Transcript Postmenopausal Hormone-Replacement Therapy(2)

Postmenopausal Osteoporosis
(PMO) (停經後骨質疏鬆症)
郝立智醫師
Clifford J. Rosen, M.D.
NEJM, Volume 353:595-603
August 11, 2005 Number 6
Outline
HLJ
Case Presentation
The Clinical Problem
Strategies and Evidence
Overview
Planning an Intervention Strategy
Nonpharmacologic Options
Physical Activity
Pharmacologic Options
Antiresorptive Agents
Postmenopausal Hormone-Replacement Therapy
Selective Estrogen-Receptor Modulators
Bisphosphonates
Calcitonin
Strontium Ranelate
Anabolic Agents
Combination Therapy
Areas of Uncertainty
Guidelines
Summary and Recommendations
Case Presentation
A 63-year-old woman presents with a
history of acute low back pain. She had
menopause at 44 years of age but never
received postmenopausal hormonereplacement therapy.
She reports a history of a Colles'
fracture at the age of 60 years. Her
mother sustained a hip fracture at 70
years of age.
Lumbar-spine films reveal a new
vertebral fracture. Dual-energy x-ray
absorptiometry (DEXA) of the hip
shows a BMD T score of –1.3.
How should her case be managed?
HLJ
The Clinical Problem (1)
PMO is a common disease with a spectrum ranging from
asymptomatic bone loss to disabling hip fracture.
The National Institutes of Health consensus conference
defined osteoporosis as a disease of increased skeletal
fragility accompanied by low BMD (a T score for BMD
below –2.5) and microarchitectural deterioration.
In the United States, there are 1.5 million osteoporotic
fractures per year, with an annual direct cost of nearly $18
billion.
It is predicted that the prevalence of fracture will increase
by the year 2025, yet less than a quarter of all women who
sustain an osteoporotic fracture currently receive
appropriate Tx for osteoporosis.
HLJ
The Clinical Problem (2)
Fractures occur because of qualitative and
quantitative deterioration in the trabecular and
cortical skeleton. Bone quality cannot be measured
clinically, but BMD can be measured painlessly,
quickly, safely, accurately, precisely, and relatively
inexpensively; several methods are available, DEXA
is currently the most validated. Low bone mass at
any skeletal site is associated with a substantially
increased risk of fracture.
Other risk factors include advancing age, low BW,
maternal history of osteoporosis, the direction of a
fall (a fall backward and to one side is most likely to
result in a fracture), and most important, the
presence of a previous fracture.
These and other risk factors for osteoporosis were
reviewed in a recent Clinical Practice article in the
Journal (Screening for osteoporosis. N Engl J Med
2005;353:164-171.).
HLJ
世界衛生組織(WHO)對於骨質疏鬆症的分級方式：
Definition
Category
QUI/Stiffness T-score
Normal
T > -1.0
More than 1SD below young
adult mean, but less than
2.5 SD below this value
Low Bone Mass
(Osteopenia)
-1.0 > T > -2.5
2.5 SD or more below the
young adult
Osteoporosis
T < -2.5
Severe Osteoporosis
(established osteoporosis)
T < -2.5
Within 1SD of the young
adult reference mean
More than 2.5 SD below young
adult mean in the presence
of one or more fragility
fractures
HLJ
國內對於骨質疏鬆症的分級方式：
QUI/Stiffness T-score
Category
T > -1.0
Normal
-1.0 > T > -2.0
Grade 1 Osteoporosis
-2.0 > T > -3.0
Grade 2 Osteoporosis
-3.0 > T > -4.0
Grade 3 Osteoporosis
-4.0 > T
Grade 4 Osteoporosis
HLJ
HLJ
Normal bone trabeculae Bone trabeculae with osteoporosis
HLJ
Figure 1. DEXA of the Spine and Hip of a 66-Year-Old Postmenopausal Woman.
Dx of osteoporosis can be made on the basis of BMD of the hip
(Panel A) and the spine (Panel B). The density of lumbar
vertebrae 1 through 4 (L1 through L4), both as a percentage of
the mean value for a young adult and as a T score, does not
indicate osteoporosis, because of the high values for L3 and L4.
Since the latter probably reflect OA changes in the spine, the use
of the two lowest values is recommended for diagnosis.
Note that in this p't the T scores at the hip are relatively high, as
compared with the spine. The density of the total hip includes the
lesser trochanter and adjacent cortical bone and thus has a
higher value. The red lines on the left side of each panel indicate
the specific area being measured, and the blue areas on the right
side indicate the expected age-related means (±1 SD) for white
women.
BMD measurement results in less than 10 mrem of radiation
exposure, as compared with 30 to 60 mrem for a CXR. The color
stripes in each panel indicate the degree of concern related to
bone density; red denotes high concern and green low concern.
HLJ
Screening for osteoporosis. N Engl J Med 2005;353:164-171.
HLJ
Figure 2. Flow Chart for Recommendations Regarding Selection of p'ts for DEXA.
For peripheral densitometry, each system will have different levels of Tscore cutoff. In most cases, DEXA will be recommended for p'ts with T
scores of –1.0 or lower. It is important to identify diseases or drugs that
are likely to cause skeletal fragility or to increase the risk of falls.
Risk factors that warrant BMD testing include an age of more than 65
years, a personal history of fracture (particularly fragility fracture) or
height loss of more than 2 cm, a family history of fracture in a firstdegree relative, low BW (less than 126 lb), and recent weight loss (more
than 5 %). Other risk factors include female sex, late menarche, early
menopause, low Ca intake, vit D insufficiency, smoking, excess alcohol
intake, physical inactivity and muscle weakness, and impaired vision or
balance.
Secondary causes include hyperparathyroidism, hyperthyroidism,
Cushing's syndrome, glucocorticoid therapy, inflammatory disorders
(including arthritis, bowel disease, and pulmonary disease),
hypogonadism (including Tx with LHRH agonists and aromatase
inhibitors), cancer (especially hematologic conditions), congenital
disorders (including osteogenesis imperfecta and homocystinuria), and
neurologic disorders (including immobilization and Tx with antiepileptic
drugs).
HLJ
HLJ
Strategies and Evidence– Overview (1)
A comprehensive management plan includes evaluation of
those at highest risk, exclusion of secondary causes of low
BMD, and selection of the appropriate Tx. A history of
fragility fractures (unrelated to substantial trauma) in a
postmenopausal woman strongly supports a diagnosis of
osteoporosis, regardless of BMD.
Secondary causes such as primary hyperparathyroidism, Vit
D deficiency due to low intake, lack of exposure to sunlight,
or malabsorption, and multiple myeloma should be excluded,
particularly if the z score (the number of standard deviations
from the mean for an age- and sex-specific reference group)
for BMD is depressed (i.e., below –2.00).
Biochemical markers of bone turnover such as N-telopeptide
or osteocalcin rarely help in establishing a diagnosis or
selecting Tx, although they may be useful in determining
whether there is accelerated bone loss, particularly during
the first few years of menopause.
HLJ
Overview (2)
Decision making should also take into account several
caveats. Osteoporosis therapy can reduce the risk of fracture
by as much as 50 %, but some women have fractures
despite Tx. Also, changes in lifestyle and the use of
pharmacologic interventions are lifetime commitments, and
therefore cost, compliance with a medication regimen, and
safety must be considered in decisions on therapy.
Moreover, a substantial percentage of osteoporotic fractures
occur in women who have T scores above –2.5. (A T score is
the number of standard deviations the BMD measurement is
above or below the young-normal mean bone density.)
In some cases, there is a substantial discrepancy between
the spine and hip T scores. Thus, decisions with regard to Tx
should not be based solely on BMD.
HLJ
Self-assessment of Osteoporosis
1.Height loss of more than 2.5 cm
2.Occiput fails to touch the wall when standing
next to the wall
3.A bend back
These are clues that you may already have
osteoporosis. Please consult your doctor if you
have these problems.
HLJ
Planning an Intervention Strategy
Therapy for PMO is considered to be primary
prevention when it is prescribed for those at risk
without a T score below –2.5 or a history of
fragility fracture and is considered to be Tx for
those with established disease, including
previous osteoporotic fracture, markedly
reduced BMD, or both.
The choice of an appropriate regimen will
depend on whether the therapy is designed
principally to prevent bone loss in p'ts with
osteopenia (a T score between –1 and –2.5) or
to reduce the likelihood of a first or subsequent
fracture in osteoporosis.
HLJ
Nonpharmacologic Options (1)
Ca supplementation should be adjunctive Tx for all women
with established osteoporosis and must be part of any
preventive strategy to ameliorate bone loss.
Increased Ca intake reduces the hyperparathyroidism
associated with advancing age and can enhance
mineralization of newly formed bone.
A recent meta-analysis of 15 Ca intervention trials involving
healthy women and PMO demonstrated an increase of
nearly 2 % in spine BMD after two years, although the risk
of vertebral and nonvertebral fracture was not reduced to a
statistically significant level.
A total Ca intake of 1200 to 1500 mg/d (through diet,
supplements, or both) is recommended for all
postmenopausal women.
HLJ
Nonpharmacologic Options (2)
Vit D is essential for skeletal maintenance and
enhancement of Ca absorption. Dietary insufficiency of this
Vit is a growing problem, with as many as two thirds of p'ts
with hip fracture classified as having a deficiency of Vit D
(defined as a serum 25-hydroxyVit D [25(OH) Vit D] level
below 15 ng/ml [37.4 nmol/l]).
Elderly persons with chronic conditions that require
assisted-living situations are particularly vulnerable to Vit D
deficiency because of lack of adequate exposure to sunlight.
One large trial showed a reduction of 33 % in hip fracture
among nursing home residents who were randomly
assigned to receive Ca and Vit D, as compared with those
given placebo.
HLJ
Vit D3 and Ca to prevent hip fractures in the elderly women
BACKGROUND. Hypovitosis D and a low Ca intake contribute
to increased parathyroid function in elderly persons. Ca and
vit D supplements reduce this 2nd hyperparathyroidism, but
whether such supplements reduce the risk of hip fractures
among elderly people is not known.
METHODS. We studied the effects of supplementation with vit
D3 (cholecalciferol) and Ca on the frequency of hip fractures
and other nonvertebral fractures, identified radiologically, in
3270 healthy ambulatory women (mean [+/- SD] age, 84
+/- 6 years). Each day for 18 months, 1634 women received
triCa phosphate (containing 1.2 g of elemental Ca) and 20
micrograms (800 IU) of vit D3, and 1636 women received a
double placebo. We measured serial serum PTH and 25hydroxyvit D (25(OH)D) in 142 women and determined the
femoral BMD at base line and after 18 months in 56 women.
HLJ
N Engl J Med 1992;327:1637-1642.
RESULTS. Among the women who completed the 18-month
study, the number of hip fractures was 43 % lower (P =
0.043) and the total number of nonvertebral fractures was
32 % lower (P = 0.015) among the women treated with vit
D3 and Ca than among those who received placebo. The
results of analyses according to active Tx and according to
intention to treat were similar. In the vit D3-Ca group, the
mean serum PTH had decreased by 44 % from the baseline value at 18 months (P < 0.001) and the serum
25(OH)D had increased by 162 % over the base-line value
(P < 0.001). The BMD of the proximal femur increased 2.7
% in the vit D3-Ca group and decreased 4.6 % in the
placebo group (P < 0.001).
CONCLUSIONS. Vit D3 and Ca reduces the risk of hip
fractures and other nonvertebral fractures among elderly
women.
HLJ
N Engl J Med 1992;327:1637-1642.
Nonpharmacologic Options (3)
In another trial, Tx with a single oral dose of 100,000 IU of Vit
D3 every four months reduced nonvertebral fractures by
nearly a third among elderly people who are able to walk.
Similarly, among older men and women in New England, Ca
citrate (500 mg/d) and Vit D3 (700 IU/d) reduced the risk of
nonvertebral fracture.
There is strong evidence that Vit D enhances muscle strength
and reduces the risk of falling.
Table 1 lists the various forms of Ca and Vit D supplements.
Counseling with regard to avoidance of smoking and excessive
alcohol intake is routinely warranted, particularly since
smoking and alcohol intake have been linked in some studies
to greater fracture risk.
HLJ
HLJ
Physical Activity
Bed rest or immobility due to other causes can result
in rapid bone loss. Moreover, the number of falls and
the percentage of falls that result in fracture increase
with age.
A recent Cochrane meta-analysis found that muscle
strengthening, balance training, assessment of the
home for hazards, withdrawal of psychotropic
medications, and the use of a multidisciplinary
program to assess risk factors all protect against falls.
Another approach is to pad the hip with a hip
protector to reduce trauma during a fall; although p't
compliance with this strategy is generally poor, when
used properly, the strategy has been reported to
reduce the risk of hip fracture.
Regular physical activity, including aerobic, weightbearing, and resistance exercise, is effective in
increasing BMD of the spine and strengthening muscle
mass in postmenopausal women, but there are no
large trials establishing whether these interventions
reduce the fracture risk.
HLJ
Pharmacologic Options
An aggressive intervention program can
reduce the risk of fracture and improve the
quality of life among PMO.
Several pharmacologic options are available,
and these can be classified according to their
mechanism of action.
Two main classes of drugs:
1. Antiresorptive agents (agents that block bone
resorption by inhibiting the activity of
osteoclasts).
2. Anabolic agents (agents that stimulate bone
formation by acting primarily on osteoblasts).
Table 2 is a review of agents that have been
approved by FDA.
HLJ
HLJ
Antiresorptive Agents
By suppressing osteoclast activity,
antiresorptive agents slow the remodeling
cycle, thereby enhancing mineralization of the
bone matrix and potentially stabilizing the
trabecular microarchitecture.
These agents increase BMD in women with
osteopenia or osteoporosis and reduce the risk
of fracture in women with osteoporosis,
although efficacy varies among the agents
(Table 2).
HLJ
Postmenopausal Hormone-Replacement Therapy(1)
HRT was once considered the primary therapy for
PMO. Estrogen slows bone resorption by blocking
cytokine signaling to the osteoclast, increases BMD,
and reduces incidence of new vertebral fractures by
nearly 50 %.
Low-dose conjugated estrogens (0.3 or 0.45 mg/d) or
ultra-low-dose estradiol (0.014 mg/d) also increases
BMD, but the antifracture efficacy of these therapies
has not been established.
Among women in the Women's Health Initiative trial,
in those randomly assigned to receive conjugated
estrogens, with or without a progestin, the reduction
in hip fracture was 33 %.
HLJ
Postmenopausal Hormone-Replacement Therapy(2)
Discontinuation of estrogen results in measurable
bone loss, although it is not certain whether
discontinuation results in a greater fracture risk than
continuation.
Recent concern about the nonskeletal risks
associated with long-term use of estrogen (including
the risk of breast cancer and the risk of CV disease),
coupled with the availability of other drugs to treat
osteoporosis has markedly lessened enthusiasm for
HRT in the Tx and prevention of osteoporosis.
HLJ
Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women
Principal Results From the Women's Health Initiative Randomized Controlled Trial
Context Despite decades of accumulated
observational evidence, the balance of risks and
benefits for hormone use in healthy postmenopausal
women remains uncertain.
Objective To assess the major health benefits and
risks of the most commonly used combined
hormone preparation in the United States.
Design Estrogen plus progestin component of the
Women's Health Initiative, a randomized controlled
primary prevention trial (planned duration, 8.5 years)
in which 16608 postmenopausal women aged 50-79
years with an intact uterus at baseline were
recruited by 40 US clinical centers in 1993-1998.
HLJ
JAMA. 2002;288:321-333.
Interventions Participants received conjugated
equine estrogens, 0.625 mg/d, plus
medroxyprogesterone acetate, 2.5 mg/d, in 1 tablet
(n = 8506) or placebo (n = 8102).
Main Outcomes Measures The primary outcome
was coronary heart disease (CHD) (nonfatal MI and
CHD death), with invasive breast cancer as the
primary adverse outcome. A global index
summarizing the balance of risks and benefits
included the 2 primary outcomes plus stroke,
pulmonary embolism (PE), endometrial cancer,
colorectal cancer, hip fracture, and death due to
other causes.
HLJ
JAMA. 2002;288:321-333.
1.
2.
3.
4.
Results
On May 31, 2002, after a mean of 5.2 years of follow-up, the data and
safety monitoring board recommended stopping the trial of estrogen plus
progestin vs placebo because the test statistic for invasive breast cancer
exceeded the stopping boundary for this adverse effect and the global
index statistic supported risks exceeding benefits.
This report includes data on the major clinical outcomes through April 30,
2002. Estimated hazard ratios (HRs) (nominal 95% confidence intervals
[CIs]) were as follows: CHD, 1.29 (1.02-1.63) with 286 cases; breast
cancer, 1.26 (1.00-1.59) with 290 cases; stroke, 1.41 (1.07-1.85) with
212 cases; PE, 2.13 (1.39-3.25) with 101 cases; colorectal cancer, 0.63
(0.43-0.92) with 112 cases; endometrial cancer, 0.83 (0.47-1.47) with
47 cases; hip fracture, 0.66 (0.45-0.98) with 106 cases; and death due
to other causes, 0.92 (0.74-1.14) with 331 cases. Corresponding HRs
(nominal 95% CIs) for composite outcomes were 1.22 (1.09-1.36) for
total CV disease (arterial and venous disease), 1.03 (0.90-1.17) for total
cancer, 0.76 (0.69-0.85) for combined fractures, 0.98 (0.82-1.18) for
total mortality, and 1.15 (1.03-1.28) for the global index.
Absolute excess risks per 10 000 person-years attributable to estrogen
plus progestin were 7 more CHD events, 8 more strokes, 8 more PEs, and
8 more invasive breast cancers, while absolute risk reductions per 10 000
person-years were 6 fewer colorectal cancers and 5 fewer hip fractures.
The absolute excess risk of events included in the global index was 19 per
10 000 person-years.
HLJ
JAMA. 2002;288:321-333.
Conclusions
1. Overall health risks exceeded benefits from use of
combined estrogen plus progestin for an average
5.2-year follow-up among healthy postmenopausal
US women.
2. All-cause mortality was not affected during the trial.
3. The risk-benefit profile found in this trial is not
consistent with the requirements for a viable
intervention for primary prevention of chronic
diseases, and the results indicate that this regimen
should not be initiated or continued for primary
prevention of CHD.
HLJ
JAMA. 2002;288:321-333.
Selective Estrogen-Receptor Modulators
Raloxifene inhibits bone resorption through the
same mechanism as do estrogens.
Raloxifene increases spine BMD slightly and
decreases the risk of vertebral fracture by 40 % in
women with osteoporosis, but it has no effect on the
risk of nonvertebral fracture.
The risk of breast cancer is reduced with long-term
use of raloxifene, although the drug is not approved
for this indication.
New selective estrogen-receptor modulators are
currently in phase 2 and 3 clinical trials.
HLJ
Raloxifene (Evista)
婦女在停經或卵巢切除以後，由於雌激素的分泌逐漸減少，使其分布在
血中的濃度逐漸下降，長時期後會影響骨骼蝕骨細胞的再吸收及骨骼生
成的不平衡，導致骨骼流失速率急速增加，如此提高了骨質疏鬆症發生
的機率，並且有可能會因此嚴重影響人生往後將近三分之一歲月的生活
品質，甚至縮短了生命，由此可見補充雌激素的必要性。然而曾有報告
指出，雌激素的補充會使得乳癌及子宮內膜癌的發生機率增加，這對於
停經後出現較少更年期症候的婦女而言，補充雌激素與否，無疑是一項
內心交戰。
選擇性雌激素受器調節劑(Selective Estrogen Receptor
Modulators , SERMs)是一種合成物，經由結合在雌激素受體
(estrogen receptor)，透過基因的調節，能夠在不同的組織中表現雌
激素的特性或拮抗性。
Tamoxifene是第一代有效的SERMs，其在乳房組織表現抗雌激素的作
用，但在骨骼、脂肪組織及子宮則表現雌激素作用，因此目前
tamoxifene被核准的適應症為治療及預防乳癌。
HLJ
新一代的Raloxifene於1997年12月經由美國FDA核准，可使
用在預防及治療停經後婦女骨質疏鬆症。目前在台灣健保給付
的適應症為，治療停經後婦女因骨質疏鬆引起骨折者。
Raloxifene在骨骼及脂肪組織表現雌激素作用，除了可降低骨
骼蝕骨細胞的骨再吸收外，並且可降低骨骼轉換率(bone
turnover)，而使得骨質密度增加。Raloxifene在乳房及子宮
內膜則是表現抗雌激素作用，因此，停經後婦女服用
raloxifene不會造成子宮內膜組織的增生，對於產生子宮內膜
癌的危險性較低，並且對於罹患乳癌具高度危險群者，
raloxifene亦是良好的選擇。
Raloxifene亦如同雌激素般可降低總膽固醇及低密度脂蛋白
(LDL)的血中濃度(約6-11%)，但並不會影響高密度脂蛋白
(HDL)及三酸甘油脂(triglycerides)的量，是否因此而具有心
血管系統保護作用，仍須待臨床證實。
HLJ
Raloxifene的口服吸收率約為60%，食物不會影響吸收，因
此不拘飯前或飯後服用，一般建議的劑量為每日一次60mg。
約95%以上會與血漿蛋白結合，因此與其他高度蛋白結合藥
物，如clofibrate, indomethacin, naproxen, ibuprofen,
diazepam, diazoxide等併用時需特別注意。在體內具有高
度的肝首渡代謝效應，絕對生體可用率為2%，肝功能不好的
患者服用此藥需要監測肝功能指數。
然而raloxifene並非經由cytochrom p450途徑代謝，所以
較少藥物交互作用問題，但與ampicillin或cholestyramine
併用時，raloxifene的吸收率會降低；與warfarin併用時，
會使得prothrombin time縮短，因此需特別留意。
Raloxifene經由肝首渡代謝後，會形成glucuronide結合型
態，主要經由糞便排泄，只有小於1% 的未結合型態會由尿
液排出。排除半衰期約27.7小時。
HLJ
Raloxifene在臨床上最常見的不良反應包括臉部潮紅(25%)以及腿部抽
筋(leg cramps, 6%)，因此建議女性在停經初期(early stage)的前兩
年，為減低臉部潮紅的停經症候群，仍以使用荷爾蒙替代療法(HRT)為佳，
之後再使用raloxifene。然而，使用荷爾蒙替代療法時的不良反應，如腹
痛、陰道出血、乳房疼痛、胃脹氣等，在使用raloxifene時則較少出現。
但有研究指出，服用raloxifene的婦女會導致靜脈血栓栓塞
(thromboembolism)發生的危險性增加，尤其是在最初使用的前四個
月，因此在長期不能活動(如長期臥床休息、手術後)期間，至少應在72
小時之前停止服藥，直到患者恢復行動能力。而進行長途旅行的患者，應
注意要時常走動。
此外，當有以下的情況時也不建議使用: (1) 懷孕或準備懷孕的婦女。
(2) 具有靜脈血栓栓塞(thromboembolism)，包括深層靜脈血栓、肺栓
塞以及網膜靜脈栓塞(retinal vein thrombosis)病史的婦女。
(3) 對於raloxifene任何成分有過敏者。
(4) 授乳婦女、停經前婦女及小孩。
(5) 同時併用雌激素或荷爾蒙替代療法。
由於raloxifene的雙重特性：雌激素及抗雌激素作用，使其不僅可用在停
經後婦女罹患骨質疏鬆症卻無法使用雌激素、荷爾蒙替代療法或
biphosphonates；亦可作為停經後婦女罹患骨質疏鬆症且有乳癌、子宮
內膜增生傾向之另一種選擇。
HLJ
Bisphosphonates (1)
The most widely prescribed antiresorptive agents and
are often considered first-line therapy for PMO. These
agents suppress resorption by inhibiting the attachment
of osteoclasts to bone matrix and enhancing
programmed cell death.
First-generation bisphosphonates include etidronate and
clodronate; neither drug is approved for osteoporosis.
Alendronate and risedronate, two second-generation
nitrogen-containing bisphosphonates, have been shown
in randomized trials to increase BMD in postmenopausal
osteopenia or osteoporosis; in women with osteoporosis,
they have been shown to reduce the incidence of hip,
vertebral, and nonvertebral fracture by nearly 50 %,
particularly during the first year.
HLJ
Bisphosphonates (2)
As is the case with other antiresorptive drugs, increases
in BMD with alendronate or risedronate account for a
small fraction of their antifracture efficacy.
Hence, follow-up DEXA may substantially underestimate
the reduction in fracture risk.
Alendronate can be safely administered for at least seven
years without adversely affecting bone strength. Moreover,
discontinuation of long-term (five years or more) alendronate
therapy results in minimal bone loss over the ensuing three
to five years.
Alendronate or risedronate once weekly has been shown to
reduce the rate of drug-induced esophagitis, as compared
with daily doses.
In a recent one-year head-to-head study, alendronate
increased spine and hip BMD slightly more than risedronate,
although the clinical significance of this finding is uncertain.
HLJ
Alendronate (Fosamax)於FDA核准之適應症為：
1. 用以治療及預防停經後婦女骨質疏鬆症(1995年)
2. 用以治療男性及女性因服用類固醇所引起的骨質疏鬆症
(1996年)
目前在台灣健保給付的適應症為：
限停經後婦女因骨質疏鬆症引起骨折之病患，其肌酸酐廓清
率(Clcr)大於每分鐘35毫升者。
Alendronate在臨床上最常見的不良反應主要在腸胃道方面，
如食道炎、食道糜爛、食道潰瘍、吞嚥困難、消化不良、胃
脹、腹痛。其他方面的副作用則有肌肉骨骼酸痛、便秘、脹
氣、頭痛。若是與鈣質補充劑、制酸劑或其他口服製劑同時
服用，可能會影響alendronate的吸收。因此，投與方式為
每日食用第一種食物、飲料或其他藥物前半小時伴以大量白
開水服用。且為了減少對食道的刺激，在服藥後至少30分鐘
內需保持身體直立姿態，直到吃過第一種食物。並且錠劑不
可咀嚼或吸吮。
服用過量的alendronate會導致低血鈣症、上腸胃道不適作
用，如胃不舒服、心灼熱、食道炎、胃炎或潰瘍等情況，可
給予牛奶或制酸劑，使其與alendronate結合。但由於
alendronate對食道有刺激性，所以對服藥過量的患者不可
催吐，並且須使病人姿勢保持直立狀態。
HLJ
Alendronate口服的生體可用率在女性約為0.78%，在男性約
為0.59%，食物會降低此藥的吸收。一般的建議劑量為每日一
次10mg。雖然不易自腸胃道吸收，但進入體內後，對於骨骼
重建區域的親和力良好。在骨骼的半衰期可達十年。約有78%
會與血漿蛋白結合。目前的資料顯示其不會被代謝，倘若沒被
骨骼吸收，剩餘藥物以原型經由尿液及糞便排泄。年老者或患
有輕度到中度腎功能不全者，不需調整劑量。但不建議使用於
Clcr小於35ml/min的患者。
此外下列患者也不建議使用：
1. 會延遲食道排空的食道不正常現象，如食道狹窄或弛緩不能。
2. 無法站立或坐直至少30分鐘者。
3. 對於alendronate任何成分有過敏者。
4. 低血鈣症者。
5. 懷孕婦女、授乳婦女及小孩。
HLJ
Bisphosphonates (3)
IV pamidronate has been used to treat women who cannot tolerate
oral bisphosphonates; however, its efficacy in reducing fracture has
not been established. Acute and delayed hypersensitivity reactions
can occur and its use is contraindicated in Vit D deficiency, since the
drug can cause a precipitous drop in serum Ca levels.
In 2005, ibandronate, at a dose of 2.5 mg/d or 150 mg monthly,
was approved by FDA for both prevention and Tx of PMO. Daily
ibandronate has been shown to reduce significantly the incidence of
vertebral fracture in women with osteoporosis and to reduce
incidence of nonvertebral fracture in women with severe
osteoporosis (T score, below –3.0).
IV zoledronate, which is approved for Tx of malignant hypercalcemia,
multiple myeloma, and skeletal metastases, can suppress bone
resorption and increase BMD in postmenopausal women for as long
as one year after a single 4-mg dose. Phase 3 trials are under way
to evaluate the safety and efficacy of this drug in reducing
osteoporotic fracture.
HLJ
Calcitonin
Calcitonin is an endogenous peptide that partially inhibits
osteoclast activity.
Nasal calcitonin and subcutaneous calcitonin are approved
for PMO. Although Tx of women with osteoporosis with
nasal calcitonin at a dose of 200 IU/d has been shown to
reduce the incidence of vertebral (but not nonvertebral)
fracture in a single randomized trial, methodologic flaws in
the study have limited enthusiasm for this agent.
In placebo-controlled studies, nasal calcitonin has reduced
the pain associated with new spine fractures, although it is
now considered preferable to treat osteoporosis with more
potent agents and to manage pain separately.
HLJ
A randomized trial of nasal spray salmon calcitonin in postmenopausal
women with established osteoporosis: the prevent recurrence of
osteoporotic fractures study. PROOF Study Group.
PURPOSE: We conducted a 5-year, double-blind, randomized,
placebo-controlled study to determine whether salmon
calcitonin nasal spray reduced the risk of new vertebral
fractures in postmenopausal women with osteoporosis.
SUBJECTS AND METHODS: A total of 1,255 postmenopausal
women with established osteoporosis were randomly
assigned to receive salmon calcitonin nasal spray (100, 200,
or 400 IU) or placebo daily. All participants received
elemental Ca (1,000 mg) and vit D (400 IU) daily. Vertebral
fractures were assessed with lateral radiographs of the
spine. The primary efficacy endpoint was the risk of new
vertebral fractures in the salmon calcitonin nasal spray 200IU group compared with the placebo group.
HLJ
Am J Med. 2000 Sep;109(4):267-76.
RESULTS: During 5 years, 1,108 participants had at least one
follow-up radiograph. A total of 783 women completed 3 years
of Tx, and 511 completed 5 years. The 200-IU dose of salmon
calcitonin nasal spray significantly reduced the risk of new
vertebral fractures by 33% compared with placebo [200 IU: 51
of 287, placebo: 70 of 270, relative risk (RR) = 0.67, 95%
confidence interval (CI): 0.47- to 0.97, P = 0.03]. In the 817
women with one to five prevalent vertebral fractures at
enrollment, the risk was reduced by 36% (RR = 0.64, 95% CI:
0.43- to 0.96, P = 0.03). The reductions in vertebral fractures
in the 100-IU (RR = 0.85, 95% CI: 0.60- to 1.21) and the
400-IU (RR = 0.84, 95% CI: 0.59- to 1.18) groups were not
significantly different from placebo. Lumbar spine BMD
increased significantly from baseline (1% to 1. 5%, P<0.01) in
all active Tx groups. Bone turnover was inhibited, as shown by
suppression of serum type-I collagen cross-linked telopeptide
(C-telopeptide) by 12% in the 200-IU group (P <0.01) and by
14% in the 400-IU group (P<0.01) as compared with placebo.
CONCLUSION: Salmon calcitonin nasal spray at a dose of 200
IU daily significantly reduces the risk of new vertebral
fractures in PMO.
Am J Med. 2000 Sep;109(4):267-76.
HLJ
Strontium Ranelate
Strontium ranelate is orally administered and
stimulates Ca uptake in bone while inhibiting bone
resorption.
In a randomized trial in PMO, daily strontium
ranelate reduced the risk of vertebral fracture by 40
%. However, a significant reduction in nonvertebral
fracture was observed only in a post hoc analysis of
a small subgroup of women.
This drug was recently approved by European
regulatory agencies, but it is not currently approved
by FDA.
HLJ
Anabolic Agents (1)
The prototypical anabolic drug is sodium fluoride, which was
widely used in the 1970s and 1980s because of its ability to
stimulate the formation of new bone. However, a randomized
trial in 1990 established that despite dramatic increases in
BMD, the risk of nonvertebral fracture actually increased with
the use of fluoride.
In 2002, synthetic PTH (1–34) (teriparatide) was the first
anabolic agent approved by FDA for PMO. Unlike
antiresorptive agents, PTH stimulates bone remodeling by
increasing bone formation. In a large randomized trial
involving postmenopausal severe osteoporosis, 20 µg of PTH
per day administered S.C. markedly increased BMD and
reduced vertebral and nonvertebral fractures by more than 50
%.
However, the trial was stopped after 20 months because of
concern about the development of osteosarcoma in rats
treated with high doses of PTH (1–34).
HLJ
Effect of PTH (1-34) on Fractures and BMD in PMO
Background Once-daily injections of PTH or its aminoterminal fragments increase bone formation and bone
mass without causing hypercalcemia, but their effects
on fractures are unknown.
Methods We randomly assigned 1637 postmenopausal
women with prior vertebral fractures to receive 20 or
40 µg of PTH (1-34) or placebo, administered
subcutaneously by the women daily. We obtained
vertebral radiographs at base line and at the end of the
study (median duration of observation, 21 months) and
performed serial measurements of bone mass by DEXA.
HLJ
N Engl J Med 2001;344:1434-1441.
Results New vertebral fractures occurred in 14 % women in the
placebo group and in 5 % and 4 %, respectively, of the women in
the 20-µg and 40-µg PTH groups; the respective relative risks of
fracture in the 20-µg and 40-µg groups, as compared with the
placebo group, were 0.35 and 0.31 (95 % confidence intervals, 0.22
to 0.55 and 0.19 to 0.50). New nonvertebral fragility fractures
occurred in 6 % women in the placebo group and in 3 % of those in
each PTH group (relative risk, 0.47 and 0.46, respectively [95 %
confidence intervals, 0.25 to 0.88 and 0.25 to 0.86]). As compared
with placebo, the 20-µg and 40-µg doses of PTH increased BMD by 9
and 13 more percentage points in the lumbar spine and by 3 and 6
more percentage points in the femoral neck; the 40-µg dose
decreased BMD at the shaft of the radius by 2 more percentage
points. Both doses increased total-body BMD by 2 to 4 more
percentage points than did placebo. PTH had only minor side effects
(occasional nausea and headache).
Conclusions Tx of PMO with PTH (1-34) decreases the risk of
vertebral and nonvertebral fractures; increases vertebral, femoral,
and total-body BMD; and is well tolerated. The 40-µg dose increased
BMD more than the 20-µg dose but had similar effects on the risk of
fracture and was more likely to have side effects.
HLJ
N Engl J Med 2001;344:1434-1441.
Anabolic Agents ( 2)
As a result, a "black-box" warning was added to the
teriparatide label. However, retrospective studies have found
no association between osteosarcoma and primary or
secondary hyperparathyroidism in humans, and no cases of
osteosarcoma have been reported in the more than 200,000
p'ts treated with PTH.
The current recommendation is that PTH therapy should be
limited to persons with moderate-to-severe osteoporosis and
that the duration of therapy should not exceed two years.
PTH (1–34) is well tolerated, although mild but asymptomatic
hypercalcemia (i.e., a serum Ca level between 10.5 and 11.0
mg/dl [2.6 and 2.8 mmol/l]) can occur rarely.
Cost and the requirement of subcutaneous administration are
major limiting factors.
HLJ
Combination Therapy
Although studies have suggested that combining antiresorptive
agents may slightly increase BMD as compared with
monotherapy, there are no data to indicate that combination
therapies are superior for reducing the risk of fracture.
There is also no evidence that combining PTH with an
antiresorptive drug results in additive or synergistic effects,
but concurrent use of cyclic PTH (i.e., daily parathyroid for 3
months followed by no Tx for 3 months for a period of 15
months) with alendronate may be just as effective as daily PTH
with alendronate.
Nevertheless, bone loss will occur after the discontinuation of
PTH, but it can be prevented if this therapy is followed by Tx
with an antiresorptive drug such as alendronate.
HLJ
Areas of Uncertainty (1)
The optimal timing and type of preventive therapy are still not
clearly defined. Many postmenopausal women have T scores
between –1.0 and –2.5 but no other risk factors.
Postmenopausal hormone-replacement therapy, once
considered the best preventive approach for these women, is
no longer recommended in light of the associated risks
reported in the Women's Health Initiative trial.
Bisphosphonates prevent bone loss in women with osteopenia
and can be used as prophylaxis, but cost-effectiveness and
concerns about the effects on skeletal mineralization over
decades may be limiting factors.
Studies such as the extension of the Fracture Intervention Trial
(evaluating alendronate) have provided some reassurance with
regard to long-term use.
HLJ
Areas of Uncertainty (2)
Also uncertain is the appropriate care for p'ts who continue to
have fractures despite aggressive pharmacologic intervention.
Whether new agents such as the synthetic Ab to the receptor
activator of nuclear factor- B ligand (AMG 162) or strontium
ranelate will be effective in preventing new fractures in such
p'ts needs to be tested.
Finally, controversy persists about the use of vertebroplasty or
kyphoplasty, procedures that introduce material to expand
compressed vertebrae and reduce the pain associated with
new fractures. Both the absence of randomized, placebocontrolled trials and concerns about the mechanical strength of
adjacent vertebrae after these procedures preclude making
recommendations for their use.
HLJ
(Guidelines)
HLJ
Summary and Recommendations (1)
A careful Hx taking and P.E. that address risk
factors for or signs of osteoporosis (particularly
previous fragility fractures, height loss, or both,
as well as possible secondary causes of bone
loss) combined with measurement of BMD
should guide therapeutic decisions.
Given the high prevalence of low levels of
25(OH) Vit D in women with osteoporosis,
measurement of a serum 25(OH) Vit D level by
a reliable laboratory is reasonable.
HLJ
Summary and Recommendations (2)
Tx plans for the woman in the vignette should include Ca
supplementation to a level of at least 1200 mg/d and 800 IU of
Vit D, as well as pharmacologic therapy. I would start with an
oral bisphosphonate (alendronate or risedronate) once weekly
or ibandronate once monthly, given the documented
reductions in the incidence of hip and vertebral fracture with
these agents.
Alternatively, one could consider PTH (1–34) for two years if a
p't cannot tolerate a bisphosphonate or has had multiple
fractures, although with this regimen, cost and compliance
need to be taken into consideration.
Irrespective of the choice of therapy, careful follow-up, with
attention to pain, lifestyle, and risk factors for future fracture,
is necessary.
HLJ
須靠醫師 預防骨鬆 補品無助
預防或治療骨質疏鬆症，你做對了嗎？醫師指出，國人最
愛的「補骨食品」：如維骨力、固樂沙敏、阿鈣、綜合維
他命、深海魚油、維他命Ｅ及Ｃ、骨頭湯等，其實對於骨
鬆症並無太大的幫助。
中華民國骨質疏鬆症學會理事長蔡克嵩表示，骨質疏鬆症
是很危險的疾病，易導致骨折，若大腿骨骨折，六十五歲
以上男性一年死亡率高達二二％、同年齡女性一年死亡率
也達一五％，相當於末期乳癌的死亡率。
蔡克嵩表示，骨鬆症的因素包括：種族、遺傳、體重和飲
食等，遺傳占很重要的比例，若父母都有骨鬆病史，子女
有骨鬆的機率是一般人的四倍；若父母僅一方有骨鬆，則
子女罹患率比一般人多出兩倍。
HLJ
2005.09.03
中國時報
根據中華民國骨質疏鬆症學會和美商默沙東藥廠共同進
行的問卷調查，國人常以為單純增加鈣質攝取量、或服
用維骨力（成分為葡萄糖胺）就可以治療骨鬆症。但蔡
克嵩表示，葡萄糖胺只是一種關節軟骨基質的補充成分，
對軟骨好，但對於骨頭並沒有幫助，因此和骨鬆症無關。
每天吃鈣片，也不見得可預防骨鬆症。
蔡克嵩建議，無論男女，只要五十歲以上就要密切注意
骨鬆症的發生，定期接受骨質密度檢測，必要時依據醫
師的指示服用藥物，配合飲食和運動，才是預防及治療
骨鬆症的不二法門。
HLJ
2005.09.03
中國時報
謝謝聆聽
HLJ
請多指教