Progesterone to prevent miscarriage in women with early pregnancy bleeding: the PRISM RCT.

BACKGROUND: Progesterone is essential for a healthy pregnancy. Several small trials have suggested that progesterone therapy may rescue a pregnancy in women with early pregnancy bleeding, which is a symptom that is strongly associated with miscarriage. OBJECTIVES: (1) To assess the effects of vaginal micronised progesterone in women with vaginal bleeding in the first 12 weeks of pregnancy. (2) To evaluate the cost-effectiveness of progesterone in women with early pregnancy bleeding. DESIGN: A multicentre, double-blind, placebo-controlled, randomised trial of progesterone in women with early pregnancy vaginal bleeding. SETTING: A total of 48 hospitals in the UK. PARTICIPANTS: Women aged 16-39 years with early pregnancy bleeding. INTERVENTIONS: Women aged 16-39 years were randomly assigned to receive twice-daily vaginal suppositories containing either 400 mg of progesterone or a matched placebo from presentation to 16 weeks of gestation. MAIN OUTCOME MEASURES: The primary outcome was live birth at ≥ 34 weeks. In addition, a within-trial cost-effectiveness analysis was conducted from an NHS and NHS/Personal Social Services perspective. RESULTS: A total of 4153 women from 48 hospitals in the UK received either progesterone (n = 2079) or placebo (n = 2074). The follow-up rate for the primary outcome was 97.2% (4038 out of 4153 participants). The live birth rate was 75% (1513 out of 2025 participants) in the progesterone group and 72% (1459 out of 2013 participants) in the placebo group (relative rate 1.03, 95% confidence interval 1.00 to 1.07; p = 0.08). A significant subgroup effect (interaction test p = 0.007) was identified for prespecified subgroups by the number of previous miscarriages: none (74% in the progesterone group vs. 75% in the placebo group; relative rate 0.99, 95% confidence interval 0.95 to 1.04; p = 0.72); one or two (76% in the progesterone group vs. 72% in the placebo group; relative rate 1.05, 95% confidence interval 1.00 to 1.12; p = 0.07); and three or more (72% in the progesterone group vs. 57% in the placebo group; relative rate 1.28, 95% confidence interval 1.08 to 1.51; p = 0.004). A significant post hoc subgroup effect (interaction test p = 0.01) was identified in the subgroup of participants with early pregnancy bleeding and any number of previous miscarriage(s) (75% in the progesterone group vs. 70% in the placebo group; relative rate 1.09, 95% confidence interval 1.03 to 1.15; p = 0.003). There were no significant differences in the rate of adverse events between the groups. The results of the health economics analysis show that progesterone was more costly than placebo (£7655 vs. £7572), with a mean cost difference of £83 (adjusted mean difference £76, 95% confidence interval -£559 to £711) between the two arms. Thus, the incremental cost-effectiveness ratio of progesterone compared with placebo was estimated as £3305 per additional live birth at ≥ 34 weeks of gestation. CONCLUSIONS: Progesterone therapy in the first trimester of pregnancy did not result in a significantly higher rate of live births among women with threatened miscarriage overall, but an important subgroup effect was identified. A conclusion on the cost-effectiveness of the PRISM trial would depend on the amount that society is willing to pay to increase the chances of an additional live birth at ≥ 34 weeks. For future work, we plan to conduct an individual participant data meta-analysis using all existing data sets. TRIAL REGISTRATION: Current Controlled Trials ISRCTN14163439, EudraCT 2014-002348-42 and Integrated Research Application System (IRAS) 158326. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 33. See the NIHR Journals Library website for further project information.

Miscarriage is a common complication of pregnancy that affects one in five pregnancies. Several small studies have suggested that progesterone, a hormone essential for maintaining a pregnancy, may reduce the risk of miscarriage in women presenting with early pregnancy bleeding. This research was undertaken to test whether or not progesterone given to pregnant women with early pregnancy bleeding would increase the number of live births when compared with placebo (dummy treatment). The women participating in the study had an equal chance of receiving progesterone or placebo, as determined by a computer; one group received progesterone (400 mg twice daily as vaginal pessaries) and the other group received placebo with an identical appearance. Treatment began when women presented with vaginal bleeding, were < 12 weeks of gestation and were found to have at least a pregnancy sac on an ultrasound scan. Treatment was stopped at 16 weeks of gestation, or earlier if the pregnancy ended before 16 weeks. Neither the participants nor their health-care professionals knew which treatment was being received. In total, 23,775 women were screened and 4153 women were randomised to receive either progesterone or placebo pessaries. Altogether, 2972 participants had a live birth after at least 34 weeks of gestation. Overall, the live birth rate in the progesterone group was 75% (1513 out of 2025 participants), compared with 72% (1459 out of 2013 participants) in the placebo group. Although the live birth rate was 3% higher in the progesterone group than in the placebo group, there was statistical uncertainty about this finding. However, it was observed that women with a history of one or more previous miscarriages and vaginal bleeding in their current pregnancy may benefit from progesterone. For women with no previous miscarriages, our analysis showed that the live birth rate was 74% (824 out of 1111 participants) in the progesterone group compared with 75% (840 out of 1127 participants) in the placebo group. For women with one or more previous miscarriages, the live birth rate was 75% (689 out of 914 participants) in the progesterone group compared with 70% (619 out of 886 participants) in the placebo group. The potential benefit appeared to be most strong for women with three or more previous miscarriages, who had a live birth rate of 72% (98 out of 137 participants) in the progesterone group compared with 57% (85 out of 148 participants) in the placebo group. Treatment with progesterone did not appear to have any negative effects.

The Prevalence of Thyroid Dysfunction and Autoimmunity in Women With History of Miscarriage or Subfertility.

OBJECTIVE: To describe the prevalence of and factors associated with different thyroid dysfunction phenotypes in women who are asymptomatic preconception. DESIGN: Observational cohort study. SETTING: A total of 49 hospitals across the United Kingdom between 2011 and 2016. PARTICIPANTS: Women aged 16 to 41years with history of miscarriage or subfertility trying for a pregnancy. METHODS: Prevalences and 95% confidence intervals (CIs) were estimated using the binomial exact method. Multivariate logistic regression analyses were conducted to identify risk factors for thyroid disease. INTERVENTION: None. MAIN OUTCOME MEASURE: Rates of thyroid dysfunction. RESULTS: Thyroid function and thyroid peroxidase antibody (TPOAb) data were available for 19213 and 19237 women, respectively. The prevalence of abnormal thyroid function was 4.8% (95% CI, 4.5-5.1); euthyroidism was defined as levels of thyroid-stimulating hormone (TSH) of 0.44 to 4.50 mIU/L and free thyroxine (fT4) of 10 to 21 pmol/L. Overt hypothyroidism (TSH > 4.50 mIU/L, fT4 < 10 pmol/L) was present in 0.2% of women (95% CI, 0.1-0.3) and overt hyperthyroidism (TSH < 0.44 mIU/L, fT4 > 21 pmol/L) was present in 0.3% (95% CI, 0.2-0.3). The prevalence of subclinical hypothyroidism (SCH) using an upper TSH concentration of 4.50 mIU/L was 2.4% (95% CI, 2.1-2.6). Lowering the upper TSH to 2.50 mIU/L resulted in higher rates of SCH, 19.9% (95% CI, 19.3-20.5). Multiple regression analyses showed increased odds of SCH (TSH > 4.50 mIU/L) with body mass index (BMI) ≥ 35.0 kg/m2 (adjusted odds ratio [aOR] 1.71; 95% CI, 1.13-2.57; P = 0.01) and Asian ethnicity (aOR 1.76; 95% CI, 1.31-2.37; P < 0.001), and increased odds of SCH (TSH ≥ 2.50 mIU/L) with subfertility (aOR 1.16; 95% CI, 1.04-1.29; P = 0.008). TPOAb positivity was prevalent in 9.5% of women (95% CI, 9.1-9.9). CONCLUSIONS: The prevalence of undiagnosed overt thyroid disease is low. SCH and TPOAb are common, particularly in women with higher BMI or of Asian ethnicity. A TSH cutoff of 2.50 mIU/L to define SCH results in a significant proportion of women potentially requiring levothyroxine treatment.

A Randomized Trial of Progesterone in Women with Bleeding in Early Pregnancy.

BACKGROUND: Bleeding in early pregnancy is strongly associated with pregnancy loss. Progesterone is essential for the maintenance of pregnancy. Several small trials have suggested that progesterone therapy may improve pregnancy outcomes in women who have bleeding in early pregnancy. METHODS: We conducted a multicenter, randomized, double-blind, placebo-controlled trial to evaluate progesterone, as compared with placebo, in women with vaginal bleeding in early pregnancy. Women were randomly assigned to receive vaginal suppositories containing either 400 mg of progesterone or matching placebo twice daily, from the time at which they presented with bleeding through 16 weeks of gestation. The primary outcome was the birth of a live-born baby after at least 34 weeks of gestation. The primary analysis was performed in all participants for whom data on the primary outcome were available. A sensitivity analysis of the primary outcome that included all the participants was performed with the use of multiple imputation to account for missing data. RESULTS: A total of 4153 women, recruited at 48 hospitals in the United Kingdom, were randomly assigned to receive progesterone (2079 women) or placebo (2074 women). The percentage of women with available data for the primary outcome was 97% (4038 of 4153 women). The incidence of live births after at least 34 weeks of gestation was 75% (1513 of 2025 women) in the progesterone group and 72% (1459 of 2013 women) in the placebo group (relative rate, 1.03; 95% confidence interval [CI], 1.00 to 1.07; P = 0.08). The sensitivity analysis, in which missing primary outcome data were imputed, resulted in a similar finding (relative rate, 1.03; 95% CI, 1.00 to 1.07; P = 0.08). The incidence of adverse events did not differ significantly between the groups. CONCLUSIONS: Among women with bleeding in early pregnancy, progesterone therapy administered during the first trimester did not result in a significantly higher incidence of live births than placebo. (Funded by the United Kingdom National Institute for Health Research Health Technology Assessment program; PRISM Current Controlled Trials number, ISRCTN14163439.).

Levothyroxine in Women with Thyroid Peroxidase Antibodies before Conception.

BACKGROUND: Thyroid peroxidase antibodies are associated with an increased risk of miscarriage and preterm birth, even when thyroid function is normal. Small trials indicate that the use of levothyroxine could reduce the incidence of such adverse outcomes. METHODS: We conducted a double-blind, placebo-controlled trial to investigate whether levothyroxine treatment would increase live-birth rates among euthyroid women who had thyroid peroxidase antibodies and a history of miscarriage or infertility. A total of 19,585 women from 49 hospitals in the United Kingdom underwent testing for thyroid peroxidase antibodies and thyroid function. We randomly assigned 952 women to receive either 50 µg once daily of levothyroxine (476 women) or placebo (476 women) before conception through the end of pregnancy. The primary outcome was live birth after at least 34 weeks of gestation. RESULTS: The follow-up rate for the primary outcome was 98.7% (940 of 952 women). A total of 266 of 470 women in the levothyroxine group (56.6%) and 274 of 470 women in the placebo group (58.3%) became pregnant. The live-birth rate was 37.4% (176 of 470 women) in the levothyroxine group and 37.9% (178 of 470 women) in the placebo group (relative risk, 0.97; 95% confidence interval [CI], 0.83 to 1.14, P = 0.74; absolute difference, -0.4 percentage points; 95% CI, -6.6 to 5.8). There were no significant between-group differences in other pregnancy outcomes, including pregnancy loss or preterm birth, or in neonatal outcomes. Serious adverse events occurred in 5.9% of women in the levothyroxine group and 3.8% in the placebo group (P = 0.14). CONCLUSIONS: The use of levothyroxine in euthyroid women with thyroid peroxidase antibodies did not result in a higher rate of live births than placebo. (Funded by the United Kingdom National Institute for Health Research; TABLET Current Controlled Trials number, ISRCTN15948785.).

Tailor management to the patient with fibroids.

Fibroids are benign, hormone-dependent tumours of uterine smooth muscle and connective tissue. They are commonly asymptomatic, but can cause symptoms such as heavy menstrual bleeding and pelvic pressure symptoms. Between 20 to 30% of women with heavy menstrual bleeding have fibroids. Fibroids are most prevalent in women aged 30-50 years and there may be a genetic predisposition. They are more common in black women than white women. Other risk factors include obesity and nulliparity. Asymptomatic women should only be referred if their uterus is palpable abdominally, if fibroids distort the uterine cavity or the uterus is larger than 12 cm in length. Symptomatic women should be referred when heavy menstrual bleeding has not responded to medical treatment, if large fibroids are causing pressure symptoms or when fibroids are associated with fertility or obstetric problems. Malignant change (leiomyosarcoma) is rare in premenopausal women. Fast track referral is indicated for women with rapid onset and progressive symptoms or rapidly enlarging fibroids, as these symptoms are suspicious of leiomyosarcoma; postmenopausal women presenting with enlarging fibroids or vaginal bleeding; and women with fibroids with any other features of cancer e.g. abnormal bleeding or weight loss.

Managing debilitating menopausal symptoms.

Severity and duration of menopausal symptoms varies markedly. Eight out of ten women experience symptoms and on average these last four years, with one in ten women experiencing symptoms for up to 12 years. A recent study found that women whose vasomotor symptoms started before the menopause suffered longest, median 11.8 years. Women whose hot flushes and night sweats started after the menopause had symptoms for a median of 3.4 years. Menopausal symptoms can begin years before menstruation ceases. Menopausal status needs to be evaluated based on history and symptoms. Testing for FSH levels should only be considered in women aged 40-45 with menopausal symptoms or those under 40 with suspected early menopause. In general, the benefits of short-term HRT outweigh the risks in the majority of symptomatic women, especially in those under 60. There is no evidence that HRT confers any cardiovascular protection (or harm) or protection against the development of dementia. Cardiovascular risk should be assessed. Women with cardiovascular disease are not necessarily unsuitable for HRT but need their cardiovascular health optimised. In those women with a high risk of venous thromboembolism a thrombophilia screen should be considered (although even if this is negative, it does not absolve risk). If there is a history of arterial disease a lipid profile should be considered. If there is a high risk of breast cancer, counsel the woman with regards to her risk and consider referring for mammography.

GPs have key role in early diagnosis of endometriosis.

Endometriosis is defined as the presence of endometrial-like tissue outside the uterus. Deposits are commonly distributed on the ovaries, uterosacral ligaments, pouch of Douglas, rectum and sigmoid colon, bladder and ureter. Endometriosis is common, affecting 10% of the female adult population and up to 50% of women with infertility. Risk factors include early menarche, late menopause, delayed childbearing, vaginal outflow obstruction and a first-degree relative affected. Women commonly present to their GP with pelvic pain, painful intercourse or subfertility. Classically the pain starts several days before the period which is extremely painful. After the period, symptoms tend to improve until mid-cycle when the pattern repeats again. Patients also complain of fatigue. Abdominal palpation, bimanual and speculum examination are important to identify signs of endometriosis, but also to exclude alternative diagnoses such as fibroid uterus, infection or pregnancy. However, a normal examination does not exclude a diagnosis of endometriosis. Serum CA125 can be raised in endometriosis but is not specific or sensitive for the condition and is therefore not recommended as a screening test. A normal pelvic ultrasound scan does not exclude a diagnosis of endometriosis. The gold standard investigation for endometriosis is laparoscopy and biopsy with histological confirmation. Referral should be considered if pain is not controlled with simple analgesia or the diagnosis is suspected in a woman who is actively trying to conceive. Early referral should be considered in women with abnormal examination findings, or an abnormal ultrasound result.

Diagnosis and management of miscarriage.

Miscarriage is defined as a pregnancy failure occurring before the completion of 24 weeks of gestation. Around 10 to 15% of all pregnancies end in early spontaneous first trimester miscarriage. Advancing maternal and paternal age are known to be associated with increasing chance of miscarriage. Other risk factors include being underweight or overweight, smoking and high alcohol consumption. Traditional practice classified miscarriage according to the history and findings on speculum examination but transvaginal ultrasound scan should now be considered the standard test to assess viability of the pregnancy. Assessment of the amount of vaginal bleeding experienced is best made in the context of time taken to saturate a sanitary pad. Changing a pad soaked with blood and clots more than once an hour is an indication of heavy bleeding that requires immediate referral. Following confirmation of a viable intrauterine pregnancy, symptoms may resolve. If the symptoms worsen, or persist beyond 14 days, a repeat referral should be made to the early pregnancy unit for further assessment. If a pregnancy is 12 weeks' gestation and the woman is rhesus negative, she will require anti-D prophylaxis if there are symptoms of bleeding. Expectant management is the first-line approach, and is encouraged for 7-14 days after diagnosis of miscarriage. Most women will miscarry spontaneously during this time and will need no further treatment. It is not appropriate if there are risk factors for haemorrhage, or if the woman is at increased risk from the effects of haemorrhage. Medical management of miscarriage can be offered using misoprostol. Surgical management may be chosen by a woman if she has had a previous adverse or traumatic experience associated with pregnancy.

Detecting ovarian disorders in primary care.

Ovarian cysts occur more often in premenopausal than postmenopausal women. Most of these cysts will be benign, with the risk of malignancy increasing with age. The risk of a symptomatic ovarian cyst in a premenopausal female being malignant is approximately 1:1,000 increasing to 3:1,000 at the age of 50. Ovarian cysts may be asymptomatic but presenting symptoms include pelvic pain, pressure symptoms and discomfort and menstrual disturbance. Functional cysts in particular can be linked with irregular vaginal bleeding or menorrhagia. Ovarian torsion is most common in the presence of an ovarian cyst. Dermoid cysts are most likely to tort. Torsion presents with sudden onset of severe colicky unilateral pain radiating from groin to loin. There may be nausea and vomiting. It is often confused with ureteric colic where the pain is similar but radiates loin to groin. Symptoms which may be suggestive of a malignant ovarian cyst, particularly in the over 50 age group, include: weight loss, persistent abdominal distension or bloating, early satiety, pelvic or abdominal pain and increased urinary urgency and frequency. CA125 levels should be checked in women who present with frequent bloating, feeling full quickly, loss of appetite, pelvic or abdominal pain or needing to urinate quickly or urgently. Symptomatic postmenopausal women, those with a cyst > or = 5 cm, or raised CA125 levels, should be referred to secondary care. Functional cysts, particularly when they are < 5 cm diameter, usually resolve spontaneously without the need for intervention. In premenopausal women simple cysts > or = 5 cm are less likely to resolve and need an annual ultrasound assessment as a minimum.

Diagnosis and treatment of ectopic pregnancy.

The most common site of localisation of an ectopic pregnancy is the fallopian tube. Rarely an ectopic pregnancy can be found in the ovary, a caesarean section scar, the abdomen or the cervix. Risk factors are previous ectopic pregnancy, PID, endometriosis, previous pelvic surgery, the presence of a coil and infertility. However, a third of women with an ectopic pregnancy have no known risk factors. NICE recommends a low threshold for offering a pregnancy test to women of childbearing age when they attend the surgery. Symptoms and signs appear when the tube starts to tear. When the tube ruptures, the woman will quickly become unwell and haemodynamically unstable because of rapid intra-abdominal blood loss. The most common symptoms of ectopic pregnancy are pelvic or abdominal pain, amenorrhoea, missed period or abnormal period and vaginal bleeding. A positive diagnosis of a urinary tract infection or gastroenteritis does not exclude an ectopic pregnancy. Signs of suspected ectopic pregnancy include pelvic, abdominal, adnexal or cervical motion tenderness, rebound tenderness and abdominal distension. Women who are haemodynamically unstable, or in whom there is significant concern about the degree of pain or bleeding, should be referred directly to A&E, irrespective of the result of the pregnancy test. Stable patients with bleeding who have pain or a pregnancy of six weeks gestation or more or a pregnancy of uncertain gestation should be referred immediately to an early pregnancy assessment (EPA) service, or out-of-hours gynaecology service if the EPA service is not available. Diagnosis is confirmed by transvaginal ultrasound scan to identify the location of the pregnancy.

Postmenopausal bleeding should be referred urgently.

Postmenopausal bleeding is an episode of bleeding 12 months or more after the last menstrual period. It occurs in up to 10% of women aged over 55 years. All women with postmenopausal bleeding should be referred urgently. Endometrial cancer is present in around 10% of patients; most bleeding has a benign cause. The peak incidence for endometrial carcinoma is between 65 and 75 years of age. Causes of postmenopausal bleeding include: endometrial carcinoma; cervical carcinoma; vaginal atrophy; endometrial hyperplasia +/- polyp; cervical polyps; hormone-producing ovarian tumours; haematuria and rectal bleeding. The aim of assessment and investigation of postmenopausal bleeding is to identify a cause and exclude cancer. Assessment should start by taking a detailed history, with identification of risk factors for endometrial cancer, as well as a medication history covering use of HRT, tamoxifen and anticoagulants. Abdominal and pelvic examinations should be carried out to look for masses. Speculum examination should be performed to see if a source of bleeding can be identified, assess atrophic changes in the vagina and look for evidence of cervical malignancy or polyps. Ultrasound scan and endometrial biopsy are complementary. Ultrasound scan can define endometrial thickness and identify structural abnormalities of the uterus, endometrium and ovaries. Endometrial biopsy provides a histological diagnosis. The measurement of endometrial thickness aims to identify which women with postmenopausal bleeding are at significant risk of endometrial cancer. If the examination is normal, the bleeding has stopped and the endometrial thickness is < 5 mm on transvaginal ultrasound scan, no further action need be taken.

Management of fibroids should be tailored to the patient.

At least one in four women will develop one or more fibroids during their lifetime. They occur most commonly in women aged 30-50 and are three times more common in women of Afro-Caribbean descent than in Caucasian women. Risk factors for fibroids include: age, nulliparity, race, family history and obesity. In two-thirds of cases there are no symptoms. If the tumours are small and not causing symptoms, they do not require treatment However, if they enlarge, they can cause abnormal bleeding, pressure on the bladderand/or bowel and the patient may have difficulty getting pregnant. Fibroids are often discovered as an incidental finding on ultrasound but may also present in the following ways: abnormal uterine bleeding and menorrhagia; infertility; pelvic mass; increasing girth; pressure symptoms (urinary frequency and/or constipation); urinary retention; acute pelvic pain due to torsion of a pedunculated fibroid. During pregnancy, fibroids enlarge and may undergo red degeneration causing pain. Medication can only be used to improve symptoms and/or shrink the fibroids prior to surgery. Women with fibroids >3 cm in diameter causing significant symptoms, pain or pressure and wishing to retain their uterus may consider myomectomy. Hysterectomy is the standard treatment for women with symptomatic fibroids who have not improved with medical treatment. If the woman's family is complete and the fibroids are multiple, hysterectomy provides a permanent cure. Uterine artery embolisation is only recommended if surgery was planned for symptomatic fibroids and if the fibroids are <20 weeks in size. Referral is recommended in the following cases: submucous fibroid and abnormal bleeding; fibroids >3 cm in diameter uterus palpable abdominally or >12 cm in size on scan; persistent intermenstrual bleeding; age >45 where treatment has failed or been ineffective. Sarcomatous change within fibroids is rare and is normally associated with rapid growth. Such cases should be referred urgently.

Premature menopause linked to CVD and osteoporosis.

Premature menopause affects 1% of women under the age of 40, the usual age of the menopause is 51. Most women will present with irregular periods or no periods at all with or without climacteric symptoms. Around 10% of women present with primary amenorrhoea. A careful history and examination are required. It is important to ask specifically about previous chemotherapy or radiotherapy and to look for signs of androgen excess e.g. polycystic ovarian syndrome, adrenal problems e.g. galactorrhoea and thyroid goitres. Once pregnancy has been excluded, a progestagen challenge test can be performed in primary care. Norethisterone 5 mg tds po for ten days or alternatively medroxyprogesterone acetate 10 mg daily for ten days is prescribed. A withdrawal bleed within a few days of stopping the norethisterone indicates the presence of oestrogen and bleeding more than a few drops is considered a positive withdrawal bleed. The absence of a bleed indicates low levels of oestrogen, putting the woman at risk of CVD and osteoporosis. FSH levels above 30 IU/l are an indicator that the ovaries are failing and the menopause is approaching or has occurred. It should be remembered that FSH levels fluctuate during the month and from one month to the next, so a minimum of two measurements should be made at least four to six weeks apart. The presence of a bleed should not exclude premature menopause as part of the differential diagnosis as there can be varying and unpredictable ovarian function remaining. The progestagen challenge test should not be used alone, but in conjunction with FSH, LH and oestradiol. There is no treatment for premature menopause. Women desiring pregnancy should be referred to a fertility clinic and discussion of egg donation. Women not wishing to become pregnant should be prescribed HRT until the age of 50 to control symptoms of oestrogen deficiency and reduce the risks of osteoporosis and CVD.