EAST 501 Lecture 15: 563 L15 - Apr 4
21 Jun 2018
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L15 – Trasler Apr 4
Osteoporosis: Pharmacological Targets, Treatment, Prevention
1
OUTLINE
- Basic of osteoporosis and bone physiology
- Hormone therapy for prevention of post-menopausal osteoporosis
o 20 years ago this was the only treatment we had à it stopped and we needed other treatments
- Alternative targets and therapies for treatment/prevention of osteoporosis
o Anti-resorptives – do not build up bone
o Anabolics – these are newer and build up bone
OSTEOPOROSIS: BY THE NUMBERS
- Systemic skeletal disease characterized by declines in bone mass and micro-architecture
o increase in bone fragility and susceptibility to fracture (hip, spine, and wrist) à usually associated with a
fall
o affects the whole of the skeleton
- Prevalence
o 1-2M in CAN
o more common in women (4:1) because aging women do not have E2 and they start with less bone
o men also get osteoporosis
- Economic impact
o $2-3B/yr in CAN (2010)
- Hip fractures
o 30k/yr in CAN (70-90% osteoporosis-related) à many of these are preventable
o 15-25% require nursing home admission
o 20-37% death rate within following year à this is a significant injury that causes other problems
o High recurrence rate (50% within 5 years)
OSTEOPOROSIS IS ASSOCIATED WITH DECLINES IN BONE MASS
AND MICRO-ARCHITECTURE
- 206 bones in the body
- the pictures of are bone in the lumbar spine
- Three-dimensional reconstruction by microcomputed
tomography of lumbar spine samples
o thickness of the bone and how interconnected
it is between it
o this bone is even more fragile than how it looks à
leads to compression fractures within the bone
- the strength of the bone is based on the thickness of the bone, but also how interconnected it is
- 2 kinds of bone:
o cancellous bone/trabecular à porous bone on the inside
o cortical bone à on the outside of bones à solid and compact – no holes (~80% of the skeleton)
OSTEOPOROSIS – CLINICAL TYPES
- Primary osteoporosis
o Type I – post-menopausal (estrogen-deficiency) – post-menopausal
o Type II – cumulative aging effects (both in men and women)
- Secondary osteoporosis
o Medical conditions – can be secondary to the use of different drugs
§ Anorexia
§ Alcoholism
§ T1DM
§ Cancer (metastasis)
o Iatrogenic
§ Glucocorticoids (GIO)
§ Thyroid hormones
§ Chemotherapy drugs
L15 – Trasler Apr 4
Osteoporosis: Pharmacological Targets, Treatment, Prevention
2
POST-MENOPAUSAL WOMEN EXHIBIT SIGNIFICANT DECLINES IN BONE MINERAL DENSITY (BMD)
- between 50-90 in women (after menopause) à decrease in cortical bone, but a greater decrease in the
cancellous bone à this is why the vertebrae are affected
o without the treatments à this just continues (down)
- prior we used HRT (starting at menopause) until ~80yo (we didn’t really know when to stop), which helped to
retain bone, because until the time that they stopped the HRT the bone was maintained à this is not done
anymore
- any treatments that you use need to be continued for a long time (or else the decline will just keep happening)
o you cannot just treat for a couple of years and expect that the treatment will suffice
AGING: EFFECTS ON BONE IN MOUSE MODEL
- mouse models are good for studying different types of treatments
- in younger (~6mo) vs. older (~2yr):
o by the time you are an older mouse the cortical bone is more porous (not as solid) à contributes to
fractures
o the cancellous bone (trabecular) à loss of complexity with age
o you can use mice to test the different types of treatments (can look at cortical and trabecular bone)
CASE STUDIES – will come back to next class
- Case 1:
o A 59yo women is referred due to a change in BMD in her spine resistant to
treatment with raloxifene (a SERM – anti-absorptive treatment).
Menopause was at age 52 at which time her BMD was normal (hip and spine).
A repeat BMD at 56yrs indicated normal hip but osteoporosis (-3.1 SD)
of the spine. Raloxifene was prescribed.
§ anything >2SD BMD = osteoporotic
§ 3 years later the bone density was down again à what would you do
§ there has already been screening à already thinking about different treatments
- Case 2:
o A 72yo woman was brought to the ER by her son-in-law after falling in her bathtub. She reported severe
pain in her R hip and upper thigh and was unable to get up after her fall. An x-ray of her hip revealed an
intertrochanteric fracture.
§ no prior screening for BMD
§ severely osteoporotic à treatment is now very difficult
§ probably will see more of this à after women stopped taking HRT à doctors did not always put
them on the new agents
- in case 1 à have done some screening and have done some treatment and at least thought about different
treatments; in case 2à did not pick up on the osteoporosis and the person has had a fracture
o probably will see more similar cases to Case 2 because after women were no longer taking HRT, not all
the physicians were putting them on the newer agents = not an insignificant problem
BONE TISSUE PROPERTIES
- bone = complex tissue made up of two tissue types (organic and inorganic)
- Organic phase (30% of bone mass)
o Collagen (type I) (90-95% of protein)
§ Assembled into fibrils
§ Scaffold for mineralization
o Osteopontin, osteocalcin, alkaline phosphatase and bone sialoprotein
§ makes up sites for mineral crystal nucleation
§ Binding of mineral crystals to the collagen matrix
§ mineralization is due to the inorganic phase
L15 – Trasler Apr 4
Osteoporosis: Pharmacological Targets, Treatment, Prevention
3
- Inorganic phase (70%)
o Calcium and phosphorus (hydroxyapatite crystals: calcium phosphate, calcium carbonate, calcium
fluoride, calcium hydroxide and citrate)
BASIC MULTICELLULAR UNITS (BMU) ARE COMPOSED OF OSTEOBLASTS AND OSTEOCLASTS (AND OSTEOCYTES)
- Osteoblasts (OBs) (bone formation)
o derived from mesenchymal stem cells
o secrete/make osteoid (unmineralized bone proteins)
o regulate mineralization of the bone
o live up to 200 days
- Osteoclasts (OCs) (bone resorption)
o Least abundant
o Large, multi-nuclear
o Derived from monocyte/macrophage lineage of hematopoietic stem cells
o Degrade bone matrix (important in resorption)
o short lived à up to 25 days
- Osteocytes (Ocytes)
o most abundant (10x OBs)
o derived from OBs
o embedded in bone matrix
o biomechanical (i.e. mechanosensory) regulation of bone mass and structure
§ exercise is important for bone health à Ocytes sense effects of exercise and biomechanical
stress on bones
o can live in the bone up to 50+ years
- bone is not a dead tissue it is a live tissue à the bone formation is often occurring very close to the capillaries
BONE REMODELLING
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Document Summary
Hormone therapy for prevention of post-menopausal osteoporosis. Apr 4: 20 years ago this was the only treatment we had it stopped and we needed other treatments. Alternative targets and therapies for treatment/prevention of osteoporosis: anti-resorptives do not build up bone, anabolics these are newer and build up bone. Systemic skeletal disease characterized by declines in bone mass and micro-architecture increase in bone fragility and susceptibility to fracture (hip, spine, and wrist) usually associated with a fall: affects the whole of the skeleton. Prevalence: 1-2m in can, more common in women (4:1) because aging women do not have e2 and they start with less bone, men also get osteoporosis. Osteoporosis is associated with declines in bone mass. 206 bones in the body the pictures of are bone in the lumbar spine. 2 kinds of bone: cancellous bone/trabecular porous bone on the inside, cortical bone on the outside of bones solid and compact no holes (~80% of the skeleton)
