Renal osteodystrophy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Nazia Fuad M.D.

Synonyms and keywords:Chronic kidney disease- mineral bone disorder

Overview

Renal osteodystrophy is defined as the complex metabolic bone disorders which are present in chronic renal insufficiency. Secondary hyperparathyroidism and 1,25-dihydroxycholecalciferol (Vitamin D3) deficiency play major role in renal osteodystrophy. It is defined as an alteration of bone morphology in patients with chronic kidney disease and is considered to be a component of chronic kidney disease - mineral bone disorder (CKD-MBD). Renal osteodystrophy is an important cause of morbidity, decreased quality of life, and extravascular calcifications that have been associated with increased cardiovascular mortality. The classification of renal osteodystrophy describes a wider clinical syndrome based on bone turnover, bone mineralization, and bone volume. For investigating renal osteodystrophy, blood levels of parathyroid hormone (PTH), calcium, phosphorus, alkaline phosphatase, bicarbonate should be ordered initially. Imaging studies should focus on finding calcification in soft tissues. Bone biopsy is indicated if the results of biochemical markers are not consistent, there is unexplained bone pain, or presence of unexplained bone fractures. However, bone biopsy is infrequently used in clinical practice due to invasiveness and lower cost effectiveness. The major objective in the prevention and management of renal osteodystrophy is either prevention of hyperparathyroidism or treatment if present already .

Historical Perspective

• Renal osteodystrophy was first defined by Kidney Disease: Improving Global Outcomes (KDIGO) in 2006.
• It was found out in 1970s and 1980s, that aluminum in water that is used for dialysis and aluminum salts that are used as phosphate binders caused osteomalacia and an adynamic bone disease. The identification of these disorders led to define renal osteodystrophy, since then the composition of dialysis fluids was changed and calcium carbonate was substituted for aluminum salts. As a result, bone disease due to deposition of aluminium is decreasing.

Classification

• Renal osteodystrophy can be classified according to histology into following subtypes:

Histologic Classification of Renal Osteodystrophy
Disorder	Description	Pathogenesis	frequency(%)
Osteitis fibrosa	Peritrabecular fibrosis, increased remodeling — resorption and formation.	Secondary hyperparathyroidism, secondary role of cytokines and growth factors	50
Osteomalacia	Increased osteoid, defective mineralization	Aluminum deposition, plus unknown factors	7
Mixed disease	Features of both osteitis fibrosa and osteomalacia	Secondary hyperparathyroidism and aluminum deposition, plus unknown factors	13
Mild disease	Slightly increased remodeling	Early or treated secondary hyperparathyroidism	3
Adynamic renal bone disease	Hypocellular bone surfaces, no remodeling	Aluminum deposition, parathyroid hormone suppression, and other factors (deficiency of bone growth factors or increased suppressors of bone remodeling)	27

• Renal osteodystrophy can be subdivided according to TMV classification which uses three descriptions- bone turnover(T), bone mineralization(M)

and bone volume(V).

• After the bone pathology is assessed by histomorphometry, it helps to define the pathophysiology and to choose the right therapy.

Pathophysiology

The following factors in chronic kidney disease are considered to be the main contributors

• Hyperphosphatemia, when GFR falls below 60 ml/min in chronic kidney disease there is impaired renal phosphorus excretion resulting in hyperphosphatemia.
• Hypocalcemia, because of decreased excretion of phosphate by the damaged kidneys.
• Low activated vitamin D₃ levels happens because the damaged kidneys are unable to convert vitamin D₃ into its active form, calcitriol, this results in further hypocalcemia.
• Hyperphosphatemia combined with hypocalcemia results in hyperparathyroidism
• Elevated level of Hyperparathyroid leads to Osteitis fibrosa .
• High levels of fibroblast growth factor 23 are found in chronic kidney disease.

Factors in the pathogenesis of hyperparathyroidism in chronic renal disease
	phosphorus retention	Hypocalcemia	Low calcitriol	Skeletal resistance	Altered parathyroid function
↓Renal mass	+		+
↑Phosphorus		+	+	+	?
↓Calcium					+
↓Calciterol		+		+	+
Skeletal resistance	+
Desensitization to PTH		+
↓Vit D recepters					+
Altered cell growth					+
Acidosis			+

Causes

• The common causes of renal osteodystrophy are
  • Chronic renal disease
  • Hypocalcemia
  • Hyperphosphatemia
  • Vit D deficiency
  • Parathyroid gland hyperplasia
  • Systemic acidosis
  • Aluminum retention(in dialysis patients)
  • Accumulation of β2M in bone and joints

Differentiating Renal Osteodystrophy from Other Diseases

Renal osteodystrophy must be differentiated from the diseases that cause abnormal bone mineralization, unexplained bone fractures and bone pain.

• Primary Hyperparathyroidism will have hypercalcemia, hyperparathyroidism, and normal-to-low phosphate in patients with either normal or slightly reduced renal function
• Tertiary Hyperparathyroidism presents as hypercalcemia, hyperparathyroidism, and normal or slightly elevated phosphate in patients with longterm chronic kidney disease and mineral bone disorder (CKD-MBD)

• Osteoporosis, patients will have normal renal function.
• Vitamin D deficiency will have normal or slight reduction in renal function.

Epidemiology and Demographics

• The prevelence of renal osteodystrophy is 8% in the adult population in US . The incidence increases in patients with chronic kidney disease who have glomerular filtration rate (GFR) less than 60 mL/min.
• Prevalence in developing countries:
  • The prevalence of renal osteodystrophy in developing countries is 24.4% to 63%.
  • Aluminium,high strontium levels and iron overload plays a major role in the development of renalosteodystrophy in patients who undergo dialysis.

Risk Factors

• The major risk factor in the development of Renal Osteodystrophy is:
  • Chronic Renal Disease
  • Dialysis
  • Diabetes Mellitis

Natural History, Complications, and Prognosis

• Common complications of Renal osteodystrophy include
  • Bone fractures
  • Vascular calcifications leading to atherosclerosis, coronary artery calcification, hypertension, left ventricular hypertrophy, and congestive heart failure.
  • Extraskeletal calcification can also affect the heart valves and the cardiac conduction system.
  • Calcification of skin arterioles may lead to a condition of ischemia and necrosis of the skin known as calciphylaxis.

• Prognosis is generally good after renal transplant, otherwise it is associated with increase risk of bone fractures, cardiovascular calcification, poor quality of life and increased morbidity and mortality in patients with chronic kidney disease.

Diagnosis

Diagnostic Study of Choice

Bone biopsy

• A definitive tool for diagnosis of renal osteodystrophy is bone biopsy according to KIDGO 2017 guidelines.

• However bone biopsy are infrequently performed because it is invasive and expensive procedure.

Serum biomarkers: 

• The following biomarkers are used in the diagnosis of renal osteodystrophy
  • Serum calcium
  • Serum phosphorous
  • Alkaline phosphatase (total or bone-specific)
  • Parathyroid hormone(PTH)
    • PTH levels are considered to be the best noninvasive option to assess bone turnover.

• The following framework is used to describe the risk for different subtypes of renal osteodystrophy:
  • PTH <100 pg/mL  means adynamic bone disease and a decreased risk of osteitis fibrosa cystica
  • PTH >450 pg/mL means osteitis fibrosa cystica and/or MUO(mixed uremic osteodystrophy)
  • Intermediate PTH levels between 100 and 450 pg/mL  Intermediate values may be due to normal or increased turnover or even reduced bone turnover   

History and Symptoms

• The patients with renal osteodystrophy are usually asymptomatic. When symptomatic, they usually present with:
  • Bone pain
  • Joint pain
  • Chest pain
  • Dyspnea
  • Palpitation or slow pulse

Physical Examination

• Patients with renal osteodystrophy usually appear sick. Physical examination of patients with renal osteodystrophy may include
  • Bone deformity
  • Bone fracture
  • Hypertension
  • Congestive heart failure
  • Heart murmur
  • Increase Pulse Pressure( due to aortic calcification)
  • Ischemia and necrosis of skin called calciphylaxix.

Laboratory Findings

•  Measurement of bone turnover on a bone biopsy is determined by labeling the bone with tetracycline.it is done at two separate times approximately 2 weeks apart. The distance between the two areas of tetracycline deposition is measured and it can be used to calculate bone growth.

• Serum calcium, levels are typically low.
• Serum phosphorous is elevated depending on the stage of chronic kidney disease, dietary phosphorous , and use of phosphate binders.
• Alkaline phosphatase (total or bone-specific) are elevated and shows increased osteoblastic activity. High levels are seen in severe osteitis fibrosa.

PTH levels are the best noninvasive option for assessment of bone turnover.

• The following parameters are used to define the risk for specific subtypes of renal osteodystrophy.
  • PTH <100 pg/mL suggests adynamic bone disease and a decreased risk of osteitis fibrosa cystica and or MUO(mixed uremic osteodystrophy)
  • PTH >450 pg/mL suggests osteitis fibrosa cystica and/or MUO.
  • Intermediate PTH levels between 100 and 450 pg/mL are not useful to predict the type of renal osteodystrophy. Intermediate values may be associated with normal or increased turnover or even reduced turnover.  

Electrocardiogram

• Electrocardiographic findings in patients with renal osteodystrophy may include:
  • Heart block
  • Non ST elevation MI

X-ray

• Routine radiographic screening are not done for bone disease in patients with end-stage renal disease (ESRD).
• Radiographic findings are less sensitive for diagnosis than PTH levels.
• Imaging is usually performed for patients with unexplained bone pain or fractures.
• Radiographic findings of osteitis fibrosa cystica include subperiosteal resorption and new bone formation especially at the radial aspect of the middle phalanges.
• Resorptive loss of bone can be seen at the terminal phalanges, distal ends of the clavicles, and in the skull.
• Radiographs are helpful to show soft tissue calcification, particularly that involves the vasculature,

Echocardiography or Ultrasound

• Echocardiography will show
  • Diastolic dysfunctiong
  • Left Ventricular Hypertrophy
  • Valvular calcifications

CT scan

• CT scan findings associated with renal osteodystrophy are the same that are related to chronic kidney disease.

MRI

• There are no MRI findings associated with renal osteodystrophy.

Other Imaging Findings

• There are no other imaging findings associated with Renal Osteodystrophy

Other Diagnostic Studies

•  DEXA bone densitometry will show low bone density.

Treatment

Medical Therapy:

• Phosphate binders and supplemental calcium are mainly used for prevention and treatment of renal osteodystrophy.

Control of Serum Phosphate

• A low-phosphate diet is mandatory in the end-stage renal disease, to keep serum phosphate concentration with in the normal limits.
• A phosphate binder, either calcium carbonate68 or calcium acetate69 is required to be taken with each meal.
• Aluminum-containing phosphate binders should be avoided.

Control of Serum Calcium

Calcium malabsorption is seen in end-stage renal disease because of deficient 1,25-dihydroxycholecalciferol.

• To prevent or suppress oversecretion of parathyroid hormone, calcium concentrations should be maintained at the high end of the normal range.
• 71 A dialysate calcium concentration of 7 mg per deciliter provides approximately 800 mg calcium per treatment.
• To control hyperphosphatemia, the increased dialysate calcium concentration may cause hypercalcemia ,in such situation the dialysate calcium concentration should be reduced to 5 mg per deciliter. this level will not affect the calcium balance.
• The timing of taking oral calcium is crucial as calcium taken between meals is more like a calcium supplement than a phosphate binder.

Use of Vit D analogue

• Calcitriol alfacalcidol, dihydrotachysterol, and calcifediol - They reduce bone pain, improve bone histologic characteristics, and suppress parathyroid hormone secretion by increasing serum calcium concentrations and inhibiting parathyroid hormone gene transcription.

Primary Prevention

• Timely recognition and treatment of hyperparathyroid patients.
• Early recognition and treatment of renal diseases to prevent chronic renal failure and consequently Renal osteodystrophy

Secondary Prevention

• Vit D administration with every session of dialysis
• Use of aluminium free phosphate binders.

Related Chapters

• osteoporosis
• osteopenia
• osteomalacia
• hyperparathyroidism
• multiple myeloma
• soft tissue calcification including collagen vascular disease
• hydroxyapatite crystal deposition disease
• hypervitaminosis

External links

Renal Osteodystrophy

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