European Journal of Clinical Pharmacology

, Volume 63, Issue 9, pp 843–849 | Cite as

Prescribing of hormone therapy for menopause, tibolone, and bisphosphonates in women in the UK between 1991 and 2005

Pharmacoepidemiology and Prescription

Abstract

Objective

The purpose of this study was to examine recent trends in the prescribing of hormone therapy for menopause, tibolone, and bisphosphonate preparations for the prevention or treatment of osteoporosis, in the UK in relation to publication of research evidence on the health effects of hormone therapy and subsequent changes in prescribing advice.

Methods

Individual patient-level data were obtained on the prescribing of hormone therapy, tibolone, and bisphosphonates by general practitioners in the UK between 1991 and 2005 to women aged 40 years and older in the UK General Practice Research Database. Overall and age-specific prescribing prevalence were calculated for each therapy type. Prescribing prevalence was also calculated for subcategories of hormone therapy and bisphosphonates.

Results

Prescribing of hormone therapy to women aged 40 years and older increased between 1991 and 1996 and remained fairly stable between 1997 and 2001. Hormone therapy prescribing has fallen by about 50% since 2002. Tibolone, a selective tissue estrogenic activity regulator, is prescribed much less commonly than hormone therapy but shows a similar pattern. Prescribing of bisphosphonates increased rapidly throughout the study period, particularly in women aged 70 years and older, with the pattern of prescribing reflecting to some extent, the availability of new weekly formulations.

Conclusions

Trends in the prescribing of hormone therapy in the UK appear to closely reflect new epidemiological evidence and prescribing advice. It is likely that the substantial fall in hormone therapy and tibolone prescribing seen since 2002 is a direct consequence of the publication of Women’s Health Initiative trial results and subsequent changes in advice given by the Committee on Safety of Medicines. The 1997 publication of results from the Collaborative Group on Hormonal Factors in Breast Cancer and 2003 publication of the Million Women Study findings may also have impacted on trends, particularly within certain age groups. The substantial and continuing increase in prescribing prevalence of bisphosphonates reinforces the need for research into the long-term risks and benefits of these therapies.

Keywords

Hormone therapy Bisphosphonates Prescribing Tibolone GPRD 

Introduction

During the late 1980s and early 1990s, it was widely believed that the health benefits associated with the use of hormone therapy outweighed the risks in postmenopausal women. This view was influenced by reports from observational studies of a reduced risk of coronary heart disease and of all-cause mortality associated with hormone therapy use [1, 2]. In the early 1990s, a number of randomised controlled trials were set up to test the hypothesis that hormone therapy reduced the risk of coronary heart disease and other vascular disease in postmenopausal women. The largest of these was the Women’s Health Initiative trial in the USA. In October 1997, the Collaborative Group on Hormonal Factors in Breast Cancer reported a significantly increased risk of breast cancer in current users of hormone therapy, based on most of the worldwide epidemiological evidence [3]. In July 2002, the oestrogen plus progestin arm of the Women’s Health Initiative trial was stopped early after a mean of 5.2 years of follow-up because results showed that overall risks of treatment exceeded benefits [4]. The trial reported increased risk of coronary heart disease, stroke, pulmonary embolism and breast cancer in the treatment group compared with placebo. In October 2002, the Committee on Safety of Medicines advised UK health professionals that hormone therapy should be used for the short-term relief of menopausal symptoms and not for the prevention of cardiovascular disease [5]. In August 2003, the Million Women Study, an observational study of women in the UK, reported a significant increase in breast cancer incidence in users of several different types of hormone therapy and in users of tibolone, a selective tissue estrogenic activity regulator (STEAR) [6]. Million Women Study investigators found that the use of oestrogen plus progestogen therapy caused a substantially greater increase in breast cancer than did oestrogen-only therapy. In April 2004, results from the oestrogen-only arm of the Women’s Health Initiative trial supported the finding of a greater effect of oestrogen plus progestogen hormone therapy than oestrogen-only therapy on breast cancer risk [7].

Use of both oestrogen-only and combined oestrogen plus progestogen hormone therapy reduces the risk of fracture in postmenopausal women [8, 9, 10]. However, in December 2003, the Committee on Safety of Medicines advised that, despite its effectiveness in preventing osteoporotic fractures, the balance of risks and benefits is such that hormone therapy should no longer be considered as first-line therapy for the prevention of osteoporosis [11]. Osteoporosis is common in postmenopausal women, and the incidence of osteoporotic fracture increases sharply with age. Due to an aging population, the impact of osteoporosis on the health and quality of life of postmenopausal women in the UK and the resultant economic pressure on the National Health Service (NHS) is likely to increase substantially in the future.

Following changes to available evidence and prescribing advice regarding hormone therapy, it is of interest to examine prescribing trends for hormone therapy and for therapies that may be used by postmenopausal women as alternatives to reduce menopausal symptoms and fracture incidence. These include tibolone and bisphosphonates. We used data from the UK General Practice Research Database (GPRD) [12] to examine trends in the prescribing of these therapies in women aged 40 years and older in the UK between 1991 and 2005.

Methods

The GPRD is a database of anonymised, longitudinal medical records from primary care in the UK. Information is downloaded directly from the clinical management software (Vision) of contributing general practices. There are over 3 million patients registered, with 356 practices currently contributing data, and almost 5.5 million patients from 388 practices have ever contributed data [12]. The database includes a record of all prescriptions issued to patients by their NHS general practitioner.

The data set for this study was extracted from the GPRD in June 2006 and includes prescription data to the end of 2005. The data set includes all women aged 40 years and older (in each year studied) who fulfil the GPRD acceptable patient criteria [12]. Prescriptions were identified for therapies within British National Formulary categories 6.4.1.1 [Oestrogens for hormone replacement therapy (HRT), which includes tibolone], 6.4.1.2 (Progestogens) and 6.6.2 (Bisphosphonates) [13]. Reasons for prescribing of bisphosphonates are not readily available in the GPRD. Therefore, to restrict analyses to bisphosphonates likely to have been prescribed for the prevention and treatment of osteoporosis, bisphosphonate preparations indicated for use in the treatment of Paget’s disease, hypercalcaemia of malignancy and bone metastases in breast cancer (clodronate, tiludronate, zoledronate, pamidronate, ibandronate 50 mg tablets and concentrate for intravenous infusion, risedronate 30 mg tablets and etidronate 200 mg tablets) were excluded. Hormone therapy preparations containing oestrogen were categorised as oestrogen-only or combined oestrogen plus progestogen according to the constituents listed in the British National Formulary. For the analyses, combined oestrogen plus progestogen hormone therapy is defined as either a single prescription for a combined preparation or a prescription for an oestrogen preparation and a separate prescription for a progestogen issued on the same day.

Prevalence of prescribing within the GPRD was calculated as the number of women with at least one prescription in a given year, expressed as a percentage of the total number of women in the age group studied registered as acceptable patients in the GPRD in that year. Women were eligible to be included in analyses from the beginning of the year in which they became 40 years old.

Prescribing data can only provide an estimate of true prevalence of use, as there will always be a proportion of prescriptions that are not dispensed or used. To minimise the impact of this, analyses excluded women who, throughout the time that they were registered with the GPRD, had only ever received one prescription for the therapy being investigated.

Results

There were 266,523 women aged 40 and older in the GPRD in 1991, increasing to 709,251 in 2005. Table 1 gives details of the study population and the number of women with at least one prescription for the therapies of interest for each year between 1991 and 2005.
Table 1

Summary of the data on population, number of prescriptions given and number of women receiving prescriptions for hormone therapy for menopause, and prescriptions of tibolone or bisphosphonates by year from 1991 to 2005 in women aged 40 years and older in the General Practice Research Database (GPRD)

Year

1991

1992

1993

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

2005

Total population of women aged 40+

266,523

315,421

342,834

360,972

385,086

407,965

452,333

496,517

533,649

599,705

649,462

700,801

705,100

723,412

709,251

Hormone therapy

Total number of prescriptions

79,433

108,221

131,130

145,071

163,235

187,202

208,583

231,580

247,009

280,597

297,222

299,382

241,230

181,468

152,026

Number of women receiving at least 1 prescription

21,982

30,787

38,233

44,158

51,208

59,023

67,150

74,945

80,648

91,509

96,380

100,211

82,042

61,020

49,673

Number of women excluded (only one prescription ever)

723

801

863

810

906

1,147

1,187

1,205

1,353

1,469

1,629

1,851

1,259

951

1,035

Tibolone

Total number of prescriptions

1,643

5,714

8,470

10,364

11,730

11,719

12,899

14,206

16,505

20,393

22,903

25,298

22,806

18,094

14,512

Number of women receiving at least 1prescription

878

2,239

3,093

3,751

4,200

3,879

4,382

4,787

5,680

6,726

7,529

8,519

7,737

5,893

4,583

Number of women excluded (only one prescription ever)

187

431

457

497

490

303

355

356

506

563

549

692

666

465

295

Bisphosphonates

Total number of prescriptions

0

1,188

3,019

4,593

6,600

11,658

17,733

24,341

31,207

40,247

60,324

97,402

138,879

188,576

218,494

Number of women receiving at least 1 prescription

0

583

1,238

1,735

2,466

3,555

5,141

6,886

8,640

11,070

14,211

18,497

22,933

27,441

29,927

Number of women excluded (only one prescription ever)

0

81

143

122

108

159

241

303

357

385

425

502

596

658

779

Hormone therapy for menopause

As shown in Fig. 1, the proportion of women aged 40 years and older in the GPRD with a prescription for hormone therapy showed a marked increase, from 8% in 1991 to 14% in 1996. Between 1997 and 2001, prescribing was fairly constant at ∼15%. Following the publication of results from the oestrogen plus progestogen arm of the Women’s Health Initiative trial in July 2002, there was a marked fall, with the proportion of women prescribed hormone therapy more than halving from 15% in 2001 to 7% in 2005.
Fig. 1

Percentage of women aged 40 years and older in the General Practice Research Database (GPRD) prescribed hormone therapy, tibolone or bisphosphonates for the prevention or treatment of osteoporosis (1991–2005)

Prescribing of both oestrogen-only and oestrogen plus progestogen hormone therapy showed broadly similar time trends to those seen overall (Fig. 1). However, before 2002, prescribing of combined oestrogen plus progestogen therapy was more common than prescribing of oestrogen-only therapy. In the years 1997–2001, ∼6% of women aged 40 years and older in the GPRD were prescribed oestrogen-only hormone therapy compared with almost 9% prescribed combined hormone therapy. The fall in prescribing after 2002 was greater for combined therapy than for oestrogen-only therapy, and by 2005 the types were prescribed with equal frequency (3.5% each).

Trends in hormone therapy prescribing between 1991 and 2005 differed somewhat between 5-year age groups (Fig. 2). Prescribing rose in all age groups between 1991 and 1996. After 1997, prescribing to women aged 40–44, 45–49 and 50–54 years levelled off or began to decrease. In women aged 55–59, 60–64 and 65–69 years, prescribing continued to rise after 1997, albeit more slowly than before. Prescribing to all age groups fell noticeably after 2001. Prescribing to women aged 40–44 years remained at less than 8% and to women aged 70 years and older at less than 5% throughout the study period. Throughout this time, women to whom hormone therapy was most commonly prescribed were those aged 50–54 years and 55–59 years. At the peak of prescribing in 1997, 35% of women aged 50–54 and 29% of women aged 55–59 years in the GPRD received a prescription for hormone therapy.
Fig. 2

Age-specific percentage of women aged 40 years and older in the General Practice Research Database (GPRD) prescribed hormone therapy (1991–2005)

Tibolone

Following its introduction in the early 1990s, prescribing of tibolone remained at ∼1% of all women aged 40 years and older in the GPRD until 2001 (Fig. 1). Prescribing fell from 1.1% in 2002 to 0.6% in 2005 (a relative decrease of 46%).

Bisphosphonates

As shown in Fig. 1, the proportion of women aged 40 and older in the GPRD with a prescription for a bisphosphonate preparation for the prevention or treatment of osteoporosis increased from 0.2% in 1992 to 4.1% in 2005. Prescribing increased at a greater rate following the introduction in 2000 of the once-weekly formulation of alendronate. By 2005, 87% of all women prescribed such bisphosphonates were using a once-weekly formulation. Figure 3a shows the prescribing of bisphosphonates by type. The most commonly used bisphosphonate in 2005 was the once-weekly formulation of alendronate, with just over 2.5% of women aged 40 years and older in the GPRD receiving at least one prescription for weekly alendronate in that year. The second most commonly prescribed bisphosphonate in 2005 was the once-weekly formulation of risedronate, at 1%, whilst prescribing was less than 0.5% for all other types.
Fig. 3

a Percentage of women aged 40 years and older in the General Practice Research Database (GPRD) prescribed bisphosphonates by type (1991–2005). b Age-specific percentage of women aged 40 years and older in the GPRD prescribed bisphosphonates for the prevention or treatment of osteoporosis (1991–2005)

Figure 3b shows the percentage of women in the GPRD with a bisphosphonate prescription by 10-year age group. Prescribing increased in all age groups throughout the period 1991 to 2005. Prescribing in 2005 was highest in the 80–89 years age group, at 11%, followed by the 70–79 years and 90+ years age groups, at 9%. Prescribing has increased most rapidly since 2000 in the 80- to 89-years and 90+ years age groups.

Discussion

Prescribing of hormone therapy to women aged 40 years and older in primary care in the UK increased rapidly between 1991 and 1996 then remained fairly constant at about 15% from 1997 to 2001. Since 2001, prescribing has fallen by over 50%. The most marked decrease closely followed the publication of results from the oestrogen plus progestogen arm of the Women’s Health Initiative trial and subsequent changes in prescribing advice in 2002. The proportion of women prescribed hormone therapy in 2005 (7%) was lower than in 1991 (8%). Tibolone, a selective tissue estrogenic activity regulator, is prescribed much less commonly than hormone therapy but shows a similar pattern, with a fall in prescribing of ∼50% since 2002. The 1997 publication by the Collaborative Group on Hormonal Factors in Breast Cancer [3] may have affected prescribing to women aged 45–54 years, in particular, as the prevalence of use of hormone therapy in this age group began to fall after 1997. The 2003 publication of the Million Women Study findings [6] may also have influenced the greater reduction in the use of combined therapy than in the use of oestrogen-only therapy.

Prescribing of bisphosphonate preparations for the prevention or treatment of osteoporosis increased rapidly throughout the study period. The pattern of prescribing seen for bisphosphonate product types closely reflects the availability of new products, with weekly formulations—which are more convenient to take than the previously available daily formulations—taking over from daily formulations soon after their introduction in 2000. The prescribing recommendations for use of hormone therapy for the prevention of osteoporosis changed in 2003. The prescribing of bisphosphonates for the prevention or treatment of osteoporosis was already increasing before 2003 and continued to do so afterwards. Bisphosphonates are prescribed predominantly to women aged 70 years and older. In 2005, 9% of women aged 70–79 years, 11% aged 80–89 years and 9% aged 90 years and older received a prescription for a bisphosphonate, likely to have been intended for the prevention or treatment of osteoporosis. These are the age groups at highest risk of osteoporotic fracture, and the age pattern is different from that of hormone therapy prescribing, which is highest at age 50–59 years, when menopausal symptoms are most common.

These are the first population-based patient-level data available from the UK showing trends in prescribing of hormone therapy in relation to new epidemiological evidence and prescribing advice. They are also the first data on recent trends in bisphosphonate prescribing in primary care in the UK.

The hormone therapy prescribing patterns are consistent with those from other studies over a similar time period using Prescription Pricing Authority and trial participant data from the UK [14, 15] and prescription database data from Ireland [16]. The results are also consistent with studies from other countries, including those from the USA [17] and Europe [18, 19]. All of these studies show a marked fall in hormone therapy prescribing in the last few years, which in the majority of cases occurred from 2002. In the Netherlands, prescribing did not begin to fall until 2003 and may reflect a response to the publication of the Million Women Study results [19]. Our results are also consistent with a previous study using GPRD data to investigate trends in hormone therapy prescribing between 1992 and 1998, prior to the publication of results from the Women’s Health Initiative trials [20].

Two studies of bisphosphonate prescribing, using data from women in the General Medical Services prescription database in Ireland [16] and aggregate, state-level data on quarterly drug use by Medicaid recipients from the USA [21] have shown a consistent increase in bisphosphonate prescribing in recent years, as was found by this study.

Strengths and weaknesses of the study

The GPRD is considered to be representative of the UK population [12]. Quality, completeness and accuracy of the data in the GPRD is ensured by training and regular feedback for contributing general-practice staff, in addition to a wide range of quality checks performed on data before inclusion in the main database [12, 22].

A limitation of all prescribing data, including that used here from the GPRD, is that it is not possible to determine whether prescriptions have subsequently been dispensed and the therapy taken by the patient. Sensitivity analyses showed that the exclusion of women who, throughout the time that they were registered with the GPRD, had only ever received one prescription for a given therapy made no difference to the prescribing patterns seen. The numbers of women excluded for each therapy and year are shown in Table 1.

An advantage of using prescribing data from the GPRD over dispensing data such as that held by the Prescription Pricing Division is the availability of individual patient data. This allowed, for example, those women who received prescriptions for an oestrogen-only hormone therapy preparation and a separate progestogen on the same day to be classified as users of combined oestrogen plus progestogen therapy. It also enabled stratification of results for all therapies by age group and the restriction of analyses of bisphosphonate prescribing to women only.

Unanswered questions and future research

Despite the fall in prescribing following the publication of the Women’s Health Initiative trial and changes in prescribing advice, hormone therapy is still a widely used treatment, with 7% of women aged 40 years and older—an estimated 1.1 million women in the UK— receiving a prescription in 2005. Hormone therapy has been, and continues to be, subject to observational and experimental research, which has led to the risks and benefits associated with hormone therapy becoming increasingly well understood. Tibolone has been less widely studied but has recently been shown to increase the risk of breast [6] and endometrial cancer [23, 24] and of incident and fatal stroke [25].

In 2005, 4% of women aged 40 years and older were prescribed a bisphosphonate for the prevention or treatment of osteoporosis— an estimated 600,000 women in the UK. Bisphosphonates are thought to be associated with short-term gastrointestinal adverse events, and a safety warning has been issued in the UK [26]. There is concern, however, about possible longer-term effects of bisphosphonate use, such as bones becoming brittle and more susceptible to fracture [27]. It is therefore important that continued emphasis is placed on the need for research into the long-term risks and benefits of these therapies. The substantial and continuing increase in prescribing prevalence of bisphosphonates and the continuing introduction of new formulations (such as the new monthly formulation of ibandronate) make this research particularly urgent.

Conclusion

Trends in the prescribing of hormone therapy in the UK appear to closely reflect new epidemiological evidence and prescribing advice. It is likely that the substantial fall in hormone therapy and tibolone prescribing seen after 2001 is a direct consequence of the publication of the Women’s Health Initiative trial result in 2002 and the subsequent changes in the advice given by the Committee on Safety of Medicines.

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Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  1. 1.Cancer Research UK Epidemiology UnitUniversity of OxfordOxfordUK
  2. 2.Pharmacoepidemiology Research Unit, Vigilance & Risk Management of Medicines (VRMM)Medicines and Healthcare Products Regulatory AgencyLondonUK

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