OsteoporosisDr.Farzad Ravari

Specialist Orthopedic Surgeon

Cedars J.A Int.l Hospital

Normal Bone Structure

• Lamellar– Cortical– Cancellous

• Woven– Immature– Healing– Pathological

composition of bone

• The matrix– 40% organic

• Type 1 collagen (tensile strength)• Proteoglycans (compressive strength)• Osteocalcin/Osteonectin• Growth factors/Cytokines/Osteoid

– 60% inorganic• Calcium hydroxyapatite

• The cells – osteo-clast/blast/cyte/progenitor

Calcium metabolism• What is the recommended daily intake?• 1000mg• What is the plasma concentration?• 2.2-2.6mmol/L• How is calcium excreted?• Kidneys - 2.5-10mmol/24 hrs• How are calcium levels regulated?• PTH and vitamin D (+others)

Calcium metabolism• Normal plasma concentration?• 0.9-1.3 mmol/L• Absorption and excretion?• Gut and kidneys• Regulation• Not as closely regulated as calcium• but PTH most important

PTH• Physiological role• Production related to plasma calcium levels• Control of calcium levels

– target organs• bone - increased Ca/PO4 release• kidneys

– increased reabsorption of Ca– increased excretion of PO4

• gut - indirect increase in calcium reabs by• stimulting activation of vitamin D metabolism

Calcitonin• Calcitonin is a hormone that is produced in humans by the parafollicular

cells (commonly known as C-cells) of the thyroid gland.

• Physiological role

• Levels increased• when serum Ca >2.25mmol/L• Target organs

– Bone - suppresses resorption– Kidney - increases excretion

Vitamin D (cholecalciferol)• Normal daily requirement• 400IU/day

Vitamin D metabolism

calcium PTHCalcium Resorption

from bone

Renal calcium excretion

Renal Production 1,25 Dihydroxy Vit D

calcium

Factors affecting bone turnover

Osteomalacia vs osteoporosisOsteomal acia osteoporosis

Generalized bone pain Asympt till #

Muscle weakness Normal

Alk Phos. Normal

PO4 Normal

Ca x PO4<2.4 Ca xPO4>2.4

Ill not Ill

x-linked dominant

growth decr +++ and severe deformity with wide epiphyses

Biochemical tests

• Ca/PO4 - plasma/excretion• Alkaline phosphatase/osteocalcin (o’blast

activity)• PTH• vit D uptake • hydroxyproline excretion

Pagets• Bone enlargement and thickening• o-clast/blast activity -> increased tunrover• Etiology: unknown • M=F, >50, pain not severe unless fracture or

tumour

Osteoporosis

• characterized by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility. The disease often does not become clinically apparent until a fracture occurs .

Normal bone formation and remodeling

Alterations in bone formation and resorption• hallmark of osteoporosis is a reduction in skeletal mass caused by an

imbalance between bone resorption and bone formation.• Aging and loss of gonadal function are the 2 most important factors • 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

EstrogenIL1,6

Tumor necrosing factor(TNF)

Osteoclast

Bone Absorption

Aging• 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 ????• White spots are probably the most common ‘abnormality’ that can be observed in fingernails. Many

people associate them with calcium deficiency, but the truth is that usually they do not relate to any health problem at all! In medical science white spots in fingernails are also known as ‘leukonychia punctata’ – which related to the presence of nucleated keratinocytes (contrary: narrow white lines in the nails are known as ‘transverse leukonychia’). Usually white spots are caused by random minor trauma – which also explains why they are relatively common in the hands of children

Risk factors• 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

Prevalence of Osteoporosis Among Racial and Ethnic Groups

Race/Ethnicity Sex (age ≥50 y) % Estimated to have osteoporosis

% Estimated to have low bone mass

Non-Hispanic white; Asian

Women 20 52

Men 7 35

Non-Hispanic black Women 5 *

Men 4 19

Hispanic Women 10 49

Men 3 23

. Types of Primary OsteoporosisType of Primary Osteoporosis

Characteristics

Juvenile osteoporosis Usually occurs in children or young adults of both sexesNormal gonadal functionAge of onset: usually 8-14 yearsHallmark characteristic: abrupt bone pain and/or a fracture following trauma

Idiopathic osteoporosis Postmenopausal osteoporosis

(type I osteoporosis)

Occurs in women aged 50-65 yearsCharacterized by a phase of accelerated bone loss, primarily from trabecular boneFractures of the distal forearm and vertebral bodies common

Age-associated or senile osteoporosis (type II osteoporosis)

Occurs in women and men older than 70 yearsRepresents bone loss associated with agingFractures occur in cortical and trabecular boneWrist, vertebral, and hip fractures often seen in patients with type II osteoporosis

Causes of Secondary Osteoporosis in AdultsCause Examples

Genetic/congenital Renal hypercalciuria – one of the most important secondary causes of osteoporosis; can be treated with thiazide, diuretics,Cystic fibrosis,Ehlers-Danlos syndrome,Glycogen storage disease,Gaucher diseaseMarfan syndrome,Menkes steely hair syndrome,Riley-Day syndrome,Osteogenesis imperfectaHemochromatosis,Homocystinuria,Hypophosphatasia,Idiopathic hypercalciuria,Porphyria,Hypogonadal states

Hypogonadal states

Androgen insensitivity,Anorexia nervosa/bulimia nervosa,Female athlete triadHyperprolactinemia,Panhypopituitarism,Premature menopauseTurner syndrome,Klinefelter syndrome

Endocrine disorders Cushing syndrome,Diabetes mellitus,Acromegaly,Adrenal insufficiency,Estrogen deficiencyHyperparathyroidism,Hyperthyroidism,Hypogonadism,Pregnancy,Prolactinoma

Deficiency states Calcium deficiency,Magnesium deficiency,Protein deficiency,Vitamin D deficiencyBariatric surgery,Celiac disease,Gastrectomy,Malabsorption,MalnutritionParenteral nutrition,Primary biliary cirrhosis

Inflammatory diseases Inflammatory bowel disease,Ankylosing spondylitis,Rheumatoid arthritisSystemic lupus erythematosus

Hematologic and neoplastic disorders

Hemochromatosis,Hemophilia,Leukemia,Lymphoma,Multiple myeloma,Sickle cell anemiaSystemic mastocytosis,Thalassemia,Metastatic disease

Medications Anticonvulsants:,Antipsychotic drugs,Antiretroviral drugs,Chemotherapeutic/tFurosemide,Glucocorticoids and corticotropin: prednisone (≥5 mg/day for ≥3 mo)Heparin (long term),Hormonal/endocrine therapies: gonadotropin-releasing hormone (GnRH) agonists, luteinizing hormone-releasing hormone (LHRH) analogues, depomedroxyprogesterone, excessive thyroxine,Lithium,Selective serotonin reuptake inhibitors (SSRIs)

Miscellaneous Alcoholism,Amyloidosis,Chronic metabolic acidosis,Congestive heart failure,Depression,Emphysema,Chronic or end-stage renal disease,Chronic liver disease,HIV/AIDS,Idiopathic scoliosis,Immobility,Multiple sclerosis,Ochronosis,Organ transplantationPregnancy/lactation,Sarcoidosis,Weightlessness

Complications• Vertebral compression fractures often occur with minimal

stress, such as coughing, lifting, or bending. The vertebrae of the middle and lower thoracic spine and upper lumbar spine

• In many patients, vertebral fracture can occur slowly and without symptoms

Hip fractures • . Fractures are more likely to occur in falls to the side; less subcutaneous tissue is

available to dissipate the impact. Secondary complications of hip fractures include

nosocomial infections and pulmonary thromboembolism.

Clinical Course

Physical Examination• * inspection of the patient• * active and passive range of motion (ROM), spine, hip, wrist• * neurologic examination to rule out spinal cord and/or peripheral nerve

compromise• * Thoracic kyphosis• *, a dowager hump• Areas of concern include the following:• A history of loss of height• Low body weight (body mass index < 19 kg/m2)• Signs that might indicate existing osteoporosis (eg, kyphosis or dowager

hump; point tenderness over a vertebrae or other suspected fracture site)• Signs suggestive of secondary osteoporosis• Signs in older patients that may indicate increased fall risk (eg, difficulty

with balance or gait, orthostatic hypotension, lower-extremity weakness, poor vision or hearing, cognitive impairment

Screening in Men• Risk factors for osteoporosis in men include the

following:• Age older than 70 years• Low body weight (body mass index [BMI] < 20 to 25

kg/m2)• Greater than 10% weight loss (relative to the usual

young or adult weight or weight loss in recent years)• Physical inactivity• Corticosteroid use• Androgen deprivation therapy• Previous fragility fracture

Diagnostic Consideration• X-Ray

• 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.

Laboratory StudiesBaseline 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 osteomalaciaCreatinine 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 patientsMagnesium 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

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

Computed Tomography• Quantitative CT scanning• Quantitative computed tomography (QCT) scanning is another method employed

to measure spinal bone mineral density (BMD). It measures BMD as a true volume density in g/cm3, which is not influenced by bone size. This technique can be used in both adults and children but assesses BMD only at the spine. QCT scanning of the spine is the most sensitive method for diagnosing osteoporosis, because it measures trabecular bone within the vertebral body.

• QCT scanning may be useful in identifying fractures. It can be used to identify not only the fracture line but also areas of callus formation and sclerosis, consistent with healing fracture. It may also be used for evaluation of metastatic bone disease.

• Compared with DXA scanning, QCT is more expensive, has relatively poor reproducibility, and requires a higher radiation dose

• Single-photon emission CT scanning• Single-photon emission computed tomography (SPECT)• offers better image contrast and more accurate lesion localization than planar

bone scanning.

Dual-Energy X-Ray Absorptiometry (DXA)

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])

T-Score==

Z score

Bone density match with control group

Bone density match with same age , sex

Ultrasonography

• Quantitative ultrasonography (QUS) of the calcaneus is a low-cost portable screening tool

Magnetic Resonance Imaging

• may be useful in identifying fractures and in the assessment of metabolic bone disease. Using fat suppression sequences, marrow edema consistent with fracture may be noted as areas of hypointensity on T1-weighted images in association with corresponding areas of hyperintensity on T2-weighted images. MRI is a very sensitive modality and is believed by some to be the diagnostic imaging method of choice in the detection of acute fractures, such as sacral fractures.

• MRI can be used to discriminate between acute and chronic fractures of the vertebrae and occult stress fractures of the proximal femur.

Bone Scanning

• obtained in 3 phases of the bone scanning process (immediate-flow study, immediate static blood pool study, and delayed static study). Acute fractures are visible in all phases of bone scanning and may remain beyond the reference range for up to 2 years.

Biopsy and Histologic Features• Bone biopsy can help to exclude underlying pathologic conditions such as

multiple myeloma, which may be responsible for presumed osteoporotic fracture. Typically, iliac crest biopsy is performed either in the minor procedure suite or in the operating room.

• Tetracycline double labeling is a process used to calculate data on bone turnover. In this procedure, patients are given tetracycline, which binds to newly formed bone. This appears on biopsy samples as linear fluorescence. A second dose of tetracycline is given 11-14 days after the first dose; this appears on a biopsy sample as a second line of fluorescence. The distance between the 2 fluorescent labels can be measured to calculate the amount of bone formed during that interval, which may potentially indicate that too little bone formation or too much bone resorption is the cause of osteoporosis in a patient.

Approach Considerations• Medical care includes the administration of adequate calcium, vitamin D, and

anti-osteoporotic medication such as bisphosphonates,] parathyroid hormone (PTH), raloxifene, and estrogen. In addition, potentially treatable underlying causes of osteoporosis such as hyperparathyroidism and hyperthyroidism should be ruled out or treated if detected.

• Surgical care includes vertebroplasty and kyphoplasty. Vertebroplasty and kyphoplasty are minimally invasive spine procedures used for the management of painful osteoporotic vertebral compression fractures.

• The first goal of rehabilitation in osteoporosis patients is to control pain if a fracture has occurred. Spinal compression fractures can be extremely painful and can cause short- and long-term morbidity. Oral analgesics on a regular schedule can be implemented. Pain-relieving modalities such as moist hot packs and transcutaneous electrical nerve stimulation should also be considered

• • A comfortable mechanical support for the spine and, in some cases, a thoracic

orthosis may need to be prescribed

Pharmacologic Therapy• 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: teriparatide(PTH)

Hormone replacement therapy• 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.

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

Vertebroplasty and Kyphoplasty

Dietary Measures• Adequate 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.

• 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.

• 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, have been strongly associated with bone loss.

Calcium and vitamin D supplementation• Current recommendations from the American Association of Clinical

Endocrinologists (AACE) for daily calcium intake are as follows :• 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• 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

Vitamin D• The minimum daily requirement in patients with osteoporosis is 800 IU of

vitamin D3, or cholecalciferol.• 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.

• Calcium and vitamin D studies• Several large studies have demonstrated that supplementation with a

combination of calcium and vitamin D can reduce fracture risk.[117]

• Another meta-analysis concluded that vitamin D alone is not effective in preventing fractures, although, when administered with calcium, hip fractures and total fractures (and possibly vertebral fractures) were reduced

Physical and Occupational Therapy• Physical therapy• Physical therapy focuses on improving a patient's strength, flexibility, posture, and balance to prevent falls

and maximize physical function. Postural retraining is key in this population. Spinal bone mineral density (BMD) is directly correlated with the strength of the back extensors; therefore, maintaining and strengthening the back extensors should be emphasized

• Occupational therapy• Home modification focuses on reducing the risk of falling by installing handrails and grab bars in hallways,

stairs, and bathrooms. The use of a shower chair, tub bench, and adaptive bathing devices also can be beneficial. The application of nonskid tape to steps (indoors and outdoors), as well as the removal of throw rugs, greatly improves home safety.

• Exercise• Aerobic low-impact exercises, such as walking and bicycling, generally are recommended.• exercises that place flexion forces on the vertebrae tend to cause an increase in the number of vertebral

fractures in patients.• Proper therapy for osteoporosis includes 3-5 sessions per week of weight-bearing exercises, such as

walking or jogging, with each session lasting 45-60 minutes• Although swimming is not a weight-bearing exercise that will improve BMD, it does provide chest

expansion, spinal extension, and low-impact cardiopulmonary fitness. Isometric exercises should also be used to strengthen abdominal muscles, aiding in the prevention of a kyphosis

• . Balance training incorporates the strengthening of various parts of the body (eg, trunk, legs), proprioception, and vestibular input. Several different exercises have been shown to be beneficial in patients with osteoporosis

Prevention of Osteoporosis• Primary prevention of osteoporosis starts in childhood.

Patients require adequate calcium intake, vitamin D intake, and weight-bearing exercise.

• • risk of developing osteoporosis: cigarette smoking; physical

inactivity; and intake of alcohol, caffeine, sodium, animal protein, and calcium

• 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.

Long-Term Monitoring

• Dual-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.

Thanks

Bone metabolic disorders

• Presentation?• Skeletal abnormality

– osteopenia - osteomalacia/osteoporosis– osteitis fibrosa cystica - replacement of bone with fibrous

tissue usually due to PTH excess• Hypercalcaemia• Underlying hormonal disorder• When to investigate?

– Under 50– repeated fractures or deformity– systemic features or signs of hormonal disorder

Osteomalacia

• Types• Vitamin D deficient• Hypophosphataemic

– growth decr +++ and severe deformity with wide epiphyses

– x-linked dominant– decreased tubular reabs of PO4– Ca normal but low PO4– Rx PO4 and vit D

WHO definition of osteoporosis

• 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.

• • For each standard deviation (SD) reduction in BMD,

the relative fracture risk is increased 1.5-3 times.

Endocrine disorders• Cushings• Hypopituitarism - GH def - prop dwarf or

Frohlich adiposogenital syndrome• Hyperpituitarism - gigantism or acromegaly• Hypothyroidism - cretinism or myxoedema• Hyperthyroidism - o’porosis• Pregnancy - backache, CTS, rheumatoid improves

SLE gets worse

The Fracture Risk Assessment (FRAX) tool

• White women between the ages of 50 and 64 years with ≥10-year fracture risks based on specific risk factors include the following persons[63] :

• A 50-year-old current smoker with a body mass index (BMI) less than 21 kg/m2, daily alcohol use, and parental fracture history

• A 55-year-old woman with a parental fracture history• A 60-year-old woman with a BMI less than 21

kg/m2 and daily alcohol use• A 60-year-old current smoker with daily alcohol use

Signs of fracture• a thoracic kyphosis with an exaggerated cervical lordosis (dowager hump).• loss of lumbar lordosis• . After each episode of vertebral compression fracture and progressive

kyphosis, the patient's height may decrease by 2-3 cm.• • Patients with acute vertebral fractures may have point tenderness over

the involved vertebrae. Palpation of the spinous processes often does not aid the examiner in localizing point tenderness, but percussion may be helpful in acute or subacute vertebral compression fractures.

• Patients with hip fractures may have severe pain with ambulation. A faber (ie, flexion in abduction and external rotation) hip joint test may reveal limited ROM with end-range pain.

• an antalgic gait pattern• Patients with pubic and sacral fractures may report marked pain with

ambulation and tenderness to palpation, percussion, or both• examination techniques used to assess the sacroiliac joint, such as the

faber, Gaenslen, or squish test.

Signs of collagen defects & Balance difficulties

• a short fifth digit, dentinogenesis imperfecta, hyperlaxity, hearing loss, pes planus, bunions, and blue sclerae.

• decreased balance• *difficulty performing tandem gait and

performing single limb stance• *with severe kyphosis

Biochemical Markers of Bone Turnover• 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)

•

WHO T-score and Z-score criteria• a normal T-score value as within 1 standard deviation (SD) of the mean

BMD value in a healthy young adultT-score of –1 to –2.5 SD indicates osteopenia

• T-score of less than –2.5 SD indicates osteoporosis• T-score of less than –2.5 SD with fragility fracture(s) indicates severe

osteoporosis• For each SD reduction in BMD, the relative fracture risk is increased 1.5-3

times• • premenopausal women, men younger than 50 years, or children. Instead,

Z-scores adjusted for ethnicity or race should be used, with values of –2.0 SD or lower defined as "below the expected range for age" and those above –2.0 SD being "within the expected range for age." The diagnosis of osteoporosis in these groups should not be based on densitometric criteria alone.

Single- and Dual-Photon Absorptiometry

• offers low radiation exposure, but it is relatively insensitive for detecting early-stage osteoporosis because it measures cortical rather than trabecular bone

• Bisphosphonates • 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.

• 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. 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.

• 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

• Treatment interval and complications with bisphosphonate therapy• • newly recognized complications of bisphosphonate use, including osteonecrosis of the jaw and atypical (subtrochanteric or femoral

shaft) femur fractures• 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• Patients at high risk may be continued on bisphosphonates after 5 years;

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

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

• Teriparatide is given for a maximum of 2 years• using a combination of concurrent PTH and bisphosphonate therapy showed decreased benefit

compared with therapy with either agent alone• 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. 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.

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%.

• 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 remodelingIt decreases bone resorption by inhibiting osteoclast activity

• It is indicated to increase bone mass in men and 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.