Osteoporosis is a common disorder that affects approximately 10 million people in the United States. Although the prevalence varies considerably according to gender and race, being less common in men, African Americans, and Hispanic Americans, 25 to 30 percent of Caucasian women over age 65 suffer from osteoporosis. Recent data suggests that this diagnosis may also be common among older men who suffer from either absolute or relative androgen insufficiency (Ebeling, 1998).
The World Health Organization (1994) has defined osteoporosis and its precursor, osteopenia, as follows: osteopenia is defined as having a bone density one or more standard deviations below the gender-specific mean for a normal 25 year old; osteoporosis is defined as greater than 2.5 standard deviations below the same mean; severe osteoporosis is defined as greater than 2.5 standard deviations below the mean with clinical fractures. It should be noted that these definitions are not based on a pathologic classification of the disease but merely attempt to quantitate the degree of the problem according to relative bone mineral density (BMD), as measured by dual-energy x-ray absorptiometry scanning.
Although BMD is not a perfect intermediate outcome measure, several studies have demonstrated a good relationship between BMD and the risk of future fracture development (Cummings et al., 1993; Melton et al., 1993). Therefore, a decrease in BMD is the most frequent outcome measure in recent studies of osteoporosis, while clinically relevant end points such as fracture incidence are less commonly determined.
Osteoporosis is associated with considerable morbidity and mortal-
ity. The National Osteoporosis Foundation estimates that there are approximately 1.5 million osteoporosis-related fractures each year: 300,000 at the hip, 700,000 at the spine, 250,000 at the wrist, and 300,000 at other sites (National Osteoporosis Foundation, 1999). The impact of hip fractures on the mortality of the Medicare-age population is significant. A hip fracture is associated with a 20 to 25 percent 1-year mortality rate in women (higher in men), a 25 percent rate of admission to a long-term care setting, and a less than 50 percent likelihood of regaining baseline functional status (National Osteoporosis Foundation, 1999). In 1995, the cost of hip fractures in individuals over 45 years of age were estimated to be $8.7 billion in the United States (Ray et al., 1997). It has also been predicted that these costs could double in the next 30 years (Cummings et al., 1990). While fractures at sites other than the hip are less likely to be associated with mortality, their association with functional impairment, pain, fear, isolation, and depression may not be easily measured but should not be underestimated.
Multiple risk factors for osteoporosis have been defined, and include: (1) estrogen/testosterone deficiency, (2) Caucasian or Asian race, (3) small or thin body habitus, (4) inactivity, (5) alcohol and tobacco use, (6) chronic renal/liver disease, hyperthyroidism, and diabetes, (7) chronic use of pharmacological agents such as glucocorticoids, barbiturates, and phenytoin, (8) inadequate calcium intake, and (9) vitamin D deficiency. This chapter focuses on these last two risk factors, reviewing the role of diet and nutritional supplementation in preventing, delaying, and treating osteoporosis.
ROLE OF DIET IN ONSET AND TREATMENT OF OSTEOPOROSIS
Assessing Dietary Intake of Calcium
Most studies assessing the dietary intakes of free-living (communitydwelling) elderly populations (greater than 65 years of age) in the United States indicate that few individuals are consuming the level of calcium intake recommended as adequate for those over 50 years of age, 1,200 mg/day (IOM, 1997). Indeed, estimates of calcium intake in older women in the United States in 1994 (ARS, 1997) showed an adjusted median intake of 571 mg/day for women 51 to 70 years of age, and a median intake of 517 mg/day for those 71 years and older (IOM, 1997). Only 1 percent of those over age 50 were reported to consume this recommended intake. These estimated intakes are in all likelihood underestimates because the Continuing Survey of Food Intakes by Individuals did not include calcium intakes from supplements or from foods recently available in the market that may have been fortified with calcium.
While it is recognized that such national surveys may underreport intakes by as much as 20 percent (Mertz et al., 1991), a recent evaluation of the Third National Health and Nutrition Examination Survey data suggested that only 2 percent of people over age 50 took any calcium supplement (Bendich et al., 1999), while the National Health Interview Survey (Moss et al., 1989) suggested that close to 21 percent of people over age 65 had taken a calcium supplement within the last 2 weeks. In any case, it is clear that at present, average intakes of calcium by those over age 50 in the United States are far below the recommended 1,200 mg/day (IOM, 1997). This has been borne out in most of the randomized controlled trials discussed below where baseline calcium intake was almost uniformly below 800 mg/day. It should be noted, however, that in some studies, subjects were specifically selected for average reported daily intakes of less than 1,000 mg of calcium.
Many studies have assessed the extent to which increased calcium intake can mitigate the bone loss seen in the elderly and therefore decrease the risk and sequelae of osteoporosis. Most of the studies conducted have measured BMD, a widely available and useful technique to screen for osteoporosis and osteopenia. Most of the studies have enhanced calcium intake by providing calcium supplements because of the presence of confounding variables related to changes in intake of food with different amounts of calcium.
Because of substantial improvements in the technology for measuring BMD in the last decade, this review focuses only on the most recent randomized controlled trials. However, it should be noted that a review of calcium supplementation studies prior to 1991 (Dawson-Hughes, 1991) in general supports the more recent findings.
Aloia and colleages (1994) compared 70 healthy women in the United States treated for 3 years with either a placebo, a supplement of 1,700 mg of calcium alone or a combination of 1,700 mg of calcium supplement with hormone replacement therapy (HRT). All subjects were given 10 mg (400 IU) of vitamin D as a supplement. At baseline, calcium intake was reported to average about 500 mg/day, with 90 percent of the subjects consuming less than 800 mg/day. At the end of the study the calcium-only group lost less total body and femoral neck bone mass compared to the placebo group; however, there was no difference seen at the spine or proximal radius sites. The calcium and HRT group had the best outcome during the 3-year study, having less change in total body calcium and femoral neck BMD than the placebo group.
A 4-year study from New Zealand (Reid et al., 1995) examined 78
healthy white women who were at least 3 years postmenopausal. This was a 2-year continuation of a previously reported 2-year investigation in which subjects were provided either a 1,000 mg/day of calcium supplement or a placebo. At baseline, and throughout the 4 years, usual dietary intake of calcium was approximately 750 mg/day for each group. This study found that the positive effect of calcium supplementation on total BMD that had been noted during years 1 and 2 of the study continued in years 3 and 4. Bone loss at specific sites (lumbar spine, proximal femur, trochanter) tended to be reduced most in the supplemented group during the first year of the study, but an overall difference at 4 years was still detected. Significantly fewer incident fractures were noted in the calcium-supplemented group.
Recker and colleagues (1996) evaluated the effect of a daily supplement of 1,200 mg of calcium on spine fractures in older women with and without previous spinal fractures. At baseline, dietary calcium intake was estimated to be less than 500 mg/day. After the 4-year follow-up period, calcium supplementation significantly reduced the incidence of new fractures in the group with prior spine fractures and greatly reduced bone loss compared to the placebo control group. No significant difference in incident fractures was found in the group without prior fractures at baseline compared to control subjects.
A long-term follow-up study in Australia evaluated the effect of a daily 1,000 mg calcium supplement compared to a placebo for 4 years in women who were at least 10 years postmenopause at baseline (Devine et al., 1997). The baseline dietary intake in this study was estimated to be close to 1,000 mg/day. Thus, the actual comparison was between 1,000 and 2,000 mg/day. Investigators found a significant reduction in bone loss at every site in the supplemented group compared to placebo. Of interest, when a subgroup of subjects were compared (who were non-compliant with the calcium supplement during the last 2 years and thus averaged only 1,000 mg/day of total calcium intake per day in years 3–4), they lost more bone than the more compliant subjects.
A recent study looked at the effect of 1,000 mg/day of calcium supplementation for 2 years on seasonal bone loss in nonosteoporotic women over age 65 living in the state of Maine, with an estimated baseline calcium intake of less than 800 mg/day (Storm et al., 1998). The investigators compared a placebo control group to two different calcium supplementation regimens: (1) milk (four 8 ounce glasses/day) and (2) calcium carbonate (CaCO3) tablets (500 mg of calcium twice daily). The milk group was unable to maintain the expected supplementation level and had an estimated total calcium intake of 1,000 mg/day; this was an intermediate total daily intake between the placebo (700 mg/day) and CaCO3 (1,700 mg/day) groups. The reduction in bone loss seen was related to
the total daily calcium intake, but only the CaCO3 group was different from the placebo group at the spine, femoral neck, and greater trochanter. The CaCO3 supplemented group was noted to have an increase in bone density after 2 years. It is interesting to note that after the first year, the milk supplemented group experienced an even larger percent increase in greater trochanter BMD than the CaCO3 group despite a lower total calcium intake (1,600 versus 1,000 mg/day).
Most of the bone loss in the greater trochanter and femoral neck occurred during the winter months and was halted with CaCO3 or milk (in the case of the greater trochanter) treatment. In addition, winter was associated with a 20 percent decline in vitamin D levels. The importance of calcium supplementation at a level greater than 1,000 mg/day is underscored in this study since the high-calcium supplement group lost less bone in most sites than the milk drinkers who were also receiving vitamin D supplementation in their milk.
Vitamin D Supplementation
Other studies have recently looked at the effect of vitamin D intake as part of an overall approach to maintaining bone mass. It has been demonstrated that primary vitamin D deficiency, diagnosed as serum 25-hydroxyvitamin D [25-(OH)D] concentrations below 10 ng/mL (25 mmol/L), is common in older individuals, especially during the winter months, and in those living at more northern latitudes or with little direct sun exposure (Gloth and Tobin, 1995; Kinyamu et al., 1997). Elderly groups confined indoors have been shown to have low serum 25-(OH)D concentrations in 45 percent of individuals, with vitamin D intakes estimated to range from 3 to 7 mg (121–282 IU) per day (Gloth and Tobin, 1995). A recent report of older patients in a U.S. hospital found that 66 percent had low serum 25-(OH)D levels (Thomas et al., 1998). Furthermore, 46 percent of those taking a multiple vitamin, frequently supplying 10 mg (400 IU) of vitamin D, were still found to have low serum levels. Although this hospitalized population might have had diseases or had been taking drugs that could have negatively affected their vitamin D status, inadequate intake, winter season, and homebound status were all independent predictors of inadequate vitamin D level. This high percentage of probable vitamin D deficiency is supported by an earlier study that found low vitamin D levels in almost 80 percent of older Dutch women (Lips et al., 1988).
There is strong evidence that these low serum 25-(OH)D levels are more than just an innocuous biochemical abnormality. Indeed, serum vitamin D concentration is inversely associated with parathyroid hormone levels and markers of accelerated bone turnover (Chapuy et al.,
1996), and has been inversely linked to the occurrence of hip fractures (LeBoff et al., 1999). Most importantly, clinical trials now suggest that oral supplementation of vitamin D can reduce bone loss. In a 2-year trial in healthy postmenopausal women living in a northern latitude of the United States, whose estimated baseline dietary intake of vitamin D was only 2.5 mg (100 IU) per day, supplementation with an additional 2.5 mg (100 IU) or 17.5 mg (700 IU) was compared (Dawson-Hughes et al., 1995). Both groups received a calcium supplement of 500 mg/day in addition to their usual dietary calcium intake of about 450 mg/day. The higher dose of vitamin D (17.5 mg) reduced femoral neck bone loss by more than 50 percent, with much of the benefit occurring during the winter and spring months. Spine and whole body BMD did not differ between the groups.
A 36-month follow-up study of over 3,000 elderly French women (mean age 84 years) living in nursing homes compared fracture incidence in a group receiving both calcium (1,200 mg/day) and vitamin D (20 mg [800 IU] per day) supplementation to a double placebo control group (Chapuy et al., 1994). The calcium and vitamin D supplemented group had 29 percent fewer hip fractures and 24 percent fewer nonvertebral fractures (odds ratio of 0.7 for both).
A study of similar design (500 mg additional calcium and 17.5 mg [700 IU] vitamin D per day versus double-placebo) has recently been reported in a younger, healthier U.S. population (Dawson-Hughes et al., 1997). The supplemented groups, with average ages of 70 (males) and 71 (females), had less bone loss at all sites after year 1, but the groups (supplemented versus double-placebo) differed significantly only in total BMD after years 2 and 3. The cumulative incidence of a first fracture was 6 percent in the treatment group and 13 percent in the placebo group by the end of the study (relative risk = 0.5). In the men, supplementation significantly reduced bone loss from the spine, hip, and total body. In the women, the reduction was significant from the total body only. As expected, most of the fractures occurred in the women. The effect of supplementation on fracture rates in men has not been demonstrated.
As is evident in reviewing these studies, not all studies agree; a large study of Dutch women (receiving no calcium supplementation) found no effect of added vitamin D supplementation (Lips et al., 1996).
COST AND QUALITY-OF-LIFE CONSIDERATIONS
Recent studies have attempted to evaluate the potential economic and quality-of-life effects of treating osteoporosis. Given the high rate of expenditure for osteoporosis-related problems and the substantial data demonstrating that treatment can significantly reduce both bone loss and fracture rate, it is not surprising that these studies support economic ben-
efits due to therapeutic management of osteoporosis. In one study that specifically evaluated the effect of calcium supplementation, the predicted cost for avoiding one hip fracture was $33,000 when treating all men and women over 65 years of age (male and female), $14,000 for treating all women over 75 years of age, and $8,000 for treating all women over 85 (Bendich et al., 1999). This study probably overestimates the true cost of dietary intervention for preventing osteoporosis, since the cost of nonhip fractures is not included.
It should be noted that this estimate is greatly influenced by the percentage of the population already taking calcium supplementation (estimated between 2 and 21 percent, see above). It should also be noted that there are other, possible non-osteoporosis-related benefits of increased calcium intake. Although not yet determined to be a primary indication for calcium supplementation, some recent studies suggest positive influences of higher calcium intakes on blood pressure (Griffith et al., 1999) and colon tumors (Baron et al., 1999).
Studies have also attempted to evaluate the cost of treating osteoporosis per quality-adjusted life year (QALY). This type of evaluation is important because of the tremendous overall impact that osteoporosis can have on quality of life. These models, while complicated, generally assume a given level of fracture reduction and also assume a utility figure describing the trade-off value between years with a condition and years of perfect health. Nevertheless, the estimate in one study of $30,000 per QALY for treating osteoporosis is similar to that estimated for treating hypertension (Tosteson, 1997). An earlier study also suggested that the cost per QALY for treating osteoporosis is similar to that for treating hypertension (Jonsson et al., 1995; see chapter 14 for economic analyses related to osteoporosis for Medicare).
FUTURE AREAS OF RESEARCH
There are considerable data supporting the effectiveness of treatments for osteoporosis in reducing bone loss and subsequent fracture rate. While there is not total agreement, many recent studies strongly support a role for calcium and vitamin D as part of this treatment strategy. These studies include multiple randomized, controlled trials; reviews and metaanalyses; and consensus opinions from professional organizations. However, gaps remain in the understanding of this important issue that deserve future attention:
There are relatively few published intervention studies in men and non-Caucasian women.
There is a need for better dose–response data to determine the
lowest levels of intake or supplementation that are necessary and to evaluate the interactions between estrogen, calcium, and vitamin D with respect to determining minimum levels necessary.
The importance of seasonal vitamin D and/or calcium intake should be examined further.
There is a need for more studies demonstrating clinically relevant outcome measures such as fracture incidence. In addition, newer intermediate outcome measures such as microstructure of bone (by computed tomography) may help to reduce the variance noted in the relationship between changes in bone mass and fracture.
Better evaluation is needed of the long-term potential side effects of calcium and vitamin D supplementation.
Population-based estimates of the QALY utility value have to be developed to define more accurately the true cost per QALY models.
Studies are needed to assess behavior related to the use of calcium and vitamin D-fortified foods and supplements by individuals to chronically enhance calcium and vitamin D intake and the long-term efficacy of such interventions. This is especially important because of the potential added value of consuming foods that contain other nutrients and components thought to be beneficial to health as opposed to pure supplement forms. The development of culturally appropriate calcium and vitamin D-fortified foods may also be indicated to increase intake.
SUMMARY AND RECOMMENDATIONS
Enhanced intake of calcium and vitamin D for both the prevention and treatment of osteoporosis in the at-risk Medicare population is strongly supported by a considerable body of data including multiple randomized controlled trials. It must be noted that adequate calcium and vitamin D are also critical for the accretion of maximal bone mass, which occurs much earlier in life. The exact amounts of calcium and vitamin D intake that are necessary and safe have been reviewed at length (IOM, 1997) and are not specifically addressed in this report.
While consumption of calcium and vitamin D through food is the preferred route, it is recognized that the variability in food habits and preferences makes this a less reliable source of calcium and vitamin D to those at increased risk of osteoporosis. Although a variety of calcium-fortified foods continue to be introduced into the U.S. food supply (e.g., juices, cereals), there is currently a lack of data suggesting that those at risk for osteoporosis are able to maintain an adequate calcium and vitamin D intake without the use of supplements.
The more important and germane issue is whether counseling by a nutrition professional versus basic nutrition education by a variety of
health professionals (e.g., physicians and nurses) improves the probability of meeting adequate calcium and vitamin D intake. Current data is lacking, rather than suggestive for any specific health care provider to counsel patients regarding the use of calcium or vitamin D supplements. While a relatively simple history of the intake of calcium rich foods and supplements is indicated to ensure against the intake of excess levels of calcium (>2,500 mg/day) (IOM, 1997), such a history could be obtained by physicians, nurses, or other staff and would not likely require a comprehensive nutritional assessment by a dietitian. However, for individuals who would prefer to meet and sustain adequate intakes of calcium and vitamin D without supplements, nutrition counseling by a nutrition professional with training equivalent to that of a dietitian may be warranted, particularly for individuals with other nutrient restrictions or unique meal planning circumstances.
Summary of Evidence: Nutrition Intervention1 for Osteoporosis
Recommended as part of the standard of care by the World Health Organization (1994) and the National Osteoporosis Foundation (1999)
Strongly supportive (e.g., Chapuy et al., 1994, 1996; LeBoff et al., 1999)
Strongly supportive (Aloia et al., 1994; Dawson-Hughes et al., 1995, 1997; Devine et al., 1997; Recker et al., 1996; Reid et al., 1995; Storm et al., 1998)
Several (e.g., Dawson-Hughes, 1991)
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