Osteoporosis:
Definitions, Risk, and
Treatment
"It's better for people to do the wrong
thing or not optimal thing than to do
nothing.”
-Dennis Black, statistician, principal investigator for FIT: alendronate
trials, defending use of t-scores in defining osteoporosis
What is Osteoporosis?
“Osteoporosis is a systemic skeletal disorder
characterized by decreased bone mass and
deterioration of bony microarchitecture.”
www.mrc-hnr.cam.ac.uk
Primary and Secondary Osteoporosis
• Primary
• Type 1: Postmenopausal
women
– Thought to be due to estrogen
or testosterone deficiency
– Estrogen increasing sensitivity
to PTH?
• Type 2: Older men and
women
– Due to decreased vitamin D3?
• Secondary
– Chronic thyrotoxicosis
– Hyperparathyroidism
– Malabsorption/Calcium/Vitam
in D deficiency
– Alcohol/Smoking
– Medications
•
•
•
•
•
Glucocorticoids
Anticonvulsants
Heparin
Chemotherapy agents
Antacids with aluminum
Importance of Osteoporosis
• The theoretical concern regarding decreased
bone mass is the increased risk of fracture with
minimal trauma.
• Fractures: 1.5 million “osteoporotic” fractures in US
per year.
– 700,000 vertebral
– 300,000 hip fractures, over 37,000 patients die per year due to
complications.
• Often associated with high morbidity and mortality
with only 1/3 of patients with hip fractures returning
to their prior level of functioning,.
Prevalence of Osteoporosis
• Silent Disease or Normal Aging?
• “Osteoporosis is a major public health threat
for an estimated 44 million Americans, or 55
percent of the people 50 years of age and older.
10 Million people in the U.S. already have the
disease”
– National Osteoporosis Foundation
• How to create criteria to give the majority of
women age 50 and older a disease…
Clinical Criteria for Osteoporosis:
What is a T score?
The Definition
• The diagnostic criteria of osteoporosis is based on
measurements of bone mineral density (BMD).
• A T-score is derived using a frequency distribution curve created
with a population of healthy premenopausal young women at
peak of bone mass. The t score is the number of standard
deviations the patient is from the mean of this “healthy normal”
young population.
• A T-score of -1 to -2.5 SD = osteopenia
• A T-score of less than -2.5 SD = osteoporosis
Why use -2.5 standard deviations?
• Criteria developed by the World Health Organization
and partner, the International Osteoporosis Foundation
in 1992
• The committee cited studies indicating that 16% of
women in Rochester, MN would experience a hip
fracture in their lifetime. They also noted that when
pooling several years of BMD data, 16% of
postmenopausal women were at -2.5 sd below the mean
BMD of a healthy young woman. There was no
concrete data to link the 16% at -2.5 SD and the 16%
with hip fractures. (We won’t even go into osteopenia)
• Incidentally, the IOF’s board is composed of 30+ drug
and medical equipment companies.
Bone Mineral Density and t-scores
and the DEXA scan
Using DEXA for t-scores
• Not all machines use same standard healthy
patient
• Variations in calibration depending on
manufacturer
• More than just bone mineral density can be used
to predict future risk of fractures.
• BUT the controversy surrounding T-scores and
bone mineral density scans could take up several
presentations….so onto prevention of fractures.
Finding the population at risk of
fracture?
Does the current osteoporosis criteria really
identify those at risk for fracture or should
treatment be based on other risk factors?
– Other studies have found risks such as family history
of fracture, lower weight, greater height,
hyperthyroidism history, and inability to rise from a
chair were more predictive of future fracture than
bone mineral density (Cummings).
Goals of Treatment
• Because fractures are the main cause of the morbidity
and mortality associated with “osteoporosis”, the goal
of therapies should be directed towards prevention of a
fracture.
• Warning: Increases in bone mineral density are not
directly correlated with decreases in fractures
• Treatments should be assessed and compared based on
a decrease in fracture rate. Watch for studies that
discusses changes in BMD and do not mention fracture
rate.
Prevention of Fractures
• A balanced diet rich in calcium and vitamin D
• Weight-bearing and resistance-training exercises
• A healthy lifestyle with no smoking or excessive
alcohol intake
• Bone density testing and medication when
appropriate
– National Foundation of Osteoporosis
Reporting Relative Risk
• Can often make treatment seem more beneficial
• Example: A medication decreased the harmful
outcome from 1% in the control group to 0.5%
in the treatment group. The relative risk
reduction is 50% but the absolute risk reduction
is only 0.5%.
• RRR=relative risk reduction
• ARR=absolute risk reduction
• NNT=Number needed to treat
Comparing treatment options
Examined randomized controlled trials comparing
1) Vitamin D and calcium to placebo
2) Alendronate to placebo
– Trials involving alendronate were selected due to the large
number of trials and apparently most beneficial compared to
newer/other bisphosphonates
3) Weight bearing exercise to placebo
There were few RCTs on weight bearing exercise and fractures. The
benefit of exercise depended on the type of exercise. No RCTs compare
exercise to bisphosphonates or other medical treatment in reducing
fractures
The following slides examine the results of several trials for 1 and 2 above.
Calcium and Vitamin D
Study
Population
Outcomes
RRR/ARR
P-value
Chapuy 92
Women in nursing
homes with
osteoporosis
Hip fractures 1.5 yr
Nonvertebral fx 1.5
ARR: 2.0% RRR:
25% NNT: 50
ARR: 4% RRR: 24%
NNT: 26
.004
Dawson-Hughes
1997
Men and women
with osteoporosis >
age 65
Nonvertebral fx (3
years)
ARR of 7%
RRR of 54%
NNT: 14
.02
Record 2005
Men and women
>70 with low trauma
fractures
New fracture (2
years)
Not significant
Porthouse 2005
Age > 70 with 1 risk
factor for hip fx
Hip fractures (2
years)
Not significant: hip
fracture rate was
very low in this
group, even the
controls at 1.4%
<.001
14 NNT,
relatively
inexpensiv
e
Patients
had
fracture
Bisphosphonates
• Inhibitors of Bone resorption. May disrupt the
mevalonate pathway leading to decreased
osteoclast activity but mechanism is not clearly
understood.
Maybe we can use statins
for osteoporosis??
Site of
Bisphosphonate
action
Proteins which increase
osteoclastic activity are
reduced.
Prevention with Alendronate
Study
Population-all
postmenopausal
women
Outcomes
RRR/ARR
P-value
Liberman 1995,
Sponsored by Merck
Women with
osteoporosis.
Separate analysis in
pt with previous
fracture
Vertebral fx
RRR: 48%
ARR: 3.0%
NNT: 33
-NS
.03
Low BMD and
previous fracture
Vertebral fracture
RRR: 50% ARR:
7.0% NNT 14
RRR: 49% ARR:
1.1% NNT: 100
<.001
Black, 1996 FIT1
Sponsored by Merck
Nonvertebral fx
Hip
Cummings, 1998
FIT2 Sponsored by
Merck
Femoral neck t score
< -2.1 and no hx of
fracture
Vertebral (4 yr)
Pols 1999 FOSIT
Sponsored by Merck
Lumbar spine t score
< -2.0
Nonvertebral
Hip/other (4yr)
RRR: 44% ARR:
1.7% NNT: 59
-NS
RRR: 45% ARR:
2.0% NNT: 50
Mostly beneficial
in patients with
previous fracture
Large NNT
for hip
fractures
.002
.021
No statistically
significant benefit
on hip fractures
Cochrane Review of 11 trials of
alendronate
• Once daily dose in primary prevention
– RRR 45% ARR 2% NNT 50 for vertebral fractures
- No significant difference in primary prevention of hip fractures
• Once daily dose in secondary prevention, slightly more effective
– RRR 45%, ARR 6%, NNT 16 for vertebral fractures
– RRR 53%, ARR 1% NNT 100 for hip fractures
Conclusion: Alendronate may be beneficial and cost effective in preventing
vertebral fractures in patients who have already experienced an
osteoporotic fracture. Their benefit in preventing hip fractures is minimal
and limited to patients who have already experienced a fracture.
-Cochrane Review
And in the media…
• Sounds much more effective and promising!!
At least these
women look
older. Most
advertisement
s show
women in
their late
40s/early 50s
Other Bisphosphonates
• Most trials with alendronate.
• Similar results (or less effective) have been
found in studies of other bisphosphonates and
reduction of fractures.
• Side effect profiles vary based on type of
bisphosphonate.
Side Effects
• Esophageal Ulceration
• GI Perforations, ulcerations and bleeds
(depending on type of bisphosphonates)
• Musculoskeletal pain
• Renal Function disorders
• Hypocalcaemia
• Some reports of Atrial Fibrillation
GENERALIZAITON!!!
CAUTION in generalizing the results of studies to
larger populations.
• Most of the studies of bisphosphonates and
fractures were done in:
– Older women (mostly over age 65, some over age 80
most benefit)
– Women withOUT GI problems
– Patients who had already experience a fracture
Conclusions on bisphosphonates….
• No benefit on hip fracture in patients whose bone mineral
density is close to “normal”
• Some benefit in patients in preventing second vertebral fracture
if already have a fracture. Could benefit patients on chronic
steroids and those with increased risk of falling from another
disease (although Vitamin D was similarly effective in these “fallrisk” populations)
• Cannot be generalized to patients with GERD, history of ulcers
because risks may not outweigh benefits and studies have not
been done in this population.
• Cannot be generalized to younger patients with osteopenia.
Most studies focus on patients over 60, some with patients over
50.
General Conclusions
The measurement of osteoporosis should be redefined to
identify patients at highest risk of future fracture.
Decreasing bone mineral density with age is normal.
Calcium, vitamin D (in patients who are deficient) and
weight-bearing exercise will help prevent fractures
(among other benefits)
Bisphosphonate research indicates modest reductions in
fractures and have mostly been studied in patients who
are
-older, post menopausal women, many with previous
fractures, and without any GI problems.
References
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Hamdy, R. et al. Review of Treatment Modalities for Postmenopausal Osteoporosis.
Southern Medical Journal. 98(10) Oct 2005.
National Osteoporosis Foundation. Disease statistics.
Http://www.nof.org/osteoporosis/ Accessed February 15, 2008.
Chapuy MC et al. Vitamin D3 and calcium to prevent hip fractures in elderly women.
N England Journal of Medicine 1992; 327: 1637-1642.
Dawson-Hughes, B. et al. Effect of calcium and vitamin D supplementation on bone
density in men and women 65 years of age or older N Engl J Med 1997; 10: 670-676
Grant et al. Oral Vitamin D3 and calcium for secondary prevention of low-trauma
fractures in elderly people (RECORD) Lancet 2005: 365 1621-1628
Porthouse J, et al. Randomised controlled trial of calcium and supplementation with
cholecalciferol for prevention of fractures in primary care. BMJ 2005:; 330: 1003.
Susan Kelleher. Disease expands through marriage of marketing and machines. The
Seattle Times June 2005.
Moynihan, R et al. Selling sickness: the pharmaceutical industry and disease
mongering. BMJ 2002; 324: 886-891.
References
• Black DM et al. Fracture risk reduction with alendronate in women with
osteoporosis: Fracture Intervention Trial. FIT Research Group. J Clin
Endocrinol Metab 2000; 85: 4118-4124
• Pols et al. Multinational, placebo controlled, randomized trial of the effects
of alendronate on bone density and fracture risk in postmenopausal women
with low bone mass results of the ROSIT study. Fosamax International Trial
Study Group. Osteoporosis International. 1999;9 461-468.
• Liberman, UA et al. Effect of oral alendronate on bone mineral density and
the incidence of fractures in postmenopausal osteoporosis. The Alendronate
Phase III Osteoporosis Treatment Study. N ENgl J Med 1995; 333: 14371443
• Black, DM et al Randomized trial of effect of alendronate on risk of
fractures in women with existing vertebral fractures. FIT Lancet 12996 348:
1535-1541.
• Cummings, SR et al. Effect of alendronate on risk of fracture in women with
low bone density but without vertebral fractures: results from FIT. JAMA
1998; 280: 2077-2082.
References
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Johnell O, Gullberg B, Kanis JA, Allander E, Elffors L, Dequeker J, Dilsen G, Gennari
C, Lopes Vas A, Lyritis G, Mazzuoli G, Miravet L, Passeri M, Cano RP, Rapado A,
Ribot C 1995 Risk factors for hip fracture in European Women: The MEDOS Study. J
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Cummings SR, Nevitt MC, Browner WS, Stone K, Fox KM, Ensrud KE, Cauley J,
Black D, Vogt TM 1995 Risk factors for hip fracture in white women. Study of
Osteoporotic Fractures Research Group. N Engl J Med 332:767773.
Cummings SR, Nevitt MC, Browner WS, Stone K, Fox KM, Ensrud KE, Cauley J,
Black D, Vogt TM 1995 Risk factors for hip fracture in white women. Study of
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Kenny AM, Prestwood KM: Osteoporosis. Pathogenesis, diagnosis, and treatment in
older adults. Rheum Dis Clin North Am 2000 Aug; 26(3): 569-91
Bock O, Boerst H, Thomasius FE, Degner C, Stephan-Oelkers M, et al. Common
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risedronate in patients with osteoporosis and ways for their prevention. Journal of
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