Electrolyte–bone metabolism axis (Ca, P, Mg, Vit D, PTH, ALP, FGF-23, & calcitonin)

Calcium, Vit D, Phosphate:

• PTH increases Ca, decreases phosphate.

• Vitamin D increases both Ca and phosphate (indirectly).

• Acute alkalosis lowers ionised calcium.

• Always correct Mg before Ca; Because Low Mg²⁺ → ↓ PTH secretion results in ↓ bone resorption + ↓ renal Ca²⁺ reabsorption → persistent hypocalcaemia. IV calcium temporarily raises plasma calcium, but it drops again because the axis is still off. Once Mg²⁺ is replenished, PTH secretion and responsiveness return → calcium rises normally. Clinical clue: “Refractory hypocalcaemia” (especially in diarrhoea, alcoholism, ileostomy, or PPI use) = check magnesium.

• PTH ↑, Ca↑, PO₄↓ → Primary hyperparathyroidism.

• PTH ↓, Ca↓, PO₄↑ → Hypoparathyroidism.

• Ca↓, PO₄↓, PTH↑, ALP↑ → Vitamin D deficiency/osteomalacia.

• Ca↑, PO₄↑, PTH↓ → Vitamin D excess or bone destruction.

• Ca↓ unresponsive to calcium → check Mg²⁺.

• Tertiary hyperparathyroidism: In CKD → High phosphate (↓ phosphate excretion) + low calcitriol → ↓ serum calcium results secondary hyperparathyroidism (parathyroid glands hypertrophy). Over time, glands become autonomous — PTH secretion continues even when calcium normalises or rises. This leads to hypercalcaemia + high PTH → tertiary hyperparathyroidism.

• Pseudohypoparathyroidism: A condition in which PTH is produced in normal or high amounts, but target tissues (kidney and bone) are resistant to its action. So — PTH levels are high, but it can’t do its job. Caused by defective Gsα protein (G-protein coupled receptor) in PTH receptor signalling. Without Gsα → no cAMP generation → no biological response to PTH. It is associated with Albright’s Hereditary Osteodystrophy (AHO)

• Hypercalcemia: 

  • • Primary hyperparathyroidism rarely pushes Ca²⁺ beyond 12 mg/dL. 

    • Malignancy (PTH-related peptide, osteolysis, or calcitriol secretion) can rapidly raise Ca²⁺ >13 mg/dL, also symptoms appear abruptly — dehydration, confusion, constipation, arrhythmia — unlike the slow, chronic course of primary hyperparathyroidism.

      • • • PTHrP secretions; SCC of lung, renal, ovarian, breast

          • Osteolytic mets: Myeloma, breast cancer

          • Calcitrol-mediated; Lymphoma

ALP

• ALP is a marker of osteoblastic activity

All three — osteomalacia, Paget’s disease, and hyperparathyroidism — show raised ALP, but for different reasons and with distinct calcium–phosphate–PTH patterns.

• ↑ ALP, normal Ca and PO₄→ think Paget’s. = localised, disorganised bone remodelling. E.g.; An elderly man with bone pain, bowing of the tibia, and isolated raised ALP with normal calcium — diagnosis: Paget’s disease of bone

• Hypophosphatemia results→ impaired ATP → muscle necrosis, respiratory failure; IV replacement if < 01mg/dl or symptomatic  (Normal phosphate 2.5 to 4.5 mg/dl)

Magnesium: 

Normal value: 1.7 - 2.4 mg/dl

• • Serum Mg can look “normal” even if total body stores are low because only 1% is extracellular

  • Low Mg²⁺ makes 

    • 1. Low K⁺; Mg²⁺ inhibits the ROMK (Renal Outer Medullary K⁺) channels in the distal nephron. When magnesium is low, this inhibition is lost → K⁺ leaks continuously into the urine (renal potassium wasting).

      2. low Ca²⁺; Low Mg suppresses and blocks PTH → ↓ Ca²⁺

• In hypomagnesaemia, both hypokalaemia and hypocalcaemia are refractory to correction until magnesium is replaced — Mg²⁺ stabilises both the kidney’s K⁺ channels and the PTH axis.”

• ECG findings

  • • 1. Hypomagnesaemia: prolonged QT, flattened T, U waves, torsades

      2. Hypermagnesaemia: prolonged PR + QRS, heart block, asystole at >4 mmol/L

• Refractory Hypokalaemia + Hypocalcaemia → Think Hypomagnesaemia

• PPIs inhibit Mg2+ absorption from the gut

• High output stomas, diarrhoea causes Mg2+ loss

• Treatment points

  • • 1. Replace magnesium first (IV MgSO₄ 10–20 mmol over 4–6 h).

      2. Once Mg²⁺ normalises, → K⁺ and Ca²⁺ corrections will hold.

      3. Stop offending drugs (PPIs, aminoglycosides, diuretics).

      4. Monitor ECG and reflexes during IV Mg²⁺ infusion.

Calcitonin & FGF-23: 

Calcitonin

• Source: Parafollicular “C” cells of the thyroid

• Medullary thyroid carcinoma → marker = calcitonin ↑

FGF-23 (Fibroblast growth factor-23)

• Secreted by: Osteocytes & Osteoblasts

• It reduces both phosphate and vitamin D

CKD–Mineral and Bone Disorder: 

Renal bone disease = consequence of phosphate retention, low calcitriol, and secondary PTH excess → high-turnover bone (osteitis fibrosa), which may evolve into tertiary or adynamic forms

Clinical features

• Bone pain, fractures

• Pruritus (from Ca–PO₄ skin deposits)

• Vascular or soft tissue calcification

• Calciphylaxis (in severe cases)

Management target: Normalise Ca, PO₄, and PTH while preventing vascular calcification

• Early CKD: ↓ calcitriol → ↓ Ca → ↑ PTH (secondary hyperparathyroidism)

• Late CKD: Gland autonomy (tertiary hyperparathyroidism; clinical impact-> bone fracture and vascular calcification). Labs → ↑ Ca, ↑ PO₄, ↑ PTH (tertiary).  Tertiary = gland autonomy after chronic secondary stimulation

• ALP reflects bone turnover (↑ in high-turnover, N/low in adynamic).

• Aluminium toxicity (old dialysate) → osteomalacia.

• Calciphylaxis = due to calcium–phosphate precipitation in small blood vessels, leading to ischemic skin necrosis (painful ulcers with hard s/c calcified vessels)