Osteomalacia/Rickets

Background/Epidemiology

• Both are essentially the same condition but rickets present in childhood before the bones have grown/fused
• Characterised by defective bone mineralisation due to either
  • Vitamin D deficiency
  • Resistance to the effects of Vitamin D
  • Hypophosphataemia

Causes

• Vitamin D deficiency
  • Classical- lack of sunlight/poor diet (reduced cholecalciferol synthesis in the skin/low levels of vit D in the diet)
  • GI disease- malabsorption
• Failure of 1,25-vitamin D synthesis
  • Chronic renal disease (e.g. hyperphosphataemia)
  • Rarely, inherited conditions (e.g. vit D resistant rickets type I) (due to loss-of-function mutations of enzymes)
• Vit D receptor defects (vit D resistant rickets type II) (due to loss of function mutation in the vit D receptor)
• Defects in phosphate/pyrophosphate metabolism (rarer, mostly hereditary conditions)
  • Hypophosphataemic rickets (X-linked- mutation in PHEX)
  • Autosomal dominant hypophosphataemic rickets (mutation of FGF23)
  • Autosomal recessive hypophosphataemic rickets (mutation of DMP1)
  • Tumour induced hypophosphataemic osteomalacia (ectopic production of FGF23 by tumour)
  • Hypophosphatasia (mutations in bone specific alk phos)
• Iatrogenic/Other
  • Bisphosphonate therapy (high-dose)
  • Aluminium
  • Fluoride

Pathophysiology

• About 70% of vit D synthesised in the skin from 7-dehydrocholesterol (under UV light) and remainder is absorbed via the gut.  It is then hydroxylated first in the liver (forming 25(OH)-vit D and then in the kidney to the active form 1,25 (OH)- vit D
• Acts on the gut to increase calcium absorption and on the skeleton to stimulate remodelling
• Involved in a negative feedback loop involving the parathyroid glands:
  • ↓vit D; ↓Ca; ↑PTH; ↑renal vit D (also ↑Ca (decreased excretion, increased resorption), ↓PO4- increased excretion)
• The feedback loop eventually fails once vit D stores are deplete, leading to hypocalcaemia and hypophosphataemia and thus poor mineralisation of the skeleton (with secondary parathyroidism)

Presentation

• In children, rickets causes delayed development, muscle hypotonia and bone deformities
• In adults, osteomalacia often develops insidiously
  • Fractures can be a presenting feature (particularly mild osteomalacia)
  • In severe disease, bone and muscle pain, general malaise and fragility fractures is the classical triad seen.
    • Proximal muscle weakness is also common

Investigations

• LFTs – Alk Phos is typically raised
• Serum vit D- low/undetectable
• PTH- raised
• Ca and PO4 can be low but can be normal
• X-rays can be normal.  In severe disease they may reveal focal radioluscent areas in the ribs, pelvis and long bones.  Fractures may be seen.  Osteopenia is common.
  • In children there can be thickening of the epiphyseal plate
• Radionucleide scans (not required for diagnosis- may show hot spots of fractures which can be mistaken for mets)
• Bone biopsy (rarely required but will confirm diagnosis- increased thickness of osteoid seams)

Management

• Vitamin D (Cholecalciferol e.g. accrete D3) -initially 250-1000μg or 10,000IU daily; then 10-20μg or 1000IU after 3 months if there are no underlying absorption problems

A note about other types of osteomalacia/rickets

• Vitamin-D resistant rickets (causes see above)
  • Clinical features are similar to Vit-D deficient-rickets in the infant but these children fail to respond to vit-D treatment
  • 25(OH)-vit-D levels are usually normal (and in type II disease PTH and 1,25(OH)vit-D levels are raised)
  • Type 1 can be treated with active vit D metabolites (e.g. alfacalcidol); Type 2 can be difficult to treat
• Renal rickets
  • usually treated with active metabolites of vitamin D (alfacalcidol)
• Hypophosphataemic rickets and osteomalacia
  • FGF23 is important in regulating expression of sodium dependent phosphate transporters in the kidney.  Osteocytes are the main source of FGF23 and expression is regulated by DMP1 and PHEX, also produced by osteocytes.
  • Hereditary forms usually present with features of rickets with hypophosphataemia and renal phosphate wasting (without vit D deficiency)
  • Ectopic causes usually presents rapidly with features of osteomalacia.
    • Require whole-body imaging to look for tumour
  • Manage with phosphate supplements and active vit-D metabolites (in ectopic causes, removal of the tumour)
• Hypophosphatasia
  • Autosomal recessive disorder (inactivating mutation of TNALP gene) causing impaired Alk Phos function, resulting in accumulation of pyrophosphate and inhibition of bone mineralisation
  • Presents with osteomalacia, low Alk Phos but otherwise normal serum biochem and vitD/PTH etc
• Bisphosphonate treatment
  • Most patients on bisphosphonates receive low(ish) doses (e.g. osteoporosis)
  • Patients with diseases such as Paget’s disease, who receive higher doses may be affected
  • Resolves with changing treatment (lower dose or stop)