Diagnosis and treatment of postmenopausal osteoporosis

Diagnosis and Treatment of Postmenopausal Osteoporosis Diane Altkorn HE NATIONAL Osteoporosis Foundation 1 estimates that over 20 million postmenopausal white women have either osteoporosis or low bone density at the hip. Patients with hip fractures have an excess mortality of 10% to 20% within 1 year, and only one third of patients regain their premorbid level of independence. Although vertebral compression fractures are not associated with increased mortality, they can result in significant pain, limitation of activity, and in very severe cases, restrictive lung disease and changes in gastrointestinal (GI) function. Osteoporosis is a reduction in the mass of bone per unit volume, clinically known as bone mineral d6nsity (BMD). Any degree of skeletal fragility sufficient to increase the risk of fracture is considered osteoporosis. The reduction in bone mass results from failure to attain optimal peak bone mass a -(which occurs at age 30-35) and/or subsequent excess bone resorption compared with bone formation. After age 40 to 50, cortical bone is lost at a rate of 0.3% to 0.5% per year, with an acceleration to 5% to 7% per year in postmenopausal women. Cumulative bone mass loss can range from 20% to 30% in men to as much as 40% to 50% in some women. Postmenopausal women lose a disproportionate amount of trabecular bone and are at risk for vertebral and radial fracture; older men and women lose an excess of both cortical and trabecular bone and experience fractures of the femoral neck, proximal humerus, proximal tibia, and pelvis.

T

RISK FACTORS FOR OSTEOPOROTIC FRACTURE Low BMD is a very potent predictor of fracture risk, but fall risk also affects the chance that a From the Department of Medicine, University of Chicago, Chicago, IL. Address reprint requests to Diane Altkorn, MD, University of Chicago Hospitals, 5841 S. Maryland, MC 3051, Chicago, IL 60637. Copyright 2002, Elsevier Science (USA). All rights reserved. 0277-0326/02/2101-0000535.00/0 doi: l O.1053/sane.2002.30380

8

patient will experience the most serious osteoporotic fracture, a hip fracture. Thus, it is clinically useful to divide risk factors for osteoporotic fracture into two categories: risk factors for falls and risk factors for low BMD. In each category, some of the risk factors are modifiable, and some are not. Gait disorders, one of the most important risk factors for falls, can result from a variety of underlying illnesses, most commonly arthritic or neurologic illnesses. Other fall risk factors, derived from epidemiologic studies, include poor vision, dementia, use of sedating medications, and physical barriers and hazards (such as slippery throw rugs, lack of handrails, poorly lit stairwells, and SO on).

Risk factors for low BMD include body weight less than 127 pounds, height loss of more than 2 inches since age 25, smoking, low calcium intake, ethnicity (white or Asian), personal history of fracture as an adult, family history of low BMD or hip fracture, menopause, and older age. Medications that increase bone loss include glucocorticoids, anti-convulsants, heparin (when used for more than 6 months), and thyroxine (when patients are overreplaced). Diseases that increase bone loss include hyperparathyroidism, hyperthyroidism, malabsorption from any cause, and hypogonadism from any cause; menopause is the most obvious, but it is important to think about bone loss in patients with amenorrhea from other causes such as eating disorders and in men with low testosterone levels. DIAGNOSIS OF LOW BONE MINERAL DENSITY How to Measure Bone Mineral Density

There are several ways to measure bone mineral density, including single or dual energy absorptiometry and ultrasound. Different sites can be measured, such as the spine, hip, radius, and heel Dual-energy x-ray absorptiometry scan is the preferred method to use because it is the most precise and the most predictive of fracture risk. The most important site to measure is the hip; the spine measurement can also be used but can be artifactually increased by spine deformities.

Seminars in Anesthesia, Periaperative Medicine and Pain, Vol 21, No 1 (March),2002: pp 8-15

POSTMENOPAUSAL OSTEOPOROSIS Bone density is reported in grams per centimeter squared ,and also by a normalized score. The T score compares the current bone density to peak young adult bone mass. The World Health Organization defines osteoporosis as a T score at least 2.5 standard deviations below the peak, and osteopenia as a T score of 1 to 2.5 standard deviations (SDs) below the peak. In postmenopausal women, there is a 1.5 to 2.5 increase in the relative risk of spine or hip fracture for every decrement in SD. In other words, a patient with osteopenia has a relative risk of fracture between approximately 2 and 5, and a patient with osteoporosis has a relative risk of over 5. Additionally, a Z score is sometimes reported. It compares the current bone density with age and sex-matched controls. Fracture risk is more than doubled if the Z score is more than 2 SDs below the control. The T score is more predictive of fracture risk than the Z score and should be the measurement used to make therapeutic decisions. Another way to think about bone density results is to remember that there seems to be a "fracture threshold." Patients with a spine bone density greater than 1.0 g/cm 2 squared or a hip bone density greater than 0.7 g/cm 2 rarely fracture. Bone density changes slowly, so if you are monitoring responses to therapy, you should repeat measurements every 1.5 to 2 years. If you are monitoring patients with normal bone density for changes, every 2 to 3 years is sufficient. A recent study in the Journal of the American Medical Association found that a minority of women will have lower BMD measurements after 1 year of therapy because of random variations and will have substantially increased BMD when retested after 2 years; the investigators suggest waiting 1 year and repeating the measurement if a woman does not have the expected response to therapy. Because they are largely trabecular bone, the spine and trochanter are most responsive to therapy and therefore should be the sites monitored. The total hip measurement is the one most predictive of hip fracture. Because there is some variability between machines, it is best to use the same machine for serial measurements. Biochemical markers of bone resorption or formation, such as osteocalcin, bonejspecific alkaline phosphatase, or n-telopeptide, can be measured. Their clinical use is controversial 3 because of high variability with a precision error of over 20%.

9 However, following markers is sometimes helpful becanse they can change as much as 40% to 60% after only 3 months of treatment and predict changes in the BMD at 1 to 2 years. Measuring markers at baseline and after 3 months of therapy is particularly useful when using one of the less potent antiresorptive agents, when a patient is ambivalent about treatment and desires early confirmation of its effectiveness, or when lack of compliance or absorption is suspected.

When to Measure Bone Mineral Density There are no clinical trial data to guide decisions regarding who to screen. There are a variety of consensus recommendations and clinical decision rules available. The National Osteoporosis Foundation's (NOF) guidelines 1 for screening are widely used. They were developed by a consensus panel with representatives from a variety of specialty groups (radiology, endocrinology, rheumatotogy, geriatrics). These guidelines are more liberal than those of the US Preventive Services Task Force or the Canadian Task Force and were based on a cost-effectiveness analysis showing that screening was cost-effective. Their recommendations include screening all women over age 65 and all postmenopausal women under 65 with one or more of the following risk factors: personal history of fracture as an adult, history of fracture in a first-degree relative, white race, current cigarette smoking, low body weight ( < 127 lbs.), lifelong low calcium intake, alcoholism, or history of diseases or medications that increase the risk of osteoporosis. Some of the medications that increase risk include anticonvulsants, glucocorticoids, heparin, thyroxine, warfarin, and cyclosporine. Some of the included diseases are premature menopause, amenorrhea, hyperprolactinemia, eating disorders, hyperparathyroidism, hyperthyroidism, chronic liver diseases, and some chronic GI disorders. The guidelines also recommend measuring bone density in women who present with fractures to determine the severity of disease and when the bone density would help the patient and physician make a decision about therapy. Women on prolonged hormone replacement therapy (HRT) should be tested periodically to monitor their response to therapy because about 10% of women do not respond to HRT. Medicare would cover most

10 bone density measurements done following these guidelines. The Osteoporosis Risk Assessment Instrument (ORAI) has recently been compared with the NOF recommendations. The ORAI was equally sensitive (about 94% for both) in identifying women with low BMD and was more specific (32% v 20%), thus reducing the number of unnecessary tests ordered. The ORAI is a point system in which a woman is given two points if not on estrogen, nine points if weight <60 kg, three points if weight 60 to 69.9 kg, five points if age 55 to 64, nine points if age 65 to 74, and 15 points if age >75. Patients with scores greater than 9 should be tested. As recommended by the NOF, all women over 65 would be tested, with fewer women under 65 tested.

EVALUATION FOR SECONDARY CAUSES OF OSTEOPOROSIS Although most patients have osteoporosis because of menopause or age-associated loss, it is important to consider secondary causes. History and physical examination should focus on looking for the associated diseases already discussed. All patients should have a thyrotropin-stimulating hormone level and a serum calcium level; additional testing such as parathyroid hormone level, serum testosterone levels, vitamin D levels, and 24-hour urinary calcium measurements should be performed in selected patients.

REDUCING THE RISK OF OSTEOPOROTIC FRACTURE The primary goal of treatment for osteoporosis is to reduce the risk of hip fracture. Reducing the risk of vertebral compression fracture is the secondary goal followed by reducing the risk of other minimal trauma fractures.

Calcium and Vitamin D Calcium and vitamin D supplementation has been shown to maintain BMD, and adequate intake is the foundation for all other therapies for preventing and treating osteoporosis. Calcium intake should be reviewed with all women, and supplementation should be recommended if dietary intake is not sufficient. Vitamin D is especially important in institutionalized and other frail elderly patients; vitamin D supplementation alone has

DIANE ALTKORN been shown to reduce fracture rates in such populations. The recommended daily calcium intake for periand postmenopausal women is 1,200 mg per day of elemental calcium, and many women average only 500 to 700 mg per day in their diets. Although there are nondairy sources of calcium, most dietary calcium is obtained in dairy products: milk (8 oz) has 300 mg, yogurt (8 oz) has 400 mg, and cheese (1 oz) has 200 mg. The recommended daily vitamin D intake is 400 IU, which is the amount in a standard multivitamin; some calcium supplements contain vitamin D also. Calcium supplements are best absorbed if consumed in split doses throughout the day, with no more than 500 mg in 1 dose. Calcium carbonate contains 40% elemental calcium and should be taken with food for optimum absorption and reduction of GI side effects. Calcium citrate is 21% elemental calcium, has no GI side effects, and is well absorbed regardless of when it is taken.

Fall Prevention Falls are generally multifactorial in origin and therefore may require multiple interventions. Exercise of any kind is beneficial in improving balance and muscle tone and therefore reducing fall risk. Other interventions that can reduce fall risk include correcting poor vision, avoiding use of sedating medications, gait training, using appropriate assisfive devices, and improving the safety of the home environment (such as removing throw rugs, improving lighting, and adding handrails).

Pharmacologic Therapy The NOF recommends pharmacologic treatment of all postmenopausal women with T scores below - 2 . 0 and those with T scores below - 1 . 5 and risk factors. The greatest benefit in fracture reduction occurs in patients with preexisting vertebral fractures or T scores < - 2 . 5 ; all such patients should be treated. The following drugs are approved by the Food and Drug Administration (FDA) for the treatment of postmenopausal osteoporosis: estrogen, ratoxifene, bisphosphonates (alendronate and risedronate), and calcitonin. 4 All block bone resorption. Parathyroid hormone (PTH), which increases bone formation, is currently being studied but is not yet approved.

POSTMENOPAUSALOSTEOPOROSIS Hormone Replacement Therapy Large randomized trials examining the effect of HRT on fractures have not been conducted to date, primarily because estrogen had already received FDA approval for osteoporosis. There has been one small randomized trial showing that transdermal estrogen reduces vertebral fracture rates (relative risk [RR] = 0.39; 95% confidence interval [CI], 0.16-0.95). Observational studies show that postmenopausat estrogen reduces non-spinal fracture rates. In a study of women over 65, current estrogen users had lower risk for non-spinal fractures (RR = 0.66; 95% CI, 0.54-0.80). The overall reduction in hip fracture (RR = 0.6; 95% CI, 0.36-1.02) was not quite significant; however, hip fracture was significantly reduced (RR = 0.29; 95% CI, 0.09-0.92) for "early users," defined as women who started estrogen within 5 years of menopause. There has been a randomized, placebo controlled trial of HRT with BMD being the primary outcome. Eight hundred seventy-five osteoporotic women were assigned to estrogen alone, combined estrogen and progesterone, or placebo. Conjugated estrogen (0.625 mg daily) increased BMD by about 6% in the spine and 2.8% in the hip after 3 years. The addition of progesterone, regardless of the form or regimen, did not alter the effects of estrogen. This trial did not show reduction in fractures, possibly because it was conducted in younger women (45-64 years) who have a low incidence of osteoporotic fractures. Low-dose conjugated estrogen (0.3 mg daily) is less effective than the standard 0.625 mg daily dose, producing modest (1%-2% per year) increases in the spinal BMD either unopposed or in combination with progesterone. The increases in the hip were smaller and not statistically significant. Fracture rates are not reduced by low-dose estrogen.

Selective Estrogen Receptor Modulators Raloxifene is the first selective estrogen receptor modulator (SERM) approved for prevention and treatment of osteoporosis. The Multiple Outcomes Of Raloxifene Evaluation Study 5 was a randomized clinical trial of 7,705 women with osteoporosis and a mean age of about 66. Raloxifene (60 or 120 mg daily) increased spine BMD by 2.6% and hip BMD by 2.1% after 3 years. In women without preexisting vertebral fractures, the fracture rate

11 decreased from 4.5% in the placebo group to 2.3% in the raloxifene group, with a number needed to treat (NNT) to prevent 1 new vertebral fracture of 46. The reduction in vertebral fractures was larger in women with preexisting vertebral fractures, with rates decreasing from 21.2% to 14.7% for an NNT of 15. There was no effect on all non-vertebral fractures or hip fractures. Comparison of the Postmenopausal Estrogen/ Progestin Interventions Trial and the Multiple Outcomes of Raloxifene Evaluation Study 5 results suggests that HRT produces larger increases in BMD than raloxifene. This was also shown in a separate study that directly compared HRT and raloxifene. The non-skeletal effects of HRT and raloxifene are quite different and must be weighed when deciding whether to prescribe either one. Estrogen reduces hot flashes, whereas raloxifene has no beneficial effect on postmenopausal symptoms and sometimes increases them. Raloxifene reduces the risk of estrogen receptor positive breast cancer (RR = 0.35; 95% CI, 0.21-58; NNT to prevent 1 breast cancer over 40 months = 125), 6 whereas HRT probably increases breast cancer risk, 7 particularly after long-term use. Both increase the risk of thrombosis, with an RR of ~ 3 for both. Raloxifene and combination HRT do not increase the risk of endometrial hyperplasia, whereas unopposed estrogen does; raloxifene does not increase the risk of endometrial cancer. Both drugs decrease low-density lipoprotein cholesterol; estrogen also increases high-density lipoprotein. The effect of raloxifene on cardiovascular endpoints is unknown. The Heart and Estrogen/Progestin Replacement Study, 8 conducted in women with established coronary artery disease, showed that HRT does not reduce cardiovascular endpoints and may actually increase them during the first year of therapy. There is not yet randomized trial data regarding the use of HRT in primary prevention of cardiovascular endpoints; observational data from the Nurses' Health Study 9 suggest a reduction in endpoints in long-term current users of estrogen. Table 1 summarizes the non-skeletal effects of estrogen and raloxifene.

Bisphosphonates Alendronate is approved for osteoporosis prevention at 2.5 mg/d and treatment at 5 to 10 mg/d. The greatest benefit occurs in patients with the greatest short-term fracture risk, such as patients

DIANE ALTKORN

12 Table 1. Non-Skeletal Effects of HRT and Raloxifene

Venous thromboembolism Cardiovascular events Breast cancer Uterine cancer Menopausal symptoms

HRT

Raloxifene

]" ? 1' No effect $

1' ? ,!, No effect "['

Abbreviation: ?, effects unknown.

with T scores < - 2 . 5 or pre-existing vertebral fractures. In a 3-year trial w of alendronate in 881 postmenopausal women (age 45-80, T score < - 2 . 5 at the spine, 20% vertebral fractures at baseline), there was a significant reduction in radiographically diagnosed new vertebral fractures (RR = 0.52; 95% CI, 0.28-0.95; NNT = 33 over 3 years) but not in non-vertebral fractures. In the l#racture Intervention Trial 1J of 2,027 women (age 55-8l) with osteoporosis and baseline vertebral fractures, there was a significant reduction in clinical vertebral fractures (RR = 0.45; 95% CI, 0.270.72, N N T over 3 yr = 37), hip fractures (RR = 0.49; 95% CI, 0.23-0.99; NNT = 91), and any clinical fracture (RR = 0.72; 95% CI, 0.58-0.90; NNT = 22). In another arm 12 of the Fracture Intervention Trial Study conducted in 4432 women with low bone density but no preexisting vertebral fractures, 4 years of alendronate treatment produced a significant reduction in radiographic vertebral fractures (RR = 0.56; 95% CI, 0.39-0.80; N N T = 59) but only a trend toward a reduction in all clinical fractures (RR = 0.86; 95% CI, 0.731.01; P = 0.07). When the analysis was restricted to women with T scores of < - 2 . 5 at the femoral neck, there was a significant reduction in all clinical fractures (RR = 0.64; 95% CI, 0.50-0.82; NNT = 15) and in hip fracture (RR = 0.44; 95% CI, 0.18-0.97; N N T = 81). Risedronate is F D A approved for prevention and treatment of osteoporosis (both at 5 mg). Its effects are similar to those of alendronate. In a 3-year trial 13 of over 2,000 North American women with preexisting vertebral fractures, risedronate significantly reduced the rate of vertebral fractures (RR = 0.6, 95% CI = 0.4-0.8, NNT = 20) and non-vertebral fractures (RR = 0.6, 95% CI = 0.4-0.9, NNT = 31). Risedronate has also been shown to significantly reduce the rate of hip frac-

tures in older women with established osteoporosis (RR = 0.6, 95% CI = 0.4-0.9, NNT = 76). Randomized trials of both alendronate and risedronate have not shown significant differences in the rates of GI side effects between treatment and placebo groups. Nevertheless, some women do experience dyspepsia or abdominal pain. To ensure absorption and prevent esophageal ulceration and perforation, they must be taken while fasting with a full glass of water, followed by 30 to 60 minutes of upright posture and no food. Seventy milligrams of alendronate once weekly, a more convenient regimen, produces changes in BMD and bone markers identical to those of a daily dose of 10 mg, without any increase in GI side effects. There have been several case reports of esophageal ulceration with alendronate, most notably in a patient with dementia who was unable to follow the administration instructions. Bisphosphonates should be avoided in patients with esophageal dysmotility or inability to follow the administration instructions precisely.

Combination Therapy and Comparison of Estrogen and Alendronate Approximately 10% to 20% of women continue to lose bone on HRT alone and need additional therapy for osteoporosis. In a randomized trial of over 400 women with a mean age of 62 and on HRT for an average of 9.5 years, addition of alendronate for 1 year, compared with addition of placebo, resulted in significant increases in spine (3.5% v 1.0%) and hip BMD (2.7% v 0.5%). In a direct comparison study, 425 hysterectomized women were randomized to placebo, conjugated estrogen, alendronate, or combination therapy. After 2 years, the increase in BMD at various sites was similar in the estrogen and alendronate group and only slightly larger in the group that received combination therapy. Neither study was of sufficient size or duration to detect a difference in fracture rates.

Calcitonin Nasal calcitonin is a well-tolerated antiresorptive agent that reduced new radiographic vertebral fractures in a trial of 1,255 older women with preexisting vertebral fractures (RR = 0.67, 95% CI = 0.47-0.97, NNT = 11 over 3 years). However, the results in this study were not all consistent. There was no dose response, with significant

13

POSTMENOPAUSAL OSTEOPOROSIS Table 2. Summary of Treatment Effects

Low-dose HRT HRT Raloxifene Alendronate Risedronate Calcitonin

Spine BMD

Hip BMD

Vertebral Fractures

Hip Fractures

1' 1' 1' I' 'I' No effect

No effect i' 1" '1" 1' No effect

No effect $ $ $ J, ,1,

No effect $ No effect ,1, $ No effect

fracture reduction occurring only in the 200 IU group, despite a lack of significant change in B M D in that group; a small increase in BMD (1.5%) occurred only in the 400 IU group. A recent direct comparison study found the effect of calcitonin on BMD and bone markers to be significantly less than that of alendronate and for most sites, not significantly different from placebo, suggesting that calcitonin is less potent. In some patients, calcitonin has an analgesic effect, making it suitable for patients with acute vertebral fracture who are bedridden and thus may need to avoid bisphosphonates because of risk of esophageal injury or estrogen because of the risk of venous thromboembolism.

Parathyroid Hormone PTH stimulates both bone resorption and formation. When serum PTH levels are continuously elevated, excess bone resorption occurs. When subcutaneous PTH is given daily, there are only transient increases in serum PTH; bone formation predominates, and bone density increases. A recent randomized trial compared subcutaneous PTH with placebo in over 1,600 women with preexisting vertebral fractures. There was a significant reduction in the occurrence of a new vertebral fracture in the PTH group (RR = 0.35, 95% CI = 0.22-0.55, NNT = 11). There was also a significant reduction in non-vertebral fractures (RR = 0.65, NNT = 29). Adverse events included mild hypercalcemia, nausea, and headache. Although there were no cancers in the clinical trial, it was stopped early because of the development of osteosarcomas in a rat carcinogenicity bioassay.

ISSUES IN PERIOPERATIVE MANAGEMENT There is no harm in stopping any of these treatments during the perioperative period. W o m e n on estrogen and raloxifene have an increased risk

of venous thromboembolism. Bisphosphonates should not be restarted until the patient can fotlow the administration instructions discussed previously.

SUMMARY Table 2 summarizes the effects of the agents discussed previously. There is little data directly comparing the different medications, and none of the published studies directly compares effects on fracture rates. When choosing a medication to treat osteoporosis, it is important to consider any comorbidities that would influence the choice (such as avoiding HRT in patients with a history of breast cancer) and to discuss the benefits and risks of each agent with patient. The following examples illustrate some of the issues that need to be considered.

CLINICAL SCENARIOS 1. An active and independent 80-year-old African-American woman falls on the ice and breaks her wrist. Should you order a bone mineral density measurement? Answer: Yes. By age 80, all patients, regardless of ethnic background, are at risk for low BMD. Having experienced a fracture as an adult is also a risk factor for osteoporotic fracture. . A 55-year-old postmenopausal white woman whose mother had osteoporosis and breast cancer has a spine T score of - 1 . 2 and a hip T score of - 1 . 1 . The patient herself has not had breast cancer but has had to undergo breast biopsies to confirm that mammographic abnormalities were benign. She does not smoke, exercise regularly, and weighs 110 lbs. She is very concerned about developing

14

DIANE ALTKORN osteoporosis. What would you recommend? Answer: The patient has mild osteopenia, but does not yet meet NOF criteria for pharmacologic treatment (T score < - 2 . 0 , or < - 1 . 5 with additional risk factors). However, she is at high risk of developing low BMD because of her multiple risk factors (body weight < 127 lbs, Caucasian background, positive family history). In addition to maintaining her healthy lifestyle, she should ensure that her calcium intake is optimal. Some women with this profile will ask for pharmacologic treatment also. HRT, raloxifene, and bisphosphonates have all been shown to prevent loss in bone density and are FDA-approved for prevention of osteoporosis. HRT and raloxifene have not been shown to prevent fractures when started at this level of BMD, and alendronate reduces vertebral fracture rates only minimally in mild osteopenia. It would be reasonable to monitor her BMD every 18 to 24 months and start therapy when her T score is less than -1.5. Alternately, one could start an preventive agent after a complete discussion of the potential benefits and risks. Because of her family history of breast cancer, she might be interested in the potential breast cancer protective effects of raloxifene.

3. A 75-year-old woman has a spine T score of + l . 0 and a hip T score of -3.0. What treatment, if any, would you prescribe? Answer: The spine T score is artifactually increased owing to osteoarthritis and should be ignored. HRT, raloxifene, alendronate, risedronate, and calcitonin are all FDA-approved for treatment of osteoporosis. The evidence regarding reduction of both vertebral and hip fractures is strongest for the bisphosphonates; patients benefit within 1 year of starting therapy. My first choice for such a patient is a bisphosphonate, with calcitonin as my last choice. . An 85-year-old woman with a history of esophageal dysmotility and deep vein

thrombosis after surgery for a hip fracture has been discharged home from rehabilitation, using a walker. A BMD done just before the fracture had a hip T score of -2.6. What would you recommend to reduce her risk of recurrent fracture? Answer: Both HRT and raloxifene are contraindicated because of the recent DVT; bisphosphonates are contraindicated because of the esophageal dysmotility. Calcitonin could be used, but it has no effect on the risk of hip fracture. Other options include calcium and vitamin D supplementation, both of which have been shown to reduce fracture rates in some frail elderly populations. Meticulous attention to gait training and removal of hazards in the home environment are both especially important for this patient. Finally, specially designed hip protectors, sewn into undergarments, have been shown to substantially reduce the rate of hip fractures in frail elderly. 5. A 70-year-old woman has been on HRT since menopause and wants to stop taking it; her last BMD was - 1 . 0 at both the spine and hip. How would you counsel her? Answer: HRT is becoming increasingly controversial 14 as its benefits with regard to heart disease become less clear. There is no standard approach to such a patient, but I no longer encourage women to keep taking HRT if they want to stop. I would make sure her calcium intake was optimal, encourage exercise, and measure her BMD in 18 to 24 months. Most women do not have recurrent menopausal symptoms, even if they abruptly stop HRT. If menopausal symptoms do occur, the HRT can be tapered or alternative agents, such as clonidine, can be used.

REFERENCES 1. National Osteoporosis Foundation: Physician's Guide to Prevention and Treatment of Osteoporosis. Belle Mead, NJ, Exerpta Medica Inc, 1999 2. NIH ConsensusDevelopmentPanel: Osteoporosisprevention, diagnosis, and therapy. JAMA285:785-795, 2001 3. LookerAL, Bauer DC, Chestnut CH, et al: Clinicaluse of biochemical markers of bone remodeling: Current states and future directions. OseoporosisInt 11:467-480, 2000

POSTMENOPAUSAL OSTEOPOROSIS 4. Altkorn D, Vokes T: Treatment of postmenopausal osteoporosis. JAMA 285:1415-1418, 2001 5. Ettinger B, Black DM, Mitlak BH, et al: Reduction of vertebral fracture ~qsk in postmenopausal women with osteoporosis treated with raloxifene: Results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. JAMA 282(7):637-645, 1999 6. Cummings SR, Eckert S, Krueger KA, et al: The effect of raloxifene on risk of breast cancer in postmenopausal women: Results from the MORE randomized trial. Multiple Outcomes of Raloxifene Evaluation. JAMA 281 (23):2189-2197, 1999 7. Breast cancer and hormone replacement therapy: Collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Collaborative Group on Hormonal Factors in Breast Cancer. Lancet 350(9084):1047-1059, 1997 8. Hulley S, Grady D, Bush T, et al: Randomized trial of estrogen plus progestin tbr secondary prevention of coronary heart disease in postmenopausal women. JAMA 280:605-613, 1998 9. Grodstein F, Manson J, Colditz G, et al: A prospective observational study of postmenopausal hormone therapy and

15 primary prevention of cardiovascular disease. Ann Intern Med 133:933-941, 2000 10. Liberman UA, Weiss SR, Broll J, et al: Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. The Alendronate Phase III Osteoporosis Treatment Study Group. N Engl J Med 333(22):1437-1443, 1995 11. Black DM, Cummings SR, Karpf DB, et al: Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group. Lancet 348(9041):1535-1541, 1996 12. Cummings SR, Black DM, Thompson DE, et al: Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: Results from the Fracture Intervention Trial. JAMA 280(24):2077-2082, 1998 13. Harris ST, Watts NB, Genant HK, et al: Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: A randomized controlled trial. Vertebral Efficacy With Risedronate Therapy (VERT) Study Group. JAMA 282(14):1344-1352, 1999 14. Manson J, Martin K: Postmenopausal hormone-replacement therapy. N Engl J Med 345:34-40, 2001