Transcript Osteoporosis: “Bad to the Bone”

Osteoporosis:
“Bad to the Bone”
Mary Warden, MD
Outline
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Definition and demographics
Risk factors
Diagnosis
Secondary osteoporosis
Treatment options
Guidelines for follow-up
Definition of Osteoporosis
“Osteoporosis is defined as a skeletal
disorder characterized by a compromised
bone strength predisposing a person to an
increase risk of fracture.”
NIH Consensus Development Panel on Osteoporosis
Prevention, Diagnosis, and Therapy. JAMA. 2001;285:785-795
Definition of Osteoporosis
• Diagnosed on basis of either a health
outcome (low-impact or fragility fracture)
or an intermediate outcome (low bone
mineral density—BMD)
• Low-impact fracture: one that occurs after
a fall from standing height or less
• Fragility fracture: occurs spontaneously or
with no trauma (cough, sneeze, sudden
movement)
Bone Remodeling
• Bone remodeling occurs throughout life.
• At a given time, different sites on the bone
surface will be in different stages of the
remodeling process.
– Activation stage: cells on bone surface retract.
– Resorption stage: osteoclasts remove bone, forming
a resorption pit.
– Formation stage: osteoblasts fill the pit with new
collagen matrix.
– Mineralization stage: matrix is mineralized to form
new bone.
Pathophysiology of Osteoporosis
• Osteoporosis occurs when normal balance is upset
and bone resorption exceeds formation, resulting in
a net loss of bone tissue with associated changes in
bone architecture.
• Such an imbalance can occur with the onset of
menopause, where diminishing estrogen levels lead
to excessive bone resorption that is not fully
compensated for by an increase in bone formation.
A Major Health Threat in the US
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4-6 million women have osteoporosis.
18 million people have low bone mass.
1 to 2 million men have osteoporosis
8 to 13 million men have low bone mass.
40 -50 % of females aged 50 years or
older are at risk for developing an
osteoporosis-related fracture during their
lifetime.
Ettinger, M. Arch Intern Medicine.2003;163:2237-45.
Osteoporosis and Fractures
Vert 700,000
Hip 300,000
Wrist 200,000
Other 300,000
Adapted from Ettinger, M. Arch Intern Medicine.2003;163:2237-45.
Outcomes of Hip Fractures
• 24% excess mortality in 12 months
• 50% do not recover baseline function
• 25% require long-term nursing home
care
• 33% will fracture the opposite hip
Ray, N.F. et al. J. Bone Mineral Res. 1997;12:24-35
Consensus Develop. Conf., Am. J. Med. 1993;94:646-650
Riggs, B.J. and Melton, L.J. Bone 1995;17:505S-511S
Outcome of Vertebral Fractures
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Kyphosis
Loss of height
Pain
Loss of independence and mobility
Compression of organs leading to pain,
reflux, incontinence, and difficulty
breathing.
First Case
T. W. is a 61 year old postmenopausal woman
comes to establish care.
PMHx: HTN, Hyperlipidemia
Meds: Hctz, Lipitor
SHx: Smokes 1 ppd
FHx: Mother DM, Father Colon CA
HCM: Colonoscopy 5 yrs ago, Mammo/pap 6 mon
ago
PExam: 120/80 normal
Recent labs: Chol 180, LDL 100, Trig 150, and
HDL 50
She primarily came for refills on her
medication.
What else would be important to do for
this 61 year old female?
Risk Factors for Osteoporosis and Related
Fractures
Major Risk Factors
• Personal history of
fracture as an adult
• History of fragility
fracture in first degree
relative
• Low body weight (<127
lbs)
• Current history of
smoking
• Use of oral
corticosteroids for
more than 3 months
Additional Risk Factors
• Impaired vision
• Estrogen deficiency
• Poor health/ fragility
• Recent falls
• Low calcium intake
(lifelong)
• Low physical activity
• Excessive use of
alcohol (more than 2
drinks/ day)
National Osteoporosis Foundation. Available at
http://www.nof.org/physguide.
Further questioning and
examination….
The patient reports ….
She has never liked diary products and rarely takes calcium.
She went through menopause at the age of 55.
Last year her mother suffered a hip fracture.
Her weight is 123 lbs
Her height is 5’4” ( loss of ½ inch)
• Both men and women experience an age-related decline in BMD
starting in midlife.
• Women experience more rapid bone loss in the early years following
menopause
Risk Factors for Osteoporosis and Related
Fractures
Major Risk Factors
• Personal history of fracture as
an adult
• History of fragility fracture in
first degree relative
• Low body weight (<127 lbs)
• Current history of smoking
• Use of oral corticosteroids for
more than 3 months
Additional Risk Factors
• Impaired vision
• Estrogen deficiency
• Poor health/ fragility
• Recent falls
• Low calcium intake (lifelong)
• Low physical activity
• Excessive use of alcohol
(more than 2 drinks/ day)
*This patient has several risk factors for osteoporosis.
Indications for Bone Mineral
Density (BMD) Testing
• Women age 65 and older regardless of additional
risk factors.
• Postmenopausal women under age 65 with risk
factors (low body weight, family history of fractures)
• All adults with a fragility fracture.
• Men age 70 or older
• Adults with a disease or condition associated with
low bone mass or bone loss.
• Adults taking medications associated with low bone
mass/ bone loss.
• Any person considering pharmacological therapy or
anyone being treated.
Position Statement for International Society for Clinical
Densitometry. J Clin Endo Meta, Aug 2004, 89(8):3651-55.
Assessing BMD: Dual Energy X-ray
Absorptiometry (DXA)
• Central DXA with measurements at the posteroanterior lumbar
spine, femoral neck or total hip is the “gold standard” for
diagnosing osteoporosis.
• Central DXA provides reproducible results at important sites for
osteoporosis fractures.
• Lateral spine should not be used for diagnosis but may have a role
in monitoring.
• Forearm BMD (33% distal radius of the nondominant forearm)
should be measured when the spine and/ or hip cannot measured or
interpreted.
• Spine BMD tend to increase with degenerative arthritis and should
be interpreted with caution in the elderly.
Assessing BMD: Other Techniques
• Quantitative computed tomography can
analyze trabecular and cortical bone separately
and is sensitive to early bone loss in the
vertebrae. Application of T-scores to predict the
risk of fracture with the use of CT has not been
validated. More costly and more radiation.
• Peripheral DXA, calcaneal ultrasonography,
single or dual-photon radionuclide
absorptiometry may be useful for assessing
risk of fracture. Not recommended for diagnosis
and management of osteoporosis.
Comparison of Bone Densitometry
by Charge
Average Medicare
allowable charge
Site
Radiation
Exposure
Quantitative CT
$185
Spine
50
DXA
$128
Spine, hip, whole body
1-5
Ultrasound
$53
Calcaneus, tibia
0
Peripheral DXA and SXA
$40
Radius, calcaneus
1
Radiographic absorptiometry
$38
Hands
5
Adapted from Cummings et al. JAMA, Oct
2002, 288(15), 1889-97.
T Scores and Z Scores
T Scores
• Number of standard
deviations (SDs) from the
mean bone density
values in normal sexmatched young adults.
• Used to make the
diagnosis of osteopenia
and osteoporosis.
Z score
• Number of SDs from the
normal mean bone
density value for age- and
sex-matched controls.
• If lower than -2.0 may
suggest presence of a
secondary cause of
osteoporosis.
• Used to assess bone loss
in premenopausal
females.
Defining The T-score
OSTEOPOROSIS
-4.0
-3.5
-3.0
LOW BONE MASS
(“OSTEOPENIA”)
-2.5
-2.0
-1.5
T-score
-1.0
NORMAL BONE
MASS
-.5
0
+.5
+1
T. W. is sent for a DXA and the Tscore results are…
- 2.8 at the hip
- 2.4 at the spine
This patient has osteoporosis.
OSTEOPOROSIS
-4.0
-3.5
-3.0
LOW BONE MASS NORMAL BONE
(“OSTEOPENIA”)
MASS
-2.5
-2.0
-1.5
-1.0
-.5
0
+.5
T-score
Note: Use the lowest BMD measurement to make the diagnosis.
+1
Indications for Treatment of
Postmenopausal Osteoporosis
National Osteoporosis
Foundation:
American Association of
Clinical Endocrinology:
T score below -2.0 with no
risk factors
T score below -1.5 with
one or more risk factors
Prior vertebral or hip
fracture
T score < - 2.5
T score < -1.5 and risk
factors
Low trauma fracture and
low BMD
NOF: http://www.nof.org.
Hodgson SF et al. Endocr Pract 2003;9:544-64.
Evaluation of Osteoporosis
Comprehensive history and physical
examination
Baseline labs:
• CBC
• Serum chemistry studies( Electrolytes, Ca,
Phos, total protein, albumin, liver
enzymes, AP, Cr)
• Urinary calcium excretion
AACE Osteoporosis Guidelines
Causes for Secondary
Osteoporosis in Adults
Endocrine
Disorders
Hyperthyroidism, hypogonadism, Cushing’s
syndrome, type 1 DM, hyperparathyroidism
Nutritional
Conditions
Malabsorption syndromes and malnutrition,
chronic liver disease, gastric operations, Vit D
deficiency, calcium deficiency, alcoholism
Drugs
Glucocorticoids, anticonvulsants,
gonadotropin-releasing hormone agonists,
excessive T4, lithium
Disorders of
collagen
metabolism
Osteogenesis imperfecta, Homocystinuria,
Ehlers-Danlos syndrome, Marfans syndrome
Other
Rheumatoid arthritis, COPD, renal tubular
acidosis, hypercalciuria, smoking, organ
transplantion, immobilization, mastocytosis
Other Labs for Secondary
Osteoporosis Workup
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Serum thyrotropin
ESR
Serum PTH
Serum 25-hydroxyvit D
Urinary free cortisol
and other tests for
adrenal hypersection
• Serum or urine protein
electrophoresis
• Bone marrow aspiration
and biopsy
• Acid- base studies
• Biochemical markers
for bone turnover (Bone
specific AP, urine and
serum collagen
crosslinks)
• Serum tryptase, urine
N-methylhistamine or
other tests for
mastocytosis
AACE Osteoporosis Guidelines, Endo Prac.2003;9(6)545-564.
T. W.
• Further examination does not suggest
secondary causes of bone loss.
• Lab studies are all normal.
• What treatment options are available?
Nonpharmocologic Treatment
• Calcium 1000 mg (19 -50 years)
1500 mg (> 50 years)
• Vitamin D 400 IU/day – 800 IU/day (elderly)
• Exercise
• Smoking cessation (smokers tend to be
thinner, undergo early menopause, have
increased catabolism of endogenous
estrogen, experience more fractures)
• Moderation of alcohol
• Decrease caffeine
Effect of Calcium and Vitamin D
on Fractures
• Chapuy et al. 1994 Institutionalized French women given
calcium(1200 mg) and Vit D (800IU/day) showed significant
reduction
– Hip fractures OR = 0.73 ( 0.67 – 0.84)
– Nonvertebral fractures OR = 0.72 (0.60-0.84)
• Recker et al. 1996 Postmenopausal women with prevalent vertebral
fractures given calcium (1200 mg) showed significant reduction
– Vertebral fractures Placebo 51% Calcium 28% ( p= 0.023)
• Dawson- Hughes et al. 1997 Healthy independently living
postmenopausal women given calcium (500 mg/day) and Vit D (700
IU/day) showed significant reduction
– Nonvertebral fractures RR 0.4 (0.2-0.8)
Calcium
• Calcium supplements should be adjunct – not
monotherapy.
• Calcium carbonate is cheaper but not as
bioavailable as calcium citrate.
• Use calcium citrate in patients who are
hypochlorhydric or achlorhydric (including those
taking gastric acid-inhibiting drugs) and for
patients with history of kidney stones.
• Common adverse effects of calcium:
constipation, bloating, and gas (less with
calcium citrate).
Vitamin D
• Sufficient vitamin D intake is needed to
maintain circulating serum levels of 1,25
dihydroxyvitamin D which are adequate to
stimulate calcium absorption.
• An intake of 400-600 IU of Vitamin D per
day is recommended for all adults older
than 50.
• Recommend 800 IU/d for those at risk of
deficiency such as elderly, chronically ill,
housebound, or institutionalized.
Pharmacological Interventions
Two categories:
• Antiresorptive agents (reduce bone resorption >
promote bone formation)
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Bisphosphonates
Raloxifene
Calcitonin
Estrogen
• Anabolic agents (stimulate bone formation)
– Teriparatide
Oral Bisphosphonates for
Osteoporosis
Drug
Indication
Dose
Alendronate
Prevention
Treatment
5mg/d or 35 mg/wk
10 mg/d or 70 mg/wk
Residronate
Prevention
Treatment
5 mg/d or 35mg/wk
Ibandronate
Prevention
Treatment
2.5 mg/d or 150 mg/mon
Alendronate
• Number of randomized, clinical trials have demonstrated
its effectiveness in increasing BMD and decreasing risk
of osteoporotic fractures.
Liberman: Differences between Alendronate (10 mg/day) and
placebo
Increase in BMD (8.8% spine, 5.9 fem neck,
7.8 greater troch).
Fewer vertebral fractures ( 3.2 vs 6.2 %).
Fracture Intervention Trial – Vert study arm:
Increase in BMD (4.1 % femoral neck, 6.2
spine)
Risk reduction of vertebral fractures 50% and
hip and wrist fractures 30%.
Liberman et al. NEJM 1995; 333:1437-1443.
Black et al Lancet 1996; 348:1535-1541.
Risedronate
• Randomized, clinical trials have demonstrated its
effectiveness in increasing BMD and decreasing risk of
osteoporotic fractures.
VERT trials in North America(NA) and Multinational(MN)
-results similar
Increase in BMD lumbar spine (4.3-5.9%) and
femoral neck (2.8-3.1%)
Risk reduction new vertebral fractures 41-49%
Risk reduction is new nonvertebral fractures 39%
(NA trial- significant) and 33% (MN trial- not
significant).
Harris et al, JAMA 282: 1344-1352.
Reginster et al Osteoporosis Int 11: 83-91.
Ibandronate
• Recent FDA approval -dose 2.5 mg daily or 150 mg monthly
• Oral Ibrandronate Osteoporosis Vertebral Fracture Trial in
North America and Europe (BONE)--Placebo vs 2.5 mg vs 20 mg
every other day for 12 doses every 3 months
Results: Reduction of vertebral fracture:
62% (p=0.0001) and 50%(p=0.0006)
• Monthly Oral Ibandronate Therapy in Postmenopausal
Osteoporosis (MOBILE)- comparison of 2.5mg/daily vs 150
mg/monthly
Results: Increase in BMD lumbar (5.0 vs 6.6 %)
Similar results for hip density.
No fracture data reported.
Chestnut, et al. J Bone Miner Res 2004;19:1241.
Reginster et al. Ann Rheum Dis 2006; 65:654-61.
Bisphosphonates
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Poorly absorbed—must be taken after overnight fast
Contraindicated in severe renal impairment
Correct hypocalcemia
Proper administration is important to avoid esophageal
irritation ( upright position with 8 ounces of water).
• No eating or drinking for 30 min ( 60 min for Boniva)
• Side effects:
- GI disturbances (heartburn, abdominal pain,
esophageal ulcer)
- Severe bone, joint and/ or muscle pain
- Ocular inflammation
- Osteonecrosis of jaw (rare)
Raloxifene
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Selected estrogen receptor modulator (SERM)
Acts as an ER modulator in the bone and on
serum lipid concentrations and ER antagonist
on breast and uterine tissue
Indications: Treatment and prevention of
osteoporosis
Recommended dose: 60 mg/ day
Side effects: venous thromboembolic disease,
hot flashes, leg cramps
Ettinger et al. JAMA. 1999;282:637-645.
MORE
Multiple Outcomes of Raloxifene Evaluation
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Multicenter, double-blind, placebo-controlled trial
7705 postmenopausal women with osteoporosis
Randomized to Raloxifene 60 mg/d, 120 mg/d, or placebo
Results:
– Significant reduction in vertebral fractures
– No significant reduction in nonvertebral fractures
– Significantly increased BMD vs placebo
- 2.6% at lumber spine
- 2.1% at femoral neck
Ettinger B, et al. JAMA. 1999;282:637-645.
Calcitonin
• Slows bone loss by inhibiting osteoclastmediated bone resorption.
• Approved for the treatment (not
prevention)
• Dose: 200 IU/day nasal spray
100 IU/day SQ or IM
• Side effects: rhinitis, epistaxis
Prevent Recurrence of
Osteoporotic Fractures (PROOF)
• Multicenter, double-blind, placebo-controlled trial
• 1225 postmenopausal women with low lumbar
spine BMD and 1-5 vertebral fractures
• Nasal spray salmon calcitonin 100, 200, or 400
IU/day, or placebo
• Results: 36% reduction in vertebral fractures
No significant reduction for hip or
nonvertebral fractures
Chestnut CH et al. Am J Med, 2000;109:267-76.
Estrogen/ Hormone Therapy
• Estrogen alone or in combination with
progesterone can decrease bone turnover, bone
loss, and fractures.
• Women’s Health Initiative showed mildly
increased absolute risk of following serious
adverse events:
– Combination therapy: coronary heart disease, stroke,
venous thromboembolism and breast cancer.
– Estrogen therapy: stroke and venous
thromboembolism.
• Hormone therapy is only approved for the
prevention of osteoporosis, not treatment.
Anderson et al. JAMA. 2004;291:1701-1712.
Cauley et al. JAMA 2003;290:1729-38.
The patient decides to use alendronate 70 mg
weekly.
You give her the prescription.
Recommend Cal 1500 mg and Vit D 400 IU.
Recommend smoking cessation.
How and when should you reevaluate the
effectiveness of your treatment?
Monitoring Therapy
• Serial BMD
• Inherent variability (precision error).
• For DXA: Need BMD difference of 3-5 %
to be clinically significant in actual BMD
reading—gm/cc
• No change or even slight reduction does
not warrant alteration of therapy.
AACE Osteoporosis Guidelines, Endo Prac.2003;9(6)545-564.
Guidelines for Follow-up BMD
Measurements
• “Normal” baseline BMD ( T-score > -1.0):
follow-up every 3-5 years (if well above min.
acceptable level, may not need any further BMD
testing)
• Patients in osteoporosis prevention
program: every 1-2 years until stability
documented then every 2-3 years
• Patients on treatment: yearly for 2 years. If
stable after 2 years then every 2 years.
Otherwise annual follow-up
AACE Osteoporosis Guidelines, Endo Prac.2003;9(6)545-564.
Second Case
• TF is a 71 year old woman with a history of two vertebral
fractures, “two inch” loss in height and low BMD.
• She has been taking risedronate 35 mg once weekly
along with calcium and vitamin D for 2 years.
• She recently suffered a hip fracture and required ORIF.
• DXA last year T-score: -3.0 in the spine
-2.7 in the hip
• Repeat DXA new T- score: -3.5 in the spine
-3.2 in the hip
Are there secondary causes for her
osteoporosis and new fracture?
Remember to exclude secondary causes.
• Serum calcium ( hyperparathyroidism)
• TSH ( hyperthyroidism)
• 25-hydroxyvitamin D ( Vit D deficiency)
• 24 hr urinary calcium ( malabsorption of
calcium and renal abnormalities)
Also consider celiac disease, occult use of
glucocorticoids, endogenous Cushing’s
disease, and prolonged immobility.
Is she taking the bisphosphonate
and is it being absorbed?
• Compliance with a once-weekly
bisphosphonate may be an issue.
• Biochemical markers to assess bone
turnover/resorption ( example: Urinary Ntelopeptide) may suggest noncompliance
or incomplete absorption.
What alternative treatment is
available?
Options that are available:
• Prescribe another once weekly
bisphosphonate.
• Change bisphosphonate to raloxifene or
calcitonin ( however studies with these
medications did not demonstrate reduction
in nonvertebral fractures).
• Offer patient PTH (1-34): Teriparatide
PTH (1-34): Teriparatide
• First anabolic agent approved by the FDA for the
treatment of osteoporosis.
• Dose: 20 mcg/day SQ
• Indications:
– Postmenopausal women with severe
osteoporosis.
– Men with primary or hypogonadal
osteoporosis.
– Patients with glucocorticoid-induced
osteoporosis
PTH
• Reduced vertebral and nonvertebral fractures by
more than 50%.
• Significantly increased BMD after 19 months
8.6% at lumbar spine
3.7% at the trochanter
• Black Box Warning: osteosarcoma in rats.
• Duration of therapy: should not exceed 2 years.
• Therapy with bisphosphonate should be
discontinued - may blunt the anabolic effect
• Therapy with reabsorptive agent should be restarted
after PTH stopped.
Neer RM et al. ,NEJM 2001;344:1434-1441.
Conclusions
• Osteoporosis occurs in both women and
men (young and old).
• Manifestations are silent until a
catastrophic event occurs.
• Early identification of risk factors and
secondary causes followed by appropriate
treatment may reduce the incidence and
complications of osteoporosis.
References:
• NIH Consensus Development Panel on Osteoporosis
Prevention, Diagnosis, and Therapy. JAMA.
2001;285:785-795
• Ettinger, M. Aging Bone and Osteoporosis. Arch Intern
Medicine. 2003;163:2237-45.
• National Osteoporosis Foundation. Available at
http://www.nof.org/physguide.
• Melton LJ, Chrischilles EA, Cooper C et al.
Perspective: how many women have osteoporosis? J
Bone Miner Res. 1992;7(9):1005-10.
References:
• Ray, NF, Chan JK, Thamer M, Melton LJ. Medical
expenditures for the treatment of osteoporotic fractures
in the United States in 1995: Report from the National
Osteoporosis Foundation. J Bone Miner Res
1997;12:24-35
• Consensus Development Conference: Diagnosis,
Prophylaxis and Treatment of Osteoporosis. Am J Med
1993;94:646-650
• Mauck, KF, Clarke BL. Diagnosis, Screening, Prevention,
and Treatment of Osteoporosis. Mayo Clin Proc.
2006;81(5):662-672.
• Riggs BL, Melton LJ. The worldwide problem of
osteoporosis: Insights afforded by epidemiology. Bone
1995;17:505S-511S.
References:
• Lewiecki EM, Watts NB, McClung M. Position Statement:
Official Positions of the International Society for Clinical
Densitometry. J Clin Endo Metab. 2004;89(8):3651-55.
• Cummings SR, Bates D, Black DM. Clinical use of bone
densitometry: scientific review. JAMA 2002 288(15):
1889-97.
• Hodgson SF, Watts NB, Bilezikian JP. AACE Medical
guidelines for clinical practice for the prevention and
treatment of postmenopausal osteoporosis. Endo Prac.
2003;9(6)545-564.
• Chapuy MC, Arlot ME, Delmas PD, Meunier PJ. Effect of
calcium and cholecalciferol treatment for three years on
hip fractures in elderly women. BMJ 1994 308:1081-82.
References:
• Recker RR, Hinders S, Davies KM et al. Correcting calcium
nutritional deficiency prevents spine fractures in elderly women. J
Bone Miner Res 1996 11:1961-66.
• Dawson- Hughes B Harris SS Krall EA et al. Effect of calcium and
vitamin D supplementation on bone density in men and women 65
years of age and older. NEJM 337:670-676.
• Liberman UA Weiss SR Broll I et al. Effect of oral alendronate on
bone mineral density and the incidence of fractures in
postmenopausal osteoporosis. NEJM 1995; 333:1437-1443.
• Black DM Cummings SR Karpf DB et al. Randomized trial of effect
of alendronate on risk of fracture in women with existing vertebral
fractures. FIT research group. Lancet 1996; 348:1535-1541.
References:
• Harris ST Watts NB Genant HK et al. Effects of
risedronate treatment on vertebral and nonvertebral
fractures in women with postmenopausal
osteoporosis:VERT study group. JAMA 1999, 282: 13441352.
• Reginster J Minne HW Sorensen OH et al. Randomized
trial of the effects of risendronate on vertebral fractures
in women with established postmenopausal
osteoporosis. Osteoporosis Int 2000, 11:83-91.
• Reginster JY Adami S Lakatos P et al. Efficacy and
tolerability of once-monthly oral ibandronate in
postmenopausal osteoporosis: 2 year results from the
MOBILE study. Ann Rheum Dis 2006; 65:654-61.
References:
• Ettinger B Black DM Mitlak BH et al. MORE
Investigators. Reduction of vertebral fracture risk in
postmenopausalwomen with osteoporosis treated with
raloxifene. JAMA. 1999; 282:637-645.
• Chestnut CH Silverman S Andriano K et al. A
randomized trial of nasal spray salmon calcitonin in
postmenopausal women with established osteoporosis:
The PROOF study. Am J Med, 2000;109:267-76.
• Anderson GL, Limacher M Assaf AR, et al, Women’s
Health Initiative Steering Committee. Effects of
conjugated equine estrogen in postmenopausal women
with hysterectomy: the Women’s Health Initiative
randomized controlled trial. JAMA 2004;291:1701-1712.
References:
• Cauley JA, Robbins J, Chen Z, et al, Women’s Health
Initiative Investigators. Effects of estrogen plus progestin
on risk of fracture and bone mineral density: the
Women’s Health Initiative randomized controlled trial.
JAMA 2003;290:1729-1738.
• The Medical Letter 3:38 2005.
• Rosen CJ Black DM Greenspan SL. Vignettes in
Osteoporosis: A road map to successful therapeutics. J
Bone Min Res. 2004;19: 3-15.
• Neer RM Armaud CD Zanchetta JR et al. Effect of
parathyroid hormone on fractures and bone mineral
density in postmenopausal women with osteoporosis.
NEJM 2001;344:1434-1441.