Osteopenia and Bone Density Screening

• Definitions by T-score (standard deviations from peak bone mass of a young adult reference, measured by DEXA at the hip and lumbar spine):
• Normal: T-score ≥ −1.0
• Osteopenia (low bone mass): T-score between −1.0 and −2.5
• Osteoporosis: T-score ≤ −2.5, or any fragility fracture regardless of density
• Z-scores, comparing against age-matched peers, are used in premenopausal women, men under 50 and children; a Z-score at or below −2.0 prompts a search for secondary causes.
• Screening: the USPSTF recommends bone density screening in women 65 and older, and in younger postmenopausal women whose fracture risk equals that of a 65-year-old. Recommendations for men are less definitive.
• FRAX estimates 10-year fracture probability from clinical risk factors with or without bone density, and is what converts osteopenia into a treatment decision — pharmacotherapy is generally offered when FRAX exceeds accepted thresholds.
• Secondary causes worth excluding: hyperparathyroidism, hyperthyroidism, hypogonadism, corticosteroids, coeliac disease, multiple myeloma, and vitamin D deficiency.
• Everyone gets weight-bearing exercise, adequate calcium and vitamin D, smoking cessation, alcohol moderation and falls-risk assessment.

Non-modifiable

• Age and female sex: bone mass peaks around the third decade, then declines; women lose trabecular bone rapidly in the first years after menopause because estrogen withdrawal removes the brake on osteoclastogenesis.
• Race/ethnicity and body habitus: white and Asian women have lower peak bone mass; low body weight means less mechanical loading and less adipose aromatization of androgens to estrogen.
• Family history of hip fracture in a parent and any prior adult fragility fracture — both are discrete FRAX inputs and the strongest single predictors examiners plant in a stem.
• Early menopause, primary ovarian insufficiency, or oophorectomy — the same estrogen-deficiency mechanism, arriving decades early.

Modifiable/lifestyle

• Smoking, alcohol ≥3 units/day, physical inactivity, low dietary calcium and vitamin D — all separately reduce bone formation or increase resorption; smoking and alcohol are FRAX variables.

Drug-induced (the highest-yield group)

• Glucocorticoids: suppress osteoblasts, promote osteoblast/osteocyte apoptosis, reduce gut calcium absorption and increase renal calcium loss. Risk begins within months of chronic therapy.
• Sex-steroid deprivation: aromatase inhibitors in breast cancer, androgen deprivation (GnRH agonists) in prostate cancer, depot medroxyprogesterone.
• Others: excess thyroid hormone replacement, anticonvulsants that induce vitamin D catabolism (phenytoin, phenobarbital), long-term proton pump inhibitors, SSRIs, thiazolidinediones, heparin, calcineurin inhibitors.

Secondary disease states, by mechanism

• Endocrine: primary hyperparathyroidism (cortical bone loss), hyperthyroidism (accelerated remodeling), Cushing syndrome, hypogonadism, type 1 diabetes.
• Malabsorptive: celiac disease, inflammatory bowel disease, bariatric surgery, cholestatic liver disease — calcium and vitamin D malabsorption.
• Renal: CKD–mineral and bone disorder, idiopathic hypercalciuria.
• Marrow/infiltrative: multiple myeloma, systemic mastocytosis.
• Genetic: osteogenesis imperfecta (type I collagen defect).

• Distractor to note: thiazide diuretics reduce urinary calcium and are associated with preserved bone density — they are not a risk factor.

• Normal remodeling: bone is continuously turned over in basic multicellular units — osteoclasts resorb a packet of bone, osteoblasts refill it. Osteocytes embedded in matrix sense strain and set the local signal. Net bone mass is the arithmetic of these two limbs.
• The RANK/RANKL/OPG axis is the control point: osteoblast-lineage cells express RANKL, which binds RANK on osteoclast precursors to drive their differentiation, fusion and survival. Osteoprotegerin (OPG) is a soluble decoy receptor for RANKL. The RANKL:OPG ratio determines osteoclast number.
• Estrogen deficiency raises the RANKL:OPG ratio and increases IL-1, IL-6 and TNF-α, so remodeling units are activated more often and each resorption pit is deeper and incompletely refilled. This high-turnover loss dominates the early postmenopausal decade.
• Aging and glucocorticoid excess produce low-turnover loss instead: osteoblast recruitment and lifespan fall (glucocorticoids also increase osteocyte apoptosis and suppress Wnt signaling), so cavities are refilled slowly and incompletely. Glucocorticoids additionally lower gut calcium absorption and raise urinary calcium, adding a mild secondary hyperparathyroid drive.
• Trabecular bone goes first: it has far greater surface-area-to-volume ratio than cortical bone, so it is remodeled several times faster. Sites rich in trabeculae — vertebral bodies, femoral neck, distal radius — lose density earliest, which is exactly where fragility fractures occur.
• Architecture, not just mass: once horizontal trabecular struts are perforated they cannot be rebuilt, so connectivity is lost disproportionately to the measured density. This is why two patients with an identical T-score can have very different fracture risk, and why FRAX incorporates clinical variables rather than relying on density alone.
• Why osteopenia is asymptomatic: bone loss is painless and produces no biochemical abnormality — serum calcium, phosphate and alkaline phosphatase remain normal (contrast osteomalacia). Symptoms appear only when reduced strength meets a mechanical load, i.e. at fracture.

• Asymptomatic in the overwhelming majority: osteopenia is detected on screening densitometry or as an incidental radiographic comment, not from symptoms. There is no bone pain, no deformity and no laboratory abnormality attributable to the low bone mass itself.
• The stem's usual patient: a thin postmenopausal woman in her sixties, often white or Asian, low BMI, smoker or with modest daily alcohol, sometimes on chronic prednisone, an aromatase inhibitor, or long-term levothyroxine at a suppressive dose. Male stems typically involve androgen deprivation therapy, hypogonadism, alcohol use or chronic glucocorticoids.
• Fragility fracture is the presenting event when it presents at all — a fracture from a fall from standing height or less, or with no identifiable trauma:
• Vertebral compression fracture: the most common, and often silent. Acute onset midline thoracolumbar pain worsened by standing, relieved by lying flat; anterior wedging on lateral film. Neurologic deficit is unusual and should prompt a search for malignancy or infection.
• Hip (femoral neck/intertrochanteric) fracture: the shortened, externally rotated, abducted leg with inability to bear weight. The morbidity-defining event.
• Distal radius fracture (Colles fracture, dinner-fork deformity) from a fall on an outstretched hand — often the earliest fracture, in a relatively younger postmenopausal woman.
• Proximal humerus fracture completes the FRAX major osteoporotic fracture group — clinical spine, hip, distal forearm, and proximal humerus. Pelvic/pubic ramus fractures are common fragility fractures in the elderly but are not counted in the FRAX major osteoporotic composite.
• Findings from accumulated vertebral fractures, each mechanically explained: progressive height loss, thoracic kyphosis (dowager's hump), reduced rib–pelvis distance, protuberant abdomen with early satiety and reflux from thoracic cage shortening, and restrictive ventilatory impairment.
• Clues to a secondary cause should be sought on exam: proximal weakness and moon facies (Cushing/steroids), goiter or tremor (hyperthyroidism), diarrhea and weight loss (celiac disease), blue sclerae and dentinogenesis imperfecta (osteogenesis imperfecta), bone pain with anemia and renal failure (myeloma).

Step 1 — decide who to scan

• The USPSTF updated osteoporosis screening recommendation (final statement issued 2025, superseding the 2018 version with unchanged substance) gives a B recommendation to screen all women 65 and older with bone measurement testing, and a B recommendation for postmenopausal women younger than 65 at increased risk as identified by a formal clinical risk-assessment tool (FRAX without BMD, OST); for men the USPSTF continues to find the evidence insufficient (I statement). BHOF additionally suggests testing men 70 and older, and any adult over 50 with a fragility fracture or a condition/medication known to cause bone loss.

Step 2 — the test

• Dual-energy X-ray absorptiometry (DXA) of the lumbar spine and proximal femur is the gold standard. Use the lowest T-score among lumbar spine, femoral neck and total hip. The one-third (33%) radius is substituted when the spine/hip are uninterpretable, in hyperparathyroidism, or in very obese patients.
• T-score (vs young-adult peak mass) classifies postmenopausal women and men ≥50: osteopenia −1.0 to −2.5. Z-score (age-matched) is used in premenopausal women, men <50 and children — a Z-score ≤ −2.0 is "below the expected range for age" and mandates a secondary-cause work-up.
• Pitfall: degenerative facet disease, aortic calcification, prior vertebroplasty or compression fracture falsely elevate lumbar spine density; the ISCD advises excluding affected vertebrae and requires at least two evaluable levels.

Step 3 — risk stratification and secondary causes

• FRAX converts osteopenia into a decision by estimating 10-year probability of hip and of major osteoporotic fracture; enter femoral neck BMD when available. Vertebral fracture assessment (VFA) or lateral spine imaging finds occult vertebral fractures, which reclassify the patient as osteoporotic regardless of T-score. Trabecular bone score can refine risk.
• Laboratory screen (normal in primary disease, so abnormalities point elsewhere): CBC, calcium, phosphate, alkaline phosphatase, creatinine, albumin, 25-hydroxyvitamin D, PTH, TSH, and 24-hour urine calcium; add tissue transglutaminase IgA, SPEP/free light chains, and morning testosterone in men as the history directs.

Universal measures — everyone with osteopenia

• Calcium and vitamin D: BHOF advises roughly 1,000–1,200 mg/day of elemental calcium (diet preferred) and 800–1,000 IU/day of vitamin D in adults over 50; correct documented deficiency before any antiresorptive.
• Weight-bearing and resistance exercise, smoking cessation, alcohol moderation, and a structured falls-risk assessment (vision, orthostatics, sedating and anticholinergic medications, home hazards). Most fractures require a fall — reducing falls is as important as raising density.
• Treat the secondary cause if one is found, and taper glucocorticoids to the lowest effective dose.

When to add a drug

• Pharmacotherapy is not automatic in osteopenia. Per BHOF and the Endocrine Society, treat when the T-score is ≤ −2.5, when a hip or vertebral fragility fracture has occurred, or — in the osteopenic range — when FRAX 10-year probability is ≥3% for hip fracture or ≥20% for major osteoporotic fracture.
• The ACR recommends earlier pharmacologic treatment in patients on chronic glucocorticoids at moderate-to-high fracture risk, even with only osteopenia.

First line

• Bisphosphonates (e.g. alendronate weekly, risedronate; IV zoledronic acid annually): pyrophosphate analogues that bind hydroxyapatite and inhibit farnesyl pyrophosphate synthase, triggering osteoclast apoptosis.

Escalation / alternatives

• RANKL monoclonal antibody (denosumab, subcutaneous every 6 months) — cleared by the reticuloendothelial system rather than the kidney, so it needs no renal dose adjustment and is an option in moderate renal impairment. However, the FDA added a boxed warning (2024) for severe, symptomatic and sometimes fatal hypocalcemia in advanced CKD, including CrCl <30 mL/min and dialysis: correct vitamin D deficiency, ensure adequate calcium intake, and check serum calcium before and after each dose in these patients.
• Anabolic agents for very high risk or treatment failure: PTH/PTHrP analogues (teriparatide, abaloparatide) or the anti-sclerostin antibody romosozumab, each followed by an antiresorptive to preserve the gain.
• SERM (raloxifene) in younger postmenopausal women who also want breast-cancer risk reduction; calcitonin is a weak last resort.

Contraindicated/cautioned

• Oral bisphosphonates with esophageal stricture or achalasia, inability to sit upright 30 minutes, or CrCl below about 30–35 mL/min; any antiresorptive in uncorrected hypocalcemia, and denosumab specifically in advanced CKD/dialysis per its boxed warning. Never stop denosumab without transitioning to a bisphosphonate — rebound resorption causes multiple vertebral fractures.

Of the disease

• Fragility fracture is the only true complication of low bone mass — vertebral, hip, distal radius, proximal humerus and pelvis.
• Hip fracture carries the greatest burden: substantial one-year mortality, loss of independence, and the downstream complications of immobility — venous thromboembolism, pneumonia, pressure ulcers, delirium. Suspected hip fracture with a normal radiograph still warrants MRI for an occult fracture; missing it is the classic error.
• Vertebral compression fractures cause chronic pain, progressive kyphosis and height loss, restrictive lung physiology and early satiety. Each fracture roughly multiplies the risk of the next — the fracture cascade.
• Red flags that a "fragility" fracture is not benign: focal neurologic deficit, fever, weight loss, anemia, hypercalcemia or renal failure — think multiple myeloma or metastatic disease, and image accordingly. Cord compression is a neurosurgical emergency.

Of treatment

• Pill esophagitis and ulceration with oral bisphosphonates — retrosternal pain and odynophagia; prevented by taking the tablet with a full glass of water on an empty stomach and remaining upright.
• Acute-phase reaction after IV zoledronic acid — fever, myalgias and flu-like illness in the first 72 hours, from γδ T-cell activation.
• Hypocalcemia, most consequential with denosumab and zoledronic acid in CKD or vitamin D deficiency; perioral paresthesias, Chvostek and Trousseau signs, QT prolongation and tetany — an emergency requiring IV calcium.
• Atypical femoral fracture with prolonged antiresorptive use: transverse subtrochanteric or femoral shaft fracture, often bilateral, heralded by weeks of prodromal thigh or groin pain — image both femurs and stop the drug.
• Osteonecrosis of the jaw: exposed necrotic bone after dental extraction; rare at osteoporosis doses, far more common at oncologic dosing.
• Denosumab discontinuation rebound: multiple vertebral fractures within months if no bisphosphonate follows.
• Raloxifene: venous thromboembolism and hot flashes. Romosozumab: boxed warning for myocardial infarction and stroke — avoid after recent cardiovascular events.

• T-score −1.0 to −2.5 = osteopenia; ≤ −2.5 = osteoporosis; any fragility fracture of hip or spine = osteoporosis regardless of the number. T-score compares to young-adult peak mass; Z-score compares to age-matched peers and is the one to use in premenopausal women, men under 50 and children — a Z-score ≤ −2.0 triggers a hunt for secondary causes.
• The single best next step in an osteopenic patient is to calculate FRAX, not to write for a bisphosphonate. Treat when 10-year risk is ≥3% for hip or ≥20% for major osteoporotic fracture (BHOF thresholds).
• Labs are normal in primary osteoporosis/osteopenia — calcium, phosphate and alkaline phosphatase are unremarkable. Low calcium and phosphate with high alkaline phosphatase and low 25-OH vitamin D is osteomalacia, not osteopenia. This is the most common distractor pair.
• USPSTF: screen all women ≥65; younger postmenopausal women only if their calculated risk matches a 65-year-old's; evidence is insufficient for men. Do not claim a USPSTF male screening recommendation.
• Prodromal thigh pain in a patient on long-term bisphosphonates = atypical femoral fracture — transverse, subtrochanteric, often bilateral. Image both femurs. Contrast with osteonecrosis of the jaw after dental extraction.
• Denosumab must never simply be stopped — rebound bone resorption produces multiple vertebral fractures; bridge with a bisphosphonate.
• Glucocorticoids are the most commonly tested secondary cause, and per the ACR justify pharmacotherapy at a higher T-score than usual. Other planted culprits: aromatase inhibitors, androgen deprivation therapy, phenytoin, excess levothyroxine, and untreated celiac disease.
• Degenerative spine disease and aortic calcification falsely raise the lumbar T-score — if the spine and hip disagree implausibly in an elderly patient, trust the hip.
• Thiazides are protective (hypocalciuria); loop diuretics increase calcium loss. Do not pick the thiazide as a risk factor.