Osteoporosis By : Dr- Rahma Alsulami

content………. Definition of osteoporosis Pathopysiology. Causes. Clinical approach. Who should be screened. Treatment Monitoring of TTT

Definition Osteoporosis is characterized by low bone mass, micro architectural disruption, and increased skeletal fragility. WHO has defined osteoporosis based upon dual-energy x-ray absorptiometry (DXA) measurements

Osteoporosis results from: hereditary (primary osteoporosis) and environmental factors (secondary osteoporosis. Traditionally, osteoporosis was described as type I (postmenopausal) or type II (senile). Postmenopausal osteoporosis (PMO) is primarily due to estrogen deficiency; senile osteoporosis is primarily due to an aging skeleton and calcium deficiency

WHO has defined osteoporosis based upon dual-energy x-ray absorptiometry (DXA) measurements Bone mass category A value for bone mineral density (BMD) within one standard deviation of the young adult female reference mean (T-score greater than or equal to -1 SD). normal A value for BMD more than one but less than 2.5 standard deviations below the young adult female reference mean (T-score less than -1 and greater than -2.5 SD). Low bone mass (osteopenia) A value for BMD 2.5 or more standard deviations below the young adult female reference mean (T-score less than or equal to -2.5). Osteoporosis A value for BMD more than 2.5 standard deviations below the young adult female reference mean in the presence of one or more fragility fractures. Severe (established) osteoporosis

Causes secondary primary Aging other endocrine GIT Renal rhematology genetic other primary Estrogen deficiency Aging

secondary osteoporosis Endocrine disorders – Hyperparathyrodism , hypogonadism , hyperthyrodism ,diabetes mellitus, Cushing disease, prolactenoma , acromegaly , adrenal insuffieincy Gastrointestinal/nutritional conditions –inflammotory bowel disease, celiac disease, malnutrition, history of gastric bypass surgery, chronic liver disease, anorexia nervosa, vitamin D or calcium deficiency Renal disease - Chronic kidney disease, idiopathic hypercalciuria

Rheumatologic diseases –RA ankylosing spondilities, SLE Hematologic disease –Multipe myeloma, thalassemia, leukemia, lymphoma, hemophillia, SCAsystemic mastocytosis. Genetic disorders Cystic fibrosis, osteogenesis imerfecta, homocysteinuria,, marfan syndrome, hemochromotosis, Other - Porphyria, sarcoid, immobilization, pregnancy/lactation, (COPD), parenteral nutrition, HIV/AIDS

Medications known to cause or accelerate bone loss Corticosteroids - Prednisone (≥5 mg/d for ≥3 mo) Anticonvulsants Heparin (long-term) Chemotherapeutic/ Hormonal/endocrine therapies – (GnRH) agonists, (LHRH) analogs, depomedroxyprogesterone, excessive thyroid supplementation Lithium Aromatase inhibitors Chemotherapeutic/transplant drugs - Cyclosporine, tacrolimus, platinum compounds, cyclophosphamide,, methotrexate These agents are associated with treatment-induced vitamin D deficiency.)

Clinical History Osteoporosis is typically asymptomatic until a fracture occurs. The history should focus on a thorough review of risk factors, which include the following: Age, sex, and race Family history of osteoporosis, particularly maternal history of fractures Reproductive factors, especially regarding early menopause and estrogen replacement therapy Lifestyle factors associated with decreased bone density Smoking Alcohol consumption Low levels of physical activity Strenuous exercise (such as occurs in marathon runners) that results in amenorrhea Calcium and vitamin D intake History of low-trauma “fragility

Coexisting medical conditions. Medications hx. Risk factors for falls in older patients Poor balance Orthosttic hypotention. Weakness of the lower extremity muscles, deconditioning Use of medications with sedative effects Poor vision or hearing Cognitive impairment Signs of vertebral fracture: Vertebral fracture may be asymptomatic. Patients with vertebral fractures may note progressive kyphosis with loss of height. Some may report acute back pain after bending, lifting, or coughing. The pain is located in the midthoracic to lower thoracic or upper lumbar spine, where most vertebral fractures occur. The pain is described variably as sharp, nagging, or dull; movement may exacerbate pain. In some cases, pain radiates to the abdomen. Acute pain usually resolves after 4-6 weeks. In the setting of multiple fractures with severe kyphosis, the pain may become chronic

examination Low body weight (body mass index <19 kg/m2) Kyphosis. Point tenderness over a vertebrae or other suspected fracture site Signs that might indicate a secondary cause of osteoporosis) Signs in older patients that may indicate increased fall risk Difficulty with balance or gait

Thyroid-stimulating hormone 25-hydroxyvitamin D [25(OH)D] Laboratory Studies CBC count calcium, phosphate, creatinine, liver function tests, 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 (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. However, further study is needed to determine their clinical utility in osteoporosis management. Some of these biochemical measures include the following:

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

Other laboratory studies used to evaluate for secondary causes include the following: Twenty-four-hour urine calcium to assess for hypercalciuria Intact parathyroid hormone Testosterone level (in males) Sedimentation rate. Urinary free cortisol and tests for adrenal hypersecretion. Serum and urine protein electrophoresis. Antigliadin and antiendomysial antibodies for celiac disease. Serum tryptase, urine N-methylhistamine for mastocytosis. Bone marrow biopsy if a hematologic disorder is suspected.

Imaging Studies Dual-energy x-ray absorptiometry Bone density data from a DXA are reported as T-scores and Z-scores. . T-scores represent the number of standard deviations (SD) from the mean bone density values in healthy young adults, whereas Z-scores represent the number of SD from the normal mean value for age- and sex-matched controls

Screening   Screening for osteoporosis involves fracture risk assessment and measurement of BMD (1). Most fractures occur in women and men who do not have osteoporosis by DXA criteria. Individuals with osteoporosis are at the highest relative risk of fracture, but there are more fractures in patients with low bone mass or osteopenia (T-score between -1.0 and -2.5) because there are so many more patients in this category. Therefore, assessment of risk factors that are independent of BMD is important for fracture prediction.

Premenopausal Women 1D. Routine screening for osteoporosis with a BMD test by DXA is not recommended for premenopausal women.

The National Osteoporosis Foundation and the International Society for Clinical Densitometry (ISCD) recommend that BMD be measured in the following patients: Women aged 65 years and older and men aged 70 years or older, regardless of clinical risk factors. Younger postmenopausal women and men aged 50-70 years with clinical risk factors for fracture. Women in menopausal transition with a specific risk factor associated with increased risk for fracture (ie, low body weight, prior low-trauma fracture, use of a high-risk medication) Adults with fragility fractures Adults who have a condition (eg, rheumatoid arthritis) or who take a medication (eg, glucocorticoids, ≥5 mg/d for ≥3 mo) associated with low bone mass or bone loss Anyone being considered for pharmacologic therapy for osteoporosis Anyone being treated for osteoporosis (to monitor treatment effect) Anyone not receiving therapy in whom evidence of bone loss would lead to treatment Radiographs may show fractures or other conditions such as osteoarthritis, disk disease, or spondylolisthesis. Plain radiography is not as accurate as BMD testing. Approximately 30-80% of bone mineral must be lost before radiographic lucency becomes apparent on radiographs.26 Additional imaging modalities Quantitative 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.

Validated risk factors that are independent of BMD include the following: Advanced age Previous fracture Long-term glucocorticoid therapy Low body weight (less than 58 kg [127 lb]) Family history of hip fracture Cigarette smoking Excess alcohol intake

treatment Who should be treated

National Osteoporosis Foundation guidelines for pharmacologic intervention in postmenopausal women and men 50 years of age:

Who should be treated: History of hip or vertebral fracture. T-score -2.5 (DXA) at the femoral neck, total hip, or spine, after appropriate evaluation to exclude secondary causes. .

T-score between -1.0 and -2.5 at the femoral neck, total hip, or spine, as measured by (DXA). andOther prior fractures T-score between -1.0 and -2.5 at the femoral neck, total hip, or spine and secondary causes associated with high risk of fracture, such as glucocorticoid use or total immobilization. T-score between -1 and -2.5 at the femoral neck, total hip, or spine, and a 10-year probability of hip fracture 3 percent or a 10-year probability of any major osteoporosis-related fracture 20 percent based upon the US-adapted WHO algorithm

WHO fracture risk algorithm: This algorithm (www. shef. ac WHO fracture risk algorithm: This algorithm (www.shef.ac.uk/FRAX/) was developed to calculate the 10-year probability of a hip fracture and the 10-year probability of any major osteoporotic fracture (defined as clinical spine, hip, forearm, or humerus fracture) in a given patient. These calculations account for femoral neck BMD and other clinical risk factors, as follows:

This algorithm is most useful in identifying patients with osteopenia who are most likely to benefit from treatment. The National Osteoporosis Foundation recommends osteoporosis treatment in patients with a low bone mass in whom a US-adapted WHO 10-year probability of a hip fracture is 3% or more or in whom the risk for a major osteoporosis-related fracture is 20% or more.7

Age Sex Personal history of fracture Low body mass index Use of oral glucocorticoid therapy Secondary osteoporosis (ie, coexistence of rheumatoid arthritis) Parental history of hip fracture Current smoking status Alcohol intake (3 or more drinks per day)

NONPHARMACOLOGIC THERAPY.

NONPHARMACOLOGIC THERAPY Calcium/vitamin D    Calcium 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 total of 1200-1500 mg of calcium daily.

Vitamin D Adults younger than 50 years should receive 400-800 IU of vitamin D 3 daily. All adults older than 50 years should receive 800-1000 IU of vitamin D 3 daily

Diet — When celiac disease is a major contributor to osteopenia, a gluten-free diet will result in improvement in bone mineral density

Exercise — Women with osteoporosis (or seeking to prevent it) should exercise (prudently) for at least 30 minutes three times per week, as exercise has been associated with improvements in or maintenance of bone density and a reduced risk of hip fracture in older women.

in a prospective cohort study of over 61,000 postmenopausal women, women who walked four hours or more per week had a 40 percent lower risk of hip fracture than those who walked ≤ one hour per week .

Any weight-bearing exercise regimen, including walking, is acceptable Any weight-bearing exercise regimen, including walking, is acceptable. A meta-analysis of 18 randomized trials of exercise and bone mineral density in postmenopausal women reported that aerobics, weight bearing, and resistance exercises increases spine density, while walking increases density at both the spine and hip . These conclusions are limited by the poor quality of allocation concealment

Smoking cessation smoking cigarettes accelerates bone loss.

PHARMACOLOGIC THERAPY Bisphosphonates. Selective estrogen receptor modulators.  Estrogen/progestin therapy. Parathyroid hormone.  Calcitonin .  

Mode of action Bisphosphonates are structurally related to pyrophosphate combounds that are incorborated into the bone matrix. Impair osteoclast function and reduce their number by apoptosis.

Bisphosphonates are also used in the management of hypercalcemia, Paget disease, and in a number of malignancies including multiple myeloma, breast cancer, and prostate cancer

Alendronate ALENDRONATE —  is effective for both the treatment and prevention of osteoporosis in postmenopausal women. The optimal suppression of bone turnover and increase in bone density with minimal side effects is achieved at an alendronate dose of approximately 10 mg/day ( Weekly administration of  is as effective as daily dosing. Use in chronic kidney disease — Bisphosphonates are generally not recommended for those with CCr below 30 to 35 mL/min

Alendronate cont: Increases BMD at spine by 8% and hip by 3.5%. Reduces the incidence of vertebral fractures by 47% and nonvertebral fractures by 50% over 3 y. Approved for treatment and prevention of postmenopausal osteoporosis, male osteoporosis, and steroid-induced osteoporosis.

Risedronate Increases BMD at spine by 5.4% and hip by 1.6%. Reduces vertebral fractures by 41% and nonvertebral fractures by 39% over 3 y. Approved for treatment and prevention of postmenopausal osteoporosis, male osteoporosis, and steroid-induced osteoporosis.

randomized trial of 5445 women aged 70 to 79 years with osteoporosis it reduces hip # by 40% in contrast it wasn't effective in women >80 y.

IBANDRONATE Increases BMD at spine by 5.7-6.5% and hip by 2.4-2.8%. Reduces vertebral fractures by 50% with intermittent (non-daily) dosing over 3 y. No effects on reduction of nonvertebral fractures. Approved for postmenopausal osteoporosis. ibandronate (150 mg) appears to improve BMD more than daily administration (2.5 mg).

Zoledronic acid Most potent bisphosphonate available. Increases BMD at spine by 4.3-5.1% and hip by 3.1-3.5% compared with placebo. Reduces the incidence of spine fractures by 70%, hip fractures by 41%, and non-vertebral fractures by 25% over 3 y. Approved for the treatment of postmenopausal osteoporosis.

Bisphosphonates should not be given to patients with active upper gastrointestinal disease. Bisphosphonates should be discontinued in patients who develop any symptoms of esophagitis. The reason for taking 8 oz of water is to minimize the risk of the tablet getting stuck in the esophagus. The reason for taking the medication while fasting and waiting one-half hour until eating or drinking is that bioavailability may be seriously impaired by ingestion with liquids other than plain water, such as mineral water, coffee, or juice, or by retained gastric contents, as with insufficient fasting time or gastroparesis, or by eating or drinking too soon afterwards. Patients should remain upright (sitting or standing) for at least 30 minutes after administration to minimize the risk of reflux.

Bisphosphonates should be taken alone on an empty stomach first thing in the morning with at least 240 mL (8 oz) of water. After administration, the patient should not have food, drink, medications, or supplements for at least one-half hour (alendronate, risedronate) or one hour (ibandronate).

HRT Hormone replacement therapy (HRT) was once considered a first-line therapy for the prevention and treatment of osteoporosis in women. Data from the Women's Health Initiative confirmed that HRT can reduce fractures. However, HRT was associated with an increased risk of breast ca, MI, stroke, and VTE events..

HRT is approved for management of menopausal symptoms and prevention of osteoporosis. It is no longer recommended as a treatment of osteoporosis in postmenopausal women.

Selective Estrogen Receptor Modulator (SERMs) act as weak estrogens in some organ systems, while acting as estrogen antagonists in others. Raloxifene is approved for the prevention and treatment of postmenopausal osteoporosis. .

Raloxifene (Evista) Increases BMD at spine and hip. Reduces the incidence of spine fractures by 30-55% over 3 y. Most suitable in women <70 y at moderate risk for osteoporosis who have infrequent vasomotor symptoms of menopause (eg, hot flashes) and who are at moderate-to-high risk for breast cancer.

Parathyroid Hormone Teriparatide is a biological product that contains a portion of human parathyroid hormone. When given intermittently, it increases bone remodeling with the net effect of increased bone mass and improved skeletal microarchitecture. (This is in contrast to continuous exposure to parathyroid hormone, which increases bone resorption with a net effect of decreased trabecular bone volume).

Teriparatide is approved in the United States for postmenopausal osteoporosis and primary or hypogonadal osteoporosis in men.

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. Approved for postmenopausal osteoporosis and male osteoporosis. 20 mcg SC qd

Calcitonin This agent is a peptide hormone used to treat osteoporosis in patients in whom bisphosphonates and estrogen are contraindicated or not tolerated. It also has some analgesic effects in patients with fractures.

Calcitonin (Miacalcin, Calcimar, Cibacalcin) Increases BMD at lumbar spine by 1-1.5%. Reduced incidence of spine fracture by 33% in group receiving 200 IU/d. Available in parenteral and intranasal forms; however, intranasal form is more convenient and better tolerated.

Monitoring of TTT 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.

THANK YOU For patients starting on therapy, we suggest a follow-up DXA of the hip and spine after two years, and if BMD is stable or improved, less frequent monitoring thereafter. For patients with conditions that might interfere with drug absorption or efficacy or patients who are reluctant to take anti-osteoporosis medications regularly, we typically measure fasting urinary NTX or serum CTX before and three to six months after starting bisphosphonates or other antiresorptive therapy. If the marker has not decreased by 50 (NTX) or 30 (CTX) percent, noncompliance or poor absorption, often related to an insufficient time interval between drug intake and food ingestion, should be considered. This approach (with markers of bone resorption) is only useful with antiresorptive therapy, not with recombinant PTH, (markers would increase). (See