Chapter 28 Osteoporosis
Presentation,2005
谢瑞满 Rui-man Xie,Ph.D.,M.D,
Professor of Neurology & Gerontology
ZhongShan Hospital,Fudan University
rmxie@zshospital.net,xieruiman@yahoo.com
Objective
1,Definition,types and mechanism of osteoporosis
2,Diagnosis,prevention and treatment of osteoporosis
3, Etiology and Epidemiology of osteoporosis
times – 45 minutes× 2
Overview
Definition, Osteoporosis is a bone
disease in which the amount of bone is
decreased and the structural integrity of
trabecular bone is impaired,Cortical
bone becomes more porous and thinner,
This makes the bone weaker and more
likely to fracture,
?figures
Associated changes in body shape and vertebra
（ deleted 6 pictures）
normal 50yrs above 55yrs above
75yrs
kyphosis
Patients with risk factors or conditions
that cause osteoporosis
? Postmenopausal woman with family history of hip
fractures or kyphosis
? Medications,corticosteroids,dilantin,gonadotropin
releasing hormone agonists,loop diuretics,
methotrexate,thyroid,heparin,cyclosporin,depot-
medroxyprogesterone acetate
? Hereditary skeletal diseases,osteogenesis imperfecta,
rickets,hypophosphatasia
? Endocrine and metabolic,hypogonadism,
hyperparathyroidism,hyperthyroidism,Cushing
syndrome,acidosis,Gaucher's disease
? Marrow diseases,myeloma,mastocytosis,thalassemia
? Others,Anorexia,Malabsorption,Cystic fibrosis,Renal
insufficiency,Hypercalciuria,Hepatic disease,
Depression,Spinal cord injury,Systemic Lupus,
Weight below healthy range,Cigarette smoking
Epidemiology
? The population of older men and women has
been increasing,and therefore the number
of people with osteoporosis is increasing,
? In the USA,about 21% of postmenopausal
women have osteoporosis (low bone
density),and about 16% have had a fracture,
In women older than 80,about 40% have
experienced a fracture of the hip,vertebra,
arm,or pelvis,
? Women have more osteoporotic fractures
than men,Age is one of the most important
risks in all groups,
? The decreased physical activity may be
playing a role in increased hip fractures,
Mechanism, Bone physiology
? The bone is continuously remodelling,and the bone surface
moves in and out,The Basic Multicellular Unit (BMU) is a
wandering team of cells that dissolves an area of the bone
surface and then fills it with new bone,The sequence is
Origination,Osteoclast recruitment,Resorption,Osteoblast
recruitment,Osteoid formation,Mineralization,Mineral
maturation,Quiescence,
? Bone strength (Quality),In addition to bone porosity,the
bone strength is determined by the trabecular microstructure,
Perforations of individual trabecula occur when resorption
cavities are too deep,This,too,is seen with estrogen
deficiency,The remaining trabecula are not as well
connected and are mechanically weaker,
Mechanism, Bone physiology
? Microfracture healing is another aspect of bone strength
that is not measured by bone density,Trabeculae inside the
bone may fracture and microcalluses are formed that
resemble the calluses seen on xrays of long bones after a
"macro-fracture",Osteoporotic bone is more susceptible to
these fractures because the individual trabeculae do not
have as many reinforcing connections,The calluses may
represent a method of repairing the bone and even
connecting some of the trabecula,Bone which has lost the
ability to form these calluses will be weaker,
? The age of the bone mineral crystals may also play a role in
the strength of bone,This is an area that needs further
research,Studies suggest that older bone is more brittle,
and that one purpose of bone remodelling is to remove the
old bone and replace it with newer,more elastic bone,
Clinical manifestation and types
? Secondary osteoporosis,
Mndocrine and metabolic,hypogonadism,
hyperparathyroidism,hyperthyroidism,Cushing syndrome,
acidosis,Gaucher's disease;
Marrow diseases,myeloma,mastocytosis,thalassemia;
Medications,corticosteroids,dilantin,gonadotropin
releasing hormone agonists,loop diuretics,methotrexate,
thyroid,heparin,cyclosporin,depot-medroxyprogesterone
acetate;
Malabsorption,Hepatic disease,others；
? Hereditary skeletal diseases,
osteogenesis imperfecta,rickets,hypophosphatasia;
? Primary osteoporosis,
Clinical manifestation and types
Primary osteoporosis,
?TypeⅠ postmenopausal osteoroposis——This is
seen with estrogen deficiency,There is high bone
turnover rate,The proportion of trochanteric and
femoral neck fractures increases；
?TypeⅡ elderly osteoroposis——This is aging in
bone physiology,The compression fracture of
the spine and hip fracture are more common,
Clinical Features of Osteoroposis
The vast majority of hip fractures occur
after a fall,About 5% appear to be
“spontaneous” fractures,in which the
patient feels a fracture and then falls,
Overall about half of hip fractures are
intertrochanteric and the others are
femoral neck fractures,
Clinical Features of Osteoroposis
Vertebral compression fractures vary in
degree from mild wedges to complete
compression,The symptoms also vary,but
the degree of compression is not necessarily
related to the amount of pain,In fact,about
60% of women with compression fractures
do not realize they have had a fracture! It is
possible that some of the fractures occurred
gradually and therefore did not cause acute
pain,
Clinical Features of Osteoroposis
?When women and men do suffer painful
compression fractures,the pain usually
lasts from one to two months,is localized
to the back with accompanying muscle
spasms,then gradually subsides,
?Patients with continuing severe pain
should be evaluated for other pathologic
etiologies of the fracture,especially
malignancy or myeloma,
?Persistent pain can also be caused by
continuing fracture,muscle spasms,
spinal stenosis,or degenerative joint
disease,
Clinical Features of Osteoroposis
?To correctly interpret a spine xray,it is
important to know the definition of a
vertebral fracture,which is not quite as
straightforward as it first appears,
especially for research,
?For practical clinical purposes,a
vertebra can be considered fractured if
the anterior height is 80% or less of the
posterior height,
?A new fracture requires loss of at least
20% of anterior or posterior height,
Clinical Features of Osteoroposis
? Wrist fractures are more common in women who
are 50 to 60 years old,These are caused by falls or
other trauma,Osteoporosis does not appear to
impair the healing of the wrist fractures,and they
cause only short-term disability,
? Although spine,hip,and wrist fractures are
considered classical osteoporotic fractures,many
others are related to bone density and thus are also
osteoporotic,These include rib,pelvic and shoulder
fractures,but not finger,facial bone,skull,elbow,or
ankle fractures,
Clinical Features of Osteoroposis
? The irreversible height loss associated with
osteoporosis is one of the aspects of the disease
that is most distressing to many women,
Height loss can also occur with scoliosis,which
often gets worse after menopause,
Also,degenerative disk disease can cause height
loss of 2 inches,
Some reversible height loss is due to poor posture,
? KYPHOSIS is the feature of osteoporosis that is
identified by most patients,The hump causes
difficulty in finding clothes that will fit,let alone look
attractive,In severe cases,the ribs contact the
iliac crest and movement causes pain,
Clinical Features of Osteoroposis
?PROTRUDING ABDOMEN
The protruding abdomen which is a result of
the kyphosis is an unrecognized aspect of
osteoporosis,Women do not realize that the
curvature of the spine decreases the
abdominal space,and thus the intestines
have nowhere to go except forwards,Many
women think that they are getting fat,and
they go on a diet trying to regain their
youthful waistline,If they do successfully lose
weight,it will only increase their risk for more
osteoporotic fractures,
Clinical Features of Osteoroposis
? DECREASED PULMONARY CAPACITY
Patients with kyphosis have decreased
lung volumes,In severe cases this
leads to shortness of breath and
pulmonary symptoms of restrictive lung
disease,
Clinical Features of Osteoroposis
?REFLUX ESOPHAGITIS
Patients with kyphosis may develop
reflux esophagitis due to the changes
in abdominal space,Wearing tight
clothing can exacerbate the problem,
Laboratory tests
?For an uncomplicated patient with
osteoporosis,a lab workup would be a
chemistry panel,CBC,phosphate,TSH and
24-hour urine calcium,Males should have
testosterone measured,
?The main purpose of laboratory tests is to
check for secondary causes of osteoporosis
such as cases of renal or hepatic failure,
anemia,acidosis,hypercalciuria,and
abnormalities of calcium/phosphate,
Laboratory tests
?Alkaline phosphatase is an inexpensive
method of checking for osteoblastic
activity,It is not as sensitive or specific
as newer "bone markers" but it will
detect moderate to severe osteomalacia
or Paget's disease,
?The 24-hour urine calcium
measurement is frequently ignored but it
is a valuable and inexpensive test,High
levels are seen in idiopathic
hypercalciuria,and low levels suggest
malabsorption,
Laboratory tests
? Protein electrophoresis should be done
whenever a patient presents with new
fractures,Both serum and urine tests should
be done because some patients with
myeloma have abnormalities in only one,
? Corticosteroid excess that causes
osteoporosis can usually be detected
clinically by Cushingoid features,A urine
cortisol can be helpful in puzzling cases,
Laboratory tests
? Gonadal hormones are very important causes
of osteoporosis,In females who are
postmenopausal,it is not helpful to measure
levels of estrogens or gonadotropins,In
males,however,testosterone levels should
be measured because there is much greater
variability in the prevalence of hypogonadism,
Also,men may have low testosterone without
other clinical symptoms,
Laboratory tests
? Vitamin D and parathyroid hormone levels are expensive
tests,Mild vitamin D deficiency frequently occurs in the
absence of hypocalcemia,but if vitamin D supplementation
is routinely given,it is not necessary to perform this test in
patients with normal calcium,Primary hyperparathyroidism
nearly always causes hypercalcemia,Secondary
hyperparathyroidism may occur with normal calcium,but
most of these cases will be detected by low urine calcium or
decreased renal function,
? In patients with abnormal serum calcium or with unusually
severe bone disease,however,the 25-OH-vitamin D and
parathyroid hormone levels should be measured,
The 25 OH-vitamin D is more useful than the 1,25 (OH)2
vitamin D level,
Indications for bone density
measurements
?Over the last decade there have been many
debates about screening bone density,
Several organizations have performed
detailed cost-benefit studies and developed
guidelines; these must be continually revised
as new findings about treatment effects are
discovered,
?Bone density tests carry no physical risks,
but there is a problem of over-interpretation
of results,so that healthy ordinary average
people think they are at a much higher risk
than they actually are,
Bone density measurements
Techniques
? Several methods are available to measure bone
density,but currently the most widely used
technique is DEXA (Dual Energy Xray
Absorptiometry),This is the method used to
determine efficacy in the recent large clinical trials,
and to characterize fracture risk in large
epidemiological studies,
? Newer techniques such as ultrasound appear to
offer a more cost-effective method of screening
bone mass,Ultrasound measurements are usually
performed at the calcaneous and it is not possible
to measure sites of osteoporotic fracture such as
the hip or spine,
Bone density measurements
? Quantitative computed tomography of the spine
must be done following strict protocols in
laboratories that do these tests frequently; in
community settings the reproducibility is poor,The
QCT measurements decrease more rapidly with
aging,so the "T scores" in older individuals will be
much lower than DEXA measurements,
? Several other techniques can measure bone
density at the hand,radius or ankle,These include
single energy absorptiometry,metacarpal width or
density from hand xrays,Magnetic resonance
imaging is a new method of measuring bone density,
T & Z scores and the WHO definitions
? The WHO has based definitions on the T-score,
which is the number of standard deviations from
the mean (average) value of a 25-year-old woman,
1,Normal bone,T-score better than -1,
2,Osteopenia,T-score between -1 and -2.5
3,Osteoporosis,T-score less than -2.5
4,Established osteoporosis includes the presence of
a non-traumatic fracture,
One standard deviation is at the 16th percentile,so
by definition 16% of young women have
osteopenia!
? The Z-score is the number of standard deviations
below age-matched avereage,
Bone density measurements
DEXA reports
? Step 1,the images
? Step 2 - the graphs
? Step 3 - the basic results
? Step 4 - the reference ranges
Beware the shifting reference ranges!
Comparing a recent scan to one done
prior to about 1997,
? Step 5 - the areas and mineral contents
Bone Mineral Apparent Density
? BMAD is important when measuring bone density
in children or in patients with short stature,Another
term for this concept is "volumetric bone density",
? The DEXA technique analyzes the attenuation of
xrays as they pass through an area of the body,
The method cannot detect the depth of the bone
which is being measured,and thus is actually an
"areal" density in g/cm2 rather than a "volumetric"
or Archemdean density in g/cm3,As bones grow,
the volume increases at a faster rate than the area,
so the areal bone density will increase even if the
volumetric density remains stable,
Standardization of BMD and
Reproducibility
?The three manufacturers of DEXA
equipment do not give STANDARDIZED
RESULTS,The differences are clinically
important,making it difficult to compare a
measurement made from one machine to
the other,
?Studies frequently report reproducibility of
DEXA between 1 and 2%,This is the
average precision; the range is rarely
reported,But repeat measurements may
show as much as 7% difference,
Biochemical markers of bone
cell activity
? BIOCHEMICAL MARKERS OF BONE RESORPTION
NTX Aminoterminal cross-linking telopeptide of bone
collagen Collagen-based
CTX Carboxyterminal cross-linking telopeptide of bone
collagen Collagen-based
PYD Pyridinoline Collagen-based
DPD Free Lysyl-pyridinoline (deoxypyridinoline) Collagen-
based
TRACP Tartrate-resistant acid phosphatase Secreted by
osteoclasts
Hyp Hydroxy-proline (not very specific) Collagen-based
Biochemical markers of bone
cell activity
? BIOCHEMICAL MARKERS OF BONE FORMATION
Bone ALP,BAP Bone-specific alkaline phosphatase
Secreted by osteoblasts
PICP Procollagen type I C propeptide Collagen-based
PINP Procollagen type I N propeptide Collagen-based
OC Osteocalcin (bone gla-protein) Secreted by osteoblasts
ALP Alkaline phosphatase (not very specific) Secreted by
osteoblasts
Biochemical markers of bone
cell activity
? The biochemcial markers of bone formation and bone
resorption are frequently called markers of "bone turnover."
It is better to remember specifically which process is being
measured,because sometimes the bone formation and
resorption are not linked (for example,in steroid-induced
osteoporosis,bone formation is low but bone resorption is
high),
? These markers can NOT BE USED TO DIAGNOSE
OSTEOPOROSIS! They help us understand the physiology
of bone disease,especially in groups of patients or in
clinical trials,For individual patients,the markers are of
limited use and not recommended for screening or routine
follow-up,They do provide information which can help
decisions in complex cases,
Diagnosis of osteoroposis
(T & Z scores and the WHO definitions)
Differential diagnosis
? Remember that not all fractures are osteoporotic,
? The differential diagnosis of fractures includes,
Trauma,Pathologic fracture from neoplasm,
Osteomalacia,Paget's disease,Infections (such as
TB),Fibrous dysplasia,Peripheral neuropathy,
"March" fractures from repetitive stress
? Many of these may be diagnosed from radiographs,
bone scans,or magnetic resonance imaging
studies,Sometimes bone biopsies are necessary,
Diagnosis and differential diagnosis
Physical finding
? Patients with decreased bone density usually have no
specific abnormal physical findings,Those with vertebral
compression fractures will have kyphosis,protruding
abdomen and height loss,Back tenderness is usually only
present after an acute fracture,Gait speed and grip strength
are often reduced in patients who have or are about to have
a hip fracture,Visual acuity should be checked in geriatric
patients because it is a risk factor for falling,
? Secondary causes of osteoporosis may be associated with
physical findings,such as nodular thyroid,hepatic
enlargement,cushingoid features,skin rashes,jaundice,
abnormal dentition,and findings of hypogonadism,
Diagnosis and differential diagnosis
Xray findings
? Sometimes decreased bone density ("demineralization") can
be detected by xray,but bones can appear normal despite
loss of 30% of bone mineral,On the other hand,bones in
over-exposed films can appear demineralized when they
aren't,Bone density measurements are much more
accurate than xrays in determining bone density,
? The "Singh index" of the proximal femur correlates with
bone density,The trabeculae of the femur are lost in
sequence,depending on the physical stresses to the bone,
so the remaining trabecular pattern indicates the severity of
bone loss,
? Fractures are discussed in the clinical description page,
?Break 10 minutes
Prevention and Treatment
Basic prevention
? Calcium
?Vitamin D
?Exercise
?Fall prevention
?Nutrition and weight gain
?Stop smoking
?When to add medications
Prevention and Treatment
Calcium to treat and prevent osteoporosis
? Recommendations Calcium intake of 1 to 1.5 g/day
? Calcium content of foods
? Forms of calcium and Dietary factors
? Some practical information about calcium
? Mechanisms of action It is probably through inhibition
of PTH secretion and effects of the calcium receptor,
? Studies relating calcium intake to bone density A
study of calcium in men and women older than
65 showed that dietary calcium and vitamin D
supplementation moderately reduced bone loss
and reduced the incidence of nonvertebral
fractures,
? Side effects
Prevention and Treatment
Vitamin D
? metabolism It is formed in the skin after exposure to
ultraviolet radiation and also is absorbed from the diet,It is
hydroxylated at the liver to 25-hydroxyvitamin D,and in the
kidney to 1,25-dihydroxyvitamin D which is the active form,
? levels Measure 25(OH) vitamin D,not 1,25(OH)2 vitamin D
? supplementsnatural sunlight and fortification of dietary foods,
particulary dairy products and some cereals,
? Active Metabolites
? Disorders of vitamin D
Prevention and Treatment
Exercise
? Physical activity I recommend walking for prevention of hip
fractures,Back extension exercises and Tai Chi also are beneficial,
? Interventions in premenopausal,postmenopausal
and elderly women
? Physical therapy
? Specific exercises
? Skeletal response to mechanical forces
Prevention and Treatment
Fall Prevention
? The risk factors for falls include,
use of sedatives,previous fall,cognitive
impairment,visual impairment,lower-extremity
disability,foot problems,gait abnormalities
? At home,elderly or frail people should,
keep bathroom lights on,install grab bars,avoid
loose rugs,remove clutter,keep wires behind
furniture
? gait training or balance training
Prevention and Treatment
Hip Protection
? Thin women have less fat and soft tissue around the hips,
and if they fall the full impact is transferred to the bone,
? Padding using materials that absorb the energy can
significantly reduce the risk of hip fracture,
Smoking cigarettes
? Cigarette smoking contributes to osteoporosis,as well as a
host of other medical conditions,Perhaps concern about
osteoporosis will be the final thing that will convince
patients to stop smoking,
? The studies show negative effects of cigarette smoking on
the bone,One longitudinal study of 116,229 female nurses
found the age-adjusted relative risk for hip fracture was 1.3
in current smokers,Ten years after smoking cessation,the
risk was reduced,
Pharmaceutical treatment of osteoporosis
Physicians must pay attention to basic prevention
before writing a prescription,Medications do not work
as well (if at all) in patients who have poor nutrition,
vitamin D deficiency,or lack of exercise,Patients with
secondary osteoporosis may require different
treatments from those that are useful for primary OS,
? ESTABLISHED TREATMENT OF ESTABLISHED
OSTEOPOROSIS
Estrogen,Calcitonin,SERMs,Bisphosphonates,Intermittent PTH
? EXPERIMENTAL THERAPIES
Combinations,Fluoride,Growth Hormone,Active Vitamin D,Other
? ALGORITHMS
Women aged 50-60,Women aged 60-80,Women older than 80
Estrogen
? INDICATIONS
* Prevention of osteoporosis,in early postmenopausal women with
low bone density
*Treatment of menopausal symptoms
? CONTRA-INDICATIONS
* Pregnancy
* Breast cancer
* History of thrombophlebitis without trauma
* Active hepatitis
* Severe hypertriglyeridemia
? USE WITH CAUTION
* Lupus
* Endometriosis
* May need to adjust doses of thyroid or coumadin
* Coronary Artery Disease (don't start estrogen)
Estrogen
SIDE EFFECTS
Negative effects Positive effects
? Short-term
Breast tenderness,Vaginal bleeding Reduce hot flashes
or spotting Enlarge fibroids,Migraine headaches,Less gain of abdominal fat
Abdominal bloating,Nausea,Skin rashes,Increase Increase HDL cholesterol
triglycerides,Coronary artery disease (with progestin) Decrease LDL cholesterol
Thrombophlebitis,Stroke Helps vaginal atrophy
? Long-term
Gall stones,Fewer osteoporotic fractures
Breast cancer (especially with progestin),Decrease risk of colon cancer
Endometrial cancer (if no progestin) Improves pelvic musculature
Prevents collagen loss in skin (fewer wrinkles)
Questionable effects on Alzheimer's disease
Estrogen
Decisions about estrogen must be made on an
individual basis,
? The recommendation is to use low to moderate doses of estrogen in
women within ten years of menopause who have low bone density
(bottom 20% of population,T-score lower than -1.6) but are otherwise
healthy,
? In older women,estrogen is effective for preventing fractures,but it is
not the first choice medicine because of side effects on the heart or
strokes,Women who have already decided to use estrogen for other
symptoms will be getting good bone protection,
Dose and route of administration
? A recent study of estratabs showed dose-response between 0.3 and 1.2
mg/d in perimenopausal women,Other forms and routes of
administration appear to give similar results in terms of bone density,
Estrogen
When to start estrogen
? Epidemiological studies have suggested that the
maximum prevention of fractures occurs in women
who started estrogen within 5 years of menopause,
? In older women,estrogen increases bone density
as well as bisphosphonates,and estrogen
prevents fractures,However,as discussed above,
there is a greater risk of starting estrogen in
women who are more than ten years past
menopause,Therefore,it would not be a first
choice medication for osteoporosis in older women,
Estrogen
Studies showing beneficial effect on
bone density
?Many physicians do not realize that
estrogen improves the bone density as well
or better than alendronate,This is a
randomized study in women younger than
60,Randomized studies in older women
show similar changes in bone density
between estrogen and alendronate,
Estrogen
Other effects of estrogen
? CARDIOVASCULAR AND LIPID
1,estrogens increase HDL and decrease LDL-C
2,estrogen has been shown to have beneficial effects on the
development of arteriosclerotic plaques in the coronary arteries,
which were independent of the effects on the lipids,
? ENDOMETRIAL CANCER
? THROMBOPHLEBITIS
? OTHER EFFECTS
1,The risk of gallstones doubles,
2,Estrogens help to delay the loss of skin collagen and beneficial to
the skin,
3,Estrogen is the only effective treatment for vasomotor instability
associated with menopause,It also is used to treat vaginal atrophy,
4,There is a lower incidence of AD in women who take estrogen,
5,Contrary to popular opinion,estrogens do not cause weight gain,
What about progesterone?
? Progestins have been given to women who still
have a uterus,because estrogen alone can
increase the chance of endometrial cancer,But
there are increased risk of breast cancer and
heart disease in women taking combination
hormone therapy,
? The abstracts at the 2001 ASBMR have shown
increased bone density with
medroxyprogesterone acetate and
norethindrone,when added to estrogen,
? Progestins have several side effects,including
bloating and depression,The beneficial effects
of estrogen on the serum lipids are reduced
with progestins,
Calcitonin
? Calcitonin,produced by cells in the thyroid
gland,acts directly on osteoclasts (via
receptors on the surface),The osteoclasts
shrink and stop bone resorption,Bone
biopsies from patients treated with the drug
show no effects on mineralization,
? Indications,Prevention of vertebral
compression fractures
? Dose,Nasal spray/im,200 units/day
? Side effects,Minor adverse effects are seen in
a small number of patients,Calcitonin does not
reduce the serum calcium levels in patients
with postmenopausal osteoporosis,This
natural hormone has been in clinical use for
many years with a very good safety profile,
Biphosphonates
? The bisphosphonates are very powerful,they cause
dramatic changes in the bone physiology,and they
deserve respect,In patients with a high risk of fractures,
these medicines reduce the incidence of fractures and
improve the quality of life,
? The vast advertising in medical and public media has
increased the awareness of osteoporosis and possiblity
of treatment,which is good,but also has led many
people and physicians to think the drugs are very safe,
? The results from women in their 70's are assumed to
apply to young women,without consideration of
potential long-term effects,Until we know more about
the effect of long-term suppression of bone formation
rates,these drugs should be used carefully,
Biphosphonates
? INDICATIONS,Postmenopausal women with vertebral
compression fractures or with total hip bone density
below 650 mg/cm2 (T-2.5),Elderly men with non-
traumatic fractures,Some patients with secondary
osteoporosis due to corticosteroids,Paget's disease,
Cancer metastatic to bone,Other bone diseases with
high bone resorption
? CONTRA-INDICATIONS,Women who are pregnant or
planning pregnancy,Renal insufficiency,Low serum
calcium,Osteomalacia; Oral bisphosphonates should
not be used in,Patients with serious esophageal
disease and at bedrest who can't stay upright for 1hour
? USE WITH CAUTION,Patients with abnormal white
blood cells,Patients with high PTH,Children (no long-
term safety data)
Biphosphonates
SIDE EFFECTS
?All bisphosphonates,Hypocalcemia,
Increased PTH,Skin rash
?Oral forms,Upper GI irritation,Esophageal
ulceration
?Intravenous forms,Fever,Transient
leukopenia,Acute-phase reaction,Bone
pain,Eye inflammation,Nephrotic
syndrome
?Etidronate (Didronel),Osteomalacia,
Hyperphosphatemia
Biphosphonates
PHYSIOLOGIC EFFECTS
? Decreased bone resorption
? Decreased bone formation by 70-95%
? Increased mineralization density
? Slight increase in bone volume
? Increase bone strength first 5 years
? Decreased fracture rate first 5 years
? Half-life in bone greater than 10 years
? Increased micro-damage in animals
? Long-term effects on bone unknown
Biphosphonates
Dose for fracture prevention
? The fracture rates with the lower doses was not significantly
different from the rates in higher doses,despite greater
increases in the DEXA measurements with the higher doses,
? The FIT trial of alendronate documented significant fracture
reduction at 2 years with the 5mg/day dose,After 2 years
the dose was increased to 10mg/day,but the study design
precluded actual dose comparisons,
? Subsequent studies have shown that doses given once a
week are as effective as those given daily,Almost all
patients prefer this approach,so that is what I ususally use,
? In general,we give the lowest dose necessary to achieve a
benefit,Why the exception with the bisphosphonates? I
think it is because too many people rely on the surrogate
measurement (DEXA) instead of the important endpoint of
fracture reduction,
Mechanisms of action
Possible cellular actions of bisphosphonates
? Interfere with osteoclast cytoskeleton
? Inhibit mevalonate pathway enzymes
? Decrease protein-tyrosine phosphatases
? Stimulate apoptosis of osteoclasts
? Inhibit osteoclast attachment to bone
? Inhibit proton pump of osteoclasts
? Inhibit secretion of matrix metalloproteinases
? Act on osteoblasts to inhibit stimulator of osteoclast
recruitment
? Act on osteoblast to stimulate inhibitor of osteoclast
recruitment
? Act on osteoblasts to inhibit osteoclast activity
Intermittent PTH
? Brands,Parathyroid hormone is naturally
produced as an 84-amino-acid polypeptide,There
have been some studies with various forms of PTH,
The FDA has approved recombinant PTH 1-34,
with a new chemical name of teriparatide made by
Lilly with the brand name Forteo,
? Dose,The only dose is 20 mcg/day,given by
intermittent subcutaneous injection once a day
using a special injection device,At this time the
duration of treatment should not exceed 2 years,
? Indications,I think that 1-34 PTH will be a useful
addition to osteoporosis treatment,PTH had
demonstrated low bone formation rates and low
resorption rates,and the patients continue to have
fractures despite other osteoporosis therapy,
Intermittent PTH
? Contra-indications,
Children and adolescents,Persons who have had
bone cancer,Persons who have had radiation
therapy involving the bones,Patients with Paget's
disease,Patients with hypercalcemia,Women who
are pregnant or nursing,Patients with active gout
? Side effects,
Nausea in 8% (similar to placebo),Headache in
8%,Dizziness in 9%,Leg cramps in 3%,
Hypercalcemia in 11% (usually mild but a few
patients needed to stop PTH),Uric acid increased
by 13%
Intermittent PTH
Physiological actions
?PTH stimulates osteoblastic activity,
especially on trabecular surfaces,
?It also stimulated osteoclastic activity,
?PTH will cause more increase in bone
formation than in bone resorption,
?Micro-array analysis has shown that
different genes are expressed in bone cells
that have been exposed to continuous PTH
than those expressed after intermittent PTH
SERMs (Selective Estrogen Receptor Modulators)
raloxifene (Evista)
? SERMS are "designer" estrogen-related
medications that activate the estrogen
receptors,but have different effects on
different tissues,
? There are two kinds of estrogen receptors,and
after binding to receptors,the drug-receptor
complex can have various conformations,
? Some of these will act like estrogen,others will
inhibit the actions of estrogen,
? Raloxifene is a newer SERM that has been
approved for prevention and treatment of
postmenopausal osteoporosis,
Raloxifen
? Dose,60mg/day,
? Indications,Treatment and prevention of
postmenopausal osteoporosis,
? Contra-indications,Premenopausal women,Men,
Women who have had thrombophlebitis
? Effects on fracture rates,The medication inhibits bone
resorption,Biochemical markers of bone resorption and
formation decrease,and bone density increases,
The MORE study enrolled 7705 postmenopausal women
who had osteoporosis defined by a bone density T-
score of -2.5 or lower or a vertebral compression
fracture,The results for vertebral fractures were
significant,but there was not a significant decrease in
the non-vertebral fractures,
? Side effects,flu,hot flashes,leg cramps,diabetes
Raloxifen
Important other effects and non-effects
? There is no increased incidence of vaginal bleeding or
endometrial pathology,
? The lipid profile is more favorable,with decreases in the
LDL cholesterol,
? In the MORE study there was no significant difference in
cardiovascular endpoints,
? It is a good choice for women who have osteoporosis and
do not want to take estrogen because they are concerned
about breast cancer,It doesn’t suppress the bone formation
rate as much as the bisphosphontes,and it doesn’t deposit
in the bone,so on a physiological basis it should be a safer
drug to use for many years,
Experimental therapies
Combinations,The ideal combination would be an
antiresorptive medication combined with one that
enhances osteoblast function,
Thiazides
Fluoride,Fluoride definitely increased the bone
formation rate as well as the bone density,However,
osteomalacia still resulted,
Growth Hormone
Statins
Other
Really experimental
End of Presentation
The important thing to remember is
that being diagnosed with osteoporosis
is not the end of world,With a careful
treatment program that may include
doctor-supervised exercise,a healthy
lifestyle,and possibly medication,even
fragile bones have the chance to gain
strength,
Presentation,2005
谢瑞满 Rui-man Xie,Ph.D.,M.D,
Professor of Neurology & Gerontology
ZhongShan Hospital,Fudan University
rmxie@zshospital.net,xieruiman@yahoo.com
Objective
1,Definition,types and mechanism of osteoporosis
2,Diagnosis,prevention and treatment of osteoporosis
3, Etiology and Epidemiology of osteoporosis
times – 45 minutes× 2
Overview
Definition, Osteoporosis is a bone
disease in which the amount of bone is
decreased and the structural integrity of
trabecular bone is impaired,Cortical
bone becomes more porous and thinner,
This makes the bone weaker and more
likely to fracture,
?figures
Associated changes in body shape and vertebra
（ deleted 6 pictures）
normal 50yrs above 55yrs above
75yrs
kyphosis
Patients with risk factors or conditions
that cause osteoporosis
? Postmenopausal woman with family history of hip
fractures or kyphosis
? Medications,corticosteroids,dilantin,gonadotropin
releasing hormone agonists,loop diuretics,
methotrexate,thyroid,heparin,cyclosporin,depot-
medroxyprogesterone acetate
? Hereditary skeletal diseases,osteogenesis imperfecta,
rickets,hypophosphatasia
? Endocrine and metabolic,hypogonadism,
hyperparathyroidism,hyperthyroidism,Cushing
syndrome,acidosis,Gaucher's disease
? Marrow diseases,myeloma,mastocytosis,thalassemia
? Others,Anorexia,Malabsorption,Cystic fibrosis,Renal
insufficiency,Hypercalciuria,Hepatic disease,
Depression,Spinal cord injury,Systemic Lupus,
Weight below healthy range,Cigarette smoking
Epidemiology
? The population of older men and women has
been increasing,and therefore the number
of people with osteoporosis is increasing,
? In the USA,about 21% of postmenopausal
women have osteoporosis (low bone
density),and about 16% have had a fracture,
In women older than 80,about 40% have
experienced a fracture of the hip,vertebra,
arm,or pelvis,
? Women have more osteoporotic fractures
than men,Age is one of the most important
risks in all groups,
? The decreased physical activity may be
playing a role in increased hip fractures,
Mechanism, Bone physiology
? The bone is continuously remodelling,and the bone surface
moves in and out,The Basic Multicellular Unit (BMU) is a
wandering team of cells that dissolves an area of the bone
surface and then fills it with new bone,The sequence is
Origination,Osteoclast recruitment,Resorption,Osteoblast
recruitment,Osteoid formation,Mineralization,Mineral
maturation,Quiescence,
? Bone strength (Quality),In addition to bone porosity,the
bone strength is determined by the trabecular microstructure,
Perforations of individual trabecula occur when resorption
cavities are too deep,This,too,is seen with estrogen
deficiency,The remaining trabecula are not as well
connected and are mechanically weaker,
Mechanism, Bone physiology
? Microfracture healing is another aspect of bone strength
that is not measured by bone density,Trabeculae inside the
bone may fracture and microcalluses are formed that
resemble the calluses seen on xrays of long bones after a
"macro-fracture",Osteoporotic bone is more susceptible to
these fractures because the individual trabeculae do not
have as many reinforcing connections,The calluses may
represent a method of repairing the bone and even
connecting some of the trabecula,Bone which has lost the
ability to form these calluses will be weaker,
? The age of the bone mineral crystals may also play a role in
the strength of bone,This is an area that needs further
research,Studies suggest that older bone is more brittle,
and that one purpose of bone remodelling is to remove the
old bone and replace it with newer,more elastic bone,
Clinical manifestation and types
? Secondary osteoporosis,
Mndocrine and metabolic,hypogonadism,
hyperparathyroidism,hyperthyroidism,Cushing syndrome,
acidosis,Gaucher's disease;
Marrow diseases,myeloma,mastocytosis,thalassemia;
Medications,corticosteroids,dilantin,gonadotropin
releasing hormone agonists,loop diuretics,methotrexate,
thyroid,heparin,cyclosporin,depot-medroxyprogesterone
acetate;
Malabsorption,Hepatic disease,others；
? Hereditary skeletal diseases,
osteogenesis imperfecta,rickets,hypophosphatasia;
? Primary osteoporosis,
Clinical manifestation and types
Primary osteoporosis,
?TypeⅠ postmenopausal osteoroposis——This is
seen with estrogen deficiency,There is high bone
turnover rate,The proportion of trochanteric and
femoral neck fractures increases；
?TypeⅡ elderly osteoroposis——This is aging in
bone physiology,The compression fracture of
the spine and hip fracture are more common,
Clinical Features of Osteoroposis
The vast majority of hip fractures occur
after a fall,About 5% appear to be
“spontaneous” fractures,in which the
patient feels a fracture and then falls,
Overall about half of hip fractures are
intertrochanteric and the others are
femoral neck fractures,
Clinical Features of Osteoroposis
Vertebral compression fractures vary in
degree from mild wedges to complete
compression,The symptoms also vary,but
the degree of compression is not necessarily
related to the amount of pain,In fact,about
60% of women with compression fractures
do not realize they have had a fracture! It is
possible that some of the fractures occurred
gradually and therefore did not cause acute
pain,
Clinical Features of Osteoroposis
?When women and men do suffer painful
compression fractures,the pain usually
lasts from one to two months,is localized
to the back with accompanying muscle
spasms,then gradually subsides,
?Patients with continuing severe pain
should be evaluated for other pathologic
etiologies of the fracture,especially
malignancy or myeloma,
?Persistent pain can also be caused by
continuing fracture,muscle spasms,
spinal stenosis,or degenerative joint
disease,
Clinical Features of Osteoroposis
?To correctly interpret a spine xray,it is
important to know the definition of a
vertebral fracture,which is not quite as
straightforward as it first appears,
especially for research,
?For practical clinical purposes,a
vertebra can be considered fractured if
the anterior height is 80% or less of the
posterior height,
?A new fracture requires loss of at least
20% of anterior or posterior height,
Clinical Features of Osteoroposis
? Wrist fractures are more common in women who
are 50 to 60 years old,These are caused by falls or
other trauma,Osteoporosis does not appear to
impair the healing of the wrist fractures,and they
cause only short-term disability,
? Although spine,hip,and wrist fractures are
considered classical osteoporotic fractures,many
others are related to bone density and thus are also
osteoporotic,These include rib,pelvic and shoulder
fractures,but not finger,facial bone,skull,elbow,or
ankle fractures,
Clinical Features of Osteoroposis
? The irreversible height loss associated with
osteoporosis is one of the aspects of the disease
that is most distressing to many women,
Height loss can also occur with scoliosis,which
often gets worse after menopause,
Also,degenerative disk disease can cause height
loss of 2 inches,
Some reversible height loss is due to poor posture,
? KYPHOSIS is the feature of osteoporosis that is
identified by most patients,The hump causes
difficulty in finding clothes that will fit,let alone look
attractive,In severe cases,the ribs contact the
iliac crest and movement causes pain,
Clinical Features of Osteoroposis
?PROTRUDING ABDOMEN
The protruding abdomen which is a result of
the kyphosis is an unrecognized aspect of
osteoporosis,Women do not realize that the
curvature of the spine decreases the
abdominal space,and thus the intestines
have nowhere to go except forwards,Many
women think that they are getting fat,and
they go on a diet trying to regain their
youthful waistline,If they do successfully lose
weight,it will only increase their risk for more
osteoporotic fractures,
Clinical Features of Osteoroposis
? DECREASED PULMONARY CAPACITY
Patients with kyphosis have decreased
lung volumes,In severe cases this
leads to shortness of breath and
pulmonary symptoms of restrictive lung
disease,
Clinical Features of Osteoroposis
?REFLUX ESOPHAGITIS
Patients with kyphosis may develop
reflux esophagitis due to the changes
in abdominal space,Wearing tight
clothing can exacerbate the problem,
Laboratory tests
?For an uncomplicated patient with
osteoporosis,a lab workup would be a
chemistry panel,CBC,phosphate,TSH and
24-hour urine calcium,Males should have
testosterone measured,
?The main purpose of laboratory tests is to
check for secondary causes of osteoporosis
such as cases of renal or hepatic failure,
anemia,acidosis,hypercalciuria,and
abnormalities of calcium/phosphate,
Laboratory tests
?Alkaline phosphatase is an inexpensive
method of checking for osteoblastic
activity,It is not as sensitive or specific
as newer "bone markers" but it will
detect moderate to severe osteomalacia
or Paget's disease,
?The 24-hour urine calcium
measurement is frequently ignored but it
is a valuable and inexpensive test,High
levels are seen in idiopathic
hypercalciuria,and low levels suggest
malabsorption,
Laboratory tests
? Protein electrophoresis should be done
whenever a patient presents with new
fractures,Both serum and urine tests should
be done because some patients with
myeloma have abnormalities in only one,
? Corticosteroid excess that causes
osteoporosis can usually be detected
clinically by Cushingoid features,A urine
cortisol can be helpful in puzzling cases,
Laboratory tests
? Gonadal hormones are very important causes
of osteoporosis,In females who are
postmenopausal,it is not helpful to measure
levels of estrogens or gonadotropins,In
males,however,testosterone levels should
be measured because there is much greater
variability in the prevalence of hypogonadism,
Also,men may have low testosterone without
other clinical symptoms,
Laboratory tests
? Vitamin D and parathyroid hormone levels are expensive
tests,Mild vitamin D deficiency frequently occurs in the
absence of hypocalcemia,but if vitamin D supplementation
is routinely given,it is not necessary to perform this test in
patients with normal calcium,Primary hyperparathyroidism
nearly always causes hypercalcemia,Secondary
hyperparathyroidism may occur with normal calcium,but
most of these cases will be detected by low urine calcium or
decreased renal function,
? In patients with abnormal serum calcium or with unusually
severe bone disease,however,the 25-OH-vitamin D and
parathyroid hormone levels should be measured,
The 25 OH-vitamin D is more useful than the 1,25 (OH)2
vitamin D level,
Indications for bone density
measurements
?Over the last decade there have been many
debates about screening bone density,
Several organizations have performed
detailed cost-benefit studies and developed
guidelines; these must be continually revised
as new findings about treatment effects are
discovered,
?Bone density tests carry no physical risks,
but there is a problem of over-interpretation
of results,so that healthy ordinary average
people think they are at a much higher risk
than they actually are,
Bone density measurements
Techniques
? Several methods are available to measure bone
density,but currently the most widely used
technique is DEXA (Dual Energy Xray
Absorptiometry),This is the method used to
determine efficacy in the recent large clinical trials,
and to characterize fracture risk in large
epidemiological studies,
? Newer techniques such as ultrasound appear to
offer a more cost-effective method of screening
bone mass,Ultrasound measurements are usually
performed at the calcaneous and it is not possible
to measure sites of osteoporotic fracture such as
the hip or spine,
Bone density measurements
? Quantitative computed tomography of the spine
must be done following strict protocols in
laboratories that do these tests frequently; in
community settings the reproducibility is poor,The
QCT measurements decrease more rapidly with
aging,so the "T scores" in older individuals will be
much lower than DEXA measurements,
? Several other techniques can measure bone
density at the hand,radius or ankle,These include
single energy absorptiometry,metacarpal width or
density from hand xrays,Magnetic resonance
imaging is a new method of measuring bone density,
T & Z scores and the WHO definitions
? The WHO has based definitions on the T-score,
which is the number of standard deviations from
the mean (average) value of a 25-year-old woman,
1,Normal bone,T-score better than -1,
2,Osteopenia,T-score between -1 and -2.5
3,Osteoporosis,T-score less than -2.5
4,Established osteoporosis includes the presence of
a non-traumatic fracture,
One standard deviation is at the 16th percentile,so
by definition 16% of young women have
osteopenia!
? The Z-score is the number of standard deviations
below age-matched avereage,
Bone density measurements
DEXA reports
? Step 1,the images
? Step 2 - the graphs
? Step 3 - the basic results
? Step 4 - the reference ranges
Beware the shifting reference ranges!
Comparing a recent scan to one done
prior to about 1997,
? Step 5 - the areas and mineral contents
Bone Mineral Apparent Density
? BMAD is important when measuring bone density
in children or in patients with short stature,Another
term for this concept is "volumetric bone density",
? The DEXA technique analyzes the attenuation of
xrays as they pass through an area of the body,
The method cannot detect the depth of the bone
which is being measured,and thus is actually an
"areal" density in g/cm2 rather than a "volumetric"
or Archemdean density in g/cm3,As bones grow,
the volume increases at a faster rate than the area,
so the areal bone density will increase even if the
volumetric density remains stable,
Standardization of BMD and
Reproducibility
?The three manufacturers of DEXA
equipment do not give STANDARDIZED
RESULTS,The differences are clinically
important,making it difficult to compare a
measurement made from one machine to
the other,
?Studies frequently report reproducibility of
DEXA between 1 and 2%,This is the
average precision; the range is rarely
reported,But repeat measurements may
show as much as 7% difference,
Biochemical markers of bone
cell activity
? BIOCHEMICAL MARKERS OF BONE RESORPTION
NTX Aminoterminal cross-linking telopeptide of bone
collagen Collagen-based
CTX Carboxyterminal cross-linking telopeptide of bone
collagen Collagen-based
PYD Pyridinoline Collagen-based
DPD Free Lysyl-pyridinoline (deoxypyridinoline) Collagen-
based
TRACP Tartrate-resistant acid phosphatase Secreted by
osteoclasts
Hyp Hydroxy-proline (not very specific) Collagen-based
Biochemical markers of bone
cell activity
? BIOCHEMICAL MARKERS OF BONE FORMATION
Bone ALP,BAP Bone-specific alkaline phosphatase
Secreted by osteoblasts
PICP Procollagen type I C propeptide Collagen-based
PINP Procollagen type I N propeptide Collagen-based
OC Osteocalcin (bone gla-protein) Secreted by osteoblasts
ALP Alkaline phosphatase (not very specific) Secreted by
osteoblasts
Biochemical markers of bone
cell activity
? The biochemcial markers of bone formation and bone
resorption are frequently called markers of "bone turnover."
It is better to remember specifically which process is being
measured,because sometimes the bone formation and
resorption are not linked (for example,in steroid-induced
osteoporosis,bone formation is low but bone resorption is
high),
? These markers can NOT BE USED TO DIAGNOSE
OSTEOPOROSIS! They help us understand the physiology
of bone disease,especially in groups of patients or in
clinical trials,For individual patients,the markers are of
limited use and not recommended for screening or routine
follow-up,They do provide information which can help
decisions in complex cases,
Diagnosis of osteoroposis
(T & Z scores and the WHO definitions)
Differential diagnosis
? Remember that not all fractures are osteoporotic,
? The differential diagnosis of fractures includes,
Trauma,Pathologic fracture from neoplasm,
Osteomalacia,Paget's disease,Infections (such as
TB),Fibrous dysplasia,Peripheral neuropathy,
"March" fractures from repetitive stress
? Many of these may be diagnosed from radiographs,
bone scans,or magnetic resonance imaging
studies,Sometimes bone biopsies are necessary,
Diagnosis and differential diagnosis
Physical finding
? Patients with decreased bone density usually have no
specific abnormal physical findings,Those with vertebral
compression fractures will have kyphosis,protruding
abdomen and height loss,Back tenderness is usually only
present after an acute fracture,Gait speed and grip strength
are often reduced in patients who have or are about to have
a hip fracture,Visual acuity should be checked in geriatric
patients because it is a risk factor for falling,
? Secondary causes of osteoporosis may be associated with
physical findings,such as nodular thyroid,hepatic
enlargement,cushingoid features,skin rashes,jaundice,
abnormal dentition,and findings of hypogonadism,
Diagnosis and differential diagnosis
Xray findings
? Sometimes decreased bone density ("demineralization") can
be detected by xray,but bones can appear normal despite
loss of 30% of bone mineral,On the other hand,bones in
over-exposed films can appear demineralized when they
aren't,Bone density measurements are much more
accurate than xrays in determining bone density,
? The "Singh index" of the proximal femur correlates with
bone density,The trabeculae of the femur are lost in
sequence,depending on the physical stresses to the bone,
so the remaining trabecular pattern indicates the severity of
bone loss,
? Fractures are discussed in the clinical description page,
?Break 10 minutes
Prevention and Treatment
Basic prevention
? Calcium
?Vitamin D
?Exercise
?Fall prevention
?Nutrition and weight gain
?Stop smoking
?When to add medications
Prevention and Treatment
Calcium to treat and prevent osteoporosis
? Recommendations Calcium intake of 1 to 1.5 g/day
? Calcium content of foods
? Forms of calcium and Dietary factors
? Some practical information about calcium
? Mechanisms of action It is probably through inhibition
of PTH secretion and effects of the calcium receptor,
? Studies relating calcium intake to bone density A
study of calcium in men and women older than
65 showed that dietary calcium and vitamin D
supplementation moderately reduced bone loss
and reduced the incidence of nonvertebral
fractures,
? Side effects
Prevention and Treatment
Vitamin D
? metabolism It is formed in the skin after exposure to
ultraviolet radiation and also is absorbed from the diet,It is
hydroxylated at the liver to 25-hydroxyvitamin D,and in the
kidney to 1,25-dihydroxyvitamin D which is the active form,
? levels Measure 25(OH) vitamin D,not 1,25(OH)2 vitamin D
? supplementsnatural sunlight and fortification of dietary foods,
particulary dairy products and some cereals,
? Active Metabolites
? Disorders of vitamin D
Prevention and Treatment
Exercise
? Physical activity I recommend walking for prevention of hip
fractures,Back extension exercises and Tai Chi also are beneficial,
? Interventions in premenopausal,postmenopausal
and elderly women
? Physical therapy
? Specific exercises
? Skeletal response to mechanical forces
Prevention and Treatment
Fall Prevention
? The risk factors for falls include,
use of sedatives,previous fall,cognitive
impairment,visual impairment,lower-extremity
disability,foot problems,gait abnormalities
? At home,elderly or frail people should,
keep bathroom lights on,install grab bars,avoid
loose rugs,remove clutter,keep wires behind
furniture
? gait training or balance training
Prevention and Treatment
Hip Protection
? Thin women have less fat and soft tissue around the hips,
and if they fall the full impact is transferred to the bone,
? Padding using materials that absorb the energy can
significantly reduce the risk of hip fracture,
Smoking cigarettes
? Cigarette smoking contributes to osteoporosis,as well as a
host of other medical conditions,Perhaps concern about
osteoporosis will be the final thing that will convince
patients to stop smoking,
? The studies show negative effects of cigarette smoking on
the bone,One longitudinal study of 116,229 female nurses
found the age-adjusted relative risk for hip fracture was 1.3
in current smokers,Ten years after smoking cessation,the
risk was reduced,
Pharmaceutical treatment of osteoporosis
Physicians must pay attention to basic prevention
before writing a prescription,Medications do not work
as well (if at all) in patients who have poor nutrition,
vitamin D deficiency,or lack of exercise,Patients with
secondary osteoporosis may require different
treatments from those that are useful for primary OS,
? ESTABLISHED TREATMENT OF ESTABLISHED
OSTEOPOROSIS
Estrogen,Calcitonin,SERMs,Bisphosphonates,Intermittent PTH
? EXPERIMENTAL THERAPIES
Combinations,Fluoride,Growth Hormone,Active Vitamin D,Other
? ALGORITHMS
Women aged 50-60,Women aged 60-80,Women older than 80
Estrogen
? INDICATIONS
* Prevention of osteoporosis,in early postmenopausal women with
low bone density
*Treatment of menopausal symptoms
? CONTRA-INDICATIONS
* Pregnancy
* Breast cancer
* History of thrombophlebitis without trauma
* Active hepatitis
* Severe hypertriglyeridemia
? USE WITH CAUTION
* Lupus
* Endometriosis
* May need to adjust doses of thyroid or coumadin
* Coronary Artery Disease (don't start estrogen)
Estrogen
SIDE EFFECTS
Negative effects Positive effects
? Short-term
Breast tenderness,Vaginal bleeding Reduce hot flashes
or spotting Enlarge fibroids,Migraine headaches,Less gain of abdominal fat
Abdominal bloating,Nausea,Skin rashes,Increase Increase HDL cholesterol
triglycerides,Coronary artery disease (with progestin) Decrease LDL cholesterol
Thrombophlebitis,Stroke Helps vaginal atrophy
? Long-term
Gall stones,Fewer osteoporotic fractures
Breast cancer (especially with progestin),Decrease risk of colon cancer
Endometrial cancer (if no progestin) Improves pelvic musculature
Prevents collagen loss in skin (fewer wrinkles)
Questionable effects on Alzheimer's disease
Estrogen
Decisions about estrogen must be made on an
individual basis,
? The recommendation is to use low to moderate doses of estrogen in
women within ten years of menopause who have low bone density
(bottom 20% of population,T-score lower than -1.6) but are otherwise
healthy,
? In older women,estrogen is effective for preventing fractures,but it is
not the first choice medicine because of side effects on the heart or
strokes,Women who have already decided to use estrogen for other
symptoms will be getting good bone protection,
Dose and route of administration
? A recent study of estratabs showed dose-response between 0.3 and 1.2
mg/d in perimenopausal women,Other forms and routes of
administration appear to give similar results in terms of bone density,
Estrogen
When to start estrogen
? Epidemiological studies have suggested that the
maximum prevention of fractures occurs in women
who started estrogen within 5 years of menopause,
? In older women,estrogen increases bone density
as well as bisphosphonates,and estrogen
prevents fractures,However,as discussed above,
there is a greater risk of starting estrogen in
women who are more than ten years past
menopause,Therefore,it would not be a first
choice medication for osteoporosis in older women,
Estrogen
Studies showing beneficial effect on
bone density
?Many physicians do not realize that
estrogen improves the bone density as well
or better than alendronate,This is a
randomized study in women younger than
60,Randomized studies in older women
show similar changes in bone density
between estrogen and alendronate,
Estrogen
Other effects of estrogen
? CARDIOVASCULAR AND LIPID
1,estrogens increase HDL and decrease LDL-C
2,estrogen has been shown to have beneficial effects on the
development of arteriosclerotic plaques in the coronary arteries,
which were independent of the effects on the lipids,
? ENDOMETRIAL CANCER
? THROMBOPHLEBITIS
? OTHER EFFECTS
1,The risk of gallstones doubles,
2,Estrogens help to delay the loss of skin collagen and beneficial to
the skin,
3,Estrogen is the only effective treatment for vasomotor instability
associated with menopause,It also is used to treat vaginal atrophy,
4,There is a lower incidence of AD in women who take estrogen,
5,Contrary to popular opinion,estrogens do not cause weight gain,
What about progesterone?
? Progestins have been given to women who still
have a uterus,because estrogen alone can
increase the chance of endometrial cancer,But
there are increased risk of breast cancer and
heart disease in women taking combination
hormone therapy,
? The abstracts at the 2001 ASBMR have shown
increased bone density with
medroxyprogesterone acetate and
norethindrone,when added to estrogen,
? Progestins have several side effects,including
bloating and depression,The beneficial effects
of estrogen on the serum lipids are reduced
with progestins,
Calcitonin
? Calcitonin,produced by cells in the thyroid
gland,acts directly on osteoclasts (via
receptors on the surface),The osteoclasts
shrink and stop bone resorption,Bone
biopsies from patients treated with the drug
show no effects on mineralization,
? Indications,Prevention of vertebral
compression fractures
? Dose,Nasal spray/im,200 units/day
? Side effects,Minor adverse effects are seen in
a small number of patients,Calcitonin does not
reduce the serum calcium levels in patients
with postmenopausal osteoporosis,This
natural hormone has been in clinical use for
many years with a very good safety profile,
Biphosphonates
? The bisphosphonates are very powerful,they cause
dramatic changes in the bone physiology,and they
deserve respect,In patients with a high risk of fractures,
these medicines reduce the incidence of fractures and
improve the quality of life,
? The vast advertising in medical and public media has
increased the awareness of osteoporosis and possiblity
of treatment,which is good,but also has led many
people and physicians to think the drugs are very safe,
? The results from women in their 70's are assumed to
apply to young women,without consideration of
potential long-term effects,Until we know more about
the effect of long-term suppression of bone formation
rates,these drugs should be used carefully,
Biphosphonates
? INDICATIONS,Postmenopausal women with vertebral
compression fractures or with total hip bone density
below 650 mg/cm2 (T-2.5),Elderly men with non-
traumatic fractures,Some patients with secondary
osteoporosis due to corticosteroids,Paget's disease,
Cancer metastatic to bone,Other bone diseases with
high bone resorption
? CONTRA-INDICATIONS,Women who are pregnant or
planning pregnancy,Renal insufficiency,Low serum
calcium,Osteomalacia; Oral bisphosphonates should
not be used in,Patients with serious esophageal
disease and at bedrest who can't stay upright for 1hour
? USE WITH CAUTION,Patients with abnormal white
blood cells,Patients with high PTH,Children (no long-
term safety data)
Biphosphonates
SIDE EFFECTS
?All bisphosphonates,Hypocalcemia,
Increased PTH,Skin rash
?Oral forms,Upper GI irritation,Esophageal
ulceration
?Intravenous forms,Fever,Transient
leukopenia,Acute-phase reaction,Bone
pain,Eye inflammation,Nephrotic
syndrome
?Etidronate (Didronel),Osteomalacia,
Hyperphosphatemia
Biphosphonates
PHYSIOLOGIC EFFECTS
? Decreased bone resorption
? Decreased bone formation by 70-95%
? Increased mineralization density
? Slight increase in bone volume
? Increase bone strength first 5 years
? Decreased fracture rate first 5 years
? Half-life in bone greater than 10 years
? Increased micro-damage in animals
? Long-term effects on bone unknown
Biphosphonates
Dose for fracture prevention
? The fracture rates with the lower doses was not significantly
different from the rates in higher doses,despite greater
increases in the DEXA measurements with the higher doses,
? The FIT trial of alendronate documented significant fracture
reduction at 2 years with the 5mg/day dose,After 2 years
the dose was increased to 10mg/day,but the study design
precluded actual dose comparisons,
? Subsequent studies have shown that doses given once a
week are as effective as those given daily,Almost all
patients prefer this approach,so that is what I ususally use,
? In general,we give the lowest dose necessary to achieve a
benefit,Why the exception with the bisphosphonates? I
think it is because too many people rely on the surrogate
measurement (DEXA) instead of the important endpoint of
fracture reduction,
Mechanisms of action
Possible cellular actions of bisphosphonates
? Interfere with osteoclast cytoskeleton
? Inhibit mevalonate pathway enzymes
? Decrease protein-tyrosine phosphatases
? Stimulate apoptosis of osteoclasts
? Inhibit osteoclast attachment to bone
? Inhibit proton pump of osteoclasts
? Inhibit secretion of matrix metalloproteinases
? Act on osteoblasts to inhibit stimulator of osteoclast
recruitment
? Act on osteoblast to stimulate inhibitor of osteoclast
recruitment
? Act on osteoblasts to inhibit osteoclast activity
Intermittent PTH
? Brands,Parathyroid hormone is naturally
produced as an 84-amino-acid polypeptide,There
have been some studies with various forms of PTH,
The FDA has approved recombinant PTH 1-34,
with a new chemical name of teriparatide made by
Lilly with the brand name Forteo,
? Dose,The only dose is 20 mcg/day,given by
intermittent subcutaneous injection once a day
using a special injection device,At this time the
duration of treatment should not exceed 2 years,
? Indications,I think that 1-34 PTH will be a useful
addition to osteoporosis treatment,PTH had
demonstrated low bone formation rates and low
resorption rates,and the patients continue to have
fractures despite other osteoporosis therapy,
Intermittent PTH
? Contra-indications,
Children and adolescents,Persons who have had
bone cancer,Persons who have had radiation
therapy involving the bones,Patients with Paget's
disease,Patients with hypercalcemia,Women who
are pregnant or nursing,Patients with active gout
? Side effects,
Nausea in 8% (similar to placebo),Headache in
8%,Dizziness in 9%,Leg cramps in 3%,
Hypercalcemia in 11% (usually mild but a few
patients needed to stop PTH),Uric acid increased
by 13%
Intermittent PTH
Physiological actions
?PTH stimulates osteoblastic activity,
especially on trabecular surfaces,
?It also stimulated osteoclastic activity,
?PTH will cause more increase in bone
formation than in bone resorption,
?Micro-array analysis has shown that
different genes are expressed in bone cells
that have been exposed to continuous PTH
than those expressed after intermittent PTH
SERMs (Selective Estrogen Receptor Modulators)
raloxifene (Evista)
? SERMS are "designer" estrogen-related
medications that activate the estrogen
receptors,but have different effects on
different tissues,
? There are two kinds of estrogen receptors,and
after binding to receptors,the drug-receptor
complex can have various conformations,
? Some of these will act like estrogen,others will
inhibit the actions of estrogen,
? Raloxifene is a newer SERM that has been
approved for prevention and treatment of
postmenopausal osteoporosis,
Raloxifen
? Dose,60mg/day,
? Indications,Treatment and prevention of
postmenopausal osteoporosis,
? Contra-indications,Premenopausal women,Men,
Women who have had thrombophlebitis
? Effects on fracture rates,The medication inhibits bone
resorption,Biochemical markers of bone resorption and
formation decrease,and bone density increases,
The MORE study enrolled 7705 postmenopausal women
who had osteoporosis defined by a bone density T-
score of -2.5 or lower or a vertebral compression
fracture,The results for vertebral fractures were
significant,but there was not a significant decrease in
the non-vertebral fractures,
? Side effects,flu,hot flashes,leg cramps,diabetes
Raloxifen
Important other effects and non-effects
? There is no increased incidence of vaginal bleeding or
endometrial pathology,
? The lipid profile is more favorable,with decreases in the
LDL cholesterol,
? In the MORE study there was no significant difference in
cardiovascular endpoints,
? It is a good choice for women who have osteoporosis and
do not want to take estrogen because they are concerned
about breast cancer,It doesn’t suppress the bone formation
rate as much as the bisphosphontes,and it doesn’t deposit
in the bone,so on a physiological basis it should be a safer
drug to use for many years,
Experimental therapies
Combinations,The ideal combination would be an
antiresorptive medication combined with one that
enhances osteoblast function,
Thiazides
Fluoride,Fluoride definitely increased the bone
formation rate as well as the bone density,However,
osteomalacia still resulted,
Growth Hormone
Statins
Other
Really experimental
End of Presentation
The important thing to remember is
that being diagnosed with osteoporosis
is not the end of world,With a careful
treatment program that may include
doctor-supervised exercise,a healthy
lifestyle,and possibly medication,even
fragile bones have the chance to gain
strength,
