Renal Osteodystrophy

Bone is composed of cells and extracellular matrix  comprised of a mainly type I collagen matrix impregnated with hydroxyapatite crystals. It is constantly remodelled by the finely balanced dual action of osteoblasts which form bone and osteoclasts which reabsorb bone.  Unbalanced remodelling process leads to osteoporosis. Remodelling occurs on the bone surface and the rate of remodelling is higher in the cancellous bone as it has a larger surface area.

The incidence of chronic kidney disease (CKD) is increasing worldwide. CKD may be associated with progressive loss of renal function, cardiovascular disease and premature death. Disturbance of mineral metabolism and bone disease are common complications of CKD. The changes in bone and mineral metabolism are attributed to variations in the serum parathyroid hormone (PTH) levels.

Definition

At the 2003 National Kidney Foundation Controversies Conference on Mineral Metabolism and Bone Disease in CKD defined renal osteodystrophy as the following. ‘A constellation of bone disorders present or exacerbated by chronic kidney disease that lead to bone fragility and fractures, abnormal mineral metabolism, and extra-skeletal manifestations.’

Kidney Disease: Improving Global Outcomes (KDIGO), a global collaboration with a stated objective ‘to improve the care and outcomes of kidney disease patients worldwide through promoting coordination, collaboration and integration of initiatives to develop and implement clinical practice guidelines’  has recommended that the term renal osteodystrophy be used exclusively to denote alterations in bone morphology in patients with CKD. KDIGO has recommended the use of the term Chronic Kidney Disease – Mineral and Bone Disorder (CKD-MBD) to describe a broader clinical syndrome that develops as a systemic disorder of mineral and bone metabolism due to CKD, which is manifested by abnormalities in bone and mineral metabolism and/or extra-skeletal calcification. Renal osteodystrophy is one component of CKD-MBD.

Clinical Features

• The changes in musculoskeletal system in renal osteodystrophy can be due to secondary hyperparathyroidism(bone resorption, periosteal reactions and brown tumours) osteoporosis, osteosclerosis, osteomalacia and soft tissue and vascular calcification.
• Bone resorption can be subperiosteal, endosteal, trabecular, subchondral and subligamentous.
• Osteosclerosis is mainly seen in the axial skeleton.
• The prevalence of soft tissue calcification increases with the duration of hemodialysis.
• Other major musculoskeletal abnormalities can be aluminium deposition, amyloidosis, crystal deposition disorders, destructive spondylarthropathy, tendon ruptures and infection.
•  Hyperparathyroidism is due to inability of kidneys to excrete phosphorus leading to hyperphosphatemia which stimulates parathyroid to secrete parathormone.
• Disturbance of mineral metabolism and bone disease is associated with morbidity, decreased quality of life, extra skeletal calcification and increased cardiovascular mortality.
• Increased cardiovascular mortality is probably related to vascular calcification.
• Osteomalacia causes
  • 1α hydroxylase deficiency
  • Dysfunction of hepatic enzymes
  • Hypocalcimea
  • Inhibition of calcification by acidosis and azotemia
  • Aluminium toxicity
• Osteoporosis causes
  • Chronic metabolic acidosis
  • Azotemia
  • Hyperparathyroidism
  • Vitamin D deficiency
  • Poor nutrition
  • Steroid treatment

Diagnosis

• Bone biopsy, serum markers and imaging are the main tools used for assessment of bone disease in CKD.
• The initial evaluation should include PTH, calcium (either ionized or total corrected for albumin), phosphorus, alkaline phosphatase (total or bone-specific), bicarbonate, and imaging for soft tissue calcification.
• Diagnosis of renal osteodystrophy needs bone biopsy and histomorphometry. 
• Indication for bone biopsy in CKD patients
  • Inconsistencies among biochemical parameters
  • Unexplained skeletal fracture or bone pain
  • Severe progressive vascular calcification 
  • Unexplained hypercalcemia
  • Suspicion of overload or toxicity from aluminum
  • Before parathyroidectomy if there has been significant exposure to aluminum in the past
  • Before beginning treatment with bisphosphonates
• Histomorphometry was pioneered by Harold Frost in the 1960s.
• Histomorphometry of biopsied bone samples is considered as the gold standard for the diagnosis for renal osteodystrophy.
• Bone histomorphometry is defined as a quantitative evaluation of bone microarchitecture, remodelling and metabolism.
• Histomorphometry evaluates in vivo bone metabolism and microarchitecture.
• It helps in the diagnosis of metabolic bone disease and in their classification.
• In osteomalacia, impairment of bone mineralization characterised by increased osteoid thickness, surface and volume can be identified by histomorphometry.
• Histomorphometry should be reported using standard nomenclature recommended by the American Society for Bone and Mineral Research.
• Histomorphometry should be reported along with biopsy technique, specimen size, tetracycline protocol, assessment of sample adequacy, tissue area, magnification, minimal osteoid width, and normative data.
• Renal osteodystrophy is classified using TMV classification which takes turnover of bone, mineralization and volume into consideration for the classification.
• Classification is to be used only in adult patients with a glomerular filtration rate <60ml/min/1.73m2 and in paediatric patients with glomerular filtration rate <89ml/min/1.73m2. 
• TMV Classification
  • Turnover – Low, Normal or High
  • Mineralization– Normal or Abnormal
  • Volume– Low, Normal or High

• Turnover reflects the rate of skeletal remodelling. Bone turnover is affected by hormones, cytokines, mechanical stimuli, and growth factors that influence the recruitment, differentiation, and activity of osteoclasts and osteoblasts. It is assessed by histomorphometry using dynamic measurements of osteoblast function utilising double-tetracycline labelling.
• Mineralization reflects the level of calcification of bone collagen during the formation phase of skeletal remodeling. Mineralization reflects the level of calcification of bone collagen during the formation phase of skeletal remodeling. Mineralization is assessed by histomorphometry using static measurements of osteoid volume and osteoid thickness and also by dynamic, tetracycline-based measurements of mineralization lag time and osteoid maturation time. Causes of impaired mineralization include vitamin D deficiency, mineral deficiency, metabolic acidosis, or aluminium toxicity.
• Volume indicates the amount of bone per unit volume of tissue. It is assessed with histomorphometry by measurement of bone volume in cancellous bone. Causes of impaired mineralization include vitamin D deficiency, mineral deficiency, metabolic acidosis, or aluminium toxicity.The initial evaluation should include PTH, calcium (either ionized or total corrected for albumin), phosphorus, alkaline phosphatase (total or bone-specific), bicarbonate, and imaging for soft tissue calcification.
• Diagnosis of renal osteodystrophy needs bone biopsy and histomorphometry. 
• Indication for bone biopsy in CKD patients
  • Inconsistencies among biochemical parameters
  • Unexplained skeletal fracture or bone pain
  • Severe progressive vascular calcification 
  • Unexplained hypercalcemia
  • Suspicion of overload or toxicity from aluminum
  • Before parathyroidectomy if there has been significant exposure to aluminum in the past
  • Before beginning treatment with bisphosphonates

Bone Biopsy

• Taken by trans-iliac approach or Jamshidi approach.
• Trans-iliac approach done 2cm below and behind anterior superior iliac spine.
• A 5 or 8mm trephine used to obtain a core with inner and outer table of iliac crest with intervening cancellous bone.
• Jamshidi approach which obtains a vertical core from the iliac crest is not used in children as this region contains the physis which may lead to erroneous samples. 
• Sample processing includes five steps: fixation, dehydration, clearing, impregnation and embedding.
• Fixation is done by 70% alcohol for a minimum of 72 hours at 5ºC.
• Dehydration is achieved by increasing the ethanol saturation from 96% to 100% over a period of 24 hours at 5ºC.
• Clearing is done by replacing alcohol with xylene for 24hours at 5ºC.
• Impregnation is done in methyl methacrylate for a minimum of 72 hours at-20ºC.
• Embedding in methyl methacrylate is done at a constant temperature ranging from 5°C up to 10°C.
• Cutting is performed in a microtome machine with tungsten blade, orienting the sample with the cortical bone perpendicular to the edge of the blade.
• The cuts should be 5-10µm in thickness.
• The cut samples are mounted on a slide, followed by 48 hours of pressing at 55ºC.
• Different staining techniques available depending on the desired target, such as Toluidine Blue, von Kossa, phosphatase acid, Goldner Trichrome, Solochrome Azurine and Perl’s method.

Tetracycline labelling

• Tetracycline binds to mineralization fronts of amorphous minerals, labelling them with a yellow-green colour under fluorescent light, thus acting as a marker for bone formation and mineralization. 
• Tetracycline  taken 21 days before bone biopsy. 
• Two doses are taken with an interval of 10 days. 
• This allows the identification of two distinct lines that represent two phases of mineralization. 
• Tetracycline labelling allows the dynamic assessment of bone metabolism.

X-ray findings

• Skull
  • Salt and pepper appearance 
  • Loss of distinction between inner and outer tables
  • Loss of lamina dura of teeth
• Chest X-ray 
  • Subchondral erosion of sternal end of clavicle
  • Subligamentous erosion of acromioclavicular ligament attachments
• Hand
  • Tuft erosion
  • Subperiosteal erosion
  • Intracortical tunneling
  • Endosteal scalloping
• Subperiosteal erosion
  • First described by Camp and Ochsner in 1931.
  • Pathognomonic of hyperparathyroidism.
  • Seen on the radial aspect of middle phalanx of middle and index fingers beginning in the proximal metaphysis .
  • Seen as lace like irregularity which may progress to scalloping and spiculation.
  • Rotting fence post sign – medial femoral neck subperiosteal erosion.
• Brown tumours
  • More common in primary hyperparathyroidism than secondary hyperparathyroidism.
  • Frequently single.
  • Cause eccentric or intracoortical expansive lyric lesions.
  • Due to replacement of bone by vascularised fibrous tissue.
  • Ribs, pelvis, facial bones and femur are the common sites.
  • After parathyroidectomy, heals by calcification.
• Rickets radiological findings
  • Delay in bone age
  • Bowing of bones
  • Widening of growth plate
  • Metaphyseal cupping and fraying
  • Scoliosis
  • Biconcave vertebral end plates
  • Triradiate pelvis
• Loosers zones
  • Transverse psuedofractures due to unmineralized cartilage.
  • Seen at areas of stress or site of entry of nutrient arteries
  • Common sites are pubic rami, medial femoral neck, scapula, ribs, lesser trochanter, ischiopubic rami and long bones.
• Slipping of epiphysis
  • Seen in children with history of uraemia of >2 years and in those commenced on hemodialysis close to puberty
  • Most common in capital femoral epiphysis 
  • Other sites are proximal humerus, distal femur, distal radius, heads of metatarsals and metacarpals.
• Soft tissue calcification
  • Due to hypercalcimea, increased calcium-phosphorus product and local tissue trauma or alkalosis.
  • Common if serum calcium-phosphorus product is more than 75mg/dL.
  • Seen in ocular tissues, arteries, subcutaneous and peri articular soft tissues and viscera.
  • Subcutaneous, periarticular and vascular calcification is composed of hydroxy apatite with a molar ratio of Ca-MG-P of 30:1:18.
  • Visceral calcification is amorphous with a molar ratio of Ca-Mg-P of 4.9:1:4.6. 
  • Periarticular calcification are symmetrical, discrete, dense and cloud like opacities. Seen around phalangeal joints, wrist, elbow, shoulder, hips, knees and ankles.
  • Visceral calcification usually not seen radiologically. Most common around heart, lungs, stomach and kidneys.
  • Visceral calcification in the myocardium can lead to conduction abnormalities and death.

Treatment

• Correction of hyperphosphatemia and hypercalcimea to slow or halt extra-skeletal calcification is needed for treatment of renal osteodystrophy.