Learning objectives
- •
Raloxifene: Therapeutic profile: efficacy and adverse effects.
- •
Estrogen/progesterone: uses, limitations, adverse effects.
The case study
Reason for seeking medical help
Mrs. KA, 65-year-old woman is concerned about osteoporosis because her mother recently sustained a fragility hip fracture.
Past medical/surgical history
- •
Natural menopause at 51 years, no HRT.
- •
Menarche at 13 years, regular menstrual periods.
- •
No relevant past medical history.
- •
Asymptomatic, always enjoyed good health.
Personal habits
- •
Sedentary lifestyle.
- •
Daily dietary calcium intake about 1200 mg.
- •
No excessive sodium, caffeine, alcohol, or carbonated drinks.
- •
No cigarette smoking.
Medication
- •
Multivitamin one tablet daily.
- •
Cholecalciferol 1000 units daily.
Family history
- •
Mother sustained fragility hip fracture.
Clinical examination
- •
Weight 165 pounds, steady; height 65″.
- •
No significant clinical findings.
- •
Get-Up-and-Go test completed in 8.3 s.
Laboratory investigations
- •
Comprehensive metabolic profile, TSH, serum vitamin D levels within normal limits.
DXA scan results
- •
Left total hip −2.1, left femoral neck −1.9, L1–L4 −2.5.
Multiple choice questions
- 1.
In postmenopausal women hormonal replacement therapy (HRT):
- A.
Increases lumbar vertebrae and proximal femur BMD.
- B.
Reduces risk of vertebral and hip fractures.
- C.
Is associated with significant adverse events.
- D.
A and B.
- E.
A, B, and C.
Correct answer: E
Comment:
The Women’s Health Initiative (WHI) study documents that in postmenopausal women HRT reduces fracture risk, including hip fractures, but is associated with a number of adverse events, including coronary artery disease events, thromboembolism, breast cancer, strokes, urinary incontinence, and dementia. HRT is now no longer recommended for the treatment of osteoporosis unless alternate therapies are not appropriate. It may be used for the prevention of osteoporosis if given in the smallest effective dose and for a short period of time. The “smallest effective dose” is determined by vasomotor symptom relief.
There is also epidemiological evidence that reduced estrogen production by the ovaries is associated with an increased fracture risk. A population study on 80,955 postmenopausal women (mean age 68.8 years) documented that as HRT use decreased from 85% in July 2002 to 18% in December 2008 the age-adjusted hip fracture risk increased from 3.9 to 5.67 per 1000 women. The increased risk was observed as early as 2 years after cessation of hormonal therapy, steadily increased thereafter and was inversely correlated to T-scores.
- A.
- 2.
The WHI enrolled postmenopausal women:
- A.
1–5 years postmenopause.
- B.
T-score −2.5 or lower in the vertebrae.
- C.
T-score −2.0 to −2.5 and a moderate vertebral compression fracture.
- D.
No estrogen intake for at least 3 months.
- E.
All of the above.
Correct answer: D
Comment:
The WHI study was a randomized, double-blind, placebo-controlled study on postmenopausal women, 50–79 years old, comparing placebo to estrogen (0.625 mg) in hysterectomized women or estrogen (0.625 mg) and progesterone (2.5 mg) in nonhysterectomized women. The study was devised in such a manner that it be terminated should the potential harm outweigh the potential benefit(s) of estrogen and estrogen/progesterone. The primary endpoint was coronary heart disease events, and neither fractures nor BMD changes. Secondary endpoints, however, included fractures, strokes, thromboembolism, cancer, and all-causes mortality. Enrollment was not based on T-scores. A wash out period of 3 months was required for participants who had been on HRT.
The estrogen/progesterone study (16,608 participants) was prematurely terminated because the adverse events (increased risk of breast cancer, coronary artery disease events, strokes, and pulmonary emboli) outweighed beneficial effects (reduced fractures and colon cancer). The estrogen only study (10,739 participants) also was subsequently prematurely terminated because of increased incidence of strokes in the estrogen group.
- A.
- 3.
Hormonal Replacement Therapy (HRT) and risk of coronary artery disease (CAD) events:
- A.
Estrogen increases the risk of coronary artery disease in all age groups.
- B.
The risk is increased regardless of presence or absence of CAD.
- C.
The risk is increased regardless of estrogen dose.
- D.
All of the above.
- E.
None of the above.
Correct answer: E
Comment:
A secondary analysis of WHI data showed that adverse cardiovascular events occurred primarily in women 70 years and older and less frequently in those 60 years or younger or within 10 years of the menopause. Other studies document that HRT reduces the risk of cardiovascular events if initiated within 10 years of menopause and in women who have no preexisting atherosclerosis. The patient’s age and underlying CAD therefore may modulate CAD adverse events. Lower doses of estrogen such as 0.3 mg daily have been shown to prevent bone loss at the lumbar vertebrae and hips in early postmenopausal women.
- A.
- 4.
Match the following:
- (a)
Raloxifene.
- (b)
Estrogen.
- (c)
Both.
- (d)
Neither.
- A.
Reduced risk of hip fractures.
- B.
Reduced risk of colon cancer.
- C.
Increased hot flashes.
- D.
Increased risk of breast cancer.
- E.
Increased thromboemboli.
- A.
Correct answers: A (b); B (b); C (a); D (b); E (c)
Comment:
Estrogen with or without progesterone reduces the risk of fractures, including hip fractures, but increases the risk of breast cancer. Raloxifene reduces the risk of vertebral, but not hip fractures. Other potentially serious adverse events include deep vein thrombosis, thromboembolism, and strokes. Leg cramps, flu-like symptoms, arthralgias, peripheral edema, and excessive sweating also have been reported.
- (a)
- 5.
Estrogen increases the risk of:
- A.
Dementia.
- B.
Strokes.
- C.
Urinary incontinence.
- D.
A and B.
- E.
A, B, and C.
Correct answers: E
Comments:
Estrogen, in doses of 0.625 mg daily, increases the risk of gall bladder disease, dementia, strokes, and urinary incontinence in postmenopausal women.
- A.
- 6.
Raloxifene:
- A.
Is a selective estrogen receptor modulator (SERM).
- B.
Reduces vertebral and nonvertebral fractures.
- C.
Reduces the risk of breast cancer.
- D.
A and C.
- E.
A, B, and D.
Correct answer: D
Comment:
Raloxifene is a SERM with estrogen receptor agonistic activity on bone tissue: decreasing bone resorption and turnover, increasing BMD and reducing vertebral, but not nonvertebral fractures. Raloxifene has an estrogen receptor antagonist activity on breast and uterine tissue, thus reducing the risk of breast cancer (ER positive) and uterine cancer.
- A.
- 7.
Raloxifene is contraindicated in patients with a history of:
- A.
Venous thrombosis.
- B.
Retinal vein thrombosis.
- C.
Pulmonary embolism.
- D.
A and C.
- E.
A, B, and C.
Correct answer: E
Comment:
Raloxifene increases the risk of venous thromboembolism and therefore should not be administered to patients with a history of venous thrombosis or susceptible to venous thrombosis, including patients with the antiphospholipid antibody syndrome. Similarly, it is prudent to discontinue the use of raloxifene at least 72 h prior to an anticipated prolonged period of immobilization, including transoceanic flights.
- A.
- 8.
Raloxifene is not recommended in patients who:
- A.
Smoke cigarettes.
- B.
Have transient ischemic attacks.
- C.
Have hypertension and/or atrial fibrillation.
- D.
B and C.
- E.
A, B, and C.
Correct answer: E
Comment:
Compared to placebo, patients on raloxifene have a higher incidence of fatal strokes (2.2 versus 1.5 per 1000 person years), but no increase in the overall risk of strokes or coronary events.
- A.
- 9.
Raloxifene can be used for the:
- A.
Prevention of osteoporosis.
- B.
Primary prevention of coronary heart disease.
- C.
Secondary prevention of coronary artery disease.
- D.
A and B.
- E.
A, B, and C.
Correct answer: A
Comment:
Raloxifene can be used for the prevention of osteoporosis but neither for the primary nor secondary prevention of coronary artery disease. Raloxifene should not be administered to premenopausal women.
- A.
- 10.
After considering various medications, Mrs. KA decided to go on raloxifene. Appropriate reasons for prescribing it include:
- A.
Ease of administration.
- B.
Good patient adherence.
- C.
Mrs. KA’s fracture risk.
- D.
A and C.
- E.
A, B, and C.
Correct answer: E
Comments:
Raloxifene is easily administered: it can be taken any time of the day, with or without food. Given Mrs. KA’s T-scores, her risk of sustaining a hip fracture is only marginally increased compared to the risk of vertebral fractures. Raloxifene is therefore a reasonable choice as it reduces the risk of vertebral fractures.
- A.
Case summary
Analysis of data
Factors predisposing to bone demineralization/osteoporosis
- •
Status postmenopause, no HRT.
- •
Positive family history of osteoporosis.
- •
Sedentary lifestyle.
Factors reducing risk of bone demineralization/osteoporosis
- •
Good daily calcium intake.
- •
No excessive sodium or caffeine intake.
- •
No cigarette smoking.
Factors increasing risk of falls/fractures
- •
Mother sustained fragility hip fracture.
- •
Get-Up-and-Go test completed in less than 10 s.
Factors reducing risk of falls/fractures
- •
None.
Diagnosis
- •
Postmenopausal osteoporosis, as determined by bone densitometry.
Management recommendations
Treatment recommendation(s)
- •
Antiresorptive medication.
Diagnostic test(s)
- •
None at this stage.
Lifestyle
- •
Enroll in exercise program
DXA scans
- •
At 2 years to monitor bone mass.
Related posts:
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
