Risedronate in adults with osteogenesis imperfecta type I: increased bone mineral density and decreased bone turnover, but high fracture rate persists.

UNLABELLED: Bisphosphonates can increase bone mineral density (BMD) in children with osteogenesis imperfecta (OI). In this study of adults with OI type I, risedronate increased BMD at lumbar spine (but not total hip) and decreased bone turnover. However, the fracture rate in these patients remained high. INTRODUCTION: Intravenous bisphosphonates given to children with OI can increase BMD and reduce fracture incidence. Oral and/or intravenous bisphosphonates may have similar effects in adults with OI. We completed an observational study of the effect of risedronate in adults with OI type I. METHODS: Thirty-two adults (mean age, 39 years) with OI type I were treated with risedronate (total dose, 35 mg weekly) for 24 months. Primary outcome measures were BMD changes at lumbar spine (LS) and total hip (TH). Secondary outcome measures were fracture incidence, bone pain, and change in bone turnover markers (serum procollagen type I aminopropeptide (P1NP) and bone ALP). A meta-analysis of published studies of oral bisphosphonates in adults and children with OI was performed. RESULTS: Twenty-seven participants (ten males and seventeen females) completed the study. BMD increased at LS by 3.9% (0.815 vs. 0.846 g/cm(2), p = 0.007; mean Z-score, -1.93 vs. -1.58, p = 0.002), with no significant change at TH. P1NP fell by 37% (p = 0.00041), with no significant change in bone ALP (p = 0.15). Bone pain did not change significantly (p = 0.6). Fracture incidence remained high, with 25 clinical fractures and 10 major fractures in fourteen participants (0.18 major fractures per person per year), with historical data of 0.12 fractures per person per year. The meta-analysis did not demonstrate a significant difference in fracture incidence in patients with OI treated with oral bisphosphonates. CONCLUSIONS: Risedronate in adults with OI type I results in modest but significant increases in BMD at LS, and decreased bone turnover. However, this may be insufficient to make a clinically significant difference to fracture incidence.

Bone turnover markers in postmenopausal breast cancer treated with fulvestrant--a pilot study.

BACKGROUND: Tamoxifen has a protective effect on bone metabolism in breast cancer; aromatase inhibitors deleterious and that of fulvestrant is unknown. METHODS: Fourteen locally advanced breast cancers with clinical benefit on fulvestrant (250 mg/month) as first-line primary endocrine therapy had sequential serum bone-specific alkaline phosphatase (BAP), N-terminal propeptide of procollagen type 1 (PINP) and C-terminal telopeptide (CTX) at 0, 1, 6, 12, and 18 months. Mean percentage changes (95% CI) were calculated. RESULTS: Changes from baseline at 1, 6, 12, and 18 months with BAP (3.9-46.8 ng/ml) were +1.5 (-9.8 to +12.9), +2.2 (-22.1 to +26.6), +17.6 (-12.4 to +47.6), +10.8 (-29.9 to +51.7); with PINP (20.6-82.1 ng/ml) were +3.4 (-12.0 to 19.0), +18.8 (-36.7 to +74.2), +47.5 (-21.4 to 116.3), +33.3 (-49.5 to +116.1) and with CTX (0.14-1.35 ng/ml) were +30.8 (0.1 to +61.6), +13.9 (-22.3 to +50.2), +42.9 (-12.7 to +98.5), +45.2 (-28.3 to +118.8). CONCLUSIONS: Long-term (18 months) stability of bone markers may be exploited by using fulvestrant earlier in sequence of endocrine therapies particularly in adjuvant setting in those with pre-existing decreased bone mass.

Changes in bone mineral density, body composition and biochemical markers of bone turnover during weight gain in adolescents with severe anorexia nervosa: a 1-year prospective study.

Osteoporosis is a serious complication of anorexia nervosa and in affected adolescents may result in a permanent deficit in bone mass. The pathophysiology of this bone disease has not been clearly defined. In this prospective study of 26 young women with anorexia nervosa aged 13-20 years (mean 16.5) we have measured changes in bone mineral density, total body composition and biochemical indices of bone turnover over 1 year. Over this period there was a mean weight gain of 10 kg and significant height gain with baseline and final values for body mass index of 14.2+/-1.7 and 17.6+/-2.3 kg/m2 (P<0.001). However, no significant changes were seen in bone mineral density in the spine or proximal femur during the study; total body bone mineral content was significantly higher than baseline at 3 months and 12 months (P=0.001 and P<0.0001), but total body bone mineral density at 3 months was significantly lower than baseline (P=0.003). Serum osteocalcin and bone-specific alkaline phosphatase values increased significantly and remained higher than baseline at all time points whereas urinary NTX/creatinine excretion showed a non-significant increase over the first 6 months of the study, but at 12 months, the mean value was significantly lower than baseline. Mean serum 25-hydroxyvitamin D levels showed a significant decrease at 6 months (P<0.05), but returned towards baseline thereafter. There was a significant increase in serum parathyroid hormone levels at all time points compared to baseline, these occurring within the normal range. These results indicate that although weight gain in young anorexics is associated with linear growth, bone mineral density does not increase. Whether this deficit can be corrected subsequently requires longer-term prospective studies.

Relationship of early changes in bone resorption to the reduction in fracture risk with risedronate.

Changes in the level of biochemical markers of bone resorption with risedronate treatment for osteoporosis were examined as a surrogate for the decrease in fracture risk. Greater decreases in bone resorption markers were associated with greater decreases in vertebral (and nonvertebral) fractures. Antifracture efficacy of antiresorptive therapies is only partially explained by increases in bone mineral density. Early decreases in bone resorption may also play a role. We tested this hypothesis by measuring two bone resorption markers, the C-telopeptide of type I collagen (CTX) and the N-telopeptide of type I collagen (NTX), in osteoporotic patients in risedronate vertebral fracture trials. We studied 693 women with at least one vertebral deformity (mean age, 69 +/- 7 years) who received calcium (and vitamin D if required) and placebo or risedronate 5 mg daily for 3 years. The reductions in urinary CTX (median, 60%) and NTX (51%) at 3-6 months with risedronate therapy were significantly associated (p < 0.05) with the reduction in vertebral fracture risk (75% over 1 year and 50% over 3 years). The changes in both CTX and NTX accounted for approximately one-half (CTX, 55%; NTX, 49%) of risedronate's effect in reducing the risk of vertebral fractures in the first year and approximately two-thirds (CTX, 67%; NTX, 66%) over 3 years compared with placebo. The changes in CTX and NTX accounted for 77% and 54%, respectively, of risedronate's effect in reducing the risk of nonvertebral fractures over 3 years compared with placebo. The relationships between vertebral fracture risk and changes from baseline in CTX and NTX were not linear (p < 0.05). There was little further improvement in fracture benefit below a decrease of 55-60% for CTX and 35-40% for NTX. The decrease in bone resorption in patients taking risedronate accounts for a large proportion of the reduction in fracture risk. There may be a level of bone resorption reduction below which there is no further fracture benefit.

Circulating estradiol and osteoprotegerin as determinants of bone turnover and bone density in postmenopausal women.

Osteoprotegerin (OPG) is a recently identified cytokine that acts as a decoy receptor for the receptor activator of NF kappa B ligand. OPG has been shown to be an important inhibitor of osteoclast differentiation and activation in rodent models. Estrogen is known to suppress bone resorption, and the action of estrogen on bone may be mediated by OPG. The relationship between endogenous estrogen and circulating OPG levels and bone status in human populations is unclear. Thus, the aim of this study was to investigate the relationship between biochemical markers of bone turnover and bone density and circulating OPG and endogenous estradiol levels in a population-based cohort of postmenopausal women. Subjects were 180 women ages 55-91 yr (mean age, 67 yr). Serum estradiol was measured using an auto-analyzer. Serum concentrations of OPG were determined by ELISA. Markers of bone formation and resorption were measured by standard methods. Bone mineral density at total body, total hip, femoral neck, and lumbar spine was measured by dual energy x-ray absorptiometry. There was a significant inverse relationship between estradiol and all bone turnover markers (r-values from -0.46 to -0.23; P < 0.05). Serum estradiol was positively related to absolute bone density at all sites and to change in bone density at the hip and femoral neck by univariate analysis (r-values from 0.15-0.29; P < 0.05). We observed a weak inverse association between OPG and serum-based bone turnover markers (r-values -0.18 and -0.16; P < 0.05). There was a significant positive relationship between OPG and bone mineral density at total body, total hip, and femoral neck (r-values from 0.17-0.2; P < 0.05) by univariate analysis, which was lost after adjustment for age and body mass index. There was a significant weak positive relationship between circulating OPG and serum estradiol (r = 0.18; P < 0.02). We observed no significant relationships between OPG and bone turnover markers measured in urine. We conclude that the variation in circulating endogenous estradiol levels is an important factor contributing to levels of bone turnover and bone density at the menopause. Our observations also suggest that circulating levels of OPG may reflect OPG activity in bone and are related to circulating endogenous levels of estradiol. We have previously reported high levels of variability in urine markers of bone resorption, and we suggest that this could account for the absence of a significant association between these markers and circulating OPG.

The impact of subcutaneous oestradiol implants on biochemical markers of bone turnover and bone mineral density in postmenopausal women.

OBJECTIVE: To evaluate the anabolic effect of oestrogen on bone by comparing the response of markers of bone formation (and resorption) and bone mineral density (BMD) to subcutaneous oestradiol implants. DESIGN: One year double-blind placebo controlled randomised study. SETTING: Clinical research unit within a teaching hospital. POPULATION: Twenty-one hysterectomised postmenopausal women were randomised to 25 mg oestradiol implants at baseline and at six months or to have a sham procedure at baseline and six months. METHODS: BMD and quantitative ultrasound (QUS) were assessed at baseline and one year. Bone alkaline phosphatase (bone ALP), procollagen type I N-terminal propeptide (PINP), osteocalcin (OC), free deoxypyridinoline (iFDPD), N-telopeptide of type I collagen (NTX), serum oestradiol and intact parathyroid hormone (PTH) were measured at baseline, 4, 8, 12 and 24 weeks. MAIN OUTCOME MEASURES: Percentage change markers of bone turnover and PTH and change in oestradiol levels over first six months and percentage of changes in DXA and QUS over one year. RESULTS: PINP, bone ALP and OC increased by 28%, 7% and 9%, respectively (P < 0.01) during the first four weeks of treatment and then decreased significantly. Lumbar spine (LS) and total hip (TH) BMD increased by 5.4% and 6.0% (P < 0.001), respectively, and femoral neck (FN) BMD by 3.7% (P < 0.05) during the first year of treatment compared with control subjects. The peak serum oestradiol level was achieved four weeks after implant insertion. Mean PTH levels increased significantly in subjects receiving subcutaneous oestradiol. CONCLUSION: Subcutaneous oestrogen exerted an apparent anabolic effect on bone, which was initially reflected by an increase in bone formation markers and later by a large increase in BMD.

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 as predictors of rates of bone loss after menopause.

Biochemical markers of bone turnover may correlate with rates of bone loss in a group of postmenopausal women, but it is uncertain how useful they are in predicting rates of bone loss in the individual. The aim of this study was to determine the value of measurements of biochemical markers for the prediction of rates of bone loss in the individual. We studied 60 postmenopausal women (ages, 49-62 years), 43 of whom had gone through a natural menopause 1-20 years previously and 17 of whom had undergone hysterectomy 3-22 years ago. Lumbar spine bone mineral density (BMD) was measured using dual-energy X-ray absorptiometry (DXA) over 2-4 years. Bone formation markers (bone-specific alkaline phosphatase [ibAP] and amino terminal of type I collagen [PINP] and osteocalcin [OC]) were measured in serum. Bone resorption markers (N-telopeptide of type 1 collagen [NTx] and immunoreactive free deoxypyridinoline [iFDpd]) were measured in urine and corrected for creatinine (Cr). Rates of bone loss were calculated as percent change per year. We found significant negative correlations (Spearman rank) between all measured biochemical markers and rate of change in bone density with r values ranging from -0.35 to -0.52. When markers and rates of bone loss were divided into tertiles, prediction of bone loss in an individual was poor (kappa < 0.2). There was an exponential relationship between rate of bone loss and years since menopause (YSM) in the 43 women having a natural menopause (r2 = 0.44; p = 0.008) indicating higher rates of loss in the early postmenopausal period. Levels of NTx, iFDpd, and PINP also showed a significant negative correlation with YSM. We conclude that there is a strong relationship between rates of spinal bone loss and levels of bone turnover markers. Although this is a small study, the results also suggest that using DXA measurements of the lumbar spine as the "gold standard," it is not possible to use biochemical markers to predict rate of bone loss in the individual.

Immediate changes in biochemical markers of bone turnover and circulating interleukin-6 after parathyroidectomy for primary hyperparathyroidism.

OBJECTIVE: The time course of the immediate change in bone turnover after parathyroidectomy (PTX) for primary hyperparathyroidism (PHPT) is not clear. It is uncertain whether circulating interleukin-6 (IL-6) plays a role in mediating the acute withdrawal of the effects of parathyroid hormone (PTH) on bone turnover after PTX. The aims of this study were to determine the time course of immediate changes in biochemical markers of bone turnover after PTX and whether circulating IL-6 is involved in the immediate changes of bone turnover after PTX. DESIGN AND METHODS: IL-6 and bone turnover markers were measured in eight women (aged 55+/-11 years, mean+/-s.d. ) with PHTP at baseline and at 1-2h, and 1, 2, 5, 7 and 12 days after PTX. We compared the results with those from eight individually matched women (healthy controls) and five subjects undergoing major surgery (surgical controls). RESULTS: At baseline, serum levels of IL-6 and bone turnover markers were higher in PHPT than those in healthy controls (P<0.05). Serum levels of procollagen propeptides increased by 22 and 27% at days 2 and 5, respectively, compared with baseline (P<0.05). Serum tartrate-resistant acid phosphatase decreased by 2 days after PTX, and urinary collagen crosslinks decreased significantly by 21-41% within 24h (P<0.05). Serum IL-6 levels increased immediately in both PHPT and surgical controls at postoperative follow-up (repeated measures ANOVA). CONCLUSIONS: (1) PTX decreases bone resorption immediately and (2) circulating IL-6 is not involved in the changes in bone turnover immediately after PTX.

The effect of calcium supplementation on the circadian rhythm of bone resorption.

Bone resorption shows a circadian rhythm in human subjects, but the physiological mechanisms underlying this rhythm are unknown. We compared the circadian rhythm of bone collagen degradation in 18 premenopausal women before and after oral calcium supplementation (1000 mg calcium for 14 days). Subjects were randomized to receive calcium at either 0800 h or 2300 h. Continuous 48-h urine collections and 1 day of 4-h urine collections were obtained before and after the 14-day supplementation period. We measured urinary deoxypyridinoline (Dpd) and the cross-linked N-telopeptide of type I collagen (NTx) as biochemical markers of bone resorption. There was a significant effect of time of day on excretion of Dpd and NTx (analysis of variance, P < 0.001) with peak excretion between 0300-0700 h and a nadir between 1500-1900 h. The mean amplitude (peak to trough) was similar for Dpd and NTx (70.3% and 63.3%, respectively). Evening calcium supplementation resulted in marked suppression of the nocturnal increase in Dpd and NTx and reversed the usual nocturnal increase in the level of parathyroid hormone. In contrast, morning calcium supplementation had no significant effect on the circadian rhythm of Dpd or NTx. Evening calcium supplementation suppressed overall daily excretion of Dpd by 20.1% (P = 0.03) and NTx by 18.1% (P = 0.03). Morning calcium supplementation had no significant effect on overall daily excretion of either Dpd or NTx. We conclude that evening calcium supplementation suppresses the circadian rhythm of bone resorption. The daily rhythm of PTH secretion or calcium intake is likely to be an important determinant of this rhythm. Experimental protocols designed to investigate the effect of calcium supplementation on bone mineral density should take the timing of supplementation into account.

Biochemical markers of bone turnover in girls during puberty.

OBJECTIVE: 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. SUBJECTS: Ninety-one healthy girls (ages 11.6-15.5 years) were studied. All subjects were apparently healthy, and were not taking medications known to influence calcium homeostasis. Breast examination was performed to assess pubertal stage according to Tanner. The adult reference range for biochemical markers of bone turnover was obtained from concurrent studies on 42 healthy premenopausal women ranging in age between 20 and 45 years. DESIGN AND MEASUREMENTS: Blood samples were obtained from subjects between 0800 and 1000 h. Urine samples were collected between 1330 and 1600 h. We measured total and bone specific alkaline phosphatase, osteocalcin, and type I procollagen carboxyterminal propeptide as markers of bone formation. Tartrate resistant acid phosphatase, carboxyterminal pyridinoline cross-linked telopeptide, creatinine corrected urinary deoxypyridinoline, immunoreactive urinary pyridinolines, and urinary galactosyl hydroxylysine were measured as markers of bone resorption. RESULTS: Bone turnover as reflected by each of the markers was maximal in mid puberty (breast Tanner stages II and III) and decreased towards adult levels in late puberty (P < 0.001). However, the magnitude of the mid-pubertal increase differed between markers. In particular, the pubertal increase in levels of bone specific alkaline phosphatase, osteocalcin and urinary deoxypyridinoline were higher than the increase shown by the other markers. All markers were significantly lower after the menarche. Circulating insulin-like growth factor I and insulin like growth factor binding protein-3 were not important determinants of pubertal changes in bone turnover. In contrast, there was a significant negative correlation between oestradiol and all markers of bone formation and resorption during puberty. CONCLUSIONS: The greater pubertal increase in levels of bone specific alkaline phosphatase, osteocalcin and urinary deoxypyridinoline suggests that these markers may be relatively more sensitive as indicators of skeletal health during puberty. The differences between markers may reflect differences in the bone specificity of the analytes, or differing mechanisms of production and clearance. The negative correlation between oestradiol and markers of bone resorption and formation suggests that this hormone may be responsible for the reduction in bone turnover in late puberty.