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
Regulation of bone remodelling
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
Regulation of bone remodelling
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)
Regulation of bone remodelling
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
Regulation of bone remodelling
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
When to initiate therapy
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
When to initiate therapy
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
When to initiate therapy
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...
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