Normal fetal bone, microscopic

This normal fetal growth plate of a long bone shows features of endochondral ossification. Hyaline cartilage (♦) on the left contains proliferating chondroblasts contributing to an extracellular matrix with glycosaminoglycans and proteoglycans along with type II collagen fibers and some elastic fibers. The chondroblasts (▲) become chondrocytes (▼) within lacunae defined by a pericellular capsule and surrounded by the cartilaginous matrix. The cartilage template transforms into bone spicules (✱) of osteoid that become calcified. As this process continues, the bone lengthens. Hyaline cartilage remaining at the ends of long bones forms the articular cartilage of joint surfaces.

Normal bone osteoblasts, microscopic

The woven bone trabeculae at a healing fracture site have numerous osteoblasts (▼) lining spicule surface and generating new osteoid, or uncalcified organic bone matrix, which is formed of type I collagen on which hydroxyapatite crystal (hydrated calcium phosphate) is deposited. Osteoblasts have parathyroid hormone (PTH) receptors and when stimulated by PTH release RANKL, which binds onto pre-osteoclast RANK receptors to initiate osteoclastogenesis. Osteoblasts also secrete osteoprotegerin (OPG), a “decoy” receptor that binds to RANKL and favors bone formation.

Normal bone osteoclasts, microscopic

Remodeling of bone is done through bone resorption with release of enzymes such as carbonic anhydrase, matrix metalloproteinases, and alkaline phosphatase by osteoclasts (▼). Numerous multinucleated cells are seen here occupying Howship lacunae in bone spicules undergoing dissolution. The transmembrane receptor RANK (receptor activator for NF-κB) is expressed on osteoclast precursors. Parathyroid hormone and glucocorticoids favor osteoclast activation, while sex steroids promote osteoprotegerin production to reduce osteoclast activity.

Normal adult bone, microscopic

This cross-section through unstained adult long compact bone cortex reveals round osteons formed of concentric layers of hydroxyapatite crystal around a central Haversian canal (♦) containing the neurovascular supply. Within the crystal are entrapped osteocytes (▲) inside their lacunae. Canaliculi radiate from these lacunae to allow communication between osteocytes to respond to mechanical forces and influence local calcium and phosphorus levels to maintain optimal bone structure. In adults, mineralization of osteoid takes about 2 weeks. Bone is a warehouse for body minerals, including 99% of calcium, 85% of phosphorus, and 65% of sodium found in the human body.

Normal adult bone, microscopic

Normal trabecular (cancellous) bone, seen here with polarized light, has a regular lamellar (◀) architecture. The bone lamellae form by remodeling from primitive woven bone into a complex three-dimensional structure in response to stresses of gravity and movement to provide strength and support. Bone is constantly, albeit slowly, remodeling throughout the lifespan through the actions of both osteoblasts and osteoclasts. Children have greater bone growth in size primarily from endochondral ossification with increasing length and girth of long bones until the epiphyses close. Between the bone trabeculae are marrow spaces, seen here with hematopoietic elements and adipocytes.

Hand, bone fracture, x-ray

The radiographic appearance of normal bone density is shown by this left hand. Joint spaces are of normal size and shape. The outer rim of cortical bone is denser and appears brighter. Soft tissues have a light to dark gray appearance. Note the appearance of a recent unhealed and displaced fracture (▼) of the fifth metacarpal because of external trauma.

Fracture callus, microscopic

The region of fracture shows disrupted bony trabeculae (■) at the left and bottom. The paler pink new woven bone (♦) is forming at the right and top in response to the injury in areas of hemorrhage with early granulation tissue (✱). In the region of fracture, new woven bone is called callus . After 6 to 8 weeks, enough healing has occurred to support weight and movement. Eventually, over months to years, this new bone is remodeled into more regular lamellar bone that may attain the original shape and strength. Fracture healing is more complete in children than adults. Orthopedic procedures to stabilize fractures and provide proper alignment with appliances are often performed for fractures.

Osteogenesis imperfecta, radiograph

There are multiple fractures (▼) in these bones that are markedly osteopenic, represented here by diminished brightness. The formation of type I collagen, a major constituent of the bone matrix, is impaired, either by reduced synthesis or production of an abnormal triple helix of collagen. This leads to bone fragility and a propensity for fractures. Shown here is the perinatal lethal form (type II) of osteogenesis imperfecta. Most cases are due to an abnormal pro-α1(1) or pro-α2(1) collagen chain that leads to an unstable collagen triple helix (“dominant negative” mutation). The chest cavity is poorly formed, leading to pulmonary hypoplasia and respiratory distress on birth.

Osteogenesis imperfecta, gross

There is a bluish-gray appearance to these sclerae, which reflects deficient connective tissue structure with abnormal type I collagen synthesis. This condition is most often due to an acquired mutation, most often the COL1A1 gene, but some cases are inherited in an autosomal dominant fashion and may be due to either decreased or abnormal pro-α1(1) collagen chains. Osteogenesis imperfecta type I is compatible with normal survival and stature, but affected patients have an increased risk for fractures and osteoarthritis, and can have dental and hearing problems.

(A and B) Osteoporosis, dual-energy x-ray absorptiometry chart; gross

Bone mineral density (BMD) is best assessed with radiologic imaging, and dual-energy x-ray absorptiometry (DEXA) scans provide a standardized way of assessing risk for fracture from osteoporosis. A graphic display of a DEXA scan for the hip (femur) is shown (A), comparing BMD to age and T-score (in standard deviations above or below the comparable healthy young adult woman’s mean BMD). The asterisk representing a woman at age 48 is within the expected range for age. The circle marks the BMD for a woman age 60 and is concerning for greater bone loss from osteopenia (−1 to −2.5) but not yet osteoporosis. The X marks the BMD for a woman age 76 in the range of osteoporosis (>−2.5) with increased risk for fracture. The vertebral bodies (B) show marked osteoporosis with fewer thin bony trabeculae. One vertebral body shows a greater degree of compression fracturing (▼) than the others. Osteoporosis is accelerated bone loss for age, greater than the usual 0.7% loss per year after the fourth decade. It is most common among postmenopausal women with reduced estrogen levels, putting them at higher risk for fractures, particularly involving hip, wrist, and vertebrae. Continued physical activity and a good diet help build bone mass in youth and maintain bone mass with aging. Vitamin D deficiency in adults can lead to osteomalacia, which has gross and radiographic appearances similar to osteoporosis.

(A and B) Osteoporosis with fracture, x-rays

There is severe osteoporosis involving the femurs of this elderly woman, and consequently a right intertrochanteric fracture (▼) has occurred and has been repaired (▲) surgically. This bone should be much denser and brighter, but instead displays greater lucency in these radiographic views because of the osteopenia. Up to a third of elderly persons with such a fracture may not survive another year.

Osteoporosis, microscopic

The bone trabeculae (►) in this vertebral body are thin and sparse from osteoporosis. The bone structure is normal, but there is less of it. The bone cortex becomes thinner, and trabeculae have less complex branching, providing less three-dimensional support. This slow process yields normal laboratory measurements of serum calcium, phosphorus, alkaline phosphatase, and parathyroid hormone(PTH). In contrast, primary hyperparathyroidism yields increased or high normal PTH levels, with increased calcium and decreased phosphorus. Osteocalcin synthesized by osteoblasts is incorporated into extracellular bone matrix, and circulating levels correlate with osteoblast activity.

Paget disease of bone (osteitis deformans), radiograph

The left hip reveals a more irregular appearance to the bone than the right because of osteosclerosis (▼) with greater density along with osteolysis of greater lucency (▲). This is the mixed osteoclastic and osteoblastic stage of Paget disease of bone, which most often occurs in elderly men of European ancestry. A slow paramyxovirus infection may increase IL-6 secretion to drive osteoclast activity. In addition, osteoclasts may become more sensitive to RANKL and vitamin D. The serum alkaline phosphatase is increased, but the serum calcium and parathyroid hormone levels are normal. This abnormal bone proliferation carries an increased risk for malignancy—a Paget sarcoma, typically an osteosarcoma—in 1% of all affected patients.

Paget disease of bone (osteitis deformans), MRI

There is more irregularity to this upper left femur, with increased brighter bony sclerosis (▼) along with areas of lucency. Paget disease is mainly seen in older individuals, and the course of the disease extends over many years. Initially, there may be more osteolysis, but this is followed by the most diagnostic phase—mixed osteolytic and osteoblastic processes. Eventually, the final phase results in prominent osteosclerosis. The clinical hallmark is pain with diminished joint range of motion and arthritis of adjacent joints. The abnormally thickened bone is paradoxically weaker and prone to fracture. Skull involvement can lead to cranial nerve entrapment.

Paget disease of bone (osteitis deformans), microscopic

There is more bone turnover, with an uncoupling of osteoblast and osteoclast coordination in bone remodeling, leading to a haphazard microscopic appearance. Prominent osteoclast (▼) and osteoblast (▲) activity is shown here. The result is thicker but weaker bone that has irregular cement lines (♦), producing a “mosaic” pattern instead of an organized lamellar pattern. This proliferating bone is highly vascularized, and the increased vascular flow can lead to high-output congestive heart failure. Localized disease may require no therapy other than occasional use of analgesics. More extensive polyostotic disease can be treated with osteoclast-inhibiting bisphosphonates.

Paget disease of bone (osteitis deformans), microscopic

With polarized light microscopy the “mosaic” pattern is evident with irregular lamellae and cement lines (▶) from increased bone turnover with dyssynchronous remodeling in the mixed lytic/blastic phase. Most cases are polyostotic (multiple sites) and a sixth are monostotic. Serum markers include increased alkaline phosphatase and deoxypyridinoline. Up to half of familial cases and 10% of sporadic cases may have SQSTM1 gene mutations that enhance NF-κB dependent osteoclastogenesis.

Hyperparathyroidism, radiograph

This patient has primary hyperparathyroidism from a parathyroid adenoma with increased serum calcium, decreased phosphorus, and elevated parathyroid hormone (PTH). This is osteitis fibrosa cystica of bone, with expansile areas of lucency (▲), shown here as deformities involving the metatarsals and phalanges of this hand. Such lesions can cause pain, but the focal decrease in bone mass also predisposes to fracture. In contrast, secondary hyperparathyroidism is due to chronic renal failure with retention of phosphate that depresses serum calcium to stimulate PTH release. When secondary, the features of osteitis fibrosa cystica, osteomalacia, osteoporosis, osteosclerosis, and growth retardation are collectively known as renal osteodystrophy .

Hyperparathyroidism, “brown tumor”, microscopic

Note the nodular lesion (■) within bone. This lesion arises in response to abnormally increased parathyroid hormone secretion. The reactive fibrous tissue proliferation admixed with multinucleated giant cells is called a brown tumor because of the grossly apparent brown color imparted by the vascularity, hemorrhage, macrophage infiltration, and hemosiderin deposition that often accompany this cellular proliferation. These lesions can undergo cystic degeneration to produce focal pain and predispose to fracture. The radiograph of this lesion can show a focal radiolucency similar to osteitis fibrosa cystica.

Hyperparathyroidism, dissecting osteitis, microscopic

A bone spicule with pronounced osteoclastic and osteoblastic activity is shown. This is accelerated bone remodeling with osteoclasts (▲) that “tunnel into” the bone trabeculae and form pockets of fibrovascular tissue (♦). The fibrovascular tissue also is increased in the peritrabecular spaces. In secondary hyperparathyroidism from chronic renal failure, the metabolic renal tubular acidosis also stimulates bone resorption and drives osteomalacia. Increased circulating β ₂ -microglobulin with long-term hemodialysis can lead to amyloid deposition in bone.

Avascular necrosis, gross

Beneath the articular cartilage of this femoral head is a pale yellow wedge-shaped area of osteonecrosis (▲) in a patient with hip pain that developed after long-term use of corticosteroids. Additional risk factors include traumatic vascular disruption, thrombosis, barotrauma, vasculitis, sickle cell disease, and radiation therapy. The usual initial symptom is pain with movement, but this progresses to constant pain. Replacement of necrotic bone by new bone (creeping substitution) does not proceed fast enough to prevent focal collapse, with bone fracture and disruption of overlying articular cartilage. In contrast, infarction within the medullary cavity away from a joint may be clinically silent.

Avascular necrosis, radiograph

Note the irregular remodeling (♦) of the head of this proximal humerus because of osteonecrosis. The bones of the humeral head and the femoral head have a tenuous blood supply that can be traumatically disrupted. The devitalized bone undergoes remodeling and bone distortion, and the adjacent joint becomes painful with continued movement but decreased function. The remodeling process is inefficient and slow, and there is eventual collapse with distortion of the overlying articular cartilage, leading to secondary osteoarthritis of the joint.

Avascular necrosis, microscopic

Osteocyte nuclei are absent from their lacunae (▲) in the bony trabeculae shown, and lamellae are not well defined. Adjacent cartilage may break down and fragment (▼). Marrow adipocytes are replaced by debris and reactive proliferating cartilage and fibrous connective tissue. This proliferative response leads to scarring without revascularization of the bone, so that remodeling is abnormal and the adjacent joint surface altered to produce abnormal joint motion. Treatment may consist of joint replacement.

Bone marrow infarct, microscopic

Hemorrhage (■) with necrosis (♦) involving the marrow of a vertebral body is shown. This lesion occurred with sickle cell crisis and severe back pain. Microvascular occlusions by the “sticky” sickled red blood cells lead to release of hemoglobin that binds nitric oxide. Reduced nitric oxide favors vasoconstriction and platelet aggregation. These vaso-occlusive crises can affect multiple organs, including acute chest syndrome with pulmonary vascular bed occlusion. The pain of bone infarcts mimics acute osteomyelitis. With imaging, the term “bone infarct” is most often applied to lesions in the metaphysis and diaphysis of a bone, while the term “osteonecrosis” (avascular necrosis) is applied to lesions in bone epiphyses.

Osteomyelitis, gross

Extensive chronic bone destruction with irregular remodeling results in the appearance of a lighter colored (■) necrotic sequestrum, seen here immediately adjacent to the prosthetic device, surrounded by the darker involucrum (♦) that is the reactive new bone. This was a complication of hip replacement. Osteomyelitis may result from penetrating injury with introduction of organisms, typically bacteria, into bone. More commonly, osteomyelitis is acquired by hematogenous dissemination. In growing bones of children, most bone infections begin predominantly in the metaphyseal region, with the greatest blood flow. Osteomyelitis in adults most often begins in epiphyseal and subchondral locations.

Osteomyelitis, MRI

This proximal humeral head shows irregular darker lysis and brighter sclerosis (♦) from infection. Acute osteomyelitis may present with pain, fever, and leukocytosis, but initial radiographic findings are subtle. A blood culture may be positive. About 5% to 25% of acute cases fail to resolve and go on to chronic osteomyelitis. There may be acute exacerbations. The weakened bone is prone to fracture. A fracture complicated by osteomyelitis may fail to heal, with development of a pseudarthrosis. An uncommon complication is development of a draining sinus tract, and rarer still is development of a squamous cell carcinoma within such a sinus tract.

Osteomyelitis, microscopic

Shown here within the marrow is fibrosis (♦) accompanied by chronic inflammatory cell infiltrates (►). The bony trabeculae have become disorganized and devitalized (■). Osteomyelitis is difficult to treat and may require surgical drainage and antibiotic therapy. The most common causative organism is Staphylococcus aureus . Neonates may have Haemophilus influenzae and group B streptococcal bone infections. Patients with sickle cell anemia are at risk for Salmonella osteomyelitis. Patients with urinary tract infections and injection drug users are at risk for osteomyelitis with Escherichia coli, Pseudomonas, and Klebsiella species.

Tuberculous osteomyelitis, MRI and gross

Extensive bone destruction (♦) is seen involving the T8 and T9 mid-thoracic vertebrae in a patient with disseminated Mycobacterium tuberculosis infection. Hematogenous spread is most likely, though there may be direct extension from lung. This is Pott disease of the spine. The vertebral body destruction with collapse seen here has resulted in impingement (▲) on the spinal cord. The infection may spread into adjacent paraspinal or psoas muscles to form a “cold” abscess.

Kyphosis, radiograph, and scoliosis, CT image

The lateral chest radiograph in the left panel shows marked kyphosis of the vertebral column, so that the head and neck are bent forward, and the total chest volume is markedly reduced. This patient also had severe osteoporosis, and a fall with trauma resulted in a fracture of the humerus that required open reduction and internal fixation, evidenced by the bright metal rod seen here. The chest CT scout image in coronal view in the right panel shows marked scoliosis of the lower thoracic vertebral column, with a major curve (▶) to the right. The superior-inferior axis and the anterior-posterior axis of the vertebral column show rotation. (Note that this patient also has a mass lesion (▼) within the right lung—bronchogenic carcinoma.)

Osteoma, CT image

There is a circumscribed, rounded bony cortical irregularity known as osteoma (▼) extending into the left maxillary sinus. Such a lesion can be solitary or may occur in a patient with Plenk-Gardner syndrome caused by an APC gene mutation. The osteomas are typically an incidental finding in this syndrome. Solitary osteomas are seen in middle-aged adults as sessile periosteal or endosteal masses. Osteomas are composed of a dense mixture of woven and lamellar bone.

Osteoid osteoma, radiograph and CT image

The discrete round lucency surrounded by a thin rim of sclerosis in this proximal phalanx (left panel (▲)) and proximal femur (right panel (◀)) is an osteoid osteoma. Despite their small size (usually <2 cm), they can produce considerable pain, owing to prostaglandin production, which can be blocked by analgesics such as aspirin. Osteoid osteomas most commonly arise in the second or third decade. They are most often found in the bone cortex of the femur or tibia. They are localized and there is no malignant potential.

Osteoid osteoma, microscopic

This is the central nidus, or radiolucent portion, of an osteoid osteoma, composed of irregular reactive new woven bone (▼). Osteoid osteomas usually occur in the bone cortex. By definition, an osteoblastoma is a well-circumscribed mass that has an identical microscopic appearance but larger (defined as >2 cm) and more likely to be present in the posterior aspect of a vertebral body. These lesions are benign and cured by local resection, but they may recur if not completely resected. They may also be treated with radiofrequency ablation.

Osteosarcoma, gross

This irregular mass lesion (✱) is arising within the metaphysis of the upper tibia in this cross-section of the lower extremity. It breaks through the bone cortex and extends into adjacent soft tissue. The tumor tissue is firm and tan-white. Glistening white articular cartilage of the uninvolved femoral condyle can be seen just to the right of the tumor. Osteosarcoma is the most common primary malignant bone tumor. Most arise during the first 2 decades of life. Men are affected more than women. More than half occur around the knee. Other sites of origin include the pelvis, proximal humerus, and jaw. Familial osteosarcomas often have RB gene mutations. Most are sporadic and also have RB, as well as TP53, CDK4, INK4a, and MDM2 mutations.

Osteosarcoma, radiograph

This malignancy (▼) involves the metaphyseal region of the distal femur. Long bones are more often affected in young individuals, probably because bone growth with mitotic activity increases risk for genetic mutations. This tumor erodes and destroys the bone cortex, extending into soft tissue where irregular reactive bone formation with calcification is seen as brighter areas in the normally dull-gray soft tissues. The periosteum here is lifted off (▲) by tumor expansion to form a Codman triangle. Clinical consequences include local pain, localized swelling, and problems with adjacent joint movement.

Osteosarcoma, MRI

A mass with increased signal intensity (brightness) in the distal femur is seen with axial T2-weighted fast spin echo MRI with fat saturation. There is extensive cortical bone disruption with extension (▲) of the tumor into the adjacent soft tissue. Areas of hemorrhage and cystic degeneration impart the variegation seen here as scattered bright and dark areas. The first clinical manifestation is often pain as the tumor breaks through the bone cortex and lifts off the periosteum. Osteosarcomas, similar to sarcomas in general, are most likely to metastasize hematogenously, most often to lungs.

Osteosarcoma, microscopic

This malignant tumor is composed of very pleomorphic cells, many with a spindle shape. No normal marrow is present here. One large, bizarre multinucleated cell (▼) with very large nuclei is present. Nuclear hyperchromatism and cellular pleomorphism are features of malignant neoplasms, and are typically pronounced in osteosarcomas, most of which are high-grade. There are islands (♦) of reactive new woven bone forming in response to the infiltration and destruction of normal bone by the tumor.

Osteosarcoma, microscopic

The neoplastic pleomorphic cells of osteosarcoma are seen to be making pink osteoid (✱). Osteoid production by a sarcoma is diagnostic of an osteosarcoma. This osteoid matrix vaguely resembles primitive woven bone. Additional microscopic elements of an osteosarcoma may be derived from the microenvironment with mesenchymal stem cells, including vascular proliferation, cartilaginous matrix, fibrous connective tissue, and multinucleated giant cells. There may be considerable microscopic variation within a single tumor, and metastases of a sarcoma may not exactly resemble the primary site appearance.

Osteochondroma, gross

Longitudinal cross-sections through this excised exostosis reveal a bluish-white cartilaginous cap (▼) overlying a bony cortex. These “tumors” may not be true neoplasms, but an aberration of endochondral bone formation with lateral displacement of the growth plate. They form a slowly growing mass lesion that extends outward from bone—an exostosis. They are typically solitary, arising most often in the metaphyseal region of a long bone before growth plate closure. The knee is the most common site, but the pelvis, scapula, and ribs may be involved. Less commonly, more than one lesion can appear at multiple sites, with an onset in childhood.

Osteochondroma, radiograph and MRI

An osteochondroma (▼) of the metaphyseal region projects laterally from the distal femur in the radiographic coronal view in the left panel and in the axial T1-weighted MR image in the right panel, and has a composition very similar to the normal bone. Solitary lesions are often asymptomatic, discovered incidentally on radiologic imaging. About 15% of these lesions can be multiple, with loss-of-function mutations in either EXT1, EXT2, or EXT3 genes, and part of an inherited condition such as the autosomal dominant multiple hereditary exostosis syndrome, with increased risk for development of osteosarcoma.