Menopausal hormone therapy for the management of osteoporosis.

Postmenopausal osteoporosis is a frequent clinical condition which affects nearly 1 in 3 women. Estrogen deficiency leads to rapid bone loss which is maximal within the first 2-3 years after the menopause transition and can be prevented by menopause hormone therapy (MHT). Not only, MHT prevents bone loss and the degradation of the bone microarchitecture but it significantly reduces the risk of fracture at all bone sites by 20-40%. It is the only anti-osteoporotic therapy that has a proven efficacy regardless of basal level of risk, even in low-risk women for fracture. Following the publication of the WHI results, use of MHT has considerably declined due to safety concerns which raise the question as to whether it might still be used in the prevention of osteoporosis. Over the last years, subsequent re-analyses of the WHI and further trials have challenged the initial conclusions of the WHI. It is now clearer that the individual benefit-risk balance of MHT is dependent on the individual risk profile in each woman as well as whether estrogen is opposed or unopposed, the type of estrogens and progestogens or doses and routes of administration. It must be also reminded that to date osteoporosis is a chronic disease that cannot be cured. The choice of the 1st treatment option should thus always be made in the context of a more comprehensive long-term strategy. This is particular true in early postmenopausal women found to be at low/moderate risk of fragility fracture over the first 10 years after menopause but who may have a much greater lifetime risk. In the absence of contraindication, use of MHT should be considered as a 1st option for the maintenance of bone health in those women where specific bone active medications are not warranted. Subsequent reassessment of the individual benefit-risk balance of MHT is thereafter recommended, with the possibility of switching to another osteoporosis treatment if the balance is not considered as favourable as at the beginning of the menopause for women still at high risk of fracture.

TBS in early postmenopausal women with severe vertebral osteoporosis.

INTRODUCTION/BACKGROUND: Severe vertebral osteoporosis is a rare condition in early postmenopausal women. We seek to determine whether Trabecular Bone Score (TBS), which is a new bone texture measurement, could be of additional value in evaluating trabecular bone properties in this population. METHODOLOGY: Lumbar spine (LS) and femoral neck (FN) bone mineral densities (BMDs) and TBS were measured in 105 early postmenopausal women (group 1: "cases", mean age: 53.1 ± 2.6 yrs.) with severe vertebral osteoporosis defined as a vertebral BMD T-score ≤ 3, as well as in 105 healthy postmenopausal women matched for age (group 2) and 105 older osteoporotic women matched for vertebral BMD (group 3, mean age: 63.9 ± 4 yrs.). None of the women had a secondary cause for osteoporosis. Correlations between TBS values and BMD were calculated after controlling for clinical characteristics. RESULTS: The women in group 1 (cases) were significantly smaller and thinner and had a history of more fractures than the age-matched controls (p < 0.05). Mean LS and FN BMD values were significantly lower in the cases than in the age-matched controls (0.770 ± 0.05 vs 1.106 ± 0.11 g/cm2 and 0.700 ± 0.07 vs 0.872 ± 0.12 g/cm2, for LS and FN, respectively; p < 0.001). The mean TBS value was also significantly lower in the cases than in the age-matched controls (1.24 ± 0.08 vs 1.37 ± 0.07, p < 0.001) but significantly higher than in the older osteoporotic controls (1.20 ± 0.07, p < 0.05). After adjustment for vertebral BMD, the difference in TBS values between the cases and the age-matched controls was no longer significant although it remained significantly higher than in the older osteoporotic controls. This would suggest that in group 1, osteoporosis is rather the consequence of a low peak bone mass than of further bone degradation while the greater decrease in TBS value in elderly osteoporotic controls is more likely to reflect additional damage in bone microarchitecture associated with aging. In a multivariate analysis including age, vertebral and femoral neck BMD, height and weight (R2 = 0.60, p < 0.0001), TBS was found to be negatively and independently associated with age (r = -0.31 p < 0.0001) and height (r = -0.20 p < 0.001). The FRAX score was significantly higher in group 1 and group 3 women than in the healthy control women (group 2). There were no changes in the results after adjustment for TBS. CONCLUSIONS: Women presenting with severe vertebral osteoporosis at the beginning of menopause have TBS values that are, first and foremost, proportional to their BMD. Whether this indicates that osteoporosis in this population is the consequence of a low peak bone mass remains to be determined and further studies are required. Nevertheless, the value of measuring TBS in addition to BMD appears to be relatively negligible in early postmenopausal women with severe vertebral osteoporosis.

Bone mineral density in women with deep infiltrating endometriosis who have undergone early bilateral oophorectomy.

OBJECTIVE: To study bone mineral density (BMD) in women with and without pelvic deep infiltrating endometriosis (DIE) who underwent early bilateral oophorectomy (BO). METHODS: A case-control study was performed in 83 women who underwent early BO before the age of 45 years, 31 for DIE and 52 for another clinical condition. All the women answered a standardized computer-assisted questionnaire to record their clinical and historical data and were medically examined. Lumbar spine and femoral neck BMDs were measured by dual-energy X-ray absorptiometry after early BO. Simultaneously, serum calcium, intact parathyroid, 25-hydroxyvitamin D, and cross-linked C-telopeptide were also measured. Unadjusted and adjusted odds ratios (with 95% confidence intervals [CI]) for endometriosis were calculated using logistic regression. RESULTS: The mean lumbar spine and femoral neck BMDs were significantly higher in women who underwent early BO for DIE than in those who underwent early BO for another clinical condition. After adjusting for age at BMD measurement, years since menopause, age at menarche and body mass index, odds ratio for endometriosis associated with a 1-SD increase in lumbar spine and femoral neck BMD was 2.59 (95% CI: 1.45-4.62) and 2.16 (95% CI: 1.23-3.81), respectively. CONCLUSION: Higher lumbar spine and femoral neck BMDs are associated with an increase in the likelihood of pelvic DIE in women who underwent early BO. This might be expected to the extent that endometriosis is itself associated with enhanced estrogen status, although further studies are needed to confirm such a hypothesis. These findings suggest that BMD measurement could contribute to the hormonal management of surgical menopause in women with DIE.

24 hours calciuria: normal values, regulations: about a cohort of 317 control subjects.

In a control population, we filed the 24-hour urinary calcium to set normal values, based on weight, BMI and menopause. By assessing calcium intake, 25OHD, PTH, CTX, GFR, we wanted to study how these could influence calcium excretion. A total of 317 subjects of 55.82 ± 12.6 years were studied: 249 women (210 were postmenopausal) and 66 men. Mean urinary calcium 24h was 4.07 ± 2.53 mmol: 3.99 ± 2.89 in men, 3.54 ± 2.44 in premenopausal women, 4.18 ± 2.42 in postmenopausal women. 24-hour urine calcium was lower in overweight subjects whether they are men or women. It was positively correlated to 25OHD, CTX, GFR, serum calcium and negatively to PTH, BMI and weight. In conclusion, urinary calcium was lower in overweight subjects, it increases after menopause. Dietary calcium intake seems little involved in explaining variations in urinary calcium which depends essentially on bone remodeling (CTX), GFR, levels of vitamin D and PTH.

[Vitamin D deficiency prediction by patient questionnaire and secondary hyperparathyroidism in a cohort of 526 healthy subjects in their fifties]. / Le déficit en vitamine D, très fréquent, n'entraîne qu'exceptionnellement une hyperparathyroïdie secondaire chez des sujets sains de la cinquantaine: cohorte de 526 sujets.

INTRODUCTION: Can vitamin D deficiency be predicted by patient questionnaire? Does it lead to secondary hyperparathyroidism that may cause excessive bone resorption? We studied non-osteoporotic subjects in their fifties, in whom vitamin D levels are often tested. PATIENTS AND METHODS: Patients hospitalised for degenerative osteoarthritis or consulting for assessment of menopause, without renal failure and not treated with vitamin D, completed a questionnaire on sun exposure and underwent measurement of serum calcium, creatinine, 25OH vitamin D, PTH and CTX. RESULTS: Five hundred and twenty-six subjects, mean age 54.6 years (71% women), were investigated throughout the year. 25OH vitamin D levels were correlated with sun exposure and varied according to the month of the year, unlike PTH and CTX levels. From November to May, over 90% of subjects had 25OH vitamin D levels<30ng/mL. Of the subjects who did not expose their face, arms and legs to the sun for at least 20min/day, 94% had 25OH vitamin D levels<30ng/mL. PTH levels were negatively correlated with those of 25OH vitamin D. Serum CTX levels were not correlated with PTH or 25OH vitamin D. Only 13% of subjects presented with secondary hyperparathyroidism, characterised by serum calcium<2.55mmol/L and PTH>65pg/mL, associated with increased CTX levels. CONCLUSION: Vitamin D deficiency can be predicted by patient questionnaire. It very rarely leads to secondary hyperparathyroidism.

Fracture risk in early postmenopausal women assessed using FRAX.

OBJECTIVES: To evaluate FRAX 10-year fracture probabilities depending on the recommended management strategy in early postmenopausal women who were untreated at baseline. METHODS: We conducted a descriptive study in 494 untreated women aged 45-60 years seen for the first time at a menopause clinic. Risk factors, physical findings, and bone mineral density (BMD) values determined by dual-energy X-ray absorptiometry were collected. At the end of the clinic visit, 128 (26%) women were prescribed medications. Then, the 10-year fracture probability was estimated using the FRAX tool. RESULTS: The mean FRAX probability was 3.9%+/-2% for major osteoporotic fractures and 0.8%+/-0.9% for hip fractures. Women who were prescribed medications had significantly (P<0.001) higher probabilities than the other women. The proportion of women prescribed medications increased significantly (P<0.0001) with the FRAX probability, from 7.8% in the lowest quintile (Q1) to 50.5% in Q5. Hormone replacement therapy or raloxifene contributed 92% of the prescriptions in patients with FRAX probabilities in the first four quintiles and bisphosphonates 70% of prescriptions in patients with probabilities in Q5. CONCLUSIONS: Early postmenopausal women had low to moderate fracture risks (FRAX, 3-4%). The indications and type of drugs prescribed correlated with FRAX probabilities. Treatment thresholds should be defined to optimize the management of osteoporosis. In early postmenopausal women, treatment thresholds may vary with the type of treatment.

Fracture risk prediction using BMD and clinical risk factors in early postmenopausal women: sensitivity of the WHO FRAX tool.

The aim of this prospective study was (1) to identify significant and independent clinical risk factors (CRFs) for major osteoporotic (OP) fracture among peri- and early postmenopausal women, (2) to assess, in this population, the discriminatory capacity of FRAX and bone mineral density (BMD) for the identification of women at high risk of fracture, and (3) to assess whether adding risk factors to either FRAX or BMD would improve discriminatory capacity. The study population included 2651 peri- and early postmenopausal women [mean age (+/- SD): 54 +/- 4 years] with a mean follow-up period of 13.4 years (+/-1.4 years). At baseline, a large set of CRFs was recorded, and vertebral BMD was measured (Lunar, DPX) in all women. Femoral neck BMD also was measured in 1399 women in addition to spine BMD. Women with current or past OP treatment for more than 3 months at baseline (n = 454) were excluded from the analyses. Over the follow-up period, 415 women sustained a first low-energy fracture, including 145 major OP fractures (108 wrist, 44 spine, 20 proximal humerus, and 13 hip). In Cox multivariate regression models, only 3 CRFs were significant predictors of a major OP fracture independent of BMD and age: a personal history of fracture, three or more pregnancies, and current postmenopausal hormone therapy. In the subsample of women who had a hip BMD measurement and who were not receiving OP therapy (including hormone-replacement therapy) at baseline, mean FRAX value was 3.8% (+/-2.4%). The overall discriminative value for fracture, as measured by the area under the Receiver Operating Characteristic (ROC) curve (AUC), was equal to 0.63 [95% confidence interval (CI) 0.56-0.69] and 0.66 (95% CI 0.60-0.73), respectively, for FRAX and hip BMD. Sensitivity of both tools was low (ie, around 50% for 30% of the women classified as the highest risk). Adding parity to the predictive model including FRAX or using a simple risk score based on the best predictive model in our population did not significantly improve the discriminatory capacity over BMD alone. Only a limited number of clinical risk factors were found associated with the risk of major OP fracture in peri- and early postmenopausal women. In this population, the FRAX tool, like other risk scores combining CRFs to either BMD or FRAX, had a poor sensitivity for fracture prediction and did not significantly improve the discriminatory value of hip BMD alone.

Osteoporosis in otherwise healthy perimenopausal and early postmenopausal women: physical and biochemical characteristics.

Population studies have shown that about 3-5% of perimenopausal women already have osteoporosis according to the WHO definition of osteoporosis for postmenopausal women ( t -score

Aromatase and regulation of bone remodeling.

Estrogens play a key role in regulating bone mineralization. Bone tissue expresses the enzymes that metabolize estrogens, as well as the alpha and beta receptors that mediate responses to estrogens. After the menopause, estrogen secretion by the ovaries is promptly replaced by production within tissues, which occurs chiefly via aromatization of adrenal steroids. Therefore, aromatase activity is a major determinant of estrogen activity in postmenopausal women. Studies are beginning to shed light on the mechanisms by which aromatase activity influences bone remodeling.

[Management of postmenopausal osteoporosis]. / Traitement de l'ostéoporose post-ménopausique.

Current management of postmenopausal osteoporosis has benefited from several advances both in the screening or those women with the highest risk of fracture and the development of efficient drugs to reduce the occurrence of fracture. At the individual level, assessment of the risk of fracture must associate the level of bone mineral density which represents the major determinant of fracture and several clinical risk factors. Measurements of biochemical markers of bone turnover are sometimes useful to improving this risk evaluation. However, the 5- to 10-year absolute risk or fracture still needs to be determined as well as the threshold above which a therapeutical intervention should be warranted. Besides hormone replacement therapy, which indications are now more limited than before, the different therapeutical options include several anti-osteoclastic drugs and more recently new anabolic compounds. It should be now possible to anticipate a long term strategy for the prevention of osteoporosis based on an early screening of the women at higher risk of fracture as well as the optimal choice of treatment taking into account the age and underlying clinical conditions of each woman.

Association of cardiovascular risk factors with intima-media thickness of the carotid arteries in early postmenopausal women.

OBJECTIVE: The aim of this study was to examine the association between carotid intima-media thickness (IMT) and coronary heart diseases (CHD) risk factors in a large population of peri- and postmenopausal women. DESIGN: Participants in this study were 906 healthy peri- and postmenopausal women from southwestern France, 45 to 65 years old with no history of cardiovascular disease and no utilization of estrogen/hormone therapy. Women were classified either as perimenopausal (n = 240) or post-menopausal (n = 666) according both to the regularity of menses and to serum follicle-stimulating hormone and estradiol values. All women answered a questionnaire, which included 72 questions, related to the identification of familial and personal cardiovascular risk factors. Biological measurements were performed to evaluate their lipid-lipoprotein profiles and fasting glucose levels, ultrasonography was used to measure IMT and total body scanners by DXA were performed to determine the percentage of body fat. RESULTS: Multiple regression analyses were used to examine the ability of each variable to explain IMT values. Mean IMT of the right carotid artery was 0.520 (+/- 0.07) mm. Of the 906 women, 9% were currently taking lipid-lowering drugs, 12.8% and less than 2% were being treated for hypertension and diabetes, respectively. Additionally, 124 women were found to have current hypertension, 10% had a familial history of CHD, and 18% were regular smokers. In multiple regression analyses, only increasing age (P < 0.001) and systolic and diastolic blood pressure (P < 0.001) were independently and significantly associated with IMT. CONCLUSIONS: These results show that only a few risk factors were associated with IMT in this population of healthy peri- and postmenopausal women. These results might be related to the fact that this study was conducted in an area of France well known for having the lowest rates of CHD in women, which is further supported by the thinner IMT found in this population as compared with a higher-risk population. Therefore, these results might not be relevant for CHD in older or high-risk women.

[Current therapeutic means]. / Les moyens thérapeutiques actuels.

UNLABELLED: VARIOUS THERAPEUTIC POSSIBILITIES: Treatment of osteoporosis has greatly progressed over the past few years and, in parallel with hormone replacement therapy (HRT), new drugs (2nd and 3rd generation bisphosphonates and raloxifen) are now available, not only for primary prevention but also for secondary prevention of fractures. WHAT INDICATIONS?: The anti-fracture efficacy that has been demonstrated in large clinical trials, conducted according to the requirements of modern methodology, only appear patent in women at "high risk" for osteoporosis, i.e., those presenting a t-score < -2.5 and a prevalent fracture (particularly vertebral crushing), situation which is relatively rare at the onset of the menopause. IN PRACTICE: The initiation of such treatment in a women approaching the menopause should only be considered after prior measurement of her bone density, using a validated technique, measurement that is not always officially recognized by our Health Authorities. This problem, together with the varying conditions of prescription and reimbursement, explain some of the problems encountered in the use of these new therapeutics, notably in women at high risk of osteoporosis, who have not yet presented a fracture due to their bone fragility.

[Screening techniques]. / Les moyens de dépistage.

WOMEN "AT RISK": Assessment of the risk of osteoporosis in a woman approaching the menopause relies essentially on the evaluation of her bone mass and the study of a certain number of clinical criteria. The principle osteoporosis risk markers are age, past personal and family history of fractures due to bone fragility, low body weight, past history of early menopause and all the affections corresponding classically to "secondary" osteoporosis. OSTEODENSITOMETRY: Densitometric measurement is the corner stone of this assessment, since any decrease of 1 in the standard deviation of bone density corresponds to a two-fold greater risk of fracture. This relationship has led to a new densitometric definition of osteoporosis, based on a decrease of more than 2.5 standard deviations compared with the median value of a young adult (t-score < -2.5). THE INTEREST OF BIOCHEMICAL MARKERS: The interest of bone remodeling biochemical markers has not been clearly defined. Combined with densitometric measurements, they may permit the assessment of the level of bone remodeling and hence estimate bone loss, which is one of the determinant factors of fracture risk.