Download Osteoporosis

Osteoporosis Diagnosis and
Management:
Current Strategies
Normal Bone Physiology
• Workhorses of the Bone Remodeling World
– Osteoblasts
• Bone formation/mineralization
• Receives endocrine signaling, directs osteoclasts
– Osteoclasts
• Differentiation linked to RANKL ligand signalling (on)
vs. osteoprotegerin (off) decoy signalling
• Cytokines can enhance activation or lifespan
– **blocked by Estrogen
• Bone resorption
– Secrete HCl to chew up bone, dissolve collagen
– Osteocytes
• Mechanosensors of bone (increased wt-bearing,
muscle-contractionsincreased bone strength)
Graphic of Bone Remodelling
Normal Calcium Regulation
• PTH
–
–
–
–
–
increases Ca resorption from bone
decreases renal tubular Ca / increases Phos excretion
stimulates 1,25OH vitamin D
enhances osteoblastic bone formation (pulsatile)
stimulates osteoblasts to activate osteoclastic bone
resorption (high continuous)
• 1,25-Dihydroxyvitamin D
– increases gut resorption of both Ca and Phos
– feedback inhibits PTH and renal 1-alpha-hydroxylase
– stimulates osteoclast maturation to mobilized Ca from bone
(at high levels)
– provides substrate for osteoblast bone formation (at normal
levels)
– Requires intact liver, renal (1-alpha-hydroxylase), and
peripheral sunlight exposure
• Calcitonin
– from thyroid parafollicular c-cells (minor
player—no problems post-thyroidectomy)
– inhibits osteoclast bone resorption
– inhibits Ca and Phos gut absorption
– inhibits renal tubular Ca and Phos
rebsorption
• Estrogens/Testosterone
– enhance bone formation (weak anabolic),
inhibit bone resorption by downregulating
cytokine-mediation
– E2 causes mild suppression of Ca
– Decreases calciuria
Types of Bone
• Cortical—shafts of long bones, outer edge of all other
bones
– Only 3% renewed per year
– Forearm>Hip
– Hyperparathyroidism, Hypogonadism may affect this
preferentially
• Trabecular (cancellous)—inner core of bones of the
central skeleton
–
–
–
–
25% renewed per year (much more metabolically active)
Accounts for 80% of the total skeleton surface area
Spine>Hip>Forearm
May see changes in spine earlier than hip or forearm
• After initiation of bisphosphonate tx
• After onset of menopause without HRT
• Can be confounded by osteophytes or prior compression fractures
Peak Bone Mass
120
100
80
bone mass
bone resorption
bone formation
60
40
20
0
0
10
20
30
40
50
60
70
Osteoporosis: Definitions
• Compromised bone strength due to
decreased bone mass and quality of microarchitecture
• due to marked imbalance in bone resorption
vs. bone formation (“uncoupling”)
• fracture risk correlates well with decline in
bone density by DXA
– most commonly vertebral, hip, and distal radius
• Often a wrist fracture is the first sign
– Earlier, more trauma required
– Younger women fall forward, older fall to side or back
• Prior vertebral fx predisposes significantly to future fx
– RR 4.4 for having more vertebral fxs
– RR 2.5 for progressing to hip fx
– decrease in bone density by 1 SD = 2x fracture
risk!
Bone Densitometry
• Principle: When a beam of ionized
radiation passes through bone,
amount of radiation reaching the
detector is inversely proportional
to the mineral content of the
measured bone. This is then
divided by a measured area of
bone to give a density.
Dual Energy X-ray Absorptiometry
• DEXA is preferred method b/c…
• Dual energy is better able to penetrate through soft
tissue
• best correlated with fracture risk
• high precision, low radiation exposure
• HOWEVER, DEXA can be falsely normal if…
•
•
•
•
aortic calcifications
spine/hip hardware
osteoarthritis (osteophytes)
compression fxs (decr bone area)—can be seen on
images provided with the DEXA results; falsely improve
results
• Serial DEXAs must be done on same
machine/location
• differences in individual machine calibration do NOT
allow accurate comparisons!!
Why other modalities exist and
will continue to be sought…
• Peripheral ultrasound (ie, heel, finger, etc.)
– More portable/widely available
– Cheaper for widespread population screening
– Sensitive screening tool, but not specific for osteoporosis; no data on
efficacy as tx guide
• Qualitative CT
–
–
–
–
–
3D (vs. 2D DXA)actual vs. calculated bone area
Relatively high radiation exposure
Expensive
Better for short-statured, small-boned subjects
No good fracture data
• Tetracycline-labeled bone biopsy
– Only current method of assessing full bone quality (ie, microarchitecture)
– Too invasive for other than experimental use in most cases
Beyond Bone Mineral Density
• Clear that BMD is only one factor contributing to
overall risk of fx
• Bone quality measurements are elusive
• Residronate studies shed some light on this…
– Watts et al, J Bone Min Res, 2005
• Fx reduction of 32% largely independent of BMD changes over
3 yrs (only 12% benefit correlated with LS BMD changes, only
7% with FN BMD changes); same fx rate even if BMD
decreased!
– Bauer et al, J Bone Min Res, 2006 (FIT)
• High pre-tx bone turnover markers greatest benefit from
Residronate
• BUT, even those with normal or low bone turnover markers
often have reduction of fractures on Residronate
Quick Primer on Central DXA
interpretation of BMD
WHO Definition of
Osteoporosis
• T-score = comparison to 25-30 y.o.
white, postmenopausal women or
young men
T-score
Definition
0
Mean BMD for young
normals
> -1.0 SD
Normal bone mass
-1.1 to -2.5 SD Low bone mass
(osteopenia)
< -2.5 SD
Osteoporosis
• Z-score
– Less than or equal to –2.0 suggests
secondary cause of osteoporosis
– USE ONLY THE Z-SCORE cut-off of
of -2.0 or less when assessing
children or young adults (premenopausal women or men <50 yrs)
• t-scores were not designed for
interpretation within these age groups
since they presume achievement of
peak bone mass already and fracture
risk generally associated with older
patients
“Osteopenia”
• Low Bone Mass is the current favored term by
the International Society of Clinical Densitometry
• Osteopenia implies fracture risk, which is very
hard to predict in premenopausal women or in
men (esp. < age 70)term coined to describe
post-menopausal women’s bones only!
• Men naturally have bigger bones, which imparts
significant fracture protection regardless of BMD
• Men and younger women often have better
muscle tone/balanceless prone to falls
• Endogenous estrogens are very protective
Sample Study
• Adequate image shows
L1-L4 with minimal
curvature from AP view
and symmetric
visualization of iliac
crests
• Must have at least 2
interpretable of the 4
• Can only use the
AVERAGE of the tscores and z-scores of
the interpretable VBs
(not the worst VB
alone!)
• DJD or compression fx
can falsely increase
bone density of 1 or
more VB significantly
Sample Study
• Adequate hip image shows
no more than a hint of lesser
trochanter
• Only use FEMORAL NECK
and TOTAL HIP scores
– Best fracture correlation
– Dx = worst site overall
• Ideally need to measure two
interpretable sites to be
conclusive
– Use forearm and AP spine if
both hips have hardware,
etc.
Sample Study
• Only use 1/3 forearm
– Best fx data
• Best site for measure of cortical
bone (hyperparathyroidism or vit
D deficiency?)
• In this example, the hip and
forearm show low bone mass,
but the AP spine has avg t-score
of –2.5
– Pt has overall dx of
osteoporosis
• Remember: if pt is premenopausal or <30 yrs old, use
z-score only
– Less than –2.0 is “lower bone
mass than expected for age”
Osteoporosis Risk Factors
• Modifiable
– Low Ca or vitamin D
intake
– Estrogen/testosterone
deficiency
– Sedentary lifestyle
– Tobacco
– EtOH > 2 drinks/d
– Caffeine > 2 drinks/d
– Meds (steroids, excess
thyroid hormone)
• Non-modifiable
– Age
– Race (Caucasian,
Asian)
– Female gender
– Early menopause
– Slender build (“smallboned”)
– + FamHx
Who would WHO screen?
• Women > 65 yrs
• Postmenopausal women < 65 with RFs or recent
fragility (fall < standing height) fractures
– ***Remember: clinically confirmed fragility fracture
trumps any bone density measurementthe patient
still has osteoporosis!
• Women considering tx for osteoporosis
• Of note, Medicare allows DEXA for…
–
–
–
–
–
E2 deficiency + one other RF
Vertebral osteopenia, deformity or fracture (on X-ray)
1oHPT
Steroid tx > physiologic dose for > 3mos.
Monitoring of osteoporosis tx
Who would WHO treat??
• T-score < -2.0 w/o risk factors
• T-score < -1.5 with risk factors
• Women >70 y.o. with multiple risk
factors regardless of bone density
• Men >50 y.o. with risk factors and
t-score < -2.0; w/o risk factors and
t-score </= -2.5
• Patients on high risk medications
(ie, HD steroids >3 mos)
Osteoporosis: DDx
• Osteomalacia (vit D deficiency)
– Malabsorption
• Hyperparathyroidism
• Hyperthyroidism
• Hypogonadism (premenopausal women, or
men)
• Cushing’s syndrome
• Multiple myeloma
• Rheumatoid arthritis
• ESRD
• Osteogenesis imperfecta
Cost-effective Evaluation
• CBC, bone panel, renal panel,
TSH
• menstrual hx in pre-menopausal
female (if amenorrheic, can check
E2, LH/FSH, bHCG)
• serum total testosterone in a male
• 24hr urine Ca, Phos, and Cr
• 25-OH vitamin D (calcidiol) level
Fracture Prevention
Treatment Options:
Does change in bone density
really translate into change in rate
of fractures?
Fracture Incidence
• Age alone doubles LS fx risk per decade, increases hip fx rate too
– T-score of –2.5 in a 50 y.o. is not equivalent to t-score of –2.5 in a 70 y.o.
• In fact, the 50 y.o. is 50% less likely to fracture!
• Women
– Wrist fractures are a marker for future fxs
• Start at age 45-50, peak age 65
• Fall onto outstretched hand (FOOSH)
– Vertebral fractures peak later
• Start age 55-60, no peak (linear continuous rise)
– Hip fractures increase at age 65
• Exponential increase
– Average age of menopause is 52 yrs
– Greatest BMD loss from E2 deficiency is within the first 1-2 yrs
• Men
– No increased incidence of wrist fx
– Vertebral fxs increase after age 55-60
– Hip fxs after age 70-75
T-score Fracture Prediction vs.
Age
• Prediction of first forearm, symptomatic vertebral,
humerus, or hip fx in women in Malmo, Sweden (Kenis et
al, Ost Int 2001)
Age
50
80
70
40
Ten Year
Fracture
Probability
(%)
30
60
20
50
10
0
1.0
0.5
0.0 -0.5 -1.0 -1.5 -2.0 -2.5 -3.0 -3.5 -4.0
Femoral Neck T-score
Treatment Options for
Osteoporosis
• Non-pharmacological
– smoking and EtOH/caffeine
cessation(<3 glasses per day)
– increased weight-bearing activity
– falls prevention
– increase dairy and Ca-fortified drinks
– Increase high vitamin D foods (fish,
eggs, beans)
• Pharmacological
– 1-1.2g of elemental Ca/day with meals
– vitamin D 700-1000 IU/d
– Antiresorptive agents
•
•
•
•
Bisphosphonates
Estrogens
SERMs (Raloxifene)
(Denosumab)
– Anabolic agents (bone formation)
•
•
•
•
•
Testosterone—always do first in men if hypogonadal
PTH (Teraparatide)
GH
Fluoride
Strontium (promising, but signif potential toxicities)
Benefits of Calcium and Vitamin D
• Dawson-Hughes et al, NEJM, 1997
– 500mg calcium + 700 IU vitamin D3
(cholecalciferol) x 3 yrs
– 389 free-living, ambulatory patients >65 yrs
– Taking <1500mg of Ca++ per day at
baseline
– Results: Ca/vitD group 5.9% non-vertebral
fx rate vs. placebo group 12.9% (RR 0.5,
CI 0.2-0.9)
– Similar to large French study of 3400
elderly women given 1200mg of Ca +800
IU vit D3/day
• Bischoff-Ferrari et al, JAMA, 2004
– Vitamin D improves muscle
strength/prevents falls in the elderly
Cumulative Percentage of All 389 Subjects age
65 and older with a First Non-vertebral Fracture
Dawson-Hughes et al,NEJM, 1997.
Calcium and Vitamin D
• WHI brought controversy about usefulness of
Ca/vitD in OP prevention but consider…
• Health-conscious, active population (low risk)
– Vs. nursing home/hospitalized populations with poorer nutrition
and sun exposure
• Most had not reached age of greatest risk of hip fx by end of
study
• Majority already taking more than recommended daily Ca
intake even in placebo group (>1200 mg/d)
• Most were not vitamin D deficient to begin with, and those
that were had only mild deficiency (25OHD >25-30)
• Vitamin D dose < 700-800 IU that has shown benefit in prior
studies
• Only 60% were compliant with study med
• Subgroup that was compliant had significant hip fx risk
reduction of 29%
• RR of renal stones was increased by 17%
– Unclear clinical vs. subclinical; other risk factors not screened
Osteomalacia
• disorder of bone mineralization associated with
insufficient vitamin D, calcium, and/or phosphate
– ‘weak’ or ‘soft’ bone
– known as rickets in childhood
• impaired growth, soft skull (craniotabes), rachitic rosary, bowed
legs
– presents with
• chronic diffuse bone pain (worse with movement or palpation)
• +/- atraumatic fractures
• muscle weakness/atrophy, increased risk of falls
– may present with symptomatic hypocalcemia
• Occult vitamin D deficiency is common!
– Even seen at high frequency in Florida and CA
– Goal are levels above 30, severe def. is <10-15 ng/mL
Radiographic Findings of Osteomalacia
• Plain films
– Generalized osteopenia
– Looser zones/Milkman fractures
(pseudofractures)
• short perpendicular radiolucent lines
• bilateral in femur, pelvis, hands/feet
– complete fractures
• Bone densitometry
– osteopenia or osteoporosis (diffuse)
– cannot distinguish from regular
Osteoporosis
Bone sections are viewed under
ultraviolet light to estimate
mineralization activity by visualizing
tetracycline labels. The normal bone
reveals that the majority of the osteoid
has crisp double tetracycline labels
(white arrows), indicative of normal
mineralization activity.
The osteomalacic bone, however, has
smeared tetracycline labels without the
double label (white arrows). Moreover,
the tetracycline labels do not occupy
the majority of the osteoid-bone
interface. Such observations are
representative of the abnormal
mineralization that characterizes the
osteomalacic bone disorder.
Vitamin D Metabolism
Treatment of Osteomalacia
• ESRD (renal osteodystrophy) & VDDR
– high dose calcium and 1,25vitD (calcitriol)
• Vitamin D deficiency
– 5-10,000 IU/d or 50,000-100,000/wk of
ergocalciferol (D2)check levels in 8-10 weeks to
avoid toxicity
– Maintenance 700-2000 IU/d
– 4000 IU/d recommended for breastfeeding women
– 1gm elemental calcium/d
• Hypophosphatemic rickets
– phosphate suppl, calcitriol
• Tumor-induced osteomalacia
– find the tumor and remove it!
Estrogens/Progestins
WHI: Estrogen + Progestin and
risk of Hip Fracture
• reduced the risk of hip fracture by 33% (HR, 0.67; 95%
nCI, 0.47–0.96; 95% aCI, 0.41–1.10)
• subgroup analyses, decreased the risk of hip fracture by
60% among women who reported a baseline calcium
intake of more than 1200 mg/d but not among women
with lower calcium intake (P for interaction = .02).
• reduced the risk of hip fracture in women with a BMI of
less than 25 (HR, 0.50; 95% nCI, 0.28–0.90) and with a
BMI of 25 to less than 30 (HR, 0.67; 95% nCI, 0.37–
1.20) but not in women with a BMI of 30 or more
• risk of hip fracture was reduced to a similar degree in
women stratified by age, smoking, fall and fracture
history, past use of HRT, parental fracture hx, years
since menopause, and summary fracture risk score.
WHI Investigators, JAMA, 2003.
WHI: fracture incidence
Million Women Study
• 1996-1998, post-menopausal women age 5069 yrs in the UK
• Several different HRT formulations used
• Stopping HRT negates benefits to fx
protection and BMD within the first 12 mos
• Length of prior use makes no difference,
though effect of current use peaks at 5-9 yrs
• Decreased wrist and hip fxs, but no clear
vertebral fx benefit
• Same hip fx benefit (RR 0.62) as in WHI
study
Bisphosphonates in osteoporosis
• Oral bisphosphonates (Alendronate,
Risedronate)
– Best studied; most conclusive fx risk reduction (5060%)
– Well-tolerated
– Extension of the FIT study from 5 to 10 yrs showed
spine BMD improved further but hip remained stable
– Fx risk reduction stabilized in hip at 5 yrs, spine at 67 yrs
– Low risk patients stopping Alendronate at 5 yrs only
showed slight decreases in BMD hip or spine 5 yrs
later (Bone et al, NEJM, 2004)long-lasting incorp
into skeleton; bone turnover markers still lower than
baseline after 5 yrs off tx
Reasonable Alternatives to
Oral Bisphosphonates
• IV bisphosphonates
– Zoledronic acid now proven to decrease fracture risk in postmenopausal women by 60%(HORIZON trial, NEJM, 2008)
– Ibandronate only proven to decrease fx risk (MOBILE study, Ann
Rheum Dis, 2006) in spine, GC-mediated
– Others (Pamidronate) have similar efficacy of BMD improvement
to orals
– Bypasses GI absorption or intolerance issues
• Raloxifene (Evista)
– Selective estrogen receptor modulator (SERM)
– Significant improvements in BMD and fx risk (less than oral
bisphosphonates)
– Better for pts with hyperlipidemia or h/o breast CA
– Worsens hot flashes; equal to higher risk of VTE than E2
– Same risk of thromboembolic events as estrogens
Alendronate and Osteopenia
• Quandt et al., Mayo Clin Proc 2005 (Fracture
Intervention Trial data)
• Post-menopausal women 55-80 yrs
• Mean f/u period 3.8 yrs
• All had at least 1000mg Ca intake +250 IU
VitD
• FN osteopenia (t-score –1.6 to -2.5)
– Spine not used (concern about DJD
confounding?)
• With or without baseline vertebral fx
– Only those with clinical or radiographic prior VF
showed clear benefit of tx
– W/o prior VF, baseline fx rate was too low to see
benefit from tx with Alendronate
Bisphosphonates: Emerging Concerns?
• Osteonecrosis of the jaws (ONJ)
– Small retrospective case series
• Vast majority with high dose IV tx for malignant
hyperCa/bone pain
• Extremely rare reports with oral bisphos tx
– Direct association not established yet
• None of the large prospective oral bisphos studies have
reported it
• Dentists recommending holding tx a 3-6 months prior and
following extensive dental surgery, etc.
• Oversuppression of bone turnover, impaired
microfracture repair over time?
– No evidence of diminished mechanical strength in
high dose animal studies
– Bone bx in postmenopausal women on Bisphos have
normal mineralization/histomorphometry
Antiresorptive Agents:
Reduction in Fracture Incidence
LS
Hip
Alendronate
47-50%
30-45%
Risedronate
Estrogens
30-50%
42%
Raloxifene
Calcitonin
Calcium and
vitamin D
20-58%
33% (WHI
only)
31-49%
0%
33% (PROOF 0%
only)
Non-vertebral
(hip, wrist)
32-39%
Up to 50%
A few words on PTH
•
•
•
•
•
•
•
Most promising anabolic agent to date
FDA approved in Nov 02
High pulsatile PTH favors bone formation
Relative contraindication in renal insufficiency
Absolute contraindication-HPT
daily SQ injections for 18-24 months
preliminary data suggests combo tx with
bisphosphonate reduces effectiveness of PTH in men
and post-menopausal women
• Vertebral fx risk reported to decrease by up to 68%,
non-vertebral by up to 53% (post-menopausal
women)
• currently recommended when bisphosphonates failed
or contraindicated
– Though greatest benefit may be in bisphos-naïve pts!
Forteo (Teraparatide)
Black et al, NEJM, Sep 2003
Newer agents on the Horizon...
• Denusomab
– Monoclonal antibody against RANKL
– Blocks signally to activate osteoclast
– Similar improvements in total hip BMD
to alendronate
– Well-tolerated
– No fracture prevention data yet
• Wnt pathway agents
– Pathway leading to osteoblast
enhancement
– Potential targets for pharm
development identified
RANK-ligand and Osteoprotegerin
Questions?