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.

Need for reform in health professions accrediting.

At least 50 vocational or professional groups, exclusive of specialties within categories, now provide a health service. Many have established accrediting procedures for maintaining educational standards, and the number is increasing. So great is the demand from the accrediting bodies that universities and academic health centers find that the cost in terms of money, time, and duplication of effort has become exhorbitant, and thereby a major problem in the management of educational institutions. The duplication of effort leads to fragmentation of the entire accrediting process, and this, in turn, fosters inadequate sharing of health professions educational experiences. A model is presented that would lessen the burden of accrediting on educational institutions and simultaneously permit testing of the feasibility of a multiprofessional accrediting mechanism.

Timing of peak bone mass in Caucasian females and its implication for the prevention of osteoporosis. Inference from a cross-sectional model.

To determine the timing of peak bone mass and density, we conducted a cross-sectional study of bone mass measurements in 265 premenopausal Caucasian females, aged 8-50 yr. Bone mass and bone mineral density were measured using dual X-ray absorptiometry and single-photon absorptiometry at the spine (anteroposterior, lateral), proximal femur, radius shaft, distal forearm, and the whole body. Bone mass parameters were analyzed using a quadratic regression model and segmented regression models with quadratic-quadratic or quadratic-linear form. The results show that most of the bone mass at multiple skeletal locations will be accumulated by late adolescence. This is particularly notable for bone mineral density of the proximal femur and the vertebral body. Bone mass of the other regions of interest is either no different in women between the age of 18 yr and the menopause or it is maximal in 50-yr-old women, indicating slow but permanent bone accumulation continuing at some sites up to the time of menopause. This gain in bone mass in premenopausal adult women is probably the result of continuous periosteal expansion with age. Since rapid skeletal mineral acquisition at all sites occurs relatively early in life, the exogenous factors which might optimize peak bone mass need to be more precisely identified and characterized.

Incidence rate of type 2 diabetes is >50% lower in GrassrootsHealth cohort with median serum 25-hydroxyvitamin D of 41 ng/ml than in NHANES cohort with median of 22 ng/ml.

Higher serum 25-hydroxyvitamin D [25(OH)D] concentrations have been associated with lower risk of type 2 diabetes. This study compared incidence rates of type 2 diabetes among participants aged ≥20 years in two U.S. cohorts with markedly different median 25(OH)D concentrations. The median 25(OH)D concentration in the GrassrootsHealth (GRH) cohort was 41 ng/ml (N=4933) while in the 2005-6 National Health and Nutrition Examination Survey (NHANES) it was 22 ng/ml (N=4078) (P<0.0001). The adjusted annual incidence rate of type 2 diabetes was 3.7 per 1000 population (95% confidence interval=1.9, 6.6) in the GRH cohort, compared to 9.3 per 1000 population (95% confidence interval=6.7, 12.6) in NHANES. In the NHANES cohort, the lowest 25(OH)D tertiles (<17, 17-24 ng/ml) had higher odds of developing diabetes than the highest tertile (OR: 4.9, P=0.02 and 4.8, P=0.01 respectively), adjusting for covariates. Differences in demographics and methods may have limited comparability. Raising serum 25(OH)D may be a useful tool for reducing risk of diabetes in the population.

Vitamin D inadequacy among post-menopausal women: a systematic review.

BACKGROUND: Vitamin D inadequacy has been studied extensively, due to concerns about ageing populations, associations with osteoporosis and other disorders (including non-musculoskeletal), and high prevalence. AIM: To review recent reports on the prevalence of vitamin D inadequacy among post-menopausal women with and without osteoporosis and/or other musculoskeletal diseases. DESIGN: Systematic review. METHODS: We reviewed publications in the past 10 years reporting prevalence estimates for vitamin D inadequacy, reported as serum 25(OH)D values below various levels. Thirty published studies in the English language were identified, from January 1994 through April 2004. RESULTS: In osteoporotic populations, the prevalence of 25(OH) vitamin D concentration <12 ng/ml ranged from 12.5% to 76%, while prevalence rates reached 50% to 70% of patients with a history of fracture(s) using a cut-off of 15 ng/ml. In post-menopausal women, the prevalence of 25(OH) vitamin D concentrations

The bone-remodeling transient: implications for the interpretation of clinical studies of bone mass change.

A computer simulation of the bone-remodeling transient is described, in which the focus is explicitly on changes in clinically measurable bone mass (or density). Based upon quantitative remodeling data accumulated by histomorphometry and calcium tracer kinetics, the simulation shows that much of the apparent gain in bone produced by several agents currently employed to treat osteoporosis can be explained as a remodeling transient rather than as a fundamental alteration of remodeling balance. Even gains as large as 30% or more can be produced by nothing more than the remodeling transient under certain plausible combinations of basal remodeling rate, remodeling period, and degree of bone loss. The simulation further highlights the importance, in evaluating bone-active agents, of separating the response across the first remodeling period from bone changes that may ensue thereafter.

Fecal calcium density: a measure of calcium compliance.

We evaluated fecal calcium density (mass of calcium per g dry weight of feces) as a measure of compliance with a prescribed calcium intake regimen using 4 day fecal pools collected on a metabolic research unit from subjects ingesting measured, constant intakes. Fecal calcium density was highly correlated with intake (r = 0.897, P less than 0.001). Intake estimates based on fecal calcium density exhibited a standard error of the mean equal to 3.76 mmol calcium. Since a typical calcium supplement table contains 12.5 mmol calcium, the measurement of fecal calcium density is sensitive enough to detect regular omission of one or more pills daily. Applicability of this approach to convenience samples of feces was evaluated in 15 individuals by testing homogeneity of fecal calcium density values on up to six different 3-9 g portions (wet weight) of each volunteer's fecal sample. The within-sample coefficient of variation was 9.5% for all subsamples and 7.3% for samples from individuals with intakes above 25 mmol calcium per day. Thus feces are reasonably homogeneous in regard to calcium density. Accordingly, reasonably small fecal collections should suffice for its measurement.

Determinants of endogenous fecal calcium in healthy women.

Endogenous fecal calcium (EFC) excretion was measured in 518 studies in 191 normal perimenopausal women, most studied two to three times over a 15 year period. EFC averaged 102 +/- 25 mg/day. Absorption fraction was simultaneously determined by both double-isotope and balance methods. EFC was found to vary inversely with absorption fraction, and the observed relationship was used to calculate the total amount of calcium (TIC) entering the gut from endogenous sources. TIC averaged 140 +/- 34 mg/day and was found to be correlated with a number of intake and body size variables. Phosphorus intake was the most strongly correlated of all the variables (r = 0.404; P < 0.0001), each increment of 0.1 g phosphorus intake being associated with an increase in TIC of 6 mg. Lean body mass was the best correlated of the body size variables, with TIC rising by 1.6 mg/day for every kg lean mass. There were also small but significant correlations with protein and energy intakes, the latter suggesting that some of the variation of TIC is related to the amount of food consumed. Caffeine, previously reported as elevating TIC, did not exhibit a significant relationship in this study.

Comparison of speed of sound ultrasound with single photon absorptiometry for determining fracture odds ratios.

The purpose of this study was to compare the ability of ultrasound velocity measurement with that of single photon absorptiometry to determine the odds of history of fracture since age 40, for a population-based study. To do this we computed odds ratios and 95% confidence intervals for 809 women and 502 men, aged 50 years and older, who are participants in the prospective phase of the Saunders County Bone Quality Study. These participants received both the ultrasound and single photon absorptiometry bone measurements at the initiation of the study. In addition, a history of all fractures that had occurred to participants since age 40 was obtained. The two bone assessment methods were compared by examining the magnitude of the odds ratios, to determine which produces the highest estimate of the probability of odds of fracture, and by examining widths of the respective confidence intervals to show which estimate of odds ratio is the most precise. Ultrasound velocity estimates a higher probability of odds of both low-trauma fractures and all fractures than distal radius and ulna bone mineral content, but lower than bone mineral density at the same sites for both women and men. However, the ultrasound measure is more precise than bone mineral density, but less precise than bone mineral content. We conclude that ultrasound velocity is as good as single photon absorptiometry in estimating odds of fracture.

Bisphosphonate effects and the bone remodeling transient.

Published randomized clinical trial data for alendronate, given at a dose of 10 mg/day, were fitted by a computer algorithm to the currently accepted model of the bone remodeling process. The purpose was to determine how much of the reported improvement in lumbar spine bone density could be attributed to the inevitable remodeling transient and how much might represent positive bone balance. Very good fits to the clinical data were easily obtained, indicating the general validity of current syntheses of bone remodeling biology. The best fit was provided by simulations produced by combinations of 36-38% suppression of remodeling activation and positive remodeling balance ranging from 1.1 to 1.4% per year. Whole body bone biomarker changes would have suggested both a slightly greater degree of suppression and a higher baseline level of remodeling than could be provided by any of the simulations if they were to fit the clinical data. Either regional skeletal heterogeneity or lack of a one-to-one quantitative relationship between remodeling changes and biomarker changes may explain the discrepancies between the two approaches.

Influence of calcium load on absorption fraction.

True calcium absorption was studied as a function of the size of the ingested load in healthy adult women, under meal conditions and at loads ranging from 15 to 500 mg calcium. Fractional absorption was highly inversely correlated with the logarithm of load (P less than 0.001). At the lowest loads, absorption averaged 64.0% and at the highest, 28.6%. The parameters of the best-fit relationship permit reasonably precise calculation of the impact of various calcium dosing and dietary strategies.

Normal vertebral dimensions and normal variation in serial measurements of vertebrae.

A total of 568 lateral spine radiographs of 191 generally healthy white perimenopausal women were used to determine the limits of normal for shape and dimensions of the vertebral bodies most often involved in osteoporotic fracture. Anterior and posterior vertebral heights for T7-L4 were used to compute wedge shape, relative posterior height, and relative serial change. Wedge shape was defined as anterior height minus posterior height divided by posterior height. Relative posterior height was defined as the posterior height of a vertebra minus the posterior height of the vertebra superior divided by the posterior height of the vertebra superior. The degree of normal wedging depended on position: wedge values progressed down the spine, from a mean of -0.106 at T7 to 0.048 at L4. The minimum normal wedge value ranged from -0.209 at T7 to -0.083 at L4. Radiographs on a cohort of 28 osteoporotic women were evaluated both by ordinary clinical reading of the radiographs and by using the standards developed from the normal subjects. Initial agreement between the two modes of assessment was 85.4%, and in resolving the remaining disagreements the clinician agreed that he had initially misread the films in all but 3.2%. On the basis of this limited experience, we conclude that the use of such objective standards, in a computer-operated algorithm, is more accurate than routine radiographic assessment. Serial x-rays spanning a 15-20 year period in these women permitted determination of both reproducibility and longitudinal change in vertebral dimensions in the perimenopause. The mean relative serial change was not significantly different from zero for all vertebrae.(ABSTRACT TRUNCATED AT 250 WORDS)

Tallness versus shrinkage: do women shrink with age or grow taller with recent birth date?

This paper presents evidence that much of the high rate of age-related height loss in women reported in cross-sectional studies is actually a cohort effect rather than an aging effect. Data from a large cross-sectional study of healthy, white American women indicate that there has been a gain in peak adult height of 1.0 cm per decade for several decades from 1900 through 1965. Data from the HES, HANES I, and HANES II studies concur on this point. By contrast, data from a longitudinal study of 191 healthy white U.S. women show only a trivial rate of decline from peak adult height in the fifth and sixth decades of life. In an unselected population, some apparent height loss with age is probably due to disease processes, such as vertebral collapse. Caution is needed in using aging to interpret differences in height and in height-dependent variables, such as bone density, in cross-sectional studies.

The proportion of trabecular bone in human vertebrae.

The proportion of trabecular bone in human cadaver vertebrae was assessed by anatomic dissection. Thirty-two whole thoracic and lumbar vertebrae were obtained from 10 normal human postmenopausal female cadavers, 14 from 4 normal adult human male cadavers of similar age, and 8 from one female osteoporotic cadaver. Each vertebra was opened by saw cuts and separated into four tissue types: (1) body trabecular bone and marrow; (2) body cortical bone; (3) vertebral arch trabecular bone and marrow; and (4) vertebral arch cortical bone. Calcium was determined in each tissue type for each vertebra by ashing and atomic absorption spectrophotometry. Trabeculae accounted for 24.4 +/- 4.5% of the total calcium in whole female vertebrae, and 18.8 +/- 4.4% in whole male vertebrae (p less than 0.001). The body averaged 41.8% trabecular bone in females and 33.5% in males. The arch averaged 9.7% trabecular bone in females and 4.9% in males. The proportion of trabecular bone in the whole vertebrae in the single osteoporotic spine was 28.5 +/- 3.2%, a value not significantly different from the trabecular fraction in normal females. These data indicate that whole human thoraco-lumbar vertebrae are composed of a substantially lower proportion of trabecular bone than is usually assumed, and they suggest that cortical and trabecular bone are eventually lost in equal proportion from the vertebrae during the development of spinal osteoporosis. These results are important for the interpretation of data from noninvasive bone measurement techniques that evaluate the spine, and they suggest that studies of this type are important for any site where noninvasive bone mass measurement is done.

Calcium absorption in women: relationships to calcium intake, estrogen status, and age.

A total of 526 absorption studies, using both the double-isotope and balance-based methods, were performed in 189 middle-aged women in good general health. The study extended over 17 years of observation, with most subjects studied from two to four times at 5 year intervals. Each study was done on the woman's own self-selected calcium intake and was carried out under inpatient, metabolic balance controls. There was a highly significant inverse correlation between calcium intake and absorption fraction, with the best fit provided by an hyperbola in which absorption fraction is approximately inversely proportional to the square root of intake. The range of absorptive performance was very broad at all intake levels. Mean absorption fraction declined from a value of 0.45 at very low intakes (approximately 200 mg Ca per day) to approximately 0.15 at intakes above 2000 mg/day. There was a highly significant fall in absorption efficiency with age, amounting to approximately 0.0021 per year and a one-time decrease, amounting to approximately 0.022 at the time of menopausal estrogen loss.

Calcium absorptive consistency.

Calcium absorption efficiency was measured two or three times each in 74 premenopausal and 142 postmenopausal women under conditions predicted to alter absorptive performance. A woman's absorptive consistency was evaluated across differing loads, differing intervals, and substances of differing intrinsic absorbability. In all these circumstances there was a statistically significant correlation between a woman's absorption under differing test situations accounting for up to 60% of the variance typically found in cross-sectional studies. For example, when the same substance but at differing load levels was tested three times over an 8 week period, various coefficients of correlation ranged from +0.773 to +0.849 (P less than 0.001). Even over intervals as long as 5 years correlation of absorption fraction within individuals remained significant (r = +0.487, P less than 0.001).

Ultrasound velocity, through bone predicts incident vertebral deformity.

We followed 130 postmenopausal women without evidence of vertebral deformity by lateral spine radiographs on entry into study for 2 years, and repeat spine radiographs were taken at the end of that time. Incident deformities occurring within this 2 year period were detected by two methods, a level-specific radiogrammetric approach and visual inspection by skilled clinicians. Fourteen incident deformities were detected by the radiogrammetric method, and 19 by the clinicians. Ultrasound transmission velocity was measured at the patella in each subject on entry. Values for ultrasound velocity were significantly correlated with incident fracture occurrence, with individuals having velocity values more than one standard deviation below the mean for the group exhibiting from 3.3 to 4.6 times the probability of incident fracture as individuals with velocity values more than one standard deviation above the mean. Thus, low values for ultrasound transmission velocity at the patella detect yet-unexpressed bony fragility at the spine and predict future fracture.