by Robert C. Mellors, M.D., Ph.D.
IV. Metabolic Bone Diseases
1. General Considerations
Mature bone consists of: an organic matrix (osteoid) composed mainly of
type 1 collagen formed by osteoblasts; a mineral phase which contains
the bulk of the body's reserve of calcium and phosphorus in crystalline
form (hydroxyapatite) and deposited in close relation to the collagen
fibers; bone cells; and a blood supply with sufficient levels of calcium
and phosphate to mineralize the osteoid matrix. Bone turnover and
remodeling occurs throughout life and involves the two coupled processes
of bone formation by osteoblasts and bone resorption by osteoclasts and
perhaps osteolytic osteocytes. The metabolic bone diseases may reflect
disturbances in the organic matrix, the mineral phase, the cellular
processes of remodeling, and the endocrine, nutritional, and other
factors which regulate skeletal and mineral homeostasis. These disorders
may be hereditary or acquired and usually affect the entire bony
skeleton. The acquired metabolic bone diseases are the more common and
include: osteoporosis, osteomalacia, the skeletal changes of
hyperparathyroidism and chronic renal failure (renal osteodystrophy),
and osteitis deformans (Paget's disease of bone).
The diagnosis of metabolic bone diseases requires a careful history
and physical examination, specific radiographic examination, and
appropriate laboratory tests. Bone biopsy may be indicated in some
cases. The ilium is the standard biopsy site for the evaluation of
metabolic bone diseases. The preparation of undecalcified bone sections
permits a distinction to be made between osteoid and mineralized bone
and thus the histological identification of disorders of bone
3.Rickets and Osteomalacia
4. Bone Changes in Hyperparathyroidism (Generalized Osteitis Fibrosa
Cystica, Von Recklinghausen's Disease of Bone)
- Osteolytic tumors (metastatic cancer, multiple myeloma, leukemia)
- Tumors that produce ectopic PTH (pseudohyperparathyroidism)
- Vitamin D excess
- Excess calcium (milk) intake
- Addisonian crisis
The causes of primary hyperparathyroidism are: single parathyroid
adenoma (~80% of cases), diffuse hyperplasia of all four parathyroid
glands (15%), primary parathyroid carcinoma and/or multiple parathyroid
adenomas (the remainder).
Parathyroid adenoma usually arises in one of the inferior glands and
may be difficult to locate if in some aberrant location, such as behind
the mediastinum or elsewhere. Parathyroid adenomas are generally small
(~0.4-4 cm in diameter), encapsulated, and colored variously yellow,
tan, or red.
642: Parathyroid adenoma, sectioned in half.
Microscopically, the adenomas comprise pure or mixed cell types.
Adenomas composed largely of chief cells are the more common while
water-clear cell adenomas are seen less often.
Parathyroid carcinoma is rare and distinguishable from adenoma on the
basis of capsular and blood vessel invasion and biological behaviour,
such as recurrence after local excision and metastases to regional lymph
nodes or elsewhere.
Primary hyperplasia usually involves all four parathyroid glands
although not always symmetrically.
643: Diffuse hyperplasia of parathyroid with asymmetrical
enlargement of the glands.
The superior glands, normally smaller, are often more enlarged by
hyperplasia than the inferior pair. Chief cell hyperplasia is the more
common lesion, but water-clear cell hyperplasia generally produces
greater enlargement of the glands which may attain a total weight of
10-500 times that of all four normal glands (~0.05-0.3 g).
639: Water clear-cell hyperplasia of parathyroid, H&E.
The pathological changes of the skeleton in hyperparathyroidism
comprise: diffuse bone loss resulting from osteoclastic resorption and
fibrous replacement of bone (osteitis fibrosa); foci of cystic lesions
(osteitis fibrosa cystica) or tumor-like lesions of bone ("brown
tumors"); pathological fractures; and, rarely, profound alterations of
the demineralized and softened bones of the entire skeleton.
The osteoclastic and fibrous reaction (osteitis fibrosa) may involve
bones throughout the skeleton, including the skull, vertebrae, shaft of
long bones, and small bones, such as phalanges. Resorptions of the
medial cortex of the phalanges and the tips of the distal phalanges of
the hand are characteristic early radiographic findings.
Microscopically, the earliest changes of osteitis fibrosa are
resorptive loss and fibrous replacement of bone brought about by an
excess of osteoclastic over osteoblastic activity and by fibroblast
proliferation in the marrow space. Characteristically, numerous
osteoclasts in Howship's lacunae are seen on bone surfaces undergoing
resorption, beginning in the cancellous bone and tunneling through
Haversian canals in the cortex.
641: Osteoclastic resorption of bone, femur, H&E.
764: Osteoclastic bone resorption in hyperparathyroidism.
The marrow space is displaced and replaced by fibrocellular tissue and
bone cells. Many osteoclasts may be seen on one surface of resorbing
bone with active osteoblasts producing osteoid on the opposite surface,
reflecting a high rate of bone turnover. The osteoid seams may be wide,
but there is a normal rate of mineralization. The bone formed is often
of an immature ( woven bone) type. (These histopathological changes may
be difficult to distinguish from those of active Paget's disease of
The focal cystic lesions (osteitis fibrosa cystica) are often
multiple; usually develop in the shaft of long bones, the jaw, and
skull; are osteolytic and expansive; may form a tumor-like mass of
brown, yellow, or hemorrhagic tissue ("brown tumor"); and evoke a weak
response of bone regeneration in the adjacent bulging and thinning
cortex. The foci of bone destruction are rarefied and thus "cystic" in a
radiological sense. The bone lesions are not neoplastic.
1084 Anteroposterior (AP) and lateral views show focal osteolytic
lesions of the tibia in primary
Microscopically, the "brown tumors" of hyperparathyroidism are
composed of proliferated osteoclasts and fibroblasts in a fibrous
stroma, often located in a region of hemorrhage, and characteristically
associated with hemosiderin deposition (which imparts a brown color).
640: "Brown tumor" (reparative giant cell granuloma) of jaw
in hyperparathyroidism, H&E.
These focal lesions are sometimes referred to as reparative giant cell
The brown tumors of hyperparathyroidism must be distinguished from
true giant cell tumors of bone, which they resemble histologically and
radiographically. Giant cell tumors are true neoplasms, solitary, and
arise spontaneously, usually in the epiphysis of long bones, commonly
near the knee, and after epiphysial closure. The brown tumors of
hyperparathyroidism are not neoplastic, usually occur in the diaphysis
of long bones, the jaw, and the skull, and may be multiple.
The chief clinical manifestations of primary hyperparathyroidism are
hypercalcemia, renal stones, and bone changes.
Virtually all patients with primary hyperparathyroidism have
hypercalcemia and increased levels of serum PTH measured by
Among the many conditions included in the differential diagnosis of
hypercalcemia, the most frequently encountered is "malignant"
hypercalcemia caused by the presence in bone of metastatic osteolytic
carcinoma (of breast, lung, kidney, thyroid) or multiple myeloma.
The measurement and interpretation of serum PTH levels as determined
by conventional radioimmunoassays are complex because not all of the
immunoreactive fragments of PTH are biologically active. Recently
developed radioimmunoassays for circulating intact PTH, the main
biologically active form of the hormone, may become the future standard
for clinical evaluations of hyperparathyroidism.
Many disorders characterized by hypercalcemia and hypercalciuria may
result in the formation of calcium-containing stones in the kidney
(nephrolithiasis), bladder, or some other site in the urinary tract.
Primary hyperparathyroidism accounts for about 5% of all cases of
calcium renal stones.
The diffuse and focal bone lesions of hyperparathyroidism must be
distinguished from other skeletal disorders. The diffuse osteopenia
caused by resorptive bone loss in hyperparathyroidism may be difficult
to differentiate radiologically from common types of osteoporosis. The
focal cystlike lesions and brown tumors of hyperparathyroidism must be
distinguished from other radiolucent "bubbly" lesions of bone, among
The bone changes of primary hyperparathyroidism regress or
disappear within a few weeks after surgical removal of the parathyroid
lesion which is usually found to be an adenoma or, less commonly,
diffuse hyperplasia of the parathyroid gland.
- Fibrous dysplasia
- Giant cell tumor
- Simple bone cyst
- Aneurysmal bone cyst
- Fibrous cortical defect
- Eosinophilic granuloma
637: (Left) Focal osteolytic lesions of tibia in primary
(Right) Same patient at 10 weeks after surgical removal
functioning parathyroid adenoma. The osteolytic lesions
tibia are beginning to calcify and regress.
A fall in the serum calcium to low normal levels is usually seen within
24 hours after successful surgery. Severe postoperative hypocalcemia and
hypoparathyroidism may develop in some cases.
5. Renal Osteodystrophy
6. Paget's Disease of Bone (Osteitis Deformans)
- Metastatic osteoblastic carcinoma (of breast, prostate)
- Paget's disease of bone
- Osteogenic sarcoma
- Osteoid osteoma
- Callus formation
As noted, the cause of Paget's disease of bo