OSTEOPOROSIS
Systematic literature search to December 2000 plus some key references from 2001
OSTEOPOROSIS |
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Systematic literature search to December 2000 plus some key references from 2001 |
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3: Interventions for the Primary Prevention of Bone Mineral Loss and Osteoporosis in Women
| Primary
prevention is defined as prevention in women and men within normal BMD
range, ie within one standard deviation of the young adult reference meani. i. World Health Organisation. Assessment of Fracture Risk and its Application to Screening for Postmenopausal Osteoporosis. WHO Technical Report Series 843. Geneva: WHO, 1994 (Type V evidence expert concensus opinion based on a review of the literature) |
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| The Statements | The Evidence | |
3.1 Pre and
Perimenopausal Women
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| 3.1a. Exercise programmes
may have a positive impact in premenopausal women. The weighted treatment
effects of 4 randomised controlled trials showed that exercise training
programmes prevented or reversed almost 1% bone loss per year in both
lumbar spine and femoral neck in premenopausal women. The overall
treatment improvements in BMD were 0.91% (95% CI, 0.44-1.37)
per annum in the lumbar spine and 0.90% (95% CI, 0.29-1.50)
pa in the femoral neck i. (Health gain notation 1 "beneficial") Caveat: Individual studies were small and there were large differences in type, duration, frequency and intensity of the training among different programmes. The overall treatment effects for the controlled trials were almost twice as high as those for the randomised controlled trials. All studies but one analysed only those compliant with exercise, rather than using an intention-to-treat analysis. Thus it was difficult to draw firm conclusions about overall effect and the effect of different types of exercise (high or low impact).
Another review of 8 trials found that exercise programs resulted in 1.5% (95%
CI, 0.6-2.4%) bone loss prevented at the lumbar spine after impact
exercise and 1.2% (95% CI, 0.7-1.7%) after
non-impact exercise. More studies are required to determine the optimal
intensity and type of exercise ii. A systematic review of the effect of exercise for the prevention of low bone mass in young people is underwayiii. |
i. Wolff I, van
Croonenborg JJ, Kemper HCG, Kostense PJ, Twisk JWR. The effect of exercise
training programs on bone mass: a meta-analysis of published controlled
trials in pre- and postmenopausal women. Osteoporosis International 1999;
9(1): 1-12 (Type I evidence systematic review of studies published up to December 1996. Four randomised-controlled trials and three controlled trials looked at premenopausal women most studies did not use an intention-to-treat analysis) ii. Wallace BA, Cumming RG. Systematic review of randomized
trials of the effect of exercise on bone mass in pre- and postmenopausal
women. Calcified Tissue International 2000; 67(1): 10-18 iii. Kemper HCG, Bakker I, van Tulder MW, Kostense PJ,
Courtiex D. Exercise for preventing low bone mass in young males and
females (Protocol). Cochrane Database of Systematic Reviews. Cochrane
Library 2001, Issue 4 |
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| 3.1b. From
the results of one small trial, soy isoflavones attenuated bone
loss from the lumbar spine in perimenopausal women. Compared to control,
isoflavone rich soy had a positive effect on BMD and bone mineral content
(BMC) of 5.6% (p=0.023) and 10.1% (p=0.0032) respectively i (Health gain notation 4 "unknown") Caveat: A small trial with various potential confounders which may be of interest as a pilot study. |
i. Alekel DL, St
Germain A, Peterson CT, Hanson KB, Stewart JW, Toda T. Isoflavone-rich soy
protein isolate attenuates bone loss in the lumbar spine of perimenopausal
women. American Journal of Clinical Nutrition 2000; 72(3):
844-852 (Type II evidence 24 week randomised controlled trial of 69 perimenopausal women assigned to isoflavone-rich soy (SPI+, n=24), isoflavone-poor soy (SPI-, n=24) or whey (control, n=21) protein. All subjects received a supplement of 160 mg calcium daily) |
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3.2
Postmenopausal Women (within
normal BMD range)
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| 3.2a. A
calcium supplement of 750 mg/day prevents loss of BMD, reduces
femoral medullary expansion, secondary hyperparathyroidism, and high bone
turnoveri. (Health gain notation 1 "beneficial") A supplement of 15 micrograms/day vitamin D3 was less effective, and because its effects are seen only at low calcium intakes, this suggests that its beneficial effect is to reverse calcium insufficiency. There was no significant difference in fracture rates between groups. Gastrointestinal symptoms, mainly constipation, caused 12 subjects to drop out and 10 of these were taking the calcium supplementi. A systematic review to determine the effectiveness of concurrent vitamin
D and calcium, and vitamin D supplementation alone on bone loss in
healthy post-menopausal women is currently underwayii. |
i. Peacock M, Liu G,
Carey M et al. Effect of calcium or 25OH vitamin D3
dietary supplementation on bone loss at the hip in men and women over the
age of 60. Journal of Clinical Endocrinology & Metabolism 2000;
85(9): 3011-3019 (Type II evidence 4 year randomised controlled trial of 316 women (mean age 73.7 years) and 122 men (mean age 75.9 years). Subjects were randomised to 750 mg calcium or 15 micrograms 250H vitamin D3. Baseline median calcium intake was 546 mg/day and median serum 25OH vitamin D3 was 59 nmol/litre. Low BMD or skeletal fracture were not reasons for exclusion from this study. An intention-to-treat analysis was used) ii. Papadimitropoulos E, Shea B,
Wells G et al. Vitamin D with or without calcium for treating
osteoporosis in postmenopausal women. (Protocol) Cochrane Database of
Systematic Reviews. Cochrane Library 2001 Issue 4 |
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| 3.2b. Calcium
supplementation slows the rate of bone loss
significantly only in the first year of treatmenti. (Health gain notation - 2 "likely to be beneficial") A cost-effectiveness analysis in the United States suggested that it was cost-effective to give 34 months of calcium supplementation to women aged 75 years or over. If, as the published studies suggest, shorter periods of supplementation result in an equivalent reduction in the risk of hip fractures, calcium supplementation, for 14 months, becomes cost-effective for adults aged 65 years or overii. A systematic review to determine the effectiveness of calcium supplementation on bone loss and fracture rates in postmenopausal women is currently underway. Subgroups will include early postmenopausal women and those who have already sustained a fractureiii. |
i. Mackerras D,
Lumley T. First and second year effects in trials of calcium
supplementation on the loss of bone density in postmenopausal women. Bone
1997; 21(6): 527 - 533 (Type I evidence - systematic review and meta-analysis of 8 randomised controlled trials and 999 subjects) ii. Bendich A, Leader S, Muhuri P.
Supplemental calcium for the prevention of hip-fracture: potential
health-economic benefits. Clinical Therapeutics 1999: 21(6):
1058-1072 iii. Shea B, Tugwell P, Wells G,
Cranney A, Adachi R et al. Calcium for treating osteoporosis in
postmenopausal women. (Protocol) Cochrane Database of Systematic Reviews. Cochrane
Library 2001, Issue 4 |
|
Among 370 women who complied with 5 years of
treatment, lumbar BMD had increased by 1.5% in the HRT and by 1.8% in the
HRT + vitamin D group with a plateau after 2.5 years, whereas it had
decreased by 4.6% and 4.7% in the vitamin D and placebo groups. A positive
long-term effect of HRT on BMD was also seen in the intention-to-treat
analysis i. |
i. Komulainen M,
Krφger H, Tuppurainen MT et al. Prevention of femoral and lumbar
bone loss with hormone replacement therapy and vitamin D3 in
early postmanopausal women: a population-based 5-year randomized trial. Journal
of Clinical Endocrinology and Metabolism 1999; 84(2): 546-552 (Type II evidence randomised controlled trial of 464 women from the Kuopio Osteoporosis Study aged 52-53 years. Women were randomised to 1) HRT (sequential combination of 2 mg estradiol valerate and 1 mg cyproterone acetate days 12-21. Treatment free days 22-28); 2) Vitamin D3, 300 IU per day and 100 IU per day in final year; 3) HRT and vitamin D3 combined; or 4) placebo) ii. Hunter D, Major P, Arden N et
al. A randomized controlled trial of vitamin D supplementation on
preventing postmenopausal bone loss and modifying bone metabolism using
identical twin pairs. Journal of Bone and Mineral Research 2000; 15(11):
2276-2283 |
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| 3.2d. Estrogen
replacement therapy (HRT) (either sequential
or continuous) maintains or improves bone density in
post-menopausal womeni,ii,iii,iv,v. (Health gain notation 2 "likely to be beneficial") A meta-analysis of randomised controlled trials of current HRT use noted a significant reduction in nonvertebral fractures. However, the effect may be attenuated in older women. There was an overall 27% reduction in nonvertebral fractures in a pooled analysis (reduction favouring HRT, Relative Risk (RR) = 0.73, 95% CI 0.56-0.94, p=0.02)). This effect was greater among women who had a mean age younger than 60 years (RR=0.67, 95% CI 0.46-0.98, p=0.03). Among women with a mean age of 60 years or older, there was a reduced effect (RR=0.88, 95% CI 0.71-1.08, p=0.22)iii. In a subsequent letter, the authors updated the analysis with results from three further trials to give a pooled RR for all 25 trials of 0.79 (95% CI 0.63-0.99). For women under age 60 the RR=0.67 (0.51-0.88) and for women over age 60 the RR=0.91 (0.76-1.10)iv. Caveat: Fractures due to any cause were included in the analysis and they may not all have been defined as osteoporotic. A further meta-analysis noted a significant reduction in vertebral fractures associated with current HRT use. Overall, there was a 33% reduction (95% CI 45%-98%). In this study, the pooled relative risks for vertebral fracture in women under and over the age of 60 were similar. The relative risk for vertebral fracture in the ten trials of women without osteoporosis (6513 subjects) was not significant (0.81, 95% CI 0.50-1.33, p=0.40)v. The results of large ongoing randomised controlled trials should resolve the question as to whether HRT treatment results in a significant reduction in fracture risk. A systematic review to develop estimates of the benefits of primary prevention treatment with HRT taken for long-term in postmenopausal women, on bone density and fractures, is currently underwayvi. |
i. Udoff L,
Langenberg P, Adachi E. Combined continuous hormone replacement therapy: a
critical review. Obstetrics and Gynecology 1995; 86(2): 306
- 316 (Type I evidence - systematic review, Medline only, of 9 randomised controlled trials and 412 patients all studies showed either maintenance or improvement of BMD but significance data were not given) ii. Anonymous. Osteoporosis.
Clinical Guidelines for Prevention and Treatment. London: Royal
College of Physicians, 1999 iii. Torgerson DJ, Bell-Syer SEM.
Hormone replacement therapy and prevention of nonvertebral fractures. A
meta-analysis of randomised trials. Journal of the American Medical
Association 2001; 285(22): 2891-2897 iv. Torgerson DJ, Bell-Syer SEM. A
meta-analysis of hormone replacement therapy for fracture prevention. Journal
of the American Medical Association 2001; 286(17): 2096-2097 v. Torgerson DJ, Bell-Syer SEM.
Hormone replacement therapy and prevention of vertebral fractures: A
meta-analysis of randomised trials. BMC Musculoskeletal Disorders 2001;
2: 7 vi. Tugwell P, Wells G. Shea B et
al. Hormone replacement therapy for osteoporosis in postmenopausal women
(Protocol). Cochrane Database of Systematic Reviews. Cochrane Library 2001,
Issue 4. |
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| 3.2e. Evidence
from observational studies also suggest that HRT therapy
leads to an overall reduction in non-vertebral fractures (but see Statement
3.2d)i,ii. In a case-control study comparing women who had
never used HRT, current users had an odds ratio of 0.35 (95%
CI 0.24-0.53) for hip fracture and former users had an odds ratio
of 0.76 (95% CI 0.57-1.01). For every year of
therapy the overall risk reduced by 6% (95% CI 3%-9%)
and this was greater with regimens with progestin. After five years
without HRT the protective effect was substantially dimished. Oestrogen
treatment with skin patches gave similar risk estimates as oral regimens.
Recent use of HRT is required for optimum fracture protection, but therapy
can be started several years (nine or more) after the menopausei.
A cohort study suggested that it is possible to reduce the number of forearm
fractures and possibly the total number of fractures in recent
postmenopausal women by use of HRT as primary prevention. After adjusting
for age and spinal BMD at the start of the study, the overall fracture
risk was reduced with borderline statistical significance (relative risk,
RR=0.73, 95% CI 0.50-1.05) and forearm fracture risk
was significantly reduced (RR=0.45, 95% CI 0.22-0.90).
Compliance with HRT was 65% after 5 years and there was a statistically
significant overall reduction in fracture risk for these women. The number
of serious adverse events was too small to draw definite conclusionsii. |
i. Michaλlsson K,
Baron JA, Farahmand BY et al. Hormone replacement therapy and risk
of hip fracture: population based case-control study. British Medical
Journal 1998; 316: 1858-1863 http://www.bmj.com/cgi/content/ full/316/7148/1858 [accessed 29.11.01] (Type IV evidence case-control study of 1327 women, aged 50-81, with hip fracture and 3262 randomly selected controls) ii. Mosekilde L, Beck-Nielsen H,
Sψrensen OH et al. Hormonal replacement therapy reduces forearm
fracture incidence in recent postmenopausal women Results of the
Danish Osteoporosis Prevention Study. Maturitas 2000; 36(3):
181-193
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| 3.2f. One
small subgroup study found that response to HRT was independent of
smoking status and low Body Mass Index, two important risk factors for
osteoporosisi.
However, another study found that current smokers (p=0.003)
and women with low body weight (p=0.028) are
at increased risk of poor bone response to early postmenopausal HRT. The
authors concluded that smoking may negate the positive effects of HRT and
slender smokers in particular are candidates for a poor response to HRTii. |
i. Bjarnason NH,
Christiansen C. The influence of thinness and smoking on bone loss and
response to hormone replacement therapy in early postmenopausal women. Journal
of Clinical Endocrinology and Metabolism 2000; 85(2): 590-596 (Type II evidence subgroup analysis of 153 early postmenopausal women from a randomised controlled trial comparing treatments of 1 or 2 mg estradiol with placebo) ii. Komulainen M, Krφger H,
Tuppurainen MT, Heikkinen A-M, Honkanen R, Saarikoski S. Identification of
early postmenopausal women with no bone response to HRT: results of a
five-year clinical trial. Osteoporosis International 2000; 11(3):
211-218 |
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| 3.2g. HRT, especially
long-term use, may be associated with an increased risk of invasive epithelial
ovarian cancer. The relative risk (RR) for women who had ever used HRT
(unopposed estrogen or estrogen+progestin, 10 studies) was 1.15 (95%
CI, 1.05-1.27). For women who had used HRT for more than 10 years
the RR=1.27 (95% CI, 1.00-1.61)i.
The summary relative risk (RR) for endometrial cancer was 2.3 (95% CI, 2.1-2.5) for estrogen users vs non-users with a much higher RR associated with prolonged duration (RR for 10 or more years = 9.5, 95% CI, 7.4-12.3). The summary RR for endometrial cancer remained elevated 5 or more years after discontinuation of unopposed estrogen therapy (RR=2.3, 95% CI, 1.8-3.1). Interrupting estrogen for 5-7 days per month was not associated with a lower risk than daily use. Users of unopposed conjugated estrogen had a greater increase in risk than users of synthetic estrogens. The risk of death from endometrial cancer (4 studies) was elevated among unopposed estrogen users (RR=2.7, 95%CI, 0.9-8.0) ii. Among estrogen plus progestin users, cohort studies showed a decreased risk of endometrial cancer (RR=0.4, 95% CI, 0.2-0.6) whereas case-control studies showed a small increase (RR=1.8, 95% CI, 1.1-3.1) ii. From a more recent case-control study it was estimated that the unopposed
estrogen use, for 5 years, was associated with an adjusted odds ratio (OR)
of developing endometrial cancer of 2.17 (95% CI,
1.91-2.47). This was compared to no increase in risk (OR=1.07, 95%
CI for 10 or more days sequential estrogen-progestins
0.82-1.41 and 95% CI for continuous estrogen-progestins 0.80-1.43)
with estrogen plus progestin regimens. When progestin was given for
less than 10 days the adjusted OR was 1.87 (95% CI,
1.32-2.65). The authors concluded that this sharp distinction
suggests that the extent of endometrial sloughing may play a critical role
in determining endometrial cancer riskiii. |
i. Garg PP,
Kerlikowski K, Subak L, Grady D. Hormone replacement therapy and the risk
of epithelial ovarian cancer: a meta-analysis. Obstetrics &
Gynecology 1998; 92(3): 472-479 Reviewed as: Anonymous. Review: Postmenopausal hormone replacement therapy is associated with increased invasive ovarian cancer, especially after long-term use. ACP Journal Club 1999; 130: 23 (Type IV evidence systematic review of 10 observational studies, 4392 women with ovarian cancer. There was some heterogeneity in the results) ii. Grady D, Gebretsadik T,
Kerlikowske K, Ernster V, Petitti D. Hormone replacement therapy and
endometrial cancer risk: a meta-analysis. Obstetrics and Gynecology 1995;
85(2): 304-313 iii. Pike MC, Peters RK, Cozen W et
al. Estrogen-progestin replacement therapy and endometrial cancer. Journal
of the National Cancer Institute 1997; 89: 1110-1116 |
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| 3.2h. There
is a small increase in the risk of developing breast cancer in
women using HRT and the risk increases with duration of use. Among current
users of HRT or those who ceased use 1-4 years previously, the relative
risk of having breast cancer diagnosed increased by a factor of 1.023 (95%
CI 1.011-1.036, 2p=0.0002) for each year of use; the relative risk
was 1.35 (1.21-1.49, 2p=0.00001) for women who had
used HRT for five years or longer (average duration of use in this group,
11 years). This increase is comparable with the effect on breast cancer of
delaying menopause, since among never-users of HRT the relative risk of
breast cancer increases by a factor of 1.028 (1.021-1.034)
for each year older at menopause. Five or more years after cessation of
HRT use, there was no significant excess of breast cancer overall, or in
relation to duration of usei. (Health gain notation 3 "trade-off between beneficial and adverse effects") |
i. Collaborative
Group on Hormonal Factors in Breast Cancer. Breast cancer and hormone
replacement therapy: collaborative reanalysis of data from 51
epidemiological studies of 52705 women with breast cancer and 108411 women
without breast cancer. Lancet 1997; 350: 1047-1059 (Type IV evidence - systematic review of observational studies)
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| 3.2i. In
contrast to the results from observational studiesi, pooled
data of adverse events in a number of HRT trials do not support the
notion that postmenopausal hormone therapy prevents cardiovascular
eventsii,iii.
The calculated odds ratio for women taking hormones versus those not
taking hormones was 1.39 (95% CI 0.48-3.95) for
cardiovascular events without pulmonary embolus and deep vein thrombosis
and 1.64 (95% CI 0.65-4.18) with themii. Data from unpublished (licensing) trials also support the conclusion that
clinical trials do not result in a beneficial effect of HRT on
cardiovascular eventsiii. Pooled results from a number of trials suggest that estrogen replacement therapy reduces low-density lipoprotein (LDL) cholesterol by 15-19% and increases high-density lipoprotein (HDL) cholesterol by 6-18%iv. The risk of ischaemic stroke due to HRT was assessed as 1.12 (95% CI, 1.01-1.25). A random effects model suggested an increased risk of 18%. In contrast, a significantly reduced risk for haemorrhagic stroke of 35% was noted and there was no significant change in the risk of subarachnoid haemorrhage. No data regarding transdermal estrogen were availablev. Current HRT use is associated with risk of venous thromboembolism (VTE)vi.
The increased risk may be concentrated in new users. The adjusted odds
ratio for VTE in current users of HRT compared with non-users (never-users
and past users combined) was 3.5 (95% CI 1.8-7.0;
p<0.001). The number of extra cases appears to be only one in
about 5000 users per yearvii. Firm clinical recommendations for the use of HRT in primary prevention of cardiovascular disease await the results of ongoing randomised controlled trialsviii. |
i. Stampfer MJ,
Colditz GA. Estrogen replacement therapy and coronary heart disease: a
quantitative assessment of the epidemiological evidence. Preventive
Medicine 1991; 20: 47-63 (Type IV evidence systematic review and meta analysis of 31 case-control, cross-sectional and prospective cohort studies. The authors acknowledged the limitations of the meta-analytic approach to observational studies and adjusted for confounders) ii. Hemminki E, McPherson K. Impact of postmenopausal
hormone therapy on cardiovascular events and cancer: pooled data from
clinical trials. British Medical Journal 1997; 315: 149-153 iii. Hemminki E, McPherson K. Value of drug- licensing
documents in studying the effect of postmenopausal hormone therapy on
cardiovascular disease. Lancet 2000; 355: 566-569 iv. Umland EM, Rinaldi C, Parks SM, Boyce EG. The impact of
estrogen replacement therapy and raloxifene on osteoporosis,
cardiovascular disease, and gynecologic cancers. Annals of
Pharmacotherapy 1999; 33(12): 1315-1328 v. Oger E, Scarabin PY. Hormone replacement therapy in
menopause and the risk of cerebrovascular accident [French]. Annals dEndocrinologie
(Paris) 1999; 60(3): 232-241 vi. Anonymous. Osteoporosis. Clinical Guidelines for
Prevention and Treatment. London: Royal College of Physicians, 1999 vii. Daly E, Vessey MP, Hawkins MM, Carson JL, Gough P, Marsh S.
Risk of venous thromboembolism in users of hormone replacement therapy. Lancet
1996; 348: 977-980 viii. Mosca L, Collins P, Herrington DM et al. Hormone
replacement therapy and cardiovascular disease. A statement for healtcare
professionals from the American Heart Association. Circulation 2001;
104: 499-503 |
|
During an average follow-up of 4.1 years, treatment with HRT did not reduce the overall rate of CHAD events in postmenopausal women with established coronary disease. The treatment increased the rate of venous thromboembolic events (relative hazard = 2.89, 95% CI 1.50-5.58). There were more CHD events in the hormone group than the placebo group during year one but fewer in years 4-5i. A recent trial found that neither estrogen alone, nor estrogen plus medroxyprogesterone acetate affected the progression of coronary atherosclerosis in women with established diseaseii. Estradiol does not reduce mortality or the recurrence of stroke in postmenopausal women with cerebrovascular disease (relative risk in the estradiol group = 1.1, 95% CI 0.8-1.4)iii. The women randomly assigned to estrogen therapy had a (non-significant) higher risk of fatal stroke (RR=2.9, 95% CI 0.9-9.0), and their non-fatal strokes were associated with slightly worse neurologic and functional deficitsiii. The American Heart Association recommend that HRT should not be initiated for the secondary prevention of cardiovascular diseaseiv. |
i. Hulley S, Grady D,
Bush T et al. Randomised trial of estrogen and progestin for
secondary prevention of coronary heart disease in postmenopausal women. Journal
of the American Medical Association 1998; 280: 605-613 (Type II evidence the HERS randomised controlled trial of 2763 women with coronary disease, younger than 80 years and postmenopausal with an intact uterus. The mean age was 66.7 years. Women were assigned to 0.625 conjugated equine estrogens plus 2.5 mg medroxyprogesterone acetate daily or placebo. 82% of those assigned hormone treatment were taking it at the end of one year and 75% at the end of three years. An intention-to-treat analysis was used) ii. Herrington DM, Reboussin DM,
Brosnihan KB et al. Effect of estrogen replacement on the
progression of coronary artery atherosclerosis. New England Journal of
Medicine 2000; 343(8): 522-529 iii. Viscoli CM, Brass LM Kernan
WN, Sarrel PM, Suissa S, Horowitz RI. A clinical trial of
estrogen-replacement therapy after ischemic stroke. New England Journal
of Medicine 2001; 345(17): 1243-1249 iv. Mosca L, Collins P, Herrington
DM et al. Hormone replacement therapy and cardiovascular disease. A
statement for healtcare professionals from the American Heart Association.
Circulation 2001; 104: 499-503 |
|
| 3.2k. Primary care
guidance for the use of HRT is availablei,ii. Caveat: This does not include all the latest studies (see Statements above) |
i. Welsh
Medicines Resource Centre. Hormone replacement therapy I: The benefits and
risks. WeMeReC Bulletin 2000; 8(2): 1-4 (Type V evidence expert opinion) ii. Welsh Medicines Resource Centre. Hormone replacement therapy II: Selecting and prescribing therapy. WeMeReC Bulletin 2000; 8(3): 1-6 (Type V evidence expert opinion) |
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| 3.2l. Transdermal
estradiol (combined with oral dydrogesterone)
is effective and well-tolerated at dosages between 25-75 m g/di,ii (Health gain notation 1 "beneficial") At two years, the difference versus placebo in percentage change from baseline of lumbar spine BMD was 4.7±0.7% with estradiol @ 25m g/d, 7.3±0.7% at 50m g/d, and 8.7±0.7% at 75m g/d i. In another trial patches delivering 17beta-estradiol were well-tolerated and highly effective. At 2 years, the difference from placebo in percentage change from baseline of L1-4 spine BMD was 6.2%, 7.6% and 7.8% for 50, 75 and 100 m g/d. 50 m g/d (the lowest dose tested) was considered a suitable dose but less effective than 75m g/d. There was little clinical benefit from increasing the dosage from 75 to 100 m g/d ii. Transdermal 17beta-estradiol (E2) at doses of 25, 50, 60 and 100 m g/d for 24 months resulted in mean increases in bone mineral density of the lumbar spine of 2.37%, 4.09%, 3.28% and 4.70%. All increases, of spine and hip BMD, were statistically significant compared to placebo where lumbar spine BMD was decreased by 2.49%iii. |
i.
Cooper C, Stakkestad JA, Radowicki S et al. For the International
Study Group. Matrix delivery transdermal 17beta-estradiol for the
prevention of bone loss in postmenopausal women. Osteoporosis
International 1999; 9: 358-366 (Type II evidence randomised controlled trial of 277 early postmenopausal women with an assured calcium intake of 1g/d. Patients were allocated to one of four therapeutic groups: Transdermal 17 beta-estradiol patches delivering 25, 50 or 75 microg/d or placebo. Non-hysterectomised patients also received oral dydrogesterone 10 mg or placebo) ii. Delmas PD, Pornel B, Felsenberg D et al. For the International Study Group. A dose-ranging trial of a matrix transdermal 17beta-estradiol for the prevention of bone loss in early postmenopausal women. Bone 1999; 24: 517-523 (Type II evidence randomised controlled trial of 292 women with natural or surgical menopause for 1-6 years randomised to receive patches delivering17beta-estradiol twice weekly for 25 days per 28 day cycle (with dydrogesterone 10mg twice daily from days 11 to 24) or placebo. All women had an assured calcium intake of at least 1g/d) iii. Weiss SR, Ellman H, Dolker M. A randomized controlled trial of four doses of transdermal estradiol for preventing postmenopausal bone loss. Obstetrics and Gynecology 1999; 94(3): 330-336 (Type II evidence randomised controlled trial of 175 postmenopausal women without uteri. Only 97 women (55%) completed two-years of treatment but an intention-to-treat analysis was carried out) |
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| 3.2m. In
a small trial, tibolone (2.5 mg/d) was found to be an effective and
well-tolerated alternative to estrogen in preventing BMD loss. At 96
weeks, BMD for treatment vs control groups at the lumbar spine was +3.67
vs 0.94 (p<0.001), at the neck of femur:
+0.78 vs 3.94 (p<0.001), at Wards triangle:
+1.99 vs 3.51 (p<0.001) and at trochanter:
+3.82 vs 0.57 (p<0.01). Four women in the treated
and two in the control group withdrew due to adverse events. Vaginal
bleeding occurred in seven women, all from the tibolone treated groupi. Caveat : This was a small trial and a large prospective and controlled study is now required. |
i. Beardsworth SA,
Kearney CE, Purdie DW. Prevention of postmenopausal bone loss at lumber
spine and upper femur with tibolone: A two-year randomised controlled
trial. British Journal of Obstetrics and Gynaecology 1999; 106(7):
678-683 (Type II evidence randomised controlled trial of 47 healthy postmenopausal women, 42 were included in an intention-to-treat analysis)
|
|
| 3.2n. Exercise
may help maintain bone density in post-menopausal women i,ii. (Health gain notation - 2 "likely to be beneficial") Exercise programmes have a positive impact in postmenopausal women. 1.6% (95% CI, 1.0-2.2%) bone loss was prevented at the lumbar spine after impact exercise and 1.0% (95% CI, 0.4-1.6%) after non-impact exercise ii. More studies are required to determine the optimal intensity and type of exercise. Caveat: As noted by the authors, individual studies were small and had significant heterogeneity and some high drop out rates. No unpublished studies were included and publication bias may also be a problem. The weighted treatment effects of 25 randomised controlled trials showed that exercise training programmes prevented or reversed almost 1% bone loss per year in both lumbar spine and femoral neck in postmenopausal women iii. Overall treatment effects for the randomised controlled trials on lumbar
spine BMD were 0.96 (95% CI, 0.43-1.49) for
endurance training, 0.44 (95% CI 0.32-1.21) for
strength training and 0.79 (95% CI 0.35-1.22) for
strength and endurance training. For femoral neck BMD the overall
treatment effects were 0.90 (95% CI, 0.29-1.51),
0.86 (95% CI 0.18-1.91) and 0.89 (95%
CI 0.36-1.42) respectively iii. A systematic review of the benefits of exercise for preventing and treating osteoporosis in post-menopausal women, using bone density and fractures as outcomes, is currently underwayiv. |
i. Kelley GA.
Exercise and regional bone mineral density in post-menopausal women. A
meta-analytic review of randomized trials. American Journal of Physical
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Health Evidence Bulletins: Wales, Duthie Library, UWCM, Cardiff CF14 4XN. e-mail: weightmanal@cardiff.ac.uk