Aubrey Blumsohn

Response of Biochemical Markers of Bone Turnover to Hormone Replacement Therapy: Impact of Biological Variability

Biochemical markers of bone turnover may be useful to monitor patients taking hormone replacement therapy (HRT). The aim of this study was to assess the utility of markers in monitoring HRT by comparing the response of a large panel of markers to HRT with their within subject variability. We measured the response of markers to transdermal estradiol in 11 postmenopausal women over 24 weeks. We measured the within subject variability of markers in 11 untreated healthy postmenopausal women over the same period. The mean decrease in markers of bone formation after 24 weeks treatment ranged from 19% for procollagen type I C‐terminal propeptide (PICP) to 40% for procollagen type I N‐terminal propeptide (PINP). The mean decrease in markers of bone resorption ranged from 10% for tartrate‐resistant acid phosphatase (TRAP) to 67% for C‐terminal cross‐linked telopeptide. The least significant change (LSC at p < 0.05), calculated from the within subject variability in the untreated group, was used to define response. LSC for osteocalcin was 21%, bone alkaline phosphatase 28%, PICP 24%, PINP 21%, type I collagen telopeptide 28%, TRAP 17%, urinary calcium 90%, hydroxyproline 75%, total deoxypyridinoline 47%, free pyridinoline 36%, free deoxypyridinoline 26%, N‐terminal cross‐linked telopeptide 70%, and C‐terminal cross‐linked telopeptide 132%. The greatest number of responders after 24 weeks of treatment were found using PINP and osteocalcin (9 each), and free deoxypyridinoline (8 each) and total deoxypyridinoline (7 each). Lumbar spine bone mineral density defined four patients as responders. The ability to detect a response differs between markers and is not dependent on the magnitude of response to therapy.

Effect of feeding on bone turnover markers and its impact on biological variability of measurements

Bone turnover markers are subject to day-to-day and within-day variability, which may influence clinical interpretation. We examined the effect of fasting vs. feeding on the concentration and between-day variability of several markers. Twenty healthy premenopausal women were studied on 10 consecutive weekdays. Subjects were studied either in the fasting (no breakfast) or fed (breakfast at 08:00 h) state on alternate days, and were randomized to begin either fasting or fed. Two hour urine collections were obtained each day between 08:00 h and 10:00 h, and blood samples were collected daily at 09:00 h. The N-telopeptide cross-link of type I collagen in urine (uNTX) and serum (sNTX), the C-telopeptide in urine (uCTX) and serum (sbetaCTX), and immunoreactive free deoxypyridinoline (uifDPD) in urine were measured as resorption markers. Procollagen type I N-terminal propeptide (PINP), osteocalcin (OC), and bone alkaline phosphatase (bone ALP) were measured as formation markers. All bone formation and resorption markers were significantly lower in the fed state with the exception of bone ALP. The magnitude of the decrease ranged from 3.8 +/- 0.9% for PINP (p < 0.0001) to 17.8 +/- 2.6% (p < 0.0001) for sbetaCTX. Measurement variability was partitioned into analytical variability based on replicate assays (CV(a)) and within-subject variability (CV(i)). The CV(i) was greater (p < 0.05) for some markers in the fasting state (uifDPD, uNTX, and sNTX) but greater in the fed state for other markers (OC and sbetaCTX). In conclusion, the clinical impact of feeding vs. fasting is small with the exception of sbetaCTX; however, in clinical practice, collection of samples in the fasting state may be necessary to minimize the unpredictable effects of feeding. The mechanism of the acute effect of feeding on bone turnover remains uncertain.

Biochemical markers of bone turnover in girls during puberty

OBJECTIVES Bone turnover and the rate of bone growth increase dramatically during puberty. A number of new assays for the estimation of bone resorption and formation rates have been developed over recent years, and puberty acts as a convenient model for evaluation of these measurements. The aim of this study was to explore the interrelationships between pubertal development, biochemical markers of bone turnover, Insulin‐like growth factor I and oestradiol in healthy pubertal girls.

A Longitudinal Study of Bone Gain in Pubertal Girls: Anthropometric and Biochemical Correlates

The aim of this longitudinal study was to investigate the factors associated with bone mineral acquisition in pubertal girls. Subjects were 37 healthy, Caucasian girls aged 12.1 years (SD 0.3). Measurements were made at 6‐month intervals over a period of 18 months and included total body bone mineral content (TBBMC), total body bone mineral density (TBBMD), lean mass, and fat mass by dual‐energy X‐ray absorptiometry, anthropometry, lifestyle factors, four biochemical markers of bone turnover, hormonal status, and fractional calcium absorption. In multiple regression analysis, correlates of relative gain in TBBMC were gain in lean mass (p < 0.001) and estradiol (p = 0.008). For TBBMD, correlates were gain in lean (p < 0.001) and fat mass (p = 0.003), estradiol (p < 0.001), dietary energy intake (p = 0.003), and parathyroid hormone (p = 0.023). Statural growth and gain in bone mass were unrelated; both height velocity and bone turnover peaked ∼20 months prior to menarche, whereas gain in bone mass peaked at menarche. Bone turnover markers correlated with height velocity (0.40 < r < 0.62), but not with bone gain. Estradiol was independently and negatively associated with all markers of bone turnover (−0.67 < r < −0.80). We conclude that estradiol is an important determinant of bone mineral gain in pubertal girls and is probably responsible for the reduction in bone turnover in late puberty; lean mass was the body composition parameter most closely associated with bone gain; height gain and bone gain are dissociated during the period of rapid growth at puberty; and bone turnover markers are modestly related to height gain, but are not predictive of bone gain.

The effect of dietary sodium on calcium metabolism in premenopausal and postmenopausal women

Objective: To investigate the effects of high and low sodium diets on urinary calcium, bone turnover and calcium absorption in pre and postmenopausal women. Design: Experimental, prospective and longitudinal study. Setting: Samples were taken at the hospital and the diets were followed at home. Subjects: Volunteers were recruited from the hospital and were either hospital staff or post-graduate students. No volunteers failed to complete the study but one was omitted from analysis due to lack of compliance. Interventions: Eleven healthy premenopausal women aged 22–47 y and 11 healthy postmenopausal women ages 45–70 y followed a high (300 mmol/d) and a low (50 mmol/d) sodium diet for one week each. On the 7th day of each diet, blood and urine samples were taken. Results: On the high sodium diet 24 h urinary sodium and calcium values relative to creatinine were significantly higher for all subjects (P<0.05). Postmenopausal women on the high sodium diet had biochemical evidence of increased bone resorption in relation to the low sodium diet. However in premenopausal women there was no such change. Calcium absorption did not change significantly in either group. Conclusions: It appears that postmenopausal, but not premenopausal, women respond to a high sodium diet by an increase in bone resorption which may lead to reduced bone density. Sponsorship: Arthritis and Rheumatism Council Project Grant R44.

Bone mineral density and bone turnover in spinal osteoarthrosis.

OBJECTIVES--To determine whether there was a generalised increase in bone mineral density (BMD) in spinal osteoarthrosis (OA), and to determine the mechanism of this possible protection against osteoporosis as assessed by biochemical markers of bone turnover. METHODS--We studied 375 women (ages 50 to 85) from a population based group. Spinal OA was defined from radiographs as the presence of degenerative changes affecting intervertebral or facet joints. BMD of the lumbar spine (LS), femoral neck (FN) and total body (TB) was measured by dual energy x ray absorptiometry (Lunar DPX). Bone turnover rates were estimated from measurement of biochemical markers of bone formation and resorption (urine deoxypyridinoline (Dpyr) and serum bone specific alkaline phosphatase (BAP)). RESULTS--BMD at each site was greater in the women with spinal OA (mean increase in LS-BMD 7.9%, 95% confidence interval (CI) 1.0 to 15.1; TB-BMD 8.4%, 95% CI 1.9 to 9.7; FN-BMD 6.4%, 95% CI 0.3 to 12.6). Twenty four hour urinary excretion of Dpyr, corrected for TB bone mineral content, and serum BAP were 19% lower in the women with spinal OA (95% CI for Dpyr 4.3 to 31.9%; for BAP 6.3 to 32.0%). CONCLUSIONS--Spinal OA is associated with a generalised increase in BMD and a decreased rate of bone turnover. This suggests that the protective effect of spinal OA against osteoporosis may be mediated by decreased bone turnover.

Absence of marked seasonal change in bone turnover: a longitudinal and multicenter cross-sectional study.

The effect of season on bone turnover is controversial. No information is available on seasonality of new serum markers of bone resorption. In this study, we have been unable to confirm findings of a marked wintertime increase in bone formation and resorption within the general population. Seasonality was assessed by cosinor analysis.

Risk Factors for Vertebral and Nonvertebral Fracture Over 10 Years: A Population‐Based Study in Women

Risk factors may vary for different types of fracture, in particular for vertebral fractures. We followed 367 women >50 yr of age from a population‐based cohort for up to 10 yr. Factors that predicted vertebral rather than nonvertebral fractures related to physical weakness, poor health, and weight loss. Similar factors were also associated with greater bone loss at the hip.

Serum Retinoids and β-Carotene as Predictors of Hip and Other Fractures in Elderly Women†

There is debate about the possible deleterious effect of excessive vitamin A exposure on fracture risk. In this nested case control study in older women (312 cases and 934 controls), serum retinol, retinyl palmitate, and β‐carotene were not associated with fracture risk, and there was no evidence of excess risk with multivitamin or cod liver oil supplementation.

Prediction of bone loss in postmenopausal women

Identification of women at greatest risk of future osteoporotic fracture could allow targeting of preventative therapy. The risk of spine, hip and vertebral fractures is related to bone mineral density [I], and bone density at the time of the menopause and the rate of bone loss thereafter are likely to be major predictors of future fracture. The potential to identify those women likely to lose bone most rapidly has developed dramatically over recent years as a result of improved biochemical and densitometric methods. There is some evidence that biochemical measurements can predict the rate of bone loss soon after the menopause [2,3]. Combinations of serum total alkaline phosphatase, urinary calcium, urinary hydroxyproline and serum osteocalcin, with an estimate of body fat content can predict about 60% of the variability in measured fractional bone loss in the ‘proximal distal’ forearm in early postmenopausal women. The potential usefulness of collagen derived biochemical markers of bone turnover remain to be established. In particular, the use of urinary pyridinium crosslinks as a specific and quantitative measure of bone resorption has aroused much interest [4]. The paper by Mole et al., in this issue of the Journal highlights the possible role of urinary oestrogens and pyridinium crosslinks in the prediction of bone loss from the distal forearm. They demonstrate that a combination of urinary pyridinoline, urinary oestradiol glucuronide and body mass index could explain up to 58% of the variation in bone loss in the forearm. Despite these encouraging developments, there is as yet no convincing evidence that the use of these measurements would provide a significant benefit in the context of a screening programme. The rate of bone loss at any particular skeletal site in the early postmenopausal period is of no importance per se. Biochemical measurements must predict long-term rates of bone loss, and risk of vertebral and femoral neck fractures decades after the menopause if their use to select women for preventative therapy can be justified. Several important questions remain to be answered. Perhaps the first question that should be asked is whether the pattern of postmenopausal bone loss