BONE


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 mineralization.

2.Osteoporosis


General Considerations

Osteoporosis is the most common bone disease in the U.S. and is increasing in prevalence with the aging of the population. Presently, an estimated 10 million people, mainly postmenopausal women, in the U.S. have osteoporosis, and an additional 18 million have low bone mass, a 'silent' risk factor for bone fracture. Osteoporosis is a major cause of the hundreds of thousands of fractures (of hip ~300,000, spine, and wrist) occurring annually in the U.S. in women over the age of 45. Estimates are that approximately 10-20% of women die within 1 year following osteoporotic hip fracture.

Osteoporosis is defined as a decrease in bone density (mass per unit volume) of normally mineralized bone, resulting in thinning and increased porosity of the bone cortices and trabeculae. The bone that remains, although diminished in amount, is normally mineralized and lacks the wide osteoid seams which are typical of osteomalacia and other disorders of bone mineralization. Osteoporosis is also a broadly used clinical term for a generalized loss of bone density resulting in skeletal fragility, bone pain, and pathological fractures (of the spine, wrist, hip, and ribs), particularly in postmenopausal women and both sexes with increasing age.

Osteopenia ("too little" bone) is a descriptive term for a loss of bone density observed radiologically. Osteopenia may be local (as in disuse atrophy of an immobilized limb) or generalized. There are many causes of generalized osteopenia, among them: osteoporosis unrelated to other disease, endocrinopathies (hypercortisolism, hypogonadism, hyperparathyroidism, hyperthyroidism), deficiency states (rickets/osteomalacia, scurvy, malnutrition), neoplastic diseases ( multiple myeloma, metastatic carcinoma, leukemia), chronic diseases (malabsorption syndromes, chronic renal failure), drugs (glucocorticoids, heparin, alcohol), and hereditary diseases (osteogenesis imperfecta, homocystinuria).

Primary osteoporosis, unrelated to other disease, is classified by age groups into postmenopausal, senile, idiopathic (premenopausal women and younger men), and juvenile forms. Postmenopausal osteoporosis is the most frequent form of osteoporosis and is the commonest metabolic bone disease. The term involutional osteoporosis encompasses osteoporosis occurring in postmenopausal women and in both sexes with increasing age. Osteoporosis is an underlying factor in most of the hundreds of thousands of fractures seen annually in the U.S. in women over 45 years of age.

Etiology and Pathogenesis


The immediate causes of common postmenopausal and senile osteoporosis are uncertain. The predisposing factors are suggested by the clinical profiles of patients who are at risk (Table, modified after Vigorita, V.J.).


Risk Factors Associated with Osteoporosis

PROFILE BODY HABITUS DIETARY LIFE STYLE




Caucasian Low weight Low calcium intake Inactivity
Nulliparity Small frame High protein intake Smoking
Scoliosis Leanness High phosphorus intake High alcohol intake
Positive family history Lactase deficiency
OTHER
Low bone mass at skeletal maturity
Early or surgically induced menopause
Steroid or anticonvulsant medication

Of the potential predisposing factors in postmenopausal and senile osteoporosis, low bone mass at maturity, estrogen (and androgen) deficiency, and negative calcium balance are the most notable.

The conventional wisdom suggests that postmenopausal and senile osteoporosis is a disorder of coupling of bone formation and resorption, resulting in a net excess of resorption and a decrease in bone mass, as influenced by aging, lack of gonadal hormones, negative calcium balance or other dietary deficiency, environmental and genetic factors.

Bone turnover and remodeling occurs throughout life and involves the tightly coupled processes of bone formation by osteoblasts and bone resorption by osteoclasts. The total bone mass increases with skeletal growth as bone formation exceeds resorption, remains constant for several years during skeletal maturity when bone formation and resorption are nearly equal, and begins to decline after the age of 40 to 50, at a faster rate in women than in men, as bone resorption exceeds formation. The progressive bone loss over the ensuing decades may amount to 30-50%, or more, of the initial skeletal mass. The detrimental effect of progressive bone loss tends to be greater in those who are genetically or constitutionally predisposed to have a smaller bone mass at maturity. The osteoporosis may be asymptomatic for a time and perhaps only recognized by clinical x-rays taken for some other purpose. At some critical point, the fracture threshold is reached, the fragile skeleton fails to meet mechanical demands, and bone pain, microfractures, and overt fractures of the vertebrae and other bones ensue. This condition of symptomatic osteoporosis occurs most frequently in postmenopausal and aging white females, less commonly in white males, and rarely in blacks of either sex.

In theory, the net loss of bone in osteoporosis can be caused by either decreased bone formation relative to resorption or increased bone resorption relative to formation. An early hypothesis suggested that postmenopausal osteoporosis was caused primarily by a decreased rate of bone formation apparently without a change in the rate of bone resorption. Kinetic studies of bone turnover using radioactive calcium and quantitative bone radiography show otherwise. The bone formation rate in most osteoporotic subjects is at the normal adult level although low rates are sometimes found, whereas the bone resorption rate is often high. Although there is always a net excess of bone resorption in osteoporosis, the absolute amounts of bone formation and resorption can vary from case to case.

Although not the only consideration in pathogenesis (see: Risk Factors), sex hormone deficiency is a major factor associated with the development of postmenopausal osteoporosis. Briefly, estrogens apparently react with and signal osteoblasts directly through high-affinity estrogen-receptors. In women with a balanced state of bone mass, bone formation by osteoblasts normally offsets parathyroid hormone (PTH)- and local cytokine (IL-1, TNF-alpha, IL-6, etc.)-induced stimulation of bone resorption by osteoclasts. With a deficiency of estrogen (or of androgen, an estrogen precursor, in men), osteoclast activity predominates, resulting in an increased resorption and loss of bone.

Pathology


The excessive bone loss in postmenopausal and senile osteoporosis produces thinning and increased porosity of the trabecular bone of the axial skeleton (vertebrae, ribs, and pelvis). The cortices of cylindrical bones are also thinned from the inside by endosteal resorption, resulting in enlargement of the medullary cavity without a change in the outside diameter of the bone. The vertebral bodies, particularly in the thoracolumbar region of the spine, may be weakened by microfractures and collapse anteriorly, resulting in compression fractures and wedging of the vertebrae, a loss of stature, and kyphotic deformity of the spine ("dowager's hump").

716: Severe osteoporosis of thoracolumbar spine with compression ("crush") fractures and kyphosis. (Courtesy of Dr. V.J. Vigorita).

The bony end plates of the osteoporotic vertebrae are thinned and may be cupped inwardly by the force of adjacent, expanding intervertebral discs.

717: Severe osteoporitic crush fracture of thoracolumbar vertebrae. (Courtesy of Dr. V.J. Vigorita).

The corresponding clinical x-ray picture is termed "codfished vertebrae".The ribs in osteoporosis are fragile and brittle. The most common sequelae of osteoporosis are compression fractures of the spine and fractures of the femoral neck and distal radius (Colles' fracture).

Histologically, the amount of cortical and cancellous bone in osteoporosis is decreased compared to the normal for a similar site, sex, and age. The bone that remains has a lamellar structure and osteoid seams of normal width. The bone cortices are thinned, and the haversian canals are widened. The trabeculae of cancellous bone are decreased in size and number. The trabeculae are thin, discontinuous, and widely separated.

718: Osteoporotic bone spicule. H&E. (Courtesy of Dr. V.J. Vigorita).

Osteoblasts are not numerous. Resorptive surfaces of trabecular and endosteal bone may be smooth (graded "inactive") or irregular and scalloped ("active") by resorption cavities (Howship's lacunae) corresponding to the actual or previous locations of osteoclasts.

719: Osteoporosis with active bone resorption by osteoclasts. H&E. (Courtesy of Dr. V.J. Vigorita).

The ilium is the standard site of bone biopsy for the histological evaluation of metabolic bone diseases.

Plastic embedded, undecalcified bone sections when stained with the von Kossa stain allow an unambigious distinction between mineralized bone (black) and osteoid (red). Bone sections prepared with this protocol (courtesy of Dr. V. J. Vigorita) bring out the characteristic histological features of progressive bone loss in osteoporosis. The first biopsy shows thinning of the bone trabeculae.

721: Iliac bone biopsy. Early osteoporosis with beginning thinning of bone trabeculae. Undecalcified section. von Kossa.

The second biopsy shows further bone loss.

722: Iliac bone biopsy. Severe osteoporosis with marked loss of bone. Undecalcified section. von Kossa.

Both cortices are thinned. The trabeculae of cancellous bone are thinned and are no longer continuous from cortex to cortex. The osteoid seams are of normal width.

Clinical Aspects


Osteoporosis may be reasonably suspected in an elderly patient with a relatively atraumatic fracture of the hip or a postmenopausal woman complaining of back pain, recent or gradual loss of height, and progressive thoracic kyphosis, in the presence of risk factors and the absence of other causes of osteopenia previously noted.

Of the approximately 1 million fractures (of hip, spine, wrist) occurring annually in the U.S. in women over the age of 50, a large majority is related to osteoporosis. Further, many elderly patients die within a few months after hip fracture although prosthetic joint replacement and early ambulation have decreased the mortality from this condition.

Noninvasive scanning techniques for the measurement of bone mineral density (BMD) and evaluation of osteoporosis (applicable to distal radius, femoral neck and lumbar vertebrae) include: double energy x-ray absorptiometry (DEXA or DXA) and quantitative computed tomography (CT).

Routine laboratory tests of blood (serum calcium, phosphate, alkaline phosphatase) and urine are usually normal in the typical osteoporotic patient, except for severe acute fracture with an associated increase in serum alkaline phosphatase activity. Urinary markers of increased bone resorption after menopause include measurements of urinary cross-linked peptides derived from type I collagen.

Osteoporosis is a common condition and thus may coexist with other primary bone disorders of the aging, such as osteomalacia and Paget's disease of bone.

In addition to supplemental calcium and vitamin D, therapeutic protocols that mainly decrease resorptive bone loss in postmenopausal osteoporosis include: hormone (estrogen) replacement therapy (HRT), calcitonin, biphosphanate, such as alendronate, and a new class of agents called selective estrogen receptor modulators that have estrogen-like effects on bone. Raloxifene, a member of this class, has both estrogen-like effects on bone and anti-estrogen effects on breast and endometrium and is approved for the prevention of osteoporosis in postmenopausal women.

3.Rickets and Osteomalacia

General Considerations

The diseases resulting from vitamin D deficiency are rickets in infants and growing children and osteomalacia in adult life. The bone changes in both conditions are characterized by inadequate mineralization, resulting in a deficient amount of the mineral phase of bone and an excess of unmineralized osteoid. The osteoid excess is caused by a failure of the process of mineralization to keep up with the new formation of osteoid during bone formation and remodeling. In rickets, which mainly affects children between the ages of 6-30 months, inadequate mineralization occurs not only in bone but also in epiphysial cartilage at sites of endochondral ossification, resulting in growth disturbances, skeletal deformities, and susceptibility to fractures. Presenting symptoms of osteomalacia ("softness of bone") include diffuse skeletal pain, bone tenderness, and muscular weakness.

Etiology and Pathogenesis


Rickets and osteomalacia may be caused by: a deficiency or abnormal metabolism of vitamin D; a deficiency or abnormal utilization/excretion of inorganic phosphate (Pi).

A deficiency of vitamin D may be due to:a dietary lack of the vitamin; insufficient ultraviolet exposure to form endogenous vitamin D; and, most commonly, malabsorption interfering with the intestinal absorption of fats and fat-soluble vitamin D. An abnormal metabolism of vitamin D commonly occurs in chronic renal failure.

Vitamin D3 is photosynthesized in the skin by ultraviolet radiation of 7-dehydrocholesterol. Vitamins D2 and D3, both of which are biologically inactive, are also absorbed in the intestines from dietary sources. Vitamins D2 and D3 are enzymatically hydroxylated in the liver to 25-hydroxyvitamin D, which is transported to the kidney and converted to 1,25- and 24,25-dihydroxyvitamin D. 1,25-dihydroxyvitamin D, termed calcitriol or vitamin D hormone, is the most active metabolite of vitamin D. The main function of vitamin D is to maintain a normal serum balance of calcium and phosphate (Pi) through action of the active metabolites on target organs: the intestine, bone, and parathyroid gland. 1,25-dihydroxyvitamin D increases the intestinal absorption of calcium and Pi, thus bringing the concentration of serum calcium and Pi to a critical level required for the mineralization of newly formed osteoid. Conversely, if there is an inadequate amount of 1,25- dihydroxyvitamin D, the intestinal absorption of calcium decreases, and the serum calcium level falls, calling forth PTH secretion to support the calcium level .(Serum calcium has a negative feedback on PTH secretion by parathyroid chief cells: a low serum calcium level increases PTH secretion, and a high serum calcium level decreases PTH secretion.) The increased PTH secretion tends to restore the serum calcium level but also stimulates increased renal Pi clearance, resulting in lower serum Pi levels. If the concentrations of serum calcium and Pi fall below a critical level, mineralization of osteoid cannot take place, resulting in osteomalacia (and rickets).

An inadequate dietary intake of vitamin D sufficient to cause rickets or osteomalacia is rare in developed countries which utilize foods supplemented with vitamin D. There are exceptions: premature infants; the economically underprivileged; elderly people; dietary idiosyncrasy. . As to the historical role of limited exposure to ultraviolet radiation, rickets was described long ago as a common disease of "smokey cities and cloudy skies".

The most common cause of osteomalacia today is intestinal malabsorption of fats and fat-soluble vitamin D resulting from: hepatic disease (biliary tract obstruction, primary biliary cirrhosis, alcoholic liver disease), chronic pancreatitis, intestinal diseases ( regional ileitis, sprue), and surgical operations (gastrectomy, resection of portions of the small intestine).

Osteomalacia is often a component of renal osteodystrophy, the collection of bone disorders that occur in varying degrees of severity in almost all patients with chronic renal failure (CRF). The development of osteomalacia and rickets ("renal rickets") in CRF is due to the loss of renal parenchyma accompanied by: a decreased renal enzymatic capacity to convert 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D, resulting in impaired intestinal absorption of calcium and hypocalcemia; and a decreased renal excretion of Pi, resulting in hyperphosphatemia and a reciprocal decrease in serum calcium to a level below that required for the mineralization of osteoid. ( This stimulates the increased secretion and synthesis of PTH and secondary hyperplasia of the parathyroid gland, resulting in the superimposed bone changes of osteitis fibrosa.)

Drug-induced rickets and osteomalacia may occur in association with the use of the anticonvulsive drug phenytoin and is attributed to phenytoin's interference with vitamin D metabolism in the liver.

Rickets and osteomalacia are also associated with hypophosphatemia. An induced deficiency of serum Pi may occur in peptic ulcer patients receiving long-term treatment with antacids containing aluminum hydroxide, which forms insoluble complexes with Pi in the intestine and blocks its absorption. Rickets and osteomalacia may also accompany renal tubular disorders in which there is an impaired renal resorption of Pi, resulting in hypophosphatemia and hyperphosphaturia, or metabolic acidosis which also affects the metabolism of vitamin D, calcium, and Pi. These hypophosphatemic disorders include: renal tubular acidosis (RTA) of which there are several types; the Fanconi syndrome of sporadic or familial origin; and two hereditary forms of hypophosphatemia, namely, x-linked hypophosphatemia (also termed vitamin D-resistant rickets), which is the most common cause of rickets in the U.S. today, and vitamin D-dependent rickets (autosomal recessive), in which there is a defect in the synthesis or cellular utilization of 1,25-dihydroxyvitamin D..

Rickets is also seen in children with hypophosphatasia, a rare heritable enzyme deficiency which is characterized by extremely low levels of alkaline phosphatase in the blood and tissues.

Pathology


The morphological characteristics of rickets, in the order of their development, are as follows: failure of mineralization of the epiphysial provisional zone of mineralization, resulting in disordered endochondral ossification; failure of mineralization of newly formed osteoid, resulting in an excess of osteoid (hyperosteoidosis) as shown by wide osteoid seams; and skeletal deformities caused by interference with endochondral ossification or by bending of the osteomalacic (softened) bones. Of these changes, hyperosteoidosis caused by a failure of mineralization is common to both osteomalacia and rickets. The widened osteoid seams contain prominent osteoblasts. Osteoclasts are rare (unmineralized osteoid does not stimulate an osteoclastic reaction).

Hyperosteoidosis also occurs in other skeletal disorders, such as Paget's disease of bone and osteitis fibrosa caused by hyperparathyroidism. In these conditions , in contrast to osteomalacia and rickets, there is a high rate of bone turnover and no failure or delay of bone mineralization.

Bone biopsy is the definitive method of establishing the diagnosis of osteomalacia. Undecalcified bone sections stained with the von Kossa technique allow a clear distinction to be made between osteoid and mineralized bone. An iliac bone biopsy (courtesy of Dr. V. J. Vigorita ) of a patient with osteomalacia shows wide seams of osteoid (red) bordering the trabecular and endosteal bone (black).

723: Iliac bone biopsy. Severe osteomalacia characterized by a marked increase in osteoid (red) bordering the trabecular and endosteal bone (black). Undecalcified section. von Kossa.

A biopsy of severe osteomalacia shows that virtually all (~100%) bone surfaces are covered by osteoid (whereas in normal bone, surface osteoid is <20%).

724: Iliac bone biopsy. Severe osteomalacia in which virtually all bone surfaces are covered by an excess of osteoid (red). Undecalcified section. von Kossa.

Mineralization dynamics can be evaluated if two single 10 day-spaced doses of tetracycline (which binds to the mineralization front and is autofluorescent) are given to the patient before the bone biopsy is performed. A biopsy of normal bone shows two discrete and separated layers of fluorescent label uptake marking successive mineralization fronts. Whereas osteomalacic bone has a smudgy appearance of label uptake (or in some cases no uptake at all), indicating defective and delayed mineralization.

725: Fluorescence micrographs of bone biopsies made following two doses of tetracycline at 10 day intervals. (Left). Bone tissue of patient with relatively normal tetracycline uptake shows two discrete lines of labelling at the mineralization fronts. (Right). Bone tissue of patient with osteomalacia gives a smudgy appearance of label uptake. Undecalcified unstained sections. (courtesy of Dr. V.J. Vigorita).

Grossly, long-standing osteomalacia may produce fractures and deformities of the softened bones. The main deformities are kyphosis, bowing of the long bones, and narrowing of the pelvis. A child with severe rickets may have: a prominent forehead ("frontal bossing") due to osteoid excess; beading of the ribs at the costochondral junctions ("rachitic rosary") caused by overgrowth of cartilage and osteoid; curved limb bones; lateral flattening of the rib cage with forward displacement of the sternum ("pigeon breast"); and a depression ("Harrison's grove") at the lower margin of the rib cage produced by muscle contraction of the diaphragm.

Clinical Aspects


The diagnosis of osteomalacia (and rickets) depends upon a careful history and physical examination, x-ray studies, appropriate laboratory tests, and bone biopsy if indicated. The usual presenting symptoms are muscle weakness and diffuse bone pain. The routine laboratory tests (Table, modified, after Lane, J.M.) usually show: decreased serum calcium and Pi; increased serum alkaline phosphatase; and decreased 24-hour urinary calcium. The radiographic picture is that of diffuse osteopenia which may be indistinguishable from that of osteoporosis except for the presence in osteomalacia of characteristic bands of radiolucency ("pseudofractures/ Looser's zones"). Osteomalacia may coexist with osteoporosis in the aged. Bone biopsy is the ultimate way to establish the diagnosis of osteomalacia.

Table: Diagnosis Suggested by Initial Blood Chemistry Values

Diagnosis Suggested by Initial Blood Chemistry Values
Values
Blood ChemistryIncreasedDecreased

Serum calciumMultiple myelomaVitamin D deficiency states:
Primary hyperparathyroidismMalabsorption
Metastatic cancer Dietary deficiency
HyperthyroidismAnticonvulsant drugs
Hypervitaminosis DVitamin D dependent rickets
ImmobilizationCalcium deficiency
Renal osteodystrophy
Serum phosphateRenal osteodystrophyHypophosphatemic rickets
Metastatic cancerVitamin D deficiency states
ImmobilizationPrimary hyperparathyroidism
Hypervitaminosis D
Serum alkaline phosphatasePaget's disease of boneHypophosphatasia
Renal osteodystrophy
Primary hyperparathyroidism
Vitamin D deficiency
Hypophosphatemic rickets
Metastatic cancer
24 hour urinary calciumHypercalcemiaRenal osteodystrophy
HyperthyroidismHypophosphatemic rickets
HypercortisolismVitamin D deficiency states:
ImmobilizationCalcium deficiency
HypophosphatasiaLactose intolerance
Renal tubular acidosisDietary

4. Bone Changes in Hyperparathyroidism (Generalized Osteitis Fibrosa Cystica, Von Recklinghausen's Disease of Bone)


General Considerations

The skeletal changes in hyperparathyroidism are characterized by diffuse or focal resorptive loss and fibrous replacement of bone due to an excess of osteoclastic over osteoblastic activity and caused by an over-production of parathormone (PTH) in primary or secondary hyperparathyroidism.

Primary hyperparathyroidism is a metabolic disorder in which parathyroid cells, either neoplastic or hyperplastic and in the absence of any known stimulus, secrete excessive amounts of PTH. Primary hyperparathyroidism is usually caused by a functioning adenoma of a single parathyroid gland, less commonly by diffuse hyperplasia of all four parathyroid glands, and rarely by primary parathyroid carcinoma or multiple parathyroid adenomas.

Secondary hyperparathyroidism is associated with many conditions that lead to hypocalcemia and most often occurs as a consequence of the hyperphosphatemia and hypocalcemia of chronic renal failure. The complex bone changes in chronic renal failure are called renal osteodystrophy and include osteomalacia, rickets ("renal rickets"), osteitis fibrosa and other bone changes of hyperparathyroidism.

Some non-parathyroid carcinomas (arising in lung, kidney,or elsewhere and without bony metastases) may produce a PTH-like hormone associated with a syndrome resembling hyperparathyroidism. This syndrome is called pseudohyperparathyroidism or ectopic hyperparathyroidism and may be reversed by removal of the functioning tumor.

Primary hyperparathyroidism most frequently occurs in adults, has a peak incidence between the third and fifth decades and a female to male ratio of two or three to one, and is rarely seen in children under 10 years of age. Primary hyperparathyroidism, in the absence of renal disease, is characterized biochemically by hypercalcemia, hypophosphatemia, hypercalciuria, elevated serum alkaline phosphatase activity (in the presence of bone disease), and increased levels of PTH measured by radioimmunoassays.

The symptoms of primary hyperparathyroidism may be minimal for many years, depending upon the extent of the metabolic disorder. The clinical presentations are divisible into three categories:

  1. most commonly, manifestations of hypercalcemia, such as neuromuscular weakness, fatigue, gastrointestinal symptoms, and, rarely, coma in severe hypercalcemic crisis;
  2. renal stones (often bilateral); calcification of the kidneys (nephrocalcinosis); and metastatic calcification of other tissues;
  3. bone resorption and fibrous replacement resulting in diffuse osteopenia (which may be difficult to distinguish radiologically from common osteoporosis); in some cases, "cystic" or tumor-like lesions of bone ("brown tumors"); pathological fractures; and, rarely seen today, widespread alterations and deformities affecting the demineralized and softened bones of the entire skeleton (generalized osteitis fibrosa cystica).

The diagnosis of primary hyperparathyroidism is made on the basis of clinical findings and laboratory tests and, when indicated, confirmed by surgical and pathological examination of the parathyroid glands. In the past, the diagnosis was traditionally made in patients presenting with "stone and bone" disease. Now, a presumptive early diagnosis is often made in individuals with minimal or no symptoms. Hypercalcemia is the most common manifestation of primary hyperparathyroidism and may be detected by multiphasic screening tests. Nevertheless, many conditions are included in the differential diagnosis of hypercalcemia, among them:

  • Osteolytic tumors (metastatic cancer, multiple myeloma, leukemia)
  • Hyperparathyroidism
  • Tumors that produce ectopic PTH (pseudohyperparathyroidism)
  • Vitamin D excess
  • Hyperthyroidism
  • Excess calcium (milk) intake
  • Immobilization
  • Sarcoidosis
  • Addisonian crisis

Pathology


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 bone).

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 hyperparathyroidism.

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 granulomas.

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.

Clinical Aspects


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 radioimmunoassays.

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 them:

  • Fibrous dysplasia
  • Giant cell tumor
  • Simple bone cyst
  • Aneurysmal bone cyst
  • Fibrous cortical defect
  • Enchondroma
  • Eosinophilic granuloma
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.

637: (Left) Focal osteolytic lesions of tibia in primary hyperparathyroidism. (Right) Same patient at 10 weeks after surgical removal of a functioning parathyroid adenoma. The osteolytic lesions of the 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

General Considerations

Renal osteodystrophy (or uremic bone disease) is the term for a complex group of bone disorders that occur in patients with chronic renal failure (CRF). The bone disorders in renal osteodystrophy include: osteomalacia of adults and rickets of children (so-called "renal rickets"); osteitis fibrosa and other bone changes of secondary hyperparathyroidism; osteopenia; and osteosclerosis. Renal osteodystrophy occurs more often in children than in adults and particularly in the presence of congenital renal anomalies, such as renal hypoplasia and polycystic kidneys, that are associated with the development of slowly progressive renal insufficiency.

Pathogenesis and Pathology


The loss of functioning renal parenchyma in CRF is central to the pathogenesis of renal osteodystrophy. The bone changes are brought about by the abnormal metabolism of vitamin D, the overproduction of parathyroid hormone (PTH), and chronic metabolic acidosis.

The diminished renal mass in CRF leads to a decreased renal conversion of 25-hydroxyvitamin D into 1,25-dihydroxyvitamin D, the active metabolite of vitamin D, resulting in diminished intestinal absorption of calcium, hypocalcemia, and defective bone mineralization characterized by the presence of wide osteoid seams, osteomalacia in adults, and rickets in children.

The renal retention of phosphate in CRF causes hyperphosphatemia and further hypocalcemia, resulting in an increased synthesis and secretion of PTH, secondary hyperplasia of the parathyroid glands, and osteitis fibrosa and other bone changes of hyperparathyroidism, characterized by increased osteoclastic resorption and fibrous replacement of bone, increased osteoblastic activity, woven bone, and reparative giant-cell granulomas ("brown tumors").

The rapid remodeling and reorganization of bone in secondary hyperparathyroidism may result in osteosclerosis (increased amount of mineralized bone per unit volume).

The metabolic acidosis occurring in CRF also inhibits the conversion of 25-hydroxyvitamin D into 1,25-dihydroxyvitamin D and increases the solubility of bone mineral, contributing further to the osteopenia resulting from osteitis fibrosa and/or osteomalacia.

The bone changes of renal osteodystrophy as seen in an individual patient may reflect one or more of these metabolic abnormalities. In children, osteitis fibrosa and rickets occur separately or combined. In adults, a mixed pattern of osteomalacia, osteitis fibrosa, and osteosclerosis may be seen.

Complications of renal osteodystrophy, such as spontaneous fractures, avascular necrosis (of the femoral head), and metastatic calcification of soft tissues may occur.

Clinical Aspects


Clinical symptoms of musculoskeletal disease occur in a small proportion of patients with renal osteodystrophy and may include bone pain, muscle weakness, deformities and growth retardation in children, and complicating pathological fractures.

Skeletal abnormalities are found by radiography in about one third of patients with advanced renal failure and include: deformities and growth retardation similar to that seen in children with nutritional rickets; bone changes of secondary hyperparathyroidism typically showing resorptions and erosions of the tips of the distal phalanges and clavicles; and osteosclerosis as often noted radiographically by alternating bands of increased and normal or low density of the vertebrae (so-called "rugger jersey spine").

The laboratory findings in renal osteodystrophy include hyperphosphatemia, hypocalcemia, elevated alkaline phosphatase activity (reflecting increased osteoblastic activity), and increased PTH levels, particularly when assayed for C-terminal PTH which is an immunoreactive but biologically inactive fragment normally excreted only by the kidney.

The management of patients with renal osteodystrophy includes: treatment of hyperphosphatemia by reduction of the dietary intake and absorption of phosphate through the use of intestinal phosphate binders (aluminum hydroxide); and dietary supplementation with 1,25-dihydroxyvitamin D to treat osteomalacia and osteitis fibrosa.

6. Paget's Disease of Bone (Osteitis Deformans)

General Considerations

Sir James Paget, English surgeon, (1814-1899) is credited with the original description of three separate disease entities ( of bone, breast, and vulva) which now carry his name.

Paget's disease of bone (osteitis deformans) is a localized, although sometimes multifocal, skeletal disorder of unknown cause and is characterized by abnormal bone remodeling brought about by waves of bone resorption and reformation. The skeletal involvement may be limited to a single bone (monostotic) or affect many bones (polyostotic), notably the pelvis, femur, tibia, spine, and skull. The affected bones may be weakened by resorption or enlarged by reparative, although defective, new-bone formation. In the final stage of the disease, dense bone is formed, but it is poorly organized and predisposed to fracture and deformity.

Paget's disease, particularly in its milder form, is a common skeletal disorder of the later decades of life. It usually occurs after the age of 40, increases in incidence with aging, and has slight male preponderance. The estimated incidence of Paget's disease, in some parts of the world (U.S., U.K.), is about 3% on the basis of autopsy examinations of individuals over the age of 40 and about 1% on the basis of radiological surveys of the adult population.

Many subjects with Paget's disease are asymptomatic. The disorder in these individuals may be first recognized by radiographs of pelvic or other bones taken for another purpose or by a laboratory finding of elevated serum alkaline phosphatase activity, which is generally higher in Paget's disease than in any other common condition. Symptomatic patients may present with pain, enlargement, or deformity of involved bones or with pathological fracture, auditory, cardiac,or other complications of the disease.

Pathology


The bone changes are divisible into three phases defined radiologically: the osteolytic phase, the mixed osteolytic and osteoblastic phase, and a final osteosclerotic phase.

Paget's disease begins as a focus of active bone resorption (osteolytic phase) which may affect a single bone or progress to involve extensive areas of both cylindrical and flat bones. The osteolytic focus is characterized by the presence of numerous large osteoclasts which contain many nuclei, often randomly distributed within the cell. Radiographically, the osteolytic phase of the disease shows circumscribed areas of radiolucency, often first seen in the skull ("osteoporosis circumscripta").

The osteolytic phase is followed by the osteoblastic formation of highly vascular new bone of woven type or, more commonly, by the simultaneous occurrence of both osteoclastic and osteoblastic activity ("mixed" phase). Histologically, the mixed phase of Paget's disease is characterized by the presence of numerous osteoclasts along with an abundance of osteoblasts (which account for elevated levels of serum alkaline phosphatase activity) and osteoid.

759: Paget's disease of bone, humerus, low power view.

3777: "Mixed" phase of Paget's disease of bone.

Microscopically, the mixed phase of Paget's disease may resemble the bone changes of hyperparathyroidism. Radiologically, the advancing regions of osteolysis are followed by adjoining regions of increased density where new bone is formed.

In the final stage of Paget's disease as resorptive activity wanes, sclerotic bone is formed (sclerotic phase) with a characteristic "mosaic" pattern of histologic structure.

762: Osteosclerotic phase of Paget's disease of bone, tibia, H&E.

Note the "mosaic" pattern of cement lines outlining irregular patches of sclerotic lamellar bone. The sclerotic bone is composed of patches of lamellar bone which are outlined by a mosaic pattern of cement lines, reflecting previous waves of bone resorption and reformation. The bone trabeculae become thick and prominent, particularly along the lines of stress.The bone width may be increased and the surface roughened by periosteal new-bone formation. Although often rocklike because of a lack of remodeling, the sclerotic bone is poorly organized, structurally weak, and predisposed to transverse fracture.

763: Paget's disease of femur. Although massive, pagetoid bone is structurally weak, bowed and prone to fracture.

The osteosclerotic phase is the most characteristic radiographic stage of Paget's disease.

744: Osteosclerotic phase of Paget's disease involving pelvis and hips.

Clinical Aspects


The presence of normal serum calcium and Pi, elevated serum alkaline phosphatase activity, and characteristic radiographic findings help to distinguish Paget's disease from other metabolic bone diseases.

The majority of patients with Paget's disease of bone are asymptomatic. Their disease is usually monostotic and discovered fortuitously by radiographic findings or laboratory tests showing an elevated serum alkaline phosphatase activity.

Symptomatic patients usually have polyostotic Paget's disease which most commonly involves the pelvic bones, followed in order of frequency by femur, tibia, skull, lumbosacral and thoracic spine, clavicles, and ribs. Pain is the most common presenting symptom and may result from microfractures, bony impingement on nerves, or other causes. Additional symptoms include bone enlargement or deformity, gait disturbance, overt pathological fracture or some other disease complication.

In advanced cases, femurs and tibias may be bowed and the hips deformed; the vertebral bodies may be compressed, resulting in kyphosis or scoliosis; and some bones, such as the skull, may be enlarged. One of Paget's original patients, an elderly man, had to increase the size of his hat almost yearly, a rare but distinctive feature. Hearing loss is common in advanced Paget's disease and is caused by pagetic bone impingement on the auditory nerve at the nerve foramen or by ossicle involvement and otosclerosis.

Severe Paget's disease may be complicated by: pathological fracture of affected bones; hemodynamic changes caused by bone hypervascularity, resulting in high-output left ventricular failure; and, in about 1% of patients, neoplastic transformation of pagetic bone into bone sarcoma: most commonly, osteogenic sarcoma; less often, fibrosarcoma; and, rarely, giant cell tumor.

761: Osteogenic sarcoma (Paget's sarcoma) arising in Paget's disease of humerus.

The radiographic findings in Paget's disease reflect the pathological changes and the disease activity at the site of the examination. Different skeletal areas may show different phases of the pagetic process. The osteolytic and combined osteolytic and osteoblastic lesions are clinically active, with skeletal pain as the most common symptom. Radioisotopic bone scans may be useful in revealing areas of disease activity not detectable by conventional radiographs. The osteosclerotic lesions are usually asymptomatic as well as the most characteristic radiologic stage of Paget's disease.

Nevertheless, osteosclerotic bone lesions recognized by radiography may be found in many clinical conditions, among them:

  • Metastatic osteoblastic carcinoma (of breast, prostate)
  • Paget's disease of bone
  • Osteopetrosis
  • Myelosclerosis
  • Osteochondroma
  • Osteogenic sarcoma
  • Osteoid osteoma
  • Callus formation

As noted, the cause of Paget's disease of bo