Special Feature
Treatment Options for the Prevention of Osteoporosis
By Leon Speroff, MD
There is little controversy surrounding the active treatment of osteoporosis. Our focus is now on preventing osteoporosis-related fractures, and the pain and disability that accompany those fractures. Because the number of treatment options is ever increasing, decision-making is becoming more difficult. I would like to share with you my own "game plan" for making treatment choices.
Lifestyle Modifications
Lifestyle can have a beneficial effect on bone density. Physical activity (weight-bearing), as little as 30 minutes a day for three days a week, will increase the mineral content of bone in older women. To be effective, exercise must exert a load on bone, especially the spine. In other words, weight lifting is better for the spine than ordinary walking, although running probably helps hip bone mass. The activities that are beneficial include running, weight training, aerobics, stair climbing, and sports other than swimming. The effect of weight-bearing exercise on bone density is additive when combined with hormone therapy. Although ordinary walking has little effect on bone density, it is still reasonable to expect walking to have an overall beneficial effect on the risk of fracture. Walking improves the cardiovascular status of patients and reduces body mass. These changes, plus the exercise itself, will improve balance and decrease the risk of falling. For these reasons, walking, even after adjusting for bone density, is associated with a reduced risk of hip fracture.
Adverse habits, such as cigarette smoking or excessive alcohol consumption, are associated with an increased risk of osteoporosis. The magnitude of bone loss associated with cigarette smoking is consistent with a 40-45% increase in the risk of hip fracture. Studies have indicated that estrogen is associated with lesser protection against fractures in smokers. However, this may be correctable by titering the blood level of estrogen with the dose administered. The lower blood levels of estrogen in smokers have been correlated with an earlier menopause and a reduced bone density, therefore, the standard dose of estrogen may not totally counteract the predisposition of smoking toward osteoporosis. The titration of estrogen dosage with circulating blood estradiol levels in smokers makes clinical sense, allowing the use of higher hormonal doses to maintain bone density. Monitoring of bone response with bone density measurements or urinary markers would further aid in achieving the maximal effects of therapy.
Clinicians should always remember that exposure to excessive thyroid and glucocorticoid hormones is associated with osteoporosis and an increased rate of fractures. The bone loss associated with glucocorticoid treatment is significantly prevented by estrogen/progestin as well as alendronate therapy, and excessive thyroid effects can be avoided by annually monitoring treatment dosage with TSH levels. Specific treatment should also be offered to patients using anticonvulsants.
A high coffee intake has been reported to be associated with an increased risk of osteoporosis. However, this increase in risk is dependent upon dietary calcium intake. In women who drank at least one glass of milk (300 mg calcium) per day throughout most of their lives, increasing caffeinated coffee intake was not associated with a lower bone density. Repeatedly, we see the importance of teaching children and adolescents the merits of an adequate calcium intake. Drinking nonfat milk throughout life is good for you. An adequate calcium intake compensates for "calcium robbers," such as caffeine and soft drinks. A British study concluded that an increase of only 300 mL of milk per day in adolescents increases bone density without an increase in weight or body fat.
Calcium Supplementation
Calcium absorption decreases with age because of a decrease in biologically active vitamin D and becomes significantly impaired after menopause. A positive calcium balance is mandatory to achieve adequate prevention against osteoporosis. Calcium supplementation (1000 mg/day) reduces bone loss and decreases fractures, especially in individuals with low daily intakes. However, estrogen acts to improve calcium absorption (by increasing the levels of 1,25-dihydroxyvitamin D) and makes it possible to use effective supplemental calcium in lower doses. In order to remain in zero calcium balance, women on estrogen therapy require a total of 1000 mg of elemental calcium per day. Because the average woman receives about 500 mg of calcium in her diet, the minimal daily supplement equals an additional 500 mg. Women not on estrogen require a daily supplement of at least 1000 mg calcium.
Vitamin D Supplementation
It is now recommended that individuals older than age 70 should add 800 units of vitamin D to calcium supplementation. Because adequate and active vitamin D depends upon cutaneous generation mediated by sun exposure, women who live in cloudy areas during the winter months are relatively vitamin D deficient and lose bone. In far northern and southern areas, the winter sunlight is inadequate to stimulate dermal activation. Vitamin D supplementation is recommended for these women as well but only during the winter and at a lower level, 400 units daily (usually available in over-the-counter multivitamins or in combination with calcium). The benefit of vitamin D supplementation is clear in older women, and the lack of side effects with low doses encourages the use of vitamin D supplementation as part of the overall program for osteoporosis prevention in younger women.
Postmenopausal Hormone Therapy
With estrogen therapy, one can expect a 50-60% decrease in fractures of the arm and hip, and when estrogen is supplemented with calcium, an 80% reduction in vertebral compression fractures can be observed. This reduction is seen primarily in patients who have taken estrogen for more than five years. Protection against fractures wanes with age, and long-term estrogen use is necessary to maximally reduce the risk of fracture after age 75. For maximum effectiveness, estrogen requires initiation within five years of menopause and for current use to extend into the elderly years. The protective effect of estrogen rapidly dissipates after treatment is stopped because estrogen withdrawal is followed by rapid bone loss. Maximal protection against osteoporotic fractures requires lifelong therapy, and even some long-term protection requires 10 or more years of treatment. Standard doses of estrogen administered transdermally (50 mg) appear to protect against fractures as well as standard oral doses.
The results from the first randomized trial with hormone therapy have only recently been reported. The results are consistent with the large amount of case-control and cohort data, a 71% reduction in nonvertebral fractures in the hormone-treated group within five years, better than either the placebo group or the Vitamin D treated group.
Two more controversial issues with hormone therapy are the role of lower estrogen dose treatment and the effect of starting treatment later in life. The idea of postponing treatment to prevent osteoporosis until later in life has merit. Changes in bone density in the early postmenopausal years have no major effect on fractures later in life, except in individuals who already have low bone density. This amounts to only 5% of women in their early postmenopausal years, and most of this 5% will have risk factors such as smoking, fracture at a younger age, a thin body, and excessive alcohol consumption. However, the effect of initiating therapy later in life has not been adequately assessed. Indeed, a large cohort study could detect no significant impact on nonspinal fractures. Until we have better data, we should continue to promote early onset and prolonged use of hormone therapy.
We now know that any amount of estrogen can have an effect, although it is likely that some degree of protection is lost when doses are less than the equivalent of 0.625 mg conjugated estrogens. A lower dose of 0.3 mg daily of conjugated estrogens or 0.5 mg estradiol prevented loss of vertebral trabecular bone when combined with calcium supplementation (to achieve a total intake of 1500 mg daily). Major concerns with lower doses include the possibilities that there will be a significant percentage of nonresponders and some cardiovascular benefit will be sacrificed. Nevertheless, a lower dose of estrogen may be more acceptable (fewer side effects) in elderly women. Patients electing to be treated with lower doses should have follow-up assessments for response with measurements of either bone density or urinary biochemical markers. After six months to one year, patients on lower doses should be urged to move up to a standard regimen.
Alendronate
In women with osteoporosis, alendronate administration (10 mg daily) reduced the risk of subsequent nonvertebral fractures by at least 30% (and probably 50%) and vertebral fractures by 90% in the first three years of treatment. In normal postmenopausal women, alendronate increased bone density in both the spine and the hip, and the 5 mg dose (the preferred dose for preventive treatment) was more effective than 2.5 mg. The increase in bone density with the 5 mg dose is slightly less than that observed with estrogen-progestin therapy. It is unlikely that a difference of a few percentage points in bone density gain has an effect on the number of fractures ultimately experienced.
In the most recent data available, derived from an average follow-up of 4432 women for 4.2 years, a statistically significant reduced risk of fracture was demonstrated only in women with initial T-scores of -2.5 or less, a 36% reduction in all fractures, and a 50% reduction in vertebral fractures. Treatment obviously benefits women who already have a low BMD or previous vertebral fractures. If alendronate benefits women who do not already have osteoporosis, it will take more than four years of treatment to observe the effect.
The Early Postmenopausal Interventional Cohort (EPIC) study concludes that over a four-year period of time, alendronate and hormone therapy in the United States produces similar bone density results. Calcium and vitamin D supplementation with alendronate treatment has no added effect as long as women have a minimal intake of 800 mg of calcium daily.
Combining alendronate and hormone therapy produces an added gain in bone density. By no means is it certain that this difference will translate into a difference in the incidence of fractures later in life. Indeed, it is unlikely. Furthermore, there is a theoretical concern that oversuppression of resorption can ultimately yield more brittle bones.
Compliance with alendronate has been overrestimated by the clinical trials. It is well recognized that participants in clinical trials are better motivated, better supported, and perform better. In the Kaiser Permanente Medical Care Program in California, about one-third of patients had acid-related complaints, one in eight required treatment. About 50% of patients do not comply with instructions, and about 50% discontinue therapy by one year. Bone marker or bone density measurements are recommended to assess compliance.
Results with Raloxifene
The increase in bone density associated with raloxifene is slightly less than that seen with alendronate. The Multiple Outcomes of Raloxifene Evaluation (MORE) study of raloxifene administration to osteoporotic women has now accumulated results from two and three years of follow-up. Women with low T-scores or previous vertebral fractures have approximately a 50% reduction in vertebral fractures with raloxifene treatment. However, there has been no evidence of a reduction in hip fractures. Thus, the reduction in vertebral fractures is similar to that seen with alendronate. However, why is there no decrease in hip fractures, despite a bone density response that is only slightly less than that associated with alendronate? And like alendronate, we have no fracture data in treated women who originally had normal bone densities.
Treatment Options: Summary
Reassuring data are available for the prevention of osteoporosis and osteoporosis-related fractures for hormone therapy and alendronate. The absence of an effect on hip fractures after three years of raloxifene is of concern. For tibolone, calcitonin, and especially phytoestrogens, fracture data are not available. Based on bone density responses, we can predict that tibolone and calcitonin should have an effect on fracture incidence. We should keep in mind that the fracture data associated with alendronate are derived from women with osteoporosis.
Not all women will maintain or gain bone density on postmenopausal hormone therapy. In one study, 12% of treated women lost bone despite apparently good compliance. In the PEPI three-year clinical trial, where compliance rates were probably maximal, 4% of treated women lost bone in the spine and 6% in the hip. It is worthwhile to measure the bone density in treated women when they are in their late 60s to detect this high-risk group.
The reason why some women fail to respond is unknown. It is unknown whether these patients will respond to added treatment, such as calcitonin or a bisphosphonate, but it is worth special evaluation, treatment, and surveillance. In a woman demonstrated to be losing bone despite hormone therapy, the following steps are recommended:
• Check compliance and dose by measuring blood estrogen levels.
• Rule out other causes of bone loss (e.g., eating disorders).
• Drugs: Heparin, anticonvulsants, high intake of alcohol.
• Chronic Disease: Renal and hepatic.
• Endocrine Diseases: Excess glucocorticoids, hyperthyroidism, estrogen deficiency, hyperparathyroidism.
• Nutritional: calcium, phosphorous, vitamin D deficiencies.
• Add alendronate.
• Follow with markers or bone density measurements.
The treatment of choice for the early postmenopausal years (ages 50-65) is hormone therapy, because of its broad spectrum of benefits, most notably symptomatic relief and protection against cardiovascular disease. Furthermore, we have no data confirming that alendronate and raloxifene given to women with normal bone densities will prevent fractures in old age, and if they do, how they compare to hormone therapy. Around age 65, I recommend measurement of bone density. Low bone density should be treated with the specific drug chosen during a clinician-patient dialogue reviewing the advantages and disadvantages of each drug.
References
Available upon request
The following statements are true regarding the prevention of osteoporosis except:
a. Bone density responses do not accurately predict fracture rates when comparing various pharmacologic treatments.
b. Estrogen, alendronate, and raloxifene appear to exert a similar degree of protection against spinal fractures.
c. Estrogen, alendronate, and raloxifene appear to exert a similar degree of protection against hip fractures
d. Although combined treatment with alendronate and estrogen produces a slightly greater gain in bone density, it is not known if combined treatment produces greater protection against fractures.
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