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. , Parnian Jabbari

Synonyms and keywords:Chronic kidney disease- mineral bone disorder


Renal osteodystrophy (ROD) is within the broad spectrum of Chronic Kidney Disease (CKD)- Mineral Bone Disease (MBD). The disease occurs as a natural complication of the CKD and is characterized by abnormal levels and metabolism of calcium (Ca), phosphorus (Ph), parathyroid Hormone (PTH), and vitamin D, as well as calcification of soft tissues and bone turn over and mineralization abnormalities. Secondary hyperparathyroidism and 1,25-dihydroxycholecalciferol (vitamin D3) deficiency play a major role in ROD. Any factor leading to CKD is potentially a risk factor for ROD. Hypocalcemia, hyperphosphatemia, vitamin D deficiency, parathyroid gland hyperplasia and acidosis are the other contributors of ROD. Aluminum related ROD is mostly seen in patients who undergo dialysis. ROD is an important cause of morbidity, decreased quality of life, and extravascular calcifications that have been associated with increased cardiovascular mortality. Primary investigation of ROD includes measurement of blood levels of parathyroid hormone (PTH), calcium, phosphorus, alkaline phosphatase and bicarbonate. Imaging studies should focus on finding calcification in soft tissues. A bone biopsy is indicated if the results of biochemical markers are not consistent or when there is unexplained bone pain, or in case of presence of unexplained bone fractures. However, bone biopsies are infrequently used in clinical practice due to invasiveness and low cost-effectiveness. Common complications of ROD include bone fractures and vascular calcifications leading to atherosclerosis, coronary artery calcification, hypertension, left ventricular hypertrophy, and congestive heart failure (CHD). Extra-skeletal 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. Patients with renal osteodystrophy usually present with bone pain, arthralgia, chest pain, dyspnea, and palpitation. Physical examination of patients with renal osteodystrophy may include bone deformity, bone fracture, hypertension, ongestive heart failure, heart murmur, increased pulse pressure (due to aortic calcification) and skin ischemia and necrosis. In laboratory findings, 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 levels (total or bone-specific) are elevated and show increased osteoblastic activity. High levels of alkaline phosphatase are seen in severe osteitis fibrosa. Elecrocardiographic findings in patients with renal osteodystrophy include heart block and non-ST-elevation myocardial infarction. Radiographic findings are less sensitive for diagnosis compared to parathyroid hormone levels. Imaging is usually performed for patients with unexplained bone pain or fractures. Radiographic findings of osteitis fibrosa cystica include subperiosteal resorption. Resorptive loss of bone may be seen at the terminal phalanges, distal ends of the clavicles, and in the skull. Radiographs will show soft tissue calcification that involves the vasculature. Phosphate binders and supplemental calcium are mainly used for prevention and treatment of renal osteodystrophy. The major objective in the prevention and management of renal osteodystrophy is either prevention of hyperparathyroidism or its treatment if present.

Historical Perspective


  • Renal osteodystrophy can be classified according to histology into the following subtypes:[1][2]
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

Osteomalacia  Increased osteoid, defective


Aluminum deposition, plus

unknown factors

Mixed disease  Features of both osteitis fibrosa

and osteomalacia

Secondary hyperparathyroidism

and aluminum deposition,

plus unknown factors

Mild disease  Slightly increased remodeling Early or treated secondary


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)

  • After the bone pathology is assessed by histomorphometry, renal osteodystrophy can be subdivided according to TMV classification
  • TMV uses three descriptions- bone turnover(T), bone mineralization(M) and bone volume(V).


Overview of pathophysiology[3][4][2]:

In CKD, serum Ca levels decrease and serum Ph levels increase. Initially in the course of renal disease, compensatory mechanisms try to increase serum Ca and decrease serum Ph. These mechanisms include increased levels of fibroblast growth factor 23 (FGF23) which in turn increases urinary Ph excretion. On the other hand, increased PTH levels further increase urinary excretion of Ph. However, as the renal disease becomes chronic, these compensatory mechanisms do not respond any more and the characteristic features of ROD become evident [5]. Once an abnormality in serum levels of these minerals is established (decreased Ca and increased Ph), PTH levels increase and change bone metabolism via alterations in osteoblast and osteoclast activity. Early in CKD, due to increased FGF23, 1,25 (OH) vitamin D decreases which further leads to hyperparathyroidism (HPTH). However, some contributors to CKD-MBD alter before PTH levels are increased, an example of these contributors are sclerostin and FGF23 which are increased even before HPTH. HPTH can also insert its effects via the reduction of β-catenin which inhibits maturation of osteoblasts.

  • PTH receptors are found on preosteoblasts, osteoblasts and osteocytes and increases their proliferation. (Osteoclasts do not have PTH receptors and are activated by preosteoblasts and osteoblasts.)
  • Increased levels of PTH lead to increased bone resorption by osteoclasts [6] and osteitis fibrosa.

As a result, HPTH leads to high-turnover bone disease.

Many factors can contribute to low levels of PTH, such as increased dietary intake of Ca and Vit D, using Ph binders containing Ca dialysate. Low levels of PTH lead to low-turnover bone disease, also known as adynamic bone disease. Low PTH levels lead to excess circulating Ca (since Ca is not deposited in the bone). This excess Ca may lead to calcification of soft tissues.

Aluminum-based chelation of Ph during dialysis was among the common factors contributing to osteomalacia. However since replacement of aluminum with other chelators this factor is less prominent. [4][7][2]

CKD leads to uremia and hyperphosphatemia which change the pluripotent smooth muscle cells to osteoblasts. This coupled with increased Ca levels leads to calcification of soft tissues [8].

Overall, following factors contribute to vascular calcification [5]:

  • Hypocalcemia and hyperphosphatemia
  • Hyperparathyroidemia
  • Matrix degradation and alteration of matrix proteins
  • Apoptosis of smooth muscle cells
  • Systemic inflammation
 Factors in the pathogenesis of hyperparathyroidism in chronic renal disease
Phosphorus retention Hypocalcemia Low calcitriol Skeletal



parathyroid function

↓Renal mass + +
Phosphorus + + + Unknown
Calcium +
Calciterol + + +
Skeletal resistance +
Desensitization to PTH +
Vit D receptors +
Altered cell growth +
Acidosis +


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:[3]
Differential diagnosis of renal osteodystrophy
Calcium Phosphate Renal function
Renal osteodystrophy Markedly declined
Primary hyperparathyroidism Low to normal Normal or slightly


Tertiary hyperparathyroidism Slightly elevated Normal or slightly reduced
Osteoporosis Normal Normal Normal
Vitamin D deficiency Normal
Osteomalacia Normal

Epidemiology and Demographics

  • The prevelence of renal osteodystrophy is 8,000 per 100,000 in the adult population in US. Incidence of renal osteodystrophy increases in patients with chronic kidney disease who have glomerular filtration rate (GFR) less than 60 mL/min.[3]
  • Prevalence in developing countries:
    • The prevalence of renal osteodystrophy in developing countries is 24.4% to 63%.
    • Aluminum, increased strontium levels and high levels of iron in the blood play a major role in the development of renal osteodystrophy in patients who undergo dialysis in developing countries.
    • Extraskeletal manifestations of CKD-MBD (calcification of soft tissues) is observed in 1000 per 100,000 of CKD patients on dialysis.

Risk Factors

Any factor leading to CKD, indirectly leads to renal osteodystrophy. These factors include:

Some factors can enhance the effects of these risk factors such as Vitamin D deficiency and high-phosphate, low-calcium diet.

The major risk factors in the development of renal osteodystrophy are:[3]

Natural History, Complications, and Prognosis

CKD leads to:

  • hypocalcemia
  • hyperphosphatemia (a predictor of cardiovascular and all-cause mortality)
  • decreased Vit D levels
  • hyperparathyroidism
  • either increased bone turnover (due to HPTH and uremia) or adynamic bone disease
  • calcification of soft tissues and vessels.
  • HTN due to lessening ARB efficacy by increased levels of FGF23.
  • cardiovascular disorders (uremic cardiomyopathy) (most important cause of mortality and morbidity in CKD).
  • CKD can lead to ESRD and subsequent dialysis.

If left untreated, high-turnover bone disease leads to osteopenia and extraskeletal complications.

Common complications of renal osteodystrophy include:[3]



Diagnostic Study of Choice

Bone biopsy
Microscopic pathology of bone marrow biopsy in a patient with chronic kidney disease. Increased areas of bone absorption are seen due to increased osteoclastic activity. Courtesy of image from[10]om/photos/bc_the_path/537039421/in/photolist-Pst7n.

A definitive tool for diagnosis of renal osteodystrophy is bone biopsy according to KIDGO 2017 guidelines.[3]

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)
  • Osteocalcin
  • Tartrate-resistant acid phosphatase (TRAP)*
  • Collagen degradation products (CDP)
    • However, these products tend to accumulate in CKD regardless of MBD status*
  • Pyrodinoline (PYD)*
  • Dihydro-pyrodinoline (DPD)*
  • PTH levels are considered to be the best noninvasive option to assess bone turnover.[4]

The following levels of PTH is used to describe the risk for different subtypes of renal osteodystrophy:[1]

* Still under investigation

History and Symptoms

Protrusio of the right hip can be seen in renal osteodystrophy. Courtesy of image to

Physical Examination

Laboratory Findings

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

PTH(parathyroid hrmone) levels are the best noninvasive option for assessment of bone turnover.[2]

  • The following parameters are used to define the risk for specific subtypes of renal osteodystrophy.[2]
    • PTH <100 pg/mL is seen in adynamic bone disease and shows a decreased risk of osteitis fibrosa cystica and or MUO(mixed uremic osteodystrophy).
    • PTH >450 pg/mL is present in osteitis fibrosa cystica and/or MUO (mixed uremic osteodystrophy).
    • Intermediate PTH levels between 100 and 450 pg/mL.  Intermediate values may be associated with normal or increased bone turnover or even reduced turnover.[3]



  • Routine radiographic screenings 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 changes in ROD can be classified into four groups:

  • Osteitis fibrosa
  • Osteomalacia
  • Osteosclerosis
  • Soft-tissue calcification
  • Radiographic findings of osteitis fibrosa cystica include:
    • Subperiosteal resorption
    • New bone formation especially at the radial aspect of the middle phalanges.
    • Focal accumulation of giant cells (brown tumor) in facial bones, long bones, clavicle and phalanges.
    • Varying density in skull bone ("salt and pepper" appearance)
  • Radiographic findings of osteomalacia include:
    • Psuedofractures in ischium and pubic rami
  • Osteosclerosis is usually seen in spine, ribs and pelvis
  • Extraeskeletal calcification is usually seen in cornea and conjuctiva and is directly associated with HPTH.
  • Radiographs will show soft tissue calcification that involves the vasculature.[4]
  • Resorptive loss of bone may be seen at the terminal phalanges, distal ends of the clavicles, and in the skull.

Echocardiography or Ultrasound

CT scan

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


  • There are no specific MRI findings associated with renal osteodystrophy since associated changes are usually within the skeletal and bony tissue.

Other Diagnostic Studies

  •  DEXA bone densitometry will show low bone density.[2]
  • Deferoxamine Challenge Test (DFO) can be used to rule out aluminum-related bone disease.


Medical Therapy:

Control of Serum Calcium

  • Calcium malabsorption is seen in end-stage renal disease because of deficient 1,25-dihydroxycholecalciferol.[4]
  • To prevent or suppress oversecretion of parathyroid hormone, calcium concentrations should be maintained at the high end of the normal range.
  • In patients with calcium intakes of 800–1000 mg/day, additional calcium supplements or [][][,gcontaining medications should be avoided.
  • Patients with total calcium intakes (>approx. 1000 mg/day) should be advised to decrease calcium intake.
  • Patients with lower calcium intakes should be advised to increase calcium intake in foods,or take calcium supplements.
  • Calcium-rich foods include dairy, dark green leafy vegetables, calcium-set tofu, and calcium-fortified orange juice.
  • The timing of taking oral calcium is crucial as calcium taken between meals is more like a calcium supplement than a phosphate binder.

Control of Serum Phosphate

Use of Vit D analogue


The treatment for renal osteodystrophy is medical therapy. Surgery is considered under the following circumstances:

Primary Prevention

  • Early diagnosis and treatment of hyperparathyroid patients.
  • Reducing exacerbating factors such as smoking, uncontrolled diabetes, high-phosphate, low-calcium diet and sedentary life style.
  • Early diagnosis and treatment of renal diseases to prevent chronic renal failure and consequently renal osteodystrophy.[4]

Secondary Prevention


  1. 1.0 1.1 1.2 1.3 Hruska, Keith A.; Epstein, Franklin H.; Teitelbaum, Steven L. (1995). "Renal Osteodystrophy". New England Journal of Medicine. 333 (3): 166–175. doi:10.1056/NEJM199507203330307. ISSN 0028-4793.
  2. 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 Moe, S.; Drüeke, T.; Cunningham, J.; Goodman, W.; Martin, K.; Olgaard, K.; Ott, S.; Sprague, S.; Lameire, N.; Eknoyan, G. (2006). "Definition, evaluation, and classification of renal osteodystrophy: A position statement from Kidney Disease: Improving Global Outcomes (KDIGO)". Kidney International. 69 (11): 1945–1953. doi:10.1038/ ISSN 0085-2538.
  3. 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 3.12 3.13 3.14
  4. 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 Gonzalez, E. A.; Martin, K. J. (1995). "Renal osteodystrophy: pathogenesis and management". Nephrology Dialysis Transplantation. 10 (supp3): 13–21. doi:10.1093/ndt/10.supp3.13. ISSN 0931-0509.
  5. 5.0 5.1 Yi-Chou Hou, Chien-Lin Lu, Kuo-Cheng Lu. "Mineral bone disorders in chronic kidney disease".
  6. Lee SK, Lorenzo JA. "Parathyroid hormone stimulates TRANCE and inhibits osteoprotegerin messenger ribonucleic acid expression in murine bone marrow cultures: correlation with osteoclast-like cell formation". External link in |website= (help)
  7. Moe, S.; Drüeke, T.; Cunningham, J.; Goodman, W.; Martin, K.; Olgaard, K.; Ott, S.; Sprague, S.; Lameire, N.; Eknoyan, G. (2006). "Definition, evaluation, and classification of renal osteodystrophy: A position statement from Kidney Disease: Improving Global Outcomes (KDIGO)". Kidney International. 69 (11): 1945–1953. doi:10.1038/ ISSN 0085-2538.
  8. Jorge B, Cannata-Andνa, Minerva Rodrνguez-Garcνa; et al. (2006). "ascular calcifications: Pathogenesis, management and impact on clinical outcomes". J Am Soc Nephrol. 17: 267–73.
  9. Nissenson, Allen (2009). Current diagnosis & treatment. New York: McGraw-Hill Medical. ISBN 978-0-07-144787-4.
  10. "renal psteodystrophy microscopic pathology". External link in |website= (help)
  11. Abdullah M.W. El-Kishawi*, A.M. El-Nahas (2006). "Renal Osteodystrophy: Review of the Disease and its Treatment". Saudi J Kidney Dis Transplant. 17 (3): 373–382.

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Renal Osteodystrophy


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