What are the pathophysiology, screening methods, and risk assessment criteria for osteoporosis, including the use of the FRAX (Fracture Risk Assessment Tool), dual‑energy X‑ray absorptiometry (DXA) T‑scores, and evaluation of secondary causes of bone loss?

Osteoporosis: Pathophysiology, Screening, and Risk Assessment

Screen all women ≥65 years and men ≥70 years with DXA of the lumbar spine and hip, and use FRAX to guide treatment decisions in those with osteopenia (T-score -1.0 to -2.5), treating when 10-year hip fracture risk ≥3% or major osteoporotic fracture risk ≥20%. 1, 2, 3

Pathophysiology

Osteoporosis represents a systemic skeletal disorder characterized by:

• Low bone mineral density (BMD) and microarchitectural deterioration
• Imbalance in bone remodeling: Increased bone resorption exceeding formation
• Hormonal influences: Estrogen deficiency in postmenopausal women is critical for skeletal maintenance; men also require adequate estrogen (via aromatization) for bone health, not just testosterone 4
• Progressive trabecular thinning and cortical bone loss, particularly affecting cancellous-rich sites (spine) and cortical-rich sites (hip, radius) differently

Screening Recommendations

Who to Screen

Women:

• All women ≥65 years universally 1, 5
• Postmenopausal women <65 years with risk factors 1, 3

Men:

• All men ≥70 years 1
• Men 50-69 years with risk factors (particularly prior fracture after age 50, glucocorticoid use, hypogonadism, hyperparathyroidism) 4

Younger adults (<50 years):

• Previous fracture or major risk factors (chronic glucocorticoid use ≥5 mg prednisone daily for ≥3 months) 1

Screening Method: DXA Scan

Standard sites to measure:

• Lumbar spine (L1-L4, anteroposterior view)
• Both hips (femoral neck and total hip)
• One-third (33%) radius of nondominant arm when spine/hip cannot be interpreted or in hyperparathyroidism 2, 4, 1

Key technical points:

• Exclude up to 2 vertebral levels if falsely elevated by fracture, facet arthritis, or spondylosis; if >2 levels need exclusion, use second hip or radius 2
• DXA measures areal BMD (g/cm²), not true volumetric density—may underestimate risk in short individuals, overestimate in tall 1

DXA T-Score Interpretation

Diagnostic Thresholds (WHO Criteria)

• Normal: T-score ≥ -1.0
• Osteopenia (low bone mass): T-score -1.0 to -2.5
• Osteoporosis: T-score ≤ -2.5 at lumbar spine, femoral neck, total hip, or one-third radius 2, 3, 1

Critical caveat: Use the lowest T-score from any measured site for diagnosis 1. Once osteoporosis is diagnosed (T-score ≤-2.5), the diagnosis persists even if subsequent DXA shows improvement to >-2.5 3, 6.

Fragility fracture supersedes DXA: Any low-trauma fracture (hip, spine, forearm, humerus, pelvis) establishes osteoporosis diagnosis regardless of T-score 2, 3

Z-Score Use

• Z-scores compare BMD to age-matched controls
• Z-score ≤-2.0 suggests secondary causes of osteoporosis requiring further evaluation 2, 6
• Use Z-scores (not T-scores) in premenopausal women and men <50 years 6

FRAX Tool Application

When to Use FRAX

Apply FRAX in patients with osteopenia (T-score -1.0 to -2.5) to determine treatment need 2, 3

FRAX Input Variables

• Age (40-90 years), sex, weight, height (calculates BMI)
• Femoral neck BMD (optional but improves accuracy)
• Prior fragility fracture
• Parental hip fracture
• Current smoking
• Glucocorticoid use (≥5 mg prednisone daily for ≥3 months)
• Rheumatoid arthritis
• Alcohol ≥3 units daily
• Secondary osteoporosis causes 2, 6

Treatment Thresholds (U.S.)

Treat if:

• 10-year hip fracture probability ≥3%, OR
• 10-year major osteoporotic fracture probability ≥20% 2, 3

Important limitation: FRAX is country-specific and intended for untreated postmenopausal women and men 40-90 years; it has modest discrimination (AUC 0.60-0.80) 2, 5, 7

Secondary Causes of Bone Loss

When to Suspect Secondary Osteoporosis

• Z-score ≤-2.0 2, 6
• Fracture in younger individuals
• Rapid bone loss on serial DXA
• Inadequate response to therapy

Key Secondary Causes to Evaluate

Endocrine:

• Hyperparathyroidism (measure serum calcium, PTH; preferentially affects cortical bone—check radius BMD) 1, 2
• Hyperthyroidism
• Hypogonadism (testosterone in men, estrogen status in premenopausal women)
• Cushing's syndrome
• Type 1 diabetes 6

Medications:

• Chronic glucocorticoids (most common iatrogenic cause)
• Androgen deprivation therapy for prostate cancer 1
• Aromatase inhibitors
• GnRH agonists

Gastrointestinal:

• Malabsorption (celiac disease, inflammatory bowel disease)
• Chronic liver disease 6

Other:

• Chronic kidney disease
• Rheumatoid arthritis
• Multiple myeloma
• Osteogenesis imperfecta in adults 6

Laboratory Evaluation

Initial workup when secondary causes suspected:

• Serum calcium, phosphate, alkaline phosphatase
• 25-hydroxyvitamin D
• Parathyroid hormone (PTH)
• Thyroid-stimulating hormone (TSH)
• Complete blood count, comprehensive metabolic panel
• Testosterone (men), estradiol (premenopausal women if indicated)
• 24-hour urine calcium (if hypercalciuria suspected)
• Serum protein electrophoresis (if multiple myeloma suspected) 3, 6

Vertebral Fracture Assessment (VFA)

Indications for VFA or Spine Radiography

Perform VFA or standard radiography in patients with T-score <-1.0 AND any of:

• Women ≥70 years or men ≥80 years
• Historical height loss >4 cm (>1.5 inches)
• Self-reported undocumented prior vertebral fracture
• Glucocorticoid therapy ≥5 mg prednisone daily for ≥3 months
• Acute back pain with osteoporosis risk factors 1

Rationale: Vertebral fractures are often asymptomatic but dramatically increase future fracture risk and upgrade diagnosis to osteoporosis even with osteopenic T-scores 1

Monitoring and Follow-Up

Repeat DXA intervals:

• Every 1-2 years initially until stable
• Then every 1-5 years depending on clinical circumstances and treatment status 3, 1
• Ideally same facility, same machine for precision 3, 1

Least Significant Change (LSC): Each facility must calculate its precision error to determine meaningful BMD changes (typically 3-5% at spine, 5-6% at hip) 1

Common Pitfalls

1. Relying solely on T-scores without clinical context: A 50-year-old with T-score -2.4 and prior fragility fracture has osteoporosis and needs treatment
2. Not checking radius in hyperparathyroidism: Cortical bone loss may be missed if only spine/hip measured 2
3. Using FRAX in already-treated patients: FRAX is validated only for treatment-naïve individuals 2
4. Ignoring vertebral fractures: Height loss >4 cm mandates vertebral imaging 1
5. Underutilization after fragility fracture: Only 6.7% of fracture patients get DXA within 6 months; 70% remain undertreated 2
6. Not evaluating for secondary causes when Z-score ≤-2.0 2, 6