WO WEEK 4

1. Understand bone remodeling process

1.

2. Describe bone density changes across the life cycles

3. Line out metabolic bone diseases

Osteomalacia

Osteomalacia refers to a softening of your bones, often caused by a vitamin D deficiency. In children, this condition is called rickets. Soft bones are more likely to bow and fracture than are harder, healthy bones. Osteomalacia is not the same as osteoporosis, another bone disorder that can also lead to bone fractures. Osteomalacia results from a defect in the bone-building process, while osteoporosis develops due to a weakening of previously constructed bone. Muscle weakness and achy bone pain are the major sign and symptom of osteomalacia. Treatment for osteomalacia involves replenishing low levels of vitamin D and calcium, and treating any underlying disorders that may be causing the deficiencies.In the early stages, you may have no osteomalacia symptoms, although signs of osteomalacia may be apparent on X-ray pictures or other diagnostic tests. As osteomalacia worsens, you may experience bone pain and muscle weakness.

Bone painThe dull, aching pain associated with osteomalacia most commonly affects the:

Lower spinePelvisHipsLegsRibs

Muscle weaknessOsteomalacia may result in:

Decreased muscle toneWeakness in your arms and legsReduced ability to get around

A waddling gait

Your body uses calcium and phosphate to build strong bones. Osteomalacia may occur if you don't get enough of these minerals in your diet or if your body doesn't absorb them properly. These problems may be caused by:

Vitamin D deficiency. Sunlight produces vitamin D in your skin. Your body needs vitamin D to process calcium. Osteomalacia can develop in people who spend little time in sunlight, wear very strong sunscreen, remain covered while outside, or live in areas where sunlight hours are short or the air is smoggy.

Certain surgeries. Removing part or all of your stomach (gastrectomy) can cause osteomalacia because your stomach breaks down foods to release vitamin D and other minerals, which are absorbed in your intestines. Surgery to remove or bypass your small intestine also can lead to osteomalacia.

Celiac disease. In this autoimmune disorder, the lining of your small intestine is damaged by consuming foods containing gluten, a protein found in wheat, barley and rye. A damaged intestinal lining doesn't absorb nutrients, such as vitamin D, as well as a healthy one does.

Kidney or liver disorders. Problems with your kidneys or liver can interfere with your ability to process vitamin D.

Drugs. Some drugs used to treat seizures, including phenytoin (Dilantin, Phenytek) and phenobarbital, can cause osteomalacia.

The risk of developing osteomalacia is highest in people who have both inadequate dietary intake of vitamin D and little exposure to sunlight, such as older adults and those who are housebound or hospitalized.

In order to pinpoint the underlying cause of osteomalacia and to rule out other bone disorders, such as osteoporosis, you may undergo one or more of the following tests:

Blood and urine tests. In cases of osteomalacia caused by vitamin D deficiency or by phosphorus loss, abnormal levels of vitamin D and the minerals calcium and phosphorus are often detected.

X-ray. Slight cracks in your bones that are visible on X-rays, referred to as Looser transformation zones, are a characteristic feature of people with osteomalacia.

Bone biopsy. During a bone biopsy, your doctor inserts a slender needle through your skin and into your bone to withdraw a small sample for viewing under a microscope. Although a bone biopsy is very accurate in detecting osteomalacia, it's not often needed to make the diagnosis.

When osteomalacia arises from a dietary or sunlight deficiency, replenishing low levels of vitamin D in your body usually cures the condition. Generally, people with osteomalacia take vitamin D supplements by mouth for a period of several weeks to several months. Less commonly, vitamin D is given as an injection or through a vein in your arm.

If your blood levels of calcium or phosphorus are low, you may take supplements of those minerals as well. In addition, treating any condition affecting vitamin D metabolism, such as kidney failure or primary biliary cirrhosis, often helps improve the signs and symptoms of osteomalacia.

Ricket’s

Rickets is a disease of growing bone that is unique to children and adolescents. It is caused by a failure of osteoid to calcify in a growing person. Failure of osteoid to calcify in adults is called osteomalacia.

Rickets may lead to skeletal deformity and short stature. In females, pelvic distortion from rickets may cause problems with childbirth later in life. Severe rickets has been associated with respiratory failure in children.

Findings in rickets are illustrated in the image below.

Radiograph in a 4-year-old girl with rickets depicts bowing of the legs caused by loading.

Cholecalciferol (ie, vitamin D-3) is formed in the skin from 5-dihydrotachysterol. This steroid undergoes hydroxylation in 2 steps. The first hydroxylation occurs at position 25 in the liver, producing calcidiol (25-hydroxycholecalciferol), which circulates in the plasma as the most abundant of the vitamin D metabolites and is thought to be a good indicator of overall vitamin D status.

The second hydroxylation step occurs in the kidney at the 1 position, where it undergoes hydroxylation to the active metabolite calcitriol (1,25-dihydroxycholecalciferol). This cholecalciferol, which circulates in the bloodstream in minute amounts, is not technically a vitamin but a hormone.

Calcitriol acts at 3 known sites to tightly regulate calcium metabolism: (1) it promotes absorption of calcium and phosphorus from the intestine; (2) it increases reabsorption of phosphate in the kidney; and, (3) it acts on bone to release calcium and phosphate. Calcitriol may also directly facilitate calcification. These actions result in an increase in the concentrations of calcium and phosphorus in extracellular fluid.

This increase of calcium and phosphorus in extracellular fluid, in turn, leads to the calcification of osteoid, primarily at the metaphyseal growing ends of bones but also throughout all osteoid in the skeleton. Parathyroid hormone facilitates the 1-hydroxylation step in vitamin D metabolism.

In the vitamin D deficiency state, hypocalcemia develops, which stimulates excess secretion of parathyroid hormone. In turn, renal phosphorus loss is enhanced, further reducing deposition of calcium in the bone.

Excess parathyroid hormone also produces changes in the bone similar to those occurring in hyperparathyroidism. Early in the course of rickets, the calcium concentration in the serum decreases. After the parathyroid response, the calcium concentration usually returns to the reference range, though phosphorus levels remain low. Alkaline phosphatase, which is

produced by overactive osteoblast cells, leaks into the extracellular fluids, so that its concentration rises to anywhere from moderate elevation to very high levels.

Intestinal malabsorption of fat and diseases of the liver or kidney may produce the clinical and secondary biochemical picture of nutritional rickets. Anticonvulsant drugs (eg, phenobarbital, phenytoin) accelerate metabolism of calcidiol, which may lead to insufficiency and rickets, particularly in children who who have darkly pigmented skin and those who are kept primarily indoors (eg, children who are institutionalized).

Calcium and vitamin D intakes are low in infants who are fed vegan diets, particularly in those who are lactovegans, and monitoring of their vitamin D status is essential.[1]

Studies have noted that disorders of increased fibroblast growth factor 23 (FGF-23) function are associated with rickets.

Signs and symptoms of rickets may include:

Delayed growth

Pain in the spine, pelvis and legs

Muscle weakness

Because rickets softens the growth plates at the ends of a child's bones, it can cause skeletal deformities such as:

Bowed legs

Abnormally curved spine

Thickened wrists and ankles

Breastbone projection

Nutritional rickets

Nutritional rickets, also called osteomalacia, is a condition caused by vitamin D deficiency.

Vitamin D is a fat-soluble vitamin that is essential for the normal formation of bones and

teeth and necessary for the appropriate absorption of calcium and phosphorus from the

bowels. It occurs naturally in very small quantities in some foods such as saltwater fish

(salmon, sardines, herring, and fish-liver oils). Vitamin D is also naturally synthesized by

skin cells in response to sunlight exposure. It is necessary for the appropriate absorption of

calcium from the gut.

Infants and children most at risk for developing nutritional rickets include dark-skinned

infants, exclusively breastfed infants, and infants who are born to mothers who are vitamin D

deficient. In addition, older children who are kept out of direct sunlight or who have vegan

diets may also be at risk.

Hypophosphatemic rickets

Hypophosphatemic rickets is caused by low levels of phosphate. The bones become painfully

soft and pliable. This is caused by a genetic dominant X-linked defect in the ability for the

kidneys to control the amount of phosphate excreted in the urine. The individual affected is

able to absorb phosphate and calcium, but the phosphate is lost in the urine. This is not

caused by a vitamin D deficiency. Patients with hypophosphatemic rickets typically have

obvious symptoms by 1 year of age. Treatment is generally through nutritional supplements

of phosphate and calcitriol (the activated form of vitamin D).

Renal (kidney) rickets

Similar to hypophosphatemic rickets, renal rickets is caused by a number of kidney disorders. Individuals suffering from kidney disease often have decreased ability to regulate the amounts of electrolytes lost in the urine. This includes calcium and phosphate, and therefore the affected individuals develop symptoms almost identical to severe nutritional rickets. Treatment of the underlying kidney problem and nutritional supplementation are recommended for these patients.

Pathophysiology

Treatment for rickets may be administered gradually over several months or in a single-day dose of 15,000 mcg (600,000 U) of vitamin D.[5] If the gradual method is chosen, 125-250 mcg (5000-10,000 U) is given daily for 2-3 months until healing is well established and the alkaline phosphatase concentration is approaching the reference range. Because this method requires daily treatment, success depends on compliance.

If the vitamin D dose is administered in a single day, it is usually divided into 4 or 6 oral doses. An intramuscular injection is also available. Vitamin D (cholecalciferol) is well stored in the body and is gradually released over many weeks. Because both calcitriol and calcidiol

have short half-lives, these agents are unsuitable for treatment, and they bypass the natural physiologic controls of vitamin D synthesis.

Risk factors

Age. Children 6 to 24 months old are most at risk of rickets because their skeletons are growing so rapidly.

Dark skin. Dark skin doesn't react as strongly to sunshine as does lighter colored skin, so it produces less vitamin D.

Northern latitudes. Children who live in geographical locations where there is less sunshine are at higher risk of rickets.

Premature birth. Babies born before their due dates are more likely to develop rickets.

Anti-seizure medications. Certain types of anti-seizure medications appear to interfere with the body's ability to use vitamin D.

Exclusively breast-fed. Breast milk doesn't contain enough vitamin D to prevent rickets. The American Academy of Pediatrics recommends vitamin D drops for breast-fed babies.

Rickets is initially diagnosed clinically with a complete medical and nutritional history and

with a complete physical exam by a health professional. If rickets is suspected in a child and

the child has no acute symptoms such as seizures or tetany, X-rays of long bones (radius,

ulna, and femur) and ribs are obtained.

Vitamin D levels, alkaline phosphatase, parathyroid hormone (hormone involved in calcium

and phosphate control), and electrolytes, including indirect measurements of kidney function

(BUN and creatinine), should be evaluated if the X-rays show any of the following

characteristics that are consistent with rickets:

Widening or abnormally shaped metaphysis (most actively growing part of the bone below

the growth plate)

Obvious bowing of the femurs

Osteopenia (bones which are not as dense, a sign of decreased mineralization)

Rib flaring (rachitic rosary)

Multiple fractures at different healing stages

Different causes of rickets will reveal different findings on laboratory tests. For the scope of this article, we will focus on vitamin D deficiency. In these cases, the active form of vitamin D will be decreased, parathyroid hormone will be increased, and calcium and phosphate will be decreased.

The treatment for rickets depends upon the cause as mentioned above in the discussion of hypophosphatemic rickets and renal rickets. In cases of nutritional rickets and vitamin D deficiency, treatment is simple. The first step is to prevent the complications of calcium and phosphate deficiency by correcting any abnormal levels with supplemental calcium or phosphate as well as the activated vitamin D (calcitriol). Once the diagnosis of rickets is confirmed, initiation of vitamin D supplementation is recommended, as well as a diet rich in calcium. This is especially important for children on vegan diets. The treatment for some of the bony abnormalities depends on the severity of the cases and may require referral to an orthopedic provider for evaluation.

Treatment for rickets is with cholecalciferol, which may be gradually administered over several months or in a single-day dose.[5] The single-day therapy avoids problems with compliance and may be helpful in differentiating nutritional rickets from familial hypophosphatemia rickets (FHR). In nutritional rickets, the phosphorous level rises in 96 hours and radiographic healing is visible in 6-7 days. Neither happens with FHR.

Vitamin D is well stored in the body and is gradually released over many weeks. Because both calcitriol and calcidiol have short half-lives, they are unsuitable; they would bypass the natural physiologic controls of vitamin D synthesis.

Paget

Background

Paget disease is a localized disorder of bone remodeling that typically begins with excessive bone resorption followed by an increase in bone formation. This osteoclastic overactivity followed by compensatory osteoblastic activity leads to a structurally disorganized mosaic of bone (woven bone), which is mechanically weaker, larger, less compact, more vascular, and more susceptible to fracture than normal adult lamellar bone.

Approximately 70-90% of persons with Paget disease are asymptomatic; however, a minority of affected individuals experience various symptoms, including the following:

Bone pain (the most common symptom)

Secondary osteoarthritis (when Paget disease occurs around a joint)

Bony deformity (most commonly bowing of an extremity)

Excessive warmth (due to hypervascularity)

Neurologic complications (caused by the compression of neural tissues)

Paget disease may involve a single bone but is more frequently multifocal. It has a predilection for the axial skeleton (ie, spine, pelvis, femur, sacrum, and skull, in descending order of frequency), but any bone may be affected. After onset, Paget disease does not spread from bone to bone, but it may become progressively worse at preexisting sites.

Sarcomatous degeneration of pagetic bone is an uncommon but often deadly complication. Pagetic sarcoma is malignant, and the course usually is rapid and fatal

Although the etiology of Paget disease is unknown, both genetic and environmental contributors have been suggested. Ethnic and geographic clustering of Paget disease is well described. Paget disease is common in Europe (particularly Lancashire, England), North America, Australia, and New Zealand. It is rare in Asia and Africa. In the United States, most, although not all, individuals with Paget disease are white. (See Epidemiology.)

A familial link for Paget disease was first reported by Pick in 1883, who described a father-daughter pair with Paget disease. This was followed shortly thereafter with a sibling case of Paget disease described by Lunn in 1885. Approximately 40% of persons with Paget disease report a family history of the disease, although the true prevalence of the disease is likely higher.

Some studies suggest a genetic linkage for Paget disease located on chromosome arm 18q. This has not been demonstrated in most families with Paget disease, however, which suggests genetic heterogeneity.

An environmental trigger for Paget disease has long been considered but never proven. Bone biopsies in patients with Paget disease have demonstrated antigens from several different Paramyxoviridae viruses, including measles virus and respiratory syncytial virus, located within osteoclasts. However, the putative antigen or antigens remain unknown.

Measurement of serum alkaline phosphatase—in some cases, bone-specific alkaline phosphatase (BSAP)—along with several urinary markers, can be useful in the diagnosis of Paget disease. Plain radiographs and bone scanning should be performed upon initial diagnosis. (See Workup.) Medical therapy is principally with bisphosphonates; surgical therapy may be indicated. (See Treatment.)

Pathophysiology

Three phases of Paget disease have been described: lytic, mixed lytic and blastic, and sclerotic. In an individual patient, different skeletal lesions may progress at different rates. Thus, at any one time, multiple stages of the disease may be demonstrated in different skeletal regions.

Paget disease begins with the lytic phase, in which normal bone is resorbed by osteoclasts that are more numerous, are larger, and have many more nuclei (up to 100) than normal osteoclasts (5-10 nuclei). Bone turnover rates increase to as much as 20 times normal.

The second phase, the mixed phase, is characterized by rapid increases in bone formation from numerous osteoblasts. Although increased in number, the osteoblasts remain morphologically normal. The newly made bone is abnormal, however, with collagen fibers deposited in a haphazard fashion rather than linearly, as with normal bone formation. As the osteoclastic and osteoblastic activities of bone destruction and formation repeat, a high degree of bone turnover occurs.

In the final phase of Paget disease, the sclerotic phase, bone formation dominates and the bone that is formed has a disorganized pattern (woven bone) and is weaker than normal adult bone. This woven bone pattern allows the bone marrow to be infiltrated by excessive fibrous connective tissue and blood vessels, leading to a hypervascular bone state.

After a variable amount of time, osteoclastic activity may decrease, but abnormal bone formation continues. Some pockets of normal-appearing lamellar bone may replace immature woven bone. Eventually, osteoblastic activity also declines, and the condition becomes quiescent. This is the sclerotic, or burned-out, phase. Continued bone resorption and formation are minimal or absent.

Paget disease can affect every bone in the skeleton, but it has an affinity for the axial skeleton, long bones, and the skull. The skeletal sites primarily affected include the pelvis, lumbar spine, femur, thoracic spine, sacrum, skull, tibia, and humerus. The hands and feet are very rarely involved.

Complications of Paget disease depend on the site affected and the activity of the disease. When Paget disease occurs around a joint, secondary osteoarthritis may ensue. Skull involvement may lead to the following:

Deafness

Vertigo

Tinnitus

Dental malocclusion

Basilar invagination

Cranial nerve disorders

Frequently, erythema is present over the affected bone area, which is due to the increased hypervascularity. In patients with Paget disease who have extensive bony involvement, this increased bone vascularity may cause high-output cardiac failure and an increased likelihood of bleeding complications following surgery.

Vertebral involvement of Paget disease may be associated with serious complications, including nerve root compressions and cauda equina syndrome. Fractures, which are the most common complication of Paget disease, may occur and may have potentially devastating consequences. Rarely, pagetic bone may undergo a sarcomatous transformation.

Standard serum chemistry values, including serum calcium, phosphorus, and parathyroid hormone levels, are normal in persons with Paget disease. However, hypercalcemia may complicate the course of Paget disease, most frequently in the setting of immobilization. Elevated levels of uric acid and an increased prevalence of gout have been reported in patients with Paget disease.

levels of bone turnover markers (including markers of bone formation and resorption) are elevated in patients with active Paget disease and may be used to monitor the course of disease. The degree of elevation of these biomarkers helps identify the extent and severity of bone turnover.

Markers of bone turnover that are useful to monitor in persons with Paget disease include the following:

Bone-specific alkaline phosphatase (marker of bone formation)

Deoxypyridinoline (marker of bone resorption)

N -Telopeptide of type I collagen (marker of bone resorption)

Alpha-alpha type I C -telopeptide fragments

Alpha-alpha type I C-telopeptide fragments are sensitive markers of bone resorption for assessing disease activity and monitoring treatment efficacy in persons with Paget disease.[2] Serum osteocalcin, a marker of bone formation, is not a useful parameter to assess in persons with Paget disease. Upon successful treatment of Paget disease, the level of these bone markers is expected to decrease.

The juvenile form of Paget disease differs greatly from the adult version. Juvenile Paget disease is characterized by widespread skeletal involvement and has distinctly different histologic and radiologic features.

Etiology

The cause of Paget disease is unknown. Both genetic and environmental factors have been implicated.

Genetic predisposition

The geographic distribution of the disease may be explained by genetic transmission and dissemination by population migration. Studies have found a positive family history in 12.3% of 788 patients in the United States, 13.8% of 407 patients in Great Britain, and 22.8% of 658 patients in Australia. In the former 2 studies, a 7- to 10-fold increase in the incidence of Paget disease was observed in relatives of patients diagnosed with the condition, compared with control groups.

In one study, 15-40% of affected patients had a first-degree relative with Paget disease. Numerous other studies have described families exhibiting autosomal dominant inheritance.

Studies of potential genetic markers for Paget disease have found an association between human leukocyte antigen–A (HLA-A), HLA-B, and HLA-C (class I) and clinical evidence of disease. Two studies reported an increased frequency of DQW1 and DR2 antigens (class II HLA). The studies on HLA have not been conclusive, however; variation among families tested suggests that genetic heterogeneity is likely.[3]

Subsequent genome linkage studies identified several loci associated with Paget disease. Mutations in the sequestosome SQSTM1/p62 gene were identified in 30% of familial Paget cases. The SQSTM1/p62 protein is a selective activator of NFB (nuclear factor kappa-B) transcription factor, which is involved in osteoclast differentiation and activation in response to the cytokines interleukin-1 (IL-1) and RANKL (receptor activator of nuclear factor kappa-B ligand). How germline DNA mutations can cause bone disease that is focal in nature remains unclear.

Alterations in cytokine expression have been found in persons with Paget disease[4] : elevated interleukin-6 (IL-6) levels are found in bone marrow plasma and peripheral blood in patients

with Paget disease but not in healthy controls. One hypothesis is that some unidentified viral infection up-regulates IL-6 and the IL-6 receptor genes; however, this has not been shown conclusively.[5, 6]

Osteoclast precursors in patients with Paget disease also appear to be hyperresponsive to vitamin D (specifically, 1,25(OH)2 D3, the active form of vitamin D3

[7] ) and calcitonin and have up-regulation of the c-fos proto-oncogene[8] and BC12,the antiapoptosis gene. Treatment efficacy of bisphosphonates in Paget disease may be due to suppression of RANKL-induced bone resorption, with decreases in RANKL and increased osteoprotegerin production.

Macrophage-colony stimulating factor (M-CSF) may play a role in Paget disease. M-CSF is a growth factor produced by many cells, including osteoblasts and marrow fibroblasts. Significantly high levels of M-CSF have been found in patients with untreated Paget disease; however, its exact role remains to be determined.

Environmental factors

Environmental factors also may contribute to the pathogenesis of Paget disease. Supporting observations include the variable penetrance of Paget disease within families with a genetic predisposition; the fact that the disease remains highly localized to a particular bone or bones rather than affecting the entire skeleton; and data that reveal a declining incidence and severity of the disease over the past 20-25 years.

Viral infection

The leading hypothesis for an infectious etiology in Paget disease is the slow virus theory. According to this hypothesis, bone marrow cells (the progenitors of osteoclasts) are infected by a virus, causing an abnormal increase in osteoclast formation. Clinical expression of these viral infections may take years, which may account for the advanced age of most people diagnosed with Paget disease. Familial and geographic clustering also may support the theory of a viral process.

Suspected viruses are paramyxoviruses, such as measles or canine distemper viruses. Respiratory syncytial virus also is suspected; however, no virus has been cultured from pagetic tissue, and extracted ribonucleic acid (RNA) has not confirmed a viral presence.

Some studies have found viral inclusion particles in pagetic osteoclasts.[9] Measles virus messenger RNA sequences have been found in osteoclasts and other mononuclear cells of pagetic bones. Canine distemper virus nucleocapsid antigens have also been found in osteoclasts from patients with Paget disease. However, the presence of these paramyxovirus-like nuclear inclusions does not prove that these are responsible for the development of pagetic lesions; rather, these inclusions may be markers of the disease itself.

Other suggested etiologies

The possibility of an inflammatory cause of Paget disease is supported by evidence of clinical improvement after treatment with anti-inflammatory medications. Elevated parathyroid hormone in Paget disease also has been observed, but no firm evidence links the 2 disorders, and one case of Paget disease was diagnosed in a patient with idiopathic hypoparathyroidism. An osteogenic mechanism also has been proposed. Autoimmune, connective tissue, and vascular disorders are proposed as other possible etiologies.

Alkaline Phosphatase

Because of increased osteoblastic activity and bone formation, bone-specific alkaline phosphatase (BSAP) levels are elevated. Measuring total alkaline phosphatase levels may be useful in patients with normal liver function. However, BSAP is more specific than total alkaline phosphatase for Paget disease.

A strong relationship exists between the extent of disease activity measured by scintigraphy and the degree of the elevation of alkaline phosphatase in persons with untreated Paget disease.

In patients with monostotic disease or local disease, the total alkaline phosphatase level may be normal. Consequently, a normal alkaline phosphatase level does not exclude the disorder. In this scenario, a BSAP level should be ordered. In patients with abnormal liver function or other causes of elevated alkaline phosphatase activity not due to bone, BSAP is a reasonable means of assessing Paget disease activity.

BSAP had the highest diagnostic sensitivity (84%) in a comparative study of different markers of bone turnover in patients with Paget disease. The next most sensitive marker was total alkaline phosphatase, which had a sensitivity of 74%.[19]

Urinary Markers

Urinary hydroxyproline levels are elevated in Paget disease, as a reflection of increased osteoclastic activity and bone resorption. Hydroxyproline is a product of collagen breakdown. Approximately 20-30% of total hydroxyproline levels are from bone resorption.

Measurement of total urinary hydroxyproline previously was the criterion standard as a marker for bone resorption, hydroxyproline levels having been demonstrated to correlate with the extent and activity of disease. However, the hydroxyproline assay is difficult to perform and is not widely available.

Dietary sources of collagen may increase hydroxyproline excretion in 24-hour urine collections; therefore, an overnight fast often is necessary before testing. Patients with skin disease also may have elevated hydroxyproline levels, since the skin is a major site of collagen synthesis.

Measurement of the urinary excretion of bone-specific pyridinium collagen cross-links has been found to be a sensitive and specific index of bone resorption. Additionally, levels of excreted bone-specific pyridinium collagen cross-links may be better indicators of bone resorption and response to treatment than the hydroxyproline assay. The urinary pyridinoline collagen cross-link assay may replace assessment of hydroxyproline levels as the test of choice.

Urinary N -telopeptide (NTx) and alpha-C telopeptide (CTx) have emerged as sensitive biochemical markers for bone resorption. An abnormally high alpha-CTx/beta-CTx ratio is present in patients with active Paget disease. This ratio returns to the reference range following treatment with bisphosphonates.[20]

Radiographs

The radiographic appearance of pagetic bone reflects the underlying process. Lytic lesions may be the only finding early in the disease. As the disease progresses, radiographs may demonstrate both osteolysis and excessive bone formation. (See the images below.)

Radiograph showing a 44-year-old African American man with characteristic changes of Paget disease in the left hemipelvis. Radiograph showing a 72-year-old white woman with Paget disease of the lower leg and typical bowing.

The initial pathologic lesion, which is osteolysis, appears as a radiolucency on the radiograph and is particularly evident in the frontal and occipital bones of the skull, where it is termed osteoporosis circumscripta. The body’s previous attempts to repair these areas are seen as areas of increased density or as coarsened trabecula. In some areas, an overt sclerotic appearance may be seen.

Osteolysis of the tubular bones usually occurs subchondrally in the epiphysis, with extension into the metaphysis and diaphysis. Advancing osteolysis may appear as a V- or wedge-shaped radiolucent area that may resemble a blade of grass or flame. The remaining trabeculae may be obliterated and a hazy ground-glass or washed-out pattern observed. Focal radiodensities have a cotton-wool appearance. Areas of lysis and radiodensities may be separate or superimposed. In the pelvis, Paget disease may produce the "brim sign," which is the thickened iliopectineal line.

Paget disease of the spine typically affects the vertebral bodies and posterior elements. The enlarged coarse trabeculae combined with the prominent radiodense peripheral contour of the vertebral body gives the appearance of a picture frame that is diagnostic of Paget disease. A homogeneous increase in osseous density in the vertebral body gives the manifestation of an ivory vertebra. Skeletal metastasis and lymphoma also may produce ivory vertebrae.

Furthermore, altered vertebral body shape is common as a result of structurally weak pagetic bone. Biconcave-shaped vertebral bodies, also called fish vertebrae, may be seen in osteomalacia, hyperparathyroidism, and osteoporosis. The biconcave shape is caused by intervertebral disc compression of the weakened vertebrae.

Intervertebral disc space narrowing may occur from secondary degenerative disc and joint disease. Vertebral body ankylosis may be seen. Loss of vertebral height is observed commonly as a result of bone remodeling and compression fractures. Posterior element involvement may manifest as increased pedicular radiodensities that also are seen in osteoblastic metastasis.

Later in the disease, evidence of lysis may be absent because only sclerotic thickened bones may remain. The osteosclerotic is most notable in the axial skeleton and pelvis. An enlarged bone with increased radiodensity and trabeculations is characteristic. Radiographic evidence of remineralization may occur after initiation of appropriate treatment, such as with the bisphosphonates.

Osteoporosis

Osteoporosis is a disease of the bone that leads to an increased risk of fracture. In osteoporosis the bone mineral density (BMD) is reduced, the bone microarchitecture is disrupted, and the amount and variety of non-collagenous proteins in the bone is altered. Basically, there is a thinning of the bone structure which affects the bone’s strength (Fig. OP1 ). It may affect every bone in the body. Some bones, such as the wrist bone, the femur and the vertebrae, however, are more prone to develop symptoms or to fracture due to their anatomical structure and mechanical exposure.

The decrease in mechanical strength may cause vertebral fractures to simply happen without trauma or injury. It is estimated that up to 50% of females (30% for males) experience at least one osteoporotic vertebral fracture during their life. Vertebral fractures due to osteoporosis can give rise to a sudden onset of pain. The patient feels a sudden sharp pain (often associated with a “crack” in the back). It is usually worse during activities and reduced at rest. An X-ray or magnetic resonance scan (MRI) will confirm/reveal the fractured vertebra.

4. Explain pathogenesis of osteoporosis

PathophysiologyIt is increasingly being recognized that multiple pathogenetic mechanisms interact in the development of the osteoporotic state. Understanding the pathogenesis of osteoporosis starts with knowing how bone formation and remodeling occur.

Normal bone formation and remodeling

Bone is continually remodeled throughout our lives in response to microtrauma. Bone remodeling occurs at discrete sites within the skeleton and proceeds in an orderly fashion, and bone resorption is always followed by bone formation, a phenomenon referred to as coupling.

Dense cortical bone and spongy trabecular or cancellous bone differ in their architecture but are similar in molecular composition. Both types of bone have an extracellular matrix with mineralized and nonmineralized components. The composition and architecture of the

extracellular matrix is what imparts mechanical properties to bone. Bone strength is determined by collagenous proteins (tensile strength) and mineralized osteoid (compressive strength).[10] The greater the concentration of calcium, the greater the compressive strength. In adults, approximately 25% of trabecular bone is resorbed and replaced each year, compared with only 3% of cortical bone.

Osteoclasts, derived from mesenchymal cells, are responsible for bone resorption, whereas osteoblasts, from hematopoietic precursors, are responsible for bone formation (see the images below). The 2 types of cells are dependent on each other for production and linked in the process of bone remodeling. Osteoblasts not only secrete and mineralize osteoid but also appear to control the bone resorption carried out by osteoclasts. Osteocytes, which are terminally differentiated osteoblasts embedded in mineralized bone, direct the timing and location of bone remodeling. In osteoporosis, the coupling mechanism between osteoclasts and osteoblasts is thought to be unable to keep up with the constant microtrauma to trabecular bone. Osteoclasts require weeks to resorb bone, whereas osteoblasts need months to produce new bone. Therefore, any process that increases the rate of bone remodeling results in net bone loss over time.[11]

This image depicts bone remodeling with osteoclasts resorbing one side of a bony trabecula and osteoblasts depositing new bone on the other side.

Osteoclast, with bone below it. This image shows typical distinguishing characteristics of an osteoclast: a large cell with multiple nuclei and a "foamy"

cytosol. In this image, several osteoblasts display a prominent Golgi apparatus and are actively synthesizing osteoid. Two osteocytes can also be seen.Furthermore, in periods of rapid remodeling (eg, after menopause), bone is at an increased risk for fracture because the newly produced bone is less densely mineralized, the resorption sites are temporarily unfilled, and the isomerization and maturation of collagen are impaired.[12]

The receptor activator of nuclear factor-kappa B ligand (RANKL)/receptor activator of nuclear factor-kappa B (RANK)/osteoprotegerin (OPG) system is the final common pathway for bone resorption. Osteoblasts and activated T cells in the bone marrow produce the

RANKL cytokine. RANKL binds to RANK expressed by osteoclasts and osteoclast precursors to promote osteoclast differentiation. Osteoprotegerin is a soluble decoy receptor that inhibits RANK-RANKL by binding and sequestering RANKL.

Bone mass peaks around the third decade of life and slowly decreases afterward. A failure to attain optimal bone strength by this point is one factor that contributes to osteoporosis, which explains why some young postmenopausal women have low bone mineral density (BMD) and why some others have osteoporosis. Therefore, nutrition and physical activity are important during growth and development. Nevertheless, hereditary factors play the principal role in determining an individual's peak bone strength. In fact, genetics account for up to 80% of the variance in peak bone mass between individuals.[13, 14]

Alterations in bone formation and resorption

The hallmark of osteoporosis is a reduction in skeletal mass caused by an imbalance between bone resorption and bone formation. Under physiologic conditions, bone formation and resorption are in a fair balance. A change in either—that is, increased bone resorption or decreased bone formation—may result in osteoporosis.

Osteoporosis can be caused both by a failure to build bone and reach peak bone mass as a young adult and by bone loss later in life. Accelerated bone loss can be affected by hormonal status, as occurs in perimenopausal women; can impact elderly men and women; and can be secondary to various disease states and medications.

Aging and loss of gonadal function are the 2 most important factors contributing to the development of osteoporosis. Studies have shown that bone loss in women accelerates rapidly in the first years after menopause. The lack of gonadal hormones is thought to up-regulate osteoclast progenitor cells. Estrogen deficiency leads to increased expression of RANKL by osteoblasts and decreased release of OPG; increased RANKL results in recruitment of higher numbers of preosteoclasts as well as increased activity, vigor, and lifespan of mature osteoclasts.

Estrogen deficiency

Estrogen deficiency not only accelerates bone loss in postmenopausal women but also plays a role in bone loss in men. Estrogen deficiency can lead to excessive bone resorption accompanied by inadequate bone formation. Osteoblasts, osteocytes, and osteoclasts all express estrogen receptors. In addition, estrogen affects bones indirectly through cytokines and local growth factors. The estrogen-replete state may enhance osteoclast apoptosis via increased production of transforming growth factor (TGF)–beta.

In the absence of estrogen, T cells promote osteoclast recruitment, differentiation, and prolonged survival via IL-1, IL-6, and tumor necrosis factor (TNF)–alpha. A murine study, in which either the mice's ovaries were removed or sham operations were performed, found that IL-6 and granulocyte-macrophage CFU levels were much higher in the ovariectomized mice.[15] This finding provided evidence that estrogen inhibits IL-6 secretion and that IL-6 contributes to the recruitment of osteoclasts from the monocyte cell line, thus contributing to osteoporosis.

IL-1 has also been shown to be involved in the production of osteoclasts. The production of IL-1 is increased in bone marrow mononuclear cells from ovariectomized rats. Administering IL-1 receptor antagonist to these animals prevents the late stages of bone loss induced by the loss of ovarian function, but it does not prevent the early stages of bone loss. The increase in

the IL-1 in the bone marrow does not appear to be a triggered event but, rather, a result of removal of the inhibitory effect of sex steroids on IL-6 and other genes directly regulated by sex steroids.

T cells also inhibit osteoblast differentiation and activity and cause premature apoptosis of osteoblasts through cytokines such as IL-7. Finally, estrogen deficiency sensitizes bone to the effects of parathyroid hormone (PTH).

Aging

In contrast to postmenopausal bone loss, which is associated with excessive osteoclast activity, the bone loss that accompanies aging is associated with a progressive decline in the supply of osteoblasts in proportion to the demand. This demand is ultimately determined by the frequency with which new multicellular units are created and new cycles of remodeling are initiated.

After the third decade of life, bone resorption exceeds bone formation and leads to osteopenia and, in severe situations, osteoporosis. Women lose 30-40% of their cortical bone and 50% of their trabecular bone over their lifetime, as opposed to men, who lose 15-20% of their cortical bone and 25-30% of trabecular bone.

Calcium deficiency

Calcium, vitamin D, and PTH help maintain bone homeostasis. Insufficient dietary calcium or impaired intestinal absorption of calcium due to aging or disease can lead to secondary hyperparathyroidism. PTH is secreted in response to low serum calcium levels. It increases calcium resorption from bone, decreases renal calcium excretion, and increases renal production of 1,25-dihydroxyvitamin D (1,25[OH]2 D)—an active hormonal form of vitamin D that optimizes calcium and phosphorus absorption, inhibits PTH synthesis, and plays a minor role in bone resorption.

Vitamin D deficiency

Vitamin D deficiency can result in secondary hyperparathyroidism via decreased intestinal calcium absorption. Interestingly, the effects of PTH and 1,25[OH]2 D on bone are mediated via binding to osteoblasts and stimulating the RANKL/RANK pathway. Osteoclasts do not have receptors for PTH or 1,25[OH]2 D.[10]

Osteoporotic fractures

Osteoporotic fractures represent the clinical significance of these derangements in bone. They can result both from low-energy trauma, such as falls from a sitting or standing position, and from high-energy trauma, such as a pedestrian struck in a motor vehicle accident. Fragility fractures, which occur secondary to low-energy trauma, are characteristic of osteoporosis.

Fractures occur when bones fall under excess stress. Nearly all hip fractures are related to falls.[16] The frequency and direction of falls can influence the likelihood and severity of fractures. The risk of falling may be amplified by neuromuscular impairment due to vitamin D deficiency with secondary hyperparathyroidism or corticosteroids.

Vertebral bodies are composed primarily of cancellous bone with interconnected horizontal and vertical trabeculae. Osteoporosis not only reduces bone mass in vertebrae but also decreases interconnectivity in their internal scaffolding.[10]Therefore, minor loads can lead to vertebral compression fractures.

An understanding of the biomechanics of bone provides greater appreciation as to why bone may be susceptible to an increased risk of fracture. When vertical loads are placed on bone, such as tibial and femoral metaphyses and vertebral bodies, a substantial amount of bony strength is derived from the horizontal trabecular cross-bracing system. This system of horizontal cross-bracing trabeculae assists in supporting the vertical elements, thus limiting lateral bowing and fractures that may occur with vertical loading.

Disruption of such trabecular connections is known to occur preferentially in patients with osteoporosis, particularly in postmenopausal women, making females more at risk than males for vertebral compression fractures (see the images below).

Osteoporosis is defined as a loss of bone mass below the threshold of fracture. This slide (methylmethacrylate embedded and stained with Masson's trichrome) demonstrates the loss of connected trabecular bone. The bone loss of osteoporosis can be severe enough to create separate bone "buttons" with no connection to the surrounding bone. This easily leads to insufficiency fractures.Rosen and Tenenhouse studied the unsupported trabeculae and their susceptibility to fracture within each vertebral body and found an extraordinarily high prevalence of trabecular fracture callus sites within vertebral bodies examined at autopsy, typically 200-450 healing or healed fractures per vertebral body.[17] These horizontal trabecular fractures are asymptomatic, and their accumulation reflects the impact of lost trabecular bone and greatly weakens the cancellous structure of the vertebral body.

The reason for preferential osteoclastic severance of horizontal trabeculae is unknown. Some authors have attributed this phenomenon to overaggressive osteoclastic resorption.

Osteoporosis versus osteomalacia

Osteoporosis may be confused with osteomalacia. The normal human skeleton is composed of a mineral component, calcium hydroxyapatite (60%), and organic material, mainly collagen (40%). In osteoporosis, the bones are porous and brittle, whereas in osteomalacia, the bones are soft. This difference in bone consistency is related to the mineral-to-organic material ratio. In osteoporosis, the mineral-to-collagen ratio is within the reference range, whereas in osteomalacia, the proportion of mineral composition is reduced relative to organic mineral content.

Additional factors and conditions

Endocrinologic conditions or medications that lead to bone loss (eg, glucocorticoids) can cause osteoporosis. Corticosteroids inhibit osteoblast function and enhance osteoblast apoptosis.[18] Polymorphisms of IL-1, IL-6 and TNF-alpha, as well as their receptors, have been found to influence bone mass.

Other factors implicated in the pathogenesis of osteoporosis include polymorphisms in the vitamin D receptor; alterations in insulin-like growth factor-1, bone morphogenic protein,

prostaglandin E2, nitrous oxide, and leukotrienes; collagen abnormalities; and leptin-related adrenergic signaling.[11]

5. Line out risk factors of osteoporosis

Risk factors (medscape)

Risk factors for osteoporosis, such as advanced age and reduced bone mineral density (BMD), have been established by virtue of their direct and strong relationship to the incidence of fractures; however, many other factors have been considered risk factors based on their relationship to BMD as a surrogate indicator of osteoporosis.

Risk factors for osteoporosis include the following:

Advanced age (≥50 years)

Female sex

White or Asian ethnicity

Genetic factors, such as a family history of osteoporosis

Thin build or small stature (eg, body weight less than 127 lb)

Amenorrhea

Late menarche

Early menopause

Postmenopausal state

Physical inactivity or immobilization

Use of drugs: anticonvulsants, systemic steroids, thyroid supplements, heparin, chemotherapeutic agents, insulin

Alcohol and tobacco use

Androgen or estrogen deficiency

Calcium deficiency

Dowager hump

A potentially useful mnemonic for osteoporotic risk factors is OSTEOPOROSIS, as follows:

L O w calcium intake

S eizure meds (anticonvulsants)

T hin build

E thanol intake

Hyp O gonadism

P revious fracture

Thyr O id excess

R ace (white, Asian)

O ther relatives with osteoporosis

S teroids

I nactivity

S moking

A study by Cummings et al evaluated 9516 white women aged 65 years for an average of 4.1 years and found an indirect relationship between the number of risk factors and bone density values. The study also identified factors that did not increase the risk of fracture, including hair color, number of children breastfed, prior smoking history, or use of short-acting benzodiazepines. An interesting finding of this study was that dietary intake of calcium was not correlated with the risk of hip fracture; however, the authors of the study did agree with other experts that dietary calcium would only help if the patient was calcium deficient.

6. Describe investigative findings in osteoporosis (Laboratory, X-ray, Bone Densitometry)

Laboratory Studies(medscape)

Laboratory studies are used to establish baseline conditions or to exclude secondary causes of osteoporosis.

Baseline Studies for Baseline Conditions in Osteoporosis

Baseline test Disorder

Complete blood count (CBC)

CBC results may reveal anemia, as in sickle cell disease (patients with anemia, particularly those older than 60 years, should also be evaluated for multiple myeloma), and may raise the suspicion for alcohol abuse (in conjunction with results from serum chemistry tests and liver function tests)

Serum chemistry levels

Calcium levels can reflect underlying disease states (eg, severe hypercalcemia may reflect underlying malignancy or hyperparathyroidism; hypocalcemia can contribute to osteoporosis) 

levels of serum calcium, phosphate, and alkaline phosphatase are usually normal in persons with primary osteoporosis, although alkaline phosphatase levels may be elevated for several months after a fracture 

levels of serum calcium, phosphate, alkaline phosphatase, and 25(OH) vitamin D may be obtained to assess osteomalacia

Creatinine levels may decrease with increasing parathyroid hormone (PTH) levels or may be elevated in patients with multiple myeloma 

Creatinine levels are also used to estimate creatinine clearance, which may indicate reduced renal function in elderly patients

Magnesium is very important in calcium homeostasis[71] ; decreased levels of magnesium may affect calcium absorption and metabolism 

Serum iron and ferritin levels

These tests are helpful when malabsorption or hemochromatosis are suspected

Liver function tests Increased levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), bilirubin, and alkaline phosphatase may indicate alcohol abuse

Thyroid-stimulating hormone (TSH) level

Thyroid dysfunction has been associated with osteoporosis and should therefore be ruled out

25-Hydroxyvitamin D level

This test assesses for vitamin D insufficiency; inadequate vitamin D levels can predispose persons to osteoporosis

An important study by Tannenbaum evaluated 173 healthy women (ages 46-87 years) for secondary causes of osteoporosis and found that 55 (32%) had a previously undiagnosed disorder of bone or mineral metabolism. Given that occult disorders are so common in patients with osteoporosis, minimal laboratory screening is indicated in all patients who present with decreased bone mass.

Tests for Secondary Causes of Osteoporosis

Tests for Secondary Causes of Osteoporosis Disorder

24-Hour urine calcium level This study assesses for hypercalciuria to help rule out benign familial hypocalciuric hypercalcemia (FHH), in which urinary calcium levels are low

Parathyroid hormone (PTH) level

An intact PTH result is essential in ruling out hyperparathyroidism; an elevated PTH level may be present in benign FHH

Thyrotropin level (if on thyroid replacement)

Experts are divided on whether to include thyrotropin testing, regardless of a history of thyroid disease or replacement; however, one study showed reduced femoral neck bone mineral density (BMD) in women with subclinical hypothyroidism and hyperthyroidism

Testosterone and gonadotropin levels in younger men with low bone densities

These tests may help evaluate a sex hormone deficiency as a secondary cause of osteoporosis

Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels

Some practitioners include ESR and CRP values in the workup, although their utility in this setting has not been proven in an evidence-based manner

Urinary free cortisol level and tests for adrenal hypersecretion

These tests are used to exclude Cushing syndrome, which, although uncommon, can lead to rapidly progressive osteoporosis when the condition is present; a urine free cortisol value or overnight dexamethasone suppression test should be ordered in suspected cases

Serum protein electrophoresis (SPEP) and urine protein electrophoresis (UPEP)

These are used to identify multiple myeloma

Antigliadin and antiendomysial antibodies

These tests can help identify celiac disease

Serum tryptase and urine N-methylhistamine

These tests help identify mastocytosis and are used to exclude the presence of multiple myeloma; serum tryptase may be performed to rule out plasma cell dyscrasias

Bone marrow biopsy This study is obtained when a hematologic disorder is suspected

Biochemical Markers of Bone Turnover (medscape)

Biochemical markers of bone turnover reflect bone formation or bone resorption. These markers (both formation and resorption) may be elevated in high-bone-turnover states (eg, early postmenopausal osteoporosis) and may be useful in some patients for monitoring early response to therapy.

Currently available serum markers of bone formation (osteoblast products) include the following:

Bone-specific alkaline phosphatase (BSAP)

Osteocalcin (OC)

Carboxyterminal propeptide of type I collagen (PICP)

Aminoterminal propeptide of type I collagen (PINP)

Currently available urinary markers of bone resorption (osteoclast products) include the following:

Hydroxyproline

Free and total pyridinolines (Pyd)

Free and total deoxypyridinolines (Dpd)

N-telopeptide of collagen cross-links (NTx) (also available as a serum marker)

C-telopeptide of collagen cross-links (CTx) (also available as a serum marker)

Currently available serum markers of bone resorption include cross-linked C-telopeptide of type I collagen (ICTP) and tartrate-resistant acid phosphatase, as well as NTx and CTx. Of all the biochemical markers of bone turnover mentioned above, the ones most commonly used in clinical practice are BSAP, OC, urinary NTx, and serum CTx.

BSAP can be mildly elevated in patients with fractures. In addition, patients with hyperparathyroidism, Paget disease, or osteomalacia can have elevations of BSAP. Serum OC levels, if high, indicate a high-turnover type of osteoporosis. Elevation of urinary NTx (>40 nmol bone collagen equivalent per mmol urinary creatine) indicates a high turnover state. NTx levels may also be used to monitor responses to anti-osteoporotic treatments.

Significant controversy exists regarding the use of these biochemical markers, and concerns have been raised about intra-assay and interassay variability. At the primary author's institution, a urine NTx value normalized to creatinine excretion from the second urination of the day is used primarily to identify osteopenic patients in a high-turnover state who would benefit from therapy and to monitor the response to therapy in all patients. However, further study is needed to determine the clinical utility of these markers in osteoporosis management.

Plain Radiography (X-ray) (medscape)

Plain radiography is recommended to assess overall skeletal integrity. In particular, in the workup for osteoporosis, plain radiography may be indicated if a fracture is already suspected or if patients have lost more than 1.5 inches of height (see the following image).

Asymmetric loss in vertebral body height, without evidence of an acute fracture, can develop in patients with osteoporosis. These patients become progressively kyphotic (as shown) over time, and the characteristic hunched-over posture of severe osteoporosis develops eventually.

Obtain radiographs of the affected area in symptomatic patients. Lateral spine radiography can be performed in asymptomatic patients in whom a vertebral fracture is suspected, in those with height loss in the absence of other symptoms, or in those with pain in the thoracic or upper lumbar spine (see the following images). A scoliosis series is useful for detecting occult vertebral fractures.

Severe osteoporosis. This radiograph shows multiple vertebral crush fractures. Source: Government of Western Australia Department of Health.

This radiograph of the spine shows a lateral wedge fracture of L3 (yellow asterisk) and compression fracture of L5 (red asterisk) in an osteoporotic patient who suffered a recent fall. More detailed imaging, usually with computed tomography (CT) scanning, is often needed to better evaluate compression fractures and to determine the urgency of surgical interventions.

Radiographic findings can suggest the presence of osteopenia, or bone loss, although they cannot be used to diagnose osteoporosis. Using the second metacarpal or the metaphysis of a

long bone, the cortical width should be at least equal to the medullary width. Osteopenia is suggested by a cortical width that is less than the medullary width. Radiographs may also show fractures or other conditions, such as osteoarthritis, disk disease, or spondylolisthesis.

Plain radiography is not as accurate as BMD testing. Because osteoporosis predominantly affects trabecular bone rather than cortical bone, radiography does not reveal osteoporotic changes until they affect the cortical bone. Cortical bone is not affected by osteoporosis until more than 30% of bone loss has occurred. Approximately 30-80% of bone mineral must be lost before radiographic lucency becomes apparent on radiographs. Thus, plain radiography is an insensitive tool for diagnosing osteoporosis.

WHO Definition of Bone Densitometry in Osteoporosis (medscape)

Bone mineral density (BMD) in a patient is related to peak bone mass and, subsequently, bone loss. Whereas the T-score is the patient’s bone density compared with the BMD of control subjects who are at their peak BMD, the Z-score reflects a bone density compared with that of patients matched for age and sex.

The World Health Organization’s (WHO) definitions of osteoporosis based on BMD measurements in white women are summarized in Table 1, below. For each standard deviation (SD) reduction in BMD, the relative fracture risk is increased 1.5-3 times.

The WHO definition applies to postmenopausal women and men aged 50 years or older. Although these definitions are necessary to establish the prevalence of osteoporosis, they should not be used as the sole determinant of treatment decisions. This diagnostic classification should not be applied to premenopausal women, men younger than 50 years, or children.

Table 1. WHO Definition of Osteoporosis Based on BMD Measurements by DXA

Definition Bone Mass Density Measurement T-Score

Normal BMD within 1 SD of the mean bone density for young adult women

T-score ≥ –1

Low bone mass (osteopenia)

BMD 1–2.5 SD below the mean for young-adult women

T-score between –1 and –2.5

Osteoporosis BMD ≥2.5 SD below the normal mean for young-adult women

T-score ≤ –2.5

Severe or “established” osteoporosis

BMD ≥2.5 SD below the normal mean for young-adult women in a patient who has already experienced ≥1 fractures

T-score ≤ –2.5 (with fragility fracture[s])

Sources: 

(1) World Health Organization (WHO). WHO scientific group on the assessment of osteoporosis at primary health care level: summary meeting report. Available at: http://www.who.int/chp/topics/Osteoporosis.pdf. Accessed February 6, 2012.

(2) Kanis JA. Assessment of fracture risk and its application to screening for postmenopausal

osteoporosis: synopsis of a WHO report. WHO Study Group. Osteoporos Int. Nov 1994;4(6):368-81.(3) Czerwinski E, Badurski JE, Marcinowska-Suchowierska E, Osieleniec J. Current understanding of osteoporosis according to the position of the World Health Organization (WHO) and International Osteoporosis Foundation. Ortop Traumatol Rehabil. Jul-Aug 2007;9(4):337-56.

BMD = bone mass density; DXA = dual x-ray absorptiometry; SD = standard deviation; T-score = a measurement expressed in SD units from a given mean that is equal to a patient's BMD measured by DXA minus the value in a young healthy person, divided by the SD measurement in the population.

Z-scores should be used in premenopausal women, men younger than 50 years, and children. Z-scores adjusted for ethnicity or race should be used, with Z-scores of –2.0 or lower defined as "below the expected range for age" and with Z-scores above –2.0 being defined as "within the expected range for age." The diagnosis of osteoporosis in these groups should not be based on densitometric criteria alone.

7. Describe the physiological balance of calcium and phosphate, the role of parathyroid hormone, calcitonin, and vitamin D the GI tract and kidney in this balance.

8. Line out the management of osteoporosis.

Pharmacologic TherapyExpert recommendations

The National Osteoporosis Foundation (NOF) recommends that pharmacologic therapy should be reserved for postmenopausal women and men aged 50 years or older who present with the following[35] :

A hip or vertebral fracture (vertebral fractures may be clinical or morphometric [ie, identified on a radiograph alone])

T-score of -2.5 or less at the femoral neck or spine after appropriate evaluation to exclude secondary causes

Low bone mass (T-score between -1.0 and -2.5 at the femoral neck or spine) and a 10-year probability of a hip fracture of 3% or greater or a 10-year probability of a major osteoporosis-related fracture of 20% or greater based on the US-adapted WHO algorithm

The American College of Physicians has reviewed the evidence and has proposed guidelines for pharmacologic treatments of osteoporosis.[67] The agents currently available for osteoporosis treatment include bisphosphonates, the selective estrogen-receptor modulator (SERM) raloxifene, calcitonin, denosumab, and an anabolic agent, teriparatide (human recombinant PTH [1-34]).[27, 81, 82] All therapies should be given with calcium and vitamin D supplementation.

Guidelines from the American Association of Clinical Endocrinologists (AACE), published in 2010, include the following recommendations for choosing drugs to treat osteoporosis[83] :

First-line agents: alendronate, risedronate, zoledronic acid, denosumab Second-line agent: ibandronate Second- or third-line agent: raloxifene Last-line agent: calcitonin Treatment for patients with very high fracture risk or in whom bisphosphonate therapy has

failed: teriparatideThere are no studies that have shown that combination therapy with 2 or more agents have a greater effect on fracture reduction than single therapy. The AACE guidelines advise against the use of combination therapy, until the effect of combination therapy on fracture is better understood.

Bisphosphonates

Bisphosphonates are the most commonly used agents for osteoporosis. They have been employed for both treatment and prevention. Oral and intravenous options are available.

Alendronate (Fosamax) is approved for the treatment of osteoporosis in men, in postmenopausal women, and in patients with glucocorticoid-induced osteoporosis. It has been shown to increase spinal and hip mineral density in postmenopausal women. Well-conducted controlled clinical trials indicate that alendronate reduces the rate of fracture at the spine, hip, and wrist by 50% in patients with osteoporosis. The treatment dose of alendronate is 70 mg/wk, to be taken sitting upright with a large glass of water at least 30 minutes before eating in the morning. Alendronate is also available in combination with cholecalciferol (vitamin D3). The combination alendronate/vitamin D3(Fosamax Plus D) is indicated for the treatment of osteoporosis in men to increase bone mass.

The results of a population-based, national register–based, open cohort study of 38,088 patients suggest that elderly patients who use proton pump inhibitors in conjunction with alendronate have a dose-dependent loss of protection against hip fracture.[84]

Other oral bisphosphonates include risedronate (Actonel) or risedronate delayed-release (Atelvia), given daily, weekly, or monthly. It is also available as a combination product with calcium as risedronate/calcium carbonate (Actonel with Calcium). Risedronate reduced vertebral fractures by 41% and nonvertebral fractures by 39% over 3 years. Ibandronate (Boniva) is another bisphosphonate that can be given orally once a month. Intravenous bisphosphonates are excellent choices for patients intolerant of oral bisphosphonates or for those in whom adherence is an issue. Ibandronate is also available as an intravenous formulation that is given every 3 months. Ibandronate has not shown efficacy in nonvertebral fractures in clinical trials.

Zoledronic acid

Zoledronic acid (Reclast) is the most potent bisphosphonate available. It increases BMD at the spine by 4.3-5.1% and the hip by 3.1-3.5%, as compared with placebo. Over 3 years, it reduces the incidence of spine fractures by 70%, hip fractures by 41%, and nonvertebral fractures by 25%. Zoledronic acid is a once-yearly intravenous infusion approved for the treatment of osteoporosis in men, in postmenopausal women, and in patients with glucocorticoid-induced osteoporosis.[85] A randomized, placebo-controlled, double-blind trial suggested that a once-yearly 5-mg dose of IV zoledronic acid increases bone mass in men within 90 days of hip fracture repair; similar increases were noted in women.[86]

In September 2011, the FDA updated the prescribing information for zoledronic acid (Reclast) to provide improved information regarding the risk of kidney failure. Acute renal failure requiring dialysis and fatal outcomes have been reported to the FDA following the use of zoledronic acid. It is contraindicated with moderate to severe renal impairment (ie, CrCl < 35 mL/min) or in patients with evidence of acute renal impairment. Other risks for renal impairment include coadministration of zoledronic acid with nephrotoxic or diuretic medications, severe dehydration before or after administration, or advanced age.[87]

Bisphosphonates and bone turnover

Over time, bisphosphonate therapy decreases bone turnover and, at very high levels in animals, decreases bone strength and resilience. Some limited reports, including that by Odvina et al, describe patients on long-term bisphosphonate therapy developing transverse stress fractures; biopsy specimens of these individuals have suggested extremely low turnover states.[88] Therefore, although the bisphosphonates are outstanding in their efficacy, bone turnover markers should be monitored. If these markers become profoundly suppressed, the patient should be taken off the bisphosphonates and given a rest period until return to therapeutic levels (N-telopeptide of collagen cross-links [NTx], 20-40).

Treatment interval and complications with bisphosphonate therapy

The limited trial data available regarding long-term treatment with bisphosphonates has raised questions about the optimal length of treatment with these medications.[89]This issue has become more important, given newly recognized complications of bisphosphonate use, including osteonecrosis of the jaw and atypical (subtrochanteric or femoral shaft) femur fractures (see the images below).

Normal femoral anatomy. Stable intertrochanteric fracture of the femur.Some studies have sought to clarify the true risks of complications in patients receiving bisphosphonates. A Canadian study by Park-Willie et al found the estimated absolute risk of a subtrochanteric or femoral shaft fracture to be low in 52,595 women with at least 5 years of bisphosphonate therapy (0.13% during the subsequent year and 0.22% within 2 years).[90] Overall, a patient’s risk of fracture can be used to help guide length of treatment. Patients at high risk may be continued on bisphosphonates after 5 years; however, in some patients, especially those with a lower risk of fracture, bisphosphonate treatment may be stopped.[91]

The AACE recommends that if osteoporosis is mild, clinicians should consider a drug holiday after 4-5 years of bisphosphonate treatment; if fracture risk is high, a drug holiday of 1-2 years may be considered after 10 years of treatment.[83] BMD and bone turnover markers should be monitored during the drug holiday, and treatment should be restarted if density declines substantially, bone turnover markers increase, or a fracture occurs.[83]

Selective estrogen receptor modulator

Selective estrogen receptor modulators (SERMs) are considered to provide the beneficial effects of estrogen without the potentially adverse outcomes. Raloxifene (Evista) is indicated for the treatment and prevention of osteoporosis in postmenopausal women. The usual dose is 60 mg given orally daily. It can also be given in combination with calcium and vitamin D. It is the first SERM studied for breast cancer prevention, and it decreases bone resorption through actions on estrogen receptors. It has been shown to prevent bone loss, and data in females with osteoporosis have demonstrated that raloxifene causes a 35% reduction in the risk of vertebral fractures. It has also been shown to reduce the prevalence of invasive breast cancer.

Raloxifene may be most useful in younger postmenopausal women without severe osteoporosis. It has been shown to increase the incidence of deep vein thrombosis and hot flashes. In 601 postmenopausal women who had daily therapy with raloxifene, BMD was increased, serum concentrations of total low-density lipoprotein cholesterol were lowered, and the endometrium was not stimulated.

Pooled mortality data from large clinical trials of raloxifene (60 mg/day) were analyzed by Grady et al in 2010. When compared with placebo, all-cause mortality was 10% lower in older postmenopausal women receiving raloxifene. The primary reduction was in noncardiovascular, noncancer deaths.[92]

Parathyroid hormone

Teriparatide (Forteo) is a human recombinant parathyroid hormone (1-34) (PTH [1-34]) and is the only available anabolic agent for the treatment of osteoporosis. It is indicated for the treatment of women with postmenopausal osteoporosis who are at high risk of fracture, who have been intolerant of previous osteoporosis therapy, or in whom osteoporosis treatment has failed, as well as to increase bone mass. It is indicated in men with idiopathic or hypogonadal osteoporosis who are at high risk of fracture, who have been intolerant of previous osteoporosis therapy, or in whom osteoporosis therapy has failed. Teriparatide is also approved for the treatment of patients with glucocorticoid-induced osteoporosis. Before treatment with teriparatide, levels of serum calcium, PTH, and 25(OH)D need to be monitored.

When PTH is given continuously, it is associated with increased osteoclastic and osteoblastic turnover, leading to a net loss of bone. However, in an intermittent subcutaneous administration of 20 mcg/day, PTH has been demonstrated to lead to a very active anabolic phase, with bone mass increasing up to 13% over 2 years in the spine and to a lesser degree in the hip.[93, 94, 95]

Indications for PTH in men and women are a bone density decline while on bisphosphonate therapy, bone density stabilization while on extremely low-level bisphosphonate therapy, a fracture occurring while on bisphosphonate therapy, or a very low initial bone turnover rate for which an anabolic effect is clearly warranted. Teriparatide should be considered in younger and older postmenopausal women with severe osteoporosis.

Most studies with PTH have been performed on women. The medication decreases the risk of vertebral and nonvertebral fractures to the same extent as bisphosphonates. Teriparatide is given for a maximum of 2 years, after which time the gains in BMD achieved with PTH are secure and can even be augmented with bisphosphonate therapy; otherwise, the BMD slowly deteriorates to pretreatment levels.[96]

According to Finkelstein et al, initial studies using a combination of concurrent PTH and bisphosphonate therapy showed decreased benefit compared with therapy with either agent alone; therefore, the general recommendation is that these drugs be given separately and in sequence.[97]

A study by Cosman and colleagues challenged this conclusion by giving 3-month-on, 3-month-off pulses of teriparatide while the patients were on weekly alendronate; BMD in the spine increased above that of the alendronate-only arm.[147] This pulsed regimen appears to take advantage of the 3- to 4-month so-called anabolic window, in which the markers of bone formation rise more quickly than the markers of bone resorption.

Studies by Deal et al and Ste-Marie et al on women have shown that the concurrent use of estrogen or raloxifene can enhance the bone-forming effects of teriparatide.[99, 98] Data on the use of PTH in men are much more limited, but they appear to have relatively comparable efficacy.

In a retrospective analysis of the data from the Fracture Prevention Trial and the Multiple Outcomes of Raloxifene Evaluation trial, Bouxsein et al found that teriparatide reduced fracture risk to a greater extent than raloxifene in postmenopausal osteoporotic women. Compared with placebo, teriparatide reduced the risk of any new fractures by 72%, new adjacent fractures by 75%, and new nonadjacent vertebral fractures by 70%. Raloxifene reduced the risks by 54%, 54%, and 53%, respectively.[100]

A study performed by the Austrian group using PTH 1-84 to treat pelvic fractures clearly demonstrated that the anabolic agent used in osteoporosis also has the ability to both increase the rate of union and enhance the speed of the process. Using CT evaluation of the fracture site, the authors not only proved their primary goal of improved fracture healing but also noted a significant decrease of pain and improved function over the placebo arm. This clinical study supports the extensive animal data that predicted a clear role for PTH in fracture repair.[101]

Calcitonin

Calcitonin-salmon (Fortical, Miacalcin) is a hormone that decreases osteoclast activity, thereby impeding postmenopausal bone loss. It is indicated for the treatment of women who are more than 5 years post menopause and have low bone mass relative to healthy premenopausal women. Calcitonin-salmon should be reserved for patients who refuse or cannot tolerate estrogens or in whom estrogens are contraindicated. It is recommended in conjunction with adequate calcium and vitamin D intake to prevent the progressive loss of bone mass. It is available as an injection and as an intranasal spray. The intranasal spray is delivered as a single daily spray that provides 200 IU of the drug. The drug can be delivered subcutaneously, but this route is rarely used.

Results from a single controlled clinical trial indicate that calcitonin may decrease osteoporotic vertebral fractures by approximately 30%. In the first 2 years, calcitonin has been found to increase spinal bone mineral density (BMD) by approximately 2%. Calcitonin also has an analgesic property that makes it ideally suited for the treatment of acute vertebral fractures.

Calcitonin is an option for patients who are not candidates for other available osteoporosis treatments. Common side effects of nasally administered calcitonin include nasal discomfort, rhinitis, irritation of nasal mucosa, and occasional epistaxis. Nausea, local inflammatory

reactions at the injection site, sweating, and flushing are side effects noted with parenteral use.

Denosumab

Denosumab (Prolia) is a humanized monoclonal antibody directed against the receptor activator of the nuclear factor-kappa B ligand (RANKL), which is a key mediator of the resorptive phase of bone remodeling.[98] It decreases bone resorption by inhibiting osteoclast activity. Denosumab was approved by the US Food and Drug Administration in June 2010. It has been studied in cancer patients and in patients with postmenopausal osteoporosis.[102, 103]

It is indicated for the treatment of postmenopausal women with osteoporosis who are at high risk of fracture (defined as a history of osteoporotic fracture), have multiple risk factors for fracture, are intolerant to other available osteoporosis therapies, or in whom osteoporosis therapies have failed. In postmenopausal women with osteoporosis, denosumab reduces the incidence of vertebral, nonvertebral, and hip fractures.

Denosumab also increases bone mass in men at high risk for fracture who are receiving androgen deprivation therapy for nonmetastatic prostate cancer. In these patients, denosumab also reduces the incidence of vertebral fractures. It is also used to increase bone mass in women at high risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer. Approved dosage is 60 mg given subcutaneously every 6 months.

In patients with multiple myeloma or bone metastases from breast cancer, a single subcutaneous dose of denosumab decreases bone turnover markers within 1 day, and this effect is sustained through 84 days at higher doses. Denosumab has been shown to increase BMD and decrease bone resorption in postmenopausal women with osteoporosis over a 12-month period.

In a randomized, placebo-controlled trial of 7868 women aged 60-90 years with osteoporosis who received either denosumab 60 mg SC or placebo every 6 months for 36 months, denosumab decreased the risk of vertebral, nonvertebral, and hip fractures.[104]

Smith et al reported a reduction in incident vertebral fractures when denosumab was used in 734 men receiving androgen-deprivation therapy for prostate cancer.[105] In this study, denosumab significantly increased lumbar spine, hip, femoral neck, and radial BMD.

Because the overactivity of RANKL is a major factor in bone loss in patients with autoimmune and inflammatory disorders, such as ulcerative colitis, denosumab may become first-line therapy for these patients.[106]

Hormone replacement therapy

Hormone replacement therapy (HRT) was once considered a first-line therapy for the prevention and treatment of osteoporosis in women. Although HRT is not currently recommended for the treatment of osteoporosis, it is important to mention because many osteoporosis patients in a typical practice still use it for controlling postmenopausal symptoms.

Data from the Women's Health Initiative confirmed that HRT can reduce fractures.[107]However, the results of the Women's Health Initiative were distressing with respect to the adverse outcomes associated with combined estrogen and progesterone therapy (eg, risks for breast cancer, myocardial infarction, stroke, and venous thromboembolic events) and estrogen alone (eg, risks for stroke and venous thromboembolic events).

Other agents

Strontium ranelate is approved for the treatment of osteoporosis in some countries in Europe. It reduces the risk of both spine and nonvertebral fractures.[108, 109] Strontium is not approved for the treatment of osteoporosis in the United States.

Based on preliminary data that suggest women on nitrates have higher BMDs and lower fracture risk, Jamal et al conducted a randomized placebo-controlled trial of women who applied daily nitroglycerin ointment for 24 months.[110] The nitroglycerin ointment increased BMD and decreased bone resorption, although headaches were a limiting factor for many patients. Other nitrate preparations may be better tolerated and could show efficacy for fracture risk reduction.

Vertebroplasty and KyphoplastyThe goals of surgical treatment of osteoporotic fractures include rapid mobilization and return to normal function and activities. Traditional operative management of vertebral compression fractures is uncommon and is usually reserved for gross spinal deformity or for threatened or existing neurologic impairment.

Operative interventions include anterior and posterior decompression and stabilization with placement of such internal fixation devices as screws, plates, cages, or rods. Bone grafting is routinely performed to achieve bony union. The failure rate of spinal arthrodesis is significant because achieving adequate fixation of hardware in osteoporotic bone is difficult. Moreover, patients who are elderly have a reduced osteogenic potential.

Vertebroplasty and balloon kyphoplasty are indicated in patients with incapacitating and persistent severe focal back pain related to vertebral collapse (see the images below).

In kyphoplasty, a KyphX inflatable bone tamp is percutaneously advanced into the collapsed vertebral body (A). It is then inflated, (B) elevating the depressed endplate, creating a central cavity, and compacting the remaining trabeculae to the periphery. Once the balloon tamp is deflated and withdrawn, the cavity (C) is filled under low pressure with a viscous preparation of methylmethacrylate (D).

Reduction in kyphotic angulation after kyphoplasty.

Osteoporosis. Lateral radiograph demonstrates multiple osteoporotic vertebral compression fractures. Kyphoplasty has been performed at one level.

Osteoporosis. Lateral radiograph of the patient seen in the previous image following kyphoplasty performed at 3 additional levels.This procedure has been successful both in reducing the amount of kyphosis and in restoring vertebral body height. It also has successfully reduced pain. Studies have shown kyphoplasty to be a safe and minimally invasive spine procedure that results in improved function in elderly patients, allowing them to participate in increased activities, with resulting improvements in independence and quality of life.

For more information, see the Medscape Reference article Percutaneous Vertebroplasty and Kyphoplasty.

Dietary MeasuresAdequate calcium and vitamin D intake are important in persons of any age, particularly in childhood as the bones are maturing. Patients who ingest inadequate amounts of vitamin D and calcium should receive oral supplementation. Recommendations for patients with osteoporosis include daily dosages of 1200-1500 mg of calcium and 400-800 IU of vitamin D.

Adequate calcium intake is essential in the prevention and treatment of osteoporosis. Premenopausal women and men younger than 50 years without risk factors for osteoporosis should receive a total of 1000 mg of calcium daily. Postmenopausal women, men older than 50 years, and other persons at risk for osteoporosis should receive a daily calcium intake of 1200 mg. Good sources of calcium include dairy products, sardines, nuts, sunflower seeds, tofu, vegetables such as turnip greens, and fortified food such as orange juice. See the National Osteoporosis Foundation Website for further calcium recommendations.

Adults younger than 50 years should receive 400-800 IU of vitamin D3 daily. All adults older than 50 years should receive 800-1000 IU of vitamin D3 daily. Good sources of vitamin D

include eggs, liver, butter, fatty fish, and fortified food such as milk and orange juice. See the National Osteoporosis Foundation Website for further vitamin D recommendations.

A meta-analysis of 12 double-blind, randomized, controlled trials for nonvertebral fractures and 8 trials for hip fractures found that nonvertebral fracture prevention with vitamin D was dose dependent and that a higher dose reduced fractures by at least 20% for individuals aged 65 years or older.[111] However, a longitudinal and prospective cohort study concluded that gradual increases in dietary calcium intake did not further reduce fracture risk or osteoporosis in women.[112]

Alcohol and anorexia nervosa can interfere with nutrition. Excessive alcohol intake can interfere with calcium balance by increasing PTH production and by inhibiting the enzymes that convert inactive vitamin D to its active form; in addition, alcohol can result in hormonal deficiencies and can increase the tendency for falls. Poor nutritional states, such as in anorexia nervosa,[113] have been strongly associated with bone loss. Nutritional and endocrine factors contribute to bone loss; in particular, low estrogen states, which result from low body weight, result in significant bone loss.

Calcium and vitamin D supplementation

Calcium

The goal of the current recommendations for daily calcium intake is to ensure that individuals maintain an adequate calcium balance. Current recommendations from the American Association of Clinical Endocrinologists (AACE) for daily calcium intake are as follows[83] :

Age 0-6 months: 200 mg/day Age 6-12 months: 260 mg/day Age 1-3 years: 700 mg/day Age 4-8 years: 1000 mg/day Age 9-18 years: 1300 mg /day Age 19-50 years: 1000 mg/day Age 50 years and older: 1200 mg/day Pregnant and breastfeeding women age 18 years and younger: 1300 mg/day Pregnant and breastfeeding women age 19 years and older: 1000 mg/day

Commonly used calcium supplements include calcium carbonate and calcium citrate. Calcium carbonate is generally less expensive and is recommended as a first choice option. Calcium carbonate has better absorption with food, as opposed to calcium citrate, which is better absorbed in the fasting state. Also, fewer tablets are needed with calcium carbonate than with calcium citrate.

Vitamin D

Vitamin D is increasingly being recognized as a key element in overall bone health and muscle function. It plays a significant role in bone health, calcium absorption, balance (eg, reduction in risk of falls),[114] and muscle performance. The minimum daily requirement in patients with osteoporosis is 800 IU of vitamin D3, or cholecalciferol. Many patients require higher levels (continuously or for a short period) to be considered vitamin D replete, which is defined as a serum 25-hydroxyvitamin D level of 32 ng/mL.

Vitamin D is available as ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3). Vitamin D is metabolized to active metabolites. These metabolites promote the active

absorption of calcium and phosphorus by the small intestine, elevating serum calcium and phosphate levels sufficiently to permit bone mineralization.

Physical and Occupational TherapyExercisePrevention of OsteoporosisPrimary prevention of osteoporosis starts in childhood. Patients require adequate calcium intake, vitamin D intake, and weight-bearing exercise. Beyond this, prevention of osteoporosis has 2 components: behavior modification and pharmacologic interventions.

The National Osteoporosis Foundation (NOF) specified that the following behaviors should be modified to reduce the risk of developing osteoporosis: cigarette smoking; physical inactivity; and intake of alcohol, caffeine, sodium, animal protein, and calcium.[35] Patients should be counseled on smoking cessation and moderated alcohol intake. Patients who have disorders or take medications that can cause or accelerate bone loss should receive calcium and vitamin D supplementation and, in some cases, pharmacologic treatment.[132]

Pharmacologic prevention methods include calcium supplementation and administration of raloxifene or bisphosphonates (alendronate or risedronate). Raloxifene and bisphosphonates should be considered as first-line agents for the prevention of osteoporosis.[133]

When alendronate or risedronate is used for prevention, the recommended dosage is the equivalent of 5 mg/d. In a study by Hosking et al, doses of 2.5 mg and 5 mg of alendronate were evaluated in postmenopausal women who did not have osteoporosis.[134] They found that the women who received placebo lost BMD at all measured sites, whereas the women treated with 5 mg/d of alendronate had a mean increase in BMD of 3.5% ± 0.2% at the lumbar spine, 1.9% ± 0.1% at the hip, and 0.7% ± 0.1% for the total body.

In 2010, the American College of Rheumatology published revised recommendationsfor the prevention and treatment of glucocorticoid-induced osteoporosis. Recommendations included the categorization of patients by fracture risk (using the FRAX score) and initiation of treatment in appropriate patients including alendronate, risedronate, zoledronic acid, and teriparatide (in those patients at highest risk).[135]

Estrogen-progestin therapy is no longer considered a first-line approach for the treatment of osteoporosis in postmenopausal women, because it is associated with an increased risk for breast cancer, stroke, venous thromboembolism, and perhaps coronary disease. Estrogen is now only recommended if patients are also seeking relief of postmenopausal symptoms.

Regular monitoring may be helpful. Periodic bone densitometry helps in diagnosing osteoporosis in the early phase and aids in preventing fractures. According to the NOF, evaluating BMD on a periodic basis is the best way to monitor bone density and future fracture risk.[35] Bone density checks are recommended every 2 years in postmenopausal women. Regular weight-bearing exercises and back extensor strengthening help delay bone loss.

ConsultationsLong-Term MonitoringDual-energy x-ray absorptiometry (DXA) should be repeated every 2-3 years if the baseline test results are normal. DXA should be performed every 1-2 years in patients who are undergoing osteoporosis treatment.

Orthotics are used to decrease the flexion forces to prevent the worsening of kyphosis and to reduce the pressure on the fracture site in the acute phase of disease.[139, 140]Common orthotics used include the following:

Thoracolumbosacral orthosis (TLSO) Cruciform anterior spinal hyperextension (CASH) brace Jewett brace