Endocrine

Osteoporosis: USPSTF screening, FRAX, and pharmacotherapy

Clinical Overview and When to Suspect Osteoporosis

— Postmenopausal woman ≥ 65, or man ≥ 70

— Younger postmenopausal woman or man 50–69 with risk factors: prior fragility fracture, parental hip fracture, low body weight (<127 lb / BMI <21), current smoking, ≥3 alcoholic drinks/day, chronic glucocorticoids (≥5 mg prednisone ≥3 months), RA, malabsorption, hypogonadism, hyperthyroidism, hyperparathyroidism, CKD, early menopause (<45), aromatase inhibitor or ADT therapy

— Height loss >1.5 in (4 cm) from peak, thoracic kyphosis, or back pain after trivial trauma

— Incidental vertebral compression deformity on chest imaging

— Screen women ≥ 65 with bone measurement testing (Grade B)

— Screen postmenopausal women < 65 at increased risk using a clinical risk assessment tool (e.g., FRAX, OST) then DXA if elevated (Grade B)

— Insufficient evidence (I statement) for screening men — but AACE/Endocrine Society endorse screening men ≥ 70 and at-risk men 50–69

Definition: skeletal disorder of compromised bone strength predisposing to fragility fracture; operationally defined by DXA T-score ≤ −2.5 at femoral neck, total hip, or lumbar spine, OR by a fragility fracture of the hip or vertebra regardless of T-score.

Epidemiology: ~50% of postmenopausal white women and ~20% of men >50 will sustain an osteoporotic fracture in their lifetime; hip fractures carry ~20–25% 1-year mortality.

When to suspect in ambulatory practice:

USPSTF (2025) recommends:

Step 3 management: in the outpatient clinic, frame osteoporosis as a fracture-prevention problem, not a "low T-score" problem — every encounter should ask "what is this patient's 10-year fracture risk and what modifiable factors am I missing?"

Board pearl: a fragility fracture of the hip or vertebra by itself establishes the diagnosis — you do not need a DXA T-score ≤ −2.5 to start pharmacotherapy.

Presentation Patterns and Key History

— Asymptomatic screening DXA in a postmenopausal woman

— Acute fragility fracture (hip after low fall, distal radius after FOOSH, vertebral compression after lifting/coughing)

— Incidental finding (height loss, kyphosis, vertebral wedge on CXR/CT)

— Fracture history: any fracture after age 50 from a fall from standing height or less = fragility fracture

— Parental hip fracture (FRAX input)

— Menstrual/menopausal history: age at menopause, amenorrhea >6 months in premenopause, hypogonadism in men (low libido, ED)

— Medications: glucocorticoids, PPIs (long-term), SSRIs, anticonvulsants (phenytoin, carbamazepine), aromatase inhibitors, ADT, thyroid over-replacement, heparin, thiazolidinediones, loop diuretics

— Lifestyle: smoking, alcohol ≥3/day, dietary calcium intake, sun exposure, weight-bearing activity, fall history (≥2 falls in past year = high risk)

— GI: celiac, IBD, bariatric surgery (malabsorption of Ca/vit D)

— Endocrine: hyperthyroidism, hyperparathyroidism, Cushing, T1DM, hypogonadism

— Multiple myeloma, mastocytosis, hemochromatosis, CKD-MBD, hypercalciuria, vitamin D deficiency

Osteoporosis is clinically silent until fracture — most board stems present one of three patterns:

Targeted history at the index visit:

Secondary causes to actively elicit (15–30% of women, up to 50–80% of men and premenopausal women with osteoporosis have a secondary cause):

Key distinction: osteoporotic vertebral fractures are often painless and discovered radiographically — do not require trauma; ask specifically about height loss and check the chart for serial heights.

Board pearl: a 55-year-old man with a vertebral compression fracture warrants a secondary workup including testosterone, 25-OH vitamin D, SPEP/UPEP, TSH, PTH, 24-hour urine calcium, and tissue transglutaminase — assume secondary disease until proven otherwise.

Physical Exam Findings and Functional Assessment

— Measure standing height at every visit on a stadiometer; historical height loss > 1.5 in (4 cm) or prospective loss > 0.8 in (2 cm) suggests occult vertebral fracture → order thoracolumbar spine films or vertebral fracture assessment (VFA) on DXA

— Thoracic kyphosis ("dowager's hump"), reduced rib-to-pelvis distance (<2 fingerbreadths), wall-occiput distance >0 cm (cannot touch occiput to wall when heels against wall)

— Spinous process tenderness over a recent vertebral fracture

— Timed Up and Go > 12 seconds = increased fall risk

— 30-second chair stand, gait speed < 0.8 m/s

— Orthostatic vitals, visual acuity, footwear, home hazards

— Polypharmacy review (benzodiazepines, anticholinergics, antihypertensives, hypoglycemics)

— Blue sclerae, hearing loss, dentinogenesis → osteogenesis imperfecta

— Moon facies, central obesity, striae → Cushing

— Goiter, tremor, tachycardia → hyperthyroidism

— Café-au-lait, precocious puberty → McCune-Albright/fibrous dysplasia

— Skin hyperextensibility, joint hypermobility → Ehlers-Danlos

— Testicular atrophy, gynecomastia → hypogonadism

Osteoporosis itself produces no specific exam findings — the exam is directed at complications, secondary causes, and fall risk.

Anthropometrics and spine:

Fall-risk and functional assessment (essential at every Medicare AWV):

Exam clues to secondary causes:

Step 3 management: the fall-risk assessment is the highest-yield intervention you can do at the visit — fall prevention (PT, vitamin D ≥800 IU, vision correction, deprescribing sedatives, home safety) reduces hip fractures independent of pharmacotherapy and is a Medicare quality measure.

Board pearl: wall-occiput distance > 0 cm and rib-pelvis distance < 2 fingerbreadths are validated bedside signs of occult thoracic vertebral fracture — both should trigger lateral spine imaging.

Diagnostic Workup — DXA, FRAX, and Initial Labs

— T-score (postmenopausal women, men ≥ 50): compares to young adult reference

— Z-score (premenopausal women, men < 50, children): compares to age-matched; Z ≤ −2.0 = "below expected for age" → mandatory secondary workup

— Use the lowest of the three sites; exclude vertebrae with degenerative artifact, compression fracture, or hardware

— Inputs: age, sex, BMI, prior fracture, parental hip fracture, current smoking, glucocorticoids, RA, secondary osteoporosis, alcohol ≥3/day, femoral neck BMD (optional but preferred)

— Outputs: 10-year probability of major osteoporotic fracture (MOF: hip, spine, wrist, humerus) and hip fracture

— US treatment thresholds (NOF/BHOF): MOF ≥ 20% or hip ≥ 3% in a patient with osteopenia (T −1.0 to −2.5)

— CBC, CMP (Ca, Cr, alk phos, albumin), 25-OH vitamin D, TSH, PTH, 24-hr urine calcium + creatinine

— Men: total testosterone

— Targeted: SPEP/free light chains (age >50 or unexplained), tissue transglutaminase IgA, tryptase, urinary cortisol, iron studies

DXA (dual-energy X-ray absorptiometry) of the lumbar spine (L1–L4) and hip (femoral neck + total hip) is the gold standard.

Normal: ≥ −1.0

Osteopenia (low bone mass): −1.0 to −2.5

Osteoporosis: ≤ −2.5

Severe osteoporosis: ≤ −2.5 + fragility fracture

FRAX (WHO Fracture Risk Assessment Tool):

Initial labs to exclude secondary causes (order in essentially everyone with new osteoporosis):

Step 3 management: in osteopenia, do not reflexively treat on T-score alone — run FRAX; this is the most common Step 3 trap.

Board pearl: FRAX is not validated in patients already on osteoporosis pharmacotherapy or in those < 40 or > 90.

Diagnostic Workup — Vertebral Fracture Assessment and Bone Turnover Markers

— Women ≥ 70 or men ≥ 80 with T-score ≤ −1.0

— Women 65–69 or men 70–79 with T-score ≤ −1.5

— Any postmenopausal woman or man ≥ 50 with: historical height loss >1.5 in, prospective loss >0.8 in, prior non-vertebral fragility fracture, or glucocorticoids ≥5 mg/d ≥3 months

— Formation: P1NP (procollagen type 1 N-terminal propeptide), bone-specific alk phos

— Resorption: serum CTX (C-telopeptide), urine NTX

— Uses: confirm adherence to oral bisphosphonates (CTX should fall ≥30% by 3–6 months), detect rebound after denosumab discontinuation, monitor anabolic response

— MRI or bone scan for acute back pain to date a vertebral fracture (edema on STIR = acute) and guide kyphoplasty candidacy

— Skeletal survey if myeloma suspected

Vertebral fracture assessment (VFA) — lateral spine image at time of DXA, low radiation; indicated when:

Plain thoracolumbar films if VFA suggests deformity — Genant grading (mild 20–25%, moderate 25–40%, severe >40% vertebral height loss).

Trabecular bone score (TBS): a textural analysis of the lumbar spine DXA image that estimates trabecular microarchitecture; low TBS adjusts FRAX upward and is particularly useful in diabetes, where BMD overestimates bone strength.

Bone turnover markers (BTMs) — adjuncts, not diagnostic:

When to image beyond DXA:

Key distinction: osteomalacia mimics osteoporosis on DXA but is vitamin D deficiency–driven with low Ca, low phos, high alk phos, high PTH, and pseudofractures (Looser zones) — repleting vitamin D, not bisphosphonates, is the answer.

Board pearl: in type 2 diabetes, patients fracture at higher BMD than non-diabetics — incorporate TBS and consider treating at a higher T-score threshold; FRAX underestimates risk in diabetes (add a "secondary osteoporosis" check or use a TBS-adjusted FRAX).

Risk Stratification and Treatment Thresholds

— T-score ≤ −2.5 at femoral neck, total hip, or lumbar spine

— Hip or vertebral fragility fracture at any T-score

— Other fragility fracture (wrist, humerus, pelvis) AND T-score ≤ −2.5, or with elevated FRAX

— Osteopenia (T −1.0 to −2.5) with FRAX 10-yr MOF ≥ 20% or hip ≥ 3%

— Glucocorticoids ≥ 7.5 mg prednisone-equivalent ≥ 3 months in any postmenopausal woman or man ≥ 50 (ACR 2017)

— T-score ≤ −3.0

— Multiple vertebral fractures

— Fracture within past 12 months ("imminent fracture risk")

— Fracture on therapy

— Hip T-score ≤ −2.5 plus prior fracture

— FRAX hip ≥ 4.5% or MOF ≥ 30%

— Calcium 1000–1200 mg/day (diet preferred; supplement only the gap)

— Vitamin D3 800–2000 IU/day; target 25-OH D ≥ 30 ng/mL

— Weight-bearing + resistance exercise ≥3×/week

— Smoking cessation, alcohol ≤2 drinks/day

— Fall-prevention program

Indications for pharmacotherapy (NOF/BHOF, AACE, Endocrine Society — converge):

Very high fracture risk (favor anabolic-first strategy — teriparatide, abaloparatide, or romosozumab → followed by antiresorptive):

Universal foundational measures for everyone (treated or not):

Step 3 management: the right answer for a postmenopausal woman with osteopenia + FRAX hip 3.2% is to start an oral bisphosphonate, not "lifestyle and recheck in 2 years."

Board pearl: routine calcium supplementation > 1200 mg/d is associated with possible CV risk and kidney stones — food-first is the guideline-endorsed approach; reserve supplements for documented deficiency.

Pharmacotherapy — First-Line Antiresorptives

— Alendronate 70 mg PO weekly (most evidence, cheapest)

— Risedronate 35 mg PO weekly or 150 mg monthly (gentler GI, delayed-release option)

— Ibandronate 150 mg PO monthly — no hip fracture data, generally avoid as primary

— Administration: morning, fasting, 8 oz plain water, remain upright 30–60 min, no food/other meds for 30–60 min

— Contraindications: CrCl < 30–35 mL/min, esophageal stricture/achalasia, inability to remain upright, hypocalcemia, pregnancy

— Zoledronic acid 5 mg IV yearly — preferred when oral intolerance, adherence concern, malabsorption, or post-hip fracture

— Pre-infusion: correct vitamin D, ensure Ca normal, hydrate; acetaminophen for acute-phase reaction (flu-like, common with first dose)

— Preferred when CrCl < 35, intolerant of bisphosphonates, or high fracture risk

— Critical caveat: discontinuation causes rebound bone loss and multiple vertebral fractures within 6–18 months — must transition to a bisphosphonate (oral or IV) when stopping; never simply stop denosumab

— Check Ca and vitamin D before each dose; severe hypocalcemia risk in CKD

— Raloxifene — reduces vertebral fractures + reduces ER+ breast cancer; increases VTE and hot flashes

— Estrogen — only for women < 60 or within 10 yr of menopause primarily for vasomotor symptoms

Oral bisphosphonates = first-line for most patients (osteoporosis without very high risk):

IV bisphosphonate:

Denosumab (RANKL inhibitor) 60 mg SQ every 6 months:

Estrogen / SERMs — niche roles:

Step 3 management: in a 68-year-old woman with T −2.7 and normal renal function, alendronate 70 mg weekly + calcium/vitamin D is the first-line answer.

Board pearl: never stop denosumab without a bisphosphonate bridge — give zoledronic acid 6 months after the last denosumab dose.

Pharmacotherapy — Anabolic Agents and Sequencing

— Duration: lifetime maximum 2 years

— Black box: osteosarcoma risk in rats → avoid in Paget disease, prior skeletal radiation, unexplained alk phos elevation, open epiphyses, bone metastases, hypercalcemia

— Side effects: transient hypercalcemia, orthostasis with first dose, leg cramps, nausea

— Dual action: stimulates formation AND inhibits resorption

— Black box: MI, stroke, CV death — contraindicated if MI or stroke within prior 12 months

— Best evidence for hip fracture reduction among anabolics

— After 5 years oral or 3 years IV bisphosphonate, reassess

— If moderate risk (no fractures, hip T > −2.5): hold for 1–5 years, monitor BMD/BTM

— If high risk (T ≤ −2.5 at hip, prior vertebral fracture, ongoing glucocorticoids): continue to 10 years oral / 6 years IV

— Rationale: reduce atypical femur fracture (AFF) and osteonecrosis of jaw (ONJ) risk

— No drug holiday for denosumab, teriparatide, abaloparatide, or romosozumab

Anabolic ("bone-building") agents — indicated up front in very high fracture risk patients; produce larger BMD gains and faster vertebral fracture reduction than antiresorptives.

Teriparatide (PTH 1-34) 20 mcg SQ daily:

Abaloparatide (PTHrP analog) 80 mcg SQ daily; similar 2-year cap; possibly less hypercalcemia.

Romosozumab (anti-sclerostin monoclonal) 210 mg SQ monthly × 12 months:

Mandatory sequencing principle: anabolic effects are lost without antiresorptive follow-up. After any anabolic course → transition to bisphosphonate or denosumab for consolidation.

Pharmacotherapy holidays (only for bisphosphonates):

Step 3 management: a 72-year-old with two vertebral fractures and hip T −3.2 should start romosozumab or teriparatide first, then transition to zoledronic acid — not alendronate first.

Board pearl: sequence matters — anabolic → antiresorptive is good; antiresorptive → anabolic blunts the anabolic response (especially after denosumab).

Special Populations — Elderly, Renal, and Hepatic Impairment

— Fracture risk is overwhelmingly driven by falls, not BMD — pair pharmacotherapy with PT, vitamin D, deprescribing

— Zoledronic acid within 90 days of hip fracture reduces mortality (HORIZON-RFT) — strong Step 3 talking point

— Life-expectancy threshold: most experts treat if life expectancy > 3 years (bisphosphonate fracture-reduction benefit emerges ~12–18 months)

— Use caution with denosumab adherence — missed doses → rebound fractures

— CrCl 30–35 mL/min: bisphosphonates contraindicated per labeling

— CKD G4–G5 (eGFR < 30): must distinguish osteoporosis from CKD-MBD before treating — check PTH, Ca, phos, 25-OH D, alk phos; bone biopsy may be needed if PTH/turnover ambiguous

— Denosumab is not renally cleared but causes severe hypocalcemia in advanced CKD — pre-treat with calcium + active vitamin D (calcitriol), monitor Ca within 2 weeks

— Teriparatide can be used in CKD without renal osteodystrophy

— Romosozumab: limited CKD data; avoid in advanced CKD

Elderly (≥ 80):

Chronic kidney disease:

Hepatic impairment: no specific dose adjustments for bisphosphonates; teriparatide/abaloparatide/denosumab/romosozumab not significantly hepatically metabolized.

Dental considerations (any age, especially elderly): comprehensive dental exam before initiating IV bisphosphonate or denosumab; complete invasive dental work first to minimize ONJ risk (incidence still <1/10,000 patient-years in osteoporosis dosing).

Step 3 management: an 82-year-old admitted with a hip fracture should get zoledronic acid 5 mg IV ≥ 2 weeks post-op (after Ca/D repletion and CrCl ≥ 35) — this is a CCS-style order set with mortality benefit.

CCS pearl: in the inpatient hip-fracture order set, include calcium, vitamin D, DEXA (outpatient), PT consult, fall-risk eval, and "consult endocrine or schedule outpatient bone health clinic" — Step 3 loves transitions-of-care completeness.

Special Populations — Premenopausal Women, Men, and Glucocorticoid-Induced

— Use Z-scores, not T-scores; Z ≤ −2.0 = "below expected" triggers secondary workup

— Causes: anorexia/RED-S, hyperprolactinemia, hypothalamic amenorrhea, celiac, IBD, glucocorticoids, idiopathic

— Treat the cause; pharmacotherapy generally reserved for fragility fractures or glucocorticoid exposure

— Bisphosphonates relatively contraindicated in women planning pregnancy (long skeletal half-life, fetal skeletal concerns) — prefer teriparatide if anabolic needed, or treat after childbearing

— Pregnancy- and lactation-associated osteoporosis is rare but real; presents with vertebral fractures in late pregnancy or early postpartum

— Management: wean lactation, calcium/vitamin D, teriparatide is the preferred pharmacotherapy

— Screen at age 70, or 50–69 with risk factors (hypogonadism, GC, ADT, alcohol, smoking, low BMI, prior fracture)

— Always check morning total testosterone; if low, evaluate hypogonadism

— Same drug options as women — alendronate, risedronate, zoledronic acid, denosumab, teriparatide, abaloparatide, romosozumab all FDA-approved in men

— Bone loss is fastest in first 3–6 months; fracture risk rises at doses as low as 2.5 mg prednisone/day

— All adults on ≥ 2.5 mg/d for ≥ 3 months: calcium 1000–1200 mg, vitamin D 600–800 IU, fall-risk assessment, baseline DXA

— Treat pharmacologically if: adult ≥ 40 with FRAX (GC-adjusted) MOF ≥ 10% or hip ≥ 1%, prior fragility fracture, or T ≤ −2.5; adults < 40 with fragility fracture or T/Z ≤ −3

— First-line: oral bisphosphonate; alternatives: zoledronic acid, teriparatide (preferred in very high risk)

Premenopausal women:

Pregnancy and lactation:

Men:

Glucocorticoid-induced osteoporosis (GIO) — ACR 2017:

Board pearl: in androgen-deprivation therapy for prostate cancer or aromatase inhibitor therapy for breast cancer, treatment thresholds are lowered — denosumab 60 mg q6 mo is specifically FDA-approved for AI- and ADT-related bone loss.

Complications and Adverse Outcomes

— Hip fracture: ~20–25% 1-year mortality, 50% never regain prior function, 25% require long-term care

— Vertebral fracture: chronic pain, kyphosis, restrictive lung disease, GERD, early satiety; each prior vertebral fracture multiplies subsequent fracture risk 5-fold

— Imminent risk window: fracture risk highest in first 1–2 years after any fragility fracture — drives the "very high risk" anabolic-first strategy

— Oral bisphosphonates: esophagitis, dyspepsia, hypocalcemia, acute phase reaction (less than IV), musculoskeletal pain

— IV zoledronic acid: flu-like acute-phase reaction (30% with first dose, declines with subsequent), uveitis (rare), AKI if dehydrated or infused too fast (give over ≥ 15 min)

— Atypical femur fracture (AFF): subtrochanteric/diaphyseal, prodromal thigh pain, often bilateral; risk rises with bisphosphonate duration > 5 yr (still rare: ~1/10,000 patient-years) — drives drug holidays

— Osteonecrosis of the jaw (ONJ): exposed bone > 8 weeks; risk ~1/10,000 in osteoporosis dosing, far higher in oncology dosing; minimize with pre-treatment dental exam

— Denosumab: hypocalcemia (especially CKD), serious infections (cellulitis), eczema, rebound vertebral fractures on discontinuation

— Teriparatide/abaloparatide: hypercalcemia, orthostasis, nausea

— Romosozumab: MI, stroke, CV death (black box); hypersensitivity; hypocalcemia

— Raloxifene: VTE, hot flashes, leg cramps, fatal stroke in women with CHD

Fracture-related morbidity and mortality:

Pharmacotherapy-related adverse effects:

Step 3 management: new-onset thigh or groin pain in a patient on long-term bisphosphonates → obtain bilateral femur films ± MRI; if AFF identified, stop bisphosphonate, orthopedics consult, consider teriparatide to promote healing.

Board pearl: rebound vertebral fractures after denosumab cessation are the single most-tested complication — the question stem will describe multiple new compression fractures 9–12 months after the patient "stopped her shots."

When to Escalate — Referral, Inpatient, and Specialty Consultation

— Unexplained osteoporosis in a premenopausal woman or man < 50

— Z-score ≤ −2.0 in pre-menopausal or young patient

— Multiple secondary causes or complex endocrinopathy

— Fracture on therapy (after adherence and absorption confirmed)

— CKD G4–G5 with mineral-bone disorder

— Considering anabolic therapy and unfamiliar with sequencing

— Suspected mastocytosis, myeloma, or genetic bone disorder (osteogenesis imperfecta)

— Acute hip fracture → orthopedic surgery within 24–48 hours reduces mortality

— Acute vertebral fracture with intractable pain unresponsive to outpatient analgesia, neurologic deficit, or instability

— Symptomatic hypercalcemia from teriparatide overdose

— Severe hypocalcemia post-denosumab in CKD (especially with tetany, QT prolongation, seizures)

— NPO after midnight, ortho consult, pre-op labs (CBC, BMP, coags, type-and-screen, ECG)

— VTE prophylaxis (LMWH preferred; mechanical until 12 hr post-op)

— Delirium prevention bundle: avoid benzodiazepines/anticholinergics, address vision/hearing, mobilize early

— Multimodal analgesia: scheduled acetaminophen, fascia iliaca block, opioid-sparing

— Geriatrics/co-management consult ("ortho-geriatric")

— PT/OT on day 1 post-op, weight-bearing as tolerated

— Pre-discharge: DXA pending, vitamin D, calcium, zoledronic acid scheduled, fall-prevention referral, bone-health clinic appointment in 4–6 weeks

Refer to endocrinology or bone-health clinic when:

Hospitalize for:

CCS inpatient hip-fracture order set (Step 3 favorite):

Step 3 management: the post-hip-fracture bone-health gap — only ~20% of US hip-fracture patients ever start anti-osteoporosis therapy — is a recognized quality measure (MIPS); ordering pharmacotherapy before discharge is the high-value answer.

CCS pearl: "advance clock 4 weeks → see in bone-health clinic, check 25-OH vitamin D, plan zoledronic acid" is the kind of follow-up sequence the simulation rewards.

Key Differentials — Other Causes of Low BMD or Fragility Fracture

— Low Ca, low phos, high alk phos, high PTH, low 25-OH D

— X-ray: Looser zones / pseudofractures (Milkman lines)

— Treat: vitamin D ± phosphate, not bisphosphonates

— High Ca, high PTH, low phos; cortical bone loss (distal radius)

— DXA characteristically worse at 1/3 radius than spine

— Treat: parathyroidectomy if indications met

— Anemia, AKI, hypercalcemia, bone pain; lytic lesions on skeletal survey, not photopenia

— SPEP/UPEP/free light chains; refer heme-onc

Same-category mimics of "primary osteoporosis":

Osteomalacia (vitamin D deficiency, anticonvulsants, renal phosphate wasting):

Primary hyperparathyroidism:

Multiple myeloma:

Hyperthyroidism / excess levothyroxine: high turnover, low TSH

Cushing syndrome / glucocorticoid use: covered above

Hypogonadism in men or premature ovarian insufficiency

Renal osteodystrophy (CKD-MBD): high PTH, high phos, low/active vit D — needs nephrology

Osteogenesis imperfecta: blue sclerae, dentinogenesis imperfecta, family history, multiple childhood fractures

Paget disease of bone: focal, very high alk phos, characteristic radiographic appearance; bisphosphonates treat both but for different reasons — distinguish or you'll mis-stage

Mastocytosis: flushing, GI symptoms, urticaria pigmentosa, elevated tryptase

Idiopathic juvenile osteoporosis and pregnancy-associated osteoporosis: rare, diagnoses of exclusion

Key distinction: low alk phos with osteoporosis → think hypophosphatasia (ALPL gene); bisphosphonates are contraindicated because they further suppress already-deficient alkaline phosphatase activity — use asfotase alfa or teriparatide.

Board pearl: in a patient with osteoporosis + nephrolithiasis + hypercalciuria, screen for idiopathic hypercalciuria with 24-hr urine — a thiazide reduces both stones and fracture risk.

Key Differentials — Non-Osteoporotic Causes of Back Pain and Fracture

— Red flags: night pain, constitutional symptoms, age > 50 with new pain, history of cancer, weight loss, neuro deficit

— Imaging: MRI of spine; lytic vs blastic patterns; pedicle ("winking owl") destruction suggests metastasis, not osteoporotic compression

— Osteoporotic vertebral fractures characteristically preserve the posterior cortex and pedicles and involve anterior wedging

— Fever, IVDU, recent bacteremia, immunosuppression, diabetes

— Elevated ESR/CRP; MRI with contrast; blood cultures, biopsy

When a patient presents with back pain ± vertebral deformity, do not anchor on osteoporosis:

Malignancy (metastatic breast, lung, prostate, renal, thyroid; multiple myeloma):

Infection (vertebral osteomyelitis, discitis, epidural abscess):

Spondyloarthropathies: ankylosing spondylitis predisposes to transverse spinal fractures from minor trauma (rigid spine), often missed on plain films — get CT/MRI

Trauma: high-energy mechanism does not equal fragility fracture; do not over-attribute to osteoporosis

Mechanical low back pain / degenerative disc disease: no red flags, no fracture on imaging — manage conservatively

Cauda equina syndrome: saddle anesthesia, urinary retention, bilateral sciatica → emergent MRI and neurosurgical decompression

Aortic pathology: AAA or dissection presenting as back pain — palpate, image when suspected

Renal: pyelonephritis, nephrolithiasis — flank pain, UA, CT

Pancreatic and retroperitoneal disease: epigastric pain radiating to back

Key distinction: in a 70-year-old with new "compression fracture," screen for myeloma (CBC, BMP, SPEP, free light chains, UPEP) and obtain MRI if there are any red flags or unusual fracture morphology — missing myeloma on a Step 3 stem is a high-stakes error.

Board pearl: osteoporotic vertebral fractures spare the pedicles; pedicle destruction or posterior cortex involvement = malignancy until proven otherwise.

Secondary Prevention and Long-Term Treatment Plan

— Calcium intake 1000–1200 mg/d (diet first; supplement gap only)

— Vitamin D3 800–2000 IU/d; check 25-OH D and target ≥ 30 ng/mL

— Weight-bearing aerobic + resistance training ≥ 3×/wk; balance training (tai chi, PT)

— Tobacco cessation; alcohol ≤ 2/day

— Annual fall-risk assessment and home safety review

— High risk (T ≤ −2.5, no fractures): alendronate or risedronate weekly × 5 yr → reassess for drug holiday

— Intolerant/CKD/adherence concerns: zoledronic acid 5 mg IV yearly × 3 yr or denosumab q6 mo (commit indefinitely or bridge)

— Very high risk (multiple vertebral fractures, recent fracture, T ≤ −3): romosozumab × 12 mo or teriparatide × 24 mo → bisphosphonate or denosumab consolidation

— Post hip fracture: zoledronic acid during admission or within 90 days (mortality benefit)

— After 5 yr PO / 3 yr IV, if hip T > −2.5 and no fractures → hold 1–5 yr, monitor DXA q2 yr and CTX

— Resume if BMD declines significantly, new fracture occurs, or CTX rises

— No holiday for denosumab, teriparatide, abaloparatide, romosozumab — sequence to a bisphosphonate instead

Foundational lifelong measures (every patient, every visit):

Pharmacologic plan templates:

Drug-holiday decision tree (bisphosphonates only):

Adherence support: persistence with oral bisphosphonates at 1 yr is ~50% — use weekly/monthly dosing, mailed reminders, pharmacist-led programs; consider switching to IV/SQ if non-adherent.

Insurance/value: most generics (alendronate, risedronate) inexpensive; anabolics require prior authorization documenting very high risk and failure/intolerance of antiresorptives in some plans.

Step 3 management: "treat to target" — repeat DXA at 1–2 years on therapy; rising BMD or stable BMD with no fracture = success; falling BMD or fracture on therapy = re-evaluate adherence, absorption, secondary causes, then escalate to anabolic.

Board pearl: the answer to "patient stopped denosumab 8 months ago, now has back pain" is lateral spine imaging and start a bisphosphonate immediately.

Follow-Up, Monitoring, and Counseling

— On therapy: every 1–2 years at the same facility/machine until stability, then every 2–3 years

— Untreated osteopenia: every 2–5 years depending on baseline T-score (closer to −2.5 → sooner)

— Treated osteoporosis with stable/improving BMD on bisphosphonate: every 2 years; consider less frequent if highly stable

— Optional but useful for adherence: check serum CTX at baseline and 3–6 months after starting oral bisphosphonate; a >30% drop confirms biologic effect

— Rising BTMs suggest non-adherence, malabsorption, or rebound (denosumab discontinuation)

— 25-OH vitamin D and serum Ca annually

— Pre-each-dose Ca and Cr before zoledronic acid; Ca within 2 weeks of denosumab in CKD

— Annual creatinine to reassess CrCl for bisphosphonate eligibility

— Medication administration technique (especially oral bisphosphonate rules)

— Dental hygiene; report jaw pain, exposed bone, tooth mobility

— Report new thigh, groin, or hip pain (AFF surveillance)

— Importance of completing anabolic-to-antiresorptive transition

— Continued calcium/vitamin D regardless of pharmacotherapy

— Exercise program adherence and fall-prevention

— Primary care quarterback; dental clearance before IV agents; PT for balance/strength; dietitian if intake low; geriatrics for complex elderly; endocrinology for refractory/complex disease

— Document fracture-prevention plan in the after-visit summary — a transitions-of-care safety net

Monitoring DXA:

Bone turnover markers:

Laboratory monitoring:

Counseling at every visit:

Care-team coordination:

Step 3 management: schedule the next denosumab dose at the time of injection and flag the patient in the EHR — a missed dose by > 1 month risks rebound; the system-level fix is a recall registry.

CCS pearl: in CCS-style follow-up, "advance the clock 6 months, recheck Ca/Cr/CTX, schedule next zoledronic acid infusion, repeat DXA at 24 months" wins points for longitudinal completeness.

Ethical, Legal, and Patient Safety Considerations

— Patients must understand lifetime cumulative exposure and rare but serious risks: AFF, ONJ (bisphosphonates, denosumab); CV events (romosozumab); osteosarcoma signal (teriparatide); VTE (raloxifene)

— Document discussion of alternatives (lifestyle alone vs pharmacotherapy) and the absolute fracture-risk reduction — for high-risk patients NNT to prevent one hip fracture is ~50–100 over 3 years; for low-risk patients NNT is much larger and benefit may not exceed risk

— A 60-year-old with T −1.4 and FRAX MOF 8% should usually not be started on a bisphosphonate; pushing pharmacotherapy here is over-treatment

— Conversely, not treating a 75-year-old with prior vertebral fracture is a clear lapse in care

— Post-hip-fracture treatment rates < 25% in the US; a discharge bundle that includes pharmacotherapy initiation, vitamin D, fall-prevention, and bone-health clinic follow-up is both an ethical obligation and a recognized quality measure (CMS, MIPS)

— Denosumab must be tracked across care transitions; a patient who switches insurance or moves and misses a dose can fracture multiply within months

— Repeated fragility fractures with unexplained mechanism, hesitant patient, controlling caregiver → consider elder abuse; report per state mandatory reporter laws

— Document the home environment, polypharmacy, and caregiver burden

— Sedative-hypnotics, anticholinergics, and tricyclics in older adults increase falls — deprescribing prevents fractures more cost-effectively than any drug

— Hispanic and Black women are under-screened and under-treated; apply USPSTF screening uniformly

— FRAX has US race/ethnicity-specific calibrations — choose the correct version

Informed consent for pharmacotherapy:

Shared decision-making in low-risk osteopenia:

Transitions of care — the single biggest safety gap:

Mandatory reporting and elder safety:

Polypharmacy and deprescribing (Beers criteria):

Equity:

Step 3 management: the highest-yield ethical answer on Step 3 is rarely a refusal to treat — it's document shared decision-making and offer evidence-based therapy with explicit discussion of AFF/ONJ and the much larger fracture-prevention benefit in a high-risk patient.

Board pearl: failing to initiate osteoporosis therapy after a hip fracture is now considered a system-level safety failure, not just an oversight.

High-Yield Associations and Rapid-Fire Facts

USPSTF: screen all women ≥ 65; screen postmenopausal < 65 if elevated risk by tool — Grade B for both; men: I statement.

Diagnostic T-score: ≤ −2.5 at femoral neck, total hip, or lumbar spine — use the lowest.

Fragility fracture of hip or vertebra = osteoporosis regardless of T-score.

FRAX treatment thresholds in osteopenia: MOF ≥ 20% or hip ≥ 3%.

First-line drug: oral alendronate or risedronate.

Post-hip-fracture mortality benefit: zoledronic acid (HORIZON-RFT).

CrCl < 30–35: avoid bisphosphonates → denosumab (with caution and Ca/D) or teriparatide.

Denosumab cessation → rebound vertebral fractures → must bridge to bisphosphonate.

Romosozumab black box: MI/stroke within 12 months = contraindication.

Teriparatide and abaloparatide: 2-year lifetime cap.

Anabolic → antiresorptive sequencing maximizes BMD gains.

Drug holiday applies only to bisphosphonates (5 yr PO, 3 yr IV → reassess).

AFF: subtrochanteric/diaphyseal, prodromal thigh pain, bilateral, long-duration bisphosphonates.

ONJ: more common with IV/oncology dosing; pre-treatment dental exam.

Osteomalacia: high alk phos, low Ca/phos, Looser zones — treat with vitamin D, NOT bisphosphonates.

Hypophosphatasia: low alk phos — bisphosphonates contraindicated.

Glucocorticoid threshold: ≥ 2.5 mg prednisone ≥ 3 months triggers GIO evaluation; ≥ 7.5 mg almost always treat.

Aromatase inhibitor / ADT bone loss: denosumab 60 mg q6mo is FDA-approved indication.

Diabetes: fractures at higher BMD; consider TBS.

Calcium intake target: 1000–1200 mg/d; vitamin D 800–2000 IU/d; target 25-OH D ≥ 30 ng/mL.

Height loss > 1.5 in or wall-occiput distance > 0 → image the spine.

Pedicle destruction on imaging → malignancy, not osteoporosis.

Premenopausal/young: use Z-score; Z ≤ −2.0 triggers secondary workup.

Board pearl: the top three Step 3 traps in this topic are (1) not treating osteopenia with elevated FRAX, (2) stopping denosumab without a bridge, and (3) missing the hip-fracture inpatient pharmacotherapy initiation.

Board Question Stem Patterns

Stem 1 — USPSTF screening: 66-year-old healthy woman, never screened. Best next step? → DXA of hip and spine (Grade B).

Stem 2 — Osteopenia with elevated FRAX: 62-year-old postmenopausal woman, T −1.8 femoral neck, parental hip fracture, smoker. FRAX hip 3.4%. → Start oral bisphosphonate (alendronate), not "lifestyle and recheck."

Stem 3 — Fragility vertebral fracture, normal-ish DXA: 70-year-old with T −2.1 and new T8 compression fracture after a sneeze. → Diagnose osteoporosis and start pharmacotherapy (T-score not required).

Stem 4 — Post-hip fracture: 80-year-old admitted for hip fracture. Pre-discharge plan? → Vitamin D repletion + zoledronic acid (within 90 days or before discharge), fall-prevention referral, bone-health follow-up.

Stem 5 — Renal impairment: Woman with osteoporosis and eGFR 28. → Denosumab (with Ca/D and monitoring) or teriparatide; not alendronate.

Stem 6 — Denosumab discontinuation: Patient stopped q6-month injections 9 months ago, now multiple new vertebral fractures. → Lesson: bridge to bisphosphonate; treat acute with zoledronic acid.

Stem 7 — Very high risk / anabolic-first: 72-year-old with two vertebral fractures, hip T −3.3. → Romosozumab or teriparatide first, then bisphosphonate. Wrong answer: alendronate alone.

Stem 8 — Glucocorticoid-induced: 55-year-old on prednisone 10 mg/d for GCA for 6 months. → Calcium, vitamin D, DXA, start oral bisphosphonate.

Stem 9 — AFF surveillance: 75-year-old on alendronate × 7 yr with new thigh pain. → Bilateral femur X-rays, stop bisphosphonate, ortho consult, consider teriparatide.

Stem 10 — Premenopausal woman with low BMD: 32-year-old amenorrheic distance runner, Z −2.6. → Diagnose RED-S/hypothalamic amenorrhea, restore energy availability and menses; treat cause, not bisphosphonate.

Stem 11 — Mimic: Elderly woman with diffuse bone pain, low Ca, low phos, high alk phos. → Osteomalacia from vitamin D deficiency — repletion, not alendronate.

Stem 12 — Pedicle destruction: Compression fracture with pedicle erosion on MRI. → Work up metastatic disease or myeloma, not osteoporosis alone.

Step 3 management: when the stem features a patient on aromatase inhibitor for breast cancer with new osteopenia → denosumab 60 mg SQ q6mo is the FDA-labeled answer.

Board pearl: if the stem mentions "stopped his denosumab", the test point is always rebound fractures and the need for a bisphosphonate bridge.

One-Line Recap

Osteoporosis is a fracture-prevention disease: screen women ≥ 65 (and at-risk younger postmenopausal women) per USPSTF, treat any patient with a fragility hip or vertebral fracture, a T-score ≤ −2.5, or osteopenia with FRAX MOF ≥ 20% or hip ≥ 3%, starting with an oral bisphosphonate for most and an anabolic agent first for very-high-risk patients — always layered on calcium, vitamin D, fall prevention, and proper sequencing.

Screening: USPSTF Grade B for women ≥ 65 and postmenopausal women < 65 with elevated risk; consider men ≥ 70 per specialty guidelines. Use DXA + FRAX (with femoral neck BMD) to drive decisions.

Diagnostic anchors: T-score ≤ −2.5 OR hip/vertebral fragility fracture OR osteopenia + FRAX above threshold = treat. Always run a secondary-cause panel (Ca, Cr, 25-OH D, PTH, TSH, testosterone in men, SPEP/UPEP, 24-hr urine Ca, tTG).

Pharmacotherapy: alendronate/risedronate first-line; zoledronic acid for adherence/intolerance/post-hip-fracture (mortality benefit); denosumab for CKD or AI/ADT bone loss (never stop without a bisphosphonate bridge); romosozumab/teriparatide/abaloparatide for very high risk, followed by antiresorptive consolidation.

Safety and follow-up: bisphosphonate drug holiday after 5 yr PO / 3 yr IV if moderate risk; monitor for AFF (thigh pain) and ONJ (dental exam pre-IV); repeat DXA every 1–2 yr on therapy; calcium 1000–1200 mg, vitamin D 800–2000 IU, exercise, and fall prevention are universal.

Board pearl: the highest-yield Step 3 moves are treating osteopenia when FRAX is elevated, initiating pharmacotherapy before discharge after a hip fracture, and never stopping denosumab without a bisphosphonate bridge.