Calcium_Phosphate_SJM_2_year

State the normal total serum calcium range and explain how calcium partitions among ionized, protein-bound, and complexed fractions. Include clinical implications of changes in albumin.

Total Ca: -2.1–2.6 mmol/L (8.5–10.5 mg/dL). -45% ionized (free, -1.15–1.30 mmol/L), -40% albumin-bound, -15% complexed (citrate/phosphate). Low albumin lowers total Ca but not ionized Ca—use ionized Ca or albumin-corrected total Ca (mg/dL: +0.8 per 1 g/dL albumin below 4).

List eight major biological functions of calcium and link each to a representative cellular process or tissue.

Excitation–contraction (skeletal/cardiac muscle); neurotransmitter release (synaptic vesicle fusion); second messenger (Ca2+–calmodulin signaling); coagulation (factors II, VII, IX, X); exocytosis/secretion (endocrine cells); enzyme cofactor (kinases/phosphatases); cell adhesion (cadherins); bone/teeth mineralization (hydroxyapatite).

Summarize phosphorus handling in the body: intestinal absorption, bone storage, renal excretion, and how low calcium intake affects phosphate excretion.

Intestine: NaPi-IIb + paracellular absorption. Bone: major store as hydroxyapatite. Kidney: proximal-tubule NaPi-IIa/IIc reabsorption is decreased by PTH → phosphaturia. Low Ca → ↑PTH → ↑phosphate excretion; 1,25(OH)2D promotes intestinal phosphate uptake.

Give the normal serum phosphate reference interval and convert it between mg/dL and mmol/L.

Adults: -0.8–1.5 mmol/L (2.5–4.5 mg/dL). Conversion: mg/dL × 0.323 = mmol/L; mmol/L ÷ 0.323 = mg/dL.

Compare the body distributions of calcium, phosphorus, and magnesium (total content; % in skeleton vs soft tissues) and relate this to their physiological roles.

Ca -1–1.2 kg (-99% bone/teeth); P -700 g (-85% bone); Mg -25 g (-50–60% bone, rest intracellular). Dominant skeletal stores buffer ECF levels while soft-tissue fractions support enzymatic and energetic roles (ATP, nucleic acids).

Differentiate transcellular versus paracellular mineral transport and name the main drivers and co-transported ions for each route.

Transcellular: through cells via channels/transporters (e.g., TRPV6/5, NCX1, PMCA1b), driven by electrochemical gradients and ATP pumps. Paracellular: between cells via claudin tight junctions, driven by lumen-to-blood gradients and solvent drag; often coupled with Na+ movement.

Describe the composition of bone mineral (hydroxyapatite): chemical formula, crystal size, and common ionic substitutions that occur in vivo.

Hydroxyapatite: Ca10(PO4)6(OH)2. Nanocrystals -50×25×4 nm within collagen gap zones. Substitutions: CO3 2− for PO4 3− or OH−; F− for OH−; Mg2+, Na+ for Ca2+—these alter solubility and mechanics.

Explain why bone remodeling is continuous and list three purposes it serves beyond calcium homeostasis.

Remodeling repairs microdamage, adapts architecture to mechanical load (mechanostat), and renews old matrix to maintain material quality; additionally, it helps in acid–base buffering and releases growth factors.

Detail the osteoclast resorption mechanism: formation of the sealing zone, acidification via vacuolar H+-ATPase, and enzymatic digestion (TRAP, cathepsin K, MMPs).

Osteoclasts attach via αvβ3 integrins (sealing zone) → ruffled border forms. V-ATPase + ClC-7 pump H+ and Cl− to acidify resorption lacuna (pH -4.5), dissolving mineral; cathepsin K and MMPs digest collagen; TRAP dephosphorylates matrix proteins.

Outline osteoblast roles from osteoid deposition to mineralization; distinguish primary versus secondary mineralization and possible fates of osteoblasts.

Osteoblasts secrete type I collagen osteoid + ALP/vesicles → primary mineralization (rapid) then secondary (slow maturation). Fates: become osteocytes, quiescent lining cells, or undergo apoptosis.

Explain the OPG–RANKL–RANK system and justify why the RANKL/OPG ratio is considered the conclusive determinant of bone resorption.

RANKL (on osteoblasts/osteocytes) binds RANK on pre-osteoclasts → maturation/activation. OPG is a soluble decoy receptor that sequesters RANKL. A higher RANKL/OPG ratio drives osteoclastogenesis and resorption; a lower ratio suppresses it.

List key systemic (PTH, calcitonin, 1,25(OH)2D3, glucocorticoids, and sex steroids) and local (growth factors, cytokines, prostaglandins) regulators of bone homeostasis and their broad effects.

PTH: ↑resorption (intermittent dosing can be anabolic). Calcitonin: antiresorptive. 1,25D: ↑Ca/PO4 absorption, modulates formation. Estrogens: ↓RANKL, ↑OPG; glucocorticoids: ↓formation, ↑resorption. Local: TGF-β, IGFs, BMPs (formation); IL-1, TNF, PGE2 (resorption).

Describe parathyroid hormone biosynthesis (pre-pro-PTH → PTH 1–84), how the CaSR controls its secretion, and the intracellular signaling pathways engaged by the PTH receptor.

Prepro-PTH → pro-PTH → PTH(1–84). CaSR senses extracellular Ca2+: high Ca suppresses PTH secretion, low Ca stimulates. PTH1R couples to Gs (↑cAMP/PKA) and Gq (↑IP3/DAG/PKC).

Predict the kidney’s response to PTH with respect to calcium reabsorption, phosphate handling, and 1α-hydroxylase activity; explain how this alters serum Ca and PO4.

PTH ↑Ca reabsorption in distal nephron; ↓proximal phosphate reabsorption (internalizes NaPi-IIa/IIc) → phosphaturia; ↑1α-hydroxylase → ↑1,25D. Net: ↑serum Ca, ↓serum phosphate.

Explain how PTH indirectly stimulates osteoclastogenesis via osteoblasts/osteocytes and RANKL expression.

PTH binds PTH1R on osteoblasts/osteocytes → ↑RANKL, ↓OPG, ↑M-CSF → recruits/matures osteoclasts (indirect, as osteoclasts lack PTH1R).

Identify calcitonin’s cellular source, structure, stimulus for release, and its principal targets; summarize its net effect on serum calcium.

Source: thyroid parafollicular C cells; 32-aa peptide; stimulated by hypercalcemia and some GI hormones. Targets osteoclasts (↓activity) and kidney (↑Ca, PO4 excretion). Net: lowers serum Ca (short-lived in adults).

According to the lecture, how does calcitonin influence OPG/RANKL expression in osteoblasts and what is the downstream effect on osteoclast activity?

Calcitonin tends to ↑OPG and/or ↓RANKL expression by osteoblast-lineage cells, tipping the balance against osteoclast formation—thus reducing resorption.

Trace vitamin D metabolism from skin/liver/kidney to 1,25(OH)2D3; describe transport (DBP, albumin), and how VDR/RXR complexes regulate gene transcription via VDREs.

UVB converts 7-dehydrocholesterol → cholecalciferol; liver 25-hydroxylation → 25(OH)D; kidney 1α-hydroxylase → 1,25(OH)2D3. Transported on DBP/albumin. 1,25D binds VDR, heterodimerizes with RXR, binds VDREs to regulate transcription.

Diagram intestinal calcium absorption (CaT1/TRPV6, CaM–BBMI, calbindin, Ca-ATPase) and specify which steps are upregulated by 1,25(OH)2D3.

Apical TRPV6 entry → cytosolic buffering by calbindin-D9k → basolateral PMCA1b/NCX1 extrusion. 1,25D upregulates TRPV6, calbindin, and PMCA1b.

Summarize vitamin D–dependent renal calcium reabsorption in the distal tubule and compare the transport proteins to those in intestine.

DCT uses TRPV5 (not TRPV6) apically, calbindin-D28k intracellularly, and NCX1/PMCA1b basolaterally. 1,25D enhances these proteins—analogous to intestinal pathway but with TRPV5 and D28k.

Describe stage-dependent effects of vitamin D on osteoblast proliferation, differentiation, apoptosis, and matrix mineralization.

1,25D tends to inhibit proliferation of immature osteoblasts, promotes differentiation and expression of osteocalcin/ALP, supports mineralization at physiologic levels; excess can upregulate inhibitors (e.g., osteopontin) and impair mineralization.

Explain vitamin K’s role as a cofactor for γ-glutamyl carboxylase in bone; name key vitamin K–dependent proteins (e.g., osteocalcin) and the consequences for mineral binding.

Vitamin K enables γ-carboxylation of glutamate residues in osteocalcin and MGP, creating Ca2+-binding Gla domains; deficiency → undercarboxylated proteins with reduced affinity for mineral and increased vascular calcification risk.

Provide epidemiologic context for osteoporosis, then connect the pathophysiology to imbalance between bone formation and resorption.

Highly prevalent in postmenopausal women and elderly; fractures of hip/vertebrae/wrist dominate morbidity. Estrogen loss and aging shift balance toward resorption (↑RANKL, ↓OPG; ↓osteoblast number/function).

List postoperative risks for hypocalcemia/hypoparathyroidism after thyroid surgery and the role of vitamin D deficiency in postoperative hypocalcemia risk.

Risks: parathyroid devascularization or removal, hungry bone after hyperthyroidism, transient hypoparathyroidism. Low pre-op 25(OH)D increases risk/severity; management: Ca++ ± calcitriol supplementation.

Explain why simultaneous upregulation of RANKL and downregulation of OPG drives bone loss; give one clinical scenario that could shift this balance.

Because more RANKL with less decoy OPG maximally stimulates osteoclastogenesis. Scenarios: estrogen deficiency, glucocorticoid therapy, chronic inflammation (↑IL‑1/TNF).

Compare how PTH versus calcitonin modulate the OPG–RANKL–RANK axis and predict their effects on bone turnover.

PTH (continuous) ↑RANKL/↓OPG → ↑resorption; calcitonin shifts the balance toward ↓osteoclast formation/activity → ↓resorption. Net: PTH catabolic (unless intermittent); calcitonin antiresorptive.

Predict the effects of chronic kidney disease on phosphate retention, 1,25(OH)2D3 synthesis, PTH (secondary hyperparathyroidism), and bone.

CKD → ↓phosphate excretion (hyperphosphatemia), ↓1α-hydroxylase (low 1,25D), hypocalcemia → secondary hyperparathyroidism, renal osteodystrophy (high-turnover bone disease ± adynamic bone).

Describe the role of phosphate as a buffer in acid-base balance and how this relates to its distribution in plasma and bone.

H2PO4−/HPO4 2− buffers renal tubular fluid and intracellular pH; bone phosphate can accept H+ (buffering chronic acidosis) at the cost of demineralization.

Explain why decreased calcium intake can increase phosphate excretion and infer the hormonal mediators involved.

Low Ca intake → ↑PTH to defend Ca; PTH downregulates proximal NaPi transporters → phosphaturia. 1,25D may rise, increasing gut PO4 uptake but renal effect dominates.

Give examples of when paracellular versus transcellular calcium transport predominates in the gut and kidney, and what drives each pathway.

Gut: jejunum/ileum—paracellular (bulk flow); duodenum—transcellular (vitamin D–regulated). Kidney: PT—mostly paracellular/solvent drag; DCT—transcellular, hormonally regulated (PTH/1,25D).

List key calcium transport players at the cellular level (channels, pumps, exchangers, binding proteins) and where ATP hydrolysis is required.

Channels: TRPV5/6; Exchangers: NCX1; Pumps: PMCA1b (ATP), SERCA (ATP); Buffers: calbindins; Mitochondrial uniporter; ATP needed for PMCA/SERCA.

Discuss osteoblast → osteocyte transition and how embedded osteocytes participate in regulating bone remodeling.

Osteoblasts become encased, extend processes via canaliculi, and differentiate into osteocytes that sense strain and secrete sclerostin (↓Wnt signaling) and RANKL, coordinating local formation/resorption.

Differentiate primary from secondary mineralization in time course and effect on bone material properties.

Primary: rapid deposition to -60–70% mineral within days; Secondary: slow maturation over months—crystal growth and packing increase stiffness/ brittleness but strength to a point.

Relate hydroxyapatite nanostructure and collagen strain under load to bone’s mechanical behavior.

Mineralized collagen fibrils share load: collagen provides toughness/ductility; mineral confers stiffness. Shear at the mineral–collagen interface dissipates energy and resists crack propagation.

According to the slides, how does calcitonin affect renal handling of calcium and phosphate and 1α-hydroxylase expression?

It modestly increases urinary Ca and phosphate excretion and can reduce renal 1α-hydroxylase activity—overall contributing to lower serum Ca (transient).

Describe how the CaSR functions as a sensor for extracellular Ca2+ in parathyroid chief cells and the consequence of its activation/inhibition on PTH secretion.

CaSR (GPCR) activation by high Ca2+ suppresses PTH secretion; low Ca2+ (or inactivating CaSR mutations) permits/increases PTH release—explaining familial hypocalciuric hypercalcemia with low urinary Ca.

Provide two examples each of endocrine and mechanical cues that shift bone toward net formation or net resorption.

Toward formation: intermittent PTH, estrogens; cyclic loading/mechanical strain. Toward resorption: glucocorticoids, hyperthyroidism; immobilization/unloading.

List three ways calcified tissue interfaces with cells (hydroxyapatite moieties, type I collagen, non-collagenous proteins) to influence adhesion/behavior.

Integrin-mediated binding to RGD-containing proteins (osteopontin/bone sialoprotein), collagen receptors (α1β1/α2β1), and direct interaction with mineral surfaces—modulating adhesion, differentiation, and resorption.

Explain the effect of hypoalbuminemia on total versus ionized calcium and why clinical interpretation relies on the ionized fraction.

Total Ca falls with low albumin, but ionized Ca (biologically active) is unchanged; thus ionized Ca or albumin-corrected totals should guide decisions.

Analyze a case: post-thyroidectomy patient develops perioral tingling and carpopedal spasm—identify the hormonal deficit and immediate biochemical change.

Acute hypoparathyroidism → ↓PTH → ↓serum Ca2+ (ionized), ↑phosphate; treat with IV calcium gluconate if symptomatic, then oral Ca ± calcitriol