OSTEOPOROSIS
Systematic literature search to December 2000 plus some key references from 20
OSTEOPOROSIS |
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Systematic literature search to December 2000 plus some key references from 20 |
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Because of the large amount
of overlap within and between studies, the research described in this
chapter covers postmenopausal women
Interventions have been ordered according to the balance of evidence, from randomised controlled trials, for their anti-fracture efficacy in postmenopausal womeniii. Information concerning the status of the participants in individual studies is provided in the statements (eg BMD values). The effect of treatment on both BMD changes and fracture outcomes are provided for completeness but it should be stressed that fracture data are the clinically important outcomes. i. World Health Organisation. Assessment
of Fracture Risk and its Application to Screening for Postmenopausal
Osteoporosis. WHO Technical Report Series 843. Geneva: WHO, 1994 |
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| 4.1. Established efficacy
against vertebral and non-vertebral fractures:
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| The Statements | The Evidence | ||||
| 4.1a. Alendronate prevents
early postmenopausal bone lossi.ii. (Health gain notation - 2 "likely to be beneficial") Four years treatment with alendronate (5mg/d) increased BMD by 3.8±0.3% at the spine, 2.9±0.2% at the hip and 0.9±0.2% in the total body. During this period, BMD in the placebo group decreased by 1-6% (p<0.001). A residual effect was seen 2 years after alendronate therapy was stopped; however, continuous alendronate treatment was more effective in preventing postmenopausal bone loss than 2 years of alendronate followed by 2 years of placeboi. Adverse events, including gastrointestinal events, were similar across all treatment groups. Caveat: Estrogen-medroxyprogesterone acetatate produced similar increases and estradiol-norethisterone acetate produced increases that were substantially greater at all skeletal sites. No formal comparison of the two estrogen-progestin regimens was carried out because of the generic differences in the drugs and environmental differences in US and European centres. Two different regimens of alendronate (5mg/day for 5 years or 20 mg/day for 2 years followed by 3 years off therapy) prevented postmenopausal bone loss. 5 mg alendronate for 5 years increased BMD at the spine and trochanter by 2.5-3.2% and stabilised BMD in the total body and femoral neck. After withdrawal of adendronate (20mg) bone loss resumed at the normal early postmenopausal rate of 0.5-2.0% per yearii. |
i. Ravn P, Bidstrup
M, Wasnich RD et al. Alendronate and estrogen-progestin in the
long-term prevention of bone loss: four-year results from the early
postmenopausal intervention cohort study. A randomized, controlled trial. Annals
of Internal Medicine 1999; 131: 935-942 (Type II evidence randomised controlled trial of 1609 postmenopausal women, 45-59 years of age, randomly assigned to 2.5 or 5 mg/d alendronate, placebo or open-label estrogen-progestin (two-types) the EPIC study. Advice regarding adequate calcium intake was given to all women. An intention-to-treat analysis was carried out on the 1404 participants who received the same treatment over 4 years) ii. Ravn P, Weiss SR, Rodriguez-Portales JA et al. Alendronate
in early postmenopausal women: effects on bone mass during long-term
treatment and after withdrawal. Alendronate Osteoporosis Prevention Study
Group. Journal of Clinical Endocrinology and Metabolism 2000; 85(4):
1492-1497
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| 4.1b. For
postmenopausal women with low bone mass or osteoporosis, alendronate produced
a significant reduction in the risk of vertebral fracturei,ii. (Health gain notation - 1 "beneficial") The relative risk for new, radiographically defined, vertebral fractures in the alendronate vs placebo group was 0.53 (95% CI 0.41-0.68). The relative hazard for clinically apparent vertebral fractures was 0.45 (95% CI 0.27-0.72) and for any clinical fracture was 0.72 (95% CI 0.58-0.90). There was no significant difference between the groups in numbers of adverse experiences including upper-gastrointestinal disordersi. In the second part of this study, alendronate at 5 mg for 2 years
and 10 mg for the remainder of a 4 year trial (an average of 4.2 years)
was well tolerated and showed significant treatment benefits for women
compared to control at the femoral neck (mean 4.6%, p<0.001),
total hip (mean 5.0%, p<0.001) and lumbar spine
(mean 6.6%, p<0.001). Overall, alendronate
reduced the risk of new radiographic vertebral factures by 44% (Relative
risk, RR=0.56, 95% CI, 0.39-0.80. NNT=60).
Alendronate reduced clinical fractures by 36% for women with baseline
osteoporosis at the femoral neck (relative hazard, RH=0.64, 95%
CI 0.50-0.82, NNT=15) but the overall reduction in clinical
fractures was not significant ii. |
i.
Black DM, Cummings SR, Karfp DB et al. Randomised trial of effect
of alendronate on risk of fracture in women with existing vertebral
fractures. Fracture Intervention Trial Lancet 1996; 348:
1535-1541 (Type II evidence Three year randomised controlled trial of 2027 women, aged 55-81 and at least 2 years postmenopausal, with low femoral neck BMD and an existing vertebral fracture. Subjects were assigned to placebo or alendronate (5 mg/day for 24 months, increased to 10 mg/day for the remainder of the study. Follow-up radiographs were obtained for 1946 women (98% surviving participants). Subjects reporting a calcium intake of 1000 mg/day or less received a supplement of 500 mg calcium and 250 IU cholecalciferol.) ii. Cummings SR, Black DM, Thompson DE et al. Effect
of alendronate on risk of fracture in women with low bone density but
without vertebral fractures Results from the Fracture Intervention
Trial. Journal of the American Medical Association 1998; 280:
2077-2082 |
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| 4.1c. For
postmenopausal women with low bone mass or osteoporosis, alendronate produced
a significant reduction in the risk of nonvertebral fracturei,ii. (Health gain notation - 1 "beneficial") In a meta-analysis of early studies, a 29% reduction in the risk of non-vertebral fracture in patients treated with 2.5 mg or more alendronate per day for 2 years or more was observed (relative risk = 0.71; 95% CI 0.502-0.997). The authors noted that this result may be an underestimate of the potential effect of 10 mg/day alendronate, the currently marketed dosei. In a larger, more recent trial, at 12 months, mean increases in BMD were significantly greater in the alendronate (10 mg/day) than the placebo group by 4.9% (95%CI, 4.6-5.2%) at the lumbar spine, 2.4% (95%CI, 2.0-2.8%) at the femoral neck, 3.6% (95%CI, 3.2-4.1%) at the trocanter and 3.0% for the total hip (95%CI, 2.6-3.4%). The incidence of non-vertebral fractures was significantly lower in the treatment group representing a 47% risk reduction (95% CI, 10-70%). Incidences of adverse events, including upper gastrointestinal adverse events, were similar in the two groupsii. |
i. Karpf DB, Shapiro
DR, Seeman E et al. Prevention of nonvertebral fractures by
alendronate: a meta-analysis. Journal of the American Medical
Association 1997; 227: 1159-1164 (Type II evidence - meta-analysis of five prospective randomised controlled trials, 1602 women aged 42-85 years and postmenopausal for at least 4 years. Subjects had a lumbar spine BMD at least two standard deviations below the normal young adult mean. All women were screened for vitamin D deficiency, given supplements if necessary, and received 500 mg calcium daily during the study. All data were analysed using an intention-to-treat approach) ii. Pols HAP, Felsenberg D, Hanley DA et al. Fozamax
International Trial Study Group. Multinational, placebo-controlled,
randomized trial of the effects of alendronate on bone density and
fracture risk in postmenopasual women with low bone mass: Results of the
FOSIT study. Osteoporosis International 1999; 9: 461-468 |
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| 4.1d. Reductions in fracture risk during treatment with alendronate are consistent in women with existing vertebral fractures and in those without vertebral fracture (but with BMD in the osteoporosis range). The relative risks (95% CI) for fractures were as follows: hip RR=0.47 (0.26-0.79); radiographic vertebral RR=0.52 (0.42-0.66); clinical vertebral RR=0.55 (0.36-0.82) and all clinical fractures RR=0.70 (0.59-0.82). A reduction in risk for clinical fractures was significant 12 months into the triali. | i. Black DM, Thompson
DE, Bauer DC et al. Fracture risk reduction with alendronate in
women with osteoporosis: The Fracture Intervention Trial. Journal of
Clinical Endocrinology & Metabolism 2000; 85(11): 4118-4124 (Type II evidence randomised controlled trial of alendronate treatment for 3-4 years using pooled data on 3658 women (aged 55-80) with existing vertebral fracture, or with T score of less than 2.5 at the femoral neck (but no vertebral fracture). Alendronate dosage was 5 mg/d for two years, then 10 mg/d for the remainder of the study) |
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| 4.1e. Long-term
alendronate treatment is effective.
Increases in spinal BMD continued for at least 7 years (by 11.4% compared
to baseline for 10mg/d alendronate) and other skeletal benefits are
maintained. Discontinuation does not lead to accelerated bone loss, but
continuous treatment yields better skeletal benefits than shorter
treatment. The safety and tolerability profile were similar to those of
placebo i. (Health gain notation - 4 "unknown") Caveats: Women were self-selected. No data were found on withdrawals other than those due to adverse events and unclear whether an intention-to-treat analysis was used. It is unknown whether treatment beyond five years is necessary to maintain a reduction in fractures. Research in this area is very limited. |
i. Tonino RP, Meunier
PJ, Emkey R et al. Skeletal benefits of alendronate; 7-year
treatment of postmenopausal osteoporotic women. Phase III Osteoporosis
Treatment Study Group. Journal of Clinical Endocrinology &
Metabolism 2000; 85(9): 3109-3115 (Type II evidence a second 2-year extension of a clinical trial among postmenopausal women. 235 women (mean age, 63 years) continued blinded treatment with 5 or 10 mg alendronate daily, and 115 women who had been treated with alendronate for 5 years switched to blinded placebo. The mean spinal BMD was 0.71 (SD=0.08) g/cm2 and 21% had existing vertebral fractures at baseline. All patients received 500 mg/day calcium) |
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| 4.1f. In
postmenopausal women with preexisting vertebral fracture, alendronate
therapy for 3 years reduced the number of days of bed disability and days
of limited activity caused by back pain. Women receiving alendronate
reported an average of 3.2 fewer days of bed rest (p=0.001)
and 11.4 fewer days of limited activity (not including days of bed rest)
because of back pain (p=0.04) during the three-year
follow-up than those receiving placebo. The Relative Risk vs placebo for 1
or more rest days was 0.68 (95% CI 0.53-0.87)), 7 or
more bed-rest days (RR=0.44 (95% CI 0.30-0.64)), and
7 or more limited-activity days (RR=0.87 (95% CI 0.76-0.99)).
There were no statistically significant differences between treatment
groups in the frequency of days of back pain or increases in back-related
disability i. (Health gain notation - 1 "beneficial") |
i. Nevitt MC,
Thompson DE, Black DM et al for the Fracture Intervention Trial
Research Group. Effect of alendronate on limited-activity days and
bed-disability days caused by back pain in postmenopausal women with
existing vertebral fractures. Archives of Internal Medicine 2000; 160(1):
77-85 (Type II evidence randomised controlled trial of 2027 postmenopausal women, aged 55-81 years, with low femoral neck density and a preexisting vertebral fracture. Women received alendronate at 5 mg/day for the first two years and 10 mg/day for the third year)
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| 4.1g. In older women, upper GI tract complaints, particularly dyspepsia and abdominal pain, were common. The overall incidence of upper GI events was similar in the alendronate and placebo groups (47.5% vs 46.2%; Relative Risk, RR=1.02; 95% CI 0.95-1.10). Esophageal events occurred in 10.0% and 9.4% of patients in the alendronate and placebo groups respectively (RR=1.06; 95% CI 0.91-1.24). Esophagitis not reported as reflux was more common in the alendronate group (0.7%) than in the placebo group (0.4%), but not significantly so (RR=1.71; 95% CI 0.90-3.39). Thus, alendronate treatment was not associated with an increased incidence of upper GI tract events, even in high-risk subgroups i. | i. Bauer DC, Black D,
Ensrud K et al. Upper gastrointestinal tract safety profile of
alendronate: the Fracture Intervention Trial. Archives of Internal
Medicine 2000; 160(4): 517-525 (Type II evidence adverse event analysis of a 3-year randomised controlled trial (mean follow-up of 3.8 years) of 6459 women with low bone mineral density, aged 54-81 years, allocated to 5mg/day alendronate or placebo. After 2 years the alendronate dose was increased to 10 mg/day) |
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| 4.1h. In
phase III trials, alendronate at 5 mg or 10 mg a day was well tolerated,
with no increase relative to placebo in the incidence or overall adverse
experiences. The incidence of upper gastrointestinal adverse experiences,
overall, was similar among alendronate 5 mg or 10 mg and placebo, with
abdominal pain and dysphagia being the only individual adverse experiences
that were significantly increased (with alendronate 10 mg). Esophageal
adverse experiences were uncommon, being reported in 8 (2.0%) patients
receiving placebo and 9 (4.6%) patients taking alendronate at 10 mg/day.
None of the events occurring on alendronate therapy were serious or
resulted in discontinuation. Tolerability was not affected by a wide range of concomitant medications including nonsteroidal anti-inflammatory drugs. Additional analyses of the 2027 postmenopausal women with vertebral fractures enrolled in FIT demonstrated that alendronate use was not associated with a significant increase in upper GI events, esophageal events, or gastroduodenal adverse events, even among women at high risk for upper GI complications (those older than 75 years, those with previous upper-GI disease or those using NSAIDs). Esophageal adverse experiences (including esophagitis and esophageal ulcers) have been reported with alendronate in postmarketed use. The authors concluded that a high proportion of these reports involved patients who did not follow the dosing instructions, and probably relate to the irritant potential of refluxed gastric acid containing alendronatei. |
i. Watts N, Freedholm
D, Daifotis A. The clinical tolerability profile of alendronate. International
Journal of Clinical Practice 1999; Suppl. Issue 10: 51-61 (Type II/IV evidence adverse event reports from two phase III trials (994 women treated for up to 3 years), the Fracture Intervention Trial (FIT, 2027 women), an endoscopy study and postmarketing experience. Two authors were based at Merck Research Laboratories, New Jersey. No statistical analysis was carried out on the results.)
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| 4.1i. In
older women with established vertebral osteoporosis, twelve months
treatment with continuous alendronate, cyclical alendronate and
cyclical etidronate were effective in terms of the gain in BMD at
the anteroposterior spine and total hip in a comparable treatment
population. These treatments are more effective than calcitriol and were
generally well tolerated. In comparison with calcitriol, the mean changes
in BMD at the spine and hip respectively were greater in the other groups;
continuous alendronate 3.7% (95% CI, 1.4-8.3%), 2.2%
(95% CI, 0.7-4.0%); cyclical alendronate: 2.1% (95%
CI, 1.2-6.4%), 1.2% (95% CI, -0.3-3.0%);
cyclical etidronate: 2.9% (95% CI, 1.9-6.5%), 1.6% (95%
CI, 0.9-3.1%). Continuous alendronate showed a trend toward a
larger gain in BMD and greater suppression of bone turnover markers than
the other treatment groups, but had a higher incidence of adverse events
particularly within the older subgroup. Cyclical alendronate offers a
lower adverse event profile and appears to be effective in comparison with
continuous treatment, and may possibly be an alternative in the elderlyi. (Health gain notation - 2 "likely to be beneficial") Further studies are necessary, with fracture end-pointsi. |
i. Sahota O, Fowler
I, Blackwell PJ et al. A comparison of continuous alendronate,
cyclical alendronate and cyclical etidronate with calcitriol in the
treatment of postmenopausal vertebral osteoporosis: A randomized
controlled trial. Osteoporosis International 2000; 11(11):
959-966 (Type II evidence 12 month open-label randomised controlled trial of 140 postmenopausal women (aged 60-82 years) with established vertebral osteoporosis. Treatment regimens were as follows: Continuous alendronate (10 mg/day); cyclical alendronate (10 mg, once daily, in three-monthly cycles on/off); cyclical etidronate (400 mg/day for 14 days followed by calcium carbonate, 1.25 g (equivalent to 500 mg calcium) for 76 days, continuing three-monthly cycles); calcitriol (25 ng twice daily). Patients with vitamin D insufficiency were excluded from the study and further vitamin D and calcium supplementation (apart from the etidronate group) were not given. An intention-to-treat analysis was not used.)
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| 4.1j. One
small trial suggested that intermittent alendronate at low doses is
very well accepted, and is able to significantly increase BMD at the spine
and femoral neck and to decrease the markers of bone turnover. After 1
year, for the weekly (20mg once per week) and cyclical (10mg daily for 1
month in 3) regimens as compared to calcium and vitamin D supplements
alone, significant increases at both the spine (+2.2±2.6 and +2.5±2.9)
and femoral neck (+1.6±4.8 and +1.5±2.2) were observed for the weekly
and cyclical regimens respectivelyi. Caveat: There was no comparison with the licensed dose and a lack of frequent biochemical markers; Thus this study may be misleading. Over 12 months, Alendronate given as 70mg once weekly was as
effective for BMD increase as 35 mg twice weekly and 10mg daily. Mean
increases in lumbar spine BMD were 5.1% (95%CI, 4-8-5.4)
in the once-weekly group versus 5.4% (95%CI, 5.0-5.8)
in the daily group. Clinical fractures, captured as adverse experiences,
were similar among the groups. There were fewer serious upper GI adverse
experiences and a trend toward a lower incidence of esophageal events in
the once-weekly dosing group compared to the daily dosing group. Thus
weekly dosing may provide patients with a more convenient, therapeutically
equivalent alternative to daily dosing, and may enhance complianceii. |
i. Rossini M, Gatti
D, Girardello S, Braga V, James G, Adami S. Effects of two intermittent
alendronate regimens in the prevention or treatment of postmenopausal
osteoporosis. Bone 2000; 27(1): 119-122 (Type II evidence randomised controlled trial of 124 women (age range 52-75 years with at least 7 years since menopause) with osteoporosis and osteopenia but without a history of previous osteoporotic fracture) ii. Schnitzer T, Bone HG, Crepaldi
G et al. Alendronate Once-Weekly Study Group. Therapeutic
equivalence of alendronate 70mg once-weekly and alendronate 10mg daily in
the treatment of osteoporosis. Aging (Milano) 2000; 12(1):
1-12
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| 4.1k. A systematic review to determine the efficacy of alendronate therapy in the treatment of postmenopausal osteoporosis is currently underwayi. | i. Cranney A, Welsh
V, Tugwell P et al. Alendronate for osteoporosis in postmenopausal
women. (Protocol) Cochrane Database of Systematic Reviews. Cochrane
Library 2001, Issue 4 (Type I evidence - systematic review and meta-analysis of randomised controlled trials, including early postmenopausal women without osteoporosis and women with osteoporosis. In progress) |
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| 4.1l. Risedronate (Actonel)
(5mg/d) provided effective and well-tolerated therapy for severe
postmenopausal osteoporosis (2 or more vertebral fractures), reducing the
incidence of new vertebral fractures (by 49% over 3 years compared to
control, p<0.001) and improving bone density. The
risk of non-vertebral fractures was reduced by 33% compared to control
over 3-years (p=0.06). The adverse events profile,
including gastrointestinal events, was similar to the control profile. The
2.5 mg/d risedronate group was discontinued after 2 years because of other
data showing that the 5 mg dose produced a more consistent effect in
increasing BMD while having a similar safety profile to the 2.5 mg dosei. (Health gain notation - 1 "beneficial") In women with at least one vertebral fracture, 5 mg/d risedronate compared with placebo decreased the cumulative incidence of new vertebral fractures by 41% (95% CI, 18-58%) over 3 years (11.3% vs 16.3%, p=.003). The cumulative incidence of non vertebral fractures over 3 years was reduced by 39% (95% CI, 6-61%; 5.2% vs 8.4%; p=0.02). BMD increased significantly compared with placebo at the lumbar spine (5.4% vs 1.1%), femoral neck (1.6% vs 1.2%), femoral trochanter (3.3% vs 0.7%) and midshape of the radius (0.2% vs 1.4%) ii. The overall incidence of adverse events was similar in treatment and placebo groups for both the above studiesiii. Risedronate significantly reduces the risk of hip fracture among
elderly women with confirmed osteoporosis but not among elderly women
selected primarily on the basis of risk factors other than low bone
mineral density. In the group of women with osteoporosis (those 70 to 79
years old) the incidence of hip fracture was 1.9% compared to 3.2% among
those assigned to placebo (relative risk, 0.6, 95% CI
0.4-0.9; p=0.009)iv. In the group of women selected primarily on the basis on
nonskeletal risk factors (those at least 80 years of age) the incidence of
hip fracture was 4.2% among those assigned to risedronate and 5.1% among
those assigned to placebo (p=0.35). The incidence of
adverse events involving the upper gastrointestinal tract was similar
among the women assigned to risedronate and those assigned to placeboiv. |
i. Reginster J-Y,
Minne HW, Sorensen OH et al. Vertebral Efficacy with Risedronate
Therapy (VERT) Study Group. Randomized trial of the effects of risedronate
on vertebral fractures in women with established postmenopausal
osteoporosis. Osteoporosis International 2000; 11(1): 83-91 (Type II evidence randomised controlled trial of 1226 postmenopausal women with two or more prevalent vertebral fractures. All subjects received 1000 mg/d calcium, and 500 IU/d vitamin D if baseline levels were below 40 nmol/l. An intention-to-treat analysis was used) ii. Harris ST, Watts NB, Genant HK et al. for the
Vertebral Efficacy with Risedronate Therapy (VERT) Study Group. Effects of
risedronate treatment on vertebral and nonvertebral fractures in women
with postmenopausal osteoporosis. A randomized controlled trial. Journal
of the American Medical Association 1999; 282(14): 1344-1352 iii. Anonymous. Osteoporosis. Clinical Guidelines for
Prevention and Treatment. London: Royal College of Physicians, 1999 iv. McClung MR, Geusens P, Miller
PD et al; for the Hip Intervention Program Study Group. Effect of
risedronate on the risk of hip fracture in elderly women. New England
Journal of Medicine 2001; 344: 333-340
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| 4.1m. Risedronate
(5mg) increases BMD rapidly and effectively, and is well tolerated in
postmenopausal women with low bone mass, regardless of time since
menopause. At 24 months, lumbar spine BMD increased by 4.1% ±0.35% with
5mg risedronate and 1.4%±0.50% in the 2.5mg group. Increases were also
seen at the trochanter and femoral neck, compared to a decrease in the
placebo group. The study was not powered to detect effect on fractures but
positive trends towards reduction in fracture incidence were recorded. The
tolerability of risedronate was similar to placebo, even in patients with
previous gastrointestinal disorders i. (Health gain notation - 1 "beneficial") |
i. Fogelman I, Ribot
C, Smith R, Ethgen D, Sod E, Reginster JY. Risedronate reverses bone loss
in postmenopausal women with low bone mass: results from a multinational,
double-blind, placebo-controlled trial. BMD-MN Study Group. Journal of
Clinical Endocrinology & Metabolism 2000; 85(5): 1895-1900 (Type II evidence randomised controlled trial of 543 women (up to age 80 and postmenopausal for at least one year) with a mean lumbar spine T-score of 2 or less allocated to risedronate (2.5 or 5 mg per day) or placebo. All subjects received 1g/day calcium. Data were analysed on an intention-to-treat basis) |
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| 4.1n. Targeting higher
risk patients with bisphosphonate therapy is
likely to be cost effective. Based on data suggesting that
alendronate reduces hip fractures by 50% in women with a prior vertebral
fracture and low BMD (see statement 4.1b) about 23 hip fractures per 1,000
women would be prevented. Assuming each hip fracture which occurs in the
community costs about £20,000, then preventing 23 hip fractures would
save £460,000 leaving a net treatment cost of £159,000 per 1,000 womeni. (Health gain notation - 2 "likely to be beneficial") Caveat: All the costings given in these studies will be out of date. For example, costs for BMD scans in three sites in Wales (October 2001) vary from £50-£75ii. Cost savings
for bisphosphonate treatment compared to no treatment to prevent fracture
in a 79 year-old woman with severe vertebral fracture and low BMD at
femoral neck living in the community (hip fracture rate 54 per 1,000
annually) were estimated as follows in an analysis carried out in 2000:
Alendronate - £56.80 per woman; Cyclical etidronate - £70.86 per woman;
Risedronate - £117.75 per womaniii. Two Markov models to estimate treatment costs of women aged 75 years with a previous vertebral fracture (published in abstract form only) suggest that, compared with no therapy, risedronate saves £606iv or £381v per patient to the UK healthcare system, while etidronate saves £375 iv or £231v per patient. A more recent estimate of costs (in 2001) for the same patient group were
a saving of £341.93 per woman for any second generation bisphosphonate (eg
alendronate or risedronate)iii. |
i. Torgerson DJ,
Iglesias CP, Reid DM. The economics of fracture prevention. In Barlow DH,
Francis RM, Miles A (eds). The Effective Management of Osteoporosis. Key
Advances in Clinical Practice Series 2001. London: National Osteoporosis
Society, UeL Centre for Public Health Policy and Health Services Research,
2001 (Type V evidence expert review of economic evaluation studies with some cost estimates calculated by the authors) ii. Personal communication from Dr A. Borg (author). iii. National Osteoporosis Society. Section 4. Is this strategy
cost-effective? In Reducing fractures and osteorporosis in Scotland. A
strategy for Health Boards, Local Health Care Co-operatives, Acute and
Primary Care Trusts. London: National Osteoporosis Society, November
2000 pp. 19-21 iv. Iglesias C, Torgerson D. Is risedronate more cost-effective than etidronate for fracture prevention? A cost-utility analysis. Abstract presented at the 3rd Annual European Conference of the International Society of Pharmacoeconomics and Outcomes Research, 5th November 2000, Antwerp, Belgium. (Abstract only) v. Torgerson D, Bose UK,
Bhattacharyya SK. Rational prescribing in osteoporosis. Abstract in Osteoporosis
International 2000; 11(suppl.5): S18. Abstract.
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| 4.1o. In women with osteoporosis, 12 months of therapy with alendronate (10 mg/d) produced significantly greater increases in BMD of the lumbar spine (5.16% vs. 1.18%, p<0.001), trocanter (4.73% vs. 0.47%, p<0.001) and femoral neck (2.78% vs. 0.58%, p<0.001)and greater decreases in bone turnover than intranasal calcitonin (200 IU/d). Changes in BMD with calcitonin were greater than with placebo at the femoral neck, but were not different from placebo at either the trochanter or lumbar spine. Similar percentages of patients in each group reported an adverse experience during the study i. | i. Downs RW Jr, Bell
NH, Ettinger MP et al. Comparison of alendronate and intranasal
calcitonin for treatment of osteoporosis in postmenopausal women. Journal
of Clinical Endocrinology and Metabolism 2000; 85(5): 1783-1788 (Type II evidence randomised controlled trial of 299 women, at least 5 years postmenopausal and with BMD > two standard deviations below the normal young adult mean. Women were randomised to 10 mg alendronte (n-118), matching alendronate placebo (n=58) or open lable intranasal calcitonin 200 IU daily (n=123). Women with a prevalent vertebral fracture or BMD >4 standard deviations below the normal mean were excluded due to the use of placebo in the study. Patients receiving less than 1000 mg/day dietary calcium had supplements to bring their intake up to at least 1000 mg and all received a vitamin D supplement of 400 IU daily. Analysis was by intention-to-treat) |
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| 4.1p. Addition
of alendronate (10 mg/d) to ongoing hormone replacement therapy
significantly increased BMD at both spine and hip trochanter, and was
generally well tolerated with no significant between-group differences in
upper gastrointestinal adverse events or fractures. Compared with HRT
alone, at 12 months, alendronate plus HRT produced significantly greater
increases in BMD of the lumbar spine (3.6% vs 1.0%, p<0.001)
and hip trochanter (2.7% vs 0.5%, p<0.001) but
the difference at the femoral neck was not significanti. Caveat: An increase in BMD does not necessarily translate into decrease in fracture risk and some concern re over-suppression of bone turnover. (Health gain notation 4 "unknown") The combined use of alendronate and estrogen in postmenopausal women with low bone mass who had undergone hysterectomy produced somewhat larger increases in BMD than either agent alone and was well tolerated. At 2 years, placebo treated patients showed a mean 0.6% loss in lumbar spine BMD, compared with mean increases in women receiving alendronate, conjugated equine estrogen (CEE) or alendronate + CEE of 6.0 % (p<0.001 vs placebo), 6.0% (p<0.001 vs placebo) and 8.3% (p<0.001 vs placebo, p<0.022 vs alendronate)ii. |
i. Lindsay R, Cosman
F, Lobo RA et al. Addition of alendronate to ongoing hormone
replacement therapy in the treatment of osteoporosis: a randomised,
controlled clinical trial. Journal of Clinical Endocrinology and
Metabolism 1999; 84(9): 3076-3081 (Type II evidence randomised controlled trial of 428 postmenopausal women with osteoporosis, who had been receiving HRT for at least one year, randomised to either alendronate (10 mg/day) or placebo. HRT was continued in both groups. Assessed calcium intake was at least 1 g/d and 400 IU vitamin D was provided to all participants) ii. Bone HG, Greenspan SL,
McKeever C et al. Alendronate/Estrogen Study Group. Alendronate and
estrogen effects in postmenopausal women with low bone mineral density. Journal
of Clinical Endocrinology and Metabolism 2000; 85(2): 720-726
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| 4.1q. In
a subgroup of patients (with high bone turnover and/or severe
osteoporosis), specific combination treatments such as HRT with
bisphosphonates, calcitonin or androgens provide additional benefits over
a single drug therapy, in terms of BMD measures i. (Health gain notation 4 "unknown") |
i. Wimalawansa SJ.
Prevention and treatment of osteoporosis: Efficacy of combination of
hormone replacement therapy with other antiresorptive agents. Journal
of Clinical Densitometry 2000; 3(2): 187-201 (Type V evidence expert opinion and summary of nine clinical trials) |
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| 4.1r. Current
use of estrogen appears to decrease the risk for fracture in older
women and women with established osteoporosisi,ii,iii,iv.
In an observational study, after adjustment for potential confounders, current estrogen use was associated with a decrease in the risk for wrist fractures (relative risk, RR, 0.39, 95%CI 0.24-0.64) and for all non spinal fractures (RR, 0.66, 95% CI 0.54-0.80) when compared with no estrogen use. Results were similar for women using unopposed estrogen or estrogen plus progestin, for women younger or older than 75 years of age, and for current smokers or nonsmokersi. A recent meta-analysis of randomised controlled trials of HRT (which included some women with pre-existing low BMD or osteoporosis) noted a statistically significant reduction in nonvertebral fractures. This effect appeared to be greater in women younger than 60 years than in older womenii,iii. (See Statement 3.2d) The relative risk of vertebral fracture in three small studies of women with established osteoporosis (210 subjects in all) was 0.47 (95% CI 0.25-0.89, p=0.02)iv. See also Statements 3.2g 3.2j concerning the influence of HRT on cancer and cardiovascular risks. |
i. Cauley JA, Seeley
DG, Ensrud K, Ettinger B, Black D, Cummings SR. Estrogen replacement
therapy and fractures in older women. Study of Osteoporotic Fractures
Research Group. Annals of Internal Medicine 1995; 122: 17-23 (Type IV evidence prospective cohort study of 9704 ambulatory, non black, women aged 65 or over) ii. 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 iii. 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 iv. 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 |
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| 4.1s. Hormone replacement
therapy has been shown to be cost-effective,
in terms of fracture prevention, for women with menopause before the age
of 50 or prior fractures. The cost per averted fracture for a woman
presenting with a second fracture, aged 57, who has had an early menopause
is estimated as £955. Thus, HRT, targeted to women at highest risk can
actually be cost saving event if there is no cardiovascular benefiti. In another analysis looking at women aged between 50-54 years with a previous hysterectomy (at <50 years) and one or more previous fractures (all fracture rate 35 per 1,000 annually) the additional costs of HRT treatment were estimated as £12.20 per woman, or £678 per fracture avertedii. An analysis carried out in Canada also concluded that, under most circumstances, hormone replacement therapy is cost effective in the treatment of osteoporosisiii. In contrast, in terms of hip fracture risk, hormone replacement
therapy was not judged cost-effective for any age cohort of women with
uterus intact, but is deemed cost-effective in 70+ year old women,
post-hysterectomy, where the risk change for both hip fracture and breast
cancer is highiv. |
i. Torgerson DJ,
Iglesias CP, Reid DM. The economics of fracture prevention. In Barlow DH,
Francis RM, Miles A (eds). The Effective Management of Osteoporosis. Key
Advances in Clinical Practice Series 2001. London: National Osteoporosis
Society, UeL Centre for Public Health Policy and Health Services Research,
2001 (Type V evidence expert review of economic evaluation studies with some cost estimates calculated by the authors) ii. National Osteoporosis Society.
Section 4. Is this strategy cost-effective? In Primary Care Strategy
for Falls and Osteoporosis. London: National Osteoporosis Society,
July 2001 pp. 20-21 iii. Coyle D, Cranney A, Lee KM,
Welch V, Tugwell P. Cost-effectiveness research in osteoporosis. Drug
Development Research 2000; 49(3): 135-140 iv. Zethraeus N, Johannesson M,
Jonsson B. A computer model to analyse the cost-effectiveness of hormone
replacement therapy. International Journal of Technology Assessment in
Health Care 1999; 15(2): 352-365 |
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| 4.1t. The recommendation to use oestrogen for postmenopausal osteoporosis, given both the lack of fracture trials and the rare trials on long-term use of HRT in (late) postmenopausal women is not well supported. Fracture trials could overcome shortcomings of the current level of evidencei. (See also statements 4.1r & 4.2k) | i. Dφren M, Samsioe
G. Prevention of postmenopausal osteoporosis with oestrogen replacement
therapy and associated compounds: Update on clinical trials since 1995. Human
Reproduction Update 2000; 6(5): 419-426 (Type I evidence narrative systematic review of open label and double-blind prospective randomised controlled trials published between 1995 and February 2000. Trials examined oestradiol, CEE, oestriol, ERT, progestogen, progestin, progesterone, tibolone, HRT, raloxifene and tamoxifen) |
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| 4.1u. Continuous low-dose HRT with conjugated equine estrogen (CEE, 0.3 mg/d) and oral medroxyprogesterone (2.5mg/d) combined with adequate calcium and vitamin D provides a bone-sparing effect that is similar or superior to that provided by other higher-dose HRT regimens in elderly women. During 3.5 years of observation, spinal bone mineral density increased by 3.5% (p<0.001) in an intention-to-treat analysis (of subjects who completed at least one year) and by 5.2% among patients with greater than 90% adherence to therapy. This combination is well tolerated by most patients. Most side-effects associated with HRT disappeared within six months i. | i. Recker RR, Davies
KM, Dowd RM, Heaney RP. The effect of low-dose continuous estrogen and
progesterone therapy with calcium and vitamin D on bone in elderly women.
A randomized, controlled trial. Annals of Internal Medicine 1999; 130(11):
897-904 (Type II evidence randomised controlled trial of a convenience sample of 128 healthy white women, aged > 65 years, with low bone mass spinal mineral density of 0.90 g/cm2 or less. 108 subjects completed the trial and the drop-out rate was not significant between treatment and placebo groups (18/64 and 12/64 respectively))
|
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| 4.1v. Treatment of postmenopausal osteoporosis with parathyroid hormone (1-34) decreased the risk of vertebral and nonvertebral fractures; increased vertebral, femoral and total-body BMD; and was well tolerated. The 40΅g dose increased BMD more than the 20΅g dose but had similar effects on the risk of fracture and was more likely to lead to side effects (occasional nausea and headache). The respective relative risks of vertebral fracture in the 20΅g and 40΅g groups, as compared to placebo, were 0.35 (95% CI 0.22-0.55) and 0.31 (95% CI 0.19-0.50) respectively. For nonvertebral fractures these RRs were 0.47 (0.25-0.88) and 0.46 (0.25-0.86) respectivelyi. | i. Neer RM, Arnaud DC, Zanchetta JR et
al. Effect of parathyroid hormone (1-34) on fractures and bone mineral
density in postmenopausal women with osteoporosis. New England Journal
of Medicine 2001; 344: 1434-1441 (Type II evidence randomised controlled trial of 1637 postmenopausal women with prior vertebral fractures to 20΅g or 40΅g parathyroid hormone (1-34) or placebo, administered subcutaneously by the women daily. The duration of treatment was 17±6 to 18±6 months depending on study group. All women received daily supplements of 1000mg calcium and 400-1200IU vitamin D. The average rate of compliance with injections was 79-83% and did not vary between groups. An intention to treat analysis was used. Follow up radiographs were available for 1326 women (81%)) |
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| 4.1w. One
small trial suggested that sequential treatment of osteoporosis with parathyroid
hormone (PTH) and alendronate results in a greater increase in
vertebral density than reported by alendronate or estrogens alone. After switching to alendronate for 1 year in women who had previously received PTH, mean changes in BMD were 13.4±6.4% at the spine, 4.4±7.2% at the femoral neck and 2.6±3.1% for the whole body. Thus, this combination of drugs may be a useful approach to maximizing bone density in women with vertebral osteoporosis i. |
i. Rittmaster RS,
Bolognese M, Ettinger MP et al. Enhancement of bone mass in
osteoporotic women with parathyroid hormone followed by alendronate. Journal
of Clinical Endocrinology and Metabolism 2000; 85(6): 2129-2134 (Type II evidence randomised controlled trial of 66 postmenopausal osteoporotic women treated for 1 year with 50, 75 or 100 ΅g recombinant human PTH or placebo, and then 10 mg alendronate daily for an additional year. Women were aged 50-75, at least 5-years postmenopausal and with a vertebral BMD at least 2.5 standard deviations below the young adult mean) |
||||
| 4.1x. Women who develop a vertebral fracture are at substantial risk for additional fracture within the next year. In an analysis of data from four large osteoporosis treatment trials, the authors found that the presence of one or more vertebral fractures at baseline increased the risk of sustaining a vertebral fracture five-fold during the initial year of study compared to subjects without prevalent vertebral fracture at baseline (relative risk = 5.1, 95% CI 3.1-8.4, p<0.001). The increased fracture risk in the immediate period following a fracture, which applied even though subjects all received calcium and vitamin D supplements, demonstrates the urgency of identification and intervention for this segment of the populationi. | i. Lindsay R, Silverman SL, Cooper C et
al. Risk of new vertebral fracture in the year following a fracture. Journal
of the American Medical Association 2001; 285(3): 320-323 (Type IV evidence analysis of data concerning postmenopausal women who had been assigned to the placebo groups of four large three-year osteoporosis treatment trials, and whose vertebral fracture status was known at entry (n=2725)) |
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| 4.2.
Established efficacy against vertebral fractures:
|
|||||
| 4.2a.
Salmon calcitonin
nasal spray at a dose of 200 IU daily, but not 400 IU, significantly
reduced the risk of new vertebral fractures in postmenopausal women with
osteoporosisi. (Health gain notation - 2 "likely to be beneficial") The 200 IU dose of salmon calcitonin significantly reduced the risk of new vertebral fractures by 33% compared to placebo (Relative Risk, RR=0.67; 95% CI 0.47-0.97). In the 817 women with one to five prevalent vertebral fractures at enrolment, the risk was reduced by 36% (RR=0.64; 95% CI 0.43-0.96). The reductions in vertebral fractures in the 100 IU and 400 IU groups were not significantly different to placebo. The distribution of adverse events was similar among the calcitonin and placebo groups except for a significant increase in rhinitis related to the study drug which occurred in 22% of treated compared to 15 % of placebo participants (p<0.01)i. Caveat: The investigators were not blinded to the BMD results and this may have, in part, explained the high drop out rate. The authors did not propose a theory for the apparently poor response to the 400 IU dose although the lack of dose-response was noted. A systematic review suggested that the relative risk of any fracture for
individuals taking calcitonin, when compared to control was 0.43 (95%
CI, 0.38-0.50) for total number of fractures and
0.74 (95% CI, 0.60-0.93)
when individual patients with fractures, rather than the total number of
fractures, were identified. The separate effects of vertebral and
non-vertebral fractures were of borderline significanceii. |
i. Chesnut III CH,
Silverman S, Andriano K et al. A randomized trial of nasal spray
salmon calcitonin in postmenopausal women with established osteoporosis.
The Prevent Recurrence of Osteoporotic Fractures (PROOF) Study. American
Journal of Medicine 2000; 109(4): 267-276 (Type II evidence five year randomised controlled trial of 1,255 postmenopausal women with established osteoporosis receiving 100, 200 or 400 IU salmon calcitonin or placebo daily. All women received 1g calcium and 400 IU vitamin D daily. Only 41% completed the five year study but rates of discontinuation were similar in all groups. An intention-to-treat analysis was carried out) ii. Kanis JA, McCloskey EV. Effect
of calcitonin on vertebral and other fractures. QJ Medicine 1999; 92:
143-149
|
||||
| 4.2b. Cyclical etidronate
therapy prevents bone loss. A large two year
study of early postmenopausal women found that bone loss in the spine was
increased by 0.14% for etidronate versus a reduction in 1.49% for placeboi.
Results for the femoral neck were -0.06% vs 2.22% and there was no
difference in the greater trochanter or Wards trianglei.
Another smaller study (without an intention-to-treat analysis) suggested
larger treatment effects after 2 years of 2.79% (95% CI
0.47-5.10) for the lumbar spine, 3.23% (95% CI
0.63-5.82) for the femoral neck and 3.77% (95% CI
1.09-6.45) for the greater trochanter ii.
Following the withdrawal of cyclical etidronate therapy (after two years) bone loss resumes at a normal or moderately accelerated rate for the proximal femur and lumbar spine respectively. The mean % change (SEM) for year 2 to year 3 for spinal BMD in the former cyclical etridronate group was 2.87% (0.48%) versus 0.99% (0.36%) in the placebo group. In the femoral neck, the BMD changes were 0.86% (0.42%) versus 1.01% (0.41%). A positive effect on BMD at both cortical and trabecular sites was maintained for one year after treatment withdrawaliii. |
i. Adami S, Bruni V,
Bianchini D et al. Prevention of early postmenopausal bone loss
with cyclical etidronate. Journal of Endocrinological Investigation 2000;
23(5): 310-316 (Type II evidence randomised controlled trial of 107 women who were within 6 months to 3 years of the menopause 77 completed the study. The intervention group received 400 mg etidronate daily for 2 weeks in each 90-day cycle and calcium supplementation for the remaining 76 days. An intention-to-treat analysis was used) ii. Heath DA, Bullivant BG, Boiven
C, Balena R. The effects of cyclical etidronate on early postmenopausal
bone loss: An open, randomized controlled study. Journal of Clinical
Densitometry 2000; 3(1): 27-33 iii. Fogelman I, Herd RJM, Blake
GM, Balena R. Cyclical etidronate therapy for prevention of postmenopausal
bone loss: a 1-year open-lable follow-up study. Calcified Tissue
International 2000; 66(5): 348-354 |
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| 4.2c. A
systematic review showed that both calcitonin and etidronate
increase vertebral bone mineral density in postmenopausal women and
prevent vertebral fracturesi. The existing evidence did not
allow the superiority of either to be established. The aggregated number
of vertebral fractures prevented by the treatment was 59.2 per 1000
patient years (95% CI 55.1-63.3) for calcitonin and
28.3 (95% CI 26.2-30.4) for etidronate. Data in the
studies on hip fracture rates were lacking. Caveat: Treatments with etidronate were more uniform but those with calcitonin varied widely. Adverse events were presented in different ways and were impossible to pool. They were commonly qualified as mild and reversible. A more recent systematic review of randomised controlled trials of
etidronate suggested a reduction in vertebral fractures with a
pooled relative risk of 0.63 (95% CI 0.44 0.92).
A pooled estimate of eight studies showed no statistical difference
between placebo and etidronate for the risk of withdrawal due to side
effectsii. A Cochrane review is in preparationiii. |
i. Cardona JM, Pastor
E. Calcitonin versus etidronate for the treatment of postmenopausal
osteoporosis: a meta-analysis of published clinical trials. Osteoporosis
International 1997; 7(3): 165-174 (Type I evidence systematic review, searching Medline only to 1995, of 24 randomised controlled trials. 4 trials with calciton and 3 with etidronate considered vertebral fractures as an outcome.) ii. Cranney A, Guyatt G, Krolicki
N et al., and the Osteoporosis Research Advisory Group (ORAG). A
meta-analysis of etidronate for the treatment of postmenopausal
osteoporosis. Osteoporosis International 2001; 12: 140-151 iii. Cranney A, Welch V, Tugwell P
et al. Etidronate for treating osteoporosis in postmenopausal
women. (Protocol) Cochrane Database of Systematic Reviews. Cochrane
Library 2001, Issue 4 iv. Cranney A, Shea B, Wells G,
Reginster JY, Adachi R, Tugwell P. Calcitonin for treating osteoporosis in
postmenopausal women. (Protocol) Cochrane Database of Systematic Reviews. Cochrane
Library 2001, Issue 4 |
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| 4.2d. Observational
evidence suggested that cyclic etidronate reduces the risk of
non-vertebral fractures by 20% and hip fracture by 34% relative to control
patients. The relative risk of non-vertebral fracture was 0.80 (95%
CI 0.70-0.92), of hip fracture was 0.66 (95% CI
0.51-0.85) and of wrist fracture was 0.81 (95% CI
0.58-1.14) i.
In contrast, the results of a meta-analysis of randomised controlled trials of etidronate therapy suggested that there was no effect on non-vertebral fractures (relative risk = 0.99, 95% CI 0.69-1.42)ii. |
i. van Staa TP,
Abenhaim L, Cooper C. Use of cyclical etidronate and prevention of
non-vertebral fractures. British Journal of Rheumatology 1998; 37:
87-94 (Type IV evidence data from the General Practice Research Database of 7977 patients taking cyclic etidronate and 7977 age-, sex- and practice-matched controls. Subjects were followed for a mean period of 1.29 years) ii. Cranney A, Guyatt G, Krolicki
N et al., and the Osteoporosis Research Advisory Group. A
meta-analysis of etidronate for the treatment of postmenopausal
osteoporosis. Osteoporosis International 2001; 12: 140-151 |
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| 4.2e. One
small study found that alendronate (for 1.3±0.1 years) increased
bone density at the spine and hip in patients who had not responded to
intermittent cyclical etidronate (for 3.3±0.4 years). After
treatment with 10 mg/d alendronate, bone mineral density increased
significantly at the lumbar spine (4.4±0.7% annualized) i. Caveat: Upper gastrointestinal side effects forced 4 of 25 patients (16%) to discontinue therapy. |
i. Watts NB, Becker
P. Alendronate increases spine and hip bone mineral density in women with
postmenopausal osteoporosis who failed to respond to intermittent cyclical
etidronate. Bone 1999; 24(1): 65-68 (Type III evidence before and after study of 25 women with postmenopausal osteoporosis and no increase in spine bone mineral density after intermittent cyclical etidronate treatment. All women had 500 mg supplementary calcium and 400 IU vitamin D daily) |
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| 4.2f. The results of a Bayesian analysis found that etidronate and alendronate effectively reduce the risk of new vertebral fractures, but alendronate was somewhat more effective. To obtain equal cost-effectiveness alendronate should be priced 40-70% higher than etidronatei. | i. Aursnes I, Storvik
G. Gεsemyr J, Natvig B. A Bayesian analysis of bisphosphonate effects and
cost-effectiveness in postmenopausal osteoporosis. Pharmacoepidemiology
& Drug Safety 2000; 9(6): 501-509 (Type IV evidence cost-effectiveness comparison of etidronate and alendronate, for the prevention of vertebral fractures in postmenopausal women with osteoporosis, using Bayesian statistics, probability distributions and point and interval estimates for key parameters. The authors based their analysis on the results of two randomised controlled trials of alendronate and two of etidronate therapy (3510 women in total)). |
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| 4.2g. In
early postmenopausal women, raloxifene prevents bone loss in the
lumbar spine, proximal femur and total body (mean difference in BMD
between treatment and control groups is between 2% and 3%) and it does not
stimulate the endometriumi.
At 24 months, the mean (±SE) difference in BMD between women receiving 60 mg raloxifene per day versus placebo was 2.4±0.4% for the lumbar spine, 2.4±0.4% for the total hip, and 2.0±0.4% for the total body (p<0.001 for all comparisons). Caveat: The women all had a BMD at base line ≤2.5 SD below the level for normal postmenopausal women (ie none had osteoporosis) but nearly 55% had low bone-mineral density (osteopenia). Although noting a low incidence of adverse effects in this trial, the authors noted that an increase in hot flushes had been reported in treated women in unpublished trials. |
i. Delmas PD,
Bjarnason NH, Mitlak BH et al. Effects of raloxifene on bone
mineral density, serum cholesterol concentrations and uterine endometrium
in postmenopausal women. New England Journal of Medicine 1997; 337
(23): 1641-1647 (Type II evidence randomised controlled trial of 601 postmenopausal women, aged 45-60, randomly assigned to receive 30, 60 or 150 mg raloxifene or placebo daily. A 25% drop-out rate occurred but an intention-to-treat analysis was carried out. All women received a daily supplement of 400-600 mg calcium.)
|
||||
| 4.2h. Raloxifene treatment in postmenopausal women increases total BMD by 2.2%. It reduces low-density lipoprotein (LDL) cholesterol by 6.2-14.1% and increases high-density lipoprotein (HDL) cholesterol by 1.5-5.7%. Preliminary and limited data suggest that raloxifene has favourable to neutral effects on gynecologic cancersi. | i. 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 (Type I evidence systematic review, Medline only searched to September 1998, of 11 randomised controlled trials and other studies of raloxifene or HRT. Outcomes examined were BMD, fracture, cardiovascular and gynaecologic cancer risks) |
||||
| 4.2i. Raloxifene preserves BMD at
important skeletal sites, lowers serum low-density lipoprotein cholesterol
levels, and has a tolerability profile comparable to placebo. Lumbar spine
BMD changed from baseline to 36 months as follows: Placebo (mean % change
± SE), -1.32% ± 0.22%; Raloxifene 30mg, +0.71% ± 0.23%; Raloxifene
60mg, +1.28% ± 0.23%; Raloxifene 150mg, 1.20% ± 0.24%. No fracture data
were providedi. Caveat: Use is contraindicated for patients with endometrial or breast cancer. |
i. Johnston CC, Bjarnason NH, Cohen FJ et
al. Long-term effects of raloxifene on bone mineral density, bone
turnover, and serum lipid levels in early postmenopausal women
Three-year data from 2 double-blind, randomized, placebo-controlled
trials. Archives of Internal Medicine 2000; 160(22):
3444-3450 (Type II evidence Three year data from two parallel randomised controlled trials. 1145 healthy European and North American women, aged 45-60, randomised to raloxifene hydrochloride, 30, 60 or 150mg, or placebo daily. All groups received 400-600 mg calcium daily. All analyses were by an intention-to-treat approach) |
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| 4.2j. An analysis of two large randomised controlled trials suggested that most women with the greater loss of BMD during the first year of treatment with alendronate or raloxifene are most likely to gain BMD if the same treatment is continued for a second year. Specifically, among women taking 5 mg/day alendronate whose hip BMD decreased by more than 4% during the first year, 83% (95% CI 82-84%) had increases in hip BMD during the second year, with an overall mean increase of 4.7%. In contrast, those who seemed to gain at least 8% during the first year lost an average of 1% (95% CI 0.1-1.9%) during the next year. Similar results were observed among women taking raloxifene for two yearsi. | i. Cummings SR,
Palermo L, Browner W et al. Monitoring osteoporosis therapy with
bone densitometry: Misleading changes and regression to the mean. Journal
of the American Medical Association 2000; 283(10): 1318-1321 (Type IV evidence Analysis of postmenopausal women with low BMD who adhered to study medication and BMD monitoring for 2 years in the Fracture Intervention Trial (5 mg/d alendronate, N=2634) and the Multiple Outcomes of Raloxifene Evaluation Trial (60 or 120 mg/d raloxifene, N=3954)
|
||||
| 4.2k. A
trial found that raloxifene had smaller effects on bone turnover
and bone density than conjugated equine estrogens (CEE) but was
associated with fewer side-effectsi . Significant differences
between groups were seen in lumbar spine and total body BMD with CEE
having an approximately 2-fold greater effect than raloxifene. The
increases at all proximal femoral sites were greater with raloxifene than
CEE, but these differences were not statistically significant. Caveat: The incidence of discontinuations due to adverse events was significantly higher in the CEE group (6/26) than in the raloxifene group (1/25). Thus estrogen replacement therapy remains the standard for the prevention and treatment of osteoporosis in postmenopausal women. Its use increases total bone mineral density (BMD) by up to 12.1% and reduces hip fracture risk by 66-73% (but see also statement 4.1t). Raloxifene increases total BMD by 2.2%. Raloxifene, while more costly, is an alternative therapy that may have a lower associated risk of breast cancerii. |
i. Prestwood KM,
Gunness M, Muchmore DB, Lu Y, Wong M, Raisz LG. A comparison of the
effects of raloxifene and estrogen on bone in postmenopausal women. Journal
of Clinical Endocrinology and Metabolism 2000; 85(6): 2197-2202 (Type II evidence randomised controlled trial for 24 weeks of 51 women, postmenopausal for at least 5 years, assigned to 10 mg/d raloxifene (Evista) or 0.625 mg/d conjugated equine estrogens (Premarin). An intention-to-treat analysis was used) ii. 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 |
||||
| 4.2l. Raloxifene
increased bone mineral density in the spine and femoral neck and reduced
radiographically defined vertebral fractures but not nonvertebral
fractures in postmenopausal women with osteoporosis. 10.1% of women
treated with placebo vs 6.6% of women treated with 60 mg/d raloxifene and
5.4% of women receiving 120 mg/d had new vertebral fractures after three
years. The relative risk of vertebral fracture for the 60 mg/d group was
0.7 (95% CI 0.5-0.8) and the relative risk for the
120 mg/d group was 0.5 (95% CI 0.4-0.7). For
nonvertebral fractures these values were 9.3% for placebo vs 8.5% for
raloxifene. The relative risk was 0.9 (95% CI 0.8-1.1)
for both raloxifene groups combinedi. Caveat: Women in the raloxifene group withdrew from the study more often because of adverse events and developed more thrombosis (1% vs 0.3%). Drop out rates were high in both groups (10.3% in the raloxifene and 8.8% in the placebo group). The risk of invasive breast cancer was decreased by 76% during 3 years treatment with raloxifene (NNT=126). Raloxifene decreased the risk of estrogen receptor-positive breast cancer by 90% (relative risk = 0.10, 95% CI 0.04-0.24), but not estrogen receptor-negative invasive breast cancer (RR=0.88, 95% CI 0.26-3.0). Raloxifene increased the risk of venous thromboembolic disease (RR=3.1, 95% CI 1.5-6.2) but did not increase the risk of endometrial cancer (RR=0.8, 95% CI 0.2-2.7)ii. |
i. Ettinger B, Black
DM, Mitlak BH et al. Reduction of vertebral fracture risk in
postmenopausal women with osteoporosis treated with raloxifene: results
from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene
Evaluation (MORE) investigators. Journal of the American Medical
Association 1999; 282(7): 637-645 (Type II evidence randomised controlled trial of 7705 women, mean age 67 years, 96% white. All women had osteoporosis defined by the presence of vertebral fractures or a femoral neck or spine T-score of at least 2.5 standard deviations below the young healthy mean. Women received 500 mg calcium , 400-600 IU cholecalciferol and 120 mg/d raloxifene (N=2572), 60mg/d reloxifene (N=2557) or placebo (N=2576) reviewed in Anonymous. Raloxifene reduced vertebral fractures in postmenopausal women. ACP Journal Club 2000; 132(2): 58) ii. Cummings SR, Eckert S, Krueger
KA et al. The effect of raloxifene on risk of breast cancer in
postmenopausal women: results from the MORE randomized trial. Multiple
Outcomes of Raloxifene Evaluation. Journal of the American Medical
Association 1999; 281(23): 2189-2197
|
||||
| 4.2m. Raloxifene
use is associated with favourable effects of biochemical markers of
cardiovascular risk in healthy postmenopausal womeni.
Compared with placebo at six months, raloxifene significantly
lowered low-density lipoprotein cholesterol by 12% (p<0.001)
similar to the 14% reduction with HRT (p<0.001).
Raloxifene also decreased fibrinogen lipoprotein (a) levels and increased
high-density lipoprotein cholesterol without raising triglycerides. In
contrast to HRT, raloxifene had no effect on high-density lipoprotein
cholesterol and plasminogen activator inhibitor-1, and a lesser effect on
high-density lipoprotein-2-cholesterol and lipoprotein (a). Hot flushes
were the most common adverse event in the raloxifene groups, with the
highest incidence (22%) occurring at the 120 mg dosage. In contrast,
vaginal bleeding was the most common event in the HRT group (45%).
Significantly more patients in the HRT group discontinued the study (p<0.001)
primarily because of vaginal bleedingi. |
i. Walsh BW, Kuller
LH, Wild RA et al. Effects of raloxifene on serum lipids and
coagulation factors in healthy postmenopausal women. Journal of the
American Medical Association 1998; 279(18): 1445-1451 (Type II evidence randomised controlled trial of 390 healthy postmenopausal women randomised to receive one of four treatments: raloxifene, 60 mg/day, raloxifene, 120 mg/day, HRT (conjugated equine estrogen, 0.625 mg/day & medroxyprogesterone acetate, 2.5 mg/day) or placebo. An intention-to-treat analysis was used) ii. Mosca L, Barrett-Connor E,
Kass Wenger N et al. Design and methods of the Raloxifene Use for
the Heart (RUTH) study. American Journal of Cardiology 2001; 88:
392-395 |
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| 4.2n. Continuous
treatment of postmenopausal osteoporosis with calcitriol for three
years is safe and stabilises the rate of new vertebral fracture. The women
who received calcitriol had a significant reduction in the rate of new
vertebral fractures during the second and third years compared to those in
the calcium group (third year, 9.9 versus 31.5 fractures per 100 patient
years; p<0.001). The groups also differed
significantly in the number of peripheral fractures (11 fractures in 11
women in the calcitriol group vs 22 fractures in 24 women in the calcium
group; p<0.05). There was no significant difference between groups in
the incidence of side effects requiring withdrawal of treatment (8.6% in
the calcitriol group vs 6.5% in the calcium group)i. Caveat: This result was due to a significant increase in the fracture rate of women in the calcium group during the course of the study, rather than a decrease in women treated with calcitriol. |
i. Tilyard MW, Spears
GFS, Thomson J, Dovey S. Treatment of postmenopausal osteoporosis
with calcitriol or calcium. New England Journal of Medicine 1992; 326:
357-362 (Type II evidence Three year randomised controlled trial of 622 women with one or more vertebral compression fractures assigned to calcitriol (0.25 microgram twice/day) or supplemental calcium (1g elemental calcium daily). Only 432 women completed the study but withdrawals were similar in both groups)
|
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4.3.
Established efficacy against non-vertebral fractures:
|
|||||
| 4.3a. Supplementation
with vitamin D3 and calcium is well tolerated and
reduces the risk of hip fractures and other non-vertebral fractures among
elderly women. 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
non-vertebral fractures was 32% lower (p=0.015). The results of analyses
were similar according to active treatment and by intention-to-treati.
In men and women 65 years of age or older who are living in the community,
dietary supplementation with calcium and vitamin D moderately reduced bone
loss measured in the femoral neck, spine, and total body over three years
and reduced the incidence of non-vertebral fractures (p=0.02). The
supplements were generally well toleratedii. If the lightest 50% of women in nursing homes are treated with calcium and vitamin D there is clear evidence of cost-savings and health gain in terms of averted fracturesiii,iv. Taking women below mean body weight (<67kg) with a mean age of 81 years living in nursing homes or sheltered accommodation (hip fracture rate 40 per 1,000 annually), the estimated cost savings are £8.02 per treated womaniv. |
i. Chapuy MC, Arlot
ME, Dubeouf F et al. Vitamin D3 and calcium to prevent
hip fracture in elderly women. New England Journal of Medicine 1992;
327: 1637-1642 (Type II evidence 18 month randomised controlled trial of 3270 ambulatory women (mean age (±SD) 84±6) living in nursing homes or apartment homes for elderly people. Less than 1% of the women had received ERT after menopause. Women were randomised to tricalcium phosphate (containing 1.2g elemental calcium) and 20 micrograms (800 IU) vitamin D3 or double placebo) ii. Dawson-Hughes B, Harris SS,
Krall EA, Dallal GE. Effect of calcium and vitamin D
supplementation on bone density in men and women 65 years of age or older.
New England Journal of Medicine 1997; 337: 670-676 iii. Torgerson DJ, Iglesias CP,
Reid DM. The economics of fracture prevention. In Barlow D, Francis R,
Miles AP (eds). The Effective Management of Osteoporosis. Key
Advances in Clinical Practice Series 2001. London: National Osteoporosis
Society, UeL Centre for Public Health Policy and Health Services Research,
2001 iv. National Osteoporosis Society.
Section 4. Is this strategy cost-effective? In Primary Care Strategy
for Falls and Osteoporosis. London: National Osteoporosis Society,
July 2001 pp. 20-21 |
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| 4.3b. Uncertainty
remains about the efficacy of regimens which include vitamin D
alone or its analogues in fracture prevention in elderly men and women
with involutional or post-menopausal osteoporosisi,ii. Further
randomised controlled trials with economic evaluation are desirable before
community fracture prevention programmes employing vitamin D
supplementation can be confidently introducedi. (Health gain notation - 4 "unknown") Two regimens, each represented by one large trial, that showed limited evidence of efficacy in reducing the incidence of hip or other appendicular skeletal fractures were:
Regimens showing limited effectiveness in reducing the incidence of vertebral deformity were:
A large multicentre, randomised controlled, trial is currently underway to examine whether vitamin D or calcium alone, or a combination of the two, taken orally, will reduce the incidence of subsequent fractures in elderly men and women (aged 70+) who have sustained a recent fractureiii. |
i. Gillespie WJ,
Avenell A, Henry DA, OConnell DL, Robertson J. Vitamin D and Vitamin D
analogues in the prevention of fractures in involutional and
post-menopausal osteoporosis [updated 12 November 2000]. Cochrane
Database of Systematic Reviews. Cochrane Library 2001, Issue 4 http://www.update-software.com/ abstracts/ab000227.htm [accessed 29.11.01] (Type I evidence - systematic review and meta-analysis of 14 quasi- randomised and controlled trials, 7220 elderly men and women (*check ages); 25% of the patients were lost to follow-up. The last substantial amendment to this review was made on 26 August 1996) ii. Lips P, Graafmans WC, Ooms ME,
Bezemer D, Bouter LM. Vitamin D supplementation and fracture
incidence in elderly persons: a randomized, placebo-controlled clinical
trial. Annals of Internal Medicine 1996; 124: 400-406 iii. The MRC Record Trial. MREC
97/0/7. A randomised placebo controlled trial of daily oral vitamin D and
calcium for the secondary prevention of osteoporosis related fractures in
the elderly. Ends 2003.
|
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| 4.4. Established efficacy
against hip fractures:
|
|||||
|
|||||
| 4.5a. Cyclical
intravenous clodronate therapy is a safe and effective therapy for
established osteoporosis but further comparative clinical trials are
necessary. BMD increased significantly and the upward trend persisted
for all 6 years of therapy. After 6 years the lumbar spine BMD of the
treatment group was +5.69% (±0.184%) versus 1.47% (±0.813%) in the
control group (p<0.0001). From year 3 onwards
clodronate reduced the incidence of new vertebral fractures i. Caveat: The data for 72 (24%) of the original 307 patients who dropped out of the study before the end of year one, mostly through non-compliance, were not included in the analysis. Data for the full 6 years were only available for 44 patients. Caveat: This is not a licensed indication After 2 years, continuous clodronate regimens caused an increase in BMD both at lumbar spine and proximal femur (L1-4 BMD = 3.07% and 2.69%; femoral neck = 2.12% and 2.09%, respectively, with intramuscular and oral regimens). Intermittent clodronate administration was associated with a small increase or a stabilization in bone mass (L1-4 BMD = 0.53% and 1.22%; femoral neck = 0.30% and 0.77%, respectively, with 1- and 6-day intravenous infusion regimens)ii. |
i. Filipponi P,
Cristallini S, Rizzello E et al. Cyclical intravenous clodronate in
postmenopausal osteoporosis: Results of a long-term clinical trial. Bone
1996; 18(2): 179-184 (Type III evidence trial of cyclical clodronate therapy (200 mg IV infusion every 3 weeks) on 235 women with postmenopausal osteoporosis, 90 of whom had vertebral fractures. A retrospective analysis of clinical and instrumental findings in 183 postmenoapusal osteoporotic patients was used as control data.) ii. Filipponi P, Cristallini S,
Policani G, Schifini MF, Casciari C, Garinei P. Intermittent versus
continuous clodronate administration in postmenopausal women with low bone
mass. Bone 2000; 26(3): 269-274
|
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| 4.5b. A
systematic review examining exercise for the treatment and
prevention of osteoporosis in women revealed that, although the trials
were too heterogeneous for the planned meta-analysis, there was a strong
suggestion that regular physical exercise, particularly weight bearing
exercise, can reduce the risk of osteoporosis and delay the decrease in
BMDi. Caveat: This review considered a heterogeneous group of studies covering women with various degress of osteoporosis, undertaking various types of exercise. Treatments including exercise for elderly adults reduce the risk of falls. The adjusted fall incidence ratio for treatment arms including general exercise was 0.90 (95% CI, 0.81-0.99) and for those including balance was 0.83 (95% CI, 0.70-0.98)ii. A systematic review to determine the effectiveness of exercise in preventing and treating osteoporosis in postmenopausal women is currently underwayiii. |
i. Ernst E. Exercise
for female osteoporosis. A systematic review of randomised clinical
trials. Sports Medicine 1998; 25(6): 359-368 (Type I evidence narrative systematic review of 21 randomised controlled trials. The literature search was completed at the beginning of 1997) ii. Province MA, Hadley EC,
Hornbrook MC et al. The effects of exercise on falls in elderly
patients. A preplanned meta-analysis of the FICSIT trials. Journal of
the American Medical Association 1995; 273(17): 1341-1347 iii. Bonaiuti D, Shea B, Iovine R et
al. Exercise for preventing and treating osteoporosis in
postmenopausal women (Protocol). Cochrane Database of Systematic Reviews. Cochrane
Library 2001, Issue 4 |
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| 4.5c. A
10-week ambulatory exercise programme, for women with at least one
spinal crush fracture, improved balance and level of daily function and
decreased experience of pain (p=0.01) and use of analgesics (p=0.02).
Quality of life was improved even 12 weeks beyond the active training
period (p=0.0008)i. Caveat: This was an unblinded study and the control group received no intervention so that risk of a Hawthorne effect cannot be excluded. |
i. Malmros B,
Mortensen L, Jensen MB, Charles P. Positive effects of physiotherapy on
chronic pain and performance in osteoporosis. Osteoporosis
International 1998; 8(3): 215-221 (Type II evidence randomised controlled trial of 53 women, aged 62-71, with at least one spinal crush fracture and pains within the last 3 years. Analysis by questionnaire)
|
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| 4.5d. Calcium salts
(generally in excess of 1g daily) are capable of slowing the rate of bone
loss in women with osteoporosisi.
The available evidence supports the current clinical and public health
policy of recommending increased calcium intake among older women
for fracture preventionii,iii. Four randomised controlled
trials of calcium supplements (mean calcium dose: 1050 mg) found relative
risk (RR) reductions between 25% and 70%. The pooled results of 16
observational studies of dietary calcium and hipe fracture gave an odds
ratio (OR) of 0.96 (95% CI 0.93-0.99) per 300 mg/day
increase in calcium intake (the equivalent of one glass of milk)iii. 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 fractureiv. |
i. Kanis JA. Calcium
nutrition and its implications for osteoporosis. Parts I and II. European
Journal of Clinical Nutrition 1994; 48: 757-767, 833-841 (Type V evidence expert opinion) ii. Heaney RP. Calcium, dairy
products and osteoporosis. Journal of the American College of Nutrition
2000; 19(2): 83S-99S iii. Cumming RG, Nevitt MC.
Calcium for prevention of osteoporotic fractures in postmenopausal women. Journal
of Bone and Mineral Research 1997; 12(9): 1321-1329 iv. Shea B, Cranney A, Tugwell P,
Welch V et al. Calcium for treating osteoporosis in postmenopausal
women. (Protocol) Cochrane Database of Systematic Reviews. Cochrane
Library 2001, Issue 4
|
||||
| 4.5e. Although fluoride has an ability to increase BMD at lumbar spine (weighted mean difference between control and treatment groups, WMD=16.1% (95% CI 14.65-17.5), it does not result in a reduction of vertebral fractures (relative risk at four years, RR=0.9, 95% CI 0.71-1.14). The RR for new non-vertebral fractures was not significant at 2 years but was increased at 4 years in the treated group (RR=1.85, 95% CI 1.36-2.5), especially if used at high doses and in a non-slow release form. The risk of gastrointestinal side-effects was also increased at 4 years in the treated group (RR=2.18, 95% CI 1.69-4.57) especially if used at high doses and in a non-slow release formi. | i. Haguenauer D,
Welch V, Shea B, Tugwell P, Wells G. Fluoride for treating postmenopausal
osteoporosis. [updated 30 August 2000]. Cochrane
Database of Systematic Reviews. Cochrane Library 2001, Issue 4 http://www.update-software.com/ abstracts/ab002825.htm [accessed 29.11.01] (Type I evidence - systematic review and meta-analysis of 11 randomised controlled trials, 1429 subjects) |
||||
| 4.5f. Combined tibolone
and fluoride treatment induced a highly
significant increase in BMD at the lumbar spine without simultaneous loss
of the cortical bone allowing for a meaningful reduction of the fluoride
dose when given in combination with tibolone. In women who completed the
two-year trial, there was a mean increase in BMD at the lumbar spine
(measured by dual photon absorptiometry, DPA) of 25.3% and 12.3% in
tibolone+fluoride and placebo+fluoride groups respectivelyi. Caveat: There was a high drop-out rate from both groups due to gastrointestinal effects. |
i. Reginster J-Y,
Agnusdei D, Gennari C, Kicovic PM. Association of tibolone and fluoride
displays a pronounced effect on bone mineral density in postmenopausal
osteoporotic women. Gynecological Endocrinology 1999; 13:
361-368 (Type II evidence randomised controlled trial of 94 women, mean age=61.1 years, postmenopausal for 13.5 years on average with low bone mineral density at baseline. Subjects were randomised to 2.5 mg tibolone plus 26.4 mg fluoride (T+F) or placebo plus 26.4 mg fluoride P+F) daily over 2 years. All subjects received a supplement of 1000 mg/day calcium. 55 (58.5%) subjects completed the study, the main reason for discontinuation being untoward gastrointestinal effects: 16 (33.3%) dropped out of the P+F and 23 (50%) of the T+F groups respectively.) |
||||
| 4.5g. In
a small trial, a low dose of fluoride (20 mg/d) in addition to HRT
(a patch releasing 50 m g/d) resulted in an increase in spinal BMD after
96 weeks that was significantly greater than the increase in the HRT group
(11.8% versus 4.0%, p<0.05). The increase with fluoride alone was 2.4%
and no change was recorded in the placebo groupi. Caveat: 48% of women were osteoporotic according to WHO criteria and one third had 1-3 vertebral fractures. |
i. Alexanderson P,
Riis BJ, Christiansen C. Monofluorophosphate combined with hormone
replacement therapy induces a synergistic effect on bone mass by
dissociating bone formation and resorption in postmenopausal women: a
randomized study. Journal of Clinical Endocrinology and Metabolism 1999;
84(9): 3013-3020 (Type II evidence randomised controlled trial of 100 healthy postmenopausal women (aged 60-70 years) in three intervention and one control group 68 completed the study. All patients received 1g/d calcium supplementation) |
||||
| 4.5h. Observational
studies suggest that thiazides can reduce the risk of hip
fracture by 20%, (odds ratio 0.82, 95% CI: 0.73 - 0.91).
It is estimated that a definitive randomised controlled trial, to detect
fracture reduction, would require a minimum of 7000 person years in
high-risk (>80years) women, and this is unlikely to be conductedi.
In a trial of healthy older adults, low-dose hydrochlorothiazide was shown to preserve bone mineral density at the hip and spine. At 36 months, the differences in total hip bone density were 0.79% (95% CI 0.12%1.71%) for 12.5mg and 0.92% (95% CI 0.001%1.85%) for 25mg hydrochlorothiazide. These modest effects over 3 years, if accumulated over 20 years, may explain the reduction in risk of hip fractures seen in observational studies ii. Thiazides have a long-term well-documented safety profile as long as potassium, uric acid and glucose levels are monitored.. Their beneficial effects on bone could be considered in decisions about long term pharmacologic therapy for high blood pressure i,ii. |
i. Jones G, Nguyen T,
Sambrook PN, Eisman JA. Thiazide diuretics and fractures: Can
meta-analysis help? Journal of Bone and Mineral Research 1995; 10(1):
106 - 111 (Type IV evidence systematic review and meta-analysis of 13 cohort and case controlled studies and 29,600 patients) ii. LaCroix AZ, Ott SM, Ichikawa
L, Scholes D, Barlow ME. Low-dose hydrochlorothiazide and preservation of
bone mineral density in older adults. A randomized, double-blind,
placebo-controlled trial. Annals of Internal Medicine 2000; 133(7):
516-526 |
||||
| 4.5i. Hip protectors appear
to reduce the risk of hip fracture within a selected population at high
risk. The summation of the results of six trials gave an occurrence of hip
fractures of 29/1313 (2.2%) for those allocated to wear hip protectors
against 130/2099 (6.2%) to those not wearing hip protectors.
Cost-effectiveness is unclear. Compliance in the long term was poor due to
discomfort and practicality. Other trials are ongoingi. (Health gain notation - 1"beneficial") |
i. Parker MJ,
Gillespie LD, Gillespie WJ. Hip protectors for preventing hip fractures in
the elderly [updated 1 March 2001]. Cochrane
Database of Systematic Reviews. Cochrane Library 2001, Issue 4 http://www.update-software.com/ abstracts/ab001255.htm [accessed 29.11.01] (Type I evidence systematic review of 7 randomised controlled trials involving 3553 participants) |
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| 4.6. Guidelines for Prevention and Treatment | |||||
| 4.6a. Guidelines
for good practice in the diagnosis and treatment of osteoporosis are
availablei,ii,iii,iv.
The recent update of the Royal College of Physicians guidelines provides an algorithm for management ii. Guidelines specifically for use in general practice are also published by the Primary Care Rheumatology Societyv. |
i. Anonymous. Osteoporosis:
Clinical Guidelines for Prevention and Treatment. London: Royal
College of Physicians, 1999. http://www.doh.gov.uk/osteorep.htm [accessed 29.11.01] (Type V evidence Guidelines based on a systematic review of the literature) ii. Anonymous. Osteoporosis: Clinical
Guidelines for Prevention and Treatment. Update on pharmacological
interventions and an algorithm for management. London: Royal College
of Physicians, 2000 ii. Kanis JA, Delmas P, Buckhardt
P, Cooper C, Torgerson D, on behalf of the European Foundation for
Osteoporosis and Bone Disease. Guidelines for diagnosis and management of
osteoporosis. Osteoporosis International 1997; 7: 390-406 iv. Eddy DM, Johnston CC, Cummings
SR et al. Osteoporosis: Review of the evidence for prevention,
disgnosis and treatment and cost-effectiveness analysis. Osteoporosis
International 1998; 8(suppl.4): S1-S88 v. Primary Care Rheumatology
Society. Osteoporosis: Minimum Standard Guidelines. Northallerton,
North Yorkshire: Primary Care Rheumatology Society, 1999 |
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| 4.6b. Recommendations from the World Health Organisation (WHO) are also availablei. | i. Genant HD, Cooper
C, Poor G et al. Interim report and recommendations of the World
Health Organization Task-Force for Osteoporosis. Osteoporosis
International 1999; 10(4): 259-264 (Type V evidence expert opinion) |
||||
| 4.6c. Comprehensive guidelines regarding physiotherapy for the prevention and management of osteoporosis are availablei,ii. | i. The Chartered
Society of Physiotherapy. Physiotherapy Guidelines for the Management
of Osteoporosis. London: The Chartered Society of Physiotherapy, 1999 (Type V evidence evidence-based guidelines from a systematic review of the literature) |
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| 4.6d. Comprehensive guidance concerning diet and bone health is availablei,ii. | i. National
Osteoporosis Society. Diet and Bone Health. London: National
Osteoporosis Society, 1999. pp. 8-9 (Type V evidence expert opinion and guidelines) Available from the National Osteoporosis Society, PO Box 10, Radstock, Bath BA3 3YB (tel. 01761 471771) ii. National Dairy Council. Diet and Bone Health, Topical
Update. November 1999 London: National Dairy Council, 1999 |
||||
| 4.6e. Guidelines for the management of osteoporosis in coeliac disease and inflammatory bowel disease are availablei. | i. Scott EM, Gaywood
I, Scott BB. Guidelines for osteoporosis in coeliac disease and
inflammatory bowel disease. British Society of Gastroenterology. Gut 2000;
46S1: i1-i8 (Type V evidence expert opinion and guidelines) |
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Health Evidence Bulletins: Wales, Duthie Library, UWCM, Cardiff CF14 4XN. e-mail: weightmanal@cardiff.ac.uk