ميحرلا نمحرلا الله مسب

Zahra Rezaieyazdi. MD.

Professor of Rheumatology

Ghaem Hospital

MUMS 19 AUG 2014

شدنزيم نيرفا لقع هک تسا يماج شدنزيم نيبج رب رهم ز هسوب دص فيطل ماج نينچرهد رگ هزوک نيا شدنزيم نيمز رب زاب و دزاسيم

مايخ

O STEOPOROSIS

D EFINITION



Disturbed balance between the activity of bone producing and bone resorbing cells



Low bone density



Deterioration of bone micro architecture Reduce bone strength and increase the risk of fracture

S PICULE OF B ONE B ONE LINING

CELLS

Osteoprogenitor cells Osteoblasts Osteoclast Cell process

©Copyright 2007, Thomas G. Hollinger, Gainesville, Fl

B ONE STRUCTURAL UNIT BONE REMODELING :

D

IFFERENTIATION

Osteoclast precursors 1. systemic factors 2. 1,25 dihydroxyvita min D, 3. parathyroid hormone 4. tumor necrosis factor (TNF) 5. thyroxin

RANKL PATHWAY M-CSF

C

ALCIUM HOMEOSTASIS

- PTH

ACTION

-ve feedback PTH Increased Ca Turnover with Net Resorption 1:25-DHCC Decreased Ca Clearance Increased Ca Absorption Plasma/ICF Ca++

D ETERMINANTS OF P EAK B ONE M ASS

Genetics Nutrition PEAK BONE MASS

20-22 years of age

Lifestyle Hormones

E STROGEN      

Increase osteoblast proliferation Attenuate the osteoblast response to PTH Osteoblastic collagen gene expression IGFII production inhibiting RANKL production and increasing production of the protein OPG

Bone mineral density in men as well as women is dependent on sufficient estrogen levels

BONE MASS AS A FUNCTION OF AGE

PEAK BONE MASS BONE MASS NORMAL FAILURE TO REACH PEAK ACCELERATED LOSS THEORETICAL FRACTURE THRESHOLD AGE

Effects of aging on Bone Loss:

ESTROGEN DEFICIENCY REDUCE OPG LEVELS DECREASE ABSORPTION OF CALCIUM INCREASE LEVELS OF IL DECREASE IGF , TGF -



-6 IL -1 DECREASE CALCITONIN LEVELS & VIT .

D AND TNF SECRETION -



P ATHOGENESIS OF TO B ONE L OSS C ALCIUM /V ITAMIN D D EFICIENCY IN THE A GED D UE

Impaired renal function Estrogen deficiency Decreased calcium absorption Decreased vitamin D synthesis Low dietary Calcium intake Secondary hyperparathyroidism Decreased sunlight exposure BONE LOSS

Why is osteoporosis such a disaster to us?

    At least 1.5 million fractures occur each year as a consequence of osteoporosis.

There are about 700,000 vertebral crush fractures per year in the About 300,000 hip fractures occur each year, most of which require hospital admission and surgical intervention. high incidence of deep vein thrombosis and pulmonary embolism (20–50%) and a mortality rate between 5 and 20% during the year after surgery.

16

Risk is equal to a combined risk of uterine, breast and ovarian cancer Mortality rate is 20%, and 50% never fully recover

17

C

LINICAL MANIFESTATIONS

O NO CLINICAL MANIFESTATION UNTIL THERE IS A FRACTURE



Osteoporosis is a silent Thief

19

C LINICAL MANIFESTATIONS



Fracture (may be asymptomatic)



Vertebral fractures (T8-L3)



Colles' fracture of distal forearm



Hip fractures



Other sites

Back pain Loss of height Dowager’s hump (dorsal kyphosis, and cervical lordosis)

21

Vertebral Fracture Cascade

DIAGNOSTIC INVESTIGATION

D IAGNOSIS



Examination



Measurements of height, posture, gait, strength, balance, and reflex testing

A SSESSMENT OF O STEOPOROTIC B ONE R ISK D ENSITY ,

Conventional radiography is an insensitive technique for diagnosing bone loss Demineralization or compression fractures of vertebral bodies Estimated 25% to 50% of bone mass must be lost to show osteopenia on radiographs

Radiographic Assessment

Radiographs may demonstrate signs of secondary osteoporosis subperiosteal resorption in hyperparathyroidism local sites of lytic destruction in malignancy pseudofractures in osteomalacia

DEXA (gold standard) :

dual-energy x-ray absorptiometry (DEXA) is both precise and safe, with a low radiation exposure.

With reproducibility errors of approximately 0.6% to 1.5%, newer DEXA techniques measure bone density rapidly, in 0.5 to 2.5 minutes.

Bone Mineral Density Compared with: peak bone mass of young, healthy controls (T score) age-matched controls ( Z score)

bone densitometry identifies patients with an increased gradient of risk for fracture.

in women older than 65 years, hip bone density is predictive of spine and hip fracture

1 SD decreased in BMD = 2 times increased in fracture risk

BMD measurement:

I NDICATIONS FOR B ONE D ENSITOMETRY

Indications for Bone Densitometry

 All postmenopausal women < 65 yr who have one or more additional risk factors for osteoporosis (besides menopause)  All women > 65 yr regardless of additional risk factors  To document reduced bone density in patients with vertebral abnormalities or osteopenia on radiographs  Estrogen-deficient women at risk for low bone density who are considering use of estrogen or an alternative therapy  to monitor the efficacy of a therapeutic interventions for osteoporosis(23 month)  To diagnose low bone mass in glucocorticoid-treated individuals  To document low bone density in patients with asymptomatic primary or secondary hyperparathyroidism

Screening normal premenopausal women is not cost-effective

The World Health Organization criteria for osteoporosis: 1. Normal bone density if the T score is greater than − 1 2. Osteopenia (low bone mass) is defined as T score between − 1 and − 2.5

3. Osteoporosis is defined as a bone density measurement less than 2.5 SD below that of young, healthy controls (T score < 2.5)

The National Osteoporosis Foundation recommends treatment for all individuals who have a lumbar spine, hip, or femoral neck T score of − 2.5 or lower. bone density between − 1 and − 2.5 Performing a Fracture Risk Assessment (FRAX)

FRAX provides a 10-year risk of a hip fractures or a major osteoporotic fracture (proximal humerus, and wrist).

The clinical risk factors in the FRAX program: age, weight, height, history of a fracture as an adult, parental history of a hip fracture, current glucocorticoid use, secondary cause of osteoporosis, alcohol intake and current smoker

Threshold to recommend treatment 10-year risk of: hip fracture ≥ 3% or major osteoporotic fracture ≥ 20% it is important to enter the country in which you are practicing medicine.

Evaluation of Osteoporosis

Evaluation for Secondary Bone Loss

For All Patients Laboratory tests including CBC, TSH, PTH, ESR serum calcium, phosphorus, alkaline phosphatase, 25-hydroxyvitamin D levels, measurement or estimate of 24-hr urinary calcium and creatinine levels For Selected Patients (Children, premenopausal women, men younger than 60 yr, patients with rapidly progressive disease) Definitive tests for endocrine, neoplastic, and gastrointestinal disorders liver function tests, Bone biopsy markers of bone turnover serum and urine protein electrophoresis for patients older than 50 years In men, serum testosterone and luteinizing hormone

M ANAGEMENT AND TREATMENT

Management of Osteoporosis

Lifestyle



Diet



Exercise



Smoking



Sunlight Exposure Pharmacological



Drugs altering BMD



Analgesia Non-pharmacological



Physiotherapy



Pain Relief Falls Assessment

P

AIN CONTROL IN FRACTURE



Oral analgesics

are first-line therapy for the relief of acute pain due to vertebral compression fractures.

 For inadequate pain relief with oral analgesics, adding

calcitonin



NOT using vertebroplasty or kyphoplasty

for the acute management of pain associated with osteoporotic compression fractures 

NOT using skeletal muscle relaxants

for the acute management of pain in patients with osteoporotic compression fractures  If bracing is used to relieve pain,

braces should be discarded as soon as possible

, since they promote immobility of the spine and the potential for disuse osteoporosis

A

DEQUATE

I

NTAKE OF

C

ALCIUM

&V

IT

D

 The NOF :  women age 51 & older :  1,200 mg per day of calcium.

 men age 50-70 :  1,000 mg per day of calcium  men age 71 and older :  1,200 mg per day of calcium.

I

NTAKE OF

C

ALCIUM

 excess of 1,200 to 1,500 mg per day :  may increase the risk of developing   cardiovascular disease  kidney stones stroke

A

DEQUATE

I

NTAKE OF

C

ALCIUM

& V

ITAMIN

D

 Increasing dietary calcium is the first-line approach, but calcium supplements should be used when an adequate dietary intake cannot be achieved  A balanced diet rich in low-fat dairy products, fruits and vegetables provide calcium

W

HO NEED CALCIUM PILL SUPPLEMENTATION

 Patient treated for osteoporosis  Patient treated with gluococorticoids  Individuals with low calcium intake

C

ALCIUM



Carbonate with meals & need acid for absorption



Calcium citrate don ’ t need acid & don ’ t produce renal stones



Night is good time for calcium supplementation



If over 500 mg must used divided dose especially breakfast



Calcium supplementation reduce iron absorption by 50%

Vitamin D plays a major role:



In calcium absorption



bone health

• 400 IU daily • Vitamin D is in milk (100 IU in 1 cup)

A

DEQUATE

I

NTAKE OF

V

ITAMIN

D



Vitamin D supplements should be recommended in amounts sufficient to bring the serum 25(OH)D level to approximately 30 ng/ml

F ALL PREVENTION 90% of all non vertebral fractures are related to fall

 Correction of decreased

visual

acuity  Reduction of

drug

consumption that altered wakefulness & balance  Improve

cardiac & neurologic

function  Improve

muscle

strength  Improving

home

environment  Wearing hip

protectors

Pharmachologic Therapy

Current treatments in OP

 Antiresorptive    Estrogens and SERMs Calcitonin Bisphosphonates  Denosumab – Anabolic (stimulate bone formation)  Parathyroid hormone  Dual action agents  Strontium ranelate

Osteoclast Inhibition of resorption Osteoblast Stimulation of formation

Hormone replacement therapy



Estrogen therapy decreased the risk of hip fractures by 25% to 30% and the risk of vertebral fractures by 50%.

H ORMONE REPLACEMENT THERAPY

•

Increased risk of seven more cardiac events, eight more breast cancer , eight more stroke, eight more pulmonary emboli, six fewer colorectal cancers, five fewer hip FX

T ESTOSTERONE

•

Men with hypogonadism may benefit from TES replacement therapy

Selective estrogen receptor modulators



Raloxifene (Evista): breast cancer Increased BMD, decreased risk of vertebral fractures (but not non-vertebral), LDL, risk of invasive



Dose: 60 mg/day



Adverse effect: Hot flushes, DVT

S ELECTIVE E STROGEN R ECEPTOR M ODULATOR

 SERMs are not recommended for premenopausal women.

C ALCITONIN



A less popular choice for treatment of osteoporosis is nasal spray



200 units (1 spray) daily



IM/SQ



100 units/every other day



Should perform skin test prior to initiating therapy

C ALCITONIN

 We prefer other drugs to calcitonin  Weak anti-fracture efficacy compared with bisphosphonates & parathyroid hormone  No significant effect in the hip region

Bisphosphonates

   

Alendronate (Fosamax) Risedronate (Actonel) better GI profile Ibandronate (Boniva) no hip protection Zoledronic Acid (Aclasta) once a year

Bisphosphonates

* •

Alendronate: 70 mg weekly for treatment, 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

B

ISPHOSPHONATES

: I

NDICATIONS

 Treatment and prevention of postmenopausal osteoporosis  Prevention and/or treatment of glucocorticoid induced osteoporosis  Treatment of men with low bone density

Bisphosphonates

– Tablets taken on an empty stomach after overnight fast with plain water while in an upright position – Patients should not eat or lie down for at least 30 minutesnate – Calcium and vitamin D supplements, if needed, should be taken at a different time of day

B ISPHOSPHONATE H OLIDAYS

 In patients at high risk for fractures (previous fractures, older age, high risk for fall, etc), 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.

Bisphosphonates

Side effects:



Heart burn, Reflux,Esophagitis, Ulcer



Artheralgia, myalgeia



Flu-like symptoms



Hypocalcemia



Atrial fibrillation (2%)



Osteonecrosis of Jaw: more common with potent ( Zoledronic acid), 1/10,000 to 1/100,000 Risk factors: Chemotherapy, Steroids, Dental extraction, and periodontal disease



Subtrochanteric fractures: Prevalence?

Rate higher in alendronate users

T

ERIPARATIDE

(

CINNOPAR

)

The only treatment agent that: stimulates bone formation • 20 μg daily (subcutaneously) for no more than 2 years • Forteo ® prefilled pen contains 28 daily doses

Befor TX After Tx

D ENOSUMAB

 Denosumab is a humanized monoclonal antibody against RANKL that reduces osteoclastogenesis.

RANK Ligand Is an Essential Mediator of Osteoclast Activity

Vitamin D IL-11 TNF-



IL-1 PTH RANKL Many different factors can affect osteoclast activity, but most do so through the osteoblast and RANK ligand (RANKL) PGE 2 Osteoblast PTHrP Osteoclast Glucocorticoids

TNF  =tumor necrosis factor-alpha; PTHrP=parathyroid hormone-related peptide; PTH=parathyroid hormone; IL-1, IL-11=interleukins-1, and -11; PGE 2 =prostaglandin E 2 .

Adapted from: Boyle WJ, et al.

Nature.

2003;423:337-342.

Hofbauer LC, et al.

JAMA

. 2004;292:490-495.

D ENOSUMAB (P ROLIA ®) 60 MG SUBCUTANEOUS INJECTION EVERY 6 MONTHS

 Denosumab is approved by the FDA for  Treatment of osteoporosis in postmenopausal women at high risk of fracture  To increase bone mass in men  Treat bone loss in women with breast cancer  To treat bone loss in men receiving certain treatments for prostate cancer 

Used in renal failure

O

THER THERAPIES

• Calcitriol : Effective in preventing glucocorticoid induced and posttransplant-related bone loss  Strontium ranelate (Protelos)  Vitamin K   Tibolone Folate/vitamin B12  Growth factors  Androgens  Isoflavones  Fluoride

Choice of therapy

o o o o o

The bisphosphanates should remain first line agents First: alendronate or Risedronate, if intolerance: Zoledronic or Ibandronate Raloxifen, Calcitonin, and PTH should remain second line agents PTH may be an option for women who have failed other treatment Denosumab FDA approved for woman with breast cancer and for posmenopauseal women with osteoporosis, renal failure

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