Treating Postmenopausal Osteoporosis with Hormone Therapy - Reanalysis after the Women’s Health Initiative (WHI)

Case 1: 52 year old postmenopausal woman with vasomotor symptoms and vaginal atrophy and unknown bone status

A 52 year old woman goes to see her primary care doctor and reports severe hot flashes, night sweats, poor sleep, fatigue, vaginal dryness, mood changes and a family history of osteoporosis. Her last menstrual period was 12 months ago. The physician mentions hormone therapy as an option for relieving her symptoms, but the patient is hesitant due to fear of breast cancer and heart disease as reported in the media. She has previously taken hormonal contraception and has no history of VTE. Her yearly screening mammogram was recently normal. Her physical exam reveals vaginal atrophy.

How would you counsel this patient regarding her concerns on hormone therapy?

This is a healthy postmenopausal woman who is suffering from severe vasomotor symptoms. Hormone therapy remains the gold standard treatment for these menopausal symptoms as well as the only therapy. Since she still has an intact uterus, she would need a combined estrogen-progestin therapy (EPT) to minimize the risk for uterine cancer.

The original WHI publication in 2002 on EPT has stirred much concern on certain disease risks like breast cancer^[1,2] and stroke^[1]. In a recent analysis of the WHI-EPT, although breast cancer risk increased by 8 cases per 10,000 women per year compared to placebo, this increase was not significant after adjustment for baseline risk factors for breast cancer.^[3,4] The same is true with the risk of stroke which is increased by 8 events per 10,000 women treated per year compared to placebo. However, this difference was not significant after adjusted analysis. Being young (<60 years) and being in the early phase of menopause (<10 years post-menopause) would offer her more benefits than risks. The most recent age stratified data from the WHI revealed that early initiation of HT has been shown to be associated with a 30 percent reduction in overall mortality and 34 percent reduction in coronary heart disease relative to placebo among women aged 50-59 years.^[3,5] The greatest risk of HT regardless of age is related to venous thromboembolism. However, the risks of stroke and VTE are low for women overall and still lower for women who are within 10 years of menopause or younger than age 60 years when they start HT.^[3,5,6] This patient previously had used hormonal contraception without adverse VTE events

There is also a potential for preventing diabetes mellitus, a benefit that is underappreciated.^[7,8] Combination estrogen-progestin (hazard ratio 0.79, 95% CI 0.67-0.93, p=0.004) as well as estrogen alone (hazard ratio 0.88, 95% CI 0.77-1.01, p=0.072) have been shown to reduce the incidence of type 2 diabetes mellitus compared with placebo in the WHI. This is possibly mediated by a decrease in insulin resistance. Consistent with these data, the American Association of Clinical Endocrinologists issued a position statement in 2008 recommending use of HT for young symptomatic women in early menopause as the benefits of HT exceed the risks.^[9] There is inadequate evidence, however, to recommend HT for the sole or primary indication for diabetes prevention in peri- or postmenopausal women.

Does this patient need to have a bone density test now?

If the patient has risk factors for osteoporosis, such as personal history of fragility fracture as an adult, family history of osteoporosis or osteoporotic fracture in a first degree relative, current smoking, low body mass index, chronic systemic steroid use, etc, then she should have a bone density done. Screening for osteoporosis is recommended for all postmenopausal women with risk factors and all women age 65 and older regardless of risk factors.^[10] Note that the risk of osteoporosis increases with age and hormonal changes. The greatest decline in bone density occurs in the first few years after menopause. Screening postmenopausal women prior to age 65 is also advisable if they have a medical condition that increases their risk for osteoporosis especially if the results will influence therapeutic and patient management decisions. For many menopausal women who are symptomatic with menopausal symptoms, knowing their bone status may further help them decide about using hormone therapy.

Most women who fracture are in the ‘low bone mass’ (osteopenia) category and furthermore, most recently, menopausal women, by virtue of relatively young age who have low femoral neck T-score or ‘osteopenia’ will not be at high enough risk using the FRAX ^® tool^[11] to reach the National Osteoporosis Foundation fracture risk cut-off recommendations for starting osteoporosis therapy which is a 10 year risk of hip fracture at 3 percent or more or a 10 year risk of a major osteopororotic fracture at 20 percent or more.

Hence a symptomatic menopausal woman who has osteopenia not only gets menopausal therapeutic effect with HT but benefits on bone density as well.

If she decides to take hormone therapy, will she be protected from osteoporosis?

Most likely. The WHI data showed that the risk of any fracture was reduced by 24 percent in women randomized to EPT compared with placebo, which was statistically significant and translated to 47 fewer fractures per 10,000 women per year of therapy.^[12] This is particularly impressive given that this group of women did not necessarily have osteoporosis and many agents that are FDA approved to treat osteoporosis have not shown hip fracture reduction (i.e. calcitonin, raloxifene, and ibandronate.) However, although hormone therapy use has been shown to prevent bone loss, some women are hormone “non-responders” and a definite percent of long-term estrogen users still develop osteoporosis and experience fractures.^{[13,14 ]} Therefore, protection from osteoporosis is likely but should not be completely assumed and the patient who is at risk for osteoporosis should be periodically assessed with central bone mineral density testing. She should also be advised to ingest adequate calcium and vitamin D and engage in weight-bearing exercises to decrease her risk of osteoporosis and related fractures.

If the patient decides to take hormone therapy, what dose should she take and for what duration?

Some groups have recommended the lowest dose of HT that relieves symptoms, for the shortest period of time consistent with the indications for using HT. However, the duration of use is one of the most challenging issues regarding HT. Existing studies do not provide a clear indication as to whether longer duration of HT improves or worsens the benefit-risk ratio. Data from large randomized controlled trials (RCT) such as the WHI^[1] and Heart and Estrogen/Progestin Replacement Study (HERS)^[15] should be extrapolated with caution as these studies predominantly involve asymptomatic older postmenopausal women in their 60s, most of whom were 10 years or more past menopause at the time HT was started. So, if this patient decides to start hormone therapy, she should start with a low dose and increase if needed until symptoms are controlled and undergo periodic reassessment to see if continued treatment is warranted. The magnitude and risks associated with HT are in the range of risks of several commonly prescribed medicines such as statins, aspirin, diabetic agents and raloxifene.^[3] For instance, the risk of stroke associated with HT is less than that of fatal stroke (ischemic or hemorrhagic stroke leading to death) with raloxifene^{[16 ]}and the comparative risks of breast cancer in randomized trial of HT and statin therapy are comparable^[17] (Table 1). If HT use needs to be extended, risks and benefits should be discussed and the patient should be monitored periodically just as with any prescriptive agent.

According to the North American Menopause Society (NAMS) 2010 position statement on HT, “extended use of HT is an option for women who have established reduction in bone mass, regardless of menopause symptoms, for prevention of further bone loss, and/or reduction of osteoporotic fracture when alternate therapies are not appropriate or cause side effects; or when the benefits of extended use are expected to exceed the risks.”^[18]

If she takes hormone therapy for 5 years and then stops, what will happen to the patient’s bone density?

Age-related bone loss occurs at the rate of about 0.5-1 percent per year.^[19] With menopause, bone loss accelerates to 1-2 percent per year for 5-10 years.^[20] Similar rates of bone loss occur once estrogen is stopped. As much as 5 percent can be lost in the first year after discontinuation of HT.^[21] However, she should be no worse off for having taken HT and stopped than for never taking HT at all. Therefore, she should have her first bone density test at age 60- 65 unless there is some other indication to have it earlier. Women who stop HT because they no longer have menopausal symptoms need to be told they will have bone loss and those who use only vaginal estrogen products for vaginal atrophy need to be told that they will not obtain the benefits of systemic estrogen.

Case 2: 67 year old woman in whom HT was abruptly stopped

A 67 year old postmenopausal woman presents for the evaluation of hot flashes, vaginal dryness causing dyspareunia, and decreased libido. She was previously on estrogen-progestogen therapy (EPT) consisting of daily conjugated equine estrogen (CEE) and medroxyprogesterone acetate (MPA) for 15 years starting at the time of natural menopause. The HT was abruptly stopped less than 6 months ago by her primary care physician after the initial release of data from the WHI trial, and the patient is now seeking a second opinion regarding resumption of HT.^[22]

Would you restart HT in this patient?

The abrupt cessation of HT certainly contributed to her symptoms. It is just like going through menopause once again. Considering the short duration of time she is off HT and the fact that she has been on it for 15 years without any problems, restarting HT is not unreasonable. However, prior to re-initiating treatment, careful assessment of risk factors such as breast cancer, stroke, cardiovascular disease and lipid profiles, should be done. If risks are acceptable to you and the patient, you can offer a lower dose regimen. A CEE dose of 0.3 mg/day may be as effective in a 67 year old woman as 0.625 mg is in a younger woman in terms of relieving vasomotor symptoms, depending on individual metabolism (metabolism slows down in older individuals). There is evidence from the Heart Outcome Prevention Evaluation (HOPE) Trial that 0.3 mg/day of CEE is effective for relieving vasomotor symptoms.^[23] In addition, data from the Nurses’ Health Study show no increased risk of stroke with 0.3 mg/day compared to 0.625 mg/day which showed an increased risk.^[24]

Would you be worried about her fracture risk after abrupt cessation of HT?

Certainly. Again, abrupt cessation of HT creates a new menopausal state leading to a rapid decline in bone mass and an increased fracture risk. In this regard, a bone density test is advisable to assess her bone status. Note that if she resumes HT, her risk of all types of fracture may be reduced.

Case 3: A 66 year-old woman on estrogen

This is a 66 year old woman who has been taking estrogen alone since age 51 after a surgical menopause. She appears healthy and has no family history of osteoporosis or other risk factors for osteoporosis.

Should she stop taking the estrogen?

She may try to taper or stop the estrogen and see if her symptoms would recur. If her symptoms do recur, then restarting estrogen hormone therapy, provided that the benefits outweigh the risks, is reasonable just as discussed in Case 2. If, however, she remains asymptomatic after discontinuing estrogen therapy, she may consider local vaginal estrogen to maintain genital health and would need periodic assessment of her bone density. In women age 60-80 years with T-scores between -1.0 and -2.0, an ultra low dose of estrogen in the form of a weekly Menostar 0.014 mg patch has been used and shown to maintain bone density.^[25] Similarly, 0.25 mg of 17-B estradiol has been shown to increase bone density at the hip, spine, and total body and reduced markers of bone turnover after 3 years of treatment with a side effect profile (breast tenderness, endometrial changes and bleeding)^{[ ]}similar to placebo.^[26] When ultra low doses of estrogen are used then progestin opposition in a woman with a uterus can be done one to 2 times yearly. There are several individualized options for hormone therapy and the age, symptoms, metabolism and bone density need to be taken into account.^[27]

Should this patient have a bone density test to help her decide whether or not to stop estrogen?

She should have a bone density test done, but not necessarily because she is considering stopping estrogen. She is 66 years old, which is reason enough to obtain a bone density test.

If she stops taking estrogen, should she take another agent to protect her bones?

That depends. If her bone density is normal, then obviously she does not need to take any medication except for maintaining adequate calcium and vitamin D intake. A total of 1,200mg of calcium per day in divided doses is recommended in women of her age. Vitamin D recommendations are for at least 1,000 IU daily. If her bone density is low, alternative agents may be considered versus continuing on low dose estrogen. The patient should also participate in weight-bearing exercise.

What are other treatment options for this patient if she was found to have osteoporosis?

Agents approved for treatment of postmenopausal osteoporosis are bisphosphonates (oral alendronate, oral risedronate, oral or IV ibandronate and most recently yearly IV zoledronic acid), selective estrogen receptor modulators (SERM) now termed ‘estrogen agonist antagonists’, calcitonin, and injectable parathyroid hormone (PTH, teriparatide). Bisphosphonates have been shown to decrease the risk of both hip and vertebral fractures except for ibandronate which has only been shown to decrease risk of vertebral fracture.^[28-31] The estrogen agonist antagonist, raloxifene, has also been shown to decrease risk of vertebral fracture and may be particularly helpful in women who are at high risk for breast cancer who do not have menopausal vasomotor symptoms and are not an increased risk for stroke.^[32] Calcitonin has been shown to decrease vertebral fractures only and is approved for treatment but not for prevention of osteoporosis.^[33] It is reserved as an alternative for those who cannot tolerate other agents and may be helpful in relieving pain due to compression fractures. Teriparatide or recombinant human PTH is an expensive anabolic agent administered as a daily subcutaneous injection that has been shown to reduce the incidence of both vertebral and non-vertebral fractures.^[34]

The Women’s Health Initiative

The WHI was established by the NIH in 1991 to address the most common causes of death, disability and impaired quality of life in postmenopausal women.^[1] It was the largest U.S. prevention trial in older women that addressed cardiovascular disease, cancer, and osteoporosis. The WHI consisted of a set of clinical trials and an observational study, which together involved 161,808 generally asymptomatic older American postmenopausal women. The clinical trials were designed to evaluate the effects of postmenopausal hormone therapy, diet modification, and calcium and vitamin D supplementation on heart disease, fractures, breast cancer and colorectal cancer.

The hormone trial enrolled 27,347 postmenopausal women aged 50-79 years at baseline. Majority of the women were 60 years of age and older and were more than 10 years past menopause. It comprised two parallel randomized trials: the estrogen-plus-progestin (CEE 0.625mg + MPA 2.5mg) study of 16,608 women with a uterus and the estrogen-alone (CEE 0.625mg) study of 10,739 women without a uterus. In both hormone therapy trials, women were randomly assigned to either the hormone medication being studied or to placebo. Women in both trials were asked to stop taking their study medication and stay in the follow-up phase of the trial.

The WHI was conducted at 40 clinical centers throughout the United States. Ten of these centers primarily recruited minority populations. The program was designed to be reviewed by a Data Safety and Monitoring Board that would seek to minimize the risk to the patient population. For this reason, interval analyses were planned, which included an analysis not only of the main outcomes but also of a non-validated global health index.

The global health index was an artificial construct that took into account the relative benefit or risk regarding the primary clinical outcome designated as coronary heart disease (CHD), stroke, breast cancer, endometrial cancer, colorectal cancer, hip fractures, and death due to other causes. The non-validated global index tool was used to summarize the overall balance of risks and benefits in the study so as to quickly determine any unacceptable risk in this population of asymptomatic older women.^[1,35]

Reanalysis of the Risks and Benefits of Hormone Therapy

The original WHI publication in 2002 which included non-adjudicated data initially indicated that hormone therapy strictly used as global ‘prevention’ poses more risks than benefits, which has caused much public concern and discontinuation of HT use in almost all age groups.^[1]

The WHI-EPT arm reportedly showed an increased incidence of breast cancer compared with placebo, which led to its early termination after 5.2 years. Other reported adverse events included increased risks of stroke, CHD, and VTE.^[1] Similarly, the estrogen-only arm was halted in 2004, after about 7 years of use, due to reported increased risk of stroke but no increase or decrease in overall risk for CHD or breast cancer.^[36,37] It is important to emphasize though that this is mainly a prevention study involving elderly, asymptomatic women who were mostly ten or more years past menopause

Since 2002, an extensive collection of data has been published analyzing the results of the WHI hormone trial. Recent analyses assessed the cardiovascular effects of estrogen therapy (ET) and EPT overall and according to subject age and years since menopause have reflected very similar data to prior observational data. Other analyses after the initial WHI publication have analyzed the effects of HT according both to duration of use and secondary end points. A review article by Hodis, published in 2008, clearly presented the summary of the risks and benefits of clinical events with EPT vs. placebo and ET vs. placebo looking at both nominal and adjusted confidence intervals (CI).^[3]

EPT vs. Placebo

The relative and absolute risks and benefits of clinical events in the EPT vs. placebo trial are presented in Table 1.

Table 1

Relative and absolute risks and benefits of clinical events with EPT compared with placebo in the WHI randomized trial, 2007 update

Health Event	Overall hazard ratio	95 percent CI, nominal	95 percent CI, adjusted	Absolute risk per 10,000 women/year	Absolute benefit per 10,000 women/year
[a] Adjusted for age, race/ethnicity, body mass index, physical activity level, smoking, alcohol use, parity, oral contraceptive use, family history of breast cancer and fractures, frequency of screening mammography, and vasomotor symptoms.
*Without adjustment for covariates in the preceeding footnote, the hazard ratio was 1.24 (95 percent CI, 1.02-1.50)
NR = not reported
Hodis, H. Assessing benefits and risks of hormone therapy in 2008: New evidence, especially with regard to the heart. Cleveland Clinic Journal of Medicine. May 2008, 75;4:S3-12.[3] Reprinted with permission. Copyright © 2008 Cleveland Clinic. All rights reserved.
Coronary heart disease	1.23	0.99–1.53	NR	8	-
Stroke	1.31	1.03–1.68	0.93-1.84	8	-
Breast cancer	1.20[a]	*	0.94–1.53[a]	8	-
Venous thromboembolism	2.06	1.57–2.70	NR	18	-
Colorectal cancer	0.56	0.38–0.81	0.33-0.94	-	7
Hip fracture	0.67	0.47–0.96	0.41-1.10	-	5
Any fracture	0.76	0.69–0.83	NR	-	47
New-onset diabetes	0.79	0.67–0.93	NR	-	15

Although the point estimate for CHD is increased, the 95 percent CI indicates that the risk in the EPT arm is not significantly increased compared to placebo. The risks of stroke and breast cancer were originally significantly increased (by an additional 8 per 10,000 women per year) in the EPT arm vs. placebo but these increases were not significant after adjustment.^[4,5] The risk of VTE, however, is significantly increased, resulting in an excess of 18 events per 10,000 women per year of therapy. This was significant across the entire cohort of women in the WHI and remains the most clinically significant risk.^[3,38]

On the benefit side, EPT has been shown to significantly reduce the risk of colorectal cancer^[39], any fractures^[12], and diabetes^[7]. The risk of any fracture was significantly reduced by 24 percent and translated into 47 fewer fractures per 10,000 women per year of therapy.^[3,12]

ET vs. Placebo

The relative and absolute risks and benefits of clinical events in the ET vs. placebo trial are shown in Table 2.

Table 2

Most current relative and absolute risks and benefits of clinical events with ET compared with placebo in the WHI randomized trial

Health Event	Overall hazard ratio	95 percent CI, nominal	95 percent CI, adjusted	Absolute risk per 10,000 women/year	Absolute benefit per 10,000 women/year
NR = not reported
Hodis, H. Assessing benefits and risks of hormone therapy in 2008: New evidence, especially with regard to the heart. Cleveland Clinic Journal of Medicine. May 2008, 75;4:S3-12.[3] Reprinted with permission. Copyright © 2008 Cleveland Clinic. All rights reserved.
Coronary heart disease	0.95	0.78–1.16	NR	-	3
Stroke	1.33	1.05–1.68	0.97-1.99	11	-
Breast cancer	0.82	0.65–1.04	NR	-	8
Venous thromboembolism	1.32	0.99–1.75	NR	8	-
Colorectal cancer	1.08	0.75–1.55	0.63–1.86	1	-
Hip fracture	0.61	0.41–0.91	0.33–1.11	-	6
Any fracture	0.70	0.63–0.79	0.59–0.83	-	56
New-onset diabetes	0.88	0.77–1.01	NR	-	14

There was no significant difference between ET compared to placebo with respect to CHD risk in the overall cohort of women, with an average age of 64 years.^[5] The risk of stroke (11 per 10,000 women per year) was greater in the ET arm compared to placebo but was not significantly increased in the adjusted analysis.^[5] Interestingly, a trend toward reduction of breast cancer risk, although not significant, was apparent in the ET arm with 8 fewer cases per 10,000 women per year of therapy. However, among the women who were adherent to their study regimen (consuming >80 percent of their study medication), there was a significant 33 percent reduction in breast cancer diagnosis with ET vs. placebo, found across all age ranges studied.^[6,30] Interestingly, the risk of VTE with ET relative to placebo is not statistically significant (so it appears that EPT increases risk of VTE more than ET alone).^[40]

Similar to the EPT arm, the risk of any fracture was reduced significantly in the ET arm relative to placebo (56 fewer fractures per 10,000 women per year of therapy)^[6] and that reduction in the risk of new-onset diabetes nearly achieved statistical significance (14 per 10,000 women per year of therapy).^[8]

How does duration of hormone therapy and timing of hormone therapy initiation affect clinical outcomes?

CHD. The rate of CHD events increased during the first year of EPT use compared with placebo or non-use as shown in the Heart and Estrogen/Progestin Replacement Study (HERS)^[8], the randomized WHI-EPT^[41], and the WHI observational study^[42]. The rate of CHD events though declined over time with rates ending up lower than the placebo group or non-users of HT after 5 years of therapy. Similarly, CHD events declined over time with ET use in either the WHI randomized trial or the WHI observational study although not as pronounced compared to EPT.^[43] In the WHI observational study, ET use for over 5 years was associated with a significant reduction of 27 percent (HR 0.73; 95 percent CI 0.61-0.84) in CHD events compared to non-use.^[44]

Initiating HT (both ET and EPT) less than 10 years after menopause has also been shown to reduce the risk of CHD in a recent analysis of the WHI randomized trial. The further that a woman is from menopause when HT is initiated, the greater the risk of CHD (Figure 1). The risk of CHD also increased progressively with HT initiation in women older than 60 years of age.^[5,45]

Effect of timing of hormone therapy initiation on risk of coronary heart disease events.

Mortality. The WHI-ET and EPT trials both have shown a significant 30 percent reduction in overall mortality (HR 0.70, 95 percent CI 0.51-0.96) relative to placebo among women 50-59 years old.^[5] This information is very reassuring when considering counseling women under age 60 on the use of HT.

Stroke. Stroke is not increased with ET in women age 50-59 years (2 fewer events per 10,000 women per year of therapy relative to placebo). The risk of stroke with EPT in the same age group was increased by 5 per 10,000 women per year of therapy relative to placebo and 3 per 10,000 women per year of therapy if initiated within 5 years of menopause.^[3,5]

VTE. The risk of VTE was significantly increased in all age groups on HT. However, the absolute risk of VTE was lower in the younger vs. older women (Table 4).^[38,40]

The Role of Hormone Therapy in Managing Menopause

Hormone therapy has long been considered the most effective treatment for common menopausal symptoms including hot flashes, sleep disturbance, mood changes, urogenital symptoms, and quality of life. When considering initiation of HT in a symptomatic postmenopausal woman, risks and benefits should be carefully evaluated and discussed with the patient. Decision to treat should be done on a case-by-case basis, as there is no “one size fits all” treatment regimen. HT should not be initiated solely for primary prevention of CHD and caution observed in older postmenopausal women and women who are more than 10 years past menopause as risks may far outweigh the benefits.

The Role of Hormone Therapy in Prevention of Osteoporosis

Studies on estrogen therapy or combined estrogen-progesterone therapy have shown a significant increase in spine and hip bone density relative to placebo, and a reduction in hip, vertebral, and total fracture risk in postmenopausal women.^[12,18,46] Hormone therapy, therefore, has a role in the prevention of osteoporosis. Although no HT product has been approved by the FDA for treatment of osteoporosis, many systemic HT products have been approved for prevention of postmenopausal osteoporosis.

When hormone therapy is discontinued, bone mass can decline as much as it does in untreated women during the early years of menopause (20 percent in the first 5-7 years following menopause). If this occurs, other bone preserving measures should be taken.

If the sole indication to use HT is osteoporosis, then other agents should be considered as well, each with their own risk benefit equation as discussed in Case 3.

Table 3

Comparison of absolute and relative risks of breast cancer in randomized, controlled trials of postmenopausal hormone and statin therapies

Study	No. of breast cancers (annualized percent)		RR	95 percent CI	No. of additional breast cancer cases per 10,000 women per year of therapy
	Placebo	Therapy
RR, relative risk; Statin, 3-hydroxy-3methylglutaryl coenzyme A reductase inhibitor; PROSPER, Prospective Study of Pravastatin in the Elderly Risk; AFCAPS/TexCAPS, Air Force/Texas Coronary Atherosclerosis Prevention Study; 4S, Scandinavian Simvastatin Survival Study; CARE, Cholesterol and Recurrent Events Trial; LIPID, Long-term Intervention with Pravastatin in Ischemic Disease; ALLHAT- LLT, Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial; HPS, Heart Protection Study; CEE + MPA, oral daily continuous combined conjugated equine estrogens (0.625 mg) plus medroxyprogesterone acetate (2.5 mg); WHI-EP, Women’s Health Initiative estrogen + progestin trial; HERS, Heart and Estrogen/progestin Replacement Study; CEE alone, oral daily conjugated equine estrogens (0.625 mg); WHI-E, Women’s Health Initiative estrogen trial; 17B-E2, oral daily 17B-estradiol (1mg); WEST, Women’s Estrogen for Stroke Trial.
Hodis H, Mack WJ. Postmenopausal hormone therapy in clinical perspective. Menopause 2007; 14;944-957. Reprinted with permission.
Statin
PROSPER	11 (0.23)	18 (0.38)	1.65	0.78–3.49	15
AFCAPS/TexCAPS	9 (0.35)	13 (0.50)	1.44	0.62–3.36	15
4S (10-y follow-up)	5 (0.11)	7 (0.17)	1.44	0.46–4.52	5
CARE	1 (0.07)	12 (0.84)	12.17	2.48–59.80	77
LIPID	10 (0.22)	10 (0.22)	1.00	0.42–2.42	0
ALLHAT-LLT	37 (0.30)	34 (0.28)	0.93	0.58–1.48	–2
HPS	51 (0.40)	38 (0.30)	0.75	0.49–1.13	–10
CEE+MPA
WHI-EP	150 (0.33)	199 (0.42)	1.24	0.97–1.59	9
HERS	25 (0.45)	32 (0.57)	1.30	0.77–2.19	12
CEE alone
WHI-E	161 (0.42)	129 (0.34)	0.82	0.65–1.04	–8
17B-E2 alone
WEST	5 (0.55)	5 (0.53)	1.00	0.30–3.50	–2

Table 4

Absolute risks of venous thromboembolism with estrogen/progestin therapy (EPT) and estrogen therapy (ET) use per age group^[37,39]

Age (in years)	Absolute risk per 10,000 women per year
	EPT	ET
50-59	11	4
60-69	16	7
70-79	35	11

WHI=Women’s Health Initiative (randomized trial); E+P = estrogen plus progestin; E = estrogen.

Rossouw JE, Prentice RL, Manson JE, et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA 2007; 297:1465-1477. Reprinted with permission.

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22. McKenzie M, Sikon AL, Thacker HL, et al. Putting the latest data into practice: case studies and clinical considerations in menopausal management. Cleve Clin J Med 2008;75(4):25-32.
23. Utian WH, Shoupe D, Backmann G, et al. Relief of vasomotor symptoms and vaginal atrophy with lower doses of conjugated equine estrogens and medroxyprogesterone acetate. Fertil Steril 2001;75:1065-1079.
24. Grodstein F, Manson JE, Colditz GA, et al. A prospective, observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease. Ann Intern Med 2000;133:933-941.
25. The American College of Obstetricians and Gynecologists. Menostar: an ultra low dose estrogen patch OB-GYN 2005; 105:432-433
26. Prestwood KM, Kenny AM, Kleppinger A, et al. Ultralow-dose micronized 17beta-estradiol and bone density and bone metabolism in older women: a randomized controlled trial. JAMA 2003;290(8):1042-8.
27. Thacker HL. Cleveland Clinic guide to menopause. February 2009. Kaplan Publishing
28. Black DM, Cummings SR, Karpf DB, et al. Randomized trial of effect of alendronate on risk of fracture in women with existing vertebral fractures: Fracture Intervention Trial Research Group. Lancet 1996; 348:1531-1541.
29. McClung MR, Geusen P, Miller PD, et al. Effect of risedronate on the risk of hip fracture in elderly women. Hip Intervention Program Study Group. N Engl J Med 2001; 344:333-340.
30. Reginster JY, Minne HW, Sorensen OH, et al. Randomized trial of effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Vertebral Efficacy with Risedronate Therapy (VERT) Study Group. Osteoporos Int 2000; 11:83-91.
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34. Neer RM, Arnaud CD, Zanchetta JR, et al. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 2001;344:1434-1441.
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37. Stefanick ML, Anderson GL, Margolis KL, et al. Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy. JAMA 2006;295(14):1647-1657.
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Continuing Education

CE Credit

After participating in this activity, the reader has the option of taking a post-test to qualify for continuing education credit for this activity. It is estimated it will take 1.0 hour(s) to complete the reading and take the post-test. Continuing education credit will be available for two years from the date of publication.

The National Osteoporosis Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.  The National Osteoporosis Foundation designates this educational activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)TM. Physicians should only claim credit commensurate with the extent of their participation in the activity.

The National Osteoporosis Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation.

The National Osteoporosis Foundation designates this educational activity for a maximum of 1.0 continuing nursing education credit(s).

Other healthcare providers will also be able to receive a certificate of completion; nurse practitioners and physician assistants may request an AMA PRA Category 1 Credit(s)™ certificate.

If you wish to receive continuing education credit, please click here to access the Continuing Education Application. Print this form and complete offline. Complete the registration form then take the 10-question post test and circle your answers on the CE Reporting Form. Then complete the activity evaluation found at the bottom of the CE Reporting Form. You must complete the Post-Test and CE Reporting Form in order to receive credit.

There is a $10.00 fee for this continuing education activity. Payment may be made by check, VISA or MasterCard. We cannot accept any other forms of payment. Please complete the payment information on the CE Reporting Form.

Once the Continuing Education Application is complete, return it with your payment to NOF at the address indicated on the form. Your continuing education certificate will be emailed to you within 3 weeks of receipt.

Software Requirement: Adobe Acrobat Reader is required to read the text for this continuing education activity.

Editorial Board

The Osteoporosis Clinical Updates Editorial Board is comprised of medical specialists, nonspecialists, and a variety of other healthcare professionals involved in research in and management of osteoporosis.

DISCLOSURE OF COMMERCIAL SUPPORT
It is the policy of the National Osteoporosis Foundation (NOF) to ensure balance, independence, objectivity, and scientific rigor in all its sponsored publications and programs. NOF requires the disclosure of the existence of any significant financial interest or any other relationship the sponsor, Editorial Board or Guest Contributors have with the manufacturer(s) of any commercial product(s) discussed in an educational presentation. All authors and contributors to this continuing education activity have disclosed any real or apparent interest that may have direct bearing on the subject matter of this program.

Please be advised that NOF’s accreditation status with ACCME and ANCC does not imply endorsement by NOF, ACCME, or ANCC of any commercial products displayed in conjunction with this activity.

STATEMENT ON OFF-LABEL USE

Please be advised that any publication of the Osteoporosis Clinical Updates that discusses off-label use of any medications or devices will be disclosed to the participant.

EDITORIAL BOARD DISCLOSURES

Editor-in-Chief
Angelo Licata, MD, PhD
Director, Center Space Medicine
Department of Endocrinology
Cleveland Clinic 
Disclosures: Speaking/Teaching: Eli Lilly, Novartis, Amgen, Consulting: Merck

Adrienne Berarducci, PhD, ARNP, BC 
Associate Professor
University of South Florida and 
Azure Medical Group
Disclosure: No relationships to disclose

Carolyn J. Bolognese, RN, CDE
Bethesda Health Research Center
Disclosure: Consulting: Amgen, Merck
Speaking/Teaching: Amgen, Merck

JoAnn Caudill, RT, BD, CDT
Bone Health Program Manager
Redwood / Erickson Retirement Communities
Disclosures: No relationships to disclose

Peggy Doheny, PhD, RN, CNS, ONC
Professor and Adult CNS Program Director
Kent State University College of Nursing
Disclosures: No relationships to disclose

Patricia Graham, MD, PC
Owner, Physical Medicine and Rehabilitation / Integrative Medicine
Disclosures: No relationships to disclose

Craig Langman, MD
Head, Kidney Diseases
Childrens Memorial Hospital
Professor, Feinberg School of Medicine
Northwestern University
Disclosure: No relationships to disclose

Barbara Messinger-Rapport, MD, PhD
Director, Center for Geriatric Medicine of the Medicine Institute
Cleveland Clinic
Disclosure: No relationships to disclose

Paul D. Miller, MD
Distinguished Clinical Professor of Medicine
Colorado Center for Bone Research
Disclosures: Consulting: Warner Chilcott, Baxter, Genentech, Eli Lilly, Merck, Novartis, Amgen, GlaxoSmithKline
Speaking/Teaching: Warner Chilcott, Genentech, Eli Lilly, Merck, Novartis, Amgen
Advisory Committee: Warner Chilcott, Genentech, Eli Lilly, Merck, Novartis, Amgen
Research/Grants: Warner Chilcott, Eli Lilly, Merck, Novartis, Amgen

Jeri Nieves, PhD
Associate Professor of Clinical Epidemiology
Columbia University, Helen Hayes Hospital
Disclosure: Consulting: Merck

Mary Beth O’Connell, PharmD, BCPS
Associate Professor, Wayne State University
Eugene Applebaum College of Pharmacy and Health Sciences
Disclosures: Research Grants: Merck

Carol Sedlak, PhD, RN, CNS, ONC, CNE
Professor & Nurse Educator Program Director
Kent State University College of Nursing
Disclosures: No relationships to disclose

Kathy M. Shipp, PT, MHS, PhD 
Assistant Professor, Division of Physical Therapy 
Department of Community and Family Medicine 
Duke University School of Medicine 
Disclosure: Speaking/Teaching: Amgen

Andrea Sikon, MD, FACP, CCD, NCMP
Chair, Department of Internal Medicine
Cleveland Clinic
Disclosure: Stockholder: Amgen, Pfizer

Kelly Trippe, MA
Managing Editor, Osteoporosis Clinical Updates
National Osteoporosis Foundation
Disclosure: No relationships to disclose

Susan Randall, RN, MSN, FNP-BC
Senior Director, Science and Education
National Osteoporosis Foundation
Disclosure: No relationships to disclose