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Fact Sheets: Article

Title: Medical Alternatives to Hormone Replacement Therapy

Introduction

Publicity after publication of the Women's Health Initiative and the Million Women Study has lead to women stopping hormone replacement therapy. They may then be troubled with hot flushes and night sweats (vasomotor symptoms) or pain during intercourse (dyspareunia) and are concerned about their risk of osteoporosis. The use of standard medical alternatives is discussed.

Treating vasomotor symptoms

Progestogens such as norethisterone 5mgs/day or megestrol acetate 40 mg/day can be effective in controlling vasomotor symptoms. Of concern doses which achieve vasomotor symptom control increase risk of blood clot (venous thromboembolism). Short term studies show that selective serotonin-reuptake inhibitors such as venlafaxine, fluoxetine and paroxetine are effective in treating hot flushes and increase the range of options. However there are concerns about safety and addiction and their efficacy has been questioned in longer studies. Limited evidence also shows that gabapentin is effective. Clonidine is of limited value and effectiveness and propranolol is ineffective.

Prevention and treatment of osteoporosis

All agents except for parathyroid hormone and strontium ranelate act mainly by inhibiting bone resorption ( Table 1 ). Most studies have been undertaken in elderly women with osteoporosis or at increased risk of the disease and the placebo group received calcium and vitamin D supplements. There is very little information about the use of these agents on fracture in young women especially in those with a premature menopause. Calcium and vitamin D are particularly relevant to populations in northern latitudes where there is much evidence of vitamin D insufficiency. Most studies show that about 1.5G of elemental calcium is necessary to preserve bone health in postmenopausal women not taking HRT . Anti-fracture benefit has been found in elderly women and there is no evidence that calcium on its own is capable of reversing bone loss in the perimenopause. Vitamin D alone appears to reduce the risk of vertebral and nonvertebral fracture.

 

Table 1 Drug treatments for the prevention and treatment of osteoporosis

Source: the British Menopause Society osteoporosis care pathway 2004 eds Rees M and Purdie DW

  spine hip
1 Bisphosphonates    
Etidronate A B
Alendronate A A
Risedronate A A
Ibandronate A ND
2 Calcium and Vitamin D ND A
3 Calcium A B
4 Calcitriol A ND
5 Calcitonin A B
6 Oestrogen A A
7 Raloxifene A ND
8 Strontium ranelate A A
9 Parathyroid hormone peptides A ND

( ND= not demonstrated)

The levels of evidence for the various agents detailed below are:

A= meta-analysis of RCTs or from at least one RCT/ from at least one well designed controlled study without randomisation

B= from at least one other type of well designed quasi- experimental study / from well designed non- experimental descriptive studies eg comparative studies, correlation studies, case- control studies

 

Bisphosphonates

Alendronate, risedronate, ibandronate and etidronate, are used in the prevention and treatment of osteoporosis, and also corticosteroid-induced osteoporosis. Limited data suggest that in combination with estrogen, gain in bone mineral density is greater than that achieved by either agent alone.

Alendronate is administered either daily (10mg) or (70mg) once weekly.

Risedronate is administered either daily (5mg) or (35mg) once weekly.

Ibandronate is  administered either orally  daily (2.5 mg) or  monthly (150 mg); or  intravenously (3mg) every 3 months.

Etidronate is given intermittently ( 400mg, 14 out of every 90 days) with 1,250mg of calcium salts during the remaining 76.

The question of how long to prescribe a bisphosphonate has not been fully clarified yet, because of concerns about “frozen bone”, with complete turning off of bone remodelling with long-term use and also development of osteonecrosis in the jaw. Five years of treatment with a two-year “holiday” have been proposed for alendronate, but differences may exist with individual bisphosphonates. This may not be applicable to steroid-induced osteoporosis.

The vast majority of reports of osteonecrosis refer to high dose intravenous bisphosphonates used in the oncological setting. Very few cases have been reported in women using oral bisphosphonates for osteoporosis. At this stage clinical practice should not necessarily be altered, but dental review could be considered in women with significant dental disease.

Metabolism of bisphosphonates is an extremely slow process, indeed the half life of alendronate has been estimated as high as 12 years. There are concerns about effects on the fetal skeleton and bisphosphonates are not advised in women who wish to become pregnant.

All bisphosphonates are poorly absorbed from the gastrointestinal tract and must be given on an empty stomach. Food or calcium containing drinks (except water) inhibit absorption which at best is only 5-10% of the administered dose. The principal side effect of all bisphosphonates is irritation of the upper gastrointestinal tract. Symptoms resolve quickly after drug withdrawal. The question of how long to prescribe a bisphosphonate has not yet been fully clarified since bone mass appears to be maintained after cessation of treatment. Five years treatment with a 2-years “holiday” have been proposed for alendronate, but there may be differences with individual bisphosphonates. This may not be applicable to glucocorticoid-induced osteoporosis.

Selective Oestrogen Receptor Modulators (SERMs) Compounds that possess estrogenic actions in certain tissues and anti-estrogenic in others are called Selective estrogen Receptor Modulators or SERMs. Raloxifene is licensed for the prevention of osteoporosis-related vertebral fracture and is administered daily (60mg). Raloxifene does not treat menopausal symptoms and indeed may induce them and is therefore only suitable for asymptomatic post-menopausal women. It reduces the risk of breast cancer in women with osteoporosis.

Parathyroid hormone peptides Recombinant 1-34 parathyroid hormone, given as a subcutaneous daily injection of 20 µg, reduces vertebral and non-vertebral fractures in postmenopausal women with osteoporosis. The full 1-84 parathyroidhormone peptide is given in the same way in a daily dose of 100 µg. They both reduce the risk of vertebral but not hip fractures. Because they cost more than other options, they are reserved for patients with severe osteoporosis who are unable to tolerate or seem to be unresponsive to other treatments.

Strontium ranelate stimulates bone formation and inhibits bone resorption. In randomised placebo-controlled trials vertebral and hip fracture were reduced. The most common side effects are nausea and diarrhoea.

Calcitriol This is the active metabolite of vitamin D and facilitates the intestinal absorption of calcium. Evidence of efficacy is conflicting and the need to measure calcium levels in those receiving therapy limit its use.

Calcitonin Parenteral calcitonin is expensive and produces side effects such as nausea, diarrhoea and flushing and results in the production of neutralising antibodies in some patients. Its analgesic properties are useful for the pain of acute vertebral collapse. Nasal calcitonin has also been shown to reduce vertebral fractures but is not available in all countries

Dyspareunia

A variety of vaginal lubricants and bioadhesive moisturisers are available and can be bought without prescription. Some are available on prescription.

Further reading

Basu N, Reid DM. Bisphosphonate-associated osteonecrosis of the jaw. Menopause Int 2007;13:56-9.

Committee on Safety of Medicines. Selective serotonin reuptake inhibitor (SSRI) antidepressants - findings of the Committee on Safety of Medicines (CSM) Working Group. 6 December 2004

Poole KES, Compston JE. Osteoporosis and its management. BMJ 2006; 333: 1251-1256.

Rees M, Mander T. Managing the menopause without oestrogen. RSM Press. 2004.

Royal College and Obstetricians and Gynaecologists. Alternatives to HRT for the Management of Symptoms of the Menopause. Scientific Advisory Committee Opinion Paper 6. London: RCOG; 2006 [www.rcog.org.uk/index.asp?PageID=1561].

Suvanto-Luukkonen E, Koivunen R, Sundstrom H, et al. Citalopram and fluoxetine in the treatment of postmenopausal symptoms: a prospective, randomized, 9-month, placebo-controlled, double-blind study. Menopause 2005;12:18-26.

Vasilakis C, Jick H, del Mar Melero-Montes M. Risk of idiopathic venous thromboembolism in users of progestagens alone. Lancet. 1999 6;354:1610-1.

Writing Group on Osteoporosis for the British Menopause Society Council, Al-Azzawi F, Barlow D, Hillard T, Studd J, Williamson J, Rees M. Prevention and treatment of osteoporosis in women. Menopause Int 2007;13:178-81.

Margaret Rees

Sally Hope

March 2005 reviewed January 2008.

Whilst great care has been taken to ensure the accuracy of information contained in the fact sheets, the authors and the BMS cannot accept any responsibility for any errors omissions, mis-statements or mistakes or for any loss or damage arising from actions or decisions based on information contained in this publication. Ultimate responsibility for the treatment of patients and interpretation of published material lies with the medical practitioner. The opinions expressed are those of the authors, not necessarily those of the BMS. The inclusion in the publication of material relating to a particular product, method or technique does not amount to an endorsement of its value or quality, or of claims made by its manufacturer.
Margaret Rees and Sally Hope January 2008

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