Osteoporosis

Adapted and presented by:Taraneh Dormohammadi Toosi, MD

Assistant professor of internal medicine Rheumatology

Tehran university of medical scienceValiasr hospita

Definition

• A reduction in the strength of bone that leads to an increased risk of fractures

• Loss of bone tissue is associated with deterioration in skeletal microarchitecture

Osteoporosis

• Prevalent – Postmenopausal women – Men and women • Underlying conditions • Major risk factors associated with bone

demineralization

The World Health Organization (WHO) definition

• A bone density that falls 2.5 standard deviations (SD) below the mean for young healthy adults of the same (T-score of –2.5)

• Low bone density– A T-score <–1.0– Increased risk of osteoporosis– More than 50% of fractures among postmenopausal

women

Epidemiology

• United States– 8 million women and 2 million

men have osteoporosis (T-score <–2.5)

– 18 million individuals have bone mass T-score <–1.0

• The epidemiology of fractures – Follows the trend for loss of bone density– Fractures of the distal radius increase in frequency

before age 50 and plateau by age 60– Hip fractures double every 5 years after age 70

• A hip fracture (50 years –old) – 14% for women – 5% for men

• Hip fractures – Deep vein thrombosis – Pulmonary embolism (20–50%) – Mortality rate between 5 and 20% (after surgery)

• Multiple vertebral fractures – Height loss (often of several inches)– Kyphosis– Pain and discomfort – Thoracic fractures – Restrictive lung disease

• Lumbar fractures • Abdominal symptoms – Distention, early satiety, and constipation

Risk factors for osteoporotic fracture

Bone mass

• Genetic factors primarily determine peak skeletal mass and density

• Nutrition and lifestyle also play an important role in growth

• Heritability – 50–80% for bone density and size

• Candidate genes – Vitamin D receptor– Type I collagen– The estrogen receptor (ER)– Interleukin 6 (IL-6)– Insulin-like growth factor I (IGF-I)]

• Genetic locus on chromosome 11 is associated with high bone mass

• Families with high bone mass – Point mutation in LRP5 (low-density lipoprotein

receptor–related protein)

Physiopathology

Remodeling

• A process that results initially in bone resorption by osteoclasts, followed by a period of repair during which new bone tissue is synthesized by osteoblasts

Bone remodeling has two primary functions1) Repair micro damage within the skeleton to maintain skeletal strength and 2) Supply calcium from the skeleton to maintain serum calcium

Remodeling

• RANK ligand (RANKL) – The cytokine – Receptor activator of nuclear factor-kappa-B (NFκB)– A member of the TNF family– Secreted by osteoblasts

• RANK– The osteoclast receptor

• Activation of RANK by RANKL is a final common path in osteoclast development and activation

Remodeling

• Osteoprotegerin– A humoral decoy for RANKL– Secreted by osteoblasts

• Modulation of osteoclast recruitment and activity appears to be related to the interplay among these three factors

• Additional influences – Nutrition (particularly calcium intake) – Physical activity level

• After age 30–45– Resorption exceeds formation

• Exaggerated in women after menopause

• Excessive bone loss – An increase in osteoclastic activity And/or – Decrease in osteoblastic activity

Calcium Nutrition

• Peak bone mass may be impaired by inadequate calcium intake during growth

• During the adult phase of life– Insufficient calcium intake contributes to relative

secondary hyperparathyroidism – Increase in the rate of bone remodeling

• PTH– Stimulates the hydroxylation of vitamin D in the

kidney– Increased levels of 1,25-dihydroxyvitamin D

[1,25(OH)2D] – Enhanced gastrointestinal calcium absorption– Reduces renal calcium loss

• Total daily calcium intakes – The recommended daily required intake • 1000–1200 mg for adults

Vitamin D

• Optimal targets for serum 25(OH)D are >75 nmol/L (30 ng/mL)

• An intake of 800–1000 units/d

• Estrogen deprivation– The life span of osteoblasts may be decreased– Longevity and activity of osteoclasts are increased

Physical Activity• Inactivity such as prolonged bed rest or

paralysis, results in significant bone loss• Concordantly, athletes have higher bone mass

than does the general population

Other Risk Factors

Chronic Disease

• Hypogonadal states – Turner's syndrome – Klinefelter's syndrome– Anorexia nervosa – Hypothalamic amenorrhea – Hyperprolactinemia

• Endocrine disorders – Cushing's syndrome – Hyperparathyroidism – Thyrotoxicosis – Type 1 diabetes mellitus – Acromegaly Adrenal insufficiency

• Nutritional and gastrointestinal disorders – Malnutrition – Parenteral nutrition – Malabsorption syndromes– Gastrectomy– biliary cirrhosis Pernicious anemia

• Rheumatologic disorders – Rheumatoid arthritis – Ankylosing spondylitis

• Hematologic disorders/malignancy – Multiple myeloma– Lymphoma and leukemia – Malignancy-associated parathyroid hormone (PTHrP)– Mastocytosis – Hemophilia – Thalassemia

• Selected inherited disorders– Osteogenesis imperfecta – Marfan's syndrome – Hemochromatosis – Hypophosphatasia – Glycogen storage diseases – Homocystinuria – Ehlers-Danlos syndrome – Porphyria– Menkes' syndrome – Epidermolysis bullosa

• Other disorders – Immobilization – Chronic obstructive pulmonary disease– Pregnancy and lactation – Scoliosis – Multiple sclerosis – Sarcoidosis – Amyloidosis

Medications

• Cigarette Consumption– Toxic effects on osteoblasts – Indirectly by modifying estrogen metabolism– Intercurrent respiratory and other illnesses– Frailty– Decreased exercise– Poor nutrition– Need for additional medications • Glucocorticoids for lung disease

Measurement of Bone Mass

• DXA is a highly accurate x-ray technique – Standard for measuring bone density – Usually are made of the lumbar spine and hip

• Portable DXA machines have been developed that measure the heel (calcaneus), forearm (radius and ulna), or finger (phalanges)

• DEXA– Can not estimate the depth

or posteroanterior length of the bone

– Lower than average bone mineral density (BMD)

– Bone spurs• Falsely increase bone density of

the spine

"Normal" values – T-scores• Compare individual results to those in a young population

that is matched for race and sex

– Z-scores • Compare individual results to those of an age-matched

population that also is matched for race and sex

– A T-score below –2.5 in the lumbar spine, femoral neck, or total hip is taken as a diagnosis of osteoporosis

• CT – Spine – Hip– Three-dimensional – A true density – Analyze trabecular bone and cortical bone content

and volume separately• Expensive, involves greater radiation

exposure, and is less reproducible than DXA

• US – Low cost and mobility– A screening procedure

• The hip is the preferred site of measurement in most individuals

• In younger individuals such as perimenopausal or early postmenopausal women, spine measurements may be the most sensitive indicator of bone loss.

When to Measure Bone Mass

When to Treat Based on Bone Mass Results

• T-score ≤–2.5• Postmenopausal women with fracture risk factors – Age– Prior fracture– Family history of hip fracture– Low body weight– Cigarette consumption– Excessive alcohol use– Steroid use– Rheumatoid arthritis

Assessment of fracture risk

• FRAX calculators (http://www.shef.ac.uk/FRAX/tool.jsp?

locationValue=9)

Laboratory Evaluation• A general evaluation – Complete blood count– Serum and 24-h urine calcium– Renal and hepatic function

• An elevated serum calcium – Hyperparathyroidism – Malignancy

• A reduced serum calcium level – Malnutrition – Osteomalacia

Laboratory Evaluation• A low urine calcium (<50 mg/24 h)– Osteomalacia, malnutrition, or malabsorption

• A high urine calcium (>300 mg/24 h)– hypercalciuria • A renal calcium leak• Absorptive hypercalciuria

– Idiopathic or associated – Increased 1,25(OH)2D in granulomatous disease

• Hematologic malignancies • Excessive bone turnover

– Paget's disease, hyperparathyroidism, and hyperthyroidism.

Laboratory Evaluation

• Cushing's syndrome– Urinary free cortisol levels or a fasting serum cortisol

• Bowel disease, malabsorption, or malnutrition is suspected– Serum albumin, cholesterol, and a complete blood

• Asymptomatic malabsorption – Anemia

• Macrocytic—vitamin B12 or folate deficiency• Microcytic—iron deficiency

– Low serum cholesterol or urinary calcium levels

Laboratory Evaluation

• Asymptomatic celiac disease – Antigliadin, antiendomysial, or transglutaminase

antibodies – Require endoscopic biopsy– A trial of a gluten-free diet can be confirmatory

Laboratory Evaluation

Mastocytosis• Osteoporosis with • Rash, multiple allergies, diarrhea, or flushing, • 24-h urine histamine collection or serum

tryptase

Laboratory Evaluation

• Myeloma – Bone pain – Punched-out lesions on radiography

• Serum and urine electrophoresis and evaluation for light chains in urine are required to exclude this diagnosis– A bone marrow biopsy

Biochemical Markers

Bone turnover markers

• Response to therapy • Long-term adherence to treatment• Monitoring the effects of 1-34hPTH

• A decline in resorptive markers – After treatment with bisphosphonates or estrogen

• Less marked – After treatment with either raloxifene or

intranasal calcitonin

Treatment

• Management of acute fractures • Treatment of the underlying disease• Education

• Calcitonin – Reduce pain related to acute vertebral

compression fracture• Vertebroplasty or kyphoplasty– Percutaneous injection of artificial cement

(polymethylmethacrylate) into the vertebral body• Immediate pain relief

• Early mobilization is recommended

Severe pain usually resolves within 6–10 weeks

• Chronic pain – Abnormal strain on muscles, ligaments, and

tendons – Facet-joint arthritis – Thoracic and/or abdominal shape

Treatment

• Education– Reduce the impact of modifiable risk factors

associated with bone loss and falling– Medications • Glucocorticoid

– As low as possible

• Levothyroxin

– Smoking cessation– Reducing risk factors for falling

Nutritional Recommendations

• Calcium – Dairy products and other foods• Milk, yogurt, and cheese, fortified foods

– Calcium supplementation

Adequate Calcium intake

Calcium content

• Calcium supplements containing carbonate are best taken with food since they require acid for solubility

• Calcium citrate supplements can be taken at any time

Vitamin D

• Serum 25(OH)D consistently >75 μmol/L (30 ng/mL)

• Daily intakes – 200 IU for adults <50 years of

age– 400 IU for 50–70 years– 600 IU for >70 years

• Higher doses (≥1000 IU) – Elderly and chronically ill

Other Nutrients

• Salt, high animal protein intakes, and caffeine may have modest effects on calcium excretion or absorption

• Adequate vitamin K status is required for optimal carboxylation of osteocalcin

• Cola intake is controversial – Reduced bone mass through factors that are

independent of caffeine

Exercise

• Young individuals increases the likelihood that they will attain the maximal genetically determined peak bone mass

Exercise

• Beneficial effects on neuromuscular function

• Improves coordination, balance, and strength

• Reducing the risk of falling– A walking program – Dancing, racquet sports, cross-

country skiing, and use of gym equipment

– At least three times a week

Pharmacologic therapies

Estrogens

• Reduce bone turnover• Prevent bone loss• Induce small increases in bone mass of the

spine, hip, and total body

Estrogen effects

• The indirect estrogen actions primarily decrease bone resorption– Increasing IGF-I and TGF-β and – Suppressing IL-1 (α and β), IL-6, TNF-α, and

osteocalcin synthesis

SERMs

• Raloxifene, which is approved for the prevention and treatment of osteoporosis

• Tamoxifen, which is approved for the prevention and treatment of breast cancer

Mode of Action of SERMs

• All SERMs bind to the ER, but each agent produces a unique receptor-drug conformation

Bisphosphonates

• Alendronate and Risedronate

– Approved for the prevention and treatment of steroid-induced osteoporosis

– Approved for treatment of osteoporosis in men

Mode of Action

• Impair osteoclast function • Reduce osteoclast number– Inducing apoptosis

Calcitonin

• Approved by the FDA – Paget's disease– Hypercalcemia– Osteoporosis in women >5 years past menopause

• Not indicated for prevention of osteoporosis

Mode of Action

• Suppresses osteoclast activity by direct action on the osteoclast calcitonin receptor

Denosumab

• Given twice yearly/SC • Increase BMD in the spine, hip, and forearm • Reduce vertebral, hip, and nonvertebral

fractures

• Denosumab was approved by the FDA in 2010 – Treatment of postmenopausal women who have a

high risk for osteoporotic fractures– Failed or are intolerant to other osteoporosis

therapy

Mode of Action

• Fully human monoclonal antibody to RANKL• Inhibit its ability to initiate formation of

mature osteoclasts • Reducing the survival of the osteoclast• Serious adverse reactions – Hypocalcemia, infections, and dermatologic

reactions such as dermatitis, rashes, and eczema

Parathyroid Hormone

• PTH also can exert anabolic effects on bone• Teriparatide has been approved for the

treatment of established osteoporosis in both men and women

• 20 μg PTH(1–34) daily by SC injection reduced vertebral fractures by 65% and nonvertebral fractures by 45%

• Single daily injection given for a maximum of 2 years

• Increases in bone mass and mediates architectural improvements in skeletal structure

• Side effects – Mild and can include muscle pain, weakness,

dizziness, headache, and nausea– Osteogenic sarcomas

Mode of Action

• Direct actions on osteoblast activity• Stimulates IGF-I and collagen production and

appears to increase osteoblast number • Produces a true increase in bone tissue and an

apparent restoration of bone microarchitecture

Fluoride

• Despite increments in bone mass of up to 10%, there are no consistent effects of fluoride on vertebral or nonvertebral fracture

Strontium Ranelate

• Increases bone mass throughout the skeleton• Modestly antiresorptive while at the same

time not causing as much of a decrease in bone formation

• Small increased risks of venous thrombosis, seizures, and abnormal cognition

Treatment Monitoring

• Consider BMD as a monitoring tool– Changes must exceed 4% in the spine and 6% in

the hip to be considered significant – The hip is the preferred site due to larger surface

area and greater reproducibility– BMD should be repeated at intervals >2 years

Treatment Monitoring

• Biochemical markers of bone turnover – Determination should be made before therapy is

started and repeated ≥4 months after therapy is initiated

– A change in bone turnover markers must be 30–40% lower than the baseline

Primary Hyperparathyroidism

• A generalized disorder of calcium, phosphate, and bone metabolism

• Increased secretion of PTH• Hypercalcemia and hypophosphatemia

• The annual incidence – 0.2% in patients >60– Peak incidence between the third and fifth

decades

Etiology

• Parathyroid tumors – Isolated adenomas – Hereditary syndromes such as MEN syndromes– Secondary to underlying disease• Excessive stimulation in secondary hyperparathyroidism

– Chronic renal failure– Lithium therapy

Solitary Adenomas• A single abnormal gland –∼80% of patients– A benign neoplasm or adenoma – Rarely a parathyroid carcinoma

• ∼15% of patients– All glands are hyperfunctioning

Pathology

• Adenomas – Inferior parathyroid glands– 6–10% • Thymus, the thyroid, the pericardium, or behind the

esophagus

– Microscopic examination of biopsy specimens of several glands is essential

Parathyroid carcinoma

• Not aggressive• More aggressive form– Distant metastases

• Lung, liver, and bone

• Hyperparathyroidism due to parathyroid carcinoma – More severe clinically– Calcium values of 3.5–3.7 mmol/L (14–15 mg/dL) are

frequent with carcinoma – Genetic basis of parathyroid carcinoma

Signs and Symptoms

• One-half – Asymptomatic

• Kidney involvement– Deposition of calcium in the renal parenchyma • Decreased renal function and phosphate retention

– Recurrent nephrolithiasis• Urinary tract obstruction, infection, and loss of renal

function

• Manifestations– Recurrent nephrolithiasis– Peptic ulcers– Mental changes– Extensive bone resorption– Milder form of the disease • Asymptomatic HPT

– Hypercalcemic parathyroid crisis• Occur abruptly • Marked dehydration and coma, so-called

• Osteitis fibrosa cystica– 10–25% of patients in series reported 50 years ago

• Histologically– An increase in the giant multinucleated osteoclasts – Replacement of the normal cellular and marrow

elements by fibrous tissue• X-ray changes – Resorption of the phalangeal tufts – Subperiosteal resorption– Osteitis fibrosa cystica

In symptomatic patients• Dysfunctions – CNS, peripheral nerve and muscle, gastrointestinal

tract, and joints also occur– Severe neuropsychiatric manifestations

• May be reversed by parathyroidectomy

• Neuromuscular manifestations – Proximal muscle weakness– Easy fatigability– Atrophy of muscles

• Complete regression of neuromuscular disease after surgical correction of the hyperparathyroidism.

• Gastrointestinal manifestations – Vague abdominal complaints and disorders of the

stomach and pancreas– Duodenal ulcer• In MEN 1 patients

• Asympomatatic primary hyperparathyroidism – Biochemically confirmed hyperparathyroidism – The absence of signs and symptoms

• Cardiovascular disease – Left ventricular hypertrophy, cardiac functional

defects, and endothelial dysfunction – Reversible after surgery

• Diagnosis– PTH immunometric assays combined with

simultaneous blood calcium measurements

Treatment

Treatment

• Hyperparathyroidism– Surgical excision – Evidence favoring surgery, if medically feasible, is

growing • Concerns about skeletal, cardiovascular, and

neuropsychiatric disease, even in mild hyperparathyroidism

• Preoperative 99mTc sestamibi scans with single-photon emission CT (SPECT) – Predict the location of an abnormal gland

• A decline in serum calcium – Within 24 hours after successful surgery– Usually blood calcium falls to low-normal values

for 3–5 days • Acute postoperative hypocalcemia – Only if severe bone mineral deficits – Injury to all the normal parathyroid glands occurs

during surgery

• Hypocalcemia – Muscle twitching– A general sense of anxiety– Positive Chvostek's and Trousseau's signs – Serum calcium consistently <2 mmol/L (8 mg/dL)

• Parenteral calcium replacement in symptomatic patient

• If symptoms worsen or if parenteral calcium is needed for >2–3 days, therapy with a vitamin D analogue and/or oral calcium (2–4 g/d) should be started

• Hypoparathyroidism– Calcium falls to <2 mmol/L (8 mg/dL) And– Phosphate level rises simultaneously

• Unexpected hypocalcemia– Coexistent hypomagnesemia

Surgery in asymptomatic patient

Monitoring in asymptomatic patient

Other Parathyroid-Related Causes of Hypercalcemia

• Lithium Therapy– Hypercalcemia in 10% of treated patients∼– Remitting and recurring when lithium is stopped

and restarted– Shift the PTH secretion curve to the right in

response to calcium