OsteoporosisDiagnosis and Treatment

Osteoporosis is the most common bone disease in humans, representing a major public health problem as outlined in

Bone Health and Osteoporosis: A Report of the Surgeon General (2004) [1].

Osteoporosis is a silent disease until it is complicated by fractures—fractures that occur following minimal trauma or in some cases, with no trauma.

Fractures are common and place an enormous medical and personal burden on the aging individuals who suffer them and take a major economic toll.

Osteoporosis can be prevented, diagnosed, and treated before fractures occur.

Even after the first fracture has occurred, there are effective treatments to decrease the risk of further fractures.

WHO diagnostic classification

Osteoporosis is defined by BMD at the hip or lumbar spine that is less than or equal to 2.5 standard deviations below the mean BMD of a young-adult reference population.

Diagnosis History

Thorough clinical examination assessing risk factors and secondary causes of osteoporosis

Lifestyle factorsAlcohol abuse, Excessive thinness Excess vitamin AHigh salt intake ImmobilizationInadequate physical activity Low calcium intake Smoking (active or passive)Vitamin D insufficiency

Genetic diseasesCystic fibrosis Ehlers-DanlosGaucher’s diseaseGlycogen storage diseases Hemochromatosis HomocystinuriaHypophosphatasia Marfan syndromeMenkes steely hair syndromeOsteogenesis imperfecta Parental history of hip fracture PorphyriaRiley-Day syndrome

Hypogonadal statesAndrogen insensitivityAnorexia nervosa Athletic amenorrheaHyperprolactinemia Panhypopituitarism Premature menopause (<40 years)Turner’s and Klinefelter’s syndromes

Endocrine disordersCentral obesityCushing’s syndrome Diabetes mellitus (types 1 and 2)Hyperparathyroidism Thyrotoxicosis

Gastrointestinal disordersCeliac disease Gastric bypass Gastrointestinal surgeryInflammatory bowel disease Malabsorption Pancreatic diseasePrimary biliary cirrhosis

Hematologic disordersHemophiliaLeukemia and lymphomas Monoclonal gammopathiesMultiple myeloma Sickle cell disease Systemic mastocytosisThalassemia

Rheumatologic and autoimmune diseasesAnkylosing spondylitisRheumatoid arthritis Systemic lupus

Neurological and musculoskeletal risk factorsEpilepsy Multiple sclerosis Muscular dystrophyParkinson’s disease Spinal cord injury Stroke

Miscellaneous conditions and diseasesAIDS/HIV Amyloidosis Chronic metabolic acidosisChronic obstructive lung disease Congestive heart failure DepressionEnd-stage renal disease Hypercalciuria Post-transplant bone disease Sarcoidosis

MedicationsAluminum (in antacids)Anticoagulants (heparin) AnticonvulsantsAromatase inhibitors Barbiturates Cancer chemotherapeutic drugsDepo-medroxyprogesterone GlucocorticoidsGnRH (gonadotropin-releasing hormone) agonistsLithium cyclosporine A and tacrolimus Methotrexate Total Parental nutritionProton pump inhibitors Selective serotonin reuptake inhibitorsTamoxifenThiazolidinediones

The diagnosis of osteoporosis is established by measurement of BMD or by the occurrence of adulthood hip or vertebral fracture in the absence of major trauma

Relationship Between Bone Density and Bone Strength

Bone density accounts for 60% to 80% of bone strength in untreated patients

Best early predictor of fracture risk

Permits diagnosis before fractures T-score

Rel

ativ

e R

isk

of H

ip F

ract

ure

0

10

20

30

-5 -4 -3 -2 -1 0

Guidelines for Bone Density Testing Screening

– All women age 65 and older– All men age 70 and older

Test postmenopausal women and men >50 if:– Fracture after age 50– Clinical risk factors for osteoporosis– Conditions/medications associated with bone loss

Ways of testing BMD Dual energy X-ray absorptiometry (DEXA) Peripheral dual energy X-ray absorptiometry (P-DEXA) Dual photon absorptiometry (DPA) Quantitative Computed Tomography (QCT) Quantitative Ultrasound

DEXA

Most accurate and standardized way of measuring bone density

Non invasive

Uses two different low dose X-ray beams to estimate bone density in spine and hip.

P-DEXA Portable

Measure density in peripheral sites

Results – Quicker than DEXA

Disadvantage – Inability to monitor treatment of osteoporosis

Sites of measurement Apart from hip and spine peripheral parts where bone density is

measured are Distal 1/3 Radius – Efficient in predicting fracture risk

Proximal phalynx

5th metatarsus

Mid shaft tibia- Monitoring of osteoporosis treatment

Contraindications for BMD

Pregnancy Recent gastrointestinal contrast studies. (recommended waiting for

atleast 72 hrs) Body weight exceeding limit for DEXA >120-130 kgs Hip replacement or spinal instrumentation

BMD measurement is not recommended in children or adolescents and is not routinely indicated in healthy young men or premenopausal women unless there is a significant fracture history or there are specific risk factors for bone loss.

Interpretation of Results Dexa measures BMD in grams of mineral per square centimeter of

scanned bone

Results are reported as T score (compared to a young-adult reference population of the same sex) Z score (compared to the BMD of an age-, sex-, and ethnicity-matched

reference population)

The difference between the patient’s BMD and the mean BMD of the reference population, divided by the standard deviation (SD) of the reference population, is used to calculate T-scores and Z-scores.

FRAX

FRAX® was developed by WHO to calculate 10-year probability of a hip fracture and 10-year probability of a major osteoporotic fracture (defined as clinical

vertebral, hip, forearm, or proximal humerus fracture) taking into account femoral neck BMD and the clinical risk factors

FRAX® algorithm is available at www.nof.org as well as at www.shef.ac.uk/FRAX, also available on newer DXA machines.

Additional bone densitometry technologies CT-based absorptiometry: Quantitative computed tomography

(QCT) measures volumetric integral, trabecular, and cortical bone density at the spine and hip and can be used to determine bone strength, QCT and pQCT are associated with greater amounts of radiation exposure than central DXA or pDXA.

Trabecular Bone Score (TBS) is an FDA-approved technique which is available on some densitometers. It may measure the microarchitectural structure of bone tissue and may improve the ability to predict the risk of fracture.

Quantitative ultrasound densitometry (QUS) does not measure BMD directly but rather speed of sound (SOS) and/or broadband ultrasound attenuation (BUA) at the heel, tibia, patella, and other peripheral skeletal sites.

Validated heel QUS devices predict fractures in postmenopausal women (vertebral, hip, and overall fracture risk) and in men 65 and older (hip and nonvertebral fractures)

vertebral imaging All women age 70 and older and all men age 80 and older if BMD Tscore at the

spine, total hip, or femoral neck is ≤−1.0

Women age 65 to 69 and men age 70 to 79 if BMD T-score at the spine, total hip, or femoral neck is ≤−1.5

Postmenopausal women and men age 50 and older with specific risk factors Low-trauma fracture during adulthood (age 50 and older) Historical height loss of 1.5 in. or more (4 cm)b

Prospective height loss of 0.8 in. or more (2 cm)c

Recent or ongoing long-term glucocorticoid treatment

If bone density testing is not available, vertebral imaging may be considered based on age alone

Current height compared to peak height during young adulthood and Cumulative height loss measured during interval medical assessment

If bone density testing is not available, vertebral imaging may be considered based on age alone

(Current height compared to peak height during young adulthood and Cumulative height loss measured during interval medical assessment)

Presence of a single vertebral fracture

increases the risk of subsequent fractures by 5-fold and the risk of hip and other fractures 2-3 fold

Vertebral imaging can be performed using

lateral thoracic and lumbar spine X-ray or

lateral vertebral fracture assessment (VFA), available on most modern DXA machines.

VFA can be conveniently performed at the time of BMD assessment, while conventional X-ray may require referral to a standard X-ray facility.

Exclusion of secondary causes of osteoporosis Blood or serum Complete blood count (CBC) Chemistry levels (calcium, renal

function, phosphorus, and magnesium) Liver function tests Thyroid-stimulating hormone (TSH)

+/− free T4 25(OH)D Parathyroid hormone (PTH) Total testosterone and

gonadotropin in younger men Bone turnover markers Consider in selected patients Serum protein electrophoresis

(SPEP),

serum immunofixation, serum-free light chains Tissue transglutaminase antibodies

(IgA and IgG) Iron and ferritin levels Homocysteine Prolactin Tryptase Urine 24-h urinary calcium Consider in selected patients Protein electrophoresis (UPEP) Urinary free cortisol level Urinary histamine

Biochemical markers of bone turnover may :

Predict risk of fracture independently of bone density in untreated patients

Predict rapidity of bone loss in untreated patients

Predict extent of fracture risk reduction when repeated after 3–6 months of treatment with FDA-approved therapies

Predict magnitude of BMD increases with FDA-approved therapies

Help determine duration of “drug holiday” and when and if medication should be restarted

Osteoporosis management Universal recommendations for all patients

Adequate intake of calcium and vitamin D lifelong participation in regular weight-bearing and muscle-strengthening

exercise cessation of tobacco use identification and treatment of alcoholism Treatment of risk factors for falling

Benefits of exercise

Small (1% to 2%) effect on adult BMD

Reduces the loss of muscle mass

May reduce risk of falls by improving strength and balance

Regular walking decreases risk of hip fractures

Calcium Intake Recommendations

Vitamin D Intake Recommendations

Calcium supplements

Calcium salt Elemental calcium (%)

Carbonate 40

Tricalcium phosphate 38

Citrate 21

Lactate 13

Gluconate 9

The body can absorb only about 500 milligrams of a calcium supplement at any one time

An extra 500-700mg of calcium per day is sufficient for most people to achieve their appropriate daily calcium intake

Carbonates – require gastric acidity Citrates – readily absorbable ( not dependent on acidic medium )

Interactions Decrease levels of the drug digoxin

calcium and vitamin D supplements with digoxin or thiazides may also increase the risk of hypercalcemia

Also interact with fluoroquinolones, levothyroxine, antibiotics in the tetracycline family, and phenytoin decreasing their absorption.

Aluminum and magnesium antacids can both increase urinary calcium excretion

Proton pump inhibitors decrease gastric acidity decreased calcium absorption

Mineral oil and stimulant laxatives can both decrease dietary calcium absorption

Calcium and bisphosphonates Bisphosphonate drugs are poorly absorbed from the GI tract and can

bind calcium

Therefore, bisphosphonate drugs should be taken on an empty stomach with a 30–60 minute post-dose fast.

To ensure adequate absorption, it is prudent to avoid taking calcium supplements around the dose of oral bisphosphonates.

Phytates (found in cereals, bran, soy beans, seeds) and oxalates (found in spinach, rhubarb, walnuts), caffeine

Inadequate vitamin D – Less calcium is absorbed in the intestines of people with inadequate vitamin D levels.

Long term treatments with steroids Kidney disease

Side effects Nausea , vomitings , constipation, bloating, flatulence calcium supplements are associated with an increased risk of kidney stones in

people with a pre-existing high dietary calcium intake (≥1200mg/per day)

Vitamin D supplementation Most available supplements are Vit-D3 (cholecalciferol) D2 – Ergocalceferol is produced by UV light irradiating a plant

compound (ergostrol) A moderately fair person

needs to expose their hands, face and arms (or equivalent area of skin which is about 15% of the body surface) to sunlight

for about 6-8 minutes 4-6 times a week just before 10am or just after 3pm in summer

Longer exposures would be needed in darker skinned individuals

GROUPS AT RISK OF VITAMIN D DEFICIENCY ARE the elderly people who are house-bound or in residential care naturally dark-skinned people those who cover their skin for cultural or religious reasons babies of vitamin D deficient mothers.

Dietary sources of vitamin D

fatty fish such as salmon, mackerel, and sardines which provide 300 to 600 units/3.5 ounces

egg yolks which provide 20 units/yolk cod liver oil which provides 400 units/teaspoonful fortified foods such as milk, orange juice, and some cereals which

provide about 100 units per serving

Serum Vit D level between 20 and 40 (+/-10) ng/mL -- Normal

An intake of 800 to 1000 international units (IU) of vitamin D3 per day for adults over age 50 is recommended.

The safe upper limit for vitamin D intake for the general adult population was set at 2,000 IU per day

Adults who are vitamin D deficient may be treated with

50,000 IU of vitamin D2 or vitamin D3 once a week

or the equivalent daily dose (7000 IU vitamin D2 or vitamin D3) for 8–12 weeks to achieve a 25(OH)D blood level of approximately 30 ng/ml

Followed by maintenance therapy of 1500–2000 IU/day

Hypervitaminosis D

fatigue loss of appetite weight loss excessive thirst excessive urination dehydration constipation irritability, nervousness ringing in the ear (tinnitus)

muscle weakness nausea, vomiting dizziness confusion, disorientation high blood pressure heart arrhythmias

Long-term complications of untreated hypervitaminosis D include:

kidney stones kidney damage kidney failure excess bone loss calcification (hardening) or arteries and soft tissues

Prevention Treatment

Approved Therapeutic Options

EstrogenAlendronateRisedronateIbandronate

Zoledronic acidRaloxifene

Calcitonin

PTH (teriparatide)Denosumab

Antiresorptive Decrease bone resorption Most treatment agents Examples: Bisphosphonates, SERMs, calcitonin,

estrogen, denosumab Anabolic

Stimulate bone formation Example: Teriparatide

Bisphosphonates Bisphosphonates are potent inhibitors of osteoclast-mediated bone

resorption widely used in the management of osteoporosis and other diseases of high bone turnover

synthetic analogs of pyrophosphate, an endogenous regulator of bone mineralization

Two major classes Non-nitrogen containing class (e.g., clodronate, tiludronate and etidronate) Nitrogen-containing class (e.g., pamidronate, alendronate, ibandronate,

riserdronate and zoledronate)

Cellular Mechanism of Action

1. Osteoclast actively reabsorbs bone matrix

2. BISPHOSPHONATE ( ) binds to bone mineral surface

3. BISPHOSPHONATE is taken up bythe osteoclast

4. Osteoclast is inactivated

5. Osteoclast becomes apoptotic (‘suicidal’) and dies

51

inhibiting farnesyl pyrophosphate synthase (FDPS)

Bisphosphonates Alendronate: 10 mg daily (tablet) or 70 mg weekly (tablet or liquid) for

treatment, 5 mg daily or 35 mg weekly for prevention Risedronate: 5 mg daily or 35 mg weekly (tablet); 150 mg monthly

(tablet) Ibandronate: 150 mg monthly by tablet; 3 mg intravenously over 15 to

30 seconds every 3 months Zoledronic acid: 5 mg by intravenous infusion over a minimum of 15

minutes once every year for treatment—and every other year for prevention

Indications Treatment and prevention of postmenopausal osteoporosis

Alendronate, risedronate, ibandronate, zoledronic acid

Prevention and/or treatment of glucocorticoid-induced osteoporosis Risedronate, zoledronic acid, alendronate

Treatment of men with low bone density Alendronate, risedronate, zoledronic acid

Increased bone density in the spine by 5% to 8% and at the hip by 3% to 6% after 3 years

Reduced incidence of vertebral fractures by 40% to 70%

Alendronate, risedronate and zoledronic acid reduced non-vertebral fractures (25% to 40%), including hip fractures (40% to 60%), in women with osteoporosis

Ibandronate: Overall, no effect observed on non-vertebral or hip fractures. In a post-hoc analysis, non-vertebral fracture reduction was seen in a high-risk subgroup with a baseline femoral neck T-score less than -3.0

Contraindications/Warnings/Precautions

Hypocalcemia

Creatinine clearance <30 cc/min (<35 cc/min for zoledronic acid)

For oral dosing: Esophageal stricture or impaired esophageal motility (alendronate); inability to stand or sit for at least 30 minutes (alendronate/risedronate) or 60 minutes (ibandronate)

Oral dosing requirements Tablets (with exception of delayed release risedronate) taken on an empty

stomach after overnight fast with 6 to 8 oz of plain water while in an upright position

Patients should not eat or lie down for at least 30 minutes (alendronate and risedronate) or 60 minutes (ibandronate)

Calcium and vitamin D supplements, if needed, should be taken at a different time of day than the oral bisphosphonate

Side effects

gastrointestinal problems such as difficulty swallowing and inflammation of the esophagus and stomach.

Osteonecrosis of the Jaw Atypical Fractures of Femur

Bisphosphonate holiday

In patients at high risk for fractures, continued treatment seems reasonable. Consider a drug holiday of 1 to 2 years after 10 years of treatment

For lower risk patients, consider a “drug holiday” after 4 to 5 years of stability

Follow BMD and bone turnover markers during a drug holiday period, and reinitiate therapy if bone density declines or markers increase

Hormone replacement therapy HRT has been shown to significantly decrease the number of fractures at

hip and spine

Skeletal effects: Decrease in biochemical markers of 50% to 60%

2-year BMD increase of 4% to 6% at hip and spine

Decreased incidence of vertebral and hip fractures (34%) after 5 years

Adverse effects of HRT

Breast cancer Venous thromboembolism Stroke Ovarian cancer Endometrial cancer Coronary heart disease Dementia

HRT HRT is available in a wide variety of oral as well as transdermal

preparations including estrogen only, progestin only and combination estrogen–progestin.

HRT dosages include cyclic, sequential, and continuous regimens.

Recommendations: HRT should be considered for women younger than 60 in which the benefits

outweigh the risks especially for those who cannot tolerate other osteoporosis treatments

Recommended as a treatment option for osteoporosis in women who have undergone an early menopause

For all women, the lowest effective dose should be used for the shortest time

The Concept of a SERMSelective Estrogen Receptor Modulator (EAAs: Estrogen Agonist/Antagonists)

Binds to the estrogen receptors

Produces an estrogen agonist effect in some tissues (bone, serum lipids, and arterial vasculature)

Produces an estrogen antagonist effect in others ( breast and uterus )

Raloxifene

• Raloxifene (60 mg daily)• Skeletal effects:

Decrease in biochemical markers of 30% 3-year BMD increases of 2% to 3% at hip and spine Decreased incidence of vertebral fractures (30% to 50%) in

women with pre-existing vertebral fractures or low bone density. No effect on non vertebral or hip fractures has been observed

• Extra-skeletal effects: reduction in invasive breast cancer

Raloxifene

Adverse effects Hot flashes 2- to 3-fold increased risk of venous

thromboembolic events No increased risk of stroke, but increased risk

of death following stroke Leg cramps

Denosumab

Monoclonal antibody to RANKL 60 mg subcutaneous injection every 6 months 9% increase in spinal BMD after 3 years in the pivotal

FREEDOM trial; 4% to 5% increase in hip BMD Reduction in fracture risk after 3 years:

68% decrease in new vertebral fractures 40% decrease in hip fractures 20% decrease in nonvertebral fractures

8-year data: continued increase BMD, reduced bone turnover, good safety

Denosumab Adverse Events

Serious infections leading to hospitalization Dermatitis, eczema, rashes Back pain, pain in the extremity, musculoskeletal pain,

hypercholesterolemia, cystitis Pancreatitis Osteonecrosis of the jaw Significant suppression of bone remodeling

Calcitonin

Calcitonin (200 units daily by nasal spray) Skeletal effects:

Decrease in biochemical markers of 20% Small effect (1% to 2%) on bone density in spine Reduced incidence of vertebral fractures (36%) in women with pre-

existing vertebral fractures No effect on nonvertebral or hip fractures has been observed

Adverse effects Nasal stuffiness, rhinitis, epistaxis Possible increased cancer risk

Calcitonin

Approved for the treatment of osteoporosis in women who are at least 5 years postmenopausal when alternative treatments are not suitable

Teriparatide: rhPTH [1-34]

The only treatment agent that is anabolic—stimulates bone formation rather than inhibiting bone resorption

20 μg daily (subcutaneously) for no more than 2 years

Indication: treatment of men and postmenopausal women

with osteoporosis who are at high risk for fracture

Effects:

Increased bone density in spine by 9% and hip by 3% vs placebo over 18 months

Reduced incidence of vertebral fractures (65%) and nonvertebral fragility fractures (53%) in women with pre-existing vertebral fractures

Studies too small to evaluate effect on hip fractures

Adverse reactions: arthralgia pain Nausea osteosarcoma risk in rats

Sequential and combination therapy For more severe osteoporosis, sequential treatment

with anabolic therapy followed by an antiresorptive agent is generally preferred to concomitant combination therapy.

few indications for combining two antiresorptive treatments, considered in the short term in women who are experiencing active bone loss while on low dose HT for menopausal

symptoms or raloxifene for breast cancer prevention.

Duration of treatment

No pharmacologic therapy should be considered indefinite in duration All nonbisphosphonate medications produce temporary effects that

wane upon discontinuation Bisphosphonates may allow residual effects even after treatment

discontinuation Evidence of efficacy beyond 5 years is limited

Monitoring treatment encourage continued and appropriate compliance with their

osteoporosis therapies review their risk factors and encourage appropriate calcium and

vitamin D intakes, exercise, fall prevention, and other lifestyle measures

Accurate yearly height measurement is a critical determination of osteoporosis treatment efficacy

Loss of 2 cm (or 0.8 in.) or more in height either acutely or cumulatively repeat vertebral imaging test to determine if new or additional vertebral fractures have occurred

Physical medicine and rehabilitation reduce disability improve physical function lower the risk of subsequent falls

Recommendations improve posture and balance and strengthen quadriceps muscles to allow a

person to rise unassisted from chair

prescription for assistive device for improved balance with mobility

complete exercise recommendation that includes weightbearing aerobic activities for the skeleton, postural training, progressive resistance training for muscle and bone strengthening

Advise patients to avoid forward bending and exercising with trunk in flexion, especially in combination with twisting.

Thank you