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)

• Calcium: 

  • • Corrected Ca (mg/dL)=Measured Ca+0.8×(4.0−Albumin g/dL)

    • For every 0.1 unit ↑ in pH, ionised calcium ↓ by ~0.05 mmol/L (~0.2 mg/dL).

    • Deficit (mg)=(8.8−Measured Ca)×Body weight (kg)×20

    • 10% Ca gluconate (10 mL amp) = 90 mg

• Hypercalcemia: 

  • • Primary hyperparathyroidism rarely pushes Ca²⁺ beyond 12 mg/dL. 13 or more = malignancy

    • Approach: Confirm true hypercalcaemia. 

      • • Correct total calcium for albumin. Correction factor is 0.8 (normal albumin is 4mg/dl) & Exclude artefacts (prolonged tourniquet, dehydration, hemoconcentration)

        • "Look for, is it PTH dependent? 1. Primary hyperparathyroidism —> 24-hr urine Ca (↑), neck imaging, 2. Tertiary hyperparathyroidism —> Longstanding secondary HPT in CKD"

        • If PTH-independent (suppressed PTH), consider malignancy, vit d mediated (toxicity or lymphoma or sarcoidosis) or adrenal insufficiency (volume contracture)

    • 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

• Treatment

  • • • 1. IV fluids (0.9 % saline) – first line

        2. IV bisphosphonate (zoledronic acid)

        3. Calcitonin for acute control

        4. Steroids, if vitamin D-mediated cause

        5. Dialysis if refractory or renal failure

• Osteoblastic versus osteoclastic (ALP & Ca)

  • • Osteoblastic

      • • Bone formation (mineralise)

        • ↑ ALP (it hydrolyses phosphate esters → increases local phosphate→ promotes hydroxyapatite deposition)

        • Ca normal

        • Examples: Paget's disease, Rickets/osteomalacia, healing fractures, and mets

• Osteclasitc

  • • Bone resorption (break down)

    • Normal ALP

    • ↑ Ca (released from bone)

    • Examples: Vit D excess, hyperparathyroidism, PTHrP (malignancy), immobilisation

• Vitamin D:  

  • • ↑ 1,25-(OH)₂-vitamin D (calcitriol) →↑ intestinal absorption of Ca²⁺ and phosphate

    • Vitamin D increases both Ca and phosphate

    • Vitamin D excess

      • • Granulomatous diseases (e.g., sarcoidosis, TB, lymphoma); In granulomas and lymphomas, macrophages express 1-α-hydroxylase, which continues to convert 25-OH-D to 1,25-(OH)₂-D, independent of PTH regulation.

        • Vitamin D intoxication

        • Treatment; Steroid (↓ 1-α-hydroxylase activity in macrophages → ↓ calcitriol formation)

    • Vitamin D Deficiency (Osteomalacia or rickets in children)

      • • Mechanism: ↓ vitamin D → ↓ Ca²⁺ and PO₄³⁻ absorption → poor bone mineralisation.

        • Low Ca²⁺ → ↑ PTH (secondary hyperparathyroidism) → further phosphate loss.

        • Bone turnover ↑ → ↑ ALP (from active osteoblasts).

        • Pattern: ↓ Ca, ↓ PO₄, ↑ ALP, ↑ PTH.

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

• Paget's v/s Myeloma

  • • “Bone pain + very high ALP but normal calcium → Paget’s disease.”

    • “Bone pain + anaemia + hypercalcaemia + normal ALP → Myeloma.”

    • Paget’s = osteoblastic overdrive, Myeloma = osteoclastic destruction

• 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. 

Magnesium conversion factor; mg/dL = (mmol/L ) x 2.5

• • 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.”

• Clinical Clue: Tetany or carpopedal spasm despite calcium replacement → check Mg²⁺. 

  • • ECG: prolonged QT.

• 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

• Magnesium (Mg²⁺) is essential for PTH synthesis, secretion, and action.

• 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.

Hypermagnesemia

“In renal failure, magnesium accumulation suppresses insulin release acutely, prolongs insulin action chronically, blunts counter-regulatory response, and depresses cardiac conduction — leading to hypoglycaemia with bradycardia.”

• Magnesium excess suppresses insulin release acutely, but paradoxically in CKD:

  • • It can prolong insulin half-life (since insulin degradation is renal), plus reduce hepatic gluconeogenesis.

    • Together → persistent hypoglycaemia, even if not diabetic or on insulin.

    • Also, magnesium depresses adrenal and sympathetic responses to hypoglycaemia → blunted counter-regulation.

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

Rule:

• In CKD, any ion that depends on renal excretion accumulates — except calcium.”

• Ca²⁺ drops, everything else (K⁺, PO₄³⁻, Mg²⁺, H⁺) rises; the body pays with bone and conduction

• 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)

• “Low Ca + high PO₄ + high PTH = secondary HPT.”

• “High Ca + high PO₄ + very high PTH = tertiary HPT.”

• “Low PTH + low ALP = adynamic/aluminium bone.”

• “Painful necrotic skin + high Ca×PO₄ = calciphylaxis.”

• “First change in CKD bone disease = low calcitriol production.”

• Tertiary HPT: High Ca + high PO₄ + very high PTH even off treatment → gland autonomy.

• Adynamic bone: Normal/high Ca + low PTH + low ALP → oversuppression of bone activity. 

  • • • Long-term CKD + excessive vitamin D or calcium therapy → PTH oversuppression.

      • With very low PTH, both osteoclast (bone resorption) and osteoblast (bone formation) activity shut down.

      • The skeleton becomes metabolically “silent” — bone turnover almost stops (Low-turnover bone → fragile, brittle skeleton → fractures despite “normal” calcium. Also causes extraosseous calcification, because calcium has nowhere to go)

      • Low ALP = low osteoblast activity — hallmark of adynamic bone disease

“PTH is the metronome of bone turnover; if you silence it, the skeleton goes quiet.” In CKD, adynamic bone disease is not hypo-PTH failure; it’s hypo-PTH over-suppression. High vs Low Turnover CKD Bone Disease. Basically, CKD breaks the PTH–calcium link (PTH is shouting, but the kidney can’t hear). High PTH = high bone turnover But serum calcium depends on renal function and vitamin D status.

• If kidneys work → high PTH = high Ca

• If kidneys fail → high PTH = low/normal Ca (because calcitriol and renal Ca reabsorption fail)

• High ALP + High PTH → “Fibrosa cystica” (high turnover).

• Low ALP + Low PTH → “Adynamic bone disease” (low turnover)

Stages

1. Early CKD; Low calcitriol → secondary HPT

• • • ↓ Ca, ↑ PO₄, ↑ PTH

2. Dialysis stage (secondary HPT); Compensatory PTH rise

• Normal/↓ Ca, ↑ PO₄, ↑↑ PTH

3. Post years of stimulation (tertiary HPT); Gland autonomy

• ↑ Ca, ↑ PO₄, ↑↑ PTH

Evolution of Renal Bone Disease (CKD–MBD)

1. Normal Kidney Function

• • • Adequate GFR → Normal phosphate excretion

    • Normal calcitriol production → Normal calcium absorption

    • Normal Ca², Phosphate, and PTH levels

2. Early CKD (Reduced GFR)

• ↓ Phosphate excretion → ↑ phosphate

•  Phosphate binds calcium → ↓ Ionised Ca²

• ↓ 1-α-hydroxylase → ↓ Calcitriol → ↓ Ca absorption

• ↓ Ca² + ↑ phosphate→ ↑ PTH (Secondary HPT)

• Bone turnover ↑ (osteitis fibrosa cystica; a skeletal disorder caused by excessive PTH activity, which leads to bone loss, weakness, and the formation of cyst-like brown tumours)

• ALP ↑ (osteoblastic activity)

• Lab: Ca ↓/N, Phosphate ↑, PTH ↑↑, ALP ↑

3. Advanced CKD (Chronic Secondary HPT)

• Parathyroid hyperplasia → gland autonomy (altered set-point for calcium suppression)

• PTH secretion persists despite normal or high Ca

• Tertiary Hyperparathyroidism:

• Ca ↑, Phosphate ↑, PTH ↑↑↑, ALP ↑

• High bone turnover, disorganised architecture

4. Overtreatment / Oversuppression

• Excess vitamin D / calcium → ↓ PTH

• ↓ Osteoblast and osteoclast activity → Adynamic Bone Disease

• Ca N/↑, Phosphate N/↑, PTH ↓, ALP ↓, very low bone turnover

5. Special Situation - Calciphylaxis

• Calciphylaxis: Ca×Phosphate product ↑ → vascular calcification, skin necrosis

• Calciphylaxis is not primarily a bone disease, but a vascular extension of disordered mineral metabolism

• ↑ Ca×PO₄ product (>55 mg²/dL²), ↑ PTH, ↑ ALP

Key Concepts

• Secondary HPT: PTH high, Ca normal/low, Phosphate high, ALP high.

• Tertiary HPT: PTH autonomous, both Ca and Phosphate high.

• Adynamic: PTH and ALP low, bone turnover suppressed.

• Calciphylaxis: Ca×Phosphate overload → soft-tissue necrosis.

“Early CKD raises PTH to survive, late CKD turns PTH rogue, overtreatment silences the skeleton.”

Multiple Myeloma (Myelomatosis/plasma cell myeloma/Kahler disease) is a multifocal proliferation of plasma cells based in the bone marrow.