Metabolic Bone Disease

Key questions

1. Q1What are the two jobs of bone?

   Structural (support, protection of viscera, locomotion and respiration, housing hematopoietic marrow) and metabolic (reservoir of calcium, phosphorus, sodium, magnesium and carbonate that keeps blood levels steady).
2. Q2What is bone made of?

   Inorganic mineral — calcium hydroxyapatite — plus an organic part: bone cells and matrix proteins (mostly type I collagen, laid down as osteoid).
3. Q3Who are the four cells, and what does each do?

   Osteoprogenitor cells (mesenchymal cells that become osteoblasts); osteoblasts (make matrix/osteoid); osteocytes (the most abundant bone cell; a canalicular network that senses mechanical force, regulates Ca²⁺/phosphate and signals formation vs resorption); osteoclasts (multinucleated, from monocyte–macrophage lineage, resorb bone).
4. Q4How does woven bone become lamellar bone?

   Osteoblasts lay osteoid on a cartilage scaffold → woven bone; osteoclasts resorb it and osteoblasts replace it with stronger, organized lamellar bone. Woven bone in an adult always means a pathologic or reparative process.
5. Q5What is the bone multicellular unit (BMU)?

   Osteoclasts + osteoblasts + blood supply + nerve supply + connective tissue working as a unit. Resorption and formation are tightly coupled, directed by osteocytes, and repair microdamage.
6. Q6How does RANKL/OPG control resorption?

   RANKL on osteoblasts/stromal cells binds RANK on osteoclast precursors → osteoclast formation and activity. OPG (made by osteoblasts) is a decoy that binds RANKL and blocks it.
7. Q7Which hormones push toward formation vs resorption?

   Estrogen and calcitonin inhibit osteoclasts. Vitamin D (1,25(OH)₂D) supports mineralization and osteoblasts. PTH acts on osteoblasts and raises RANKL → indirectly activates osteoclasts (net resorption when continuous).

Key questions

1. Q8When is peak bone mass reached?

   In early adulthood — the 2nd to 3rd decade. After that, bone mass slowly declines.
2. Q9What determines how high the peak is?

   Genetics, ethnicity, physical activity (mechanical loading), nutrition (calcium, vitamin D, protein) and hormonal status (estrogen/testosterone, GH).
3. Q10How does timing of menarche affect peak bone mass?

   Early menarche = longer estrogen exposure → less resorption → higher peak bone mass. Late menarche, amenorrhea or early menopause lower it.
4. Q11Why does peak bone mass matter?

   Osteoporosis later in life = how high you started minus how fast you lose. A low peak (poor diet, inactivity, early hypogonadism) is one of the three routes to osteoporosis.
5. Q12What lowers bone mass after the peak?

   Age (fewer, less active osteoblasts and fewer growth factors), estrogen loss at menopause, inactivity, low calcium/vitamin D and secondary causes such as glucocorticoids.
6. Q13What is the most practical way to raise peak bone mass?

   Weight-bearing exercise and adequate calcium/vitamin D before about age 30.

Key questions

1. Q14What goes wrong in scurvy?

   Vitamin C deficiency → inadequate hydroxylation of proline/lysine in procollagen → collagen cannot form a stable triple helix or cross-link → weak, easily degraded collagen.
2. Q15Who gets scurvy?

   Elderly people living alone with poor diets; alcoholics (vitamin C is used up and intake is poor); dialysis patients (water-soluble vitamins are dialyzed out — uncommon); gastric bypass and other malabsorption; fad dieters; infants on unsupplemented formula.
3. Q16How does scurvy present?

   Bleeding from fragile vessels (perifollicular purpura, bleeding gums), poor wound healing, joint pain/swelling from hemarthrosis, subperiosteal hemorrhage; anemia. X-ray: ground-glass osteopenia with subperiosteal hemorrhage.
4. Q17What skeletal changes occur in children with scurvy?

   Defective osteoid → cartilage overgrows into the marrow → bowing of long bones, depressed sternum, outward-projecting ribs.
5. Q18What is the defect in osteogenesis imperfecta?

   Mutations in COL1A1/COL1A2 (α1 and α2 chains of type I collagen); rare recessive forms involve CRTAP or LEPRE1. "Too little bone" — brittle bones.
6. Q19Which organs does OI affect and why?

   Everywhere type I collagen matters: bone (many fractures), joints (laxity), skin, eyes (blue sclerae — thin sclera shows the choroid), ears (conductive + sensorineural hearing loss), teeth (dentinogenesis imperfecta: gray-blue/yellow-brown, fragile teeth).
7. Q20How do the OI types differ?

   Type I: AD, ↓ amount of normal collagen, postnatal fractures, blue sclerae, normal stature (most common, mildest). Type II: perinatal lethal. Type III: progressive deforming, short, sclerae blue → white. Type IV: moderate, short stature, normal sclerae.
8. Q21What is a classic OI trap?

   Multiple fractures in a child can look like abuse — look for blue sclerae, dental problems, hearing loss and family history.

Key questions

1. Q22What does PTH excess do to bone?

   Increases osteoclast activity → resorption, especially of cortical bone (subperiosteal resorption of the radial side of middle phalanges, distal clavicle; osteopenia at the distal forearm/wrist).
2. Q23What are the two classic bone findings in hyperparathyroidism?

   Dissecting osteitis — osteoclasts tunnel into the center of trabeculae ("railroad track" appearance). Brown tumors — masses of multinucleated giant cells (osteoclast-like), hemorrhage (hemosiderin → brown) and reparative fibrous tissue. Advanced disease = osteitis fibrosa cystica.
3. Q24How do primary, secondary and tertiary hyperparathyroidism differ?

   Primary: autonomous adenoma (most) or hyperplasia → ↑ Ca²⁺, ↑ PTH, ↓ phosphate. Secondary: low Ca²⁺ or vitamin D deficiency (often CKD) drives compensatory ↑ PTH with low/normal Ca²⁺. Tertiary: after long secondary disease the glands become autonomous → ↑ PTH and ↑ Ca²⁺.
4. Q25How does primary hyperparathyroidism present?

   "Stones, bones, groans, moans": kidney stones and hypercalciuria, fractures/osteopenia, abdominal pain, and neuropsychiatric symptoms ("brain fog"). Often found by incidental hypercalcemia. Sestamibi scan localizes the adenoma.
5. Q26What is rickets vs osteomalacia?

   The same defect — failure to mineralize osteoid — in children (rickets, open growth plates) vs adults (osteomalacia, closed growth plates).
6. Q27What are the causes?

   Vitamin D problems (poor sun exposure/dark skin/low intake; malabsorption — celiac, gastric bypass, biliary or pancreatic disease; liver disease; renal failure or 1α-hydroxylase defect; P450 inducers such as phenytoin, rifampin, phenobarbital; vitamin D receptor defects) or phosphate depletion (antacids, X-linked hypophosphatemic rickets).
7. Q28What does rickets look like?

   Growth plate cartilage keeps accumulating and thickens; chondrocytes lose columns; hypertrophic zone expands. Clinically: bowed legs, rachitic rosary (costochondral beading), craniotabes (soft skull), frontal/parietal bossing, pigeon chest, waddling gait. X-ray: cupping and fraying of metaphyses.
8. Q29What does osteomalacia look like?

   Excess unmineralized osteoid (wide osteoid seams) → bone pain, proximal muscle weakness, fractures (pseudofractures/Looser zones).
9. Q30What are the labs in vitamin D–deficiency rickets?

   Low 25-OH vitamin D, low/normal calcium, LOW phosphate, HIGH PTH (secondary hyperparathyroidism), HIGH alkaline phosphatase.

Key questions

1. Q31What is osteoporosis?

   Reduced bone mass with increased porosity and fracture risk. Cancellous (trabecular) bone is hit first: trabeculae thin and lose their connections → microarchitectural instability.
2. Q32What are the three routes to osteoporosis?

   Failure to reach peak bone mass (genetics, nutrition, lifestyle), increased breakdown (estrogen deficiency, hyperparathyroidism, low Ca²⁺/vitamin D, inactivity) and inadequate formation (aging — impaired cell renewal, fewer growth factors).
3. Q33Primary vs secondary osteoporosis?

   Primary = postmenopausal (estrogen loss → ↑ RANKL, ↓ OPG, ↑ IL-6) and senile. Secondary = multiple myeloma; endocrine (hyperthyroid, hyperparathyroid, hypogonadism, Cushing, growth hormone deficiency); GI (celiac, bariatric surgery, liver disease); renal osteodystrophy; drugs (corticosteroids, aromatase inhibitors, chemo, anticoagulants, anticonvulsants); immobility.
4. Q34What are its complications?

   Vertebral compression (anterior wedge) fractures → back pain, height loss, kyphosis, 5× risk of more spine fractures. Hip fracture → 8–34% higher 1-year mortality, 2.5× future fracture risk, 20% need long-term nursing care. Distal radius (Colles) fractures.
5. Q35What is osteopetrosis?

   Defective osteoclast resorption — often a defect in acidifying the resorption pit (carbonic anhydrase II) or in osteoclast activation (e.g., RANKL pathway). AR forms are severe (infancy); AD form is mild and found later ("marble bone").
6. Q36What does osteopetrosis look like?

   Diffusely sclerotic, dense bones on X-ray; histology shows persistent primary spongiosa (calcified cartilage cores), woven bone without lamellar bone and no marrow space. Bones are dense but brittle → fractures.
7. Q37What are the consequences of no marrow space?

   Pancytopenia/anemia, infections, extramedullary hematopoiesis → hepatosplenomegaly; narrowed foramina → cranial nerve palsies (vision, hearing, facial).
8. Q38What is Paget disease (osteitis deformans)?

   Localized, disordered remodeling in three phases: osteolytic → mixed osteoclastic/osteoblastic → osteosclerotic ("burnt out"). Net bone mass rises, but the bone is thick, weak and prone to fracture and deformity.
9. Q39How does Paget present?

   Older adult (usually >40–50, often Northern European descent), frequently asymptomatic with isolated ↑ alkaline phosphatase (normal Ca²⁺ and phosphate) and increased uptake on bone scan. Skull, spine, pelvis and lower-limb long bones. Bone pain, warmth over bone, enlarging hat size, hearing loss, spinal stenosis, bowing, fractures, high-output heart failure (AV shunting).
10. Q40What are the classic Paget findings?

    X-ray: "cotton-wool" skull, mixed lytic/sclerotic lesions, thickened cortex. Histology: mosaic pattern of lamellar bone with irregular cement lines; huge osteoclasts with many nuclei and intranuclear inclusions; marrow replaced by vascular fibrous tissue.
11. Q41What causes Paget, and what is its worst complication?

    Possibly paramyxovirus infection (measles, RSV) → IL-6 → osteoclast activation, plus genetics (SQSTM1 and other loci). Complications include secondary osteosarcoma (and giant cell tumor).
12. Q42Why are Paget osteoclasts overactive?

    Their precursors are hypersensitive to vitamin D and RANKL, and IL-6 released by bone cells recruits even more osteoclasts.