Fundamental therapy keyed to the failure mode
The framework turns disease into a failed loop element and so names the fundamental therapy. Set-point reset, arm restoration, reservoir refill over withdrawal-slowing, threshold avoidance, and root-driver removal are mapped; two predictions are demonstrated and all four frontier hypotheses (generalised sensor reset, dual Wnt-antagonist refill, acid-base arm restoration, otoconial calcite stability) are now quantified.
Naming the failed loop element names the fundamental fix. Setpoint drift calls for resetting the set-point; loop-gain drop for restoring the failed arm; reservoir depletion for refilling (not just slowing withdrawal); threshold crossing for staying below it; a root driver for removing it.
The failure-keyed therapy map
| failure mode | fundamental fix | established example (cited) |
|---|---|---|
| setpoint drift (comparator reset) | reset the set-point (allosteric sensor modulator) | calcimimetic (cinacalcet, etelcalcetide) for 2deg/1deg hyperPTH; calcilytic (encaleret) for ADH1 (Phase 3 CALIBRATE positive 2025) |
| loop-gain drop (limiting arm) | restore the failed arm's gain at its source | active vitamin D / calcitriol (VDR slow arm); alkali / restore renal HCO3 transport in RTA; thiazide raises renal Ca-reabsorption gain |
| reservoir depletion | REFILL the reservoir (anabolic) > slow withdrawal (anti-resorptive) | anabolic: teriparatide/abaloparatide (intermittent PTH), romosozumab (anti-sclerostin, dual action); anti-resorptive: bisphosphonates, denosumab |
| threshold/spinodal crossing | stay below the solubility/precipitation threshold | hydration + citrate (raise Ca-oxalate solubility) for stones; phosphate binders / anti-FGF23 (burosumab) to control the Ca*PO4 product |
| upstream root driver | remove the driver | estrogen/SERM for post-menopausal bone loss; mechanical loading lowers sclerostin (non-drug anabolic input); parathyroidectomy removes the PTH source |
Two falsifiable predictions
Set-point reset: in a setpoint-drift disease, an allosteric modulator that shifts the comparator back normalizes the defended value (1.150 → 1.000). This is the calcilytic/calcimimetic paradigm (encaleret resets the CaSR set-point up in ADH1; cinacalcet resets it down in hyperparathyroidism), expressed in the framework's own language.
Reservoir refill versus withdrawal-slowing: for a depleted reservoir, raising formation (anabolic) refills it (1.00), while only reducing withdrawal (anti-resorptive) rebuilds slowly (0.85) and the untreated reserve keeps falling (0.33). The anabolic is the more fundamental fix for a depleted reservoir — the clinical anabolic-first-then-anti-resorptive sequence, derived.
Frontier hypotheses (framework-derived)
- H-RESET any mis-calibrated IONIC SENSOR is a set-point-reset target -- the encaleret/CaSR paradigm generalizes to OTOP1/ASIC/ENaC sensor diseases (allosteric recalibration over symptom control).
- H-DUAL sustained reservoir refill needs to remove the FORMATION BRAKE, not just push formation: romosozumab's anabolic window closes as DKK1 rises (cited), so DUAL anti-sclerostin + anti-DKK1 should sustain refilling longer than either alone.
- H-ARM chronic acid-base disease is better fixed by restoring the FAILED ARM at source (renal HCO3 transporter / ventilatory drive) than by lifelong exogenous buffering (which leaves loop gain low).
- H-OTOC BPPV recurrence reflects otoconial CaCO3 instability; a fundamental approach targets the otoconial micro-pH/Ca environment (OTOP1-dependent) to stabilize/repair biomineral, beyond repositioning.
All four are now quantified
H-RESET (the set-point reset generalizes): a homeostatic sensor is a comparator with a defended set-point, and the defended attractor equals that set-point for every comparator steepness — a structural identity, not a fit. So an allosteric reset (encaleret resets CaSR up in ADH1, Phase-3 CALIBRATE; cinacalcet resets it down in hyperparathyroidism) relocates the defended value durably, while symptom control normalises only while administered and relapses to the mis-set attractor on withdrawal (a residual of 0.15 versus ~0 after reset). Across a family of ionic sensors (CaSR, ENaC, ASIC, OTOP1) the direction holds for every one — the [V] result; generalisation to non-CaSR allosteric recalibrators is [H] and the absolute residuals are [O].
H-DUAL (remove the formation brake): sclerostin inhibition raises DKK1 as negative feedback (Florio 2016, a β-catenin target), so the single-agent anabolic window closes while dual anti-sclerostin + anti-DKK1 sustains it. Modelling the integrated window reproduces the ordering dual (12.79) > single (1.08) > untreated (0.00) — the [V] result is the ordering; the absolute window size is [O] and human clinical efficacy remains [H].
H-ARM (restore the failed arm, do not just buffer): the acid-base setpoint is a two-timescale buffer whose loop gain comes from a working arm (renal HCO₃ regeneration / ventilatory drive). In distal renal tubular acidosis the renal arm transporter fails and the standard of care is lifelong alkali (ADV7103/Sibnayal) — it cancels the mean acidosis but leaves loop gain low. Reusing the volume's own OU law (err=load/k, Var=σ²/2k), arm restoration (raising k) tightens the variance and rejects a fresh acid load by the factor k_high/k_low (≈4.0×: the fresh-load excursion falls from 2.00 under buffering to 0.50 after restoration), while buffering improves neither and must be sustained — the [V] direction; the absolute gains are [O] and clinical arm-restoration remains [H].
H-OTOC (otoconial calcite stability): otoconia are calcite, whose stability is the saturation Ω = [Ca²⁺][CO₃²⁻]/Ksp; carbonate speciation makes Ω a steep function of pH, and OTOP1 sets endolymph pH. With the physiological state at the Ω=1 boundary, acidosis drops Ω to 0.695 and hypocalcemia to 0.755 — both undersaturated, dissolution-prone (the BPPV seam). The [V] result is the direction; the absolute Ω=1 threshold is [O] and clinical OTOP1/pH targeting remains [H].
The failure-keyed map and every simulation here are the reproduced results; named-drug efficacy is cited [L], and where the framework predicts beyond current practice (non-CaSR sensor recalibration, transporter/drive restoration) it is flagged [H], never asserted.