CHAPTER 19 Bone Health and Osteoporosis
Osteoporosis, literally “porous bones,” is one of the most common disorders faced by older women in our society today. The National Institutes of Health Development Consensus Panel on Osteoporosis Prevention, Diagnosis, and Therapy states, “Osteoporosis is defined as a skeletal disorder characterized by compromised bone strength predisposing a person to an increased risk of fracture. Bone strength primarily reflects the integration of bone density and bone quality.”1 This panel was formed in response to the significant impact osteoporosis has the health of older Americans (Box 19-1).
Rapid growth in both bone size and strength occurs during childhood, but growth is not complete until an individual is approximately 30 years old. Bone mass attained early in life is perhaps the most important determinant of lifelong skeletal health. After the third decade, bone resorption accelerates, with a loss of 0.5% bone mass per year.2 At this time, no accurate measure of overall bone strength exists.
Box 19-2 lists the risk factors for osteoporosis that have been identified.3
DIAGNOSIS OF OSTEOPOROSIS
Postmenopausal women younger than 65 years with at least one risk factor: oral steroid use, thyroid problems, eating disorders, amenorrhea lasting 3 months or longer, family history of osteoporosis, smoking, alcoholism, very thin frame, low calcium intake
The World Health Organization has provided guidelines based on bone mass measurements. Osteopenia is defined as a BMD T-score (T-score is the number of standard deviations [SD] above or below the young adult mean) of 1.0 to 2.5 SD below the mean for healthy adults.4 Osteoporosis is defined as a BMD T-score at least 2.5 SD below the mean. For every SD below normal, the risk of fracture doubles. As with most diagnostic tests, these numbers are part of a continuum, and a T-score of −2.2 SD below the mean should be appropriately addressed to reduce the risk of fracture even if, by strict definition, it does not meet the criteria for the diagnosis of osteoporosis.
TREATMENT
Hormone Replacement Therapy
Bone tissue is quite sensitive to estrogens. It is not entirely understood why women demonstrate accelerated bone loss with menopause; it has been shown that estrogen replacement therapy arrests bone loss.5 Estrogen’s beneficial effect on bone may be due to its ability to increase calcitonin levels, leading to decreased bone resorption. Estrogen receptors are also present on osteoblast bone-forming cells, resulting in a relative increase in collagen production.6 Mean bone mass is increased by about 5% and bone remodeling is reduced to premenopausal levels with estrogen therapy. This effect persists for the duration of therapy.7
Observational and retrospective data suggest a 50% reduction in the incidence of vertebral, hip, and forearm fractures with estrogen replacement therapy.8 Although researchers have believed for years that estrogen reduces the risk of fractures, it was not until the publication of the Women’s Health Initiative (WHI) study that more reliable data were available to support this observation. In this study, the risk of hip and spinal fracture in women who received a combination of conjugated equine estrogen and progestin was reduced by 34%.9 However, to prevent a fracture, a woman must be willing to accept a greater risk of other diseases, such as heart disease, stroke, and breast cancer, especially because the hormones must be taken for a long period. The unfavorable risk/benefit profile of hormone replacement therapy (HRT) strongly limits its use for prevention of osteoporosis, given that other medications have been shown to reduce the incidence of fractures.10 The combination therapy used in the WHI was stopped before its completion because of the unacceptable numbers of adverse effects (breast cancer, stroke, blood clots).
The estrogen-only arm of the WHI was designed to determine whether estrogen prevents heart disease in healthy older women. Hip fractures were the major secondary outcome, and breast cancer the major possible risk. When the study was stopped by the NIH in early 2004 because of increased risk of stroke and no effect on heart disease, it also found a decreased risk of hip fracture and no increased breast cancer.11 Increasing numbers of researchers are exploring the effectiveness of very low-dose estrogen for the reduction of the incidence of fractures in postmenopausal women. The findings of a 3-year randomized, placebo-controlled study of postmenopausal women taking low-dose 17β-estradiol appear promising. Healthy women (n = 167), older than 65 years at the time of enrollment, were randomized to receive either 0.25 mg/day of micronized 17β-estradiol (n = 83) or placebo (n = 84); all women who had not undergone hysterectomy received 100 mg/day of oral micronized progesterone for 2-week periods every 6 months. Mean bone mineral density (BMD) increased at all sites in participants taking low-dose estrogen, compared with placebo (P < 0.001). The researchers noted increases in BMD of 2.6% for the femoral neck, 3.6% for the total hip, 2.8% for the spine, and 1.2% for the entire skeleton. The levels of two markers of bone turnover, N-telopeptides of type 1 collagen and bone alkaline phosphatase, decreased significantly (P < 0.001) in participants taking low-dose estrogen, whereas concentrations of estradiol, estrone, and sex hormone–binding globulin increased. The adverse effects profiles of the two groups were similar: Specifically, no statistically significant difference was noted with regard to breast tenderness, changes in endometrial thickness or pathologic effects, or annual mammography results.12 Although this study did not determine whether the incidence of fractures was reduced, the findings are encouraging. It is also interesting to note that oral micronized progesterone was used at 6-month intervals instead of being taken daily or on a monthly basis. If low-dose estrogen can offer protection for the bone, without increased risk of stroke or cancer, this should be more fully explored given the number of baby boomer women who will be confronted with osteoporosis in the near future.
Raloxifene
The authors of the Multiple Outcomes of Raloxifene Evaluation (More) trial studied the effects of placebo and raloxifene 60 or 120 mg/day in 7705 postmenopausal women with osteoporosis. All women received 500 mg of calcium and 400 to 600 International Units of cholecalciferol daily; follow-up was conducted from 1994 through 1998 at 180 clinical centers in the United States and Europe. Those taking 60 or 120 mg of raloxifene had fewer new fractures (6.6% and 5.4%, respectively) than those taking placebo (10.1%), but the actual incidence of fracture did not differ significantly between treatment groups.13 No statistically significant difference was observed between the treatment and placebo groups for nonvertebral fractures.
The most common adverse effects of raloxifene in clinical trials are hot flashes and leg cramps; the most serious adverse effect is venous thromboembolism. Women in the MORE trial who received raloxifene had three times the number of venous thromboembolism events than those in the placebo group, and the authors estimated that one case would occur for every 155 women treated with raloxifene for 3 years.14 Women with a history of thromboembolism and those who are at increased risk should not be prescribed raloxifene.
Bisphosphonates
Several antiresorptive agents have been used successfully in the treatment of postmenopausal osteoporosis. Bisphosphonates inhibit bone resorption through their effect on osteoclasts.15 Recent trials of these agents have revealed evidence of efficacy in the prevention of both vertebral and nonvertebral fractures.
Alendronate (Fosamax), an analogue of pyrophosphate, is adsorbed onto the hydroxyapatite of bone, resulting in the inhibition of bone resorption. It was the first bisphosphonate approved by the U.S. Food and Drug Administration (FDA) for the prevention and treatment of osteoporosis. The Fracture Intervention Trial, a randomized, placebo- controlled trial involving 6459 postmenopausal women with low femoral neck BMD, demonstrated an approximate 50% decrease in the risk of new vertebral, hip, and wrist fractures in women who reported at least one preexisting vertebral fracture at baseline.16 In this study, women received supplemental calcium and vitamin D if their dietary intake was insufficient. The daily alendronate dose was 5 mg during the first 2 years and 10 mg during the third and fourth years of the study. In addition to fracture reduction, a small increase in BMD (4% to 8%) was noted.
Risedronate is the second bisphosphonate approved for use in osteoporosis. Data from the Vertebral Efficacy with Risedronate trial (2458 patients) showed a 41% reduction in the incidence of new vertebral fractures and a 39% reduction in the incidence of nonvertebral fractures with a dose of 5 mg/d.17 In a study of 5445 women ages 70 to 79 years with documented low BMD, a significant reduction in the incidence of hip fracture was documented.18
Calcitonin
Calcitonin, a naturally occurring peptide hormone, inhibits osteoclast activity and thereby acts as an antiresorptive agent. Calcitonin receptors have been found on osteoblasts and renal cell membranes. Stimulation of these receptors results in a decrease in osteoclast activity and may cause an increase in the production of 1,25-dihydroxyvitamin D with a secondary increase in intestinal calcium absorption. Because it is a polypeptide, calcitonin is not effective when taken by mouth and was initially given by injection. The FDA approved nasal formulations of synthetic salmon calcitonin for the treatment of osteoporosis in women in 1995. Calcitonin inhibits bone resorption and increases BMD in the spine, reducing the incidence of recurrent vertebral fractures by 60% to 66%.19 One epidemiologic study showed a 31% reduction in the incidence of hip fracture20; however, randomized clinical trials have shown little effect on bone density of the femoral neck. A 5-year study revealed that although nasal calcitonin 200 International Units/day only increased spinal BMD by 1.2%, the risk of new vertebral fracture was reduced by 36% compared with patients who received only calcium and vitamin D supplementation.21 Evidence is accruing to suggest that calcitonin has inherent analgesic properties, making it beneficial for those with osteoporotic vertebral fractures.22 Women with established osteoporosis and back pain generally experience a decline in back pain and an increase in mobility during the first 6 months of treatment.
Diet and Nutrition
Role of dietary protein.
Contrary to popular belief, protein does not reduce bone density, and adequate amounts of protein are needed, as part of a balanced diet, for maintenance of bone health. A 4-year study involving 572 women and 388 men ages 55 to 92 years found that for every 15 g/day of protein consumption, BMD increased by 0.016 g/cm3 at the hip (P = .005), 0.012 g/cm3 (P = .005) at the femoral neck, and 0.015 g/cm3 at the spine (P = .04). The investigators found a negative association between vegetable protein intake and BMD. The association between animal protein intake and increased BMD was statistically significant among the women in the study.23 Another randomized, controlled study, this one 3 years long, of 342 healthy men and women revealed that BMD was increased with higher protein intake.24 The negative association between vegetable-protein intake and BMD is interesting, given the research with soy, a rich source of vegetable protein in numerous cultures, and its beneficial effect on bone.
Phytoestrogens.
Phytoestrogens in the diet may play a role in the modulation of hormone-related diseases, judging from their structural similarity to 17β-estradiol and the weak estrogen/antiestrogen tamoxifen. The presence and position of the hydroxyl groups are considered essential for estrogenic activity.25 Asian populations with low rates of breast and prostate cancer consume 20 to 80 mg/day genistein, an isoflavone present in many plants, almost entirely derived from soy. Soy is a common source of nutrition in China and a primary source of protein. Dietary intake of genistein in the United States has been estimated to range from 1 to 3 mg/day.34
A great deal of research has been conducted on soy, which is a particularly rich source of isoflavones and the major dietary source of phytoestrogens in many populations. Soy is consumed in a variety of forms, including soybeans, tempeh, soy milk, tofu, and soy protein. Foods that were once found only in health food stores, such as soy hot dogs, soy cheese, and soy yogurt, can now be purchased in many mainstream grocery stores. The amount of isoflavones in these soy foods varies considerably, depending on the amount and type of processing they undergo. Soy protein, primarily in the form of nontoasted, defatted soybean flakes, can be isolated from the whole bean and contains up to 50% of the phytoestrogens found in unprocessed soybeans.25
A growing body of data suggests that soy consumption has a modest effect on some menopausal symptoms such as hot flashes and night sweats. However, few human clinical trials have been conducted to address the question of whether the consumption of soy or isolated soy isoflavones such as genistein can prevent or ameliorate osteoporosis. Data from in vitro and animal studies modeling postmenopausal osteoporosis demonstrate a significant bone-sparing effect of the soy isoflavones genistein and daidzein (these isoflavones are also present in red clover extract, another popular menopause remedy). A review of in vitro studies of cultured bone cells, 24 in vivo studies of animal models for postmenopausal osteoporosis, 15 human observational or epidemiologic studies, and 17 dietary intervention studies that focused specifically on the potential influence of phytoestrogens on bone suggest that diets rich in phytoestrogens have bone-sparing effects in the long term.26 The authors noted that the magnitude of the effect and the exact mechanism(s) of action are speculative or unknown.
Although promising, the data are far from conclusive. Most studies have been of short duration and have involved relatively small sample sizes, making the observation of significant and accurate changes in bone difficult. Intake of soy protein and isoflavones varies, and the optimal isoflavone intake for bone-sparing effects is not known.27 No studies have been conducted to determine the effects of phytoestrogens on fracture rate. Methodologically rigorous prospective human clinical trials of longer duration are needed for the accurate assessment of the role of phytoestrogens in the prevention and treatment of osteoporosis. However, considering the safety and other beneficial health effects of soy, until more definitive recommendations can be made, it seems reasonable for women to add these foods to their diets if they enjoy them.
Ipriflavone.
Ipriflavone, a synthetic derivative of naturally occurring isoflavones, is sold as a dietary supplement in the United States and is commonly recommended by practitioners of integrative medicine for the treatment of osteoporosis and its prevention in those at high risk. Ipriflavone is thought to inhibit osteoclast activity through modulation of intracellular free calcium28 while stimulating maturation of osteoblasts.29 More than 60 studies have evaluated the effectiveness of ipriflavone for both the treatment and prevention of osteoporosis. As of 1997, 2769 patients had been treated for a total of 3132 patient years.30 Five of seven placebo-controlled trials showed that ipriflavone maintains BMD in the spine or distal radius. Two small trials showed an increase in BMD of the distal radius and a reduction in the incidence of spinal fractures. Two problems arise when evaluating most ipriflavone studies. The first is a problem found in many studies of osteoporosis treatments: Fracture is not an endpoint. The second problem is that different BMD measurement techniques were used at different anatomic sites, making comparison difficult.
The largest ipriflavone trial to date is the Ipriflavone Multicenter European Fracture Study, a prospective, randomized, double-blind, placebo-controlled 4-year study conducted in 4 centers in Belgium, Denmark, and Italy between August 1994 and July 1998.31 Four hundred seventy-four postmenopausal white women, ages 45 to 75 years, with low BMD were randomly assigned to receive ipriflavone 200 mg (n = 234) or matching placebo (n = 240) three times per day; all received 500 mg/day calcium. The primary outcome measure was reduction in fracture incidence. During the study period, no difference was noted in the occurrence of vertebral fractures among women taking ipriflavone compared with those taking placebo. However, only a small number of women in the ipriflavone group sustained vertebral fractures during the 36-month follow-up. One concerning adverse effect noted in this study was significant lymphopenia, which developed in 29 of the 237 women receiving ipriflavone.
Questions have been raised regarding the safety of long-term ipriflavone treatment on breast and uterine tissue. Is ipriflavone estrogenic? Few data exist on this topic at this time. Fifteen postmenopausal women were given 600 or 1000 mg/day ipriflavone or placebo and then evaluated for changes in serum levels of luteinizing hormone, follicle-stimulating hormone, prolactin, and estradiol. No differences were found between the ipriflavone and placebo groups after a single oral dose of 600 or 1000 mg ipriflavone or after 7, 14, or 21 days of treatment.32 Another study showed that after 21 days of treatment with ipriflavone (600 mg/d), conjugated estrogen (0.625 mg/day), or placebo, vaginal cytologic findings were unchanged in the groups receiving placebo and ipriflavone, compared with a considerable increase in superficial vaginal cells in the group receiving estrogen.32 Animal studies have shown that ipriflavone inhibits bone resorption in a manner similar to that of estrogen but without uterotropic effects.33
Excluding the Ipriflavone Multicenter European Fracture Study, pooled results from 2769 patients participating in small clinical trials revealed adverse effects in 14.5% of patients receiving ipriflavone and in 16.1% of women taking placebo.31 Complaints in both groups were primarily gastrointestinal: heartburn, vomiting, abdominal pain, constipation, and diarrhea. The largest study, the Ipriflavone Multicenter European Fracture Study, revealed a significant incidence of lymphopenia in the group receiving ipriflavone, compared with placebo.31 In most cases lymphopenia resolved within 12 to 24 months of discontinuation of the supplement. Dosage reduction is recommended in patients with renal insufficiency. Those with a creatinine clearance of 40 to 80 mL/min should reduce the dosage to 400 mg/d; those with creatinine clearance of less than 40 mL/min should reduce the dosage to 200 mg/day.34 Reduced theophylline metabolism and elimination were observed in a theophylline-treated patient during ipriflavone administration. After the withdrawal of ipriflavone, the serum theophylline concentration returned to its previous level.35 In vitro studies indicate a possible inhibitory effect on cytochrome P-450 enzymes.35
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