Depression and Osteoporosis

“PROFOX” - The post HRT nightmare

The imaginary hybrid drug PROFOX is an anxious prediction of a therapeutic disaster for post menopausal women who need treatment for low bone density, depression , pelvic atrophy and vasomotor symptoms but are denied estrogens.

Physicians and psychiatrists have been slow to accept the clear benefits of estrogen therapy in the treatment of osteoporosis and depression. Is it an honest fear of side effects, ignorance of hormone therapy, misinterpretation of the data or simply a territorial hold on the condition which then condemns women to sub optimal therapy?

Although estrogens have been proven to prevent fractures in a mixed risk population and that the benefits on bone density and histology are dose dependant it has been relegated to a treatment to be used if others fail or if the woman has severe menopausal symptoms. This protection from estrogens effects not only the skeleton but also the intervertebral discs which make up one quarter of the length of the spinal column. This latter benefit is not produced by bisphosphanates. This failure of physicians to familiarise themselves with estrogen therapy has, in their minds, been justified by the results of the WHI study and by the regulatory bodies who have advised that estrogen should not be first choice therapy for osteoporosis. But in reality the physicians objections to estrogen therapy antedated the WHI study by many years. Specialists are a product of their training which for non gynaecologists does not include the subtleties of the use , the dose and route of various estrogens , gestogens and occasionally androgens.

Updated information and interpretation of the WHI study indicates that HRT, particularly estrogen alone, is both safe and protective in the younger postmenopausal woman below the age of 60. Such therapy is associated with fewer fractures , less colon cancer , fewer heart attacks , possibly less breast cancer and certainly fewer deaths. It should, in the minds of many workers, be first line therapy in this situation. However, Fosamax Once Weekly is an inexpensive alternative recommended by NICE as first line therapy and preferred by physicians. It produces lesser skeletal and systemic benefit than estrogens but it does not confuse the medical attendant with hormonal side effects such as bleeding, mastalgia and occasional PMS symptoms. These are problems that can be dealt with by any competent general practitioner but have not been learned by specialist bone physicians and rheumatologists who also seem to be complacent about considerable long term side effects of bisphosphanates.

A similar ‘turf war’ occurs with the commonplace depression in perimenopausal women. These women with estrogen responsive depression often have a history of postnatal depression and premenstrual depression which have all been shown to be effectively treated by transdermal estrogens in good controlled trials in the most prestigious journals . It is therefore surprising that none of these studies have been repeated by those mostly responsible for the treatment of depression in women. This neglect is either due to the unlikely belief that these studies are perfect or because psychiatrists and the pharmaceutical industry do not want to show the benefits or even the superiority of estrogens. For example there is only one placebo controlled study demonstrating that transdermal estrogens are effective in treating severe premenstrual depression by suppressing ovulation but there are now 50 similar studies showing that SSRIs are useful. Why should the industry fund studies that reveal that their high profit in patent drug is less effective than the much less profitable estrogens?

Psychiatrists almost invariably refuse to accept these data relying upon psycho therapy , SSRI’s and even ECT particularly in the private sector. Once again it is to the disadvantage of the women that psychiatrists have not chosen to become aware of this modality of treatment. It is commonplace to see women with perimenopausal depression who have been taking many mood stabilizing drugs for many years .They claim to have been last well during their last pregnancy after which they started or recommenced antidepressants for post natal depression , later pre menstrual depression and climacteric depression. It is difficult to obtain precise data but antidepressants are now used by about 30% percent of women in the UK and there is even a move to use this drug for the treatment of vasomotor symptoms. It is barely effective but it is becoming a new indication for SSRI therapy.

The nightmare for the future is that postmenopausal women with hot flushes, depression , sexual problems and low bone density, who need estrogens perhaps with testosterone, will be given a SSRI and bisphosphanate combination . PROFOX, a Frankenstein combination of PROzac and FOsamaX . As these two drugs are now available as cheap generics they are already being prescribed together. Unfortunately this warning of a single preparation is not a fanciful aberration as we already have close to the market a combination of a SERM for osteoporosis combined with oestrogens to prevent the symptoms of oestrogen deficiency. This was a joke comment at a British Menopause Society debate 10 years ago but has now become a reality. Unless the regulatory authorities consider the current safety data in the under 60s and modify their resistance to HRT the spectre of PROFOX will be upon us. It is a vision of the future which must be avoided.

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Oestrogens for the prevention and treatment of osteoporosis in women below the age of sixty

John Studd

In spite of the evidence that estrogens produce the greatest dose dependent increase in bone density and that they have been shown to be effective in preventing osteoporotic fractures  of the hip and spine their use has been relegated to second line or even unacceptable therapy in the hands of bone physicians and rheumatologists. This may be the result of the post WHI recommendations that

• HRT should be used as a short term treatment for menopausal symptoms, using the lowest dose for the shortest time necessary.
• HRT may be used as a second line treatment for osteoporosis for those who are unable to tolerate other osteoporosis drugs.

If so the advice is inappropriate for women under the age of 60 and in reality the physician’s objection to HRT ante dated the WHI studies by many years .Could it be that they were not comfortable with the minor side effects of HRT such as mastalgia, endometrial hyperplasia, and the PMS symptoms of progestogen intolerance which could be dealt with by any competent general practitioner?.

It is worth considering the pros and cons of hormone therapy in this age group as well as outlining the disadvantages of non hormonal therapy. Although the benefits on the skeleton may be small it is not disputed that such patients be given life style advice on alcohol, smoking and exercise as well as calcium and vitamin D supplementation. In this article the value or otherwise of estrogen therapy will be discussed.

The beneficial effects of estrogens should be considered noting that different symptoms need different hormone in different does by different routes depending on the age and surgical status of the woman. The one dose fits all treatment of asymptomatic 50-79 year olds of the WHI study was a decision of monumental clinical incompetence from which women now denied HRT continue to suffer.

Typical menopausal symptoms of flushes, night sweats, insomnia, tiredness together with pelvic atrophy causing dyspareunia and recurrent cystitis respond well to low dose estrogens. Depression, loss of libido and other quality of life issues usually are helped with estrogens often with the addition of testosterone. In fact most patients on the correct dose and mixtures of hormones feel so well that they are unwilling to discontinue HRT after 5 or 10 years if this is the duration ultimately recommended by advisory bodies. Hence there is a reluctance to take bisphosphanates

In the first three years after the menopause women lose 25% of their body collagen most notable from the skin, ligaments, tendons, nails, the intervertebral discs and the bone matrix. It has been shown that estrogens can replace the missing skin collagen and skin thickness but how does the skeletal system benefit from preservation or replacement of collagen?

Histomorphometric studies of biopsies of 16 osteoporotic women taken before and after 6 years percutaneous estradiol, when the spinal bone density has increased by 28% showed a 26% increase in collagen in cancellous bone and a 7% increase in cortical bone. There was also an increase in intermediate and mature collagen cross links indicating continuing collagen production. Similar biopsy studies of 22 patients with a mean increase vertebral bone density of 29% showed an increase in wall thickness, volume of cancellous bone increased trabecular thickness The repair of the microfractures of osteoporotic bone is strongly suggested by the increase in trabecular buds and the decrease in trabecular ends. This indicates that the therapy is not merely thickening broken trabeculae but new strong bone is being produced All of these quantifiable beneficial changes have a direct significant correlation with the plasma estradiol levels achieved during therapy.  There are no such studies of bone histology showing similar benefits from bisphosphanates

More recent work on the intervertebral disc is equally reassuring. The discs are 100% collagen and make up ¼ of the length of the spine. Two studies performed independently   have shown that estrogens protect the spine by maintaining the size of the disc space and the length of the spine. Bisphosphanates do not. This information publishes in journals o gynaecological endocrinology have not yet come to the attention of bone physicians

On this evidence HRT would seem to have a better effect on flesh and bone , general wellbeing , mood and sexuality than non hormonal options. But is it safe?

The optimism of HRT has been challenged by the much criticised WHI and Million Women studies which revealed an increase in breast cancer and surprisingly an increase in heart attacks and strokes when all but one case control studies indicated a considerable decrease in heart attacks. Indeed the data on heart attacks was so convincing that the prevention of coronary disease became a principle indication for HRT particularly in the USA

The data collection from a single questionnaire of the Million Women’s Study is so eccentric and has been so severely criticised that it is difficult to judge the value of any of the conclusions from these papers.  The extrapolation of data over time from the single questionnaire is completely unsound and it is fair to say that internationally this is recognised.  A comprehensive analysis of these reviews has recently been published.

On the other hand the epidemiology of the WHI study as a randomised control study was sound but they chose asymptomatic patients of the wrong age, with 22% starting therapy over the age of 70, using the wrong dose and coming to the wrong conclusions.  Even though Prempro combination of Premarin 0.625 mgs and Provera 2.5 mgs as continuous therapy is not available in this country, there was still an excellent result in patients who start this therapy below the age of 60 with fewer heart attacks occurring, a slight increase in breast cancer and a significant reduction in fracture of the hip (spine), colon cancer and mortality.

It seems from various studies it is the progestogen which is the risk factor for breast cancer.  This the oestrogen only arm of the WHI study showed a decrease in breast cancer, heart attacks, osteoporotic fractures and mortality.  As 97% of our patients on HRT start this therapy below the age of 60, this is the important group in our clinical practice.  Thus there should be no proscription on the use of oestrogens, particularly oestrogens alone for the prevention and treatment of osteoporosis in women under the age of 60.

Oestrogens would be the correct first line therapy in women under the age of 60 and the less effective bisphosphanates, which are not without long term side effects should be used in women where there is the rare contraindication to oestrogen therapy or those that are non responders.  It should be remembered that 25% of women do not have an increase in bone density with the use of Bisphosphonates although this is a very rare occurrence in patients using HRT.

The rejection of oestrogens as a simple safe and effective therapy in patients below the age of 60 is incorrect. It is also clear that the thrombogenic potential of Prempro with its continuous daily progestogen and oral oestrogen is not reproduced by the use of transdermal oestradiol. The future for the older osteoporotic patient with osteoporosis may be by this route of oestradiol as much as by non  hormonal preparations with their own side effects.

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Oestrogens and Osteoporosis

Osteoporotic fractures occur in one third of women, principally the hip (neck of femur), the vertebral bodies and the wrist. Apart from the life-threatening fracture of the hip which occurs in the older age group of women, the collapse fractures of the lumbar and thoracic vertebra produce pain, loss of height and the deformity of the dowager's hump. The capacity of the chest is diminished and women have their heart and lungs squashed up into small volume producing greater distress.

The tragedy is that osteoporotic fractures should be preventable as it is, for the most part, a product of post-menopausal oestrogen loss and can be prevented by oestrogen replacement. There are other causes such as anorexia as these women can have several years without periods and hence oestrogen production. Similarly, a previous hysterectomy with removal of ovaries produce profound, prolonged oestrogen deficiency. Steroid therapy, renal disease, thyroid disease, malnutrition as a growing child and, of course, family history are all important risk factors.

It is also important to realise that oestrogens can substantially increase bone density (not just prevent bone loss) particularly in the over 60's with low bone density. Hence it is never too late, nor the patient too old to start oestrogen therapy. Oestrogens will not, of course, correct the deformities that have occurred through osteoporotic fractures.

Unfortunately many women find it difficult to take oestrogens for a long period of time because of the side-effects of bleeding, breast discomfort, PMS-type symptoms as well as the fear of breast cancer and weight gain.

The acceptability of oestrogen therapy can be improved by using the correct dose, i.e. the dose that makes women feel better without producing side-effects, perhaps using a non-bleeding combination so that the woman does not experience unwanted cycles and perhaps the addition of testosterone in the woman who has loss of energy, loss of libido and depression.

It is clearly important to use a dose that works and use an oestrogen where the blood levels can be measured in the case of an inadequate or inappropriate response. Oestradiol is the most satisfactory oestrogen to use, either by tablets, patches, creams or implants in a dose which produces an oestradiol level of at least 300 pmol/l . Tibolone, a more complex oestrogen, which allows non-bleeding treatment is also effective in the post-menopausal woman.

Reference

1. Studd, JWW., Arnala, I., Kicovic, PM., Zamblera, D., Kroger, H., Holland, EFN. (1998) A randomised study of Tibolone on bone mineral density in osteoporotic post-menopausal women with previous fractures. Obstetrics & Gynecology 92, 574-9.
   
   
2. Studd, J., Zamblera, D. (1994) Estrogen therapy in women over 60 years og age. Gynecol. Endocinol. 8, 191-196.
   
   
3. Studd, J., Holland, EFN., Leather, A., Smith, R. (1994). The dose-response of percutaneous oestradiol implants on the skeletons of post-menopausal women. BJOG 101, 787-791.
   
   
4. Holland, EFN., Studd, JWW., Mansell, JP., Leather, AT., Chambers, TJ (1994) Histomorphometric changes in the skeleton of post-menopausal women with low bone mineral density treated with percutaneous estradiol implants. Obstet. & Gynecol 83, (3), 387-391.
   
   
5. Holland, EFN., Leather, AT., Studd, JWW., Garnett, TJ. (1993). The effect of a new sequential oestradiol valerate and levonorgestrel preparation on the bone mineral density of post-menopausal women. BJOG, 100, 966-967.

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