Recent advances in the prevention and treatment of osteoporosis have increased the options available to menopausal women. Approved antiresorptive agents include estrogen, raloxifene, calcitonin, and the bisphosphonates: etidronate, alendronate, and risedronate. Advising the menopausal woman involves three areas of consideration: prevention versus treatment, bone-specific versus broad-spectrum therapy, and compliance issues. Lifestyle counseling is essential. Motivation to adhere to lifestyle changes and treatment can be assisted by bone-mass measurement. Women at high risk for osteoporosis or likely to require therapy are best assessed with dual-energy X-ray absorpiometry (DEXA). Calcaneal ultrasound measurements are better suited to general population screening.
What is the primary-care physician to do when faced with an array of treatment choices, pharmaceutical and health-food industry claims, and patients of all ages arriving in the office with T-scores from one machine or another?
Women and their physicians now have a variety of screening, assessment, and therapeutic options for preventing and treating postmenopausal osteoporosis. Choosing the most appropriate option is not always easy, and requires not only a basic understanding of recent progress, but also an understanding of the health goals and concerns of each woman.
Osteoporosis should be considered a preventable cause of morbidity and mortality, even though postmenopausal bone loss to levels low enough to contribute to osteoporotic fractures may be within the statistical norms for an aging population. In 1993, direct costs of osteoporosis in Canada were estimated to be $1.3 billion. Increasing longevity and rising numbers of aging baby boomers indicate a looming major public health problem unless we can initiate effective measures to reduce osteoporotic fractures.
In healthy women, the acquisition of peak bone mass around age 30 is typically followed by an annual bone loss averaging 0.6% before and after menopause. For the first 5 to 10 years after menopause, however, bone loss is significantly greater as low estrogen levels result in increased activity of the bone resorbing osteoclasts. Despite this phase of rapid bone loss, very few women suffer fractures before age 65—but the stage is set for the years that follow.
All of the therapies for osteoporosis currently approved by the Health Protection Branch are antiresorptive. This includes estrogen, raloxifene, etidronate, alendronate, and risedronate for prevention in the early postmenopause, and all of the above and calcitonin for treatment of established osteoporosis. Calcium and vitamin D are also antiresorptive, potentiate the other antiresorptive therapies, and should always be included in any regimen.
Though the various trials and studies are often not directly comparable, the rate of fracture reduction noted with antiresorptive agents can be ranked as follows:
• For vertebral fractures, alendronate or risedronate are the most potent, followed by estrogen and raloxifene, etidronate, and calcitonin.
• For nonvertebral fractures, only alendronate and risedronate have shown statistically significant reductions.
The primary-care physician, faced with an array of treatment choices, pharmaceutical and health-food industry claims, and patient beliefs about osteoporosis, should begin with a review of the woman’s lifestyle and risk factors (Table 1). Modification of these risks, where possible, is fundamental to a discussion of osteoporosis at any age. Weight-bearing exercise, such as a 45-minute daily walk, smoking cessation, and adequate calcium and vitamin D intake, are particularly important. The Osteoporosis Society of Canada recommends a daily calcium intake of 1000 mg to 1500 mg and a vitamin D intake of 200 IU for healthy adults under age 65, and 400 IU to 800 IU of vitamin D daily for those over age 65 or with osteoporosis. A change in eating habits to include soy protein can help to maintain, though not increase, bone mass as well as to diminish hot flushes (also referred to as “hot flashes”). With rare exceptions, such universal health recommendations are the only management appropriate for premenopausal women. A premenopausal woman with a low T-score and no secondary causes for this (Table 2), rarely suffers fragility fractures. She does, however, represent a higher risk for fractures later in life, as a low bone density and increasing age are the two greatest risk factors for osteoporotic fractures. Therefore, a woman entering menopause with a low bone mineral density (BMD) is of particular concern and will likely benefit most from successful counseling, management, and follow-up. The more risk factors she has, the more aggressive should be her management.
Advising the menopausal woman regarding the prevention and treatment of osteoporosis involves three categories of considerations: prevention versus treatment, bone-specific versus broad-spectrum treatment, and compliance issues, including acceptability of treatment, tolerance, and cost.
For optimal protection against osteoporotic fractures, preventive measures should be initiated at menopause and continued lifelong. Elderly women who start estrogen soon after menopause and continue to take it have 75% fewer fractures than those who do not.
Unfortunately, taking estrogen for only the first 10 years after menopause has little impact on later fracture risk because accelerated bone loss follows the discontinuation of estrogen. Long-term prevention, therefore, requires either 15 to 20 years of hormone replacement after menopause or initiating another drug when estrogen is discontinued earlier. For example, estrogen use for the first 5 years after menopause will alleviate menopausal symptoms, provide broad health benefits, and not increase the risk of breast cancer. Changing to raloxifene at 5 years will avoid the risk of breast cancer associated with further estrogen use and maintain, or possibly improve upon, general health.
If prevention of osteoporotic fractures is a woman’s only concern, then contrary to earlier belief, antiresorptive therapy can be started 10 or more years after menopause with rapid and substantial reduction in fracture risk. The US National Osteoporosis Foundation, in an extensive cost-effectiveness study, showed that for the average woman, the ideal time to begin a drug for prevention of osteoporotic fractures is age 60 to 65.
The Early Postmenopausal Intervention Cohort study of 1609 women between age 45 and 59 who were at least 6 months postmenopausal demonstrated that 5 mg of alendronate daily prevented bone loss, had an excellent tolerability profile, and proved to be a good alternative to estrogen. There is new evidence that giving the alendronate as a 35-mg to 40-mg dose once a week would accomplish the same goal and improve compliance.
The woman who has already suffered an osteoporotic fracture is at very high risk of new fractures (7% per year). Based on current efficacy data and a theoretical concern that long-term use of potent bisphosphonates may reduce the number of bone remodeling units and result in poor quality “frozen bones,” a reasonable approach for an osteoporotic woman would be a “quick fix” with alendronate or risedronate followed by a long-term maintenance regimen. Quick-fix alendronate would be 10 mg daily for 2 years or, based on more recent data, 70 mg once a week (not yet approved in Canada). This dosage is as effective as 10 mg daily, currently less expensive, and offers improved GI tolerance and patient compliance. Currently, alendronate is marketed as 5-mg, 10-mg, and 40-mg tablets. Risedronate is available as 5-mg and 30-mg tablets with the approved dosage being 5 mg daily. Risedronate at 30 mg once a week (not approved in Canada) also appears to produce significant increases in BMD in osteoporotic women. Etidronate is significantly less effective than alendronate and risedronate. Maintenance therapy for an osteoporotic patient could be a lower dosage of a bisphosphonate, such as alendronate 40 mg once a week or risedronate 5 mg every other day, or a switch to estrogen or raloxifene for additional health benefits.
The bisphosphonates and calcitonin offer no benefit beyond bone benefits. Many women, however, will benefit from the “health package” provided by estrogen or raloxifene. These benefits include effects on lipid levels, possible primary prevention of coronary artery disease and neoplasms, possible protection against other degenerative diseases, and (with estrogen) improvement of menopausal symptoms and quality of life. By contrast, the newer bisphosphonates, such as alendronate and risedronate, have greater bone effects than HRT or raloxifene.
For the occasional patient who continues to lose bone despite adherence to estrogen or raloxifene, and in whom other causes of bone loss have been ruled out, a bisphosphonate can be added. There is positive BMD data for combined raloxifene and a bisphosphonate as well as for combined estrogen and a bisphosphonate, though there is no fracture data. Again, there is some concern that over-suppression of bone resorption and remodeling may eventually lead to weaker bone. Thus far, the 7-year data on alendronate are very reassuring, with continued reduction in fracture incidence.
Despite the proven benefits of estrogen replacement therapy (ERT) for quality of life and survival, ERT is unacceptable to many women. The increased risk of breast cancer is the most frequently expressed concern. For women who are prescribed ERT, long-term compliance is very low, with only 14% to 17% compliance at 1 year. Uterine bleeding and breast tenderness are significant reasons for discontinuation. Low-dose estrogen regimens, such as 0.3 mg conjugated equine estrogen daily with 2.5 mg continuous medroxyprogesterone daily, or infrequent cycling for a woman who has not had a hysterectomy, are often better tolerated. In contrast to earlier studies that suggested 0.625 mg conjugated equine estrogen daily was required for bone maintenance, more recent and better-designed studies show a linear dose response and significant bone benefit from 0.3 mg.
Though more costly than ERT, raloxifene at 60 mg daily has bone benefit equal to low-dose conjugated equine estrogen, without the adverse breast and uterine effects. Ongoing studies with raloxifene show a 76% reduction in breast cancer in 3 years. Thromboembolic events are shown to increase three-fold for patients on both raloxifene and ERT. Raloxifene does not eliminate bothersome menopausal symptoms such as hot flushes—in fact the incidence is slightly increased in placebo-controlled studies, and hence is better targeted at women beginning treatment 3 to 5 years after menopause.
All things considered, and recognizing that osteoporosis prevention is only one concern, the most appropriate treatment for many women in the early postmenopause will be estrogen, with raloxifene offering a better health package after age 60. Women who are at high risk of fracture, who have had previous fractures, or who are elderly are most appropriately initiated on a bisphosphonate.
Osteoporosis is asymptomatic until fractures occur. While an increasing number of risk factors has predictive value for osteoporotic fractures, there are many people who have good bone mass despite multiple risk factors, and there are those who have poor bone mass despite few or no risk factors. Thus objective bone-mass measurement has been shown to be the best predictor of fracture risk, particularly when combined with age. A bone-mass measurement at any site, by any currently available technique, is the strongest single predictor of fracture risk. Standard X-rays do not correlate well with BMD.
Bone mass can be measured by several methods, including dual-energy X-ray absorptiometry (DEXA) and quantitative ultrasound (QUS). Most bone-mass measurements done in BC currently utilize DEXA of the hip and/or spine, or QUS of the calcaneus. Since women in the early postmenopausal period experience bone loss primarily at the spine, the sensitivity of peripheral measurements is greatest in older women.
The following discussion is limited to the use of BMD screening at menopause or in the 10 years that follow.
The Osteoporosis Society of Canada 1999 guidelines recommend BMD testing in postmenopausal women according to the criteria in Table 3.
For women younger than 65 years of age, it is recommended that DEXA be done at both spine and hip. For women older than 65, spine DEXA may give falsely high values because of degenerative spinal changes.
In clinical practice, the decision to order a DEXA can be further supported when it will be used effectively:
• As a baseline in women who are almost sure to require treatment of low bone mass.
Most primary-care physicians in British Columbia have experienced anxious patients arriving in the office with a low calcaneal T-score. The appropriate management of these patients requires some understanding of this measurement technique.
Calcaneal ultrasound is an excellent screening method because it is inexpensive, portable, does not use radiation, and, providing there is good quality control, accurately measures the bone mass and, possibly, the quality of bone at the calcaneus. It predicts hip fracture risk almost as well as DEXA of the hip and better than DEXA of the spine, and predicts vertebral fractures better than a hip DEXA.
The calcaneus loses bone mass later than the spine, so it functions best as a predictor of fractures in women age 60 and older. The majority of 50-year-old women with low calcaneal T-scores, in the absence of other disease, simply had a low peak bone mass. The same women, however, should be the focus of fracture prevention because with average rates of accelerated bone loss in the first 10 years after menopause, these women will reach fracture threshold at a younger age than women entering menopause with a higher peak bone mass.
The authors have found the calcaneal ultrasound result combined with lifestyle counseling to be an effective motivational tool in many menopausal women. Calcaneal ultrasound, however, is not currently recommended to follow treatment of osteoporosis.
T-scores from DEXA and calcaneal ultrasound are not equivalent. The T-score is the number of standard deviations that a particular result is away from the mean peak young bone mass of a population. Each reduction in a T-score integer is associated with a doubling of fracture risk. For DEXA of hip and spine, the World Health Organization has defined a T-score better than -1.0 as normal, -1.0 to -2.5 as osteopenia, and greater than -2.5 as osteoporosis. For calcaneal ultrasound, the United States National Osteoporosis Foundation guidelines recommend a treatment threshold T-score of -2.0 in the absence of risk factors and -1.5 if the patient has one or more risk factors—risk factors include age greater than 65 but not white race.
This calcaneal T-score must be placed into an overall clinical context for each patient and community (DEXA is unavailable in many regions of BC). Some patients will need a DEXA for confirmation or treatment baseline, others will need lifestyle counseling only, and others may proceed directly to treatment.
As prospective data become available, reporting formats for DEXA and QUS will undoubtedly change and will emphasize the patient’s prospective risk of fracture rather than T-score, not only simplifying the interpretation but also improving the clinical relevance of the result.
Physicians using knowledge, technology, and treatment already available can effectively screen for, prevent, and treat osteoporosis in women in the postmenopausal years. Given the increasing complexities and choices for the effective prevention and treatment of osteoporosis and the projected epidemic of osteoporosis fractures in the coming decades, it is clear that the primary-care physician plays a key role in assisting women to choose their best options.
• Personal history of fracture as an adult
• Current cigarette smoking
Bone densitometry is indicated if one of the following risk factors is present:
Bone densitometry is indicated if two or more of the following risk factors are present:
To monitor treatment
2. Hochberg, M. Preventing fractures in postmenopausal women with osteoporosis. A review of recent controlled trials of antiresorptive agents. Drugs Aging 2000;4:317-330. PubMed Abstract
3. National Osteoporosis Foundation. Physician’s Guide to Prevention and Treatment of Osteoporosis 1999. Washington, DC: National Osteoporosis Foundation. http://www.nof.org/professionals/clinical/clinical.htm (2000; retrieved 10 August 2001).
4. Glazier M, Bowman M. A review of the evidence for the use of phytoestrogens as a replacement for traditional estrogen replacement therapy. Arch Intern Med 2001;161:1161-1172. PubMed Abstract
5. Cauley JA, Seeley DG, Ensrud K, et al. For the Study of Osteoporotic Fractures Research Group. Estrogen replacement therapy and fractures in older women. Ann Intern Med 1995;122:9-16. PubMed Abstract
7. Schneider DL, Barrett-Connor EL, Morton DJ. Timing of postmenopausal estrogen for optimal bone mineral density. JAMA 1997;277:543-547. PubMed Abstract
8. Hosking D, Chilvers CED, Christiansen C, et al. Prevention of bone loss with alendronate in postmenopausal women under 60 years of age. N Engl J Med 1998;338:485-492. PubMed Abstract
9. Luckey M, Insogna K, Gilchrist N, et al. Therapeutic equivalence of alendronate 35 mg once weekly and 5 mg daily in the prevention of postmenopausal osteoporosis [abstract]. Osteoporos Int 2000; 11(suppl 2). Abstract 566.
10. Schnitzer T, Bone HG, Crepaldi G, et al. Therapeutic equivalence of alendronate 70 mg once-weekly and alendronate 10 mg daily in the treatment of osteoporosis. Aging Clin Exp Res 2000;12:1-12. PubMed Abstract
12. Johnell O, Scheele W, Lu Y, et al. Effects of raloxifene, alendronate, and raloxifene plus alendronate on bone mineral density and biochemical markers of bone turnover in postmenopausal women with osteoporosis. J Bone Miner Res 1999;14(suppl 1). Abstract 1100.
13. Lindsay R, Cosman F, Lobo RA, et al. Addition of alendronate to ongoing hormone replacement therapy in the treatment of osteoporosis: A randomized, controlled clinical trial. J Clin Endocrinol Metab 1999;84:3076-3081. PubMed Abstract Full Text
14. Tonino RP, Meunier PJ, Emkey JA, et al. Long-term (seven year) efficacy and safety of alendronate in the treatment of osteoporosis in postmenopausal women. Osteoporos Int 2000;11(suppl 2). Abstract 543.
15. Ettinger B. Personal perspective on low dosage estrogen for postmenopausal women. Menopause 1999;6:273-276. PubMed Abstract
16. Cummings SR, Eckert S, Krueger KA, et al. The effect of raloxifen on risk of breast cancer in postmenopausal women. Results from the MORE randomized trial. JAMA 1999;281:2189-2197. PubMed Abstract
17. Papaioannou A, Parkinson W, Adachi J, et al. Women’s decisions about hormone replacement therapy after education and bone densitometry. CMAJ 1998;159: 1253-1257. PubMed Abstract
R.C. Offer, MD, FRCPC, FACR, and S.W. Offer, BSN
Dr Offer is a rheumatologist in private practice in Penticton, BC, and medical adviser to the South Okanagan Osteoporosis Society and the Arthritis Society. Ms Offer is the nurse manager and educator for the South Okanagan Osteoporosis Society in Penticton.
Above is the information needed to cite this article in your paper or presentation. The International Committee
of Medical Journal Editors (ICMJE) recommends the following citation style, which is the now nearly universally
accepted citation style for scientific papers:
Halpern SD, Ubel PA, Caplan AL, Marion DW, Palmer AM, Schiding JK, et al. Solid-organ transplantation in HIV-infected patients. N Engl J Med. 2002;347:284-7.
About the ICMJE and citation styles
The ICMJE is small group of editors of general medical journals who first met informally in Vancouver, British Columbia, in 1978 to establish guidelines for the format of manuscripts submitted to their journals. The group became known as the Vancouver Group. Its requirements for manuscripts, including formats for bibliographic references developed by the U.S. National Library of Medicine (NLM), were first published in 1979. The Vancouver Group expanded and evolved into the International Committee of Medical Journal Editors (ICMJE), which meets annually. The ICMJE created the Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals to help authors and editors create and distribute accurate, clear, easily accessible reports of biomedical studies.
An alternate version of ICMJE style is to additionally list the month an issue number, but since most journals use continuous pagination, the shorter form provides sufficient information to locate the reference. The NLM now lists all authors.
BCMJ standard citation style is a slight modification of the ICMJE/NLM style, as follows:
- Only the first three authors are listed, followed by "et al."
- There is no period after the journal name.
- Page numbers are not abbreviated.
For more information on the ICMJE Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals, visit www.icmje.org