Vitamin D Deficiency and Osteomalacia

Introduction

Vitamin D is a fat-soluble hormone precursor whose principal role is to maintain the calcium and phosphate concentrations required to mineralise bone. When it is deficient, the body continues to lay down bone matrix (osteoid) normally, but that osteoid fails to mineralise - producing soft, weak, painful bone.¹

This single pathological process produces two clinically distinct diseases, separated only by whether the growth plates are still open:

• Rickets - in children, before epiphyseal fusion. The unmineralised growth plate is soft and disorganised, so bones deform under load and growth is impaired.
• Osteomalacia - in adults, after epiphyseal fusion. There is no growth plate left to deform, so the disease presents instead with bone pain, muscle weakness and fractures.

Vitamin D deficiency is extremely common in the UK: a substantial proportion of the population has a level below the threshold at which the risk of deficiency-related bone disease rises, particularly at the end of winter, because at UK latitudes there is insufficient ambient UVB to synthesise vitamin D in the skin between roughly October and March.² Frank rickets and osteomalacia are much rarer than biochemical deficiency, but both are still seen, and both are eminently treatable once recognised.

Physiology and pathophysiology

The activation pathway

Vitamin D requires two sequential hydroxylations to become biologically active, and each step is a point at which disease can interrupt the pathway.¹

1. Source. Around 80-90% comes from synthesis in the skin, where UVB converts 7-dehydrocholesterol to cholecalciferol (vitamin D3). Only a small proportion comes from the diet - oily fish, egg yolk, liver and fortified foods (and ergocalciferol, vitamin D2, from plant and fungal sources).
2. Hepatic 25-hydroxylation. The liver converts cholecalciferol to 25-hydroxyvitamin D (calcidiol). This is the storage form with a long half-life, and the form measured in the laboratory - which is why 25-hydroxyvitamin D, not calcitriol, is the test used to diagnose deficiency.
3. Renal 1-alpha-hydroxylation. The kidney converts calcidiol to 1,25-dihydroxyvitamin D (calcitriol), the active hormone. This step is stimulated by PTH and by hypophosphataemia, and is the rate-limiting, tightly regulated step.
4. Action. Calcitriol increases intestinal absorption of calcium and phosphate (its dominant effect), promotes bone mineralisation, and increases renal calcium reabsorption.

How deficiency produces disease

Reduced calcitriol impairs intestinal calcium and phosphate absorption, so serum calcium falls. This triggers a compensatory rise in PTH (secondary hyperparathyroidism), which has three consequences that together explain the entire biochemical picture:

• Calcium is restored towards normal by mobilising it from bone - which is why calcium is often only low-normal rather than frankly low, and why a normal calcium does not exclude deficiency
• Phosphate falls further, because PTH is phosphaturic - giving the characteristic combination of low/low-normal calcium with low phosphate
• Bone turnover increases, releasing alkaline phosphatase from osteoblasts - hence the raised ALP that is such a useful clue

The end result is an inadequate calcium-phosphate product at the mineralisation front, so newly formed osteoid is deposited but not mineralised. In children this affects the growth plate as well as remodelling bone, which is why deformity is the dominant feature of rickets and pain and weakness the dominant features of osteomalacia.

Risk factors and causes

Clinical features

Most vitamin D deficiency is asymptomatic and detected biochemically. Symptomatic disease presents differently in children and adults.

Osteomalacia (adults)

• Diffuse, poorly localised bone pain and tenderness - classically in the pelvis, ribs, spine and proximal long bones. The bones may be tender to direct pressure, which is an unusual and useful finding.
• Proximal myopathy - symmetrical weakness of the hip girdle producing a characteristic waddling gait, difficulty rising from a chair and difficulty climbing stairs. Vitamin D is required for normal muscle function, and this weakness improves with replacement.
• Fragility fractures - and an increased tendency to fall, from the combination of muscle weakness and poor proprioception
• Symptoms of hypocalcaemia if calcium falls significantly - perioral and peripheral paraesthesiae, cramps, and in severe cases tetany with Chvostek's and Trousseau's signs, seizures or laryngospasm
• Fatigue and low mood, which are common and non-specific

Rickets (children)

• Bowing of the legs (genu varum) once weight-bearing begins, or knock-knees (genu valgum) in older children
• Widening of the wrists and ankles - palpable expansion of the soft, unmineralised metaphyses
• Rachitic rosary - visible or palpable beading at the costochondral junctions, from metaphyseal expansion of the anterior ribs
• Craniotabes - abnormally soft skull bones in infancy, and delayed closure of the anterior fontanelle; also frontal bossing
• Harrison's sulcus - a horizontal groove along the lower border of the chest where the softened ribs are drawn in by the diaphragm
• Delayed motor milestones (particularly delayed walking), delayed dentition, and growth failure with short stature
• Hypocalcaemic seizures - which may be the presenting feature in infancy, sometimes before any skeletal signs are apparent
• Increased fracture risk and, in severe untreated disease, pelvic deformity

Investigations

Biochemistry

Serum 25-hydroxyvitamin D is the diagnostic test. Calcitriol (1,25-dihydroxyvitamin D) is not used to diagnose deficiency, because secondary hyperparathyroidism drives 1-alpha-hydroxylation and can keep it normal or even raised despite profound deficiency.²

Further tests are directed at the underlying cause: U&Es and eGFR for renal impairment, LFTs for liver disease, coeliac serology (anti-tissue transglutaminase antibodies) and full blood count with ferritin, B12 and folate where malabsorption is suspected, and a magnesium level, since concurrent hypomagnesaemia impairs both PTH secretion and its action.

Imaging

Imaging is not required to diagnose deficiency, but is used where there is bone pain, deformity or suspected fracture.

• Looser zones (pseudofractures) - narrow transverse translucent bands running perpendicular to the cortex, representing unmineralised osteoid at sites of stress. Classically seen in the pubic rami, medial femoral neck, ribs, scapula and lateral scapular border. They are essentially pathognomonic of osteomalacia.
• Generalised osteopenia with coarse, indistinct trabeculae and blurred cortical margins ('washed out' bones)
• In rickets - cupping, splaying and fraying of the metaphyses (classically at the distal radius and ulna at the wrist, and around the knee), a widened growth plate, and delayed bone age
• Vertebral changes - biconcave 'cod-fish' vertebrae from soft endplates
• DEXA scan - often shows low bone density, but this reflects reduced mineral rather than osteoporosis and should be repeated after vitamin D replacement before diagnosing osteoporosis or starting a bisphosphonate
• Bone biopsy with tetracycline labelling is the definitive test showing a widened, unmineralised osteoid seam, but is essentially never needed in practice

Management

Vitamin D replacement

Colecalciferol (vitamin D3) is the preferred preparation, being more effective than ergocalciferol at raising and sustaining 25-hydroxyvitamin D. Treatment of established deficiency has two phases.^3,4

Special situations

• Chronic kidney disease - plain colecalciferol cannot be 1-alpha-hydroxylated, so an active analogue (alfacalcidol or calcitriol) is required, alongside phosphate binders and management of renal bone disease
• Severe liver disease - impaired 25-hydroxylation may also warrant an active analogue
• Malabsorption - much higher oral doses, or occasionally parenteral vitamin D, plus treatment of the underlying cause (a gluten-free diet in coeliac disease, pancreatic enzyme replacement in exocrine insufficiency)
• After bariatric surgery - lifelong supplementation with monitoring of vitamin D, calcium, iron and B12
• Hypocalcaemic tetany or seizures - treat the hypocalcaemia acutely first with intravenous calcium gluconate under cardiac monitoring, then correct vitamin D; also check and correct magnesium
• X-linked hypophosphataemic rickets - phosphate supplements with an active vitamin D analogue, or burosumab; plain vitamin D is ineffective

Monitoring and lifestyle advice

• Recheck calcium around a month after loading, particularly in anyone at risk of hypercalcaemia, and recheck 25-hydroxyvitamin D after 3 to 6 months - not sooner, as it takes that long to plateau
• Expect ALP to rise transiently as bone remineralises briskly before falling to normal; this is a sign of response, not deterioration
• Advise on sunlight - short, regular periods of exposure to arms and legs in late spring and summer, without burning
• Advise on diet - oily fish, egg yolks, red meat, liver and fortified cereals and spreads
• Do not start a bisphosphonate before vitamin D is replete, as it risks precipitating hypocalcaemia

Complications

• Fragility fractures - including insufficiency fractures through Looser zones, and hip fracture in older adults
• Falls - from proximal myopathy and impaired neuromuscular function, compounding fracture risk
• Permanent skeletal deformity in children if rickets is untreated - bowed legs, short stature and, historically, pelvic deformity complicating later childbirth
• Growth failure and delayed motor development in children
• Hypocalcaemic seizures, tetany and laryngospasm - particularly in infants, and occasionally the presenting feature
• Dilated cardiomyopathy - a rare but recognised and potentially fatal complication of severe infantile hypocalcaemic rickets
• Secondary hyperparathyroidism, which if prolonged and severe can become tertiary (autonomous)
• Chronic pain and functional impairment in adults, often mislabelled for years as fibromyalgia or non-specific musculoskeletal pain
• Dental abnormalities - enamel hypoplasia and delayed dentition

Red flags

Prognosis

The prognosis of nutritional vitamin D deficiency is excellent, and the response to treatment is one of the more satisfying in medicine. Bone pain and proximal myopathy typically begin to improve within weeks of adequate loading, and biochemistry normalises over weeks to a few months - with ALP often rising transiently first as bone remineralises before settling.

In children, established bone deformity can remodel substantially with treatment, particularly if rickets is corrected while growth continues, and most children treated early achieve normal growth and a normal skeleton. Deformity that persists into adulthood, or where treatment was very delayed, may require orthopaedic correction.

The main determinants of a poorer outcome are delayed diagnosis - adults are often treated for non-specific chronic pain for years before osteomalacia is considered - and failure to identify an underlying cause. Deficiency will simply recur if untreated coeliac disease, ongoing malabsorption, chronic kidney disease or an enzyme-inducing drug is left unaddressed, which is why the priority after replacement is establishing why the patient became deficient and arranging appropriate long-term maintenance.