Imaging Findings of Metabolic Bone Disease PDF 2016

This copy is for personal use only. To order printed copies, contact reprints @rsna.org 1871...

This copy is for personal use only. To order printed copies, contact reprints @rsna.org 1871 MULTISYSTEM/GENERAL Imaging Findings of Metabolic Bone Disease1 Connie Y. Chang, MD Daniel I. Rosenthal, MD Metabolic bone diseases are a diverse group of diseases that result Deborah M. Mitchell, MD in abnormalities of (a) bone mass, (b) structure mineral homeo- Atsuhiko Handa, MD stasis, (c) bone turnover, or (d) growth. Osteoporosis, the most Susan V. Kattapuram, MD common metabolic bone disease, results in generalized loss of bone Ambrose J. Huang, MD mass and deterioration in the bone microarchitecture. Impaired chondrocyte development and failure to mineralize growth plate Abbreviation: SD = standard deviation cartilage in rickets lead to widened growth plates and frayed me- RadioGraphics 2016; 36:1871–1887 taphyses at sites of greatest growth. Osteomalacia is the result of impaired mineralization of newly formed osteoid, which leads to Published online 10.1148/rg.2016160004 characteristic Looser zones. Hypophosphatasia is a congenital con- Content Codes: dition of impaired bone mineralization with wide phenotypic vari- 1 From the Division of Musculoskeletal Imag- ability. Findings of hyperparathyroidism are the result of bone re- ing and Intervention, Department of Radiol- ogy (C.Y.C., D.I.R., S.V.K., A.J.H.), and the sorption, most often manifesting as subperiosteal resorption in the Pediatric Endocrine Division, Department of hand. Renal osteodystrophy is the collection of skeletal findings ob- Pediatrics (D.M.M.), Massachusetts General served in patients with chronic renal failure and associated second- Hospital, 55 Fruit St, Yawkey 6E, Boston, MA 02114; and the Department of Radiology, St. ary hyperparathyroidism and can include osteopenia, osteosclerosis, Luke’s International Hospital, Tokyo, Japan and “rugger jersey spine.” Hypoparathyroidism is most commonly (A.H.). Presented as an education exhibit at the 2015 RSNA Annual Meeting. Received January due to iatrogenic injury, and radiographic findings of hypoparathy- 21, 2016; revision requested February 26 and roidism reflect an overall increase in bone mass. Thyroid hormone received March 25; accepted April 15. For this journal-based SA-CME activity, the authors, regulates endochondral bone formation; and congenital hypothy- editor, and reviewers have disclosed no relevant roidism, when untreated, leads to delayed bone age and absent, ir- relationships. Address correspondence to regular, or fragmented distal femoral and proximal tibial epiphyses. C.Y.C. (e-mail: [email protected]). Soft-tissue proliferation of thyroid acropachy is most often observed © RSNA, 2016 in the hands and feet. The findings of acromegaly are due to excess growth hormone secretion and therefore proliferation of the bones SA-CME LEARNING OBJECTIVES and soft tissues. Vitamin C deficiency, or scurvy, impairs posttrans- After completing this journal-based SA-CME lational collagen modification, leading to subperiosteal hemorrhage activity, participants will be able to: and fractures. Identify the most common metabolic © bone diseases. RSNA, 2016 radiographics.rsna.org Describe the imaging findings related to the most common metabolic bone diseases. Discussthe most common causes of Introduction these metabolic bone diseases. Metabolic bone disease encompasses a diverse group of diseases that See www.rsna.org/education/search/RG. diffusely affect the mass or structure of bones by an external process. These diseases have many causes, from genetic disorders, to nutri- tional deficiencies, to acquired conditions. The imaging manifesta- tions are also varied, and the same disease process can have a wide range of skeletal findings (1). The purpose of this article is to review the radiographic findings of numerous metabolic bone diseases, including osteoporosis, rickets and osteomalacia, hypophosphatasia, hyperparathyroidism, renal osteodystrophy, hypoparathyroidism, hypothyroidism, hyperthyroidism, acromegaly, and scurvy. 1872 October Special Issue 2016 radiographics.rsna.org pausal women and for men older than 50 years TEACHING POINTS (11,12). This definition was a radical “rebrand- Osteoporosis is the most common metabolic bone disease. ing” of several concepts. In science and medi- Rickets is the interruption of orderly development and miner- cine, an individual is usually considered to have alization of growth plates. an abnormal result if his or her result is 2 SD Osteomalacia is inadequate or abnormal mineralization of os- away from the mean of his or her age- and sex- teoid in cortical and trabecular bone. matched norm, which is measured by the z score. In 95% of patients with hyperparathyroidism, skeletal findings However, for predicting fracture risk, it is more are most readily recognized in the hand. meaningful to compare an individual’s bone min- Renal osteodystrophy refers to the complex of findings ob- served in the setting of chronic renal insufficiency. These in- eral density to that of a young healthy individual clude the findings of osteomalacia (and rickets in children) prior to the occurrence of bone loss than to that and secondary hyperparathyroidism. of an age- and sex-matched norm. The T-score therefore compares the patient’s bone mineral density to that of a young healthy reference population and is therefore an absolute quantity, Osteoporosis not a relative one. This definition has led to some Osteoporosis is defined as a condition character- confusion because of the fact that an individual ized by diminished but otherwise normal bone. can have a normal T-score and yet may still have An osteoporotic state may arise either when bone osteoporosis. The World Health Organization also formation is inadequate or when bone resorption defined osteopenia as a mild form of osteoporosis. exceeds bone formation. Osteoporosis may be Primary osteoporosis takes slightly differ- a local phenomenon (as in disuse osteoporosis) ent forms in men and women. Traditionally, or a generalized condition. The imaging features these forms were separated into types I and II, depend to some degree on the rate at which os- although these distinctions have not been used teoporosis develops. in the endocrine literature for many years. After Osteoporosis is the most common metabolic menopause, estrogen deficiency results in a bone disease, affecting 13%–18% of women older period of accelerated bone loss, chiefly manifest than 50 years and 1%–4% of men older than 50 in cancellous (trabecular) bone, but cortical years (2–5). In the years prior to reliable quanti- bone loss also plays an important role (13). Men fication of bone mass, a patient was considered experience a more linear pattern of bone loss. to have osteoporosis only when a nontraumatic Typically, by about 80 years of age, the two sexes fracture had occurred. With the development are equivalent (2,10,14). of quantitative computed tomography (CT), Several disorders can interfere with bone dual-energy photon absorptiometry, and, later, formation or promote bone resorption, leading dual-energy x-ray absorptiometry, reliable mea- to secondary osteoporosis. Hypogonadism and surement methods became available, leading to a the resultant acceleration of bone resorption are change in the definition. observed in conditions that include hyperpro- Osteoporosis results in substantial morbidity lactinemia; disorders of energy imbalance such and mortality, primarily through fractures. World- as anorexia nervosa and the female athlete triad wide, one osteoporotic fracture occurs almost ev- (disordered eating, osteoporosis, and amenor- ery 3 seconds, which results in 9 million fractures rhea); primary gonadal failure, as in Turner each year (6). One-third of women older than 50 syndrome or Klinefelter syndrome; and hypo- years and one-fifth of men older than 50 years thalamic or pituitary dysfunction. Hyperthy- will have an osteoporotic fracture (7–9). The three roidism and hyperparathyroidism are additional most common fracture locations are the forearm, causes of accelerated bone resorption, whereas the hip, and the spine (Fig 1) (10). Severe osteo- growth hormone deficiency interferes with bone porosis may prevent detection of nondisplaced formation. Hypercortisolism, whether iatrogenic fractures, and CT or magnetic resonance (MR) from exogenous glucocorticoids or from Cush- imaging may be helpful for diagnosis if the patient ing syndrome, is another important cause of low has severe pain and a normal radiograph. bone mineral density (2,15). Regional osteopo- Clinically, osteoporosis is a state of low bone rosis can also occur because of inflammatory mass and microarchitectural deterioration leading arthropathy, immobilization, transient osteopo- to increased bone fragility. In 1994, the World rosis of large joints, or complex regional pain Health Organization defined osteoporosis as a syndrome (2,16,17). bone mineral density that is 2.5 or more standard In weight-bearing bones with little cortical deviations (SD) less than that of a young healthy bone, such as the vertebral bodies, which are adult (T-score of –2.5 or less) as measured with composed of only about 5% cortical bone and dual-energy x-ray absorptiometry for postmeno- 95% trabecular bone, the vertical weight-bearing  Figure 1. Distal radius fracture in an 81-year-old man with a history of prostate cancer, chronic renal insufficiency, and osteoporosis who fell at a restaurant. (a, b) Posteroan- terior (a) and lateral (b) radiographs of the left wrist show a comminuted, impacted, dorsally angulated intra-articular fracture (arrow) of the distal radius, acquired positive ulnar variance, and an ulnar styloid fracture (circle on a). (c, d) Radiographs of the left femoral neck (c) and left proximal humerus (d) show that the same patient also frac- tured his left femoral neck (arrow on c) and left proximal humerus (circle on d). trabeculae are thicker, and the horizontal trabec- Rickets and Osteomalacia ulae are thinner and are preferentially lost early Rickets is the interruption of orderly develop- in the disease (Fig 2). Recent work has demon- ment and mineralization of growth plates. Osteo- strated that bone strength is related to structure malacia is inadequate or abnormal mineralization as well as bone mineral density (18–21). Reduc- of osteoid in cortical and trabecular bone. Prior tion of horizontal trabeculae results in a loss of to growth plate fusion, rickets and osteomalacia load-bearing capacity greater than the loss of coexist. Rickets occurs as a result of hypophos- horizontal trabecular bone cross-sectional area phatemia. Any problem in the bone mineraliza- because of the important role that the horizon- tion pathway, including insufficient calcium or tal trabeculae play in laterally supporting the phosphate levels, abnormal pH, or the presence vertical trabeculae. For example, a 50% loss of of inhibitors of mineralization, can result in horizontal trabecular bone cross-sectional area osteomalacia (Fig 3). Causes of rickets and osteo- results in a 75% loss of load-bearing capacity malacia are listed in Table 1 (23–25). (18–21). Three-dimensional analysis of CT and The radiographic findings observed in rickets MR imaging data has shown striking changes in are listed in Table 2 and illustrated in Figure 4. the shape and connectivity of the trabeculae that Rachitic manifestations are most prominent at make up cancellous bone (22). the sites of greatest growth, including the knee 1874 October Special Issue 2016 radiographics.rsna.org Figure 2. Patterns of trabecular bone loss in osteoporosis. (a) Radiograph and diagram show normal mineralization of the vertebra of a 17-year-old girl. Note the fine meshwork pattern of trabecular bone. (b) Radiograph and diagram show osteoporosis of the vertebra of a 57-year-old man. There is preferential loss of the horizontal trabecular bone, with increased prominence of the vertical trabeculae. (c) Radiograph and diagram show osteoporosis of the vertebra of an 82-year-old woman. Note the marked loss of vertical and horizontal trabecular bone, resulting in large gaps between the vertical trabeculae. Diagram of the calcium homeostasis pathway. Ingested calcium is absorbed in the gas- trointestinal tract, and vitamin D is either absorbed in the gastrointestinal tract or generated from 7-de- hydrocholesterol through exposure to UV light (UVB). Vitamin D is further processed in the liver and kidney, where it is converted to its fully active form, which promotes calcium absorption in the gut. Para- thyroid hormone acts on the bones and the kidneys to increase serum calcium levels, and high serum calcium levels in turn suppress parathyroid hormone secretion. Parathyroid hormone, calcium, and phos- phorous also modulate vitamin D metabolism in the kidney (21). 25(OH)D = 25-hydroxy-vitamin D, 1,25-(OH)2D = 1,25-dihydroxy-vitamin D. (distal femur and proximal tibia), distal tibia, proximal humerus, distal radius and ulna, and the anterior rib ends of the middle ribs. The find- ings are observed on the metaphyseal side of the growth plate because unmineralized osteoid is concentrated along the metaphyseal side of the growth plate. Failure of mineralization leads to disorganized chondrocyte growth, and hypophos- phatemia leads to impaired apoptosis of hyper- trophic chondrocytes, which results in excessively long cartilage cell columns and the radiographic ill-defined trabecular bone, because osteoid on findings of widening of the growth plate and cup- the surface of the trabeculae is intermediate in ping and fraying of the metaphyses (23–26). density between that of bone and that of marrow, Decreased bone mass is frequently observed sometimes giving the impression of a “poor-qual- in osteomalacia; however, it is not an essential ity” radiograph. feature in the diagnosis because an inability to Looser zones are another distinctive feature mineralize newly synthesized osteoid does not of osteomalacia. They occur late in the overall imply that there is low bone mass of the skeleton. course of the disease (Fig 5). Looser zones are The presence of large quantities of unmineralized the result of deposition of unmineralized osteoid osteoid can sometimes be observed as indistinct at sites of stress or along nutrient vessels. These  Table 1: Causes of Rickets and Osteomalacia (Partial List) Category of Rickets and Osteomalacia Causes Inadequate vitamin D (synthesis or diet) Poor nutrition, poor sunlight exposure Malabsorption Pancreatic insufficiency, small bowel disease, rapid intestinal transit Abnormal vitamin D metabolism Liver disease, chronic renal failure, nephrotic syndrome, vitamin D– dependent rickets type I, medications that accelerate degradation of vitamin D or metabolites Vitamin D resistance Vitamin D–dependent rickets type II Other cases (rare) Dietary calcium deficiency, X-linked phosphatemic rickets, tumor- induced osteomalacia (unregulated secretion of fibroblast growth factor 23) Body Part Active Rickets Healing Rickets Extremity Widened growth plate; irregularity and osteo- Widened growth plate (especially distal femo- penia along metaphyseal side of growth plate; ral), mild metaphyseal cupping, sclerosis flared, frayed, or fractured metaphysis; bowing; along metaphyseal side of growth plate, fracture bowing Chest Rachitic rosary, bell-shaped thorax … Skull Flat occiput, widened sutures, squared appear- … ance of skull, basilar invagination zones can occur with no or minimal trauma, are mineralization can be remarkably poor, with entire often bilateral and symmetric, and appear as segments of the spine not depicted (absent) on transverse lucent bands oriented at right angles radiographs. In the infantile and childhood forms, to the cortex that only span a portion of the bone there can be craniosynostosis; and in the child- diameter. Although known as pseudofractures, hood form, characteristic “tongues” of lucency Looser zones are a type of insufficiency fracture, extend from the growth plate to the metaphy- with locations and appearances modified by sis. Skeletal findings can improve after enzyme abnormal repair mechanisms, and Looser zones replacement therapy with asfotase alfa, a recently are typically painful. Some of the common loca- developed recombinant tissue-nonspecific alkaline tions of Looser zones are similar to those of stress phosphatase (Fig 8) (23,24,28). fractures, such as the inner margin of the femoral neck or the pubic rami. However, Looser zones also occur in non–weight-bearing bones, which Hyperparathyroidism is a pathologic state of ele- are atypical locations for stress fractures, such as vated parathyroid hormone concentrations, which the lateral aspect of the femoral shaft at the level causes increased bone resorption. Primary hyper- of the lesser trochanter, the ischium, the iliac parathyroidism is a state of autonomous parathy- wing, and the lateral scapula (23,24). roid hormone secretion by the parathyroid glands and lack of feedback inhibition by serum calcium. Primary hyperparathyroidism is usually caused Hypophosphatasia is a rare genetic disorder by a parathyroid adenoma, but in approximately caused by mutations in the gene that encodes 10% of cases, it is a result of four-gland hyperpla- tissue-nonspecific alkaline phosphatase, resulting sia, and in extremely rare cases, primary hyper- in accumulation of pyrophosphate, an inhibitor parathyroidism is due to parathyroid carcinoma of bone mineralization. The skeletal findings of (29). Secondary hyperparathyroidism is more hypophosphatasia resemble those of rickets and common than primary hyperparathyroidism and osteomalacia. The clinical spectrum of disease var- is a response to low serum calcium levels. The ies widely, and it can be roughly categorized into most common cause is chronic renal failure, in the following four clinical phenotypes of decreas- which chronically elevated serum phosphate lev- ing severity: perinatal (Fig 6), infantile, childhood els depress the serum calcium level, which leads (Fig 7), and adult (27). In the perinatal form, to compensatory hyperplasia of the chief cells of 1876 October Special Issue 2016 radiographics.rsna.org Figure 4. Nutritional rickets and femoral fracture in the setting of parental neglect of a 3-year-old girl. (a) Anteroposterior radio- graph of the skull shows a partially patent frontal suture (arrow). (b) Posteroanterior radiograph of the chest shows wide and rounded anterior rib ends (circles). This finding is often called a “rachitic rosary” because the chain of rounded rib ends resembles rosary beads at physical examination. (c) Posteroanterior radiograph of both hands shows diffuse osteopenia, age-indeterminate fractures of sev- eral metacarpals (solid arrows), and cupped fragmented frayed metaphyses of the distal radii and ulnae (ovals). A peripheral rim of bone along the metaphysis (dashed arrow) occurs by membranous ossification. (d) Anteroposterior radiograph of both knees shows a fracture of the patient’s right distal femur (black arrow), as well as age-indeterminate fractures of her right tibia and both fibulae (dashed white arrows). The metaphyses are fragmented, frayed, and fractured (solid white arrows). (e) Anteroposterior radiograph of both lower extremities obtained 2 years later than a–d shows diffuse osteopenia, bowing of the tibiae and fibulae, flared metaphy- ses, and widening of the growth plates with sclerosis and irregularity on the metaphyseal side. Transverse sclerotic metaphyseal bands (arrows) parallel to the growth plate reflect periods of intermittent adequate mineralization followed by poor mineralization. (Images courtesy of Ok-Hwa Kim, MD, Ajou University, Seoul, Korea.) the parathyroid gland. Renal insufficiency also middle and index fingers as lacelike irregularity affects parathyroid hormone metabolism, fur- and at the distal phalangeal tufts as acro-osteoly- ther increasing the serum parathyroid hormone sis (Fig 9). In later stages, the resorption can ap- levels. Secondary hyperparathyroidism can also pear similar to scalloping or “periosteal reaction” be observed in vitamin D deficiency and dietary (pseudoperiostitis) (30). Subperiosteal resorption calcium deficiency (30). can also be observed in the ribs, lamina dura In 95% of patients with hyperparathyroidism, (bone that surrounds the tooth sockets), hu- skeletal findings are most readily recognized in merus, femur, and upper medial tibia. the hand (31). The pathognomonic subperiosteal Trabecular, intracortical, endosteal, subchon- bone resorption in hyperparathyroidism begins at dral, and subligamentous or subtendinous bone the radial aspects of the middle phalanges of the resorption can also occur. In the skull, bone  Tumor-induced osteomalacia in a 41-year-old man presenting with acute left hip pain after a fall down stairs, who had a history of multiple fractures during the previous 10 years. Lateral radiograph of the thoracic spine (a) and anteroposterior radiographs of the left forearm (b) and pelvis (c) show generalized osteopenia, vertebral body fractures (arrows on a), and multiple Looser zones (arrows on b, c). The patient later underwent left total hip arthroplasty, and a fibroblast growth factor 23–secreting mesenchymal tumor was found in the specimen from resection, a finding that led to the diagnosis of tumor-induced osteomalacia. Figure 6. Hypophosphatasia in a newborn boy who presented when his mother was trans- ferred to the hospital after sudden onset of labor. No Apgar scores are available. Knowing the poor prognosis, the parents did not wish further resuscitation, and the newborn died 35 minutes after birth. The alkaline phosphatase level was less than 5 IU/L (normal range for age, 150–420 IU/L). Prenatal ultrasonography (US) disclosed short femoral length (–5 SD at 23 weeks; –7 SD at 33 weeks) (images not shown). (a) Anteroposterior skull radiograph shows severe calvarial ossification defects, with only small residual islands of bone in the frontal (dashed white arrows) and parietal (solid white arrows) regions. The skull base and the facial bones (black arrows) are only partially ossified. (b) Anteroposterior radiograph shows abnormal ossification in the axial and appendicular skeleton, including thin clavicles (white arrowheads) and ribs (solid white ar- rows); absent cervical, thoracic, and lumbar vertebral bodies (rectangles); small scapulae (dashed white arrows) and ilia (black arrowheads), absent ischia and pubic bones (oval); tonguelike me- taphyseal ossification defects of the long bones (black arrows); and absent ossification of the short tubular bones in the hands and feet. (Images courtesy of Gen Nishimura, MD, St. Luke’s International Hospital, Tokyo, Japan.) 1878 October Special Issue 2016 radiographics.rsna.org Figure 7. Hypophos- phatasia in a 6-year-old girl with short stature (–4.72 SD). (a) Lateral radiograph of the skull shows craniosynostosis, resulting in brachyceph- aly (short anteroposterior dimension of the skull) with a “beaten-copper” appearance of the cal- varia (arrows). (b) Pos- teroanterior chest radio- graph shows generalized osteopenia with a coarse trabecular pattern of all of the depicted bones, broad anterior rib ends (*), and pseudofractures (arrows) in the right and left seventh ribs. (c) An- teroposterior radiograph of the right femur shows irregular metaphyses and wide growth plates (solid arrows) and pseu- dofractures of the medial aspect of the femoral neck and the distal fe- mur (dashed arrows). (d) Anteroposterior ra- diographs of both lower legs show wide growth plates (arrows). Note mild bowing of the tibiae and fibulae and healing fractures (circles) of both fibulae. (Images courtesy of Gen Nishimura, MD, St. Luke’s International Hospital, Tokyo, Japan.) resorption is described as a salt-and-pepper ap- In the sacroiliac joint, subchondral resorption is pearance and can lead to decreased differentia- more pronounced at the iliac side and may simu- tion between the inner and outer tables of the late an inflammatory or infectious arthritis (Fig skull (Fig 10a). Trabecular resorption results in a 11a). Sternoclavicular joint resorption tends to smudgy appearance of the trabeculae. Intracorti- affect both sides of the joint equally. Subligamen- cal resorption is also described as cortical tunnel- tous or subtendinous resorption also can occur ing (Fig 10b) and is often a prominent feature of anywhere but most often occurs at the calcaneus, hyperparathyroidism. Endosteal resorption may clavicle (Fig 11c), greater and lesser tuberosities lead to cortical thinning and may obscure the of the humerus, greater and lesser trochanters of corticomedullary junction. the femur, anterior inferior iliac spine, and ischial Subchondral resorption can affect any joint, tuberosity (Fig 11b) (29–32). leading to a widened and irregular appearance. Brown tumors, also known as osteoclastomas, In the hands, subchondral resorption most often are lytic lesions that result from the parathyroid begins along the distal interphalangeal joints and hormone–driven activation of osteoclasts. Brown progresses to the metacarpophalangeal and proxi- tumors are generally solitary but can be multifo- mal interphalangeal joints. Subchondral resorp- cal and are at risk for pathologic fracture. Brown tion can also occur along the acromioclavicular tumors commonly involve the facial bones (Fig joint, more pronounced along the clavicular side. 12), ribs, pelvis, and femora and can have a large Figure 8. Hypophosphatasia in a neonate with a low serum alkaline phosphatase level (5 IU/L) who had short femoral length at prenatal US (images not shown). (a) Anteroposterior radiograph shows abnormal ossification in the axial and appendicular skeleton, with a thin calvaria, thin clavicles and ribs, small ver- tebral bodies, small scapulae and ilia, stunted ends of the long bones, and poor ossification of the short tubular bones in the hands. (b) Posteroanterior chest radiograph obtained at the age of 6 months, after administration of recombinant enzyme replacement therapy, shows a remarkable increase in the ossifica- tion of the ribs, clavicles, scapulae, vertebrae, and long bones. The ends of the ribs and long bones are broader than normal because of the accumulation of osteoid in patients with hypophosphatasia. (Images courtesy of Gen Nishimura, MD, St. Luke’s International Hospital, Tokyo, Japan.) Hyperparathyroidism in a 15-year-old boy presenting with mi- nor trauma to his left hand. His calcium level was 12.2 mmol/L (normal range, 8.5–10.2 mmol/L). Radiograph of the left hand shows a mildly angulated fifth metacarpal fracture (circle). There is re- sorption of the distal phalangeal tufts (solid arrows), a finding consistent with acro-osteolysis. Subperiosteal resorption is depicted along the distal radial aspects of the middle phalanges of the index and long fingers (dashed arrows). Renal osteodystrophy refers to the complex of findings observed in the setting of chronic renal insufficiency. These include the findings of osteo- malacia (and rickets in children) and secondary hyperparathyroidism. In any given patient, the findings of one or the other may predominate. In patients with chronic renal insufficiency, radiographs may show a diffuse increase in bone radiodensity, a finding that is seen more often associated soft-tissue component. Treatment of in the axial skeleton, which has more trabecular hyperparathyroidism may also lead to resolution bone than cortical bone (Fig 14). The etiology of of brown tumors. Brown tumors were originally this diffuse osteosclerosis is not well understood, described with primary hyperparathyroidism but although it probably reflects the anabolic effect are now more common in patients with chronic of parathyroid hormone. Despite the increased renal insufficiency and secondary hyperparathy- radiodensity, the bone is structurally weak and roidism (Fig 13) (30,33,34). prone to stress fractures (35). The spine often 1880 October Special Issue 2016 radiographics.rsna.org Figure 10. Chronic renal insuf- ficiency and secondary hyperpara- thyroidism in a 65-year-old woman. (a) Lateral radiograph of the skull shows innumerable punctate lu- cent and radiodense foci, findings consistent with a salt-and-pepper appearance. (b) Posteroanterior radiograph of the right index fin- ger shows resorption (solid arrow) along the radial aspect of the mid- dle phalanx and cortical tunneling (dashed arrow) of the proximal phalanx. Figure 11. Chronic renal insufficiency and secondary hyperparathyroidism in a 50-year-old man. (a) Anteroposterior radiograph of the sacroiliac joints shows subchondral resorption (arrows), which is more pronounced along the iliac bones. (b) Anteroposterior radiograph of the pelvis shows subten- dinous resorption at the right hamstring (solid arrow) and adductor origins (dashed arrows) on the ischial tuberosity. (c) Anteroposterior radiograph of the right clavicle shows subchondral resorption (circle) along the distal clavicle and subligamentous resorption (arrows) at the clavicular attachment of the coracoclavicular ligament. demonstrates a characteristic striped appearance (alternating bands of increased density along the endplates and decreased density in the central por- tion of the vertebral body), which is also known as the rugger jersey spine (Fig 15) (30,34,36). In addition to renal osteodystrophy, renal insufficiency may result in various soft-tissue manifestations, especially after renal transplan- tation or a prolonged period of hemodialysis. When present, soft-tissue deposits of calcium hydroxyapatite, calcium pyrophosphate dihydrate, and calcium oxalate typically occur around large Amyloid deposition can occur in patients joints (Fig 16), but such deposits can occur in undergoing long-term hemodialysis and is due any soft tissues and can be life threatening in the to !2-microglobulin deposition in bone and soft heart, lungs, stomach, and kidney. Monosodium tissues, including cartilage, joint capsules, liga- urate crystals can also be deposited in the soft ments, tenosynovium, muscles, and intervertebral tissues. All crystal deposition can lead to bursitis disks. This deposition can lead to carpal tunnel and synovitis and responds to therapy with anti- syndrome in as many as 31% of patients. Amy- inflammatory agents (30,37). loid deposition in joints leads to a destructive  Figure 12. Primary hyper- parathyroidism in a 43-year-old woman presenting to the emer- gency department with acute and chronic jaw pain 1 year after extraction of a mandibular granu- loma. (a) Axial CT image through the mandible shows a lytic lesion (*) with a large soft-tissue compo- nent, a finding consistent with a brown tumor. (b) Radionuclide image of the parathyroid gland obtained after administration of technetium 99m sestamibi shows increased uptake in the neck (cir- cle), a finding consistent with a parathyroid adenoma. Renal osteodystrophy in a 28-year-old woman with ne- phrotic syndrome and end-stage renal disease who was undergoing treatment with dialysis. Anteropos- terior radiographs of both knees show diffuse osteosclerosis (*), a finding often observed in patients with end-stage renal disease, al- though osteosclerosis is typically more common in the axial skel- eton. Lytic lesions (circles) are de- picted in both lateral femoral con- dyles, findings that are consistent with brown tumors. Figure 14. Renal osteodystrophy in a 60-year-old man after he un- derwent renal transplantation for glomerulonephritis. Anteropos- terior radiograph of the lumbar spine shows diffusely increased ra- diodensity of the depicted bones. Hypoparathyroidism is most commonly an acquired disorder caused by iatrogenic injury to the parathyroid glands during thyroid surgery or excision of the parathyroid glands or, more rarely, during wide excision of a head and neck cancer. Hypoparathyroidism may also result from auto- immune disease or genetic causes (eg, DiGeorge syndrome) (44,45). End-organ insensitivity to para- thyroid hormone is called pseudohypoparathyroid- ism and has different radiographic findings. Hypo- parathyroidism that is due to genetic causes usually arthropathy (Fig 17). Renal transplantation can manifests in childhood, but the clinical spectrum arrest progression but does not reverse dialysis- varies widely, and in some cases, hypoparathyroid- related amyloid arthropathy (30,38–43). ism may not be detected until adulthood (46,47). 1882 October Special Issue 2016 radiographics.rsna.org Renal osteodystrophy in a 28-year-old woman with ne- phrotic syndrome and end-stage renal disease who was undergo- ing treatment with dialysis. Lateral radiograph of the lumbar spine shows alternating bands of scle- rosis along the endplates (dashed arrows) and areas of lucency cen- trally (solid arrows). This pattern is known as rugger jersey spine, a finding named for the pattern of the jerseys worn by rugby players (shown at right). Figure 16. Secondary hyperparathyroidism in a 57-year-old woman with renal failure and a para- thyroid hormone level of 1313 pg/mL. (a) Lateral radiograph of the left forearm shows soft-tissue calcifi- cation (arrows) in the dorsal soft tissues of the forearm. (b) Axial nonenhanced CT image through the level of the external auditory canal shows soft-tissue calci- fication (arrows) in both pinnae. (c) Anteroposterior radiograph of the right knee shows chondrocalcinosis (arrows) of the medial and lateral menisci. (d) Axial nonenhanced CT image through the level of the pubic symphysis shows calcification with fluid-fluid levels (ar- rows) in and around the pubic symphysis, as well as erosions of both pubic bones (circles). Radiographic findings of hypoparathyroidism reflect an overall increase in bone mass, including space. In rare cases, spinal ossification similar in generalized or localized osteosclerosis and thick- appearance to the enthesitis observed in psoriatic ening of the calvaria, with a narrowed diploic arthritis can occur (47–51). Figure 17. Amyloid arthropathy in an 83-year-old man with polycystic kidney disease who had undergone treatment with hemodialysis for 18 years. (a) Lateral frog-leg radiograph of the left hip shows a large erosion (arrows) along the superolateral femoral head. The joint space is only mildly narrowed, and there is minimal pro- liferative change of the bone. (b) Axial contrast material–enhanced CT image of the left hip shows the erosion (arrow) along the superolateral femoral head, with only mild joint space narrowing and minimal bone prolifera- tive change. There is mineralized soft tissue within the erosion, consistent with amyloid deposition. Body Part Radiographic Findings Hands Spade-shaped tufts, tubulation of phalangeal shafts, exostoses, widened joint spaces, sesamoid enlargement Feet Heel pad thickness > 25 mm in men and > 23 mm in women, skin thickening, tendon insertion ossification, sesamoid enlargement Skull Thick skull bones; enlarged sella; frontal bossing; prominence of frontal and maxillary sinuses, supra- orbital ridge, and zygomatic arch; prognathism (protrusion of jaw); enlargement of the mandible etal manifestation of hyperthyroidism is osteo- Hypothyroidism may be congenital, which leads to porosis. As many as 1% of patients with Graves severe skeletal abnormalities and delayed devel- disease may have thyroid acropachy, which opment, or it may be acquired, which results in usually occurs after treatment, when the patient’s relatively mild skeletal abnormalities, if any. Acquired condition becomes euthyroid or hypothyroid. hypothyroidism may occur after surgery or after Radiographic findings of thyroid acropachy treatment (radioactive iodine therapy) or may be due are best observed in the hands and feet, in which to glandular atrophy, acute or chronic (Hashimoto) clubbing, periostitis, and soft-tissue swelling may thyroiditis, infiltrative diseases such as amyloidosis or be seen. The periostitis is greatest along the radial lymphoma, therapy with certain medications, iodine margins of the metacarpal, metatarsal, and middle deficiency, or a pituitary disorder resulting in a defi- and proximal phalangeal diaphyses. Soft-tissue ciency of thyroid-stimulating hormone (52). swelling may also be seen in the pretibial region. In children, there is delayed skeletal development, Exophthalmos, which is the result of thyroid-stim- often with absent, irregular, or fragmented distal ulating hormone receptor–stimulating antibodies femoral and proximal tibial epiphyses (Fig 18) of Graves disease stimulating proliferation of the resembling multiple epiphyseal dysplasia. Dental retro-orbital fibroblasts, may be depicted on skull development may also be delayed (52–54). radiographs or head CT images (52). Acromegaly Hyperthyroidism is most commonly due to Acromegaly is due to excess growth hormone oversecretion of thyroid hormone by the thyroid secretion from the anterior lobe of the pituitary. gland diffusely (Graves disease) or focally (single The radiographic findings of acromegaly are listed or multiple adenomas). The most common skel- in Table 3 and shown in Figure 19 (47). 1884 October Special Issue 2016 radiographics.rsna.org Figure 18. Congenital hypothyroidism in a 12-year-old boy with short stature and developmental delay. (a) Oblique radio- graph of the right hand shows ossification centers of only the capitate (arrowhead), hamate (arrow), and radius (circle). The bone age is estimated at 1.5 years. (b) Lateral radiograph of the lumbar spine shows hypoplastic vertebral bodies. L1 has a bullet-shaped vertebral body (arrow). (c) Anteroposterior radiograph of the pelvis shows mild flaring of the iliac bones with shallow acetabula (solid arrows). The femoral capital epiphyses (dashed arrows) are small and fragmented. (d) Anteroposterior radiograph of the right knee shows small and irregular distal femoral and proximal tibial epiphyses (arrows). (e) Posteroante- rior radiograph of the left hand obtained after 2 years of thyroid hormone replacement therapy shows interval ossification of all of the carpal ossification centers. The bone age remains delayed but has progressed to approximately 9 years (patient age, 14 years). (f) Anteroposterior radiograph of the right knee obtained after 2 years of thyroid hormone replacement therapy shows maturation of the epiphyses but residual irregularity of the tibial and femoral epiphyses (arrows). (Images courtesy of Ok-Hwa Kim, MD, Ajou University, Seoul, South Korea.) Scurvy The bones are diffusely osteopenic, and there are Scurvy is a nutritional deficiency of vitamin C, thin cortices, especially in the epiphyses. Along the a required cofactor for hydroxylation of many growth plates, there is decreased and disorganized proteins, including collagen. At one time the cartilage proliferation, resulting in an irregular scourge of all ocean-going seamen, scurvy is now appearance of the growth plate along the metaphy- exceedingly rare. Vitamin C deficiency results in seal side. A dense band along the metaphyseal abnormal collagen production, leading to vascular side of the growth plate in the zone of provisional fragility and abnormal bone matrix, especially in calcification (Frankel line) represents the sclerotic areas of greatest growth, such as the distal femur, provisional zone of calcification. Peripheral exten- proximal tibia and fibula (Fig 20), distal radius sion of the zone of calcification results in a pointed and ulna, proximal humerus, and distal rib ends. contour of the metaphyses known as “beaking.”  Acromegaly in a 30-year-old man who was 6 ft 7 in (201 cm) tall, had a history of diplo- pia for many years, and was later found to have a growth hormone–secreting pituitary adenoma. (a) Sagittal CT image of the head obtained near the midline shows thick frontal bones (solid arrows) and an enlarged sella (dashed arrows). (b) Postero- anterior radiograph of the right hand shows spade- shaped distal phalangeal tufts (circles). (c) Lateral radiograph of the calcaneus shows an enlarged heel pad (double-headed arrow) and thick plantar skin (arrows). Figure 20. Scurvy in a 10-year-old boy with autism spectrum disorder presenting with nutritional deficiency and an undetectable peripheral blood concentration of vitamin C. Anteroposterior radiograph of the left knee shows osteopenia, periosteal elevation and reaction (solid black arrows), metaphyseal beaking (solid white arrows), irregular appearance of the growth plate along the metaphyseal side (*), thin cortices, especially in the epiphyses (dashed black arrows), and dense bands along the metaphyseal side of the physes in the zone of provisional calcification (Frankel line [arrowhead]) with an adjacent lucent line called the Trummerfeld zone, or “scurvy line” (dashed white arrow). Fragility of the trabeculae in this region results in subepiphyseal “corner” fractures (Fig 21a). A lucent line adjacent to the Frankel line called the Trummerfeld zone, or scurvy line, reflects accu- mulation of hemorrhage in this zone, which tends to fracture. Subperiosteal hemorrhage results in periosteal elevation and periosteal reaction. At MR imaging, bone marrow is heterogeneous on T1- and T2-weighted MR images, and subperiosteal hemorrhage can be seen as periosteal elevation with increased subperiosteal T1 and T2 signal intensity (Fig 21b) (55–57). 1886 October Special Issue 2016 radiographics.rsna.org Figure 21. Scurvy in a 4-year-old boy with speech delay, a history of difficulty walking for 1 month, and a serum vitamin C level of 0.08 mg/dL (normal range, 0.2– 2.0 mg/dL). (a) Anteroposterior radio- graph of both knees shows diffuse osteo- penia, Frankel lines (arrowheads), Trum- merfeld zones or scurvy lines (dashed arrows), widening of the growth plate (solid arrows), and subepiphyseal corner fracture (circle). Because of the metaphy- seal lucent bands, the patient was initially thought to have leukemia or metastases, but the findings from histopathologic examination of the specimen from bone marrow biopsy were normal. (b) Coronal T2-weighted fat-suppressed MR image of both distal femoral metadiaphyses shows heterogeneously increased T2 signal in- tensity in the marrow (*) and around the bone (arrows). (Images courtesy of Gen Nishimura, MD, St. Luke’s International Hospital, Tokyo, Japan.) 3. O’Neill TW, Felsenberg D, Varlow J, Cooper C, Kanis JA, Conclusion Silman AJ. The prevalence of vertebral deformity in European Metabolic bone diseases are a heterogeneous men and women: the European Vertebral Osteoporosis Study. J Bone Miner Res 1996;11(7):1010–1018. group of disorders that diffusely affect the bones. 4. Looker AC, Orwoll ES, Johnston CC Jr, et al. Prevalence of Understanding the underlying mechanism of the low femoral bone density in older U.S. adults from NHANES diseases helps the radiologist to also understand III. J Bone Miner Res 1997;12(11):1761–1768. the radiographic findings and to make a correct 5. Kanis J, on behalf of the World Health Organization Scientific Group. Assessment of osteoporosis at the primary health care diagnosis. level: technical report. Sheffield, United Kingdom: World Health Organization Collaborating Centre for Metabolic Acknowledgments.—The authors thank Gen Nishimura, MD, Bones Diseases, University of Sheffield, 2007. University St. Luke’s International Hospital, Tokyo, Japan, and Ok-Hwa of Sheffield website. https://www.shef.ac.uk/FRAX/pdfs/ Kim, MD, Ajou University, Seoul, Korea, for sharing their WHO_Technical_Report.pdf. Accessed November 12, 2015. cases and thank illustrator Susanne Loomis, Massachusetts 6. Johnell O, Kanis JA. An estimate of the worldwide preva- General Hospital, Boston, Mass, for her illustrations. lence and disability associated with osteoporotic fractures. Osteoporos Int 2006;17(12):1726–1733. 7. Kanis JA, Johnell O, Oden A, et al. Long-term risk of osteopo- References rotic fracture in Malmö. Osteoporos Int 2000;11(8):669–674. 1. Skowro ska-Jó wiak E, Lorenc RS. Metabolic bone disease 8. Melton LJ 3rd, Atkinson EJ, O’Connor MK, O’Fallon WM, in children: etiology and treatment options. Treat Endocrinol Riggs BL. Bone density and fracture risk in men. J Bone 2006;5(5):297–318. Miner Res 1998;13(12):1915–1923. 2. Guglielmi G, Muscarella S, Bazzocchi A. Integrated imaging 9. Melton LJ 3rd, Chrischilles EA, Cooper C, Lane AW, Riggs approach to osteoporosis: state-of-the-art review and update. BL. Perspective: how many women have osteoporosis? J Bone RadioGraphics 2011;31(5):1343–1364. Miner Res 1992;7(9):1005–1010. 10. Riggs BL, Melton LJ 3rd. Evidence for two distinct syndromes 35. Mataliotakis G, Lykissas MG, Mavrodontidis AN, Kontogeor- of involutional osteoporosis. Am J Med 1983;75(6):899–901. gakos VA, Beris AE. Femoral neck fractures secondary to renal 11. Kanis JA, Glüer CC. An update on the diagnosis and as- osteodystrophy: literature review and treatment algorithm. J sessment of osteoporosis with densitometry: Committee of Musculoskelet Neuronal Interact 2009;9(3):130–137. Scientific Advisors, International Osteoporosis Foundation. 36. Resnick D. The sclerotic vertebral body. JAMA 1983;249 Osteoporos Int 2000;11(3):192–202. (13):1761–1763. 12. Assessment of fracture risk and its application to screening 37. Kuzela DC, Huffer WE, Conger JD, Winter SD, Hammond for postmenopausal osteoporosis: report of a WHO study WS. Soft tissue calcification in chronic dialysis patients. Am group. World Health Organ Tech Rep Ser 1994;843:1–129. J Pathol 1977;86(2):403–424. 13. Zebaze RMD, Ghasem-Zadeh A, Bohte A, et al. Intracorti- 38. Naidich JB, Karmel MI, Mossey RT, Bluestone PA, Stein HL. cal remodelling and porosity in the distal radius and post- Osteoarthropathy of the hand and wrist in patients undergoing mortem femurs of women: a cross-sectional study. Lancet long-term hemodialysis. Radiology 1987;164(1):205–209. 2010;375(9727):1729–1736. 39. Naidich JB, Mossey RT, McHeffey-Atkinson B, et al. Spon- 14. Albright F. Osteoporosis. Ann Intern Med 1947;27(6): dyloarthropathy from long-term hemodialysis. Radiology 861–882. 1988;167(3):761–764. 15. Link TM. Osteoporosis imaging: state of the art and advanced 40. Casey TT, Stone WJ, DiRaimondo CR, et al. Tumoral amy- imaging. Radiology 2012;263(1):3–17. loidosis of bone of beta 2-microglobulin origin in association 16. Guglielmi G, Muscarella S, Leone A, Peh WC. Imaging of with long-term hemodialysis: a new type of amyloid disease. metabolic bone diseases. Radiol Clin North Am 2008;46(4): Hum Pathol 1986;17(7):731–738. 735–754, vi. 41. Bardin T, Kuntz D, Zingraff J, Voisin MC, Zelmar A, Lansa- 17. Sommer OJ, Kladosek A, Weiler V, Czembirek H, Boeck man J. Synovial amyloidosis in patients undergoing long-term M, Stiskal M. Rheumatoid arthritis: a practical guide to hemodialysis. Arthritis Rheum 1985;28(9):1052–1058. state-of-the-art imaging, image interpretation, and clinical 42. Bardin T, Lebail-Darné JL, Zingraff J, et al. Dialysis ar- implications. RadioGraphics 2005;25(2):381–398. thropathy: outcome after renal transplantation. Am J Med 18. Einhorn TA. Bone strength: the bottom line. Calcif Tissue 1995;99(3):243–248. Int 1992;51(5):333–339. 43. Gielen JL, van Holsbeeck MT, Hauglustaine D, et al. Grow- 19. Townsend PR, Rose RM, Radin EL. Buckling studies of ing bone cysts in long-term hemodialysis. Skeletal Radiol single human trabeculae. J Biomech 1975;8(3-4):199–201. 1990;19(1):43–49. 20. Mosekilde L, Viidik A, Mosekilde L. Correlation between the 44. Mitchell DM, Regan S, Cooley MR, et al. Long-term follow- compressive strength of iliac and vertebral trabecular bone up of patients with hypoparathyroidism. J Clin Endocrinol in normal individuals. Bone 1985;6(5):291–295. Metab 2012;97(12):4507–4514. 21. Guise TA, Mundy GR. Cancer and bone. Endocr Rev 1998;19 45. Shoback D. Clinical practice: hypoparathyroidism. N Engl (1):18–54. J Med 2008;359(4):391–403. 22. Nawanthe S, Nguyen BP, Barzanian N, Akhlaghpour H, 46. Moley JF, Skinner M, Gillanders WE, et al. Management of Bouxsein ML, Keaveny TM. Cortical and trabecular load the parathyroid glands during preventive thyroidectomy in sharing in the human femoral neck. J Biomech 2015;48(5): patients with multiple endocrine neoplasia type 2. Ann Surg 816–822. 2015;262(4):641–646. 23. Pitt MJ. Rickets and osteomalacia. In: Resnick D, ed. Diag- 47. Resnick D. Parathyroid disorders and renal osteodystrophy. nosis of bone and joint disorders. 4th ed. Philadelphia, Pa: In: Resnick D, ed. Diagnosis of bone and joint disorders. 4th Saunders, 2002; 1901–1946. ed. Philadelphia, Pa: Saunders, 2002; 2043–2111. 24. Calder AD. Radiology of osteogenesis imperfecta, rickets 48. Steinberg H, Waldron BR. Idiopathic hypoparathyroidism: and other bony fragility states. Endocr Dev 2015;28:56–71. an analysis of fifty-two cases, including the report of a new 25. Tiosano D, Hochberg Z. Hypophosphatemia: the common case. Medicine (Baltimore) 1952;31(2):133–154. denominator of all rickets. J Bone Miner Metab 2009;27(4): 49. Taybi H, Keele D. Hypoparathyroidism: a review of the lit- 392–401. erature and report of two cases in sisters, one with steatorrhea 26. Sabbagh Y, Carpenter TO, Demay MB. Hypophosphatemia and intestinal pseudo-obstruction. Am J Roentgenol Radium leads to rickets by impairing caspase-mediated apoptosis Ther Nucl Med 1962;88:432–442. of hypertrophic chondrocytes. Proc Natl Acad Sci U S A 50. Strom L, Winberg J. Idiopathic hypoparathyroidism. Acta 2005;102(27):9637–9642. Paediatr 1954;43(6):574–581. 27. Whyte MP, Zhang F, Wenkert D, et al. Hypophosphatasia: 51. Bronsky D, Kushner DS, Dubin A, Snapper I. Idiopathic validation and expansion of the clinical nosology for children hypoparathyroidism and pseudohypoparathyroidism: case from 25 years experience with 173 pediatric patients. Bone reports and review of the literature. Medicine (Baltimore) 2015;75:229–239. 1958;37(4):317–352. 28. Whyte MP, Greenberg CR, Salman NJ, et al. Enzyme- 52. Resnick D. Thyroid disorders. In: Resnick D, ed. Diagnosis of replacement therapy in life-threatening hypophosphatasia. bone and joint disorders. 4th ed. Philadelphia, Pa: Saunders, N Engl J Med 2012;366(10):904–913. 2002; 2026–2042. 29. Khan A, Bilezikian J. Primary hyperparathyroidism: patho- 53. Hernandez RJ, Poznanski AW, Hopwood NJ. Size and skeletal physiology and impact on bone. CMAJ 2000;163(2):184–187. maturation of the hand in children with hypothyroidism and 30. Murphey MD, Sartoris DJ, Quale JL, Pathria MN, Martin hypopituitarism. AJR Am J Roentgenol 1979;133(3):405–408. NL. Musculoskeletal manifestations of chronic renal insuf- 54. Newland CJ, Swift PG, Lamont AC. Congenital hypothy- ficiency. RadioGraphics 1993;13(2):357–379. roidism: correlation between radiographic appearances of 31. Resnick D, Deftos LJ, Parthemore JG. Renal osteodystrophy: the knee epiphyses and biochemical data. Postgrad Med J magnification radiography of target sites of absorption. AJR 1991;67(788):553–556. Am J Roentgenol 1981;136(4):711–714. 55. Resnick D. Scurvy. In: Diagnosis of bone and joint disorders. 32. Resnick D, Niwayama G. Subchondral resorption of bone 4th ed. Philadelphia, Pa: Saunders, 2002; 3459–3463. in renal osteodystrophy. Radiology 1976;118(2):315–321. 56. Noordin S, Baloch N, Salat MS, Rashid Memon A, Ah- 33. Brown TW, Genant HK, Hattner RS, Orloff S, Potter DE. mad T. Skeletal manifestations of scurvy: a case report Multiple brown tumors in a patient with chronic renal failure from Dubai. Case Rep Orthop 2012;2012:624628. doi: and secondary hyperparathyroidism. AJR Am J Roentgenol 10.1155/2012/624628. Published online September 3, 2012. 1977;128(1):131–134. 57. Polat AV, Bekci T, Say F, Bolukbas E, Selcuk MB. Osteoskel- 34. Griffiths HJ, Ennis JT, Bailey G. Skeletal changes following etal manifestations of scurvy: MRI and ultrasound findings. renal transplantation. Radiology 1974;113(3):621–626. Skeletal Radiol 2015;44(8):1161–1164. TM This journal-based SA-CME activity has been approved for AMA PRA Category 1 Credit. See www.rsna.org/education/search/RG.