Prepared by :Talal A. Takroni

Supervised by: Dr.Taha A. Samman

IntroductionOsteoporosis is the most common metabolic bone disease

defined as skeletal disorder characterized by decreased bone mass and deterioration of bony microarchitecture leading to fragile bones and an increased risk of fractures, even after minimal trauma.

It represents an increasingly serious problem, particularly as the population ages. It has been most commonly recognized in elderly women, although it does occur in both sexes, all races, and all age groups.

• Osteoporosis can result in devastating physical, psychosocial, and economic consequences eventhough, it is a condition that is often overlooked and undertreated, in large part because it is a clinically silent disease until it manifests in the form of fracture.

• The commonest sites affected are the vertebrae , hip (neck of femur) and distal radius.

Epidemiology Osteoporosis is estimated to affect over 200 million people

worldwide.

Gender:

Overall, osteoporosis has a female-to-male ratio of 4:1 . Of all patients with osteoporosis , 80% are women and 20% are

men. Fifty percent of all women and 25% of all men older than 50 years

experience an osteoporosis-related fracture in their lifetime. One in 3 women older than 50 years will eventually experience

osteoporotic fractures, as will 1 in 5 men.

Epidemiology Cont. Age Risk for osteoporosis increases with age. Bone mineral density declines

with age, and fractures become more prevalent as age increases. The frequency of postmenopausal osteoporosis is highest in women

aged 50-70 years.

Senile osteoporosis is most common in persons aged 70 years or older. Secondary osteoporosis can occur in persons of any age. Ninety percent of hip fractures occur in persons aged 50 years or older.

Race

Whites (especially of northern European descent) and Asian persons are at an increased risk for osteoporosis.

PathophysiologyOsteoporosis results from hereditary (primary

osteoporosis) and environmental factors (secondary osteoporosis) that affect both bone mass and bone quality.

Homeostasis of bone is maintained by the osteoblast, which is responsible for bone formation and the osteoclast, which is responsible for bone resorption .

Calcium, vitamin D, and parathyroid hormone help maintain bone homeostasis.

Imbalance of osteoclast activity(bone resorption) and osteoblast action(decreased bone formation) may result in osteoporosis.

Osteoclasts require weeks to resorb bone, whereas osteoblasts need months to produce new bone.

Bone strength is determined by collagenous proteins (tensile strength) and mineralized osteoid (compressive strength). The greater the concentration of calcium, the greater the compressive strength

Major Risk Factors for Primary OsteoporosisAge > 65 years.Family history of fragility fractures or osteoporosis.BMI < 19 or weight <58 Kg. Estrogen deficiency- premature menopause(<45) or

surgical oophrectomy or prolonged secondary amenorrhea(> 1year).

Hypogonadism in males.Previous fragility fracture ( not hip or spine).Propensity to falls. Current smoking status .Alcohol intake (3 or more drinks per day).

Causes of Secondary Osteoporosis:Endocrine: Hyperparathroidism Thyrotoxicosis Cushing’s syndrome Uncontrolled diabetes Hypopituitarism Hypogonadism

Rheumatological: Rheumatoid arthritis Ankylosing spondylitis SLE

Gatrointestinal: Malabsorption syndrome Inflammatory bowel disease Chronic active hepatitis Biliary cirrhosis Gastrectomy

Hematological: Multiple myeloma Leukemia Lymphoma SCA Thalasemia

Genetic: Osteogenesis imperfecta Hypophosphatemia Marfan syndrome Ehler-Danlos syndrome Homocystinuria

Miscellaneous: Anorexia nervosa Immobility Idiopathic hypercalciuria Vitamin C deficiency

Organ transplantation

Drugs: Steroids Antiepileptics Chronic Hparin therapy Lithium

Diagnosis of Osteoporosis:Laboratory studies: Laboratory studies are used to establish baseline conditions or to

exclude secondary causes of osteoporosis.• CBC count • Serum chemistries including calcium, phosphate, creatinine,

liver function tests and electrolytes. 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.

• Thyroid-stimulating hormone • 25-hydroxyvitamin D [25(OH)D]

Markers of bone turnover:

Bone formation markers - Bone-specific alkaline phosphatase, osteocalcin, type I procollagen peptides.

Bone resorption markers - Urinary deoxypyridinoline and cross-

linked N- and C-telopeptide of type I collagen.

Imaging Studies: Dual-energy x-ray absorptiometry

(DXA) is the standard study used to establish or confirm a diagnosis of osteoporosis, to predict future fracture risk, and to assess changes in bone mass over time.

T-scores represent the number of standard deviations (SD) from the mean bone density values in healthy young adults.

Z-scores represent the number of SD from the normal mean value for age- and sex-matched controls.

•Bone density data from a DXA are reported as T-scores and Z-scores.

•DXA is used to calculate bone mineral density (BMD) at the hip and spine mainly. Although measurement at any site can be used to assess overall fracture risk, measurement at a particular site is the best predictor of fracture risk at that site.

Criteria by the World Health Organization (WHO) define a normal T-score value as within 1 SD of the mean bone density value in a healthy young adult.

•T-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.

Additional imaging modalitiesQuantitative CT scanning: This is used to measure 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. Other limitations include significant radiation exposure, high cost, and possible interference by osteophytes.

Peripheral DXA: This is used to measure BMD at the wrist. Peripheral DXA may be most useful in identifying patients at very low fracture risk who require no further workup.

Quantitative ultrasonography of the calcaneus: This is a low-cost portable screening tool. This method does not involve radiation but is not as accurate as other methods and cannot be used to monitor the response to treatment because of its lack of precision.

Treatment of Osteoporosis1.Medical care: This line of management can be further divided into: General measures: Life style changes: weight bearing exercise, cessation of

smoking and avoiding alcohol with avoidance of fall by the use walking canes , sticks or frames.

Adequate calcium intake: the daily intake of calcium (dietary + supplement) should be 1200-1500mg/day.

Vitamin D :

Exposure to sun for 10-15minutes 2-3times/week is recommended.

All patients should receive vitamin D supplements 600-800 units of Vit. D3 daily and higher doses if Vit.D is deficient.

Vitamin D analogues can be used especially in renal disease pt. in a dose of 0.25-0.5mcg of 1-Alpha Calcidol or Calcitriol.

Specific measures using medications: Drugs used to treat osetoporosis can be classified into: Antiresorptive agents ( inhibit bone resorption):

Anabolic agents (stimulate bone formation):

Dual Acting agents(mixed action of the above mentioned agents)

•Bisphosphonates•Calcitonin•Selective estrogen receptor modulators•HRT

•Fluoride•Parathyroid hormone rhPTH(1-34)=Teriparatide

•Stronium Ranelate

Biphosphonstes These drugs have proven efficacy in reducing vertebral and non-

vertebral fracturesAlendronate( Fosamax): Dose 70mg/week or 10mg/day.

Reflux esophagitis and esophageal ulcers are the main complications therefore should be taken in the morning at least 30 min before breakfast with a good amount of water( 8 oz) and remain in upright position.

Ibandronate: Dose 2.5mg orally once daily or 150mg once motnhly or, 3mg IV every 3 months

Pamidronate: given as an infusion in NS 30mg every 3monthsRisedronate: Dose 5 mg/day.

Selective estrogen receptor modulators( SERM)Reduces vertebral fractures, efficacy in non-vertebral

fractures is not established. Raloxifine(Evista): Dose 60mg/day.

Used by postmenopausal women in place of estrogen because it does not cause endometrial hyeprplasia, uterine bleeding , or breast cancer But does not relieve menopause symptoms as good as estrogen.

Calcitonin

Only proven efficacy is in preventing vertebral fractures in those women with previous vertebral fractures.

Calcitonin( Miacalcic ): Dose 200 units intranasal daily. It may be effective in reducing pain after a recent fracture.

Dual Acting agents

Effective in reducing vertebral and non-vertebral fractures. Stronium Ranelate(Protelos®): Dose 2mg orally once daily One sachet to be dissolved in a glass of water & taken at bedtime, after meal.

Parathyroid HormoneEndogenous 84 amino-acid parathyroid hormone (PTH) is a

primary regulator of bone and mineral metabolism. The skeletal effects of parathyroid hormone depend upon

the pattern of exposure. High dose chronic release of this hormone leads to bone resorption and bone loss (hyperparathyroidism); in contrast, once daily administration of recombinant (1-34) PTH or teriparatide preferentially stimulates new bone formation of trabecular and cortical bone.

They found that only a portion of PTH , amino acid sequence ( 1-34 ) has an anabolic effect if given as intermittently.

Approved for postmenopausal osteoporosis and male osteoporosis.

Teriparatide( Forteo®)

Teriparatide ( Forteo®) Anabolic agent increases BMD at lumbar spine by 9-13% and hip by 3-6% compared with placebo. Reduced the risk of spine fractures by 65% and nonspinal fractures by 54% in patients after an average of 18 mo of therapy.

Figure 1. Percent of postmenopausal women with osteoporosis attaining a lumbar spine BMD percent change from baseline at least as great as the value on the x-axis (median duration of treatment 19 months).

Figure 2. Cumulative percentage of postmenopausal women with osteoporosis sustaining new nonvertebral osteoporotic fractures

It is avilable as 750mcg/ 3ml-single pen.

Route of Administration: subcutaneous injection into the thigh or abdominal wall.

Dose: is 20 mcg once a day.

Length of Use: Maximum period of use 18 months.

Each FORTEO pen can be used for up to 28 days including the first injection from the pen.

No data are available on the safety or efficacy of intravenous or intramuscular injection of FORTEO.

The safety and efficacy of FORTEO have not been evaluated beyond 2 years of treatment. Consequently, use of the drug for more than 2 years is not recommended

It is stored under refrigeration at 36-46 degrees F (2-8 degrees Centigrade) at all times.

Cost: The Average Wholesale Price (AWP) of teriparatide is $7,592 per year.

Teriparatide is extensively absorbed after subcutaneous injection; the absolute bioavailability is approximately 95%.

The peptide reaches peak serum concentrations about 30 minutes after subcutaneous injection of a 20–mcg dose and declines to non–quantifiable concentrations within 3 hours.

Peripheral metabolism of PTH is believed to occur by non–specific enzymatic mechanisms in the liver followed by excretion via the kidneys. The half–life of teriparatide in serum is 5 minutes by IV injection and approximately by 1 hour SQ injection.

The longer half–life following subcutaneous administration reflects the time required for absorption from the injection site.

Human Pharmacokinetics of FORTEO

Daily administration of Forteo to men and postmenopausal women with osteoporosis in clinical studies stimulated bone formation, as shown by increases in the formation markers serum bone–specific alkaline phosphatase (BSAP) and procollagen I carboxy–terminal propeptide (PICP).

Effects on markers of bone turnover

Most side effects are mild and include:•nausea.

•dizziness or fast heartbeat. This usually happens within 4 hours of taking Forteo and goes away within a few hours.

•leg cramps.

•joint aches.

•increased calcium in the blood. (Usually manifests by continuing nausea, vomiting, constipation, low energy, or muscle weakness). These may be signs there is too much calcium in the blood.

•injection site reactions including redness, swelling, pain, itching, a few drops of blood, and bruising.

Surgical Care The goals of surgical treatment of osteoporotic

fractures include rapid mobilization and return to normal function and activities.

Fixation and stabilization of hip or wrist fracture Vertebroplasty to reduce vertebral fracture–

associated pain Kyphoplasty to restore height or to treat the

deformity associated with osteoporotic vertebral fractures

TALAL A. TAKRONIIntern (UQU)