffarpasand, M.D. [2]

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

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

Case #1

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

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

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