osteoporosisBY:DR ABHISHEK CHAUDHARY(DNB ORTHO SGITO)

Osteoporosisis defined as 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.

The World Health Organization (WHO) operationally defines osteoporosis as a bone density that falls 2.5 standard deviations (SD) below the mean for young healthy adults of the same sex—also referred to as a T-score of -2.5

DEFINITION

Classification

Localised Osteoporosis1. Disuse osteoporosis2. Sudecks osteodystrohy3. Transient osteoporosis4. Regional migratory osteoporosis5. Idiopathic chondrolysis of hip

BY FAR IT’S THE MOST COMMEN METABOLIC DISEASE

Age demographics – senile osteoporosis most common in >70 yr

Secondary osteoporosis can occur at any age

Post menopausal women have early maximum incidence in age group 50-70years

EPIDEMIOLOGY

Prevelance of vertibral # is 27% in women of aga>65.

90 % hip # occur in patiens age >50.

Over all male to female ratio is 1:4.

50 % of postmenopausal women have osteoporosis related # in their lifetime. 25% develop vertebral deformity.

Men have higher prevalence of secondary osteoporosis .

20 % of all men >50 years suffers osteoporosis related # in their lifetime

SEX DEMOGRPHICS

Racial demographics

Normal bone physiology In the embryo and the growing child, bone develops

mostly by remodeling and replacing previously calcified cartilage (endochondral bone formation) or, in a few bones, is formed without a cartilage matrix (intramembranous bone formation).

During endochondral bone formation, chondrocytes proliferate, secrete and mineralize a matrix, enlarge (hypertrophy), and then die, enlarging bone and pro-viding the matrix and factors that stimulate endochondral bone formation.

This program is regulated by both local factors, such

as IGF-I and -II, Ihh, PTH-related peptide (PTHrP), and FGFs, and by systemic hormones, such as growth hormone, glucocorticoids, and estrogen.

PATHOPHYSIOLOGY

Bone remodelling

In young adults, resorbed bone is replaced by an equal amount of new bone tissue. Thus, the mass of the skeleton remains constant after peak bone mass is achieved in adult-hood. After age 30–45,

however, the resorption and formation processes become imbalanced, and resorption exceeds formation. This imbalance may begin at different ages and varies at different skeletal sites; it becomes exaggerated in women after menopause.

osteoporosis is primarily a disease of disordered skeletal architecture

The recommended daily required intake of 1000–1200 mg for adults

Peak bone mass may be impaired by inadequate calcium intake during growth among other nutritional factors (calories, protein, and other minerals), leading to increased risk of osteoporosis later in life.

Over 99% of the 1–2 kg of calcium present normally in the adult human body resides in the skeleton, where it provides mechanical sta-bility and serves as a reservoir sometimes needed to maintain extracel-lular fluid (ECF) calcium concentration.

CALCIUM NUTRITION

CALCIUM METABOLISM

Vitamin D insufficiency may be more prevalent than previously thought, particularly among individuals at increased risk such as the elderly; those living in northern latitudes; and individuals with poor nutrition, malabsorption, or chronic liver or renal disease.

Normal level of 25 hydroxyvitamin D is 20-30 ng/ml.

To achieve this level for most adults requires an intake of 800–1000 units/d

VITAMIN D

Some studies have shown that >50% of inpatients on a general medical service exhibit biochemical features of vitamin D deficiency, including increased levels of PTH and alkaline phosphatase and lower levels of ionized calcium

Estrogen deficiency probably causes bone loss by two distinct but interrelated mechanisms:

(1) activation of new bone remodeling sites and (2) exaggeration of the imbalance between bone

formation and resorption

Marrow cells (macrophages, monocytes, osteoclast precursors, mast cells) as well as bone cells (osteoblasts, osteocytes, osteoclasts) express ERs α and β. Loss of estrogen increases production of RANKL and may reduce production of OPG, increasing osteoclast recruitment.

Estrogen also may play an important role in determining the life span of bone cells by controlling the rate of apoptosis

ESTROGEN STATUS

Hormones and growth Factors regulating bone formation

Factor Target cells and tissue

Effect

Parathyroid hormone Kidney and bone Stimulates the production of vit D and mobilizes calcium from bone into the blood stream

Calcitonin Bone osteoclasts Inhibits resorptive action of osteoclasts .

Calcitriol Bone osteoblasts

Intestine

Stimulates synthesis of collagenous & Non Collegenous proteinsStimulates activity of the osteoclastsStimulates clacium absorption

Estrogen Bone Stimulates formation of calcitonin receptors, inhibits bone resorption

Factor Target cell and tissue

Effect

Testosterone Muscle, bone Stimulates muscle growth, placing stress on the bone, increasing bone formation

Prostaglandins Osteoclasts Stimulates resorption and formation

Bone morphogenic protein

Mesenchyme Stimulates cartilage protein and bone matrix formation

Transforming growth factor

Osteoblasts , chondrocytes

Stimulates differentiation

Interleukins( IL- 1,3 , 6,11 )

Bone marrow, osteoclasts

Stimulates osteoclast formation

Tumour necrosis factor ( TNF-a)

Osteoclasts Stimulates bone resorption

Inactivity, such as prolonged bed rest or paralysis, results in significant bone loss. Concordantly, athletes have higher bone mass than does the general population.

These changes in skeletal mass are most marked when the stimulus begins during growth and before the age of puberty. Adults are less capable than children of increasing bone mass after restoration of physical activity.

More active indivudauls suffer lesser fall and further less #.

PHYSICAL ACTIVITY

Various genetic and acquired diseases are associated with an increase in the risk of osteoporosis.

Mechanisms that contribute to bone loss are unique for each disease and typically result from multiple factors, including nutrition, reduced physical activity levels, and factors that affect rates of bone remodeling.

CHRONIC DISEASE

Glucocorticoids are the most common cause of medication-induced osteoporosis.

MEDICATIONS

Lifestyle factors The use of cigarettes over a long period has

detrimental effects on bone mass. These effects may be mediated directly by toxic effects on osteoblasts or indirectly by modifying estrogen metabolism.

Risk factors for osteoporotic fractures

Age > 70 Menopause < 45 Hypogonadism Fragility fracture Hip fracture in parents Glucocorticoids Malabsorption Anorexia nervosa BMI< 18 Immobilisation Chronic renal failure Transplantation

Calcium intake < 500mg/dl Primary hyperparathyroidism Rheumatoid arthritis Estrogen deficiency Anticonvulsant therapy Hyperthyroidism Diabetes mellitus Smoking Alcohol

MAJOR MODERATE

Clinical features

Routine blood investigations Serum and 24 hr urine ca levels,LFT,RFT and 25(OH)D level S. PTH level,PTHrp levels,x ray evaluation

Bone mineral density single-energy x-ray absorptiometry (SXA) dual-energy x-ray absorptiometry (DXA) High resolution quantitative CT

Biochemical markers

Others TSH,urine cortisol,(s.albumin,cholesterol,antigliadin antibody) Tetracycline labelling,bone biopsy

INVESTIGATIONS

Osteoporosis evaluation Radiography

1. Ground glass appearance and cortical thinning

2. Vertebral bodies become bi concave , loss of height & wedging is seen is seen in vertebral fractures

3. Conventional radiographs are an insensitive way to determine osteoporosis as bone loss becomes apparent only after 30-50% reduction

KLEER KOPER Score: Normal - grade 0 Biconcave deformity - grade 1 Wedge deformity – grade 2 Compression deformity – grade 3

Singhs IndexGrade VI:        - all normal trabecular groups are visible        - upper end of femur seems to be completely occupied by cancellous bone;  - Grade V:        - principal tensile & principal compressive trabeculae is accentuated;        - Ward's triangle appears prominent;  - Grade IV:        - principal tensile trabeculae are markedly reduced but can still be                traced from lateral cortex to upper part of the femoral neck;  - Grade III:        - there is a break in the continuity of the principal tensile                trabeculae opposite the greater trochanter;        - this grade indicates definite osteoporosis;  - Grade II:        - only principal compressive trabeculae stand out prominently;        - remaining trabeculae have been essentially absorbed;  - Grade I:        - principal compressive trabeculae are markedly reduced in number and                are no longer prominent;

Bone mineral density (BMD) It is a measure of bone mass divided by bone area

which increases with age until peak bone density is achieved.

Currently there is no practical measure of bone strength. Bone mineral density (BMD) is used as a proxy measure of bone strength.

It is used to quantitatively screen and diagnose patients with osteoporosis.

It is the only method for diagnosing and confirming osteoporosis in the absence of a fracture

In subjects with a BMD in the osteoporosis range, there is approximately a five times increase in the occurrence of osteoporotic fractures

NOF GUIDELINE FOR DIAGNOSIS& TREATMENT

Postmenopausal below the age of 50

Postmenopausal between

50-65

Post menopausalAbove 65 years

Any postmenopausal With fracture

Assess risk of osteoporosisCheck secondary reasons

Assess risk of osteoporosis

DEXA

Calcium 1200 mg &VIT D 400 IU

DEXA

DEXA

Calcium 1200 mg &VIT D 400 IU

no

Yes

National Osteoporosis Foundation – February 2008

Single Photon absorptiometry1. First method employed2. Involves passing a high energy photon from

a radioactive source through a peripheral bone such as radius or calcaneus.

3. Bone density was estimated based on degree of attenuation of the beam.

Dual Energy X ray Absorptiometry(DXA) Gold standard method to determine

bone mineral density.

Advantages1. Rapid and non invasive technique2. Radiation exposure is minimal3. Precise measurements at clinically

relevant sites like hip, spine.

Disadvantages1. Not portable2. Expensive

•Used to measure bone mineral density at the hip, spine , wrist or total body.

•Patient is made to lie supine over the machine and dual X ray source is used to liberate the energy source.

•The attenuation of the photon is measured .

•The time duration for the procedure ranges from 5 to 15 minutes

Bone turnover markers Provide an integrated assessment of global disease activity .

Markers of both formation and resorption are increased in osteopororis

It also obviates the need for repeated BMD measurement , here immunoassays are done at 3 mts and a decrese in 30% level is considered a good response

Mesures of osteoblast function1. Alkaline phosphatase 2. Osteocalcin

Mesurement of osteoclast function1. Hydroxyproline2. Collagen crosslinks A. N- TelopeptideB. C – telopeptideC. Deoxypyridinoline

Quantitative CT

◦Pros: -similar accuracy to DEXA -may have slightly better predictive value in

risk of vertebral fracture◦Cons:

-more expensive (than DEXA) -less reproducible (bigger variance) -higher radiation

Ultrasound◦ It is in use since 1984

◦ Relies on transmission of ultrasound waves through accessible bone like calcaneum and phalanges

◦ Pros: -studies thus far have suggested similar predictive ability of

fracture to DEXA -No radiation -Portable

◦ Cons: -unable to provide true Bone Density Measurements (less applicable

to current diagnostic standards and treatment goals based on BMD)

It relies on transmission of ultrasound waves through accessible limb bones or the reflectance of waves from the bone surface.

water is used as a coupling agent

Treatment considerations

RISK ASSESMENT tools PREVENTION is far better and easier then treatment of

osteoporotic #.

Four major goals:

1. To prevent fracture2. To stabilize bone mass or achieve increased bone mass3. To relieve symptoms of fractures and skeletal deformity4. To maximize physical function

MANAGEMENT

FRAX tool, developed by a working party for the WHO, and available as part of the report from many DXA machines

In the United States, it has been estimated that it is cost-effective to treat a patient if the 10-year major fracture risk (including hip, clinical spine, proximal humerus, and tibia) from FRAX is ≥20%

Imperfect tool because any assessment of fall risk and secondary causes are excluded when BMD is entered

FRAX

Nutritional Recommendations

The National Health and Nutrition Examination Surveys (NHANES) have consistently documented that average calcium intakes fall considerably short of these recommendations.

Excellent Food sources of calcium are dairy products (milk, yogurt, and cheese)

If a calcium supplement is required, it should be taken in doses sufficient to supplement dietary intake to bring total intake to the required level (1000–1200 mg/d).

Doses of supplements should be ≤600 mg at a time, because the calcium absorption fraction decreases at higher doses

Calcium

Carbonates vs citrate

Several controlled clinical trials of calcium, mostly plus vitamin D, have confirmed reductions in clinical fractures, including fractures of the hip (~20–30% risk reduction).

standard practice to ensure an adequate calcium and vitamin D intake in patients with osteoporosis whether they are receiving additional pharmacologic therapy or not.

A/E- eructation and constipation with ca carbonate. h/o renal stones is relative contraindication. high intakes of calcium from supplements are associated with an increase in the risk of heart disease.

AGE GROUP

RDA

<50 years

200 IU

50-70 years

400IU

>70 years

600IU

Vitamin DLarge segments of the population do not obtain sufficient vitamin D to maintain what is now considered an adequate supply [serum 25(OH)D conSistently >(30 ng/mL)]

Vitamin D supplementation at doses that would achieve these serum levels is safe and inexpensive,.

Higher doses (≥1000 IU) may be required in the elderly and chronically ill

It is safe to take up to 4000 IU/d

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

Magnesium is abundant in foods, and magnesium deficiency is quite rare in the absence of a serious chronic disease.

Dietary phytoestrogens, which are derived primarily from soy products and legumes (e.g., garbanzo beans [chickpeas] and lentils), exert some estrogenic activity but are insuf-ficiently potent to justify their use in place of a pharmacologic agent in the treatment of osteoporosis

Other nutrients

Exercise in young individuals increases the likelihood that they will attain the maximal genetically determined peak bone mass.

Weight bearing exercise in post menopausal women helps prevent bone loss but does not appear to result in substantial gain of bone mass.

A walking program is a practical way to start.

Water exercises.

exercises

Estrogens Reduce bone turnover, prevent bone loss, and induce

small increases in bone mass of the spine, hip, and total body.

Estrogens are efficacious when administered orally or transdermally.

standard recommended doses have been 0.3 mg/d for esterified estrogens, 0.625 mg/d for conjugated equine estrogens, and 5 μg/d for ethinyl estradiol. For transdermal estrogen, the commonly used dose supplies 50 μg estradiol per day

pharmacotherapy

Epidemiologic databases indicate that women who take estrogen replacement have a 50% reduction, on average, of osteoporotic fractures, including hip fractures.

The beneficial effect of estrogen is greatest among those who start replacement early and continue the treatment; the benefit declines after discontinuation to the extent that there is no residual protective effect against fracture by 10 years after discontinuation.

relative risks included a 40% increase in stroke, a 100% increase in venous thromboembolic disease, and a 26% increase in risk of breast cancer

Two SERMs are used currently in postmenopausal women: raloxifene (60 mg/d) and tamoxifen.

A third SERM, bazedoxifene, has been complexed with conjugated estrogen, creating a tissue selective estrogen complex (TSEC). This agent has been approved for prevention of osteoporosis.proved even better then raloxifene.

Unlike estrogens tamoxifen has reduced a/e of breast cancer especially er positive ca breast(upto 65%)

Raloxifene, with positive effects on breast cancer and vertebral fractures, has become a useful agent for the treatment of the younger asymptomatic postmenopausal woman,but increase dvt and stroke so avoided in >70 yrs age.

SERMS

Alendronate, risedronate, ibandronate, and zoledronic acid are approved for the prevention and treatment of postmenopausal osteoporosis.

Zoledronic acid is a potent bisphosphonate with a unique administration regimen (5 mg by slow IV infusion annually). The data confirm that it is highly effective in fracture risk reduction.

Bisphosphonates are structurally related to pyro-phosphates, compounds that are incorporated into bone matrix.

Bisphosphonates specifically impair osteoclast function and reduce osteoclast number, in part by inducing apoptosis

Bisphosphonates

Adverse effects There was an increased risk of transient postdose

symptoms (acute phase reaction) manifested by fever, arthralgia, myalgias, and headache. The symptoms usually last less than 48 h.other a/e atrial fibrillation and transient reduction in renal function.

Recent 2 potential side effects The first is osteonecrosis of the jaw (ONJ) following

dental procedure.

The second side effect is called atypical femur fracture. These are unusual fracture. Pain precedes these #

Its physiologic role is unclear because no skeletal disease has been described in association with calcitonin deficiency or excess

mode of action Calcitonin suppresses osteoclast activity by direct action on the osteoclast calcitonin receptor

Calcitonin preparations are approved by the FDA for Paget’s disease, hypercalcemia, and osteoporosis in women >5 years past menopause.

Calcitonin is not indicated for prevention of osteoporosis and is not sufficiently potent to prevent bone loss in early postmenopausal women. Calcitonin might have an analgesic effect on bone pain, both in the subcutaneous and possibly the nasal form

Calcitonin

mode of action Denosumab is a fully human monoclonal antibody to RANKL, the final common effector of osteoclast formation, activ-ity, and survival. Denosumab binds to RANKL, inhibiting its ability to initiate formation of mature osteoclasts from osteoclast precursors.

Denosumab was approved by the FDA in 2010 for the treatment of postmenopausal women who have a high risk for osteoporotic fractures, including those with a history of fracture or multiple risk factors for fracture, and those who have failed or are intolerant to other osteoporosis therapy

Denosumab

mode of action Exogenously administered PTH appears to have direct actions on osteoblast activity, with biochemical and histomorphometric evidence of de novo bone formation early in response to PTH, before activation of bone resorption.

Teriparatide (1-34hPTH) is approved for the treatment of osteoporosis in both men and women at high risk for fracture

Dose(Teriparatide (1-34hPTH )-20 ug SC OD x maximum 2 years.

Parathyroid Hormone

Side effects of teriparatide are generally mild leg cramps,

muscle pain, weakness, dizziness, headache, and

nausea. Rodents given prolonged treatment with

PTH in relatively high doses developed osteogenic sarcomas. Long-term surveillance

studies suggest no association between 2 years of teriparatide administration and osteosarcoma risk in humans

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

The latter may actually increase when high doses of fluoride are used. Fluoride remains an experimental agent despite its long history and multiple studies

Fluoride

Not available in india MOA- by preventing resorption as well as slightly

promoting bone formation. Strontium is incorporated into hydroxyapatite, replacing calcium.

in clinical trials, the drug reduced the risk of vertebral fractures by 37% and that of nonvertebral fractures by 14%.

A/E-severe dermatologic reactions, seizures, and abnormal cognition,dvt

Strontium Ranelate

Growth harmone Anabolic steroids Statins sclerostin antibodies, which inhibit

sclerostin, activate Wnt, and might be highly anabolic to bone.

Odanacatib is a mixed antiresorptive, partial bone formation stimulator that is currently in the late stages of development

Other Potential Anabolic Agents

In all age group- Ca and vit D3

Perimenopausal and early menopause :HRT

Next 10 years :SERMS

After 65 years :prefrebly biphosphonates

High risk of # : PTH

Severe pain due to #: calcironin

Combination of above.

Drug preferences in osteoporosis

There are currently no well-accepted guidelines for monitoring treatment of osteoporosis.

it is reasonable to consider BMD as a monitoring tool.

BMD should be repeated at intervals >2 years

Biochemical markers of bone turnover may prove useful for treat-ment monitoring.

TREATMENT MONITORING

Hip #/# long bones-almost always require surgical repair if the patient is to become ambulatory again. procedures may include open reduction and internal fixation with nails and plates, hemiarthroplasties, and total arthroplasties.

Other fractures (e.g., vertebral, rib, and pelvic fractures) usually are managed with supportive care, requiring no specific orthopedic treatment.

Only ~25–30% of vertebral compression fractures present with sudden-onset back pain treated with analgesics,calcitonin,PERCUTANEOUS injection of PMMA (vertebroplasty or kyphoplasty)

MANAGEMENT OF PATIENTS WITH FRACTURES

Ganong physiology Harrison’s texbook of internal medicine. Turek’s orthopaedics Aplay system of orthopedics Tripathi pharmacology textbook Mescape Internet sources

references

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