This piece is the middle portion of Chapter 11 of Stones in the Body: More Frightening Than Cancer (Yoon Jong-won). It is a narrative containing the author's academic hypothesis, and the body, figures, and citations follow the manuscript as written.
■ Detailed Explanation by Tier
※ Flow: Tier 1 (fundamental) → Tier 2 (habit) worsening → Tier 3 (acute) vulnerability↑ → DIAH convergence → 7M spread → chronic disease
| Tier | Definition | Representative Examples |
|---|---|---|
| Tier 1 (fundamental) | Factors that weaken the life engine. They break down the rhythm of sleep, appetite, activity level, and respiration, worsening Tier 2 | Chronic stress, anxiety, depression, isolation, trauma, etc. |
| Tier 2 (habit) | Small pressures repeated every day. Slowly and surely they widen the DIAH intake gateway | Lack of exercise, overeating, unbalanced diet, smoking, drinking, lack of sleep, sedentary living, menopause/estrogen decline, aging (decreased gastric acid secretion, declining kidney function, decreased vitamin D activation, decreased intestinal absorption), long-term medication (steroids, PPI, anticonvulsants), etc. |
| Tier 3 (acute) | Events that shake the body all at once. In an instant they pass through the DIAH intake gateway | Traffic accidents, falls, fractures, infection, surgery, hemorrhage, acute poisoning, etc. |
※ These are the definitions and representative examples of each tier, Tier 1/Tier 2/Tier 3. Tier 1 (fundamental) is a matter of the mind and rhythm, Tier 2 (habit) is repeated lifestyle habits, and Tier 3 (acute) is a sudden event. In general they worsen in the order Tier 1 ※ Tier 2 ※ Tier 3.
■ Upper Classification: Funnel Entry Pathways (Tier 1/Tier 2/Tier 3)
| Tier | English / Korean | Keywords | Role |
|---|---|---|---|
| Tier 1 | Fundamental Trigger 근본 트리거 | Chronic stress, anxiety, depression, isolation, trauma, sleep rhythm collapse | Amplifies the intake gateway over the long term |
| Tier 2 | Lifestyle Trigger 생활습관 트리거 | Lack of exercise, overeating, unbalanced diet, smoking, drinking, sedentary living | Widens the intake gateway every day |
| Tier 3 | Acute Event Trigger 급성 사건 트리거 | Traffic accidents, falls, fractures, infection, surgery, hemorrhage | Suddenly passes through the intake gateway |
※ This table summarizes the three pathways of entry into the DIAH trigger. The starting point of every chronic disease is classified as one (or a combination) of these three pathways.
■ Verification Status
※ Trigger ↔ factor relationship: based on existing medical research (PMC/paper verification complete)
※ Tier 1/Tier 2/Tier 3 classification and coding system (19 items): a new proposal by the DIAH-7M Laboratory (clinical verification needed)
※ This coding system will be continuously verified and upgraded through future clinical research.
※ Coding consistency verification plan: In order to raise the reliability of this coding system from "an individual's claim" to "the reliability of a system," the following verifications will be needed going forward: ① Inter-rater reliability: verifying whether different raters assign the same code to the same disease, ② Test-retest reliability: verifying whether the same rater performs consistent coding at intervals of time, ③ Rule stability by disease group: confirming how consistently the judgment rules (the 1M/4M, 5M/6M distinctions, etc.) are applied within each disease group. Through such verification, the reproducibility of the coding system will be secured.
■ Drug-Induced Subclassification by DIAH Trigger ▸ Evidence Level Criteria
| Grade | Definition | Notation |
|---|---|---|
| Lv.3 | Meta-analysis/guideline/FDA warning | ★★★ |
| Lv.2 | RCT/large-scale cohort | ★★ |
| Lv.1 | Mechanistic study/animal experiment/case report | ★ |
▸ D (Deficiency) - Drug-Induced Deficiency Subclassification: calcium deficiency, vitamin D deficiency, magnesium deficiency, hormone deficiency, physical stimulus deficiency (P), drug-induced deficiency
| Drug Class | Representative Drugs | Mechanism | Evidence |
|---|---|---|---|
| Loop diuretics | Furosemide, torsemide, bumetanide, ethacrynic acid | NKCC2 inhibition → renal Ca excretion↑ | ★★★ |
| Anticonvulsants (CYP-inducing) | Phenytoin, phenobarbital, carbamazepine, primidone, oxcarbazepine | CYP induction → VitD breakdown↑ | ★★★ |
| Aromatase inhibitors | Anastrozole, letrozole, exemestane | Blocks estrogen production | ★★★ |
| GnRH agonists | Leuprolide, goserelin, triptorelin, buserelin | Sex hormone suppression | ★★★ |
| Depo-Provera | Medroxyprogesterone acetate | Estrogen↓ (FDA black box) | ★★★ |
| Proton pump inhibitors | Omeprazole, lansoprazole, esomeprazole, pantoprazole | Possible calcium carbonate solubility↓ (human evidence inconsistent) | ★★ |
| H2 receptor antagonists | Cimetidine, ranitidine, famotidine | Gastric acid↓ → possible effect on calcium carbonate absorption | ★ |
| Antiretrovirals | Tenofovir (TDF), protease inhibitors | Renal phosphate loss, interference with VitD metabolism | ★★★ |
| Thyroid hormone (excess) | Levothyroxine (TSH-suppressing dose) | Fracture↑ with TSH over-suppression (especially in the elderly/postmenopausal) | ★★ |
| Bile acid sequestrants | Cholestyramine, colesevelam | VitD absorption↓ (mechanistically possible, animal/indirect evidence) | ★ |
| Aluminum antacids | Maalox, Mylanta, Gelusil, Amphojel | Phosphate absorption↓ | ★ |
| SSRI | Fluoxetine, sertraline, paroxetine, escitalopram | Serotonin → osteoclast differentiation↑ | ★★ |
| SNRI | Venlafaxine, duloxetine, desvenlafaxine | Serotonin/NE pathway → bone metabolism disruption | ★★ |
| Tricyclic antidepressants | Amitriptyline, nortriptyline, imipramine | Prolactin↑ → sex hormones↓ | ★★ |
| MAO inhibitors | Phenelzine, tranylcypromine | Dopamine pathway disruption | ★ |
| Antipsychotics (typical) | Haloperidol, chlorpromazine, fluphenazine | Prolactin↑↑ → sex hormones↓ | ★★ |
| Antipsychotics (atypical) | Risperidone, olanzapine, quetiapine, aripiprazole | Prolactin↑ → sex hormones↓ | ★★ |
| Thiazolidinediones | Rosiglitazone, pioglitazone | PPARγ → stem cell → adipocyte conversion | ★★★ |
▸ I (Inflammation) - Drug-Induced Inflammation Subclassification: infection, autoimmunity, chronic inflammation, electromagnetic wave disturbance (E), drug-induced inflammation
| Drug Class | Representative Drugs | Mechanism | Evidence |
|---|---|---|---|
| Glucocorticoids | Prednisone, dexamethasone, methylprednisolone, hydrocortisone, budesonide | Osteoblasts↓, osteocyte apoptosis↑, osteoclast lifespan↑ | ★★★ |
| Calcineurin inhibitors | Cyclosporine, tacrolimus | RANKL pathway disruption | ★★ |
| Methotrexate | (high dose) | Osteoblast/osteoclast imbalance | ★★ |
| Azathioprine | Immune-bone axis disruption | ★ | |
| Mycophenolate | Immunosuppression → effect on bone metabolism | ★ |
▸ A (Acidosis) - Drug-Induced Acidosis Subclassification: metabolic acidosis, respiratory acidosis, complex toxic crystal (S), drug-induced acidosis
| Drug Class | Representative Drugs | Mechanism | Evidence |
|---|---|---|---|
| Carbonic anhydrase inhibitors | Topiramate, acetazolamide, zonisamide | Renal metabolic acidosis (RTA) → osteomalacia/osteoporosis | ★★★ |
| Metformin | (with reduced kidney function) | Risk of lactic acidosis | ★★ |
| NRTI | Stavudine, zidovudine, didanosine | Mitochondrial toxicity → lactic acidosis | ★★ |
| Valproic acid | Reports of association with metabolic abnormality (mitochondria/carnitine axis) | ★ | |
| Salicylic acid | Aspirin (excess) | Metabolic acidosis | ★★ |
| Propofol | (long-term infusion) | Propofol infusion syndrome | ★ |
| Isoniazid | Possible lactic acidosis | ★ |
▸ H (Hypoxia) - Drug-Induced Hypoxia Subclassification: vascular occlusion, anemia, respiratory failure, chain collapse (C), drug-induced hypoxia
| Drug Class | Representative Drugs | Mechanism | Evidence |
|---|---|---|---|
| Glucocorticoids | Prednisone, etc. (high dose/long-term) | Microvascular/endothelial function↓ → avascular necrosis | ★★★ |
| Vitamin K antagonists | Warfarin | Osteocalcin↓ → weakening of bone matrix | ★★ |
| Unfractionated heparin | (long-term use) | Osteoblasts↓, osteoclasts↑ | ★★ |
| Low-molecular-weight heparin | Enoxaparin, dalteparin | Lower risk than unfractionated | ★ |
| Bisphosphonates | Zoledronic acid, alendronate (long-term/high dose) | Avascular necrosis of the jawbone (especially as chemotherapy adjunct) | ★★★ |
| Denosumab | (upon discontinuation) | Rebound bone loss, risk of multiple vertebral fractures → transition treatment essential | ★★★ |
| Ifosfamide | Renal tubular phosphate loss | ★★ | |
| Cisplatin | Nephrotoxicity → electrolyte disturbance | ★★ | |
| Cyclophosphamide | Gonadal toxicity → hormones↓ | ★★ | |
| Doxorubicin | Bone marrow toxicity | ★ |
▸ Complex Trigger Drugs (Full Trigger)
| Drug | D | I | A | H | Main Pathway | Evidence |
|---|---|---|---|---|---|---|
| Glucocorticoids | ● | ● | ● | ● | I (direct suppression of bone cells) + H (avascular necrosis) | ★★★ |
| Tenofovir (TDF) | ● | ○ | ○ | D (renal phosphate/VitD) | ★★★ | |
| Phenytoin | ● | ○ | D (CYP induction → VitD↓) | ★★★ | ||
| Valproic acid | ○ | ● | A (metabolic abnormality, conditional) | ★ |
※ ● = main pathway, ○ = secondary pathway/conditional
▸ Drugs That Increase Fall Risk (Indirect Fracture)
| Drug Class | Representative Drugs | Evidence |
|---|---|---|
| Benzodiazepines | Diazepam, lorazepam, alprazolam, clonazepam | ★★★ |
| Sleep aids (Z-drug) | Zolpidem, eszopiclone | ★★★ |
| Opioids | Morphine, oxycodone, fentanyl, tramadol | ★★ |
| First-generation antihistamines | Diphenhydramine, chlorpheniramine | ★★ |
| Alpha blockers | Prazosin, doxazosin, tamsulosin | ★★ |
| Muscle relaxants | Cyclobenzaprine, methocarbamol | ★★ |
▸ Bone-Protective Drugs (Reference)
| Drug | Effect | Evidence |
|---|---|---|
| Thiazide diuretics | Renal Ca reabsorption↑ → fracture risk↓ | ★★★ |
| Lithium | Bone density protection (fracture risk 37%↓) | ★★ |
| Metformin | Promotes osteoblast differentiation (neutral to protective) | ★★ |
| Statins | Bone-protective effect in some studies | ★ |
※ D trigger - drug-induced deficiency: Certain drugs can trigger bone calcium efflux by interfering with calcium and vitamin D absorption, increasing renal excretion, or disrupting hormone balance. Loop diuretics inhibit renal NKCC2 to increase calcium excretion (★★★), and enzyme-inducing anticonvulsants activate CYP450 to promote vitamin D breakdown (★★★). Antidepressants (SSRI/SNRI) and antipsychotics can disrupt bone metabolism through the serotonin pathway or elevated prolactin (★★). Glucocorticoids are the representative "full trigger" drug that activates all four triggers, D, I, A, and H.
■ Lifestyle/Food-Induced Subclassification by DIAH Trigger
The table below organizes the pathways by which everyday lifestyle habits and foods trigger the DIAH triggers. It is a "funnel" structure that leads from Tier 1 (behavior and food) → Tier 2 (physiological change) → Tier 3 (microvascular exchange impairment/deposition conditions) → the DIAH subclassification code.
| Tier 1 Classification | Factor | Main Trigger | Linked Code | Tier 2 Physiological Change (funnel middle) | Tier 3 Core (transmission/deposition) | Evidence |
|---|---|---|---|---|---|---|
| Drinking | Heavy drinking, habitual drinking | I(inflammation)+A(acidosis) ±D(deficiency) | → A-DT → I-MT → D-NT | Increased oxidative stress, secretion of inflammatory cytokines, disruption of liver metabolism, reduced nutrient absorption | Inflammatory microenvironment formation↑, increased tissue damage/death → calcium deposition conditions | ★★★ NIAAA: alcohol → promotes oxidative stress and inflammatory response |
| Smoking | Tobacco (active/passive) | I(inflammation)+H(hypoxia) | → H-RS → I-EN | Induces inflammation and oxidative stress, inhalation of carbon monoxide (CO) → oxygen-carrying capacity↓, vascular endothelial damage | Induces microcirculatory hypoxia, vascular damage signals↑ → calcification-promoting environment | ★★★ CDC: carbon monoxide → oxygen-carrying capacity↓ |
| Sleep | Sleep deprivation, sleep apnea | H(hypoxia)+I(inflammation) | → H-RS → I-ST | Repeated nocturnal hypoxia, sympathetic overactivity, elevated inflammatory markers, increased blood pressure fluctuation | Microvascular constriction/damage environment formation↑ | ★★★ sleep apnea → cardiovascular risk↑ (many meta-analyses) |
| High-salt diet | Excess sodium (processed food, eating out, etc.) | A(acidosis)±D(deficiency) | → A-DT → D-NT | Elevated blood pressure, increased vascular tension, increased kidney burden, promotion of calcium excretion | Microvascular damage, reduced exchange area, disruption of calcium balance | ★★★ WHO recommendation: sodium <2g/day (less than 5g salt) |
| High-sugar diet | Excess sugar, refined carbohydrates, high-fructose corn syrup | I(inflammation)+A(acidosis) | → I-MT → A-DT | Glucotoxicity, AGEs (advanced glycation end products)↑, induces insulin resistance, increased oxidative stress | Endothelial cell/basement membrane damage, inflammatory microenvironment formation↑ → reinforcement of calcification conditions | ★★★ WHO recommendation: free sugars <10% (less than 5% if possible) |
| Ultra-processed foods | Excess UPF (processed meat, snacks, carbonated drinks, etc.) | I(inflammation)+A(acidosis) ±D(deficiency) | → I-MT → A-DT → D-NT | Inflammatory dietary pattern, accumulation of additives (phosphates, etc.), reduced nutrient density, increased metabolic burden | Damaged microenvironment formation↑, phosphate accumulation↑ → calcium-phosphate deposition↑ | ★★★ meta-analysis: UPF intake → cardiovascular risk↑ |
| Carbonated drinks | Phosphate-containing beverages and processed meat | D(deficiency)+A(acidosis) | → D-NT → A-DT | Disruption of calcium-phosphorus balance, increased phosphate accumulation, interference with calcium absorption, increased acid load | Calcium phosphate deposition conditions↑, promotion of bone calcium efflux | ★★ NIH ODS: phosphate excess → calcium absorption↓ |
| Caffeine | Excess coffee (when combined with a low-calcium diet) | D(deficiency) (mild) | → D-NT | Urinary calcium excretion slightly↑ (individual variation exists), slight effect on calcium absorption | Possible reinforcement of the gradient toward deficiency (D) (effect is limited) | ★ NIH ODS: slight effect (with a low-calcium diet) |
| Excessive meat consumption | High-protein, low-vegetable dietary pattern | A(acidosis) | → A-DT | Increased acid load (sulfur-containing amino acids), insufficient alkali input (vegetables and fruits↓) | Acidic microenvironment formation → deposition/inflammation conditions (protein itself can be beneficial depending on the situation) | ★★ depends on dietary "pattern" (not protein alone) |
| Dehydration, low fiber | Insufficient water, insufficient dietary fiber | D(deficiency)+A(acidosis) | → D-NT → A-DT | Increased blood viscosity, burden of processing metabolic waste, worsening of the intestinal environment, reduced mineral absorption | Stagnation of the excretion (OUT) pathway → microcirculatory impairment → reduced exchange efficiency | ★★ burden on the excretion pathway (OUT frame applied) |
※ The evidence above indicates not "confirmed causation" but a "risk gradient," and the effect may vary according to individual differences and the overall dietary pattern.
※ Linked code explanation:
D-NT (nutritional deficiency), I-MT (metabolic inflammation), I-EN (environmental inflammation), I-ST (stress inflammation)
A-DT (dietary acid load), H-RS (respiratory-type hypoxia)
※ Evidence strength: ★★★ (public health guideline), ★★ (repeated observational studies), ★ (mechanistic study/limited)
■ Chain Links Between Triggers • D(deficiency) → H(circulatory decline/hypoperfusion): lack of exercise → the muscle pump does not work → blood does not circulate • D(nutritional deficiency) → I(immune decline/infection/inflammation): insufficient nutrition → immune cells weaken → vulnerable to infection → inflammation occurs • I(chronic inflammation) → A(metabolic acidification): inflammation persists → metabolic waste accumulates → acidification of the body • A(acidosis) → D(forced mobilization of bone calcium): alkali (calcium) is needed to neutralize acid → calcium is drawn out of the bones • H(hypoxia) → I(ischemia-reperfusion inflammation): oxygen shortage → tissue damage → when oxygen returns, inflammation explodes ■ The dual pathway of lack of exercise • Pathway ①: lack of exercise → D-PH(gravity/physical stimulus deficiency) → interruption of bone stimulation signals → calcium efflux from the bones • Pathway ②: lack of exercise → H-CR(muscle pump weakening) → circulatory decline → hypoperfusion/hypoxia
"If you do not move, the bone stimulation also disappears (D-PH) and the blood does not circulate (H-CR)" is the reason lack of exercise is a core cause of chronic disease.
[ DIAH Trigger References / DIAH Trigger References ]
1. Deficiency / Deficiency (D)
1-1. StatPearls (NCBI NBK499940): PTH is secreted within seconds when blood calcium drops, stimulating osteoclasts to induce bone resorption / PTH is secreted within seconds of low serum calcium detection, stimulating osteoclasts for bone resorption 1-2. Cold Spring Harb Perspect Med (PMC6071549): during calcium deficiency, PTH promotes perilacunar remodeling of osteocytes to rapidly mobilize calcium from the bone / PTH rapidly liberates skeletal calcium stores during calcium deficiency via osteocyte perilacunar remodeling
2. Inflammation / Inflammation (I)
2-1. Immune Netw (PMC5833125): proinflammatory cytokines such as TNF-α, IL-1β, IL-6, and IL-17 induce RANKL expression, promoting osteoclast differentiation and bone resorption / Proinflammatory cytokines induce RANKL expression, promoting osteoclast differentiation and bone resorption 2-2. J Clin Invest (PMID:16294221): TNF-α stimulates M-CSF expression in stromal cells, and M-CSF induces RANK expression in osteoclast precursors, promoting inflammatory osteolysis / TNF-α stimulates M-CSF expression in stromal cells; M-CSF induces RANK in osteoclast precursors, mediating inflammatory osteolysis
3. Acidosis / Acidosis (A)
3-1. Kidney Int (PMID:15199293): during metabolic acidosis the bone acts as a pH buffer; acid promotes PGE2 and RANKL expression, activating osteoclasts / Bone buffers systemic pH during metabolic acidosis; acid stimulates PGE2 and RANKL, activating osteoclasts 3-2. Curr Opin Nephrol Hypertens (PMC9133222): acidosis induces physicochemical calcium release in the short term and cell-mediated bone resorption in the long term / Acidosis induces acute physicochemical calcium release and chronic cell-mediated bone resorption
4. Hypoxia / Hypoxia (H)
4-1. J Cardiovasc Pharmacol (PMID:1618920): with 2 hours of hypoxia exposure ATP decreases 43%, and energy deficiency raises intracellular calcium concentration / 2h hypoxia causes 43% ATP decrease; energy deficiency leads to increased intracellular calcium 4-2. Aging Dis (PMC6147588, 2018): during ischemia, ATP depletion induces ion pump failure, membrane depolarization, and calcium overload; mitochondrial dysfunction → cell death / Ischemia-induced ATP depletion triggers ion pump failure, membrane depolarization, calcium overload; mitochondrial dysfunction leads to cell death
5. Physical Stimulus Deficiency / Physical Stimulus Deficiency (D-PH)
5-1. J Bone Miner Res (PMID:15125798, Lang 2004): in long-duration spaceflight (microgravity), regional BMD decreases on a monthly basis; significant loss of hip and spine bone density / Long-duration spaceflight (microgravity) causes significant monthly BMD loss at hip and spine 5-2. Br J Sports Med (PMID:33597120, Gabel 2022): after spaceflight, tibial bone strength/bone density decreases 2.9-4.3%; bone loss is proportional to flight duration / Spaceflight causes 2.9-4.3% tibia bone strength/density loss; mission duration predicts bone loss 5-3. J Musculoskelet Neuronal Interact (PMID:15758512, LeBlanc 2000): after 4-14 months of Mir flight, loss of lumbar/hip bone density and muscle mass / Mir 4-14 month flights cause lumbar/hip BMD and lean tissue loss
6. Aging Inflammation / Inflammaging (I-AG)
6-1. J Gerontol A (PMID:24833586, Franceschi 2014): inflammaging is the chronic low-grade inflammation of aging; a major risk factor for morbidity and mortality in the elderly / Inflammaging is chronic low-grade inflammation of aging; major risk factor for morbidity and mortality in elderly 6-2. Nat Rev Endocrinol (PMID:30046148, Franceschi 2018): inflammaging contributes to the pathophysiology of age-related diseases; connection between gut microbiota and metabolic inflammation / Inflammaging contributes to age-related disease pathogenesis; gut microbiota-metaflammation connection