Prevention and treatment of osteoporosis: where are we today? [review; review, tutorial]

              Maby • Prevention and treatment of osteoporosis JAOA • Supplement 2 • Vol 103 • No 2 • February 2003 • S9
Hormone therapy was long consid-ered
the best medical therapy for
osteoporosis. If it is prescribed for bone
health, however, it is no longer the drug
of choice in view of its side effect profile.
This loss leaves a tremendous thera-peutic
gap. Indeed, osteoporosis is a
large and growing problem in the
United States. Approximately 10 mil-lion
American women have osteo-porosis;
it has been diagnosed in only
29%, and only 14% of women with diag-nosed
osteoporosis are receiving
therapy.1 With life span increasing, a
woman today can expect to live to the
age of 85 years, living one third of her
life in the postmenopausal period, and
thus subject to diseases associated with
estrogen deficiency, such as osteo-porosis.
2
Osteoporosis leaves bones fragile
and prone to fracture. Fractures, partic-ularly
certain types of fractures, are asso-ciated
with significant morbidity and
mortality in elderly patients. After a hip
fracture, for instance, 24% of patients die
within 1 year,3 50% will be permanently
incapacitated,4 and 20% will require long-term
nursing home care.5 Vertebral frac-tures
are equally devastating, leading to
acute and chronic back pain, lung dis-ease,
gastrointestinal problems, depres-sion,
and a 5% to 10% increase in mor-tality.
Preventing osteoporosis is a lifelong
goal. Teenagers should be educated on
how to achieve adequate peak bone
mass; adults, on how to maintain that
bone mass; and seniors, on how to slow
bone loss and reduce the risk of falls.
Patients also need to understand the
appropriate use of supplements, partic-ularly
calcium and vitamin D, and agents
available for the prevention and treat-ment
of osteoporosis, especially in light
of recent findings of the Women’s Health
Initiative (WHI) hormone replacement
trial.6 The Physician’s Guide to Prevention
and Treatment of Osteoporosis1 identifies
universal recommendations for all
patients to maximize and preserve bone
mass:
  adequate intake of calcium and
vitamin D,
  regular weight- bearing exercise,
  avoidance of tobacco,
  avoidance of alcohol, and
  treatment of fracture risk factors, such
as impaired vision.
Definition of osteoporosis
Osteoporosis is defined as a systemic
skeletal disease characterized by low
bone mass and deterioration of bone
tissue, with consequent increase in bone
fragility and susceptibility to fracture.4
A unit of measure called the T score was
developed by the World Health Orga-nization
to compare a patient’s bone
mass with the mean value for young,
healthy individuals, expressed as a stan-dard
deviation score. A T score of  2.5 or
lower is consistent with a diagnosis of
osteoporosis.
Preventive approaches to
the postmenopausal patient
Reducing the risk of falls for at-risk
patients is critical. Intrinsic risk factors
associated with an increased risk of hip
fracture are included in Figure 1. Age is
progressively associated with increased
risk of falls.7
Calcium
Calcium is a critical part of any prevention
program, both for women and men. Rec-ommended
daily calcium intake changes
during a patient’s lifetime. It is actually
highest during the adolescent years, when
young people are building toward peak
bone mass (Figure 2).8 For those who do
not have adequate calcium in their diet,
Dr Maby is medical director of Cobohill Health
Center, Brooklyn, NY, where she serves as director
of the osteoporosis program and its bone den-sity
laboratory.
Dr Maby has received past grant support from
Merck & Co, and she is a consultant to Eli Lilly
and Company, Novartis, and Procter & Gamble. She
is also on the speakers bureau of Eli Lilly and Com-pany
and Novartis.
Correspondence to Jan I. Maby, DO, 1000
Dahill Rd, Brooklyn, NY 11204.
E-mail: docmaby@msn.com
Prevention and treatment
of osteoporosis: Where
are we today?
Jan I. Maby, DO
  Impaired vision
  Low body weight
  Use of long-acting
benzodiazepines
  Inability to rise from a chair
without using one’s arms
  Smoking
  Less than 4 hours per day on
the feet
  History of postmenopausal
fracture
PROGRAM PROCEEDINGS HIGHLIGHTS Checklist
Figure 1. Intrinsic risk factors associated with
increased risk for falls. (Source: Cummings
SR, Nevitt MC, Browner WS, et al. Risk factors
for hip fracture in white women. Study of
Osteoporotic Fractures Research Group. N
Engl J Med. 1995;332:767-773.)
S10 • JAOA • Supplement 2 • Vol 103 • No 2 • February 2003 Maby • Prevention and treatment of osteoporosis
supplements are necessary, and physi-cians
should educate patients with regard
to the nuances of calcium pills. Supple-ments
come in two general types:
  Calcium carbonate: cost-effective,
higher percentage of calcium per tablet,
should be taken with food, may cause
constipation and gas.
  Calcium citrate: lower percentage of
calcium per tablet, easily absorbed, taken
without regard to food.
Key to the absorption of calcium is
vitamin D. Natural sources of vitamin D
include liver, cod liver oil, egg yolks, for-tified
milk, and sunshine. For the
majority of people who do not find suf-ficient
vitamin D in their diet, supple-ments
should be recommended (400 IU
for adults, 800 IU for seniors).
Bone mineral density testing
Testing for bone mineral density (BMD)
is important to any assessment of patients
at risk for osteoporosis. In fact, in
September 2002, the National Osteo-porosis
Foundation (NOF) applauded
the US Preventive Services Task Force
recommendation that all women aged
65 years and older be screened for osteo-porosis.
The NOF recommends BMD
testing for all women older than 65 years,
regardless of other risk factors.9 The NOF
also recommends testing for:
  postmenopausal women younger
than 65 years with one or more addi-tional
risk factors for osteoporosis
(besides menopause);
  postmenopausal women who have
had one or more fractures;
  women who have received hormone
replacement therapy for a prolonged
period; and
  women considering therapy for osteo-porosis
and for whom BMD test results
influence this decision.
It is also important to test for BMD
in patients starting long-term corticoste-roid
therapy, defined as greater than 7.5
mg of steroids daily for more than 6
months.10
Management of osteoporosis
The management of osteoporosis has
been dynamic during the past few years.
Several classes of agents are available for
the prevention or treatment of osteo-porosis,
including hormone therapy, cal-citonin,
bisphosphonates, and selective
estrogen receptor modulators (SERMs).
Until recently, hormone therapy was the
mainstay of preventive treatment. The
WHI hormone replacement trial showed
a decreased risk of hip fractures with
estrogen plus progestin treatment.6 How-ever,
since the cessation of the WHI
estrogen plus progestin study, recom-mendations
for the use of hormone
therapy suggest consideration of alter-native
treatment modalities for osteo-porosis.
Indeed, the label changes on
estrogen plus progestin formulations con-firm
this statement.
Calcitonin
Calcitonin is approved for the treatment
(ie, reduction in fracture risk), but not
prevention (increasing bone density) of
osteoporosis. Although calcitonin has
been available since 1984, it was not
widely used because of its high cost and
RECOMMENDED CALCIUM INTAKE
Infants aged 6 to 12 mo Children and adolescents
270 mg/d
Aged 1 to 3 y Aged 4 to 8 y Aged 9 to 18 y
500 mg/d 800 mg/d
Aged  18 y Aged 19 to 50 y
1300 mg/d 1000 mg/d
Aged 19 to 50 y Aged  50 y
1000 mg/d 1200 mg/d
1300 mg/d
Adults Pregnant and lactating women
Figure 2. Recommended calcium intake for strong bones. (Source: National Academy of Sci-ences.
Dietary reference intake for calcium. Arch Intern Med. 1997;4:39.)
Maby • Prevention and treatment of osteoporosis JAOA • Supplement 2 • Vol 103 • No 2 • February 2003 • S11
patients’ discomfort with the injectable
formulation. The nasal spray approved
by the Food and Drug Administration
(FDA) in 1995 allowed it to be more
widely used clinically. Efficacy studies
indicated a statistically significant
increase in bone density for patients
receiving calcitonin therapy for 1 and 2
years. Furthermore, 200 IU of calcitonin
delivered by nasal spray was associated
with a 33% reduction in risk of vertebral
fracture compared with placebo in a clin-ical
trial.11 Calcitonin also has an excellent
long-term safety record.
Bisphosphonates
Bisphosphonates, as a class, are currently
the most potent antiresorptive agents
available. Although many bisphospho-nates
are on the market today, comments
here are limited to the two that are
approved by the FDA for the prevention
and treatment of osteoporosis: alen-dronate
sodium and risedronate sodium.
Both medications are available in once-daily
and once-weekly formulations.
Each has a role in reducing hip fracture
in selected patients. The once-weekly
dosing has been shown to increase bone
density, yet no clinical trials have yet
been conducted to show a decrease in
hip fracture, though it is anticipated that
bisphosphonates will have such an effect.
Finally, both agents have gastrointestinal
side effects and dosing requirements,
which consist of taking the tablets on an
empty stomach with water only.
To date, eight trials have been con-ducted
with bisphosphonates; only
two—the Fracture Intervention Trial (FIT
II)12 and the Risedronate Hip Study13—
will be discussed here. The FIT II trial
examined the effect of alendronate on
reduction of hip fractures as a secondary
outcome. (The primary outcomes
included risk of radiographically evident
vertebral fractures, which decreased by
44% overall with alendronate treatment.)
In women with femoral neck T scores of
less than  2.5, alendronate significantly
reduced the risk of hip fracture by 56%.12
However, this effect was not seen in
women with osteopenia (T score between
 1.0 and  2.5).
More than 9000 women aged 70
years and older were enrolled in the rise-dronate
hip fracture study, the first study
to look at hip fracture as the primary end
point.13 Patients were enrolled in two
groups: those aged 70 to 79 years with
low bone density (group 1), and those
older than 80 years with more than one
risk factor for fracture (group 2).
McClung et al13 reported that risedronate
significantly reduced the risk of hip frac-ture
for patients in group 1, but not for
those in group 2 (Table). In group 1, the
risk reduction was limited to patients
who had a previous vertebral fracture;
other patients had no significant reduc-tion.
These findings raise several key
points. First, a previous fracture predicts
a second fracture. Women who have suf-fered
any kind of postmenopausal frac-ture—
hip, forearm, vertebrae—are more
likely to have a subsequent fracture. And,
according to this clinical study, rise-dronate
will help to prevent a second
fracture. Second, and perhaps more
important, medication alone is not suffi-cient
therapy for women who are at risk
of fracture based on clinical signs when
bone density is unknown.
Selective estrogen receptor
modulators
The last class of antiresorptive agents are
the SERMs, which are not estrogens; they
act as estrogen receptor agonists in some
tissues (bone and heart) and antagonists
in other tissues (breast and uterus). Ralox-ifene
hydrochloride is a SERM that cur-rently
is approved both for the preven-tion
and treatment of osteoporosis.
Intriguing recent data also suggest that
raloxifene may reduce the risk of breast
cancer,14 as well as cardiovascular events
in high-risk women,15 as opposed to
estrogen plus progestin, which appears
to increase the risks for breast cancer and
cardiovascular events. Like hormone
therapy, however, raloxifene does appear
to increase the incidence of venous
thromboembolism. Some women also
have reported increased incidence of hot
flashes.
The Multiple Outcomes of Ralox-ifene
Evaluation (MORE) trial examined
the use of raloxifene in postmenopausal
women.16 Compared with placebo, ralox-ifene
significantly increased BMD in both
the spine and the femoral neck. Further-more,
raloxifene decreased the risk of
vertebral fracture both in women with
and without prevalent fractures. In
women with a previous fracture, the rel-
Effect of Risedronate Sodium on Incidence of Hip Fracture in Elderly Women*
Incidence of hip fracture, %
Group Risedronate† Placebo P value
  Group 1 (aged 70 to 79 years
with low bone density‡)
  Overall 1.9 3.2 .009
  With vertebral fracture 2.3 5.7 .003
  No vertebral factures at baseline 1.0 1.6 .14
  Group 2 (aged 80 years and older
with more than one risk factor
for fracture) 4.2 5.1 .35
*Source: McClung MR, Geusens P, Miller PD, Zippel H, Bensen WG, Roux C,
et al. Effect of risedronate on the risk of hip fracture in elderly women.
Hip Intervention Program Study Group. N Engl J Med. 2001;344:333-340.
†All patients assigned to risedronate: relative risk, 0.70; 95% confidence
interval, 0.6 to 0.9; P   .02
‡Hip T score   4.
S12 • JAOA • Supplement 2 • Vol 103 • No 2 • February 2003 Maby • Prevention and treatment of osteoporosis
ative risk reduction was 0.66 (95% confi-dence
interval [CI]   0.55 to 0.81). In
women without a prevalent fracture the
relative risk reduction was 0.51 (95% CI
  0.35 to 0.73). The MORE trial also
reported an impressive finding, though
it was not a primary outcome of the
study: there was a 72% reduction in the
risk of invasive breast cancer in women
receiving raloxifene for 4 years (P .001).14
Future trends
Although a number of options are avail-able
to replace hormones in the preven-tion
and treatment of osteoporosis, many
more agents are currently under investi-gation
and in development. These pos-sibilities
include long-acting bisphos-phonates
and new SERMs, as well as
parathyroid hormone, statins, and even
soy. Agents that are currently available
act only by decreasing bone resorption.
The eventual goal, however, is not only
to prevent bone loss, but also to enhance
bone formation.
Comment
Until this year, hormone therapy was
largely regarded as being safe for short-and
long-term use, suitable for a range of
maladies from hot flashes to osteoporosis.
Cessation of the estrogen plus progestin
arm of the WHI hormone replacement
trial and the confirmed association with
cardiovascular events and breast cancer
radically change this concept of hormone
use. It is now recommended that the
estrogen plus progestin combination not
be used for the prevention of cardiovas-cular
disease or osteoporosis, but only
for the short-term amelioration of symp-toms
associated with menopause.
A number of nonhormonal prod-ucts
are available for the treatment of
osteoporosis, including calcitonin, bis-phosphonates,
and SERMs. Certain of
these, such as the SERM raloxifene, have
shown other benefits as well: raloxifene
appears to reduce the risk of invasive
breast cancer and cardiovascular disease
(among high-risk patients). At the least,
it appears that these agents do not suffer
from the significant drawbacks associ-ated
with hormone therapy and may fill
the gap in the management of osteo-porosis
left by the elimination of hor-mone
therapy.
Addendum
In December 2002, the FDA approved a
new medication for the treatment of
osteoporosis. This new agent, teri-paratide,
or parathyroid hormone, shows
great promise in reversing bone loss. Pre-viously,
all modes of therapy for osteo-porosis
were inhibitors of bone resorp-tion.
Teriparatide is the first agent
available to directly stimulate bone for-mation
by increasing the number and
action of osteoblasts. In the clinical trials
on which the FDA based its approval,
men and women with osteoporosis
treated with teriparatide, calcium, and
vitamin D had a significant increase in
bone density of the hip and spine. The
data demonstrated that teriparatide
reduced the relative risk of spine frac-tures
by 65% and lowered risk of non-spinal
fractures by 53% compared with
placebo. Teriparatide represents an
important new advance in the therapy
for osteoporosis.
References
1. National Osteoporosis Foundation. Physician’s
Guide to Prevention and Treatment of Osteo-porosis.
Washington, DC: National Osteoporosis
Foundation; 1998.
2. Campbell S. The Management of the Menopause
and Post-Menopausal Years: The Proceedings of
the International Symposium Held in London 24–26
November, 1975. Baltimore, Md: University Park
Press; 1976; p 33.
3. Ray NF, Chan JK, Thamer M, Melton LJ III. Med-ical
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.
4. Consensus Development Conference. Diagnosis,
prophylaxis, and treatment of osteoporosis. Am J
Med. 1993;94:646-650.
5. Chrischilles EA, Butler CD, Davis CS, Wallace RB.
A model of lifetime osteoporosis impact. Arch
Intern Med. 1991;151:2026-2032.
6. Writing Group for the Women’s Health Initiative.
Risks and benefits of estrogen plus progestin in
healthy postmenopausal women. JAMA.
2002;288:321-333.
7. O’Loughlin JL, Robitaille Y, Boivin JF, Suissa S. Inci-dence
of and risk factors for falls and injurious
falls among the community-dwelling elderly. Am
J Epidemiol. 1993;137:342-354.
8. National Academy of Sciences. Dietary refer-ence
intake for calcium. Arch Intern Med. 1997;4:39.
9. National Osteoporosis Foundation. Bone Mass
Measurement. Available at: http://www.nof.
org/osteoporosis/bonemass.htm. Accessed: January
27, 2003.
10. American College of Rheumatology. Recom-mendations
for the prevention and treatment of
glucocorticoid-induced osteoporosis: 2001 update.
American College of Rheumatology Ad Hoc Com-mittee
on Glucocoritcoid-Induced Osteoporosis.
Arthritis Rheum. 2001;44:1496-1503.
11. Chesnut CH III, Silverman S, Andriano K, Genant
H, Gimona A, Harris S, et al. A randomized trial of
nasal spray salmon calcitonin in postmenopausal
women with established osteoporosis: the Prevent
Recurrence of Osteoporotic Fractures (PROOF)
study group. Am J Med. 2000;109:267-276.
12. Cummings SR, Black DM, Thompson DE, Apple-gate
WB, Barrett-Connor E, Musliner TA, et al.
Effect of alendronate on risk of fracture in women
with low bone density but without vertebral frac-tures:
results from the Fracture Intervention Trial.
JAMA. 1998;280:2077-2082.
13. McClung MR, Geusens P, Miller PD, Zippel H,
Bensen WG, Roux C, et al. Effect of risedronate
on the risk of hip fracture in elderly women. Hip
Intervention Program Study Group. N Engl J Med.
2001;344:333-340.
14. Cauley JA, Norton L, Lippman ME, Eckert S,
Krueger KA, Purdie D, et al. Continued breast
cancer risk reduction in postmenopausal women
treated with raloxifene: 4-year results from the
Multiple Outcomes of Raloxifene Evaluation
(MORE) trial. Breast Cancer Res Treat. 2001;65:125-
134.
15. Barrett-Connor E, Grady D, Sashegyi A,
Anderson PW, Cox DA, Hoszowski K, et al. Ralox-ifene
and cardiovascular events in osteoporotic
postmenopausal women: four-year results from
the MORE (Multiple Outcomes of Raloxifene Eval-uation)
randomized trial. JAMA. 2002;287:847-857.
16. Delmas PD, Ensrud KE, Adachi JD, Harper KD,
Sarkar S, Gennari C, et al. Efficacy of raloxifene on
vertebral fracture risk reduction in postmenopausal
women with osteoporosis: four-year results from a
randomized clinical trial. J Clin Endocrinol Metab.
2002;87:3609-3617.