Excerpt from Osteomalacia and Renal Osteodystrophy

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Background

Osteomalacia is characterized by incomplete mineralization of normal osteoid tissue following closure of the growth plates. Osteomalacia may be part of the spectrum of osseous abnormalities that can be observed in patients with chronic renal insufficiency. This condition is referred to as renal osteodystrophy.

Renal osteodystrophy combines features of secondary hyperparathyroidism, rickets, osteomalacia, and osteoporosis. Findings of rickets and osteomalacia are present in children, and findings of osteomalacia and secondary hyperparathyroidism are present in adults.^{1, 2, 3, 4}

(See also the eMedicine articles Hyperparathyroidism, Secondary, Rickets, Osteoporosis, and Osteoporosis, Involutional, as well as Conference Brief - Understanding Pathways for the Pathogenesis of Renal Osteodystrophy, on Medscape.)   

Pathophysiology

Renal osteodystrophy is a global term applied to all pathologic features of bone in patients with renal failure. The primary retention of phosphate by abnormal kidneys results in hyperphosphatemia, which causes hypocalcemia, resulting in secondary hyperparathyroidism.^{5, 6} Therefore, the spectrum of clinical and radiographic findings in renal osteodystrophy may be a manifestation of any of these disorders.

Osteomalacia is a disorder of bone that results from hypomineralization following the cessation of bone growth. In contrast to rickets, which affects mineralization of growing bones, osteomalacia does not affect the growth plates; however, hypomineralization of trabecular and cortical bone occurs.^{7, 8}

Normal bone mineralization depends on interdependent factors that supply adequate calcium and phosphate to the bones. Vitamin D maintains calcium and phosphate homeostasis through its action on bone, the GI tract, kidneys, and parathyroid glands. Vitamin D may be supplied in the diet or produced from a sterol precursor in the skin following exposure to ultraviolet light. Sequential hydroxylation then is required to produce the metabolically active form of vitamin D. Hydroxylation occurs first in the liver and then in the kidneys to produce 1,25-dihydroxyvitamin D3. Dysfunction in any one of these metabolic steps may result in rickets and osteomalacia in the growing child, as well as osteomalacia and secondary hyperparathyroidism in the adult.

The histopathology of osteosclerosis in renal osteodystrophy is complex and incompletely understood. Histologic evaluations of patients with renal osteodystrophy typically reveal osteoclastosis, osteoblastosis, and evidence of abnormally increased bone turnover. Additionally, an increased proportion of cancellous bone often exists. Calcium may be deposited in this cancellous bone as amorphous calcium phosphate rather than hydroxyapatite. This may help explain the increased osteosclerosis noted in some patients with renal osteodystrophy. Osteosclerosis also may be due to an increase in thickness and number of trabeculae in cancellous bone. Osteosclerosis is typically evident in areas with a large proportion of cancellous bone such as the spine. Osteosclerosis concentrated beneath the vertebral body endplates gives rise to the "rugger jersey" appearance.

Bone resorption in renal osteodystrophy is also quite complex. Renal retention of phosphate results in hyperphosphatemia, which reduces serum ionized calcium levels, therefore inducing hyperparathyroidism. The hyperparathyroidism increases bone resorption, which may normalize serum calcium levels by releasing the osseous storage of calcium. The various sites of bone resorption include the subperiosteal region of the phalanges, the phalangeal tufts, proximal femur, proximal tibia, proximal humerus, distal clavicle, and calvarial trabeculae.

The cause of osteomalacia in renal osteodystrophy is multifactorial. The low serum calcium level directly induced by hyperphosphatemia is a major factor. Hyperphosphatemia also decreases the efficacy of 1-hydroxylase, which decreases the levels of 1-25 dihydroxyvitamin D and, thus, the ability of the gut to absorb calcium.⁹

Aluminum-induced bone disease is an additional cause of osteomalacia. Aluminum negatively affects bone formation through inhibition of osteoblastic activity, as well as by hydroxyapatite crystal formation. Aluminum may be introduced from dialysate solutions, antacids, or aluminum-containing phosphate-binding agents used to combat the hyperphosphatemia of renal failure.

Metastatic deposition causes soft-tissue calcifications. Elevated phosphate levels may result in a high calcium-phosphate product causing deposits in the soft tissues. This also can be affected by the degree of alkalosis, as well as by local tissue injury. Areas that are particularly affected by soft-tissue calcification include medium-sized blood vessels, periarticular soft tissues (tumoral calcinosis), and viscera such as the heart, lung, and kidney.

Frequency

United States

The US Renal Data System reports that over 485,000 persons in the United States are under treatment for end-stage renal disease (ESRD). Renal osteodystrophy rarely is seen prior to the laboratory and clinical diagnosis of renal failure.¹⁰

International

There are an estimated 920,000 patients on dialysis throughout the world, and this figure is growing by approximately 7-9% per year.

Mortality/Morbidity

Clinically, osteomalacia is subtler than rickets, particularly in mild or moderate disease. Mildly affected patients may present with nonspecific bone pain and tenderness and possibly hypotonia. Severely affected patients may have difficulty ambulating and may walk with a waddling gait. Milkman syndrome is a condition in which the patient experiences multiple insufficiency fractures that are often bilateral and symmetric.¹¹ Typical sites include the concave surface of the femoral neck, axillary margin of the scapula, pubic rami, and ribs. Skeletal deformity can occur in the vertebral bodies and skull (basilar invagination), and fractures can occur in the vertebrae and long bones.

The immature skeleton may reveal the following characteristic findings:

• In neonates, posterior flattening and squaring of the skull (eg, craniotabes) may be observed.
• In early childhood, bowing deformities of arms and legs are common (see Image 1).
• In older children, scoliosis, vertebral endplate deformities, basilar invagination of the skull, triradiate deformity of the pelvis, and slipped capital femoral epiphysis may be observed.

Renal osteodystrophy also may present with nonspecific signs and symptoms, including weakness, bone pain, and skeletal deformity. Presentation varies markedly with age. Adults may present with findings of osteomalacia, while children typically show growth retardation. As a result, complications differ depending on the patient's age. The most common complication of renal osteodystrophy is fracture, which may be insufficiency fractures through osteomalacic bone or pathologic fractures through brown tumors or amyloid deposits (see Image 2). Dialysis patients may experience carpal tunnel syndrome, osteomyelitis, septic arthritis, and osteonecrosis. Renal transplant patients may experience osteonecrosis (see Image 3), tendinitis, tendon rupture, and fracture.

Race

According to the US Renal Data System, race distribution of ESRD in the United States is as follows¹⁰:

• White - 61.0%
• Black - 31.7%
• Asian/Pacific Islanders - 4.5%
• Native Americans - 1.3%
• Other/unknown - 1.5%

The ratio of ESRD in blacks and Native Americans compared to whites is 3-5:1.

Sex

Men constitute 55.8%  and women 44.2% of ESRD patients, according to the US Renal Data System.¹⁰

Age

Rickets and osteomalacia are different manifestations of the same underlying pathologic process, depending on whether the patient is a child or an adult, respectively. The demarcation is made at the time of closure of the growth plates. Renal osteodystrophy causes rachitic and some osteomalacic changes in the child and osteomalacia and secondary hyperparathyroidism in adults.

The ESRD patient profile in the United States, by age range, according to the US Renal Data System, is as follows¹⁰:

• Younger than 20 years - 1.5% of patients
• Ages 20-44 years - 19.6% of patients
• Ages 45-64 years - 43.7% of patients
• Ages 65-74 years - 19.5% of patients
• Older than 74 years - 15.7% of patients

Anatomy

Renal osteodystrophy may cause osteosclerosis, soft-tissue calcification, and bone resorption. The changes observed depend on the degree to which bone responds to parathormone. If the bone responds with an increased activity of osteoclasts and osteocytes, the result is bone resorption, which leads to release of calcium. Parathormone also inhibits net tubular phosphate reabsorption, leading to an increase in urinary phosphate that is limited by renal failure.

A rise in the calcium-phosphate ion product results in metastatic soft-tissue calcification. If parathormone levels are mildly elevated over a long period of time, its effect on bone tends to be anabolic. These effects include excessive maturation of osteoblasts leading to new bone formation and increased laying down of osteoid, which calcifies under the influence of secondarily elevated serum calcium levels.

Sclerosis may appear patchy and nonspecific (see Image 4), or it may show a characteristic pattern, such as predominant endplate involvement in the spine (see Image 5). Soft-tissue calcifications may take the form of the large, cloudlike collections in a periarticular distribution known as tumoral calcinosis. These collections are composed mostly of calcium hydroxyapatite and may form a milky substance that may contain fluid levels. Tumoral calcinosis typically is periarticular and noted frequently around the hips and shoulders, although it also may be found around smaller joints (see Image 6).

Chondrocalcinosis may occur in fibrocartilage and hyaline cartilage and often occurs in the knee (see Image 7). Other sites commonly affected by chondrocalcinosis include the pubic symphysis and triangular fibrocartilage of the wrist (see Image 8). Calcification also may occur in ligaments and tendons (see Image 9) and in the vasculature (see Image 10).

Bone resorption typically is classified as subchondral, trabecular, endosteal, intracortical, subperiosteal, subligamentous, and subtendinous. Involvement of the hands and feet by subperiosteal resorption typically occurs along the radial aspect of the middle phalanges and the cortical bone of the tufts of the distal phalanges (see Image 11). Subperiosteal resorption at the joint margins resembles marginal erosions of rheumatoid arthritis (see Image 12). Classically, the skull is affected by trabecular bone resorption, creating a salt-and-pepper appearance in the calvarium (see Image 13).

Subligamentous and subtendinous bone resorption typically occurs in the clavicle underlying the coracoclavicular ligaments, as well as at the calcaneal attachment of the plantar aponeurosis, the triceps insertion on the olecranon, the humeral tuberosities, the femoral trochanters, and the ischial tuberosities. Subchondral bone resorption may be seen in locations that include the distal clavicles (see Image 14), sacroiliac joints (see Image 15), and pubic symphysis. Other characteristic sites involved by bone resorption include the proximal medial cortical surface of long bones (see Image 16) and the lamina dura of the mandible.

When renal osteodystrophy is encountered in children, rachitic changes and osteomalacia are the dominant findings. Rachitic changes are apparent at the growth plates and include increased lucency, widening, elongation, irregularity, and cupping of the metaphyses. Changes of osteomalacia involve the mature trabecular bone (see Image 17). The parts of the skeleton affected most are the costochondral junctions of the middle ribs (see Image 18), distal femur, both ends of the tibia, distal radius and ulna, and proximal humerus.

Clinical Details

Treatment for osteomalacia depends on the underlying cause of the disease and includes pain control and orthopedic intervention, when indicated. Medical management of renal osteodystrophy includes the maintenance of serum calcium and phosphorus levels, treatment with vitamin D and phosphate binding agents, reduction of exposure to excess iron or aluminum, and treatment with aluminum chelating agents to reduce aluminum toxicity.

Preferred Examination

Radiographic examination in patients with osteomalacia may reveal only osteopenia. Characteristically, however, coarsened trabecula is observed. Complications such as Looser zones (see Image 19) and complete fractures can be diagnosed radiographically.

The findings of renal osteodystrophy diagnosed with conventional radiography include osseous resorption, soft-tissue calcification, osteopenia, amyloid deposition, and fracture.

Bone scans may reveal diffuse skeletal uptake of radiopharmaceutical with a superscan appearance that can be confused with metastatic disease. However, the extremities typically have a greater level of increased uptake with secondary hyperparathyroidism than is expected with metastatic disease. In addition, bone scans may reveal pseudofractures or sites of extraskeletal calcification, which also may be distinctive for secondary hyperparathyroidism. Bone scan findings usually are supportive of, but are of limited primary diagnostic value to, renal osteodystrophy.

MRI helps evaluate the soft tissues for ligament rupture, and CT can help evaluate pathologic fracture. Amyloidosis may cause erosion in and around a joint, resulting in subtle radiographic signs, while amyloid deposits can be visualized directly on MRI.

Differential diagnosis

The radiographic appearance of osteomalacia may be normal or similar to findings noted with osteoporosis. However, coarseness of the trabeculae may differentiate osteomalacia from osteoporosis. The differential diagnosis of generalized osteopenia includes osteomalacia, hyperparathyroidism, and multiple myeloma.¹²

The differential diagnosis of renal osteodystrophy varies depending on the sites of involvement. The causes of soft-tissue calcification include collagen vascular disease, hydroxyapatite crystal deposition disease, hypervitaminosis, and idiopathic tumoral calcinosis.

Bone resorption in a periarticular distribution may resemble rheumatoid arthritis. Sacroiliac joint involvement by subchondral bone resorption resembles disease from ankylosing spondylitis and inflammatory bowel disease. Focal deposition of amyloid and brown tumors may resemble neoplasm (see Image 20). Diffuse spinal osteopenia may be a manifestation of multiple myeloma (see Image 21). A differential diagnosis for osseous sclerosis typically includes metastatic disease, sickle cell disease, radiation, myelofibrosis, mastocytosis, hypoparathyroidism, and Paget disease.

Chondrocalcinosis can be seen with pyrophosphate arthropathy, hemochromatosis, ochronosis, and gout. The differential diagnosis for rachitic changes includes hypophosphatasia and the Schmid type of metaphyseal chondrodysplasia.

Limitations of Techniques

Radiographic examination can demonstrate many specific findings of renal osteodystrophy; however, patients with osteomalacia may have only osteopenia. Bone scans may reveal diffuse skeletal uptake of radiopharmaceutical with a superscan appearance that can be confused with metastatic disease. Such findings on bone scan are supportive of, but are of limited primary diagnostic value to, renal osteodystrophy.

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