Eugene A. Hessel II, MD, FACS

• Professor
• Department of Anesthesiology
• University of Kentucky College of Medicine
• Lexington, Kentucky

Isolated pelvic fractures include fractures of the iliac wing bacteria divide by discount linezolid online visa, avulsion injuries at tendon attachments antibiotic resistance research grants purchase linezolid once a day, straddle injuries to the pubic rami bacteria jacuzzi discount 600 mg linezolid free shipping, insufficiency fractures antibiotic resistance deaths discount linezolid uk, and some sacral fractures antibiotics rash toddler linezolid 600 mg order fast delivery. Avulsion injuries are usually seen in young patients as Salter-Harris type injuries. Hip dislocations are categorized as anterior or posterior, and are further described by the location of associated fractures. The most common of these is femoroacetabular impingement, a general term referring to impingement of the femur against the acetabulum due to variant morphology of the femoral head/neck junction or the acetabulum. Iliopsoas impingement may refer to snapping of the iliopsoas tendon, or may produce an isolated anterior acetabular labral tear and can have a variety of causes. Ischiofemoral impingement refers to impingement of the quadratus femoris muscle between the lesser trochanter and the ischial tuberosity. Muscle and tendon injuries in the pelvis may be acute or due to chronic overuse or degeneration. In athletes, injury to the aponeurosis of the rectus abdominis/adductor longus is an important cause of groin pain. Hamstring injuries are usually caused by forceful abduction (fall on ice) while gluteus medius and minimus tears are usually a chronic, degenerative phenomenon. The acetabulum consists of contributions from the pubis, ischium, and ilium, the three bones which comprise the innominate bone. The innominate bone forms the bony bridge from the torso to the lower limb and is crucial for stability and locomotion. The anterior column extends from the sacrum to the pubic symphysis, and is recognized on radiographs by the iliopectineal line. The posterior column extends from the sacrum to the ischial tuberosity, and is represented on radiographs by the ilioischial line. The sciatic buttress is a crucial portion of the posterior column, extending from the sacrum to the acetabulum. The anterior and posterior acetabular walls form an anteverted cup stabilizing the femoral head, but do not provide structural integrity to the pelvis. Fractures of the acetabulum may be categorized as simple patterns or complex combinations of the following: Anterior or posterior wall, anterior or posterior column, or transverse. A fracture of the acetabulum is categorized as a fracture of the anterior or posterior column only when the column is disrupted in two places, i. A both-column fracture completely separates the acetabulum from the sacrum, dividing the innominate bone into superior and inferior fragments and disrupting the sciatic buttress. The similar-appearing transverse and T-type fractures are oriented 490 Anatomic Considerations the bony pelvis forms a ring which can be conceptually subdivided in several ways. The sacrum articulates via the paired sacroiliac joints with the innominate bones on either side, which articulate with each other via the pubic symphysis. The sacroiliac joints and pubic symphysis are synovial joints, but allow very limited motion. The bony pelvis can also be divided into the anterior portion of the ring, including the innominate bones from the ischial spine to the pubic symphysis, and the posterior ring, including the sacrum and the posterior portion of the innominate bones. Alternatively, the pelvis can be divided into the false pelvis above the iliopectineal line and part of the abdominal cavity, and the true pelvis which lies between the iliopectineal line and the ischial tuberosities. Pathologic Considerations Since the bony pelvis forms a ring, a high-impact injury will usually disrupt the ring in more than one place. Discovery of any pelvic disruption should prompt the search for additional injuries. Pelvic ring disruptions are also commonly associated with acetabular injuries, hip dislocations, and injuries elsewhere in the body. Care must be taken by the radiologist to look beyond the clinical diagnosis of impingement for a full evaluation of a multitude of other causes of hip pain. It is wise to remember that a single radiographic view is a two-dimensional survey and is inadequate for complete evaluation of the musculoskeletal pelvis. Radiographs can be normal in the setting of proximal femoral fracture, particularly for subcapital femoral neck fracture or pelvic insufficiency fracture. In the trauma setting, the groin lateral (cross-table lateral) is always obtained. The patient lies supine, the contralateral hip is flexed and the thigh elevated, and a cross-table beam is directed 10° cephalad centered on the affected hip. In the sports medicine setting, there are a number of different lateral views obtained, which provide visualization of slightly different portions of the anterior femoral head and neck, and different views of the acetabulum. The frog-leg lateral is obtained with the patient supine, the hip and knee flexed, and the soles of the feet placed against each other. The Lowenstein lateral view is obtained with the patient supine, posterior rotation of the pelvis by 45°, flexion of the hip and knee, and the knee flat against the table. The false profile lateral view is obtained with the patient upright, hip and knee extended, and the pelvis rotated 45-65° posteriorly. The modified Dunn lateral is obtained supine with the hip flexed 45°, the knee flexed 90°, and the foot flat against the table. These are useful not only in the setting of trauma, but in the evaluation of femoroacetabular impingement and acetabular dysplasia. Surface rendering is readily comprehended by nonradiologists, but does not show as much detail as the translucent algorithm. However, it should be reserved as a targeted examination for specific indications, rather than a global survey tool. This noncontrast protocol adds a coronal oblique imaging plane prescribed along the plane of the anterior iliac wing and high-resolution sagittal images through the pubic symphysis performed with a surface coil centered over the symphysis. This imaging strategy offers improved specificity for lesions involving the rectus abdominis/adductor aponeurosis and is the protocol of choice in young patients with groin pain or clinical athletic pubalgia. While arthrographic protocols improve conspicuity of labral and cartilage abnormalities, high-resolution noncontrast protocols are also diagnostic. The hip is injected with a mixture of gadolinium contrast diluted 1:200 with iodinated contrast, saline, and anesthetic. Oblique axial images are most suited to delineate anterosuperior femoral head/neck morphology. Intraarticular infusion of anesthetic during the arthrogram injection, with assessment of any change in symptoms during provocative hip maneuvers, can provide further diagnostic information. The pelvic binder, placed to reduce the pelvic volume and thereby reduce bleeding, may lead to underestimation of degree of ligament injury. The associated inferior pubic ramus fracture, which is always seen in this pattern, is not visible on this view. When assessing for trauma, follow the iliopectineal (iliopubic) and ilioischial lines to find subtle anterior or posterior column fractures, respectively. Epub ahead of print, 2013 Harnroongroj T et al: Posterior acetabular arc angle of the femoral head assesses instability of posterior fracture-dislocation of the hip. Natural History & Prognosis · Reduction in < 6 hr critical to reduce risk of femoral head osteonecrosis · Uncomplicated cases: Closed reduction successful in 7693% · Poorer prognosis when fractures present · Recurrent dislocations if ligamentous injury, labral tear · Complications Osteoarthritis Femoral head osteonecrosis Chronic instability ­ Prevalence not known 496 3. Though the hip was quickly reduced and fixation of the posterior wall fracture (with long reconstruction plate and short 1/3 tubular plate) is anatomic, underlying cartilage injury can lead to osteoarthritis rapidly. There is also a small fracture of the posterior acetabulum, making this a Pipkin 4 fracture. Demographics · Age Traumatic fracture: Adolescents and young adults Insufficiency fracture: Elderly, osteoporotic · Gender M>F 4. Natural History & Prognosis · Untreated have risk of premature osteoarthritis · Higher risk with Pipkin 2 and above · Risk of osteonecrosis related to hip dislocation, displaced femoral neck component Treatment · Traumatic and fatigue femoral head fractures 500 radiologyebook. The fracture is located below the level of the fovea and therefore represents a Pipkin 1 fracture. Osteonecrosis, by contrast, has a serpentine contour, and is usually centered more superiorly in the femoral head. This fracture pattern shows complete lateral displacement of the femoral shaft relative to the femoral head and varus deformity. Fracture is in varus alignment, and there is mild lateral displacement as well as overriding of the medial cortex of the femoral neck. Cortical disruption is visible medially, and there is change in orientation of trabeculae across the fracture site. A fracture oriented from superolateral to inferomedial, as seen here, is an uncommon pattern. This type of minimally impacted fracture is easily mistaken for a ring osteophyte. Fracture was not diagnosed on these radiographs, and patient presented 3 days later with a displaced fracture. Osteoid osteoma should be in the differential diagnosis, together with stress fracture. Derotational screw prevents the basicervical fracture from rotating around the dynamic hip screw. Fracture has tilted into varus compared to immediate postop image, and lucencies surrounding hardware indicate motion. Nonunion is a clinical diagnosis usually made at 6-12 months, but this appearance can be described as impending nonunion. Osteonecrosis is evident by the focal depression of the superior femoral head cortex. The Garden classification system is not intended for young patients; descriptive terms preferred. Osteoporotic patients may suffer a nondisplaced fragility fracture like this, though it is often more vertically oriented, and may be incomplete. The comminution of the lesser trochanter promotes medial impaction and varus deformity. Fracture has fallen into varus alignment, the characteristic deformity of this type of fracture. The ischial tuberosity is a useful landmark to identify the posterior pelvis when femoral anatomy is distorted by fracture. On this single image, the fracture might be of the femoral neck or intertrochanteric region. Alerting the surgeon to the nondisplaced intertrochanteric fracture altered the surgical fixation of the femoral shaft fracture. The fracture extension above the lesser trochanter differentiates it from a subtrochanteric fracture. The cross-table lateral view is often suboptimal, but it is used because it does not require moving the injured hip and potentially worsening displacement. Trabeculae are sparse because of senile osteoporosis, but density in bone marrow is that of fat, except for hematoma along the fracture lines. Patients with injured hips tend to hold them in external rotation, and that should heighten scrutiny for fracture. Loss of anteversion due to apex anterior angulation of the fracture site is a useful sign of subtle fractures. The rounded configuration of marrow replacement by tumor can usually be distinguished from the bandlike edema surrounding nonpathologic fracture. The concomitant femoral neck fracture is very difficult to see and was missed on radiographs. The fracture is inferior to the lesser trochanter, distinguishing it from the intertrochanteric fracture. The deep femoral artery and a perforator artery are intact; compare to the normal right superficial femoral artery. It is easy to see how the anterior spike of bone can damage the quadriceps muscle. However, there is focal thickening (wart) of the lateral femoral cortex, typical for an early femoral shaft bisphosphonate fracture. The cortical location and bilateral symmetry are useful clues to bisphosphonate fracture. This fracture pattern is sometimes accompanied by a Hoffa fragment, which is best depicted on sagittal images. Recognition of a Hoffa fragment is important because its presence alters surgical management. Posterior column structures are in blue, and anterior column structures are in red. The triangular projection from the isolated iliac fracture will form the spur sign seen on the obturator Judet view. As is commonly the case in posterior column fractures, the fracture exits thought the greater sciatic foramen. In addition, there is a fracture of the obturator ring, the ilioischial line is disrupted, and sciatic buttress is separated from acetabular roof, indicating both-column fracture. The fracture extending from the acetabular roof into the iliac wing is consistent with anterior column fracture, but the iliopectineal line is visibly disrupted only at the pubic fracture. On serial axial images, the fracture could be followed into the iliac wing superiorly and anteriorly as well as inferiorly into the pubic bone (not shown). Anterior column and posterior hemitransverse is a rare type of acetabular fracture. Sciatic buttress is intact, indicating that structural continuity from sacroiliac joint to hip is maintained. This view shows the characteristic comminution of the medial acetabular wall and medial displacement of the femoral head. Unlike both-column fracture, sciatic buttress is intact, and there is no extension into iliac wing. Although the fracture extends adjacent to the acetabular margin, there is no articular involvement.

Elevated skeletal muscle glucose transporter levels in exercise-trained middle-aged men antibiotics for sinus infections best ones discount linezolid 600 mg with amex. Invited review: contractile activity-induced mitochondrial biogenesis in skeletal muscle bacteria chlamydia trachomatis discount 600 mg linezolid visa. An autoregulatory loop controls peroxisome proliferator-activated receptor coactivator 1 expression in muscle antibiotics for recurrent sinus infection purchase generic linezolid on-line. Metabolic syndrome and cardiovascular disease in patients with human immunodeficiency virus antimicrobial resistance mechanisms 600 mg linezolid purchase otc. Lifestyle intervention in overweight individuals with a family history of diabetes antibiotic 10 days linezolid 600 mg buy with amex. Prediction of glucose response to weight loss in patients with non-insulin-dependent diabetes mellitus. Endocrine mechanisms mediating remission of diabetes after gastric bypass surgery. 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The cyst compresses the distal suprascapular nerve bacteria mitochondria buy discount linezolid online, causing denervation edema of the infraspinatus muscle human antibiotics for dogs discount linezolid generic. There is compression of the suprascapular nerve in the suprascapular notch (and spinoglenoid notch) with denervation edema of both the supraspinatus and infraspinatus muscles virus vs bacteria discount linezolid express. The paralabral cyst had not recurred antibiotics for uti infection linezolid 600 mg order without prescription, so this was presumed to be due to permanent nerve damage antibiotics for dogs abscess linezolid 600 mg lowest price. The cyst causes a pressure erosion of the posterior scapular neck with mild marrow edema, corresponding to the erosion seen on the radiograph. The quadrilateral space is bounded by the humerus, teres minor, teres major, and long head of the triceps muscles. The syndrome is usually from fibrous bands within the space compressing the axillary nerve. This finding is common in older patients with rotator cuff tears and is presumably due to chronic irritation of the teres minor nerve from humeral head decentering. Quadrilateral space paralabral cysts are less common than spinoglenoid notch cysts, but they can cause teres minor denervation edema from compression of the axillary nerve. The patient did not have a suprascapular paralabral cyst nor the acute onset of pain characteristic of ParsonageTurner syndrome. The patient had breast cancer and was found to have supraclavicular metastases encasing the brachial plexus. This likely is more due to a lack of familiarity with the relevant anatomy and pathology encountered in the elbow region than to any related complexity of diagnosis. The elbow is, in fact, a fairly straightforward articulation to master for the practicing radiologist. This section explores the commonly, and some of the not so commonly, encountered pathologic conditions for which advanced imaging lends advantage. Pathologic Considerations Injury to the elbow may be due to a discrete traumatic episode, which more often results in osseous injury or ligament tear, or to chronic repetitive injury, which may result in a variety of pathology involving bones, ligaments, or tendons. Injury patterns also vary depending on the age of the patient; when relevant, issues specific to the pediatric patient have been identified. Fractures of the distal humerus, proximal ulna, and proximal radius are usually the result of a discrete episode of trauma, and may be associated with significant soft tissue injury around the elbow joint, as well as other traumatic lesions elsewhere in the body. Grading systems for these injuries tend to focus on criteria that help determine the method of treatment and are described in the appropriate chapters. Ligamentous injury can be due to either acute trauma or repetitive injury and may manifest as chronic pain or with sudden onset of symptoms during activity. Ulnar collateral ligament tear is the most common and significant elbow ligament injury, and often affects overhead throwing athletes. One type of repetitive injury in particular has been paid special attention: Athletes who perform overhead throwing motions are prone to develop a particular pattern of injury due to valgus stress placed on the elbow during these activities, resulting in impaction injuries in the lateral aspect of the elbow and distraction injuries in the medial aspect. This pattern is important to recognize; when caught early in its course, appropriate treatment can make the difference between return to play and a career-ending injury. Terminology and Conventions In proper anatomic planes, the radial aspect of the elbow is labeled lateral and the ulnar aspect medial. The terms coronal and sagittal used in these chapters refer to the anatomic planes as defined by the inherent anatomy of the elbow as described in Imaging Considerations below, and thus will frequently be oblique planes (with reference to the machine axis) for any given patient. As in other chapters, degenerative changes within a tendon are referred to as tendinopathy and not as tendinitis or tendinosis in an effort to stay true to the appropriate etymologic meanings of these terms. Anatomic Considerations the elbow is, at its simplest, a hinge joint at the ulnohumeral articulation. There is also a rotational component at the radiocapitellar and proximal radioulnar joints to allow pronation and supination of the forearm. Capsular thickenings of the joint medially and laterally comprise the ulnar collateral ligament complex and the lateral collateral ligament complex, respectively. Tendinous insertions of the muscles of elbow flexion (biceps brachii and brachialis) and extension (triceps brachii) occur on the bones immediately adjacent to the elbow. Origins of the major flexor and extensor tendons of the wrist and fingers arise from the medial and lateral humeral epicondyles, respectively. The ulnar nerve is particularly vulnerable because of its superficial location in the cubital tunnel, but the median and radial nerves can be affected by a variety of congenital and acquired conditions as they pass through their respective courses in the elbow. In cases where a subtle radial head fracture is questioned, a dedicated radial head/capitellum view is available; this involves 90° of elbow flexion and a 45° tube angulation toward the radial head to best profile the radial head and neck. This usually involves placing the extended elbow in a volume coil (such as a clamshell-phased-array knee coil), which serves as a rigid frame in which to steady the extremity but may cause uncomfortable compression of tissues. The use of such a coil often requires that the patient be scanned with his/her arm raised over the head (the Superman position), as the coil must radiologyebook. Generous padding with cushions and pillows may mitigate some of the positional discomfort, but the technologist should warn the patient that the extremity may become painful or even numb during the imaging process as a result of the position in which it is kept. The second strategy involves letting the patient lie prone, arm at the side (with elbow extended), and using a flexible surface coil to image the elbow. While more comfortable for the patient and generally easier for the technologist, this method may provide clinically less desirable images due to limited signal:noise ratio, poor fat suppression due to inhomogeneity of the magnetic field at its periphery, surface coil artifact (brighter tissue signal near the coil with rapid drop-off toward the deep portion of the extremity), and artifact from motion of the adjacent torso (respiration and other movements). In fact, the arm-at-the-side position may not be possible to accomplish at all in some larger patients due to restrictions of the magnet bore caliber. A third option is to acquire images of the elbow in an opensided magnet so that the elbow remains in the center of the magnetic field, but the arm can be held only slightly abducted to the side. Field strength of such magnets is usually limited, and coil selection is more limited. Whichever method is employed for elbow imaging, the forearm will likely be held in some degree of pronation. Though true anatomic position implies supination of the forearm, in clinical practice, it can be unreasonable to expect patients to hold their arm in a supinated position for 20 to 30 minutes. This generally causes no diagnostic challenge, but one will notice that the radial tuberosity is rotated medially, with associated curving of the distal biceps tendon. Once appropriate positioning has been achieved and scout images acquired, it is important that true anatomic planes of imaging be produced. For coronal images, slices should parallel a line drawn on a true axial image through the widest point of the medial and lateral humeral epicondyles, respectively. Some authors have advocated the use of indirect arthrography, in which gadolinium contrast is injected intravenously, and delayed imaging of the elbow is performed after exercising the extremity to increase synovial blood flow and thus diffusion of intraarticular contrast into the joint fluid, as an alternative to direct puncture arthrography. Intravenous contrast administration is usually reserved for the assessment of inflammatory or neoplastic pathology (synovitis, soft tissue masses, or infection). Rather than take a purely prescriptive approach, it is best to state general guidelines for this purpose. At least one sequence in each anatomic plane (axial, coronal, and sagittal) should be acquired. If an isotropic volume acquisition is used and diagnostic reformatted images can be created in multiple planes, then of course the three-plane rule may not apply. It also is advisable to acquire at least one T1-weighted sequence without fat suppression as a way to properly characterize tissue signal and marrow. Proton density-weighted sequences without chemical fat suppression provide excellent anatomic detail with high signal:noise ratio, but are not particularly useful for tissue characterization. In general, one tends to develop a protocol that provides an acceptable combination of speed, variety, and reliability, and become comfortable with it. This view is accomplished by angling the tube 45° toward the radial head off a standard lateral view. The coronal plane of the elbow is defined by a line drawn through the widest parts of the humeral condyles. This fracture has an intercondylar component and separates both medial and lateral condyles from the humeral shaft. Scaglione M et al: the role of external fixation in the treatment of humeral shaft fractures: A retrospective case study review on 85 humeral fractures. Note the fragmentation and displacement of the trochlea and rotation and displacement of the capitellum. The fracture propagates in a horizontal plane across the proximal aspects of the humeral condyles. The transcondylar fracture is the most common elbow fracture in children and is often referred to as supracondylar. The intracapsular location of the fracture causes hemarthrosis, a finding that can serve as an important diagnostic clue on radiographs of a minimally displaced fracture at the time of injury. A true supracondylar fracture would be extracapsular and thus would not cause an effusion. Natural History & Prognosis · Good prognosis with appropriate fragment reduction and stabilization May not recover full range of motion for up to 1 year · Complications Failure of reduction Cubitus varus if not appropriately reduced Median nerve injury ­ May be traumatic or iatrogenic 236 3. Note the posterior displacement of the capitellum relative to the line along anterior cortex of the distal humerus. Because the fracture does not extend into the condyles, this is a true supracondylar fracture. There is subtle medial displacement of the distal fragment, a common finding in these injuries. Kurtulmu T et al: Paediatric lateral humeral condyle fractures: internal oblique radiographs alter the course of conservative treatment. Involvement of epiphyseal cartilage and articular surface cannot be seen here but should be assumed. The fracture extends into the articular surface lateral to the lateral trochlear ridge. Demographics · Age Peak incidence: 7-14 years Can occur in adults 244 radiologyebook. Note the coronal plane of the fracture, with anterior displacement of the fragment. This injury typically occurs in the setting of repetitive valgus stress, as seen in overheadthrowing athletes. Bilsel K et al: Coronal plane fractures of the distal humerus involving the capitellum and trochlea treated with open reduction internal fixation. Note the elevated periarticular fat pads indicating hemarthrosis from acute injury. This is a type 3 injury under both the conventional classification (a Broberg-Morrey fracture) and the Bryan and Morrey system. In the Bryan and Morrey classification, extension into the trochlea constitutes a type 4 lesion. Note the rotated & laterally displaced capitellar fragment maintaining alignment with the radial head. This patient was proven to have comminuted (type 3) capitellar fracture associated with elbow dislocation. This image demonstrates a well-defined chondral defect in the anterior articular surface of the capitellum. Subchondral marrow edema in the capitellum and irregular chondral defect are located in a more posterior position than is typical for a throwing injury. Posterior capitellar contusion or fracture is typical of hyperextension mechanism of injury. This is an unusual finding and usually results in significant ligamentous instability. Fracture of the anterior aspect of the radial head and in the posterior aspect of the capitellum is a typical pattern. Dislocated radial head with a large defect, dislocated ulna, and the radial head fracture fragment are seen. Elbow dislocation associated with radial head and coronoid fractures is termed the "terrible triad" because of its poor prognosis. There is a fragment in the medial aspect of the joint without an obvious donor site. The well-defined edges of the fragment and the age of the patient should be clues to a possible avulsed medial humeral epicondyle. The smoothly corticated edge of the condyle is expected; the lack of the expected epicondylar ossification center adjacent to it must be appreciated to make this diagnosis. The key to distinguishing this from an elbow dislocation is noting the preservation of normal alignment of the radiocapitellar and ulnotrochlear joints. Originally described as an anterior dislocation of the radiocapitellar joint combined with an angulated fracture of the proximal ulna (as depicted here), the term has been broadened to include any radiocapitellar dislocation with a concomitant angulated ulnar fracture. One constant feature of these injuries is that the ulnar fracture is angulated in the same direction as the radial displacement. Most of these injuries occur as a result of a fall on an outstretched hand with forced pronation of the forearm. The key features are anterior dislocation of the radiocapitellar joint and proximal ulnar shaft fracture with apex anterior angulation. Type 2 injuries comprise ~ 16% of Monteggia injuries and are characterized by posterior dislocation of the radiocapitellar joint and apex posterior angulation of the ulnar shaft fracture. These include lateral dislocation of the radiocapitellar joint and apex lateral angulation of a fracture of the ulnar shaft. These are characterized by a radial shaft fracture in addition to radiocapitellar joint dislocation and ulnar shaft fracture. Goyal T et al: Neglected Monteggia fracture dislocations in children: a systematic review. The radial head should line up with the capitellum on all projections; in this case, it does not, confirming a Monteggia injury. The radial head and neck are deformed, but alignment of the radiocapitellar joint is normal in this projection. There is a fracture of the radial neck with anterior displacement, but the radial head aligns with the capitellum.

Studies of males with an estrogen receptor mutation and men with an aromatase deficiency have established that estradiol is critical for bone acquisition infection under tongue generic linezolid 600 mg buy line. Hence antibiotic classes buy cheap linezolid 600 mg, there must be a threshold effect for estradiol in men infection epsom salt linezolid 600 mg buy on line, and this effect must be time dependent kaspersky anti-virus generic 600 mg linezolid visa. Acquired deficiencies in estrogen antibiotics to treat pneumonia purchase linezolid 600 mg overnight delivery, such as occur with anorexia nervosa or chemotherapy-induced ovarian dysfunction, result in low peak bone mass and lead to subsequent risk for osteoporosis. That time window is likely to be less than 3 years and earlier in girls than boys. Probably the best study that addressed this issue comes from a retrospective analysis of men in their 30s who underwent late onset of puberty. These data suggest that timing as well as quantity of gonadal steroids is critical for bone acquisition. In order to mineralize newly synthesized bone, calcium must become bioavailable to the skeletal matrix. In experimental studies in rodents and humans, it is clear that the several pools of available calcium are markedly enhanced during puberty. These sources include calcium efflux from the gastrointestinal tract and the calcium pool available for incorporation in the matrix. Genetic Factors That Determine Peak Bone Mass Probably the most important determinant of peak bone mass, albeit one that has lacked clear definition, is the genetic contribution. As noted earlier, low peak bone mass may be the most important pathogenic factor in the osteoporosis syndrome of later life. Further, it appears that at least 50% of peak bone mass is determined by genetic factors. Large homogeneous and heterogeneous populations are now being studied to ascertain genetic determinants of bone density in humans. Depending on the cohort, the phenotype, and the number of individuals studied, there are likely to be hundreds of genes that contribute to individual variation in bone mass. Notwithstanding, there has been a major effort to consolidate studies from around the world to increase power and detect rare variants that might provide even greater insight into genetic determinants, and importantly shed greater light on the biology of low bone mass. Twin studies examining discordant or concordant phenotypes are also helpful, as are sibling-pair studies, although the results have been disappointing. As a consequence, -catenin is stabilized, accumulates, and translocates into the nucleus where it regulates transcription of osteoblastic genes. In addition to the search for osteoporosis genes, intervention studies in adolescents have provided insight into the environmental impact on genetic determinants. First, osteoporosis therapy can reduce fracture risk by as much as 50%, but this means that some people will continue to have fractures despite treatment. Second, lifestyle and pharmacologic interventions may be long-term commitments, such that cost, compliance, and safety must be factored into therapeutic decisions. Studies suggest that with weekly or monthly oral bisphosphonate therapy, more than 40% of individuals treated will not continue therapy beyond 1 year. Calcium supplementation should be an adjunct to drug treatments for women with established osteoporosis and must be part of any prevention strategy to ameliorate bone loss. Increased calcium intake reduces the secondary hyperparathyroidism often seen with advancing age and can enhance mineralization of newly formed bone. Evidence that calcium and vitamin D together or individually reduce fracture risk in the osteoporotic individual remains somewhat controversial. Currently, an average total calcium intake of 1200 mg/day is still recommended by the National Institute of Medicine for all postmenopausal women. Certainly with intakes greater than 2000 mg/day, the risk of nephrocalcinosis increases. Vitamin D is essential for skeletal maintenance and for enhancement of calcium absorption. Insufficiency of this vitamin is a growing problem; as many as two thirds of all patients who have hip fractures are classified as vitamin D deficient. In a large population-based study with calcium and vitamin D, supplementation had no effect on nonvertebral fractures,309 although compliance and assessment of vitamin D levels were not sufficiently well documented to exclude an effect. Besides the potentially positive effects of vitamin D supplementation on the skeleton, particularly in older women, vitamin D may reduce the risk of falling, although there continues to be significant controversy over the effect size, as noted in a recent meta-analysis. However, in those patients with low bone mass and insufficient or deficient 25-hydroxyvitamin D levels. Upper levels of vitamin D are currently being reviewed to determine if there is toxicity at higher doses. Vitamin D analogues have been used in the treatment of osteoporosis since the early 1980s. Other studies have found little benefit with a narrow therapeutic window, particularly in relation to renal function and hypercalcemia. Currently vitamin D analogues are not recommended for the routine treatment of osteoporosis. PhysicalActivity Bed rest or immobility, particularly in elderly persons, can result in rapid bone loss. Moreover, the number of falls increases with age, and the number of falls that result in fractures also rises. A meta-analysis by the Cochrane Review Group demonstrated that muscle strengthening, balance retraining, home hazard assessment, withdrawal of psychotropic medications, and use of a multidisciplinary risk factor assessment program are beneficial in protecting against falls. Hip protectors have been shown to reduce the risk of hip fractures in at least one population, although compliance is generally poor. A more recent study failed to demonstrate the efficacy of these devices in older women in an assisted living facility. However, studies to date have been inconclusive with respect to understanding how changes in these lifestyles affect overall fracture risk. Notwithstanding, some promising data support the use of Tai Chi to enhance balance and reduce falls and fractures. Pharmacologic Approaches to the Treatment of Osteoporosis Abundant evidence indicates that an aggressive intervention program can be successful in reducing fracture risk and in improving quality of life among postmenopausal women with preexisting osteoporosis. Several pharmacologic options are available, and they can be classified by their mechanism of action. AntiresorptiveAgents Antiresorptives inhibit bone resorption by suppressing osteoclast activity. Slowing the remodeling cycle allows bone formation to catch up to resorption, thereby enhancing matrix mineralization and stabilizing trabecular microarchitecture. Estrogen replacement therapy was long considered the cornerstone of therapy for postmenopausal women with osteoporosis. However, there is also compelling evidence from at least two groups that osteoclasts have estrogen receptors and that estrogen blocks apoptosis of osteoclasts. Conversely, progesterone is a necessary part of hormone replacement therapy in women with a uterus because it prevents the development of endometrial hyperplasia and carcinoma. Discontinuation of estrogen results in measurable bone loss (3-5% in the first year), although controversy exists as to whether that translates into a greater fracture risk. Significant concern has been noted about the nonskeletal risks associated with long-term estrogen and estrogen in combination with progesterone. Particularly troublesome is the increased risk of breast cancer with the longterm use of estrogen and progesterone. Moreover, the availability of newer and effective antiresorptive drugs for the treatment of osteoporosis has lessened enthusiasm for primary hormonal therapy in osteoporotic women. Selective estrogen receptor modulators such as tamoxifen and raloxifene also inhibit bone resorption by the same mechanisms used by estradiol. Both these agents block the actions of estrogen on the breast but act like an estrogen agonist in bone; tamoxifen, but not raloxifene, has estrogen agonistic properties on the uterus and is associated with a greater risk of endometrial carcinoma with long-term use. Tissue selectivity with these selective estrogen receptor modulators and others being investigated is a subject of great scientific interest. Raloxifene and estradiol both bind to the same region of the estrogen receptor, but they induce different conformational changes in that receptor. Differing coactivating and corepressing proteins are recruited to these receptor-ligand complexes, and it is thought that these coactivators and corepressors ultimately determine the activity of the nuclear complexes. Because recruitment also depends on cell type, it is highly likely that significant tissue selectivity exists for these partners. Newer agents have been designed to facilitate particular complexes and rearrangements within the nucleus; they are being studied at both the preclinical and the clinical levels. The bisphosphonates are the most widely prescribed antiresorptives and are often considered firstline therapy for the treatment of severe postmenopausal osteoporosis. These drugs are carbon-substituted analogues of pyrophosphate that bind tightly to hydroxyapatite crystals. It is thought that these agents directly suppress resorption by inhibiting osteoclast attachment and enhancing programmed cell death. The drug has few gastrointestinal side effects, and vertebral fracture risk reduction is significant with this agent. Recent clinical trials have shown that these drugs can be safely administered for at least 5 years without adversely affecting bone strength. Moreover, discontinuation of alendronate after 5 years results in minimal bone loss over the ensuing 5 years without a significant increase in fracture risk. Once-weekly administration of alendronate has been shown to reduce the prevalence of druginduced esophagitis, and currently both alendronate and risedronate are marketed as once-weekly treatments. The former is given orally in a single monthly dose (150 mg) or intravenously every 3 months (3 mg). Compliance with the once-monthly regimen is higher than with the weekly dosing, although long-term data are not encouraging that this effect persists. First-dose hypersensitivity can occur with ibandronate, and because it is a nitrogen-containing bisphosphonate, it is also associated with esophageal reflux. It is administered as a single intravenous infusion over 15 minutes (5 mg) once yearly. Large randomized controlled trials have unequivocally established antifracture efficacy for hip, spine, and other nonspine fractures. Both newer bisphosphonates can cause side effects with the first dose, including joint pain, stiffness, and low-grade fevers. Intravenous zoledronate has been approved for the treatment of malignant hypercalcemia, multiple myeloma, and skeletal metastases. Other bisphosphonates are available for off-label use or are being studied for the treatment of osteoporosis. Intravenous pamidronate has been available since the mid1990s for the treatment of Paget disease and malignant hypercalcemia. Acute and delayed-type hypersensitivity reactions can occur with this drug, and its use is contraindicated in patients who are vitamin D deficient because it can precipitously drop serum calcium, a concern that also applies to use of zoledronic acid and denosumab. Prodromal symptoms of hip or thigh pain and associated cortical thickening or beaking in the shaft of the proximal femur are risk indicators of these fractures, which with minimal trauma can have devastating consequences in terms of quality of life and mobility. Some guidelines recommend prophylactic rod placement to prevent fractures in high-risk individuals in the ipsilateral and contralateral femora. At the present time, the prevalence of this fracture is not well established, although meta-analyses suggest that there is a causal association with bisphosphonate use. However, in osteoporosis patients, the prevalence is estimated to be less than 1 in 100,000 patients exposed to oral or intravenous bisphosphonates who are otherwise healthy. Patients with dental procedures that invade bone, such as tooth implantation and tooth extraction, are at increased risk. Concomitant treatment with glucocorticoids likely enhances the risk, and infection often accompanies the necrosis. Osteoclasts have calcitonin receptors, and calcitonin can rapidly inhibit bone resorption. Salmon calcitonin is more potent than human and is the preferred treatment choice. Nasal and subcutaneous calcitonin are both approved for the treatment of postmenopausal osteoporosis. However, the evidence favoring a strong effect from this hormone on either bone loss or fracture efficacy is lacking. In at least one placebo-controlled study, nasal calcitonin reduced the pain associated with new spine fractures. Side effects are uncommon with intranasal calcitonin and include nasal stuffiness and flushing. Strontium ranelate is orally administered and stimulates calcium uptake in bone while it inhibits bone resorption. It is thought to have some anabolic activity, although the precise mechanism of action in the skeleton, where it is incorporated, is not known. Unlike the bisphosphonates, denosumab does not persist in the skeleton and hence needs to be administered once every 6 months to maintain its efficacy. In fact, discontinuation of denosumab can lead to a rebound increase in bone resorption but no increase in fractures. Importantly, fractures of spine were reduced by 70%, and nonvertebral fractures, including hip fractures, were also significantly reduced. Surprisingly, long-term studies (in 2015, out to 8 years in the extension trial) have failed to show significant adverse events for this agent, though atypical femoral fractures occur. Cathepsin K is a proteinase that is secreted by osteoclasts and results in bone degradation, primarily of type I collagen. Odanacatib, one cathepsin K inhibitor, has been tested in postmenopausal women with osteoporosis and shown to be an effective suppressor of bone resorption. Interestingly, women treated with odanacatib have suppressed bone resorption but no change or a slight increase in bone formation. This may be due to the finding that this agent blocks breakdown of collagen but does not kill osteoclasts; hence, signals from osteoclasts to osteoblasts may be maintained, thereby preserving bone formation. If correct, this is one of the first drugs for osteoporosis that can uncouple remodeling in a positive manner. A correlative study examining the effect of odanacatib in the setting of bony metastases from breast cancer demonstrated that it suppressed a biochemical marker of bone resorption, N-terminal telopeptide, in much the way that zoledronic acid did. These so-called anabolic agents stimulate bone formation more than bone resorption.

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