Metabolic Bone Disease

Bones made up of calcium hydroxyapatite mineral deposited on a matrix/osteoid of primarily collagen. Bone is a reserve for calcium and phosphate, helping to keep serum levels constant, also maintained by gut absorption and renal tubules.

  • Parathyroid hormone (PTH) – Produced by the parathyroid glands, increases serum calcium at proximal tubules (enhanced phosphate excretion and calcium reabsorption), osteoclast-mediated surface bone resorption (increasing serum calcium and phosphate), enhanced synthesis of 1,25-hydroxy-vitamin D. Net result is increase in serum calcium while keeping phosphate stable.
  • Vitamin D – Endogenous (D3 synthesised by skin exposed to UV) or exogenous (D2, most, from dietry sources) which is converted by liver to 25-hydroxy-vitamin D and by kidney to active form 1,25-hydroxy-vitamin D (increased in hypophasphataemia and hypocalcaemia). In bones it causes transcription of osteocalcin, osteopontin and alkaline phosphatase to release calcium and phosphate, promoting maturation and mineralisation of osteoid matrix (with parathyroid hormone cofactor). In gut it causes production of calcium-binding protein, in kidney increases phosphate resorption also requiring parathyroid hormone cofactor. It inhibits release of PTH. Net result increases both serum calcium and phosphate.
  • Calcitonin – Hormone produced primarily by parafollicular cells of thyroid, physiologic antagonist to parathyroid hormone.

ALP is raised in bone production; urine hydroxyproline raised in bone resorption.


Reduced quantity in otherwise normal bone quality (cf osteomalacia). Osteopenia is reduced bone mineral density (BMD) (encompassing osteoporosis and osteomalacia). Bone loss exceeds bone production. Peak bone mass is achieved during yound adulthood, with magnitude depending on genes, physical activity, muscle strength, diet, hormonal state. Small deficits in bone formation after peak accrue over time, normally ~0.7% per year.

  • Primary/senile osteoporisis – Most common, increased risk with low body weight, less weight-bearing exercise, whites and Asians. Osteoblasts have reduced proliferative and synthetic potential. Postmenopausal osteoarthritis from reduced oestrogen. Bone loss begins in 30s in women; 40s-50s in men. Tx calcium, oestrogen, bisphosphonates (inhibits osteoclasts).
  • Secondary osteoporosis (5%) – From drugs (cortisol/steroids, heparin, phenytoin, alcohol, smoking), congenital (OI, homocystinuria, ochronosis), endocrine disorders (hyper/hypo-thyroidism, hyperparathyroidism, Cushing’s disease, type 1 diabetes, Addison disease), neoplasia (multiple myeloma, carcinomatosis), GI (malnutrition, malabsorption, hepatic insufficiency, vitamin C/D deficiency), immobilisation, pulmonary disease, anaemia.

Bone mineral denitometry (BMD) – Dual energy x-ray absorptiometry (DEXA) uses two energies which have different attenuation coefficients for bone, muscle and fat; compares density (g/mL) from several sites (usually L-spine, proximal femur ± wrist). Z-score is the standard deviations above or below average bone mineral density for that age and sex. T score compares against peak young normals of same sex. T score >-1 normal; -1 to -2.5 defined as osteopenia; <-2.5 osteoporosis. Each T score below normal increases fracture risk X3. Quantitative CT densitomery is more sensitive (can measure more affected trabecular bone. On XR 30-40% bone mineral loss is required before becoming subjectively apparant. US calcaneus can also be used. Cortical thinning (esp 2nd & 3rd metacarpal mid-diaphysis, where cortex should be >/=50% of bone width). Reduced quantity and thickness of trabecula (in proximal femur order of loss is secondary tensile, primary tensile, secondary compressive, then primary compressive). Accentuation of stress/load-bearing trabeculae (last to be resorbed). Cortical tunnelling (intracortical lucencies) parallel to long axis. Insufficiency fractures esp spine (anterior wedge, biconcavity of endplates or generalised loss of height), hip, proximal humerus, distal forearm. Bone bars (reinforcemnt lines) – transverse trabeculae in diaphysis/metaphysis. Exaggerated contrast of vertebral endplates and vertcal trabeculae.

Regional osteoporosis is often symptomatic, may be radiographically aggressive.

  • Transient regional osteoporosis (TRO, regional migratory osteoporosis) – Multiple consecutive joints with marrow oedema, esp lower limb distal to knee. Self-limiting.
  • Transient osteoporosis of the hip (TOH) – Middle-aged men and pregnant women (usually L hip). Sudden onset hip pain with marrow oedema, joint effusion, osteoporosis, increased uptake on bone scan. Self-limited, resolving in several months, Tx conservative. ?Form of TRO.
  • Reflex sympathetic dystrophy (RSD) – Dysfunction of sympathetic nervous system associated with trauma, neurologic and vascular events. Severely reduced BMD, soft tissue swelling, hyperaesthesia then atrophy and contracture.
  • Hyperaemia – Induces osteoclastic activity. From inflammatory arthropathy, hypervascular tumours, RSD, healing fractures.
  • Disuse osteoporosis – From immobilisation, commonly after fracture and casting. May be aggressive with intracortical lucencies, metaphyseal band lucencies (relative hyperaemia from rich blood supply), subcortical/subchondral resorption. May occasionally mimic a permeative lesion (pseudopermeative), but cortex in true medullary lesion remains solid (cf multiple small holes). DDx haemangioma (cortical holes from focal hyperaemia -> focal osteoporosis or blood vessels tunneling through) or radiotherapy (death of cortical osteocytes -> large lacunae, relatively larger cortical holes).


Reduced bone quality with excess nonmineralised osteoid most from lack of vitamin D. Most commonly renal from reduced 1-hydroxylation or renal tubular disorders (vitamin D resistant rickets eg X-linked hypophosphataemia and cystinosis); other causes include dietary/malabsorption (Crohn’s, small bowel resection), biliary (reduced absorption) and hepatocellular disease (reduced 25-hydroxylation), receptor resistance (rare), drugs (phenytoin, phenobarbitol), oncogenic form (rare, hormones from tumours eg haemangiomas, NOF, giant cell tumour of bone intefere with tubular resorption of phosphate).

Findings almost identical to osteoporosis with demineralisation. Bones are lucent, coarsened, smudgy. Looser fracture/zone (pseudofractures) – uncommon but pathognomonic fracture through large undermineralised osteoid on concave aspect of bone (compression, cf Paget’s convex), perpendicular and not crossing entire width esp in axillary margins scapula, ribs, pubic rami, proximal femur, dorsal proximal ulna.

Rickets – Osteomalacia in immature skeleton with undermineralised metabolically active sites (metaphyses esp proximal/distal femur, proximal tibia, proximal humerus, distal radius). Flared irregular frayed metaphyses (become dense with treatment), widened irregular zones of provisional calcification (physes), bending of long bones, rachitic rosary in ribs (diffuse costochondral enlargement), bizarre deformities (repeated insufficiency fractures), short squat bones, SH1 fractures (esp bilateral SUFE). From renal disease, biliary disease, dietary insufficiency. DDx metaphyseal dysplasia (growth plate widening due to error in enchondral ossification, normal bone mineralisation and biochemistry), hypophosphatasia (severe osteopenia, wide growth plates, multiple fractures, low ALP cf elevated in rickets).

Hyperparathyroidism (HPT)

Excessive parathyroid hormone (PTH) causes osteoclastic resorption, osteoporosis, osteomalacia. Affects cortical bone more than cancellous bone.

  • Primary HPT – From parathyroid adenomas/hyperplasia or rarely adenocarcinoma. Multiple adenomas in 10%. May be associated with MEN I or MEN II. Elevated serum calcium and reduced phosphate. Generalised weakness, urolithiasis, peptic ulcer disease, pancreatitis, bone and joint pain. 40% have skeletal abnormality on XR.
  • Secondary HPT (more common) – Mostly from renal failure with reduced capacity to excrete phosphate causing elevated serum phosphate and non-measurable reduced calcium promoting PTH secretion. Tends to be milder than primary HPT.
  • Tertiary HPT – Autonomous PTH production after correction of long-standing secondary HPT.

Subperiosteal resorption (pathognomonic esp radial aspect 2nd and 3rd middle phalanges, medial humerus, femur, tibia, superior/inferior ribs, lamina dura of teeth), intracortical, endosteal (can mimic marrow dyscrasias), trabecular, subchondral (sacroiliac, AC, sternoclavicular, TMJ, symphysis pubis) and subligamentous (trochanters, ischial tuberosities, inferior calcaneus, distal clavicle, elbow) bony resorption. Osteoclastss tunnel centrally along trabeculae (dissecting osteitis) causing osteopenia. Skull salt-and-pepper appearance. Tuft resorption/acro-osteolysis. Risk of osteopenic fractures. Soft tissue calcification, periostitis and osteosclerosis (usually diffuse, sclerotic bands at vertebral endplates = rugger jersy spine) more common in secondary HPT. CPPD and Brown tumours more common in primary HPT. Prone to tendon and ligament laxity and rupture. Bone scan increased uptake in brown tumours and Looser fractures.

Brown tumours in 40% of primary HPT (but more commonly secondary due to increased prevalance), accumulations of osteoclasts, haemorrhage, vascularity and fibrous tissue, can be multiple, tend to heal after treatment of HPT. Eccentric, cystic often expansile, may have aggressive appearance.

Renal Osteodystrophy

Osteomalacia (reduced 1-hydroxylation), secondary hyperparathyroidism (hyperphosphataemia), osteosclerosis, growth retardation and osteoporosis (metabolic acidosis stimulates bone resorption and release of calcium hydroxyapatite) from chronic renal failure. Dialysis can also cause bone toxicity (aluminium interferes with calcium hydroxyapatite deposition) or amyloidosis, also at risk of osteomyelitis and septic arthritis due to chronic immune suppression, AVN from steroids. Types include high-turnover osteodystrophy (resoroption > formation), low-turnover/aplastic disease (adynamic bone) and mixed pattern (most common). Areas of demineralisation and osteosclerosis (esp vertebral endplates = rugger jersey spine, may be diffuse. Profuse soft tissue calcifications including vascular and para-articular (may be milk of calcium, may be massive = tumoral calcinosis). Insufficiency fractures and Looser’s zones.


Parathyroid gland deficiency from parathyroid gland resection. Hypocalcaemia and hyperphosphataemia with irritability, seizures, tetany. Occasional calvarial thickening, subcutaneous and basal ganglia calcification, osteosclerosis (localised or generalised), rarely osteoporosis.

  • Pseudohypoparathyroidism – Congenital target cell resistance to PTH, normal glands. Hypocalcaemia but high PTH. Obesity, round facies, short stature, brachydactyly (tubular bones of hands and feet short esp 1st 4th and 5th metatarsals and metacarpals), early growth plate closure, thick calvaria, intracranial and soft tissue calcifications, small osteochondromas at right angles to shafts.
  • Pseudopseudohypoparathyroidism – No parathyroid or biochemical abnormality, patients resemble pseudohypoparathyroidism.

Pituitary Hyperfunction

Secreting adenoma/hyperplasia of anterior lobe of pituitary gland -> accelerated bone growth. Before physeal closure causes giantism, after closure causes acromegaly. Acromegaly – calvarial thickening, enlarged sinuses, enlarged sella turcica, prognathic jaw, hypertorphied terminal tufts of distal phalanges (spade/shovel tufts), minimally widened joint spaces (hypertrophy of cartilage), early OA (abnormal cartilage), soft tissue hypertrophy (eg heel pad).

Thyroid Dysfunction

  • Hyperthyroidism can increase skeletal maturation.
  • Hypothyroidism/cretinism causes delayed skeletal maturation (delayed ephiphyseal ossification and closure, may even be open in 3rd/4th decade), ‘stippled’ epiphyses, mild osteoporosis, soft tissue oedema, myopathy, wormian bones, bullet-shaped vertebra at thoracolumbar junction.
  • Thyroid acropachy – Rare, ?from TSH, after treatment of thyrotoxicosis. Charactersitic fluffy solid periostitis esp metacarpals/metatarsals and phalanges, invariably ulnar aspect 5th metacarpal. Clubbing, soft tissue swelling (exopthalmos and myxoedema). DDx HPOA, pachydermoperiostitis (rare idiopathic periostitis and skin thickening).


Diffuse increased bone density. Causes include:

  • Metastases – Usually prostate or breast, usually has some component of cortical destruction or lysis.
  • Paget disease – Pagets rarely diffusely sclerotic, usually causes bony enlargement, most common in pelvis with thickened ileopectineal line. Can occur in any bone. Lytic, sclerotic and mixed lytic-sclerotic phases. Lytic phase has sharp flame-shaped or blade-of-grass leading edge. In long bones (except tibia) always starts and bone end.
  • Renal osteodystrophy, or any cause of HPT – Most cause osteopenia, 10-20% osteosclerosis (unknown cause). Must have subperiosteal bone resorption.
  • Myelofibrosis (idiopathic myeloid metaplasia) – Progressive fibrosis of marrow, >50yo, anaemia, marked splenomegaly, extramedullary haematopoiesis.
  • Osteopetrosis – Hereditary, extremely dense bones. Congenital form at birth can be lethal, anaemia, jaudice, hepatosplenomegaly, infections. Tarda form (older children, adults) causes bone-in-bone appearance of vertebral bodies (small replica inside), sandwich vertebrae (densely sclerotic endplates, denser and sharper than rugger jersey).
  • Pyknodysostosis (Toulouse-Lautrec syndrome) – Congenital, short stature, hypoplastic mandibles, acro-osteolysis with sclerosis (pathognomonic, pointed dense distal phalanges).
  • Mastocytosis – Rare uniformly increased bone density, thickened small bowel folds with nodules, urticaria pigmentosa.
  • Fluorosis – Rare, from chronic intake of fluoride. Ligamentous calcification esp sacrotuberous ligament.
  • Sickle cell disease – Occasionally. Also causes bone infarcts, step-off (Lincoln log, H-shaped, fish vertebrae) deformities of vertebral endplates with central depression, AVN of hip.
  • Athletes – Increased cortical thickness causing apparent diffuse osteosclerosis. Hypertrophy of bone and muscle.

Paget Disease

(Osteitis deformans). Chronic progressive, not metabolic but similar, ?aetiology ?paramyxovirus in osteoclasts. More frequent in extreme north and south latitiudes (low incidence in Asia and Africa), late adulthood ~70yo (rare <40yo, affects 10% of >80yo), M:F 2:1, FHx (15-40% AD), decreasing over time. Localised to a few bones, can cross joints, monostotic in 15%. Can be any bone esp skull, spine, pelvis, femur; but extremely rare in fibula, ribs, small bones of hands/feet. Histologically mosaic pattern of lamellar bone, like a jigsaw puzzle. Stages often coexistant including stage I hot, osteolytic; II mixed lytic and blastic (osteoblastic activation in response to resorption); III burnt-out quiescent sclerotic phase when new equilibrium is established. Elevated ALP and hydroxyproline but normal phosphorous and calcium.

Usually begins at bone ends, extending ~1cm/yr to diaphysis (may start in diaphysis in tibia) with lytic sharply defined leading edge in flame-shape or blade-of-grass (osteoporosis circumscripta in skull). Mixed lytic and sclerotic phases behind the leading edges. Triad of bone expansion, cortical thickening, trabecular thickening. Picture frame vertebra – mixed lytic and sclerotic phase in spine. Cotton wool skull – stage II mixed sclerosis and lysis. Conductive hearing loss from otosclerosis with enlargement and reduced fuction of ossicles; sensineural hearing loss from osseous expansion narrowing IAM. Pagetic bone is soft, prone to fracture and deformity. Osteoarthritis in >50%. Platybasia with basilar skull impression/invagination in 1/3. Spinal stenosis. Neoplastic transformation to osteosarcoma/fibrosarcoma in 1% (5-10% of severe polyostotis disease) indicated by new-onset pain; in skull most comonly GCT. Higher risk of osteomyelitis (?hypervascularity), CPPD, gout, rarely high-output cardiac failure, anaemia, metastases in pagetic bone. Rapid osteolysis may occur when equilibrium between production and lysis is disrupted in disuse. Banana/chalkstick fractures – transverse distraction insufficiency fractures on covexity of deformed bone. Shephard’s crook deformity – varus proximal femur.

Fluorosis, Hypervitaminosis A and D

Overingestion of fluoride, vitamin A or D. Retinoid arthropathy – retinoic acid derivatives related to vitamin A, used for acne. Increased bone density and periostitis from metastatic deposition of calcium salts.

  • Fluorosis – Flowing ossification of ALL, mottled teeth highly resistant to caries.
  • Hypervitaminosis A – Flowing ossification of ALL, hydrocephalus, prominent periosteal new bone formation (mimics Caffey’s disease) usually sparing mandible, jaundice.
  • Hypervitaminosis D – Hypercalcaemia, hypercalciuria, phosphaturia, soft tissue calcification, cortical and trabecular thickening, dense skull, widened provisional zone of calcification in children.

Heavy Metal Poisoning

Several heavy metals esp lead damage osteoclasts, increasing bone density and undertubulation in metaphyses. Dense metaphyseal bands are common normally in metaphyses of growing children, but pathological in proximal fibular and distal ulna (DDx healing rickets, hypervitaminosis D, treated hypothyroidism, rarely scurvy).


Rarely seen now, vitamin C defiency limiting collagen formation (bone matrix, cartilage, tendon, ligaments). Diffuse bone demineralisation, insufficiency fractures, subperiosteal haemorrhage with subsequent ossification. Wimberger’s sign – sclerotic epiphyseal rim from disorganised bone at centre of ossification. Frenkel’s line – dense metaphyseal line. Pelkin’s fracture – metaphyseal corner fracture.

Gaucher’s Disease

See Genetic and Systemic Disorders