Pathophys

Lecture 31 Osteoporosis Pharmacology MacLeod

OSTEOPOROSIS: skeletal disorder characterized by COMPONENTS OF BONE TISSUE:

compromised bone strength, pre-disposing a person to an Organic Cells  Osteoblasts (matrix forming cells)
increased risk of fracture (30%) (2%)  Osteocytes (osteoblastic origin)
 Factors contributing to bone strength:  Osteoclasts (from macrophage-monocyte system in bone marrow)
 Bone mineral density (BMD) Matrix  Collagen type I (90%)
 Bone quality: (98%)  Bone proteoglycan
o Rate of turnover  Non-collagenous proteins: osteocalcin, osteonectin, bone
o Mineralization sialoprotein, matrix GLA protein, fibronectin, etc
o Microarchitecture Minerals  Hydroxyapatite
 Trabecular connectivity (70%)  Trace amounts: Mg, Na, K, Fl, Cl
 Microcracks (damage accumulation)
TYPES OF BONE:
BONE FUNCTION: Cortical  Dense and solid, with few spaces
Mechanical  Protection for internal organs (compact)  Surrounds marrow space
 Site of insertion and support for bone (80%)  Mainly mechanical & protective function
muscles & joints Trabecular  Mesh-like bone located in center of bones
Metabolic  Mineral reservoir for Ca & PO4 (cancellous)  Much larger % of surface area in contact with bone marrow, blood
homeostasis bone (20%) vessels, etc
Hematopoiesis  Bone marrow = site of blood cell  More active, subject to remodeling & turnover
production  Structure (horizontal & vertical cross-struts) contributes to its strength

BONE REMODELING: continued coupled process of bone breakdown and renewal; carried out by independent bone remodeling units = bone metabolic units (BMU)
PHYSIOLOGICAL ROLE: FUNCTION OF CELLS INVOLVED IN BONE REMODELING:
 Repair areas of microdamage to the skeleton Osteoclasts  Large multi-nucleated cells formed from hepatopoetic precursors
 Adapt skeletal mass to changing load  Function is to resorb bone
 Participate in regulation of calcium homeostasis Osteoblasts  Form new bone matrix (osteoid)
 Formed from local mesenchymal stem cells
Activators Inhibitors Osteocytes  Mechanoreceptors/effectors embedded in bone
 PTH  Calcitonin  Formed from osteoblasts trapped within the bone they formed
 Vitamin D  Estrogen Lining cells  Formed from osteoblasts that remain on the surface of bone
 Thyroid hormones  Have receptors for hormones & factors that initiate remodeling
 Interleukins/TNF α  Role in recruiting and activating osteoclasts

BONE REMODELING CYCLE:

 Resting (quiescent) bone: osteocytes secrete sclerostin, which inhibit osteoblast differentiation and function

1. Activation: microdamage and/or circulating cytokines and hormones initiate the cycle (3 weeks):
a. Sclerostin production decreases
b. Osteocytes and osteoblastic stromal cells begin to produce factors (m-CSF and RANK-ligand) that bind to osteoclast precursors
 RANKL: produced by osteocytes and osteoblast stromal cells
o Binds to receptor (RANK) on pre-osteoclasts
o Stimulates their development into fully differentiated osteoclasts and increases their activity
 Osteoprogerin (OPG): also produced by osteoblastic cells
o Binds RANKL and prevents its interaction with RANK
o Opposes the differentiation and activation of osteoclasts
 BALANCE BETWEEN RANKL AND OPG PRODUCTION DETERMINES LEVEL OF OSTEOCLAST ACTIVITY
c. Osteoclast replication and differentiation into multi-nucleated, functional osteoclasts
 Circulating T-lymphocytes and bone lining cells may also participate in the process of osteoclast activation

2. Resorption by osteoclasts:
a. Osteoclasts attach to bone by integrins and form a ruffled border
b. H+ generated by the action of intracellular carbonic anhydrase II (CAII) is actively transported across the membrane of the ruffled border by the H+-
ATPase proton pump. A chloride channel coupled to the proton pump balances the charge of ions across the membrane.
c. Organic matrix of the bone is removed by proteases such as cathepsins and collagenases.

2. Reversal:
a. After resorption is complete, osteoclasts detach and undergo apoptosis
b. Other mononuclear cells cover the surface and form a cement line  marks limit of bone resorption and cements together the old & new bone

3. Bone formation (3 months):

a. Pre-osteoblasts proliferate and mature into osteoblasts (possibly stimulated by IGF-1 and TGF-B released during resorption)
b. Osteoblasts:
 Decrease secretion of RANKL & increase OPG secretion  block further activation of pre-osteoclasts
 Secrete osteoid (bone matrix proteins) and collagen  unmineralized osteoid slowly re-fills the cavity
 Some become trapped in newly formed osteoid  become osteocytes
c. Osteoblast activity falls off and they either:
 Undergo apoptosis
 Form lining cells (single layer of osteoblasts covering surface of bone)
d. Mineralization of bone with hydroxyapatite (relatively rapidly)
 Secondary mineralization: 30% of total mineral is deposited more slowly (over period of months)
 Pathophys
Lecture 31 Osteoporosis Pharmacology MacLeod
EFFECTS ON BONE REMODELING
REGULATION OF BONE MASS WITH AGE: EFFECTS OF AGING (AND ESTROGEN) ON BONE REMODELING:
Age 0-25: resorption < formation  bone gain
Age 25-35: resorption = formation  bone mass stable
Age > 35: resorption > formation  bone loss

BONE MASS IN ADULTS > 35 IS DETERMINED BY:

 Bone mass at maturity (peak bone mass)
 Rate and duration of bone loss

FACTORS AFFECTING PEAK BONE MASS: heredity, sex,

mechanical force, hormones, nutrition, risk factors

GLUCOCORTICOIDS AND BONE:

 Oral GC most frequent cause of secondary osteoporosis
 Rate of bone density loss 10-30% per year
o Begins within first 3 months of use, peaks at 6
months, then drops to a slower steady rate
 30-50% of pts taking GC chronically will have fracture
EFFECTS OF ACCELERATED BONE LOSS ON BONE:
MECHANISMS OF GC-INDUCED BONE LOSS:  Cortical bone becomes thinner and more porous
 Inhibition of intestinal Ca2+ absorption and increased  Trabecular bone becomes weaker as a result of:
urinary Ca2+ loss o Decreased bone density
 ↑ RANKL  direct stimulation of bone resorption o Increased number and depth of resorption pits
 ↓ osteoblast-mediated bone formation o Actual loss of trabecular connectivity & perforation of trabecular plates
 High dose GCs also suppress gonadotropin production  Both bon density AND bone quality are reduced

CLASSIFICATION OF OSTEOPOROSIS: MAJOR SITES OF OSTEOPOROTIC FRACTURE:

Primary Post-menopausal: 15-20 years after menopause Vertebral  Most common
 Associated w/ disproportionate loss of trabecular bone body  Asymptomatic (2/3) but acute fractures often very painful
 Vertebral body, distal radius (wrist) most common fracture  Results in loss of height, curvature of spine
Age-associated: both men and women after age 70 Hip  Most serious
 Slower, steady rate of loss of bone, proportionately from  15% women, 5% men >80 yo
cortical and trabecular sites  20-30% mortality within 1 year
 Vertebral body and proximal femur (hip) fractures  Most occur in femoral neck and intertrochanteric region
Secondary  Due to an identifiable cause (GC therapy, hyperthyroidism) Wrist  Distal radius AKA Colles fracture

TECHNIQUES FOR MEASURING BONE MINERAL DENSITY:

Technique Common sites Comments
Dual-energy x-ray absorptiometry (DEXA)  Lumbar spine  Precise
1. X-rays from 2 different sources directed towards bone in alternating pattern  Proximal femur  Low radiation exposure
2. As emitted photons pass through subject’s tissues, they are attenuated to  Needs skilled operator
an extent that depends on the tissues mineralization  Currently gold standard
3. Measures areal BMD (g/cm2 of bone)

Single-energy x-ray absorptiometry  Forearm  Inexpensive

 Heel  Measures sites unresponsive to therapy
 Does not need skilled operator
Quantitative computed tomography (QCT)  Spine  Poor reproducibility outside experienced labs
 Accuracy comparable to DEXA
 More expensive than DEXA
Ultrasonography  Heel  Fingers  Inexpensive
 Tibia  Patella  Less precise
 Fairly portable

WHO DEFINITIION OF OSTEOPOROSIS: based on comparison of patient’s bone mineral density (BMD) with the mean BMD obtained in a healthy, young adult population
(comparison should take into account both sex and race)
T-SCORE: # of SDs below or above mean BMD RECOMMEND MEASURING BMD ONLY WHEN:
Normal bone T-score ≥ -1.0  At least one major (or two minor) risk factors of osteoporosis AND results are likely to alter pt care
Osteopenia -1.0 > T-score > -2.5  Follow-up measurements not necessary before 2 years after original measurements in most cases
Osteoporosis T-score < -2.5 o Exceptions: ≥ 7.5 mg prednisone equivalents for > 3 months; very low BMD; existing fractures
Established (severe) Includes presence of a  The objective of treating osteoporosis is to prevent or treat fractures
osteoporosis non-traumatic fracture o A distinction has to be made between diagnosing osteoporosis based on BMD vs. making
decisions regarding intervention according to absolute fracture risk
For every 1 SD decrease in BMD, risk of fracture
increases by 2 o Various tools can be used to calculate 10-year risk of fracture to assist in making a decision
about pharmacological treatment
 However, other skeletal and non-skeletal
factors also contribute to fracture risk
 Pathophys
Lecture 31 Osteoporosis Pharmacology MacLeod

RISK FACTORS FOR OSTEOPOROTIC FRACTURES:

Major risk factors Minor risk factors
 Age ≥ 65  Past history of clinical hyperparathyroidism
 Personal history of fragility fracture  Chronic anticonvulsant therapy
 Systemic glucocorticoid therapy for more than 3 months  Low dietary calcium intake
 First degree relative with osteoporotic fracture  Smoking
 Hypogonadism  Excessive alcohol intake
 Early menopause (before age 45)  Excessive caffeine intake (e.g. > 4 cups coffee/day)
 Pre-disposing medical conditions (malabsorption, hyperparathyroidism)  Weight < 57 kg
 Short-term weight loss > 10% from weight at age 25
 Chronic heparin therapy
 Rheumatoid arthritis