how to manage osteoporosis after the menopause

Best Practice & Research Clinical RheumatologyVol. 19, No. 6, pp. 1007–1019, 2005

10

How to manage osteoporosis after

the menopause

Juliet Compston* FRCPath, FRCP, FMedSci

Professor of Bone Medicine

University of Cambridge School of Clinical Medicine, Box 157, Addenbrooke’s Hospital, Cambridge CB2 2QQ, UK

Many women seek advice about bone health at the time of the menopause. Although fractureprobability is low in the majority, treatment may be cost-effective if targeted at those at highestrisk. Optimal selection of individuals for intervention is based on a case-finding approach, fractureprobability being estimated using a combination of bone mineral density and clinical risk factors. Avariety of therapeutic interventions is available for the prevention of osteoporotic fractures inpostmenopausal women. Hormone replacement therapy (HRT) is a second-line option in most,although it has a place in the management of perimenopausal women with menopausal symptomswho are at risk from fracture and in other postmenopausal women who express a preference forHRT over other options, after being fully informed about known risks and benefits.

Key words: hormone replacement therapy; osteoporosis; fracture; oestrogen; menopause.

The menopause is a time when many women seek advice about bone health and theirrisk of osteoporosis. In the majority of early postmenopausal women, fractureprobability is low and intervention to prevent bone loss is not indicated. Nevertheless,preservation of bone mass is often a factor in decisions about starting or stoppinghormone replacement therapy (HRT), and women may seek lifestyle advice to promoteskeletal health. This chapter addresses the question of when treatment should beadvocated in early postmenopausal women and reviews the options available. Inparticular, it will focus on the risks and benefits of HRT in this age group.

PATHOPHYSIOLOGY OF MENOPAUSAL BONE LOSS

In many studies, the onset of bone loss has been documented at the beginning of the fifthdecade or even earlier.1–6 However, the cessation of ovarian function at the menopause

doi:10.1016/j.berh.2005.06.010available online at http://www.sciencedirect.com

1521-6942/$ - see front matter Q 2005 Elsevier Ltd. All rights reserved.

* Corresponding author. Tel.: C44 1223 336867; Fax: C44 1223 336846.

E-mail address: [email protected].

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1008 J. Compston

is associated with a phase of rapid bone loss which probably lasts between 5 and 10years.7,8 This rapid bone loss results from an increase in bone turnover in associationwith a negative remodelling imbalance9; whilst reduced bone formation undoubtedlycontributes to the latter, there is evidence that increased osteoclastic activity also playsa role, particularly in the earlier stages of menopausal bone loss.10 The combination ofincreased bone turnover and increased resorption depth results in disruption of bonemicroarchitecture, with loss of connectivity of cancellous bone and thinning of thecortices, which also show increased porosity.

The loss of both bone mass and architecture that occurs during the menopause hasbeen used as a rationale for instigation of preventive measures, since it is argued thatprevention of bone loss early in the menopause will prevent the architectural changesand will ‘buy time’ for the skeleton, so that at any given age subsequently bone mass willbe greater and fracture risk lower. However, in the past decade or so there has been amove away from long-term preventive strategies towards shorter-term intervention inindividuals with a high fracture probability. This has been prompted by a number ofconsiderations, including cost-effectiveness and issues associated with poor con-tinuance and compliance with long-term medication; furthermore, changes in theperception of the risk/benefit balance of HRT have generally discouraged its long-termuse.11,12 Finally, the beneficial effects of many bone-protective interventions appear tohave a relatively rapid offset when treatment is stopped, and there have been someconcerns that bone loss and increased bone turnover after withdrawal of therapy mightincrease fracture risk.

The timing of intervention in early menopausal women is thus problematic; iftreatment is started at the menopause, it may need to be continued lifelong, sincefracture probability increases with age and most fractures occur in women over the ageof 75 years. Whilst this would clearly not be a cost-effective approach if widely adopted,targeted treatment in these women can be cost-effective. Thus Kanis et al13, haveestimated that intervention in a woman aged 50 years with a 10-year hip fractureprobability of only 1.4% is cost-effective if it is assumed that the treatment reduces therisk of all osteoporotic fractures. This is because in these younger women morefractures occur at sites other than the hip, and so more fractures at these sites areavoided.

SELECTION FOR TREATMENT

There is universal agreement that bone mineral density (BMD) screening at themenopause would not be cost-effective, although in North America screening ofwomen aged over 65 years is widely recommended.14,15 A case-finding approach is,therefore, utilized in which women are selected for bone density assessment on thebasis of clinical and/or historical risk factors. In the past, intervention thresholds havemainly been determined on the basis of bone density levels, a T-score of K2.5 or lowerat the spine and/or hip being used as a starting point for such decisions, but althoughthis approach has high specificity its sensitivity is low and the majority of osteoporoticfractures occur in women with a BMD above this level.16,17 The sensitivity of bonedensitometry in predicting fracture risk can be improved by the addition of risk factorsthat are independent of BMD, and hence risk assessment has moved towardsestimation of fracture probability using a combination of BMD values and such riskfactors.18–20 Risk factors that are commonly used for case-finding and for fracture risk

Table 1. Risk factors for osteoporosis.

BMD-independent BMD-dependent

Age Female sex

Previous fragility fracture Premature menopause

Glucocorticoid therapy Untreated hypogonadism

Maternal family history of hip fracture Asian or white ethnic origin

Low body mass index Immobilization

Increased falls risk Alcohol abuse

Increased bone turnover Gastrointestinal disease

Cigarette smoking Chronic liver disease

Chronic pulmonary disease

Managing osteoporosis after the menopause 1009

assessment are shown in Table 1. It is important to recognize that there may besignificant interaction between some risk factors, thus increasing the complexity offracture risk assessment. Finally, although measurement of hip BMD by dual energyX-ray absorptiometry (DEXA) remains the gold standard for the diagnosis ofosteoporosis21, measurements at other sites and using other approaches can also beused for the purposes of risk assessment.

In using this approach to risk assessment it should be noted that not all risk factorsmay be amenable to bone-protective intervention; for example, there is no evidencethat bisphosphonates reduce the risk of falls. Although most therapies have beenassessed in postmenopausal women with osteoporosis or established osteoporosis,there is evidence for some anti-resorptive therapies that anti-fracture efficacy is alsoachieved in osteopenic women.

THERAPEUTIC OPTIONS FOR THE EARLY POSTMENOPAUSALWOMAN

A number of options is now available for the prevention of osteoporotic fractures inpostmenopausal women, including bisphosphonates, raloxifene, strontium ranelate andteriparatide. These agents are considered in detail in other chapters and will beconsidered only briefly here; in contrast, the use of HRT to prevent osteoporosis willbe discussed more fully.

For many years HRT was the only treatment for osteoporosis in postmenopausalwomen. Its approval for this use was, for historical reasons, based on much lessrigorous criteria than are required today, and newer interventions with a more robustevidence base have largely superseded its use for this indication. In addition, recent datafrom large prospective studies of HRT have forced re-evaluation of its risk/benefitbalance. Nevertheless, despite the negative perceptions fostered by the media and byregulatory agencies, HRT remains a viable therapeutic option for some women withosteoporosis, particularly those in their early menopausal years.

Although HRT is often treated as a single entity, in fact it encapsulates a variety ofdifferent treatment regimens. Firstly, it may consist of oestrogen alone or thecombination of an oestrogen or progestagen. Secondly, formulations include a largevariety of oestrogenic and progestagenic compounds that may be used in varyingcombinations and doses. Thirdly, modes of administration include oral, intranasal,

1010 J. Compston

transdermal and parenteral. Finally, continuous or intermittent regimens are available.This heterogeneity makes it difficult to extrapolate data from one regimen to another;thus different progestagens are likely to differ in their cardiovascular effects, andbypassing the first-pass hepatic metabolism by transdermal administration of hormonesmay affect the pharmacological profile. In this respect, it is important to note that theWomen’s Health Initiative study, from which much of the recent evidence is derived,investigated the effects of oral premarin 0.625 mg alone or in combination withmedroxyprogesterone 2.5 mg daily.22,23

Effect of HRT on BMD and fracture risk

There is ample evidence from prospective studies that HRT prevents bone lossassociated with the menopause, and protection against bone loss has also beenreported in older postmenopausal women.24–29 This effect has been documented fororal, parenteral and transdermal preparations and for both unopposed and combinedformulations. Protection against bone loss is seen at both cancellous and cortical sitesand is primarily achieved by a reduction in bone turnover.30,31 Histomorphometricstudies also indicate that HRT preserves existing cancellous bone microarchitecture,preventing the deterioration that occurs in untreated postmenopausal women.32

Recent studies suggest that lower doses than those previously believed to be necessaryare effective in preventing menopausal bone loss.33–35 High doses of oestradiol, givenparenterally, result in larger increases in BMD and have been shown to have anabolicskeletal effects, resulting in increased bone formation.36,37

Until recently, evidence for anti-fracture efficacy of HRTwas based mainly on case–control and cohort studies, which demonstrated a reduction of around 50% in hip andother non-vertebral fractures in HRT users.38–40 In addition, some small prospectivestudies indicated protection against clinical vertebral and non-vertebral fractures.41–43

Meta-analysis of randomized controlled trials has produced conflicting results; thuswhilst Cranney et al44, concluded that there was no significant reduction in eithervertebral or non-vertebral fracture with HRT treatment, Torgeson and Bell-Syerreported that the pooled mean estimate of relative risk was significantly reduced forboth fracture types, the beneficial effect on non-vertebral fractures being mostprominent in younger postmenopausal women.45,46 These differences are likely to beattributable to the criteria used for study inclusion in the meta-analysis; nevertheless,the Cranney meta-analysis showed similar trends to those observed by Torgerson andBell-Syer.

Most recently, the Women’s Health Initiative (WHI) study reported significantreduction in the risk of clinical fractures in a population-based sample of healthypostmenopausal women aged 50–79 years.22,23 In this large randomized controlledtrial, 16 608 women were recruited to the oestrogen-plus-progestin arm of the studyand 10 739 hysterectomized women into the oestrogen-only trial. Treatment consistedof premarin 0.625 mg/dayGmedroxyprogesterone acetate 2.5 mg/day. Both trials werestopped prematurely, with a mean follow-up period of 5.2 and 6.8 years, respectively. Inboth studies, a significant reduction was demonstrated in clinical vertebral and non-vertebral fractures, including hip fractures (see Table 2). Women in this study were notselected on the basis of increased fracture risk, and their BMD status was unknown.Morphometric vertebral fractures were not assessed in these studies.

The WHI study thus provided the first robust evidence for fracture protection byHRT in postmenopausal women, albeit in a population not selected on the basis of high

Table 2. Effect of combined oestrogen and progestin and oestrogen only on clinical fracture incidence in

healthy postmenopausal women.

Fracture type OestrogenCprogestin Oestrogen only

Hazard ratio 95% CI Hazard ratio 95% CI

Hip 0.66 0.45–0.98 0.61 0.41–0.91

Vertebral 0.66 0.44–0.98 0.62 0.42–0.93

Total 0.76 0.69–0.85 0.70 0.63–0.79


risk of fracture. This benefit was similar for unopposed oestrogen and combinedtherapy and translates into a reduction of approximately 0.3 hip fractures per 1000women aged 50–59 years taking HRT for 5 years and three hip fractures per 1000women aged 60–69 years, when compared to non-HRT users in the same age groups.Clearly, these absolute benefits are small but are likely to improve if treatment istargeted to high-risk women.

Data from observational studies have consistently shown greater protection againstbone loss and fracture in current HRT users when compared to past users40,47,48,suggesting that the beneficial skeletal effects of HRTare not maintained when therapy iswithdrawn. Prospective studies indicate that bone loss resumes within 1 year ofstopping HRT and, furthermore, may occur at a rate similar to that seen in earlymenopausal women, at least for a limited period.49,50 Nevertheless, most studiessuggest that BMD remains higher than in non-users for many years, and there may alsobe residual fracture protection, although the latter remains uncertain.51

Other effects of HRT

The risk/benefit balance of HRT is complex and is influenced by age, the presence ofmenopausal symptoms, and the absolute risk of conditions that may be associated withHRT use. Recent prospective studies have produced important new data on the risksand benefits associated with HRT use in postmenopausal women; Table 3 summarizesthe main design features of three such studies, namely the two arms of the WHI studyand the Heart and Oestrogen Replacement Study (HERS)52, whilst Figures 1 and 2provide the hazard ratios for different risks and benefits from the three studies. Itshould be noted that in all three studies, non-compliance with treatment was common,ranging from 35 to 50% by the end of the study period.

Table 3. Details of three recent large randomized controlled studies of hormone replacement therapy

(HRT) in postmenopausal women.

Trial Number Mean age Medication Primary endpoint

HERS 3 years 2763 67 years CEE 0.625 mg MPA 2.5 mg CHD

WHI (1) 5.2 years 16 608 63 years CEE 0.625 mg MPA 2.5 mg CHD CHD death

breast cancer

WHI (2) 6.8 years 10 739 63 years CEE 0.625 mg CHD CHD death

breast cancer

HERS, Heart and Oestrogen Replacement Study; WHI, Women’s Health Initiative STUDY; CEE,

conjugated equine oestrogens; MPA, medroxyprogesterone acetate; CHD, coronary heart disease.

0

0.5

1

1.5

2

2.5

3

CHD Stroke PE B

HERS E+P

WHI E+PWHI E only

Hazard ratio

** *

*

*

Figure 1. Hazard ratio for risks associated with HRTuse in three recent randomized controlled trials. CHD,

coronary heart disease; PE, pulmonary embolism; HERS, Heart and Oestrogen Replacement Study; WHI,

Women’s Health Initiative STUDY. For details of the three studies see Table 3. *Indicates lower and higher 95%

confidence intervals O1. Data from Hulley and Grady (2004, JAMA 291: 1769-1771).

1012 J. Compston

The major change in perceptions about the risks and benefits of HRT has beenbrought about by the failure of prospective studies to demonstrate a reduction incoronary heart disease, as shown in observational studies53,54; indeed, some studieshave suggested an increase in incidence, particularly in the early stages of HRT.52 Thisdiscrepancy in the results of observational and prospective studies may be due to anumber of factors, including confounding bias due to the healthy user effect andcompliance bias of the former and the limited ability of observational studies to captureearly clinical events.55,56 In addition, different hormone regimens may affect coronaryartery disease risk differently, and the different age and risk profile of women in thevarious studies may also contribute. Nevertheless, on the basis of current evidence,HRT cannot be promoted, as in the past, on the basis that it reduces the risk ofcoronary artery disease.

0

0.2

0.4

0.6

0.8

1

1.2

Colon cancer Hip fracture

HERS E + PWHI E + PWHI E only

* **

Hazard ratio

Figure 2. Hazard ratio for benefits associated with HRTuse in three recent randomized controlled trials. For

details of the three studies see Table 3. HERS, Heart and Oestrogen Replacement Study; WHI, Women’s

Health Initiative study. *Indicates lower and higher 95% confidence intervals !1. Data from Hulley and Grady

(2004, JAMA 291: 1769-1771).


An increase in breast cancer risk has been documented in many observationalstudies57 and was also seen in the combined oestrogen/progestin arm of the WHI study,although in the oestrogen-only arm no increase in breast cancer risk was seen; indeedthe relative risk was somewhat reduced, although this was not statistically significant.This may partly reflect the harmful effect of progestins on breast cancer risk, but in viewof the large body of observational data suggesting an adverse effect of oestrogen aloneon breast cancer risk the findings should be interpreted with caution. In the MillionWomen Study58, a prospective cohort study of approximately 1 million womenundergoing mammography, the incidence of breast cancer associated with HRTuse wasrather higher than that reported previously, and was seen with both unopposed andcombined HRT; however, the findings of this study may have been confounded byfactors related to subject selection, surveillance bias, and incorrect treatmentclassification.

A consistent finding in recent prospective studies has been an increase in risk ofstroke in HRT users (Figure 1). This is seen both in users of unopposed and combinedHRT, and is therefore, likely to be attributable to the oestrogen component of HRT.Pulmonary embolism was also increased in HRT users, although this was onlystatistically significant in the WHI oestrogenCprogestin study. This latter finding isconsistent with observational data showing an increase in the risk of venousthromboembolism, including deep vein thrombosis, pulmonary embolus and retinalvein thrombosis.59,60

In addition to the reduction in fracture risk in HRTusers, reduction in colon cancerwas also seen consistently across studies.61 This had previously been noted inobservational studies62,63; possible, although unproven, mechanisms include effects onbile acids, receptor-mediated oestrogen-induced effects, and alterations in insulinmetabolism.

Finally, the effects of HRTon cognitive function and the risk of dementia remain to bedefinitively established. Although some observational studies suggested that HRT usewas beneficial in this respect64, no evidence for improvement of cognitive function wasdemonstrated in a sub-study of the WHI study; indeed, in treated women aged 65 yearsand over, there was an increase in the risk of probable dementia.65

For most women, the magnitude of the increase or decrease in absolute risk of allthese diseases is small, particularly for younger postmenopausal women in whom thebackground prevalence of the various conditions is relatively low. Thus for a womanaged 50–69 years, the excess incidence of breast cancer per 1000 HRT users over 5years is 3.2, whilst for stroke and pulmonary embolus the corresponding figures are 1.2and 1.6. In older women, aged 60–69 years, the corresponding figure is 4 for each ofthese conditions.

Notwithstanding some remaining uncertainties about the risk/benefit balance ofHRT, alleviation of menopausal symptoms is well documented and constitutes animportant benefit for many postmenopausal women. In those with active menopausalsymptoms and a fracture probability close to the intervention threshold, therefore,HRT is a logical treatment option; furthermore, HRT should be considered as atherapeutic option to prevent osteoporotic fractures in other postmenopausal womenwho express a wish to take HRT, provided that they are fully informed about therisk/benefit profile as currently understood. The regulatory position in Europe, namelythat healthy postmenopausal women without menopausal symptoms should be advisedagainst taking HRT, seems reasonable. However, their advice that HRT should be usedto prevent osteoporosis only in postmenopausal women who are intolerant of, orcontraindicated for, other osteoporosis therapies seems unnecessarily restrictive and

1014 J. Compston

ignores the importance of patient choice, particularly in the context of long-termtreatment.

Other therapeutic options

A number of agents are now approved for the prevention of osteoporotic fracture66,including the bisphosphonates alendronate67, risedronate68–70 and etidronate71,raloxifene72 and calcitonin.73 The majority of these have been tested for anti-fractureefficacy in populations of postmenopausal women with established osteoporosis, whilstprevention of bone loss has been documented for some74–77 in relatively short-termstudies (1–2 years) in early postmenopausal women. Until recently, only anti-resorptiveagents were available, but current options also include teriparatide78, an anabolic agent,and strontium ranelate79, which may also have stimulatory effects on bone formation.

In choosing between treatments a number of factors are relevant. Since no head-to-head comparisons have been conducted with fracture as the primary outcome,comparisons of efficacy are problematic, but an important consideration is whetheranti-fracture efficacy has been shown at both vertebral and non-vertebral sites,particularly the hip. Thus a fracture at any one site is an independent risk factor forfurther fractures at any site, and hence the ideal treatment should have proven efficacyagainst fracture at all commonly affected sites, particularly the spine and hip. Currentlyonly alendronate, risedronate and strontium ranelate are approved for the preventionof vertebral and hip fractures. Table 4 summarizes the evidence from randomizedcontrolled trials for anti-fracture efficacy at vertebral and non-vertebral sites forcurrently approved interventions.

Women undergoing treatment for osteoporosis require long-term medication thatdoes not offer symptomatic relief and may well cause side-effects and, as in otherchronic diseases, continuance and compliance with therapy are poor. The safety profileof bisphosphonates is generally good, and the introduction of once-weekly rather thandaily regimens has greatly improved their tolerability. Raloxifene and strontium ranelateare both taken as once-daily medications and also have a good safety profile.Teriparatide requires self-administered daily subcutaneous injections and is significantlymore expensive than other options; for these reasons, its use is limited to women withvery severe osteoporosis who cannot tolerate, or fail to respond to, otherinterventions. For the majority of women alendronate, risedronate or strontiumranelate will be first-line treatment options, whilst for younger postmenopausal women

Table 4. Summary of evidence for fracture reduction for currently approved interventions.

Intervention Vertebral fracture Non-vertebral fracture Hip fracture

Alendronate C C C

Etidronate C ND ND

Risedronate C C C

HRT C C CRaloxifene C ND ND

Calcitonin Ca ND ND

Calcitriol Ca ND ND

Strontium ranelate C C C

Teriparatide C C ND

a Safety and tolerability are also major considerations in making treatment decisions


with vertebral osteoporosis who do not have menopausal symptoms, raloxifene is alsoa possible choice. As noted above, patient preference is a major consideration inreaching treatment decisions, and adequate information should be provided to enablewomen to make an informed choice.

SUMMARY

Oestrogen deficiency at the menopause, resulting in rapid bone loss and disruption ofbone microarchitecture, is a major factor in the pathogenesis of postmenopausalosteoporosis. Fracture incidence increases with age, and in the majority of earlypostmenopausal women fracture probability is low; nevertheless, treatment may becost-effective in this age group when targeted to those at high risk. Selection fortreatment on the basis not only of BMD but also other risk factors that are independentof BMD is likely to provide the most effective strategy, and this approach is currentlybeing developed to provide intervention thresholds based on fracture probabilityrather than BMD T-scores.

HRT is effective in preventing bone loss during and after the menopause and hasbeen shown to reduce clinical vertebral and non-vertebral fractures in healthypostmenopausal women. Although generally regarded as a second-line option in theprevention of osteoporotic fracture, it has a place in the management of osteoporosisin women with active menopausal symptoms and in some other women who expressan informed preference for HRT over other treatments. Other treatment options forthe prevention of fractures in postmenopausal women include bisphosphonates,raloxifene and strontium ranelate.

Practice points

Identification of postmenopausal women at risk of osteoporotic fracture is madeon a case-finding basis, with subsequent estimation of fracture probability based onBMD measurements and clinical risk factors

† HRT prevents menopausal bone loss and reduces the risk of clinical vertebraland hip fractures in healthy postmenopausal women

† the risk-benefit profile of HRT is complex and dependent on age and thepresence or absence of risk factors for disease states affected by HRT

† bisphosphonates (alendronate and risedronate) and strontium ranelate aregenerally regarded as first-line treatment options for postmenopausal womenat high risk of fracture

† raloxifene is also a useful treatment option in younger postmenopausal womenwith vertebral osteoporosis

† HRT has a place in the management of osteoporosis in women withmenopausal symptoms and in other postmenopausal women who express aninformed preference for HRT over other treatments

*

*

*

Research agenda† accurate assessment of fracture probability in postmenopausal women using

BMD and clinical risk factors† demonstration of efficacy of available treatment options in postmenopausal

women with osteopenia† further development of selective oestrogen receptor modulators that avoid

unwanted effects of oestrogen but retain its benefits

1016 J. Compston

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how to manage osteoporosis after the menopause

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