Comparison of the effects of two different types of calcium supplementation on markers of bone metabolism in a postmenopausal osteopenic population with low calcium intake: a double-blind placebo-controlled trial.

OBJECTIVE: To investigate calcium supplements in postmenopausal women. Calcium supplements in postmenopausal women with a low calcium intake have been shown to prevent osteoporotic vertebral fracture, but calcium is variably absorbed and often poorly tolerated, which may limit effectiveness. METHODS: The study compared the efficacy and tolerability of 500 mg/day of calcium in the form of ossein-hydroxyapatite (OHC) versus 500 mg/day of tricalcium phosphate (TCP) and placebo in the prevention of postmenopausal bone loss. This was a prospective randomized study enrolling 153 postmenopausal osteopenic women. Serum and urine markers of bone turnover were collected at 3 and 6 months. Bone density measurement was performed at baseline and 6 months in all participants, and at 12 months in women taking OHC. RESULTS: At 3 and 6 months, both TCP and OHC decreased serum markers of bone formation significantly, compared with placebo. At 6 months, TCP and OHC decreased osteocalcin by 9.9% and 12.3%, respectively; the aminoterminal propeptide of type I procollagen (PINP) was decreased by 5.3% and 6.3%, respectively; bone-specific alkaline phosphatase was decreased by 4.3% and 6.7%, respectively, compared with baseline. The effects on bone resorption markers or on bone mineral density did not reach statistical significance, although OHC increased bone density by 0.8% at the spine at 12 months. Both forms of calcium were well tolerated and did not differ from placebo in terms of side-effects. CONCLUSIONS: While both OHC and TCP were well tolerated and significantly reduced bone turnover markers, the effect of ossein-hydroxyapatite seems slightly superior to that of tricalcium phosphate.

The effects of hormone replacement therapy on cortical bone in postmenopausal women. A histomorphometric study.

Investigations of the actions of estrogen on the skeleton have mainly focused on cancellous bone and there are no reported histomorphometric studies of the effects of oestrogen on cortical bone in humans. The aim of this study was to investigate the effects of both conventional hormone replacement therapy (HRT) and high-dose oestradiol on cortical bone in postmenopausal women. Transiliac biopsies were obtained from nine postmenopausal women aged 54-71 yr before and after 2 yr (mean, 23.5 months) of conventional HRT and in seven postmenopausal women aged 52-67 yr after long-term, high-dose oestradiol implant therapy (at least 14 yr). Indices of bone turnover, remodeling, and cortical structure were assessed by image analysis. Cortical width was highest in the women treated with high-dose oestrogen therapy (2.29 +/- 0.78 mm; mean +/- SD) and lowest in untreated women (1.36 +/- 0.60 mm; P=0.014). The proportion of canals with an eroded surface was significantly lower in the high-dose oestrogen group than in women before or after conventional HRT (3.03 +/- 3.7% vs. 11.1 +/- 7.1% and 10.5 +/- 8.6%; P=0.017 and 0.05, respectively). Bone formation rate (microm2/microm/day) in untreated women was significantly higher than in the high-dose oestrogen group (0.121 +/- 0.072 vs. 0.066 +/- 0.045, respectively; P=0.05), values in women treated with conventional HRT being intermediate. Our results provide the first histomorphometric evidence in postmenopausal women of dose-dependent oestrogen-induced suppression of bone turnover in iliac crest cortical bone. There was also a trend toward higher wall width with increasing dose of oestrogen, consistent with the previously reported anabolic effect in cancellous bone.

Factors affecting long-term adherence to hormone replacement therapy after screening for osteoporosis.

OBJECTIVE: To investigate factors likely to influence adherence to hormone replacement therapy (HRT) in women known to have low bone mass. STUDY DESIGN: This was a prospective study of bone mineral density screening in 6282 women aged 50-54 years. RESULTS: Low bone mass at either the hip or spine was found in 1462 women. The principal route of HRT delivery, transdermal or oral, as well as the presence of climacteric symptoms before starting treatment, did not influence adherence. However, adherence to HRT type was significantly superior in hysterectomized women taking unopposed estradiol (median 32 months) compared with those on sequential HRT (median 28 months; p = 0.011). Overall, a 5-year adherence to HRT of 61% was achieved. CONCLUSION: Approximately 34% of women starting HRT are likely to stop in the first 2 years of use. Following this, the discontinuation rate is low. The combination of knowledge of risk for osteoporosis and regular follow-up positively influences long-term adherence to HRT.

The maladies of James Boswell, advocate.

Literary criticism, like legal judgement, will ultimately rest upon the written word. However, since the context of that written word is conditioned by the author's physician and mental health - both of which can materially affect the content and style of the writing - these areas are worthy of serious enquiry. Where details of a great writer's health are unavailable - as with Shakespeare - speculative and often unsatisfactory conjectures have to account for variations in the quality and quantity of output. Where a disease process is known and independently attested, such as Milton's blindness, criticism of the works produced is materially enhanced. Whereas the volume of a writer's output wil be influenced by longevity and the physical ability to dictate or to lift a pen, the content and style will necessarily be influenced by his or her mental state, conditioning as it does the personal and societal environment of creativity.

Secondary prevention of osteoporosis: when should a non-vertebral fracture be a trigger for action?

The burden of non-vertebral fractures is enormous. Hip fractures account for nearly 10% of all fractures (and a much greater proportion in the elderly), while wrist fractures may account for up to 23% of all limb fractures. The best available predictors of non-vertebral fracture risk are low BMD and a tendency to fall. Hip, forearm, proximal humerus and rib fractures have all been associated with low BMD, though ankle fracture is not strongly related to osteoporosis. Although clinical risk factors identify only about one-third of postmenopausal women at increased risk of osteoporotic fracture, the occurrence of one fracture commonly predicts a second fracture. Guidelines are presented for identifying and treating patients at risk of non-vertebral osteoporotic fractures, especially those with a previous fracture, based on the algorithm recently published by the Royal College of Physicians and the Bone and Tooth Society. Prevention of falls and use of external hip protectors may reduce the occurrence of hip fracture. Treatment options for patients presenting with hip fracture include HRT, bisphosphonates, and calcium plus vitamin D, and for Colles' fracture include general measures, HRT, bisphosphonates, or calcitonin plus calcium.

The life and times of the estrogen receptors: an interim report.

The estrogens profoundly influence the growth, differentiation and function of the organs of the reproductive system such as the breast, uterus and ovary, but also have an effect on the non-reproductive tissues of the skeletal, cardiovascular and central nervous systems. Formerly, only one estrogen receptor (ER) was thought to mediate all functions. Now termed ER alpha, this agent was known to reside in the nucleus, to be activated by ligand and to direct the expression of target genes. A second oestrogen receptor (ER beta) has been identified, and estrogen influence has been further clarified through demonstration of actions which operate via membrane receptors and non-genomic pathways. This review summarizes our growing understanding of receptor structure, mechanism of action and tissue distribution, together with the implication of these data for the development and clinical delivery of estrogen replacement regimens.

Oestrogen and selective oestrogen receptor modulators (SERMs): current roles in the prevention and treatment of osteoporosis.

Post-menopausal oestrogen replacement therapy (HRT) is the agent of choice for restraint of post-menopausal bone loss. In numerous observational, and in a few intervention studies, it has been shown to reduce osteoporotic fractures. However, in order to be effective treatment has to be carried on long term. This is a task not easily achieved due to poor patient adherence. The majority of patients stop treatment after a few months. Fear of breast cancer and refusal to tolerate resumption of cyclic withdrawal bleeding are the principal objections. Newer and more user-friendly forms of treatment are needed. Ideally, these should have an efficacy similar to oestrogen on the central nervous system, cardiovascular system and bone, without adverse effects on the breast and uterus. With this in mind, Selective oestrogen Receptor Modulators (SERMs) have been developed. In this chapter we review how effective modern pharmacology has been in achieving an improved design of hormonal replacement for the post-menopausal women, and the place that it has obtained today alongside both older and newer forms of treatment.

Continued breast cancer risk reduction in postmenopausal women treated with raloxifene: 4-year results from the MORE trial. Multiple outcomes of raloxifene evaluation.

Raloxifene, a selective estrogen receptor modulator approved for the prevention and treatment of postmenopausal osteoporosis, has shown a significant reduction in breast cancer incidence after 3 years in this placebo-controlled, randomized clinical trial in postmenopausal women with osteoporosis. This article includes results from an additional annual mammogram at 4 years and represents 3,004 additional patient-years of follow-up in this trial. Breast cancers were ascertained through annual screening mammograms and adjudicated by an independent oncology review board. A total of 7,705 women were enrolled in the 4-year trial; 2,576 received placebo, 2,557 raloxifene 60 mg/day, and 2,572 raloxifene 120 mg/day. Women were a mean of 66.5-years old at trial entry, 19 years postmenopause, and osteoporotic (low bone mineral density and/or prevalent vertebral fractures). As of 1 November 1999, 61 invasive breast cancers had been reported and were confirmed by the adjudication board, resulting in a 72% risk reduction with raloxifene (relative risk (RR) 0.28, 95% confidence interval (CI) 0.17, 0.46). These data indicate that 93 osteoporotic women would need to be treated with raloxifene for 4 years to prevent one case of invasive breast cancer. Raloxifene reduced the risk of estrogen receptor-positive invasive breast cancer by 84% (RR 0.16, 95% CI 0.09, 0.30). Raloxifene was generally safe and well-tolerated, however, thromboembolic disease occurred more frequently with raloxifene compared with placebo (p=0.003). We conclude that raloxifene continues to reduce the risk of breast cancer in women with osteoporosis after 4 years of treatment, through prevention of new cancers or suppression of subclinical tumors, or both. Additional randomized clinical trials continue to evaluate this effect in postmenopausal women with osteoporosis, at risk for cardiovascular disease, and at high risk for breast cancer.

Effects of estrogens and hormone replacement therapy on breast cancer risk and on efficacy of breast cancer therapies.

This review summarises preclinical and clinical data on effects of endogenous and exogenous estrogens on probability of breast cancer diagnosis, and on the course and efficacy of breast cancer therapies. The data indicate that higher endogenous estrogen exposure (e.g. pregnancy, early menarche and late menopause, estrogen levels in future breast cancer patients, obesity) or exogenous estrogens (oral contraceptives; hormone replacement therapies) may be associated with an increased probability of breast cancer diagnosis. However, there is little evidence that estrogens have deleterious effects on the course of breast cancer. Moreover, increased incidence of breast cancer diagnosis after prolonged hormone replacement therapy (HRT) use seems to be associated with clinically less advanced disease. In studies assessing both diagnosis and mortality, HRT is frequently associated with reduced mortality compared to never users. The interaction of progestagens and estrogens on the probability of breast cancer diagnosis is complex and dependent on type of progestagens and regimens employed. Efficacy of current treatment modalities for breast cancer (surgery, irradiation, adjuvant therapy or chemotherapy) is not negatively influenced by estrogens at concentrations considerably higher than those attained with current HRT preparations. Although it cannot be excluded that estrogens increase the probability of breast cancer diagnosis, available data fail to demonstrate that, once breast cancer has been diagnosed, estrogens worsen prognosis, accelerate the course of the disease, reduce survival or interfere with the management of breast cancer. It may therefore be concluded that the prevalent opinion that estrogens and estrogen treatment are deleterious for breast cancer, needs to be revisited. However, results of ongoing prospective, randomised clinical trials with different HRT regimens in healthy women or breast cancer survivors are needed to provide more definite conclusions about risks and benefits of HRT.

Errors in the measurement of endometrial depth using transvaginal sonography in postmenopausal women on tamoxifen: random error is reduced using saline instillation sonography.

OBJECTIVE: The endometrium in women on tamoxifen is often made irregular by small cysts. The aim of this study was to assess the accuracy and precision of the measurement of endometrial depth by transvaginal sonography. METHODS: The endometrial depth from endometrial biopsies obtained with the resectoscope in 15 women receiving tamoxifen was compared to the endometrial depth measured by TVS. The inter-observer variability was measured in 58 women. RESULTS: In those biopsies of sufficient quality to allow a measurement, the corresponding depth measurement obtained by ultrasound was up to 3 mm greater than the histological measurement. The interobserver variability for the measurement of endometrial depth using TVS was assessed in 58 postmenopausal women on tamoxifen. The interobserver variability deteriorated as the mean endometrial depth increased, probably because the increase in depth resulted from greater morphological changes within the endometrium such as cyst formation which resulted in an irregular endometrial/myometrial boundary. This may, however, be improved by performing saline instillation sonography. In a prospective study of 10 postmenopausal women, the interobserver variability was significantly greater during tamoxifen treatment compared to pretreatment. CONCLUSIONS: On the basis of the above, if uterine surveillance using TVS were to be offered to postmenopausal women on tamoxifen, then the procedure should be augmented by saline instillation sonography if the endometrial depth is > 4 mm, as this will improve the measurement precision and also identify intrauterine pathology.

Consequences of long-term hormone replacement therapy.

The use of oestrogens in the longer term is an area of considerable current scientific and clinical debate. The extra-reproductive range of oestrogen actions is broad, with these steroid hormones and their receptors (ERs) being intimately involved in the normal function of, inter alia, the adult female skeleton, the cardiovascular system and the brain. Desirable as the restoration of normal circulating oestrogen may be after menopause, HRT use is compromised by the engagement of the reproductive sites of breast and uterus. This may cause concern to patient and physician alike due to the consequent imposition of cyclical bleeding and risk of breast malignancy. In the individual patient, therefore, a balance of risk against benefit has to be struck so that the patient may be precisely advised of the type and duration of oestrogen replacement which may be indicated in her own case. The advent of selective oestrogen receptor modulation with its ability to delete adverse effects in breast and endometrium, is a substantial pharmacological and clinical advance.

Bone remodeling and structure in postmenopausal women treated with long-term, high-dose estrogen therapy.

Conventional hormone replacement therapy preserves bone mass predominantly by reducing bone turnover but does not exert significant anabolic skeletal effects. In contrast, high doses of estrogen have been shown to increase bone formation in animals and we have recently reported high bone mineral density values in women treated long-term with estradiol implant therapy. The aim of this study was to investigate the mechanisms by which high doses of estrogen may increase bone mass in postmenopausal women. Iliac crest biopsies were obtained from 12 women who had received long-term treatment with estradiol implants (at least 14 years), on demand, following hysterectomy and bilateral salpingo-oophorectomy. Indices of bone turnover, remodeling balance and cancellous bone structure were assessed by image analysis and compared with those of premenopausal women. Mean wall width was significantly higher in women treated with estradiol therapy than in premenopausal women (44. 8 +/- 4.8 vs 38.8 +/- 2.8 mm; mean +/- SD; p = 0.001) and eroded cavity area was significantly lower in the implant-treated women (3612 +/- 956 vs 5418 +/- 1404 mm(2); p = 0.001). Bone formation rate at tissue level and activation frequency were lower in the women treated with implants, although the differences were not statistically significant. Indices of cancellous bone structure were generally similar between the two groups. These results provide the first direct evidence that high-dose estrogen therapy produces anabolic skeletal effects in postmenopausal women and indicate that these are achieved by stimulation of osteoblastic activity.

Changes in trabecular bone architecture in women during pregnancy.

OBJECTIVE: To examine the effect of early and late pregnancy on the microarchitecture of maternal cancellous bone. SAMPLE: Transilial bone biopsies were obtained from two groups of pregnant women one group (n = 15) in the first trimester and the other (n = 13) at term. Comparison was made with biopsy and autopsy samples from a group (n = 25) of normal premenopausal nonpregnant women. METHODS: Undecalcified sections were analysed under a low power optical microscope using an automated trabecular analysis system which measures a comprehensive range of structural variables including the bone volume, trabecular number, width, separation and connectivity. RESULTS: In early pregnancy the quantity of cancellous bone fell from a mean relative bone volume of 23.07% (SD 5.49) in nonpregnant controls to 16.72% (SD 3.91) (P < 0.001). This was primarily due to a decline in trabecular thickness from 122.9 microm (SD 10.5) to 97.2 microm (SD 21.8) (P < 0.01) and was accompanied by a loss of trabecular connectivity expressed as a reduction in the trabecular node: terminus ratio from 0.90 (SD 0.71) to 0.38 (SD 0.26) (P < 0.001). By late pregnancy the bone volume had been entirely restored to 23.41% (SD 9.76). This was primarily due to an increase in the number of trabeculae from 73.2 (SD 35.5)/field to 100.3 (SD 33.3) /field (P < 0.05)with an associated reduction in trabecular separation from 431 microm (SD 150) to 315.8 microm (SD 78.5) (P < 0.01). CONCLUSIONS: Pregnancy affects the maternal skeleton by producing a fluctuation in the cancellous bone volume in which early temporary bone loss through trabecular thinning is restored in entirety through the addition of new trabeculae to produce a modestly more complex system of thinner more numerous bars by term.

Prevention of postmenopausal bone loss at lumbar spine and upper femur with tibolone: a two-year randomised controlled trial.

OBJECTIVE: To examine the effects of tibolone on bone mineral density and its concurrent safety and subject acceptability. DESIGN: Prospective randomised controlled study. SETTING: Centre for Metabolic Bone Disease, Hull. POPULATION: Forty-seven healthy post-menopausal women aged 50-57 years with normal bone mineral density at lumbar spine. METHODS: Bone mineral density was assessed every 24 weeks at lumbar spine and proximal femur using dual energy X-ray absorptiometry. RESULTS: The bone mineral density of the tibolone treated subjects tended to increase while those of the controls tended to fall. The higher densities in the tibolone group were significant at lumbar spine from week 24 (P = 0.002) and at the trochanter from week 72 (P = 0.014). The lower bone densities in the controls were significant at Ward's Triangle and femoral neck at week 96 (P < 0.0001), and at lumbar spine from week 24 onwards (P < 0.05). Between-treatment analysis indicated that, by the 96th week, the bone densities at all sites in the tibolone group were significantly different from those in the control group. At the lumbar spine the differences were highly significant throughout the study (P < 0.0004). Four women receiving tibolone withdrew from the study due to unacceptable adverse events. Two women withdrew from the control group. There was no significant difference between the groups in the number of subjects suffering adverse experiences. Vaginal bleeding occurred in seven women, all from the tibolone treated group, resulting in one withdrawal from the study. CONCLUSION: Tibolone is thus an effective and well-tolerated alternative to oestrogen in the prevention of osteoporosis with its beneficial effects being most apparent at the lumbar spine.

Effects of sex steroids on sleep.

Sex steroid secretions are generally synchronous with the circadian rhythm and sleep, and there is evidence that prolactin secretion is sleep-dependent. Polysomnographically assessed changes in sleep during the menstrual cycle are characterized by increased EEG activity in the 14-15-Hz (sleep spindle) range in the luteal phase accompanying an increase in core temperature. There are no other consistent changes in sleep architecture associated with the menstrual cycle. The hot sweats which disturb sleep in menopausal women are attributable to oestrogen deficiency and are reduced by oestrogen replacement therapy. Although it is often assumed that the psychological changes during the menopause are attributable to chronic sleep disturbance caused by hot sweats, the evidence for this is uncertain. Sex steroids have also been shown to have a role in the aetiology of obstructive sleep apnoea and its treatment. It is clear that the sex steroids are all implicated in sleep and thermoregulatory processes, although we cannot as yet define their precise roles.

Premature greying of the hair is not associated with low bone mineral density.

In two recent case-control studies premature greying of the hair was associated with a lowering of bone mineral density (BMD) and osteopenia, suggesting that this might be a clinically useful risk marker for osteoporosis. We report a further re-examination of this proposal in 52 prematurely grey-haired women from East Yorkshire who responded to an advertisement inviting them for bone densitometry. Thirty-five had no clinical or drug history that could influence bone density. All were Caucasian with a mean age of 52.8 years. In the group as a whole the mean BMD values at the lumbar spine and femoral neck were no different from those of a young adult, but there was a trend toward a greater than average BMD than that of the local age-matched population (p = 0.097 and 0.218, respectively). Twenty women were premenopausal, with an average age of 45.3 years. Mean BMD values at the lumbar spine and femoral neck in this group were no different from those of young adults. There was, however, a trend toward a BMD greater than that of the local age-matched population at the femoral neck (p = 0.117). Fifteen women were postmenopausal with an average age of 62.9 years and an average age at menopause of 51.1 years. Mean BMD values at both the lumbar spine and femoral neck in this group were lower than those of young adults, but no different from those of the local age-matched population. In conclusion, our group of prematurely grey-haired women had average BMD for their age, and we are therefore unable to support the proposed clinical usefulness of premature greying as a risk marker for osteoporosis.