13.6 Hypocalcaemia & Metabolic Bone Disease

3. Hypocalcaemia & Magnesium-Dependent PTH Resistance

Clinical Manifestations of Neuromuscular Irritability

Hypocalcaemia lowers the threshold potential of peripheral excitable membranes, producing spontaneous depolarization:

• Symptoms: Perioral and digital tingling/paresthesias, muscle cramps, carpopedal spasm, stridor (laryngospasm), and generalized seizures.
• Physical Examination Signs:
  • Chvostek's Sign: Light tapping over the facial nerve trunk anterior to the external auditory meatus elicits ipsilateral twitching of facial muscles (orbicularis oris, corner of mouth, or nose).
  • Trousseau's Sign: Inflation of a sphygmomanometer blood pressure cuff to $20\text{ mmHg}$ above systolic blood pressure for 3 minutes precipitates painful carpopedal spasm (flexion of the wrist and metacarpophalangeal joints, extension of the interphalangeal joints, and adduction of the thumb; 'main d'accoucheur'). Trousseau's sign is significantly more sensitive ($94%$) and specific ($99%$) than Chvostek's sign.
  • Electrocardiogram: Prolongation of the ST segment and corrected QT interval (QTc), predisposing to Torsades de Pointes and ventricular arrhythmias.

Etiologies of Hypocalcaemia

1. Post-Surgical Hypoparathyroidism: Accidental excision or devascularization of parathyroid glands during total thyroidectomy, completion thyroidectomy, or radical neck dissection. Symptoms classically manifest 24 to 48 hours post-operatively.
2. Autoimmune Hypoparathyroidism: Isolated or component of Autoimmune Polyendocrine Syndrome Type 1 (APS-1).
3. Severe Vitamin D Deficiency: Nutritional deficiency, malabsorption (coeliac disease, gastrectomy, bariatric surgery), or end-stage renal disease ($CYP27B1$ deficiency).
4. Acute Pancreatitis: Extravasated pancreatic lipases hydrolyze retroperitoneal fat into free fatty acids, which chelate calcium ions to form insoluble calcium salts (fat saponification).
5. Severe Hypomagnesaemia ($< 0.5\text{ mmol/L}$): (CRITICAL EXAM PEARL): Magnesium is an obligate intracellular cofactor for adenylate cyclase and G-protein coupled receptor signalling. Severe hypomagnesaemia (caused by chronic alcohol misuse, proton pump inhibitors, loop diuretics, or malabsorption) causes both impaired parathyroid hormone secretion AND severe end-organ skeletal/renal resistance to circulating PTH. The resulting hypocalcaemia is completely refractory to intravenous calcium administration until serum magnesium is replenished.

Acute Management of Severe Hypocalcaemia

Severe or symptomatic hypocalcaemia (corrected calcium $< 1.90\text{ mmol/L}$) requires immediate emergency intervention:

• Administer intravenous calcium gluconate 10% (10 mL in 50–100 mL of 5% dextrose infused over 10–20 minutes) with continuous ECG monitoring. Calcium gluconate is preferred over calcium chloride due to a substantially lower risk of severe tissue necrosis if extravasation occurs.
• Follow with a continuous maintenance intravenous calcium infusion.
• Concomitantly replenish serum magnesium with intravenous magnesium sulphate (e.g. $4\text{ g}$ in $100\text{ mL}$ $0.9%$ saline over 30 minutes).

4. Metabolic Bone Disease

Metabolic bone disorders alter bone remodeling and mineral homeostasis through distinct pathophysiological pathways:

Osteoporosis

• Pathophysiology: Characterized by low bone mineral density and microarchitectural deterioration of bone tissue, leading to increased bone fragility. The mineral-to-collagen matrix ratio remains entirely normal (unlike osteomalacia).
• Diagnosis: Dual-energy X-ray absorptiometry (DEXA) scanning of the lumbar spine and femoral neck:
  • T-Score (compared to young healthy sex-matched reference peak bone mass):
    • Normal: $\text{T-score} \ge -1.0$
    • Osteopenia: $-1.0 > \text{T-score} > -2.5$
    • Osteoporosis: $\text{T-score} \le -2.5$
    • Severe (Established) Osteoporosis: $\text{T-score} \le -2.5$ in the presence of one or more documented fragility fractures
  • Z-Score: Compared to age- and sex-matched peers. A $Z\text{-score} \le -2.0$ suggests secondary causes (hypogonadism, hypercortisolism, coeliac disease, hyperthyroidism, myeloma).
• Fracture Risk Assessment: FRAX tool and NOGG (National Osteoporosis Guideline Group) intervention thresholds.
• Pharmacotherapy:
  • Oral Bisphosphonates (First-Line): Alendronic acid ($70\text{ mg}$ once weekly) or Risedronate ($35\text{ mg}$ weekly). Inhibit osteoclastic farnesyl pyrophosphate synthase, inducing osteoclast apoptosis.
    • Mandatory Administration Instructions: Swallow whole with a full glass of plain tap water, upon waking in the morning, on an empty stomach at least 30 minutes before any food, beverage, or other medications, and remain sitting or standing upright for at least 30 minutes to prevent chemical pill-induced oesophagitis and ulceration.
    • Rare Long-Term Complications: Osteonecrosis of the jaw (ONJ) (mandates pre-treatment dental review) and atypical femoral fractures (transverse subtrochanteric/diaphyseal fractures, often preceded by dull thigh or groin pain). Prompts consideration of a 'bisphosphonate holiday' after 5 years of oral or 3 years of IV therapy in lower-risk patients.
  • Intravenous Bisphosphonates: Zoledronic acid ($5\text{ mg}$ IV infusion once yearly). Preferred for upper gastrointestinal intolerance, malabsorption, or poor oral compliance.
  • Denosumab: Fully human monoclonal antibody directed against RANKL, preventing osteoclast formation and survival. Administered $60\text{ mg}$ subcutaneously every 6 months. Critical Caveat: Discontinuation causes a rapid rebound surge in bone resorption and a high risk of multiple vertebral fractures; treatment must never be stopped without transitioning to a bisphosphonate.
  • Teriparatide: Recombinant human PTH 1–34 administered daily subcutaneously for up to 24 months. Potent anabolic agent stimulating osteoblastic bone formation. Contraindicated in patients with prior skeletal irradiation, bone metastases, or Paget's disease due to theoretical osteosarcoma risk.

Osteomalacia & Rickets

• Pathophysiology: Defective mineralization of newly synthesized organic bone matrix (osteoid) in adults (osteomalacia) or unclosed epiphyseal growth plates in children (rickets). Most commonly caused by severe vitamin D deficiency (serum $25\text{-hydroxyvitamin D} < 25\text{ nmol/L}$) or chronic phosphate wasting.
• Clinical Presentation: Widespread diffuse, dull, aching bone pain and tenderness (particularly over the sternum, pelvis, and anterior tibiae), accompanied by severe proximal myopathy resulting in a characteristic waddling gait and difficulty rising from chairs.
• Radiological Signatures: Generalized osteopenia with pathognomonic Looser's zones (pseudofractures): narrow, transverse, radiolucent bands perpendicular to the cortex with sclerotic margins, representing unmineralized osteoid stress fractures. Classically located on the medial femoral neck, pubic rami, ribs, and lateral borders of the scapula.
• Biochemical Profile: Low or low-normal corrected calcium, low serum phosphate, elevated alkaline phosphatase (ALP), markedly suppressed $25\text{-hydroxyvitamin D}$, and secondary hyperparathyroidism (elevated PTH).

Paget's Disease of Bone (Osteitis Deformans)

• Pathophysiology: Focal disorder of accelerated, disorganized bone remodeling initiated by hyperactive, giant multinucleated osteoclasts (frequently associated with mutations in the sequestosome 1 gene, SQSTM1 / p62). Subsequent frenzied osteoblastic bone formation yields chaotic, poorly mineralized woven bone with a characteristic 'mosaic' or 'jigsaw' architectural pattern of irregular cement lines under polarized light microscopy.
• Epidemiology & Presentation: Typically presents in individuals $> 55$ years of age (highest prevalence in the UK, particularly Lancashire). Often discovered incidentally on routine blood tests showing an isolated, markedly elevated serum alkaline phosphatase (ALP) with completely normal serum calcium and phosphate.
• Clinical Signs & Complications:
  • Localized constant bone pain and skeletal deformities: increasing hat size (cranial vault expansion), frontal bossing, anterior bowing of the tibia (sabre tibia), and enlarged warm bones due to marked cutaneous hypervascularity.
  • Cranial Nerve Compression: Bony encroachment of the internal auditory meatus or temporal bone petrous remodeling leads to sensorineural hearing loss / deafness (CN VIII) in up to $30%$.
  • High-Output Cardiac Failure: Extensive pagetic bone hypervascularity functions as multiple microscopic arteriovenous shunts.
  • Malignant Transformation: Development of secondary osteosarcoma occurs in $< 1%$ of patients; suspected if there is a sudden, dramatic intensification of localized bone pain, new soft tissue mass, or rapid surge in ALP.
• Radiology: Sclerotic and lytic phases: osteolytic wedge ('blade-of-grass' or 'candle-flame' sign), thickened trabeculae, cortical expansion, and cotton-wool appearance of the calvarium.
• Treatment: Indicated for bone pain localized to pagetic sites, or involvement of high-risk locations (skull base, weight-bearing joints, vertebrae). The treatment of choice is intravenous Zoledronic acid (5 mg single infusion), which rapidly normalizes alkaline phosphatase and induces durable remission lasting years.