Vitamin D Deficiency

Vitamin D deficiency causes rickets in children (growth plate abnormalities, bowing, widened epiphyses) and osteomalacia in adults (defective mineralization, Looser zones, bone pain). Severe deficiency is defined as 25-OH vitamin D under 25 nmol/L (under 10 ng/mL); target for bone health is over 50 nmol/L, with over 75 nmol/L optimal before elective arthroplasty. A key clinical feature is proximal myopathy (waddling gait, difficulty rising from chair) due to vitamin D receptors in muscle affecting calcium-dependent contraction. Causes include inadequate sunlight, malabsorption (celiac, bariatric surgery), and CKD (impaired 1-alpha hydroxylation). Treatment: 50,000 IU weekly for 6-8 weeks loading, then 800-2000 IU daily maintenance. 30% of arthroplasty patients are deficient preoperatively, increasing infection risk (OR 2.4) and delayed healing.

Definition

Vitamin D deficiency is defined by inadequate serum 25-hydroxyvitamin D (25-OH vitamin D), the major circulating form and best marker of vitamin D status. Deficiency leads to impaired intestinal calcium absorption, compensatory secondary hyperparathyroidism, and ultimately skeletal disease: rickets in children (affecting growth plates) and osteomalacia in adults (defective bone mineralization).

Epidemiology

Global burden:

• 1 billion people worldwide have vitamin D deficiency or insufficiency
• 30-50% of community-dwelling elderly have levels less than 50 nmol/L
• 50-70% of hip fracture patients are vitamin D deficient
• Dark-skinned populations in high latitudes have 5-10 times higher risk

Global practice variation:

• Prevalence rises with latitude - populations above 35 degrees North/South have winter UVB too weak for cutaneous synthesis
• Institutionalized elderly - 40-60% deficient across high-income countries
• Post-bariatric surgery - 25-40% develop deficiency without supplementation
• South Asian, Middle Eastern and East African migrants to high-latitude countries are a recognized high-risk group (skin pigmentation plus concealing dress)

Risk factors:

• Age - elderly have reduced skin synthesis capacity
• Dark skin - melanin blocks UVB absorption (requires 3-5 times longer sun exposure)
• Institutionalized or homebound - inadequate sunlight exposure
• Malabsorption syndromes - celiac disease, Crohn's disease, post-bariatric surgery
• Chronic kidney disease - impaired activation of vitamin D
• Medications - anticonvulsants (phenytoin, phenobarbital), rifampicin

Synthesis and Activation

Activation pathway:

1. Liver (25-hydroxylation): Vitamin D3 converted to 25-OH vitamin D by 25-hydroxylase (primary storage form, half-life 2-3 weeks)
2. Kidney (1-alpha hydroxylation): 25-OH vitamin D converted to 1,25-dihydroxy vitamin D (calcitriol) by 1-alpha hydroxylase (active hormone, tightly regulated by PTH, calcium, phosphate)

Physiological Actions

Primary role - calcium homeostasis:

• Intestinal calcium absorption - upregulates calcium-binding proteins in small intestine
• Bone mineralization - provides adequate calcium and phosphate for hydroxyapatite formation
• Renal calcium reabsorption - enhances distal tubular calcium reabsorption
• PTH regulation - suppresses PTH secretion when calcium adequate

Extra-skeletal effects:

• Muscle function - vitamin D receptors in skeletal muscle regulate calcium-dependent contraction
• Immune function - modulates innate and adaptive immunity (deficiency increases infection risk)
• Cell proliferation - anti-proliferative effects in many tissues

Cascade of Metabolic Derangements

Progressive pathophysiology:

1. Vitamin D deficiency (25-OH vitamin D less than 50 nmol/L)
2. Reduced intestinal calcium absorption (efficiency drops from 30-40% to 10-15%)
3. Mild hypocalcemia triggers parathyroid glands
4. Secondary hyperparathyroidism (compensatory PTH elevation to maintain calcium)
5. PTH-mediated bone resorption releases calcium from skeleton
6. Renal phosphate wasting (PTH inhibits proximal tubular phosphate reabsorption)
7. Hypophosphatemia impairs mineralization
8. Defective bone mineralization - osteoid accumulates but cannot mineralize (osteomalacia)
9. Skeletal deformities and fractures in severe, prolonged deficiency

Skeletal Manifestations

Neuromuscular Effects

Proximal myopathy mechanism:

• Vitamin D receptors (VDR) in skeletal muscle regulate calcium homeostasis within myocytes
• Deficiency impairs calcium-dependent muscle contraction
• Results in proximal muscle weakness (hip flexors, shoulder abductors greater than distal muscles)
• Type II muscle fiber atrophy on biopsy (fast-twitch fibers)

Clinical manifestations:

• Waddling gait (Trendelenburg due to hip abductor weakness)
• Difficulty rising from chair (hip flexor and knee extensor weakness)
• Difficulty climbing stairs (quadriceps weakness)
• Difficulty reaching overhead (shoulder abductor weakness)

Muscle weakness is independent of bone disease and can occur without osteomalacia.

Symptoms

Examination Findings

Musculoskeletal:

• Antalgic or waddling gait - pain avoidance or Trendelenburg
• Bone tenderness - sternal pressure, rib compression, pelvic compression painful
• Skeletal deformities - leg bowing, kyphosis (chronic cases)
• Reduced muscle power - hip flexion (iliopsoas) and knee extension (quadriceps) grade 3-4 out of 5

Neurological:

• Proximal muscle weakness - cannot rise from squat without using hands
• Hyporeflexia - reduced deep tendon reflexes
• Tetany signs (if severe hypocalcemia):
  • Chvostek's sign - facial twitch with tapping facial nerve
  • Trousseau's sign - carpopedal spasm with blood pressure cuff inflation

General:

• Pallor (anemia of chronic disease in severe deficiency)
• Poor dentition (delayed eruption, enamel defects in rickets)

Laboratory Investigations

Primary screening test:

• 25-hydroxyvitamin D (25-OH vitamin D) - best marker of vitamin D status
  • Reflects total body vitamin D stores (cutaneous synthesis plus dietary intake)
  • Long half-life (2-3 weeks) - stable marker
  • Measure in all patients with suspected deficiency, bone disease, or preoperatively before arthroplasty

Supportive biochemistry:

• Serum calcium - may be low-normal or low (secondary hyperparathyroidism compensates initially)
• Serum phosphate - typically low (PTH-mediated renal phosphate wasting)
• Parathyroid hormone (PTH) - elevated (secondary hyperparathyroidism)
• Alkaline phosphatase (ALP) - elevated (osteoblast activity in osteomalacia)
• 1,25-dihydroxy vitamin D - NOT useful for screening (normal or elevated due to PTH stimulation)

Urine studies:

• 24-hour urine calcium - low (less than 2.5 mmol per 24 hours)
• Calcium-creatinine clearance ratio - helps exclude familial hypocalciuric hypercalcemia

Additional investigations if indicated:

• Creatinine and eGFR - assess for chronic kidney disease
• Liver function tests - screen for cholestatic disease (impairs 25-hydroxylation)
• Celiac serology (anti-TTG, anti-endomysial antibodies) - if malabsorption suspected
• Inflammatory markers - if inflammatory bowel disease suspected

Imaging Studies

DEXA scan (bone densitometry):

• Low bone mineral density (T-score less than -2.5 at spine or hip)
• Cannot distinguish osteomalacia from osteoporosis on DEXA alone
• Biochemistry essential for diagnosis

Bone Biopsy (Gold Standard)

Indications:

• Diagnostic uncertainty after clinical, biochemical, radiographic evaluation
• Suspected hypophosphatasia or rare mineralization disorder
• Exclude other bone diseases (renal osteodystrophy, osteopetrosis)

Technique:

• Iliac crest biopsy with tetracycline double-labeling
• Undecalcified sections for histomorphometry

Findings in vitamin D deficiency osteomalacia:

• Increased osteoid volume (greater than 15% vs normal less than 5%)
• Widened osteoid seams (greater than 12 micrometers thick)
• Prolonged mineralization lag time (greater than 100 days vs normal less than 25 days)
• Reduced mineralization surface
• Tetracycline double-labeling shows delayed mineralization front

Bone biopsy is rarely needed in practice - diagnosis typically made on clinical, biochemical, and radiographic grounds.

The Diagnostic Biochemical Pattern

Diagnosis rests on a low 25-OH vitamin D plus the classic supporting pattern (see the Investigations and Classification sections for full thresholds and biochemistry): low-normal calcium, low phosphate, high PTH and high ALP, with normal or elevated 1,25-dihydroxy vitamin D. Looser zones on radiographs confirm osteomalacia, but DEXA cannot distinguish osteomalacia from osteoporosis - biochemistry is essential.

Differential Diagnosis

Several conditions mimic vitamin D deficiency osteomalacia, especially when biochemistry is only partly typical. The pattern of calcium, phosphate, ALP, PTH and 25-OH vitamin D usually separates them.

Fracture Healing

Vitamin D deficiency impairs fracture healing:

• Delayed union or nonunion - inadequate mineralization of callus
• Reduced mechanical strength of healing bone
• Prolonged time to union (50-100% longer than vitamin D-replete patients)

Mechanism:

• Insufficient calcium and phosphate for mineralization
• Impaired osteoblast function and differentiation
• Reduced angiogenesis (vitamin D regulates VEGF)

Management:

• Optimize vitamin D preoperatively for elective fracture fixation
• Aggressive replacement in acute fractures (50,000 IU weekly)
• Monitor union - may require longer protected weight-bearing
• Consider bone stimulation if delayed union persists

Arthroplasty Considerations

Preoperative screening:

• Consider 25-OH vitamin D measurement before elective arthroplasty, especially in high-risk patients
• Optimize to greater than 50-75 nmol/L before surgery where deficiency is found
• Delay elective surgery if severe deficiency (less than 25 nmol/L) until repleted

Intraoperative considerations:

• Poor bone quality - soft bone, reduced screw purchase
• Risk of periprosthetic fracture during insertion (especially press-fit stems)
• Consider cemented fixation if bone very osteopenic

Postoperative complications:

• Increased infection risk (OR 2.4) - vitamin D modulates immune function
• Delayed mobilization - proximal myopathy impairs rehabilitation
• Prolonged hospital stay
• Aseptic loosening risk - impaired osseointegration of uncemented implants
• Periprosthetic fracture with minimal trauma

Management:

• Continue vitamin D and calcium indefinitely
• Aggressive physiotherapy to overcome muscle weakness
• Thromboprophylaxis (prolonged immobilization risk)

Pathological Fractures

High-risk sites in osteomalacia:

• Femoral neck - often bilateral, at sites of Looser zones
• Proximal femur - subtrochanteric, intertrochanteric
• Pelvis - pubic rami, sacrum
• Ribs - multiple, painful
• Vertebrae - compression fractures

Management principles:

1. Optimize medical management FIRST - vitamin D and calcium replacement
2. Prophylactic fixation for impending fractures (Looser zones greater than 50% cortical width, symptomatic)
3. Fracture fixation with caution - bone is soft, screw purchase poor
   • Longer plates with more screws for load distribution
   • Locking plates to minimize screw toggle
   • Cement augmentation in proximal femur fractures
   • Protected weight-bearing for 3-6 months (delayed healing)
4. Aggressive vitamin D replacement perioperatively to accelerate healing

Expected Response to Treatment

Biochemical:

• Calcium and phosphate normalize by 4-12 weeks
• PTH decreases by 3-6 months (may take longer if severe secondary hyperparathyroidism)
• Alkaline phosphatase declines by 6-12 months (may initially rise as bone heals)
• 25-OH vitamin D rises by 3 months to target (greater than 75 nmol/L)

Clinical:

• Bone pain improves by 6-12 weeks
• Muscle weakness reverses by 3-6 months (proximal myopathy resolves)
• Looser zones heal by 6-12 months (radiographic evidence of mineralization)
• Fracture risk decreases once vitamin D greater than 50 nmol/L

Poor prognostic factors:

• Severe, prolonged deficiency - may have permanent skeletal deformities
• Uncontrolled underlying cause (malabsorption, chronic kidney disease)
• Non-compliance with supplementation
• Concurrent osteoporosis - may require additional antiresorptive therapy

The exam-relevant debates in vitamin D centre on who to test, what level to aim for, and when supplementation actually helps.

Global Epidemiology

• Vitamin D deficiency or insufficiency affects an estimated 1 billion people worldwide
• Highest burden at high latitudes in winter, in darker-skinned populations, and in concealed-dress and institutionalized groups
• Nutritional rickets remains common in parts of South Asia, the Middle East and sub-Saharan Africa, and persists in migrant communities at high latitude

Side-by-Side Guidance

High- vs Limited-Resource Practice

• High-resource settings: ready 25-OH vitamin D assays, fortified foods, and cholecalciferol availability; debate is about screening intensity and targets.
• Limited-resource settings: assays may be unavailable and diagnosis is clinical plus radiographic; emphasis shifts to public-health prevention (food fortification, antenatal and infant supplementation) over individual testing.
• Calcium deficiency (low dietary intake) is a co-driver of rickets in some low-income regions, so calcium as well as vitamin D may be needed.