Variability in the measured response of bone to teriparatide.

UNLABELLED: Apparent failures of bone mineral density (BMD) response to teriparatide at spine or hip occur even in a high compliance context (15% spine and 55% hip). Apparent non-responders nevertheless show good biomarker response, suggesting that apparent BMD non-response is due to measurement imprecision. Calcium intake may be an important determinant of hip response. INTRODUCTION: Individuals vary in response to bone active agents, but that variability is poorly quantified and its basis is not well understood. The study included 203 postmenopausal women with moderately severe osteoporosis, all treated with teriparatide, calcium, and vitamin D. The study was performed at the Creighton University Medical Center, a single site. METHODS: This is a prospective study of change in bone mineral density and resorption biomarkers over a 12-month treatment period. BMD response at spine and total hip was quantified by computing slopes for each participant's values, and biomarker change by the difference in values across the 12-month study period. RESULTS: Of the total number of participants, 85.2% exhibited a significant spine BMD response, while only 44.8% had a significant change at the hip. However, mean biomarker response was marginally larger for the BMD non-responders at either site than for the responders, indicating biological, if not measurable densitometric, activity of teriparatide in essentially all participants. CONCLUSIONS: Occasional apparent failures of BMD response in patients receiving teriparatide are probably not due to failure of response at the level of the bone remodeling apparatus, but instead reflect a combination of measurement imprecision and variable bone remodeling balance. The reason for the latter remains unclear.

Diagnosis and treatment of vitamin D deficiency.

The recent discovery--in a randomised, controlled trial--that daily ingestion of 1100 IU of colecalciferol (vitamin D) over a 4-year period dramatically reduced the incidence of non-skin cancers makes it difficult to overstate the potential medical, social and economic implications of treating vitamin D deficiency. Not only are such deficiencies common, probably the rule, vitamin D deficiency stands implicated in a host of diseases other than cancer. The metabolic product of vitamin D is a potent, pleiotropic, repair and maintenance, secosteroid hormone that targets > 200 human genes in a wide variety of tissues, meaning it has as many mechanisms of action as genes it targets. A common misconception is that government agencies designed present intake recommendations to prevent or treat vitamin D deficiency. They did not. Instead, they are guidelines to prevent particular metabolic bone diseases. Official recommendations were never designed and are not effective in preventing or treating vitamin D deficiency and in no way limit the freedom of the physician--or responsibility--to do so. At this time, assessing serum 25-hydroxy-vitamin D is the only way to make the diagnosis and to assure that treatment is adequate and safe. The authors believe that treatment should be sufficient to maintain levels found in humans living naturally in a sun-rich environment, that is, > 40 ng/ml, year around. Three treatment modalities exist: sunlight, artificial ultraviolet B radiation or supplementation. All treatment modalities have their potential risks and benefits. Benefits of all treatment modalities outweigh potential risks and greatly outweigh the risk of no treatment. As a prolonged 'vitamin D winter', centred on the winter solstice, occurs at many temperate latitudes, < or = 5000 IU (125 microg) of vitamin D/day may be required in obese, aged and/or dark-skinned patients to maintain adequate levels during the winter, a dose that makes many physicians uncomfortable.

Constructive interactions among nutrients and bone-active pharmacologic agents with principal emphasis on calcium, phosphorus, vitamin D and protein.

Current and emerging bone active pharmacologic agents are capable of producing substantial gains in bone mass. However, nutrition must be adequate if this potential is to be realized. Calcium and vitamin D supplementation, for example, have both been demonstrated to augment substantially the skeletal response to estrogen therapy in postmenopausal women. The bisphosphonates and selective estrogen receptor modulator (SERMs) have all been tested only in the context of supplemental calcium and vitamin D. Therefore, it cannot be assumed that these bone active agents would be effective in the absence of these nutrients. Adequate protein intake has also been demonstrated to protect bone mass in the elderly and to improve recovery from osteoporotic fractures. Phosphorus intake, less extensively studied, may be more important than currently recognized, particularly in elderly individuals living alone, eating little meat, and receiving anti-osteoporosis treatment agents.

Hormones, weight change and menopause.

OBJECTIVE: To determine total body weight change occurring in women at mid-life, specifically with respect to occurrence of menopause and use of estrogen. DESIGN: Retrospective analysis of body weight measurements accumulated in two cohorts of healthy women participating in studies of skeletal metabolism. SUBJECTS: Cohort 1: 191 healthy nuns enrolled in a prospective study of osteoporosis risk, aged 35-45 in 1967; cohort 2: 75 women aged 46 or older and still menstruating, enrolled in 1988 in a study of bone cell dynamics across menopause. Roughly one-third of each group received hormone replacement after menopause. MEASUREMENTS: Body weight and height, age, menstrual status and use of estrogen replacement. Cohort 1: 608 measurements at 5 y intervals spanning a period from 17 y before to 22 y after menopause; cohort 2: 1180 measurements at 6-month intervals spanning a period from 5 y prior to 5 y after menopause. RESULTS: In cohort 1 weight rose as a linear function of age (both chronological and menopausal), both before and after cessation of ovarian function, at a rate of approximately 0.43% y(-1). Neither the menopausal transition nor the use of estrogen had an appreciable effect on this rate of gain. In cohort 2 the rate of gain seemed to diminish slightly at menopause. As with cohort 1, hormone replacement (or its absence) had no appreciable effect on weight. CONCLUSIONS: The long-term, total body weight trajectory at mid-life is not influenced appreciably by either cessation of ovarian function or by hormone replacement.

Calcium needs of the elderly to reduce fracture risk.

Contemporary calcium intakes in the industrialized nations are substantially lower than those to which human physiology is adapted by evolution. As a result, compensatory adjustment is required lifelong. This adjustment consists of high levels of parathyroid activity, leading to parathyroid hyperplasia, high circulating levels of 1,25(OH)2D and high bone turnover. The capacity of these compensatory mechanisms to provide sufficient calcium to offset daily losses from the body declines with age; hence, increasingly the body tears down bone to access its calcium. As a result, the calcium requirement for skeletal maintenance is said to rise with age. Supplemented intakes to a total in the range of 32.5-42.5 mmol (1300-1700 mg)/day have been shown to arrest age-related bone loss and to reduce fracture risk in individuals 65 and older and intakes of 60 mmol (2400 mg), to restore the setting of the parathyroid glands to young adult values. Intakes at such levels also minimize the expression of other disorders such as colon cancer, hypertension and obesity, all of which, while multifactorial, have a calcium deficiency component. Milk, mainly because of constructive interactions among its several key nutrients, is probably the most nutritionally and cost effective way of meeting the calcium requirement in the elderly.

Factors associated with calcium absorption efficiency in pre- and perimenopausal women.

BACKGROUND: The amount of calcium ingested by an individual may affect several chronic conditions, including osteoporosis, hypertension, and colon cancer. However, individuals vary in their ability to absorb the calcium they consume. OBJECTIVE: The purpose of this study was to examine sources of interindividual variation in the efficiency of calcium absorption in women. DESIGN: Fractional calcium absorption was estimated in 142 healthy pre- and perimenopausal women. Dietary habits, lifestyle factors, calciotropic hormones, and vitamin D receptor gene polymorphisms were also assessed. RESULTS: Calcium absorption values averaged 35% and ranged from 17% to 58%. Fractional calcium absorption was positively associated with body mass index (r = 0.22, P = 0.007), dietary fat intake (r = 0.29, P = 0.001), serum 1,25 dihydroxyvitamin D [1,25(OH)(2)D] concentrations (r = 0.23, P = 0. 006), and parathyroid hormone concentrations (r = 0.21, P = 0.015). Fractional calcium absorption was inversely associated with total calcium intake (r = -0.18, P = 0.030), dietary fiber intake (r = -0. 19, P = 0.028), alcohol consumption (r = -0.14, P = 0.094), physical activity (r = -0.22, P = 0.007), and symptoms of constipation (r = -0.16, P = 0.059). In stepwise regression analysis, dietary fat, dietary fiber, serum 1,25(OH)(2)D, and alcohol consumption emerged as independent predictors of calcium absorption, explaining 21.02% of the observed variation. Women in the lowest tertile of the ratio of dietary fat to fiber had 19% lower fractional calcium absorption values than did women in the highest tertile of ratio of dietary fat to fiber (test of trend, P < 0.001). CONCLUSIONS: There is a wide range of calcium absorption values in healthy women. The amount of dietary fat consumed relative to dietary fiber appears to have an important role in determining differences in calcium absorption performance among individuals.

The role of calcium in health and disease.

Skeletal fragility at the end of the life span (osteoporosis) is a major source of morbidity and mortality. Adequate calcium intake from childhood to the end of the life span is critical for the formation and retention of a healthy skeleton. High intakes of calcium and vitamin D potentiate the bone loss prevention effects of hormone replacement therapy in postmenopausal women. Pregnancy and lactation are not risk factors for skeletal fragility, although lactation is associated with a transient loss of bone that cannot be prevented by calcium supplementation. Low calcium intake has been implicated in the development of hypertension, colon cancer, and premenstrual syndrome, and it is associated with low intakes of many other nutrients. Encouragement of increased consumption of calcium-rich foods has the potential to be a cost-effective strategy for reducing fracture incidence later in life and for increasing patients' dietary quality and overall health.

Dietary changes favorably affect bone remodeling in older adults.

OBJECTIVE: To determine whether dietary counseling to increase milk intake could produce useful changes in the calcium economy and what, if any, other nutrition-related changes might be produced. DESIGN: Randomized, open trial. SUBJECTS/SETTING: Two hundred four healthy men and women, aged 55 to 85 years, who habitually consumed fewer than 1.5 servings of dairy foods per day. Six academic health centers in the United States. INTERVENTION: Subjects were instructed to consume 3 servings per day of nonfat milk or 1% milk as a part of their daily diets, or to maintain their usual diets, for a 12-week intervention period, which followed 4 weeks of baseline observations. MAIN OUTCOME MEASURES: Energy and nutrient intake assessed from milk intake logs and 3-day food records; serum calciotrophic hormone levels at baseline and at 8 and 12 weeks; urinary excretion of calcium and N-telopeptide at 12 weeks. STATISTICAL ANALYSES: Repeated-measures analysis of variance. RESULTS: In the milk-supplemented group, calcium intake increased by 729 +/- 45 mg/day (mean +/- standard error), serum parathyroid hormone level decreased by approximately 9%, and urinary excretion of N-telopeptide, a bone resorption marker, decreased by 13%. Urine calcium excretion increased in milk-supplemented subjects by 21 +/- 7.6 mg/day (mean +/- standard error), less than half the amount predicted to be absorbed from the increment in calcium intake. All of these changes were significantly different from baseline values in the milk group and from the corresponding changes in the control group. Bone-specific alkaline phosphatase level (a bone formation marker) fell by approximately 9% in both groups. Serum level of insulin-like growth factor-1 (IGF-1) rose by 10% in the milk group (P < .001), and the level of insulin-like growth factor binding protein-4 (IGFBP-4) fell slightly (1.9%) in the milk group and rose significantly (7.9%) in the control group (P < .05). APPLICATIONS/CONCLUSIONS: The changes observed in the calcium economy through consumption of food sources of calcium are similar in kind and extent to those reported previously for calcium supplement tablets. The increase in IGF-1 level and the decrease in IBFBP-4 level are new observations that are beneficial for bone health. Important improvements in skeletal metabolism can feasibly occur in older adults by consumption of food sources of calcium. Dietitians can be confident that food works, and that desired calcium intakes can be achieved using food sources.

Raloxifene and estrogen: comparative bone-remodeling kinetics.

The pattern of changes in human bone remodeling produced by raloxifene (60 mg/day) was compared to that of estrogen (given as hormone replacement therapy) in 33 early postmenopausal women randomly assigned to raloxifene, estrogen, or no treatment. Remodeling was measured using calcium tracer kinetic methods employed under a constant diet and full metabolic balance conditions. Studies were performed at baseline and, to detect both early and late remodeling changes, at 4 and 31 weeks of treatment. Both raloxifene and estrogen produced a significant positive calcium balance shift at each treatment measurement point: +74 and +60 mg/day at 4 weeks, and +60 and +91 mg/day at 31 weeks for raloxifene and estrogen, respectively. Externally, this balance change was due to a highly significant fall in the urinary calcium level and marginal improvement in calcium absorption efficiency. Internally, bone resorption was significantly reduced at both measurement points: -64 and -60 mg/day at 4 weeks, and -82 and -162 mg/day at 31 weeks for raloxifene and estrogen, respectively. Bone formation was not significantly affected by either agent at 4 weeks; at 31 weeks, formation was reduced by estrogen, but not by raloxifene. Thus, at 4 weeks, the general pattern of remodeling change was identical for the two agents. At 31 weeks, remodeling suppression was greater for estrogen than for raloxifene; however, remodeling balance was the same for the two agents. We conclude that raloxifene and estrogen affect the bone remodeling apparatus similarly, and that raloxifene, therefore, is acting on bone as an estrogen agonist.

Bone dimensional change with age: interactions of genetic, hormonal, and body size variables.

Changes in bony dimensions with age were assessed longitudinally from standardized X-ray films in 170 middle-aged Caucasian women, starting at age 40 years and with a median duration of observation of 21.125 years. Consistent with earlier work, cortical area of the metacarpals and radial shaft declined with age at rates ranging from 0.57 to 0.86%/year. As predicted, estrogen replacement therapy decreased this loss in a dose-dependent manner. Not previously reported is the fact that weight gain over the period of observation reduced upper extremity bone loss. Moreover, this protection was independent of the estrogen effect. In contrast with bone loss in the upper extremity, both femur shaft diameter and femur shaft cortical area increased significantly with age (0.23 and 0.26%/year, respectively). Estrogen replacement therapy inhibited femur shaft expansion but had no effect on femur cortical area. Weight change, however, strongly influenced gain (or loss) of femur cortical area: those in the highest weight change tertile gained 4 times as much cortical area as those in the lowest weight change tertile. VDR genotype also significantly influenced femoral shaft changes: women with the bb genotype had both greater shaft expansion and a greater increase in cortical area. The VDR effects were independent of the effects of weight change and estrogen. Femoral shaft expansion was of sufficient magnitude to suggest that the mechanical properties of the entire femur may change appreciably with age. Finally, contrary to widespread belief, there was significant, if modest, expansion at the femoral neck with age.

Ultrasound, densitometry, and extraskeletal appendicular fracture risk factors: a cross-sectional report on the Saunders County Bone Quality Study.

The Saunders Bone Quality Study was designed to determine the feasibility of ultrasonic bone measurement, at the patella, as a predictor of low-trauma fractures in a rural population-based study. At the first visit of this 4-year longitudinal study, anthropometric and clinical measurements and medical, surgical and fracture histories were obtained for the 1428 participants 9899 women and 529 men). Explored risk factors for low-trauma fractures included age, sex, calcium intake, alcohol and caffeine ingestion, tobacco use, body mass and grip strength, age of menopause, estrogen replacement therapy, propensity to fall, distal radius and ulna bone mineral content, and bone density. Forward multivariate logistic regression analysis showed that lower ultrasound values are more consistently associated with reported low-trauma appendicular fractures than the commonly reported forearm absorptiometry measures of radius mineral content and density. When ultrasound, age, and the extra skeletal risk factors were included in an additional multivariate model, only age and ultrasound were significantly associated with appendicular fracture history in women (P = 0.0003), whereas only ultrasound was associated in the men (P = 0.001). We conclude that ultrasound is a better measure as association with reported low-trauma fractures than the commonly reported forearm SPA measures. Even after adjustment for many of the extra skeletal risk factors, low AVU is highly associated with low-trauma fracture status for both men and women.

Vitamin D receptor gene polymorphism, bone mass, body size, and vitamin D receptor density.

We determined vitamin D receptor (VDR) gene alleles (based on the BsmI restriction site polymorphism), duodenal mucosal receptor density, bone mass at spine and total body, and body size in 32 healthy premenopausal females. While we found no relationship between allele and receptor density in duodenal mucosa, bone mineral content (BMC) at both spine and total body was significantly associated with VDR gene alleles. BMC was highest for the bb allele, lowest for BB, and intermediate for Bb. A similar association was noted between allele and body size variables, particularly weight. When BMC was adjusted for body weight, the association with VDR polymorphism disappeared. The VDR gene polymorphism may be affecting bone mass not through classical nutritional mechanisms (e.g., intestinal calcium absorption), but through an influence on body size.

The role of calcium intake in preventing bone fragility, hypertension, and certain cancers.

This paper examines the evidence that connects calcium intake and vitamin D status to bone fragility, hypertension, colon cancer, and breast cancer. Human calcium physiology, with an intestinal absorptive barrier and inefficient conservation, reflects the abundance of calcium in the primordial human food supply. The calcium intake of stone-age adults is estimated at 50 to 75 mmol/d, three to five times the median calcium intake of present-day U.S. adults. Long-term calcium restriction and/or insufficient vitamin D may promote the development of bone fragility, high blood pressure, colon cancer, and breast cancer in susceptible individuals. Conversely, improvement in calcium intake and/or in vitamin D status may help to prevent these serious health problems. At least 12 intervention studies have established the skeletal benefit of increased calcium intake among women in the late postmenopause. Other reports suggest that adequate calcium may protect against salt-sensitive and pregnancy-associated hypertension. High intakes of both dietary calcium and vitamin D are associated with reduced development of precancerous changes in colonic mucosa. Preliminary findings also suggest that vitamin D has a protective effect against breast cancer.

ADSA Foundation Lecture. Low calcium intake: the culprit in many chronic diseases.

Calcium is the fifth most abundant element in the earth's crust and is necessary for both plant and animal life today. Moreover, the natural diets of all mammals are rich in calcium. The diet of Stone Age human adults is estimated to have contained from 50 to 75 mmol of calcium (2000 to 3000 mg)/d, three to five times the median calcium intake of present-day US adults. Human physiology has adapted to this environmental abundance with an intestinal absorptive barrier and inefficient renal conservation of calcium. Although mammalian physiology contains mechanisms by which organisms can adjust to temporary environmental shortages, chronic calcium retention has a number of health consequences, most notably bone fragility, high blood pressure, and colon cancer. Evidence indicates that improvement in calcium intake (or in vitamin D status) prevents some portion of each of these multifactorial problems. At least 14 intervention studies have established the skeletal benefit of increased calcium intake during growth and among women in the late postmenopause. Other evidence suggests that adequate calcium may protect against salt-sensitive and pregnancy-associated hypertension and that high intakes of both dietary calcium and vitamin D reduce development of precancerous changes in colonic mucosa.

Bone mass, nutrition, and other lifestyle factors.

Since the proceedings of the last Consensus Conference on Osteoporosis were published as a supplement to The American Journal of Medicine in November 1991, there has been a plethora of well-documented studies reported in the literature. This article will address some of the issues concerning the relation between bone mass and nutrition raised in those studies.