• Metabolic bone diseases are disorders of bone strength, normally due to abnormalities of mineral (calcium and phosphate), vitamin D, bone mass and structures. Metabolic bone disease if left untreated can lead to fragility fractures, deformities of bone and other serious disabilities.

• This is a sequence of complex bone turnover involving bone resorption (osteoclastogenesis) and bone formation (osteoblastogenesis).
• Ninety-nine% of calcium is stored in the bone.
• Extraosseous calcium constitutes only 1% of the total body calcium but is important for the functioning of nerves and muscles as well as clotting cascade.
• Plasma calcium circulates in two forms: 50% free ionised form which is active and 50% inactive form bound to albumin.
• Normal plasma concentration of calcium is between 2.2 and 2.6 mmol/l. Plasma calcium concentration is interpreted by taking into account the level of free ionised calcium and concentration of albumin in the specimen.
• Eighty-five% of phosphate exists in the bone and functions as metabolite and buffer in enzyme systems. Plasma phosphate is mainly unbound.
• The following two hormones primarily regulate calcium and phosphate levels:

Parathyroid hormone 

• Parathyroid hormone (PTH) is the primary immediate regulator of calcium levels in the blood.
• PTH is a peptide containing 84 amino acids secreted by chief cells of parathyroid glands.
• An active PTH is formed from a 115 amino acid polypeptide “pre-pro-PTH,” which is then cleaved to a 90 amino acid chain and finally into a 84 amino acid chain.
• The half-life of PTH is 2–4 minutes. 

Vitamin D and its metabolites

• Vitamin D is fat soluble. Vitamin D is both manufactured in the skin and ingested in the diet. 
• In the skin, ultraviolet radiation converts the precursor vitamin D (7-dehydrocholesterol) into vitamin D3 (cholecalciferol).
• Vitamin D2 (ergosterol) is ingested in the diet in fish oil and some plants.
• Vitamin D3 undergoes two stages of hydroxylation, first in the liver to 25-hydroxycholecalciferol and then in the kidney to 1,25-hydroxycholecalciferol (Figure 1)

Figure 1. Schematic diagram showing Vitamin D metabolism

Table 1. Dietary needs

Table 2. Regulation of calcium and phosphate metabolism

Figure 2. Schematic diagram showing regulation of calcium homeostasis

Hormonal control of calcium balance

1.PTH

Produced in response to low serum calcium,is suppressed when serum calcium is elevated

• Increased mobilization of Ca from bone
• Increased kidney reabsorption of Ca, decreased reabsorption of Phos
• Increased kidney conversion of 25-OH to 1,25 diOH- Vitamin D

2.1,25-diOH

Formation regulated by PTH, indirectly by serum calcium

• Increased Ca and Phos absorption from gut
• Increased Ca mobilization from bone

Figure 3.PTH control of calcium balance 

Figure 4.1,25-diOH control calcium balance. 

Hormones

• Oestrogen prevents bone loss.
• Corticosteroidsincreased bone loss (reduced gut absorption, decreased bone formation).
• Growth hormonecauses positive calcium balance.

Growth factors

• Insulin-like growth factor –produced by osteoblasts, recruits osteoblasts.
• Transforming growth factors –produced during bone resorption, stimulate osteoblasts.
• IL-1 and osteoclast activating factor –activate bone resorption.
• Prostaglandins –regulate both osteoblasts and osteoclasts.

Hypercalcaemia

• Hypercalcaemia is defined by the level of calcium above 2.6 mmol/L. Patient may be asymptomatic from hypercalcaemia. However, the classic series of symptoms for this condition is “bones, moans, stones and abdominal groans.” 

• Bones: excessive bone resorption
• Stones: polyuria, polydipsia and kidney stone
• Groans (gastrointestinal): constipation, nausea, vomiting, anorexia and abdominal pain
• Moans (central nervous system effects): confusion, weakness, stupor, hyperreflexia
• Other side effects: sudden cardiac arrest, hypotension

Causes of hypercalcaemia:

1 Malignancy

• Bone destruction from bone metastases or myeloma
• PTH-like secretion of malignant tumours, e.g. squamous cell carcinoma
• 1,25-dihydrocholecalciferol synthesis in lymphoma

2 Endocrine

• Pituitary
• Thyroid: hyperthyroidism
• Adrenal: Addison’s disease

3 Genetic

• Familial: multiple endocrine neoplasia, familial hypocalciuric hypercalcaemia

4 Sarcoidosis
5 Steroids
6 Vitamin D intoxication

Hypocalcaemia

• Hypocalcaemia is defined by level of calcium less than 2.2mmol/L. Causes of hypocalcaemia include:
• Thyroid surgery or hypothyroidism 
• Hypoparathyroidism
• Clinical features of hypocalcaemia can be divided into acute and chronic:

• Acute: neuromuscular irritability (tetany, seizures), depression, perioral paraesthesia, and prolonged QT interval on ECG
• Chronic: fungal nail infections and cataracts

Primary hyperparathyroidism

• Primary hyperparathyroidism happens when there is oversecretion of PTH. This mainly affects 40–65 year olds, with a female to male ration of 2:1. Causes of primary hyperparathyroidism include:

• Parathyroid adenoma (90% of cases)
• Hyperplasia of parathyroid chief cell 
• Parathyroid carcinoma (1%)

• Clinical features: often asymptomatic, only 10% have moans, bones, stones and abdominal groans 
• Radiological features of hyperparathyroidism:

• Osteopenia (diffuse demineralisation) 
• Subperiosteal erosions (radial borders of proximal phalanges, skull, medial end clavicle)
• Osteitis fibrosa cystica (brown tumours): increased giant cell, haemosiderin staining and fibrous marrow replacement
• Chondrocalcinosis and metastatic calcification of soft tissues
• Shaggy trabeculae
• Rugger jersey spine
• Bilateral sacroiliac joint widening and erosion

• Radiological appearances are caused by increased osteoclastic resorption of bone with failure of bone repair caused by poor mineralisation due to low phosphate level.
• Blood results: increased calcium, increased PTH, decreased phosphate, normal or increased alkaline phosphatase.
• Treatment: parathyroidectomy but beware of hungry bone syndromepostoperatively (hypocalcaemia due to brisk formation of new bone).

Secondary hyperparathyroidism

• Parathyroid hyperplasia leading to over secretion in response to chronic hypocalcaemia or hyperphosphatemia.
• Associated conditions: renal osteodystrophy and chronic kidney disease.
• Blood results: normal or decreased calcium, increased PTH and increased phosphate.

Other causes of hypercalcaemia

• Multiple endocrine neoplasia (MEN I and II) 
• Malignancy 
• Hyperthyroidism 
• Addison’s (hypoadrenocorticism)
• Steroids 
• Peptic ulcers 
• Sarcoidosis 

Primary hypoparathyroidism

• Iatrogenic can be common cause after thyroidectomy 
• Blood results: low calcium, high phosphate 

Pseudohypoparathyroidism

• This is a rare condition due to lack of effect of PTH on target cell
• Clinical features: obesity, diminished intelligence, short first, fourth and fifth metacarpals and metatarsals
• Blood test: normal or high PTH, low calcium, high phosphate

Renal osteodystrophy

• Renal osteodystrophy can be caused by the following two mechanisms: 

• Tubular disease: synthesis of the active form of vitamin D is impaired as a result of damage to the renal tubules. This lead to impaired calcium absorption in the gut and loss of calcium from the kidneys.
• Glomerular disease: glomerular damage results in uraemia and phosphate retention. The elevated level of phosphate further suppresses activation of vitamin D in the kidney.

• A blood test in renal osteodystrophy shows normal or low calcium and raised alkaline phosphatase. Low serum calcium can lead to excessive parathyroid production, leading to features of hyperparathyroidism, which can be exacerbated by the elevated phosphate levels, resulting in ectopic calcification. 

• Osteoporosis is a systemic skeletal disease resulting in reduction of bone mass density secondary to uncoupling of the osteoclast–osteoblast mechanism with normal mineralisation of the bone. This includes disruption to the microarchitecture of the bone, leading to increase in fragility fractures and consequent increase in fracture risk. World Health Organization definition as below:
• Osteopenia defined as 1.0 to 2.5 standard deviations below peak bone mass of a normal healthy individual of similar gender and race, T-score = –1.0 to –2.5.
• Osteoporosis defined as 2.5 standard deviations below peak bone mass of a normal healthy individual of a similar gender and race, T-score <–2.5.
• T-score presents the result as the number of standard deviations above or below the mean peak bone mass for a population matched for sex and race.
• Z-score presents the result as the number of standard deviations above or below the mean bone mass for population matched for age, race and sex.
• T-score is used for diagnosis of osteoporosis.
• A low Z-score indicates that osteoporosis is not age related and therefore an underlying cause should be sought as there may be some treatable condition. 
• Osteoporosis can be classified either as type 1 (postmenopausal) or type 2 (age related). Type 1 osteoporosis is related to loss of oestrogen and affects mainly cancellous bone at the time of menopause, so vertebral and distal radius fractures are common. Type 2 osteoporosis is age related and affects cortical and cancellous bone. Osteoporosis affects women more than men with a ratio of 4:1. Osteoporosis is associated with fragility fractures such as vertebral bodies, hip and wrist fractures in decreasing order. 

Risk factors for osteoporosis can be divided into modifiable and non-modifiable factors:

• Non-modifiable factors:
• Increasing age
• Woman
• Early menopause
• Race, e.g. fair-skinned
• Family history
• Modifiable factors:
• Diet: deficiency of calcium and vitamin D
• Low body weight
• Malnutrition
• Chronic alcohol excess
• Cigarette smoking
• Medications: anticonvulsants and antidepressants

Investigations:

• Laboratory: low 25 hydroxyvitamin D level

Imaging

• Plain X-rays for suspicion of insufficiency fractures
• DEXA (dual energy X-ray absorptiometry) is the gold standard for diagnosing osteoporosis. This is a low radiation radiological investigation that is quick and accurate in diagnosing osteoporosis. This involves simultaneous measurement of the passage through the body of X-rays with two different energies. The usage of two different energy beams to minimise the effect of soft tissues, particularly fat on the result. Cause of false positive in the spine includes previous laminectomy and false negative in the spine is osteoarthritis with resulting osteophytes and sclerosis. 
• Quantitative ultrasound and computed tomography (CT).

Treatment:

• Lifestyle modifications – weight loading exercises, avoidance of excessive alcohol, smoking.
• Pharmacological – calcium, vitamin D, bisphosphonates and hormone replacement therapy.
• Operative – osteoporotic fractures (vertebroplasty in osteoporotic wedge fracture).

• Osteomalacia is qualitative defect of skeletal mineralisation caused by deficiency of the active metabolites of vitamin D or phosphate. There is a defective mineralisation result in a large amount of unmineralised osteoid and decreased rate of bone formation. Osteomalacia is rare and affects one in 1000 of the population.
• Risk factors: vitamin D deficient diets, renal osteodystrophy, hypophosphatemia, alcohol excess, malabsorption (e.g. coeliac disease), drugs (phenytoin, rifampicin and etidronate).
• Symptoms: generalised bone and muscle pain, long bone fractures, proximal muscle weakness, fatigue.
• Radiographic findings: Looser’s zone is an area of insufficiency fracture of medial femoral cortex (Figure 5), protrusion acetabuli and biconcave vertebral bodies.

Diagnosis of osteomalacia:

• Clinical: proximal muscle weakness, bone pain and tenderness and fracture (incomplete or bilateral).
• Blood tests: depend on underlying cause.
• Tetracycline: labelled bone biopsy test is the gold standard in diagnosis of osteomalacia.
• Treatment: large doses of oral vitamin D (1000 IU/day) and treating the underlying cause

• Rickets is the juvenile form of osteomalacia with impaired mineralisation of cartilage matrix (chondroid) due to lack of calcium and phosphate. 
• This occurs at zone of provisional calcification in a skeletally immature patient.
• This leads to increased physeal width, cortical thinning and bowing.
• Clinical features depend on the severity of the deficiency and the age of onset. 

General manifestation of rickets:

• Retarded bone growth causing short stature
• Brittle bone with physeal cupping/widening (see Figure 6)
• Long bone deformities
• Symptoms of hypocalcaemia
• Failure to thrive, restlessness, muscular hypotonia, tetany and convulsions but only minimal bone changes in those under 18 months old

Localised features of rickets (top to toe):

• Delayed fontanelle closure and frontal and parietal bossing
• Dental disease
• Rachitic rosary (enlargement/hypertrophy of costochondral junction)
• Harrison’s sulcus (groove/sulcus/depression in the sternum)
• Pigeon chest
• Kyphosis
• Protuberant abdomen, hepatomegaly
• Genu valgum or varum, anterolateral bowing of distal tibia
• Coxa vara, anterolateral bowing of femur
• Waddling gait

Table 3. Classification Rickets

Figure 6. Metaphyseal cupping and widening in Rickets

• Medical treatment of rickets includes calcitriol (1,25 Vit D3) supplementation. On the other hand, surgical intervention includes correction of bony deformities.

• Osteopetrosis is a rare congenital disease caused by defective osteoclastic resorption of immature bone. This condition affects one in three million of the population.
• The inability of osteoclast to acidify Howship’s lacuna (osteoclast dysfunction with lack of ruffled border) leads to dense bone and obliterated medullary canals. This predisposes to fracture with lower extremity affected more than upper extremity and axial skeleton. 

Table 4. Classification

Bone marrow transplant mainly in infantile malignant form

High dose calcitriol (1,25 dihydroxyvitamin D)

Interferon gamma 1-beta in autosomal dominant form

Surgical management

Neurosurgical decompression for cranial nerve compression

Operative management for fractures

Total knee and hip arthroplasty for degenerative joint diseases

Idiopathic transient osteoporosis of the hip (ITOH)

• This condition is also known as bone marrow oedema syndrome, usually unilateral, self-resolving in 6–8 months and affects predominantly men.
• The pathogenesis is local hyperaemia and impaired venous return with marrow oedema and increased intramedullary pressure.
• Patient normally presents with groin pain and stiffness without trauma or injury.
• This is a diagnosis of exclusion and other causes such as infection, tumours, avascular necrosis and stress fracture need to be ruled out.

Imaging:

• X-rays – lag behind clinical signs by 4–8 weeks, may show subchondral cortical loss, diffuse osteopenia of femoral neck, joint space always preserved
• Bone scan – increase signal uptake, precede X-rays changes
• Magnetic resonance imaging (MRI) – imaging modality of choice

• Decreased signal, loss of fatty marrow on T1 images
• High signal of marrow oedema and joint effusion on T2 images

Treatment:

• Symptomatic with avoidance of weight bearing

Paget’s disease (osteitis deformans)

Epidemiology: 

• Paget’s disease was first described by Sir James Paget in 1876. Aetiology of Paget’s disease remains unknown although this has been associated with positive family history and virus (paramyxovirus, RSV). It is thought to be related to viral infection in genetically predisposed individuals with positive family history. This disease mainly affects the western world (North America, England, Northern Europe) with slight preponderance to men.

Pathology: 

• Primary abnormality is increase in osteoclastic reabsorption of bone followed by compensatory bone formation (accelerated bone remodelling). Bone is rapidly laid down and resorbed. This leads to newly formed bone that is coarse fibred and disorganised architecturally. This leads to mechanically weak bone and the marrow tends to become fibrous with scanty haematopoietic cells. The abnormal bone is rapidly resorbed by osteoclasts and bone turnover is greatly increased. There are two forms of Paget’s disease, monostotic and polyostotic form.
• Pathological phases:
• Osteolytic: intense osteoclastic bone resorption
• Mixed: compensatory osteoblastic bone formation
• Sclerotic: intense osteoblastic bone production

Clinical features: 

• The majority of patients are asymptomatic. Mostly, incidental findings on X-rays or raised blood alkaline phosphatase level for investigations of other conditions. Bone pain can be main presenting complaint, related to acute fracture or degenerative joint diseases. Other symptoms and complications which are sequelae of bone distortion or enlargement:
• Pathological fractures
• Long bone deformities
• Spinal stenosis
• Deafness or other cranial nerve encroachment due to foramina lumen narrowing
• Metabolic: high cardiac output, gout, hypercalciuria, hypercalcaemia 
• Malignancy: 1% chance of progression to sarcomatous changes usually in diffuse long standing disease.

Investigations:

• Raised blood alkaline phosphatase or urinary hydroxyproline (increase collagen turnover).

X-rays findings:

bone deformity, degenerative joint disease, widened bones, coarse wide trabeculae, discrete area of osteolysis, protrusion acetabula.

Treatment: 

• Most patients require no active treatment. Treatment for Paget’s disease can be divided into:

Medications:

• Bisphosphonates and calcitonin (lowers the bone turnover rate by decreasing activity and number of osteoclasts.

Surgery

• ORIF and corrective osteotomy – intractable joint pain or impending pathological fracture.
• Total hip arthroplasty – technical considerations such as protrusio acetabuli, proximal femur deformity, heterotrophic ossification, increased intraoperative bleeding, and slightly higher risk of aseptic loosening.
• Total knee arthroplasty – extramedullary jig due to tibia deformity.