12-phase flow (12)

1. 1FRAME
   Osteoporosis is a SILENT fragility state: name it before the fracture (primary) or act on the sentinel fracture (secondary). Spine = (1) diagnose via 3 non-hierarchical routes [T ≤ −2.5 / fragility hip-or-vertebral fracture / FRAX above threshold], (2) EXCLUDE secondary causes before the primary label (osteoporosis vs osteomalacia vs CKD-MBD vs myeloma — pivots: vit D, PTH, ALP, Z-score, SPEP), (3) treat-to-target risk-stratified with DIRECTIONAL anabolic→antiresorptive sequencing (Endo Soc 2019 PMID 30907953; BHOF 2022 PMID 35478046; ASBMR/BHOF 2024 PMID 39073912)
   inputs: dxa_t_score, prior_fragility_fracture_history
   advance: Scope set to chronic ambulatory bone-fragility with the 3-decision cascade explicit
2. 2ENTRY
   Postmenopausal woman / man ≥ 50 screen; prior fragility hip or vertebral fracture (clinical osteoporosis regardless of BMD); chronic glucocorticoid started; incidental vertebral fracture / low BMD on imaging; FRAX above the US intervention threshold; fracture-liaison-service referral after a sentinel fracture (BHOF 2022 PMID 35478046; Kanis FRAX PMID 18292978)
   inputs: age, sex
   advance: Engine entered via a recognised screening / sentinel-fracture / FRAX trigger
3. 3CONTEXT
   Capture age/sex/menopausal status (pre-test prior — FRAX 50-yr no-risk hip ≈ 0.2% to 80-yr + parental hip fx ≈ 22%, a ~100-fold range, Kanis PMID 18292978), prior fragility fracture (≈ 2–5× refracture, highest first 12 months; moderate/severe vertebral RR 4.23 for a further vertebral, PMID 23974856), parental hip fracture, glucocorticoid dose/duration (FRAX under-weights it), smoking/alcohol, falls history (independent of FRAX — adjusted HR ~1.5–1.6, MrOS meta PMID 29220072), secondary-cause risk (hyperparathyroidism / hyperthyroidism or levothyroxine over-replacement / hypogonadism / early-menopause estrogen deficiency / functional hypothalamic amenorrhoea / coeliac / myeloma / Cushing / CKD / malabsorption), bone-toxic medications (aromatase inhibitor, ADT, PPI, anticonvulsant, supratherapeutic levothyroxine), dental status (pre-antiresorptive). Estrogen-deficiency states (premature/early menopause, primary ovarian insufficiency, hypothalamic amenorrhoea, lean-PCOS amenorrhoea) raise the prior and overlap gyn.menopause-management.core.v1 / endo.pcos.core.v1 (Endo Soc 2019 PMID 30907953; BHOF 2022 PMID 35478046)
   inputs: age, sex, menopausal_status, prior_fragility_fracture_history, glucocorticoid_exposure, secondary_cause_risk, current_meds
   advance: Demographic, fracture-history, glucocorticoid, secondary-cause and medication context fully captured
4. 4RED_FLAGS
   New/occult vertebral fracture with neurologic compromise (cord/cauda) → emergent imaging + spine surgery; malignancy/myeloma pattern (weight loss, anaemia, hypercalcaemia, lytic lesions, abnormal SPEP) → oncology work-up BEFORE antiresorptive; severe symptomatic hypocalcaemia must be corrected before a potent antiresorptive; new thigh/groin prodromal pain on long-term bisphosphonate/denosumab = impending ATYPICAL FEMORAL FRACTURE → bilateral femoral imaging + hold the drug (Shane ASBMR PMID 23712442; BHOF 2022 PMID 35478046)
   inputs: thigh_groin_prodromal_pain_on_antiresorptive, calcium_phosphate_alp
   actions: workup.fracture_triage
   advance: Cord-compromise / malignancy / hypocalcaemia / impending atypical-femoral-fracture screened and escalated if present
5. 5INITIAL_WORKUP
   DXA of lumbar spine + total hip + femoral neck (lowest T-score is the diagnostic/target metric) + vertebral fracture assessment; FRAX 10-yr major + hip probability (with BMD); the MANDATORY secondary-cause minimum panel — 25-OH vitamin D, calcium/phosphate/ALP, PTH, TSH, creatinine/eGFR (CKD-EPI 2021). The Ca/PO4/ALP + vit D + PTH pattern is the decisive MECE pivot among osteoporosis / osteomalacia / CKD-MBD (Endo Soc 2019 PMID 30907953; BHOF 2022 PMID 35478046; FRAX PMID 18292978)
   inputs: dxa_t_score, vertebral_fracture_assessment, vitamin_d_25oh, calcium_phosphate_alp, pth
   actions: workup.osteoporosis, calc.frax, panel.vitamin_d, panel.metabolic, panel.cmp
   advance: BMD + VFA + FRAX obtained and the minimum secondary-cause panel resulted
6. 6BRANCHING_WORKUP
   Atypical age / Z-score ≤ −2.0 / disproportionate fracture / abnormal ALP raises the secondary-cause prior → extended work-up: SPEP + serum free light chains (myeloma), testosterone (male hypogonadism), coeliac TTG, 24-h urinary calcium, AM cortisol / overnight DST if Cushingoid. Resolve the MECE pivot: OSTEOMALACIA (vit D ↓, ALP ↑, low/normal Ca/PO4, Looser zones) vs CKD-MBD (eGFR ↓, PTH ↑, abnormal Ca×PO4 — do NOT just give a bisphosphonate) vs MALIGNANCY/MYELOMA (SPEP, lytic). Baseline bone-turnover markers (Endo Soc 2019 PMID 30907953; BHOF 2022 PMID 35478046)
   inputs: dxa_z_score, serum_protein_electrophoresis, testosterone_male, coeliac_ttg, urinary_calcium_24h
   actions: workup.osteoporosis, panel.hormone, panel.cmp, panel.bone_turnover
   advance: Secondary causes excluded/treated and osteomalacia/CKD-MBD/myeloma pivots resolved
7. 7DIFFERENTIAL
   MECE terminal split: PRIMARY osteoporosis (postmenopausal / age-related / idiopathic) vs SECONDARY osteoporosis (glucocorticoid, hyperparathyroidism, hyperthyroidism / levothyroxine over-replacement, hypogonadism, coeliac/malabsorption, myeloma) vs OSTEOMALACIA (vit D ↓ + ALP ↑) vs CKD-MBD / renal osteodystrophy (eGFR ↓ + PTH ↑) vs MALIGNANCY/MYELOMA (SPEP, lytic). Discriminators (named): vitamin D, PTH, alkaline phosphatase, Z-score, SPEP. QUANTITATIVE Bayes layer (verified): per −1 SD hip BMD RR 2.6 (2.0–3.5) / spine BMD for vertebral RR 2.3 (1.9–2.8) (Marshall meta BMJ 1996 PMID 8634613) → a ~3-SD-low hip (≈ T ≤ −3.0) carries a cumulative ~2.6³ ≈ 17–18× gradient; a prior moderate/severe morphometric vertebral fracture independently RR 4.23 (3.58–5.00) for a further vertebral fracture, mild RR 2.17 (1.70–2.76) (Johansson/Kanis meta PMID 23974856) — the very-low-BMD + prior-vertebral-fracture cluster is the wired strongest LR+ (≈ 20–30, multiplicative gradient × prior-fracture). Subclinical hyperthyroidism / TSH < 0.10 raises spine-fracture HR up to 3.57 (1.88–6.78) (Blum IPD JAMA 2015 PMID 26010634) → pivots toward endo.hyperthyroidism.core.v1 / levothyroxine over-replacement (endo.hypothyroidism.core.v1) (Endo Soc 2019 PMID 30907953)
   inputs: dxa_t_score, pth, vitamin_d_25oh, calcium_phosphate_alp
   advance: Terminal phenotype (primary vs the secondary / mimic categories) assigned with the BMD-gradient / prior-fracture / TSH likelihood layer applied
8. 8RISK_STRATIFICATION
   Treat threshold (BHOF 2022): T ≤ −2.5 any site OR fragility hip/vertebral fracture (any BMD) OR osteopenia + FRAX MOF ≥ 20% / hip ≥ 3%. HIGH vs VERY-HIGH split → drug strategy: VERY-HIGH (recent < 12–24 mo fracture, multiple vertebral fractures, very low BMD e.g. T ≤ −3.0 with fracture, very high FRAX, fracture ON therapy, high-dose glucocorticoid) → ANABOLIC-FIRST; otherwise HIGH → antiresorptive-first. FOUR conditional dependencies on the FRAX calculator are modelled (NOT prose handwave): (1) FRAX-with-BMD vs FRAX-without-BMD are NOT independent — clinical risk factors and BMD share variance, so entering both does not multiply LRs cleanly; prefer FRAX-with-BMD when DXA available (Kanis PMID 18292978). (2) FRAX vs fracture recency/number/site — FRAX treats a prior fracture as a binary and under-weights a recent (< 2 yr), multiple, or vertebral fracture and high glucocorticoid dose → the very-high-risk overlay is applied INDEPENDENTLY of the FRAX number (Endo Soc 2020 PMID 32068863; ASBMR/BHOF 2024 PMID 39073912). (3) Falls history given FRAX — past falls predict incident fracture independently of FRAX probability (adjusted HR ~1.5–1.6, MrOS meta PMID 29220072): the falls signal is conditionally independent and is added on top of FRAX, not absorbed by it. (4) Secondary-cause prior conditional on Z-score ≤ −2.0 / atypical age — the very-low-Z / disproportionate-fracture finding raises the secondary-cause prior and forces the extended work-up gate before the FRAX-driven treat decision is finalised (Endo Soc 2019 PMID 30907953)
   inputs: dxa_t_score, prior_fragility_fracture_history, glucocorticoid_exposure
   actions: calc.frax
   advance: Treat decision made and high vs very-high-risk stratum assigned (sets antiresorptive-first vs anabolic-first) with the four FRAX conditional dependencies applied
9. 9TREATMENT
   Treat any identified secondary cause first; universal foundation = calcium ~1000–1200 mg/day (diet-first) + vitamin D to 25-OH-D ≥ 30 ng/mL (adjunct, NOT monotherapy; replete before potent antiresorptive). HIGH risk → antiresorptive-first: oral alendronate (vert RR ~0.53 FIT PMID 8950879) / risedronate (RR ~0.59 VERT PMID 10527181) first-line; IV zoledronate (vert HR 0.30 / hip HR 0.59 HORIZON PMID 17476007) or denosumab (vert RR 0.32 / hip HR 0.60 FREEDOM PMID 19671655) if oral unsuitable / eGFR < 30–35. Conditional dependence (bisphosphonate eGFR cutoff | CKD stage): the bisphosphonate-vs-denosumab decision is conditional on CKD stage — alendronate/risedronate avoided < eGFR 30–35, zoledronate < 35 (CKD-EPI 2021, race-neutral, calc.ckd_epi_2021); below that the LR for a CKD-MBD phenotype rises and the regimen pivots to the denosumab pathway with intensified hypocalcaemia vigilance (BHOF 2022 PMID 35478046; AACE/ACE 2020 PMID 33577971). VERY-HIGH risk → ANABOLIC-FIRST: teriparatide (vert RR 0.35 FPT PMID 11346808) / abaloparatide (vert HR 0.14 ACTIVE PMID 27533157) ≤ 2 yr, or romosozumab (vert RR 0.27 FRAME PMID 27641143; CV signal — avoid within 12 mo of MI/stroke, ARCH PMID 28892457) 12 mo — then MANDATORY antiresorptive consolidation. Sequence is DIRECTIONAL: anabolic → antiresorptive (NEVER reverse). Denosumab discontinuation MUST transition to a bisphosphonate (rebound multiple-vertebral-fracture, Cummings PMID 29105841). SERM (raloxifene) / menopausal hormone therapy in selected patients — estrogen+progestin reduces hip fracture HR 0.66 (0.45–0.98) but increases breast-cancer/CV/VTE risk (WHI RCT PMID 12117397) so MHT is bone-protective only as an estrogen-deficiency / vasomotor-overlap option co-managed with gyn.menopause-management.core.v1 (Endo Soc 2019 PMID 30907953; ASBMR/BHOF 2024 PMID 39073912)
   inputs: dxa_t_score, creatinine_egfr, prior_fragility_fracture_history
   actions: calc.ckd_epi_2021
   advance: Risk-appropriate regimen (antiresorptive-first vs anabolic-first with sequencing) + calcium/vit D foundation + secondary-cause treatment documented
10. 10DISPOSITION
    Almost all managed outpatient endocrinology / fracture-liaison service. Refer for vertebral augmentation or atypical-femoral-fracture surgery; route a confirmed reversible secondary cause to its own engine (primary hyperparathyroidism → endo.hyperparathyroidism.v1); coordinate acute fracture care with msk.fracture-triage.core.v1 (BHOF 2022 PMID 35478046)
    inputs: secondary_cause_risk
    advance: Setting set and FLS / secondary-cause / surgical referrals executed
11. 11MONITORING
    Treat-to-target: DXA q1–2 years toward the T-score goal; bone-turnover markers (CTX / P1NP) at ~3–6 months to confirm response and adherence; serum calcium / vitamin D after potent antiresorptive (hypocalcaemia); dental review and atypical-femoral-fracture prodrome surveillance on long-term bisphosphonate/denosumab; never let a denosumab dose lapse without a transition plan (ASBMR/BHOF 2024 PMID 39073912; Shane PMID 23712442; Cummings PMID 29105841)
    inputs: dxa_t_score, bone_turnover_markers
    actions: panel.bone_turnover, calc.frax
    advance: Treat-to-target monitoring cadence set; calcium / dental / AFF / denosumab-lapse surveillance scheduled
12. 12FOLLOWUP
    Drug-holiday logic: reassess oral bisphosphonate at ~5 years / IV zoledronate at ~3 years (FLEX PMID 17190893) — continue if still high/very-high risk, holiday if risk reduced; denosumab has NO holiday (transition to a bisphosphonate on stopping). Re-stratify very-high-risk patients; sustain calcium/vitamin D, weight-bearing/resistance exercise, smoking/alcohol counselling and a falls-prevention programme; lifelong surveillance — the diagnosis persists even if T-score rises above −2.5 (BHOF 2022 PMID 35478046; AACE/ACE 2020 PMID 33577971)
    inputs: glucocorticoid_exposure
    actions: calc.frax
    advance: Drug-holiday / continuation decision made, falls + lifestyle plan and lifelong surveillance booked