Bone Basics & Osteoporosis Partha Paul Endocrinology rounds August 19th, 2009

Bone Basics & Osteoporosis

Partha PaulEndocrinology rounds

August 19th, 2009

Bone physiology

Cortical and trabecular (cancellous) bone differ in architecture but are similar in molecular composition

Consists of cells and an extracellular matrix with mineralized and nonmineralized components. The composition and architecture of the extracellular matrix is what imparts mechanical properties to

bone.

Bone strength is determined by collagenous proteins (tensile strength) and mineralized osteoid (compressive strength)

The greater the concentration of calcium, the greater the compressive strength.

Bone physiology

Adult bone undergoes constant remodeling to maintain bone strength. Osteocytes, which are terminally differentiated osteoblasts embedded in

mineralized bone, direct the timing and location of remodeling.

Osteoblasts not only secrete and mineralize osteoid but also appear to control the bone resorption carried out by osteoclasts; thus, bone

formation and resorption are coupled.

Osteoclasts require weeks to resorb bone, whereas osteoblasts need months to produce new bone. Therefore, any process that increases the

rate of bone remodeling results in net bone loss over time.

Mineralization

Bone formed by imperfect hydroxyapetite crystals (carbonate, Mg, Na, K)

Requires Ca, Phos, and Alk Phos.

Alk Phos hydrolyzes local inhibitors of mineralization (ie pyrophosphate).

Collegen & Degradation

The organic part of matrix is mainly composed of Type I collagen. This is synthesised intracellularly as tropocollagen

and then exported, forming fibrils.

Collagen cleaved and degraded by collagenases --> matrix metalloproteases that can initiate cleavage of collegen fibrils.

Osteoclasts secrete collagenase correlating with changes in bone resporption --> synthesis regulated by local cytokines

Woven & lamellar bone

Bone is first deposited as woven bone, in a disorganized structure with a high proportion of osteocytes in young and in healing

injuries. Woven bone is weaker, with a small number of randomly oriented

collagen fibers, but forms quickly. It is replaced by lamellar bone, which is highly organized in

concentric sheets with a low proportion of osteocytes. Lamellar bone is stronger and filled with many collagen fibers parallel to other fibers in the same layer (these parallel columns are called

osteons).

Osteoblasts

Bone Formation

Secrete collagen and non-collagen proteins in oriented fasion

Bone formation sustained by arrival of new population of cells at bone surface

Some osteoblasts become embedded in the matrix as osteocytes

Osteoblasts

Also act on initiating resorption

Hormonal factors act on osteoblasts to stimulate release of receptor activator of nuclear kB ligand

(RANKL) and CSF-1 --> essential in osteoclastogensis

Also produce cytokines, prostaglandins, and growth factors.

Osteoclasts

Mice deficient in OPG have osteoporosis / Mice that overexpress have increased bone mass

Osteoclasts --> large w/ 10-20 nuclei

Regulation of bone remodelling

Activation --> resorption --> reversal --> formation

Young adults: formation = resorptionPost menopausal: resporption outpaces

formation

PTH --> induces production of RANKL & inhibits OPG production on osteoblasts -->

osteoclastogenesis


Vit D --> 1,25 necessary for normal amounts of intestinal Ca and Phos absorption. However also

increases RANKL production

Calcitonin --> acts directly on osteoclasts to inhibit bone resporption, but plays relatively small role


GH --> increases levels of IGF-1 --> GH & IGF-1 increase bone remodelling & stimulates cartilage

growth

Glucocorticoids --> decrease intestinal absorption of calcium; increase expression of RANKL; deplete osteoblastic cell population (inhibit

replication and maturation / induce apoptosis)


Thryoid hormones --> Increase bone resorption and turnover; increase transcription of

collagenase and other metalloproteases by osteoblasts

Insulin --> In vitro, insulin at physiologic concentrations stimulates osteoblastic collagen synthesis and can mimc the effects of IGF-1


Gonadal hormones --> crucial for pubertal growth spurt; deficinecy of estrogen or androgen --> increase local

synthesis and sensitivity to IL-1, IL-6, TNF, prostaglandins --> increase bone resportion; estrogens

decrease RANK signalling; With low estrogen --> increased rate of remodelling, but

resporption rate > formation rate

Local regulators: cytokines, epidermal growth factor, prostaglandins, fibroblast growth factor, platet-derived gf,

IGF

Clinical evaluation of metabolic bone disease

Bone Densiometry:Most widely used = Dual-energy x-ray absorptiometry.

Others are quantitative CT and U/S

T-scores = std deviations from young adult norm for that instrument

Z scores = SD from expected value for person of same sex, age, body size

Normative data different for members of different racial and ethnic groups

DXA

Accurate and reproducible values for BMC and BMD of lumbar spine, prox femur, distal radius, whole body.

BMD calculated from BMC and area of bone scanned (g/cm2)

Advantages = minimal rad exposure, short scanning time, low variabilty

Disadvantages = mod expensive; errors to lumbar measurements with aortic calcifications and OA changes

Primary Osteoporosis

Def: A disease characterized by low bone mass and microarchitectural deterioration of bone

tissue, leading to enhanced bone fragility and consequent increase in fracture risk

Diagnostic categories

Epidemiology

Osteoporosis is estimated to affect over 200 million people worldwide. An estimated 75 million people in Europe, the United States, and Japan

have osteoporosis.

One in 3 women older than 50 years will eventually experience osteoporotic fractures, as will 1 in 5 men. By 2050, the worldwide incidence of hip fracture is projected to increase by 240% in

women and 310% in men.

Pathogenesis

Increased fragility b/c of:1) failure to acheive optimal peak bone mass2) bone loss caused by increased resorption

3)inadequate replacement of lost bone (decreased bone formation)

Inadequate peak bone mass

Twin studies --> genetic factors responsible for up to 85% in variation in peak bone mass

(polymorphisms in genes for vit D, estrogen receptors, collagen, cytokines, growth regulators)

Environmental factors in childhood --> nutrition, physical activity, intercurrent illness

Increased resorption

Peak bone mass acheived in 3rd decade.Increased rates of bone turnover with age and in postmenopausal period --> resporption outpaces

formation --> increased fragility

Decreased formation

With age, the amount of bone formed decreases with each bone structural unit --> may be due to

age-related decline in skeletal growth factors

Nutrition & Lifestyle

Ca deficiency & decreased physical activity in early life --> failure to acheive optimal peak bone mass

Smoking shown to increase risk

Positive correlations between body fat, lean body mass & BMD

?b/c of conversion of adrenal adrogens to estrogens in fat & b/c of increased impact loading to bones

Morbidity/Mortality

Hip fractures * Hip fractures increase the one-year risk of death by 10-20%.

* Patients with hip fractures incur decreased independence and a diminished quality of life. Only one third of patients return to their

prefracture level of function.

* Among women who sustain a hip fracture, 50% spend time in a nursing home while recovering. In addition, 1 in 5 patients with hip

fractures requires long-term nursing home care.

* Persons with a hip fracture are twice as likely to experience another fracture as persons without fractures.

Morbidity/Mortality

Vertebral fractures

* Vertebral fractures increase the 5-year risk of mortality by 15%. * Only one third of people with radiographic vertebral fractures are

diagnosed clinically.

* Symptoms of vertebral fracture may include back pain, height loss, and disabling kyphosis.

* Compression deformities can lead to restrictive lung disease, abdominal pain, and early satiety.

* One in 5 postmenopausal women with a new vertebral fracture incurs another vertebral fracture within one year.

Screening

Osteoporosis Canada recommends that all postmenopausal women older than 50 be assessed for presence of risk factors

for osteoporosis

2 stages:i) identify those who should have BMD testing

ii) identify those at risk of fragilty fracture who should be considered for therapy

Postmenopausal women AND men over age 50 with at least 1 major or 2 minor risk factors should undergo BMD testing

Who should be tested?

When to initiate therapy

Previous guidelines advised pharmacologic intervention based on individual's lowest T-score and a variable threshold

based on fragility fracture hx

Weaknesses of this:1) On its own, T-score is not the optimal parameter for clinical

decision making2) >50% of osteoporotic #s occured in women w/ T score b/w

-1 and -2.53) absolute # risk can vary substantially due to modification of

risk by other factors such as age and sex


OSC proposes that age, sex, fracture hx, and glucocorticoid use be incorporated into

assessment of fracture risk

BMD + risk factors used to determine 10y absolute fracture risk

10 year fracture risk

3 categories of risk:1) low <10%

2)mod 10-20%3) high >20%

Fragility fracture after 40 yo, glucocorticoid use increase risk category to next level

If both are present, Pt should be considered high risk regardless of BMD (Pt receiving > 7.5mg prednisone for >3

mo should be initiated on bone sparing therapy)

Ten year fracture risk

10 year fracture risk - women

10 year fracture risk - men


High risk: pharmacological intervention should be strongly considered esp. those with low BMD or

prev fragility fracture

Moderate risk: May consider pharmacological intervention

Low risk: Bone hygiene counselling; adequate Ca and vit D, exercise, RF modification


Co-therapy with bisphosphonates should be initiated in women receiveing > 7.5 mg of

prednisone or equivalent daily for > 3 months

Therapeutic agents

Hormonal TherapyBisphophonates: etidronate, alendronate,

risedronateSERMs: raloxifene

CalcitoninParathryroid hormoneCombination therapy

Therapeutic Agents

MedicationDose/

FrequencyVertebral Fracture

Non-vertebral Fracture Hip Fracture

Raloxifene 60 mg/d p.o. 30%-50% - -

Alendronate10 mg/d p.o.70 mg/w p.o.

48% 49% 53%

Etidronate + Ca Cyclic p.o.

(90-day cycle)37%

(meta-analysis) Non significant -

Risedronate5 mg/d p.o., 35

mg/w p.o., 75 mg + 75 mg/m p.o.

38% 32% 40%

PTH 20 µg/d subcutaneous 65% 53% -

Zoledronic acid 5 mg IV/y 70% 25% 41%

Hormonal Therapy

HT should be prescribed to symptomatic postmenopausal

women as the most effective therapy for symptom relief

and a reasonable choice for the prevention of bone

loss and fracture

The risks outweighthe benefits if estrogen therapy is being used

solely for fractureprevention

Bisphosphonates

Pyrophosphate analogues that bind to bone mineral and then rapidly taken up by osteoclasts to inhibit resporption

S/E mainly GI, esp esophageal irritation

Must be taken on an empty stomach b/c of poor oral absorption

ONJ – exact incidence unknown, appears to be most prevalent in those on high dose IV bisphos for complications

from malignant disease

SERMs

Raloxifene (Evista)

Agonist effects of estrogen receptors of bone, but antagonist effects on breast and uterus

CI: hx of VTE, hypersensitivity, women of childbearing potential

Calcitonin

Inhibitor of bone resorption, can increase bone mass particularly in assoc w/ high turnover rates

Analgesic properties in relation to painful vertebral fractures

Questions about efficacy as 200 U/day found to decrease fracture risk, but not 100 or 400 U/day

doses

PTH

Use of intermittent low dose synthetic PTH in both men and women with OP --> increase in trabecular bone

mass.(This is in contrast to continuous exposure to parathyroid

hormone, which increases bone resorption with a net effect of decreased trabecular bone volume)

Most effective in patients who lose bone or continue to have #s on anti-resorptive therapy

Combination therapy

Combo of anti-resporptives: improves BMD but fracture data lacking

PTH + antiresoptives: Bisphosphonates may slightly blunt effect of PTH therapy if given concurrently or preceding PTH... But giving

bisphosphonates after course of PTH will enhance and maintain bone mass

Not yet in guidelines

Strontium Ranelate

Denosumab

Calcium

1000-1500 mg /day

Sources:Diet without dairy 300-400 mg/day

1 cup of milk or yogurt 300 mgCalcium supplements 200-600 mg/tablet

Calcium tablets containing vitamin D more expensive and often not enough vitamin D

Vit D

Vitamin D is essential for calcium absorptionAdequate calcium absorption prevents secondary hyperparathyroidism

and limits bone resorption

Older person has difficulty getting enough vit DFormation and processing of vitamin D may be impaired

Exposure to sunlight may be limitedDietary sources provide little vitamin D

Patient compliance with vitamin D supplementation may be inconsistent

Vit D

Multivitamin pill may contain 200-400 IUCalcium tablet containing vitamin D may have from 120

to 250 IUFortified milk amount of vitamin D fluctuates (37-50 IU

/100 ml or 111-150 IU/ cup)Main source is sunlight

Supplements 400 and 1000 IU / tabletVitamin D drops 1000IU per drop

Causes of secondary OP

GlucocorticoidsHypogonadism

MM & other MPDDrugs (heparin, anticonvulsants, methotrexate,

cyclosporine, aluminum)Other endocrine (hyperparathyroid, cushing's,

hypogonadism, hyperthyroid, prolactinoma, DM, acromegaly)

CRI, RTA, malabsorptionothers...

Documents

Bone Basics & Osteoporosis Partha Paul Endocrinology rounds August 19th, 2009