Serum C-telopeptide Of Type Research Articles

Effects of Odanacatib on BMD and Safety in the Treatment of Osteoporosis in Postmenopausal Women Previously Treated With Alendronate: A Randomized Placebo-Controlled Trial

Odanacatib (ODN) is a selective cathepsin K inhibitor being developed to treat osteoporosis. The effects of ODN were evaluated on bone mineral density (BMD), biochemical markers of bone turnover, and safety in patients previously treated with alendronate. This was a randomized, double-blind, placebo-controlled, 24-month study. The study was conducted at private or institutional practices. Postmenopausal women (n = 243) ≥ 60 years of age with low BMD at the total hip, femoral neck, or trochanter (T-score ≤-2.5 but >-3.5 without prior fracture or ≤-1.5 but >-3.5 with prior fracture) on alendronate for ≥ 3 years. The intervention included ODN 50 mg or placebo weekly. The primary end point was percentage change from baseline of femoral neck BMD at month 24. BMD was assessed by dual-energy x-ray absorptiometry at baseline and 6, 12, and 24 months. Biochemical markers of bone turnover (serum C-telopeptides of type 1 collagen, urinary N-telopeptides of type 1 collagen, serum bone specific alkaline phosphatase, and serum N-terminal propeptide of type 1 collagen) were measured at baseline and 3, 6, 12, 18, and 24 months. In the ODN group, BMD changes from baseline at the femoral neck, trochanter, total hip, and lumbar spine at 24 months (1.7%, 1.8%, 0.8%, and 2.3%, respectively) were significantly different from the placebo group. ODN significantly decreased urinary N-telopeptides of type 1 collagen to creatinine ratio and significantly increased serum N-terminal propeptide of type 1 collagen compared with placebo. Serum C-telopeptides of type 1 collagen was unexpectedly increased with ODN treatment. The safety profile appeared similar between groups. ODN provided incremental BMD gains in osteoporotic women after alendronate treatment.

Effects of PTH (1–84) on bone quality in a validated model of osteoporosis due to androgenic deprivation

Aim: The purpose of this study was to evaluate the effect of parathyroid hormone (PTH) (1–84) in a model of male osteoporosis induced by orchidectomy in rats.Methods: Six-month-old Wistar rats were used as follows: SHAM (simulated orchidectomy), orchidectomized (ORX), ORX + PTH1 (ORX and treated with 10 µg/Kg/d of PTH 1–84) and ORX + PTH2 (ORX and treated with 50 µg/Kg/d of PTH 1–84) over 3 months, with treatment beginning three months after orchidectomy.Results: Orchidectomy resulted in a decreased of femoral and lumbar bone mineral density (BMD), a worsening of trabecular and cortical microarchitecture and a decrease in biomechanical properties. Both doses of PTH (1–84) partially (low dose) or totally (high dose) restored the ORX-induced changes. Serum C-telopeptide of type I collagen/5b isoenzyme of tartrate-resistant acid phosphatase (CTX/TRAP) resorption index increased after orchidectomy. Osteocalcin (bone Gla protein; BGP) levels were not affected by orchidectomy. PTH (1–84) treatment did not produce any changes in the levels of CTX/TRAP with respect to the ORX group. BGP levels increased with PTH treatment.Conclusion: PTH (1–84) is able to restore the adverse effects of orchidectomy on bone as measured by BMD, microstructural and biomechanical properties and bone remodeling markers.

Effects of odanacatib on BMD and safety in the treatment of osteoporosis in postmenopausal women previously treated with alendronate- a randomized placebo-controlled trial

Results: In the ODN group, BMD changes from baseline at the femoral neck, trochanter, total hip, and lumbar spine at 24 months (1.7%, 1.8%, 0.8%, and 2.3%, respectively) were significantly different from the placebo group. ODN significantly decreased urinary N-telopeptides of type 1 collagen to creatinine ratio and significantly increased serum N-terminal propeptide of type 1 collagen compared with placebo. Serum C-telopeptides of type 1 collagen was unexpectedly increased with ODN treatment. The safety profile appeared similar between groups. Conclusions: ODN provided incremental BMD gains in osteoporotic women after alendronate treatment. (J Clin Endocrinol Metab 98: 4727–4735, 2013)

Genetic predictors of skeletal outcomes in healthy fertile women: The Bonturno Study

Skeletal traits as height (Ht) or bone mineral density (BMD) are strongly inherited. Low-density lipoprotein receptor-related protein 5 (LRP5) and farnesyl diphosphonate synthase (FDPS) are candidate genes for bone phenotypes. From Bonturno study, we genotyped 570 healthy Caucasian women aged 20 to 50 years (yrs) for LRP5 rs4988321 (A/G) and rs3736228 (C/T) and FDPS rs2297480 (A/C) single nucleotide polymorphisms. Serum C-telopeptide of type I collagen (CTX), osteocalcin (OC), and N-terminal propeptide of type I procollagen (P1NP) were measured in BMD-evaluated subjects at lumbar spine (LS), total hip (TH) and femoral neck (FN) sites. LRP5 rs4988321 locus correlated with FN-BMD (P=0.0230), while LRP5 rs3736228 genotypes differed in LS-BMD (P=0.0428). When clustered by age, lower FN-BMD was detected in LRP5 GG (P=0.030) subjects of 41 to 50 years but not in younger. Both LRP5 GG and CC genotypes showed higher age-adjusted values of OC, CTX and P1NP. Increased CTX values were in LRP5 GGCC subjects than in those having at least one LRP5 A plus T alleles (P=0.0190). LRP5 CC, GG or GGCC subjects with at least one FDPS C allele showed higher levels of CTX and OC in 31 to 40 yrs or older subjects. In conclusion, LRP5 and FDPS loci age-specifically affect skeletal traits in healthy fertile women.

The rhPTH (1–34), But not Elcatonin, Increases Bone Anabolic Efficacy in Postmenopausal Women with Osteoporosis

Intermittent administration of recombinant human PTH [rhPTH (1-34)] exerts an osteoanabolic effect characterized by direct effects on bone formation, increases bone density, and reduces fracture risk. This study was to investigate the anabolic effects of rhPTH(1-34) on postmenopausal osteoporosis in an Asian population and compare the time course and alteration in bone turnover marker (BTM) during rhPTH(1-34) and elcatonin treatment. 124 women with postmenopausal osteoporosis were enrolled in this prospective, open-label, active-controlled trial. The patients randomized to subcutaneous rhPTH(1-34) (20 ug, once daily) or elcatonin (200U, once week) injections for 12 months. Biochemical markers of bone formation (bone specific alkaline phosphatase [BSAP]), and bone resorption maker (serum C-telopeptide of type I collagen [CTX-I] were measured at baseline and at 0, 6, and 12 months. At 12 months, rhPTH (1-34) significantly increased lumbar spine BMD significantly compared with baseline, whereas elcatonin was ineffective. BSAP levels were gradually increased in almost all rhPTH(1-34)-treated subjects and at the end of the study, the percentage of subjects with BSAP above the postmenopausal reference interval was gradually increased as high as 91.5% at month 12. Opposite trends in percentages for CTX-I was observed in rhPTH(1-34). With rhPTH(1-34), but not elcatonin, there were significant positive correlations between ratio of BSAP and CTX-I and bone mineral density (BMD) (r=0.318) at the end of month 12. Both treatments were well tolerated and there were no significant differences detected between the 2 groups in the proportion of any adverse events and any serious adverse events. rhPTH (1-34) has more positive effects on bone formation than elcatonin for postmenopausal women with osteoporosis and was proved to be safe and well tolerated. The ratio of BSAP and CTX-I may be a useful indicator for positive bone formation.

Low fatness, reduced fat intake and adequate plasmatic concentrations of LDL-cholesterol are associated with high bone mineral density in women: a cross-sectional study with control group.

BackgroundSeveral parameters are associated with high bone mineral density (BMD), such as overweight, black background, intense physical activity (PA), greater calcium intake and some medications. The objectives are to evaluate the prevalence and the main aspects associated with high BMD in healthy women.MethodsAfter reviewing the database of approximately 21,500 BMD scans performed in the metropolitan area of São Paulo, Brazil, from June 2005 to October 2010, high BMD (over 1400 g/cm2 at lumbar spine and/or above 1200 g/cm2 at femoral neck) was found in 421 exams. Exclusion criteria were age below 30 or above 60 years, black ethnicity, pregnant or obese women, disease and/or medications known to interfere with bone metabolism. A total of 40 women with high BMD were included and matched with 40 healthy women with normal BMD, paired to weight, age, skin color and menopausal status. Medical history, food intake and PA were assessed through validated questionnaires. Body composition was evaluated through a GE-Lunar DPX MD + bone densitometer. Radiography of the thoracic and lumbar spine was carried out to exclude degenerative alterations or fractures. Biochemical parameters included both lipid and hormonal profiles, along with mineral and bone metabolism. Statistical analysis included parametric and nonparametric tests and linear regression models. P < 0.05 was considered significant.ResultsThe mean age was 50.9 (8.3) years. There was no significant difference between groups in relation to PA, smoking, intake of calcium and vitamin D, as well as laboratory tests, except serum C-telopeptide of type I collagen (s-CTX), which was lower in the high BMD group (p = 0.04). In the final model of multivariate regression, a lower fat intake and body fatness as well a better profile of LDL-cholesterol predicted almost 35% of high BMD in women. (adjusted R2 = 0.347; p < 0.001). In addition, greater amounts of lean mass and higher IGF-1 serum concentrations played a protective role, regardless age and weight.ConclusionOur results demonstrate the potential deleterious effect of lipid metabolism-related components, including fat intake and body fatness and worse lipid profile, on bone mass and metabolism in healthy women.

Dual‐energy X‐ray absorptiometry and biochemical markers of bone turnover after autologous stem cell transplantation in myeloma

To evaluate the effect of high-dose chemotherapy (HDT) followed by autologous stem cell transplantation (ASCT) on bone turnover and bone mineral density in a cohort of 39 consecutive patients with multiple myeloma (MM). Phosphorus and calcium parameters, bone turnover markers, and bone mineral density were studied. Timepoints were diagnosis (T1), just before ASCT (T2), 6 months (T3) after ASCT, and 1 yr (T4) after ASCT. No bone mineral loss was shown on dual-energy X-ray absorptiometry (DXA) at T1 (lumbar Z-score -0.02, femoral neck Z-score 0.77) or during follow-up. Chronic vitamin D deficiency (25OHD3 11.7 ± 7.7 ng/mL at T1) and relative hyperparathyroidism from T2 to T4 were observed. In spite of this moderate hyperparathyroidism, serum C-telopeptide of type I collagen (CTX) decreased significantly between T1 and T4. Bone alkaline phosphatase levels were low at diagnosis and showed no significant change after ASCT, unlike DKK1 levels that were high at diagnosis and decreased 6 months after ASCT in patients not previously treated with bisphosphonates. Bone demineralization is moderate in multiple myeloma. ASCT induces a decrease in bone resorption but no changes in bone formation, remaining low despite the decrease in DKK1. Bone mineral loss, evaluated by DXA, is moderate in multiple myeloma. High-dose chemotherapy followed by ASCT leads to decreased bone resorption but osteoblastic bone formation remains low, in spite of reduced circulating DKK1.

Odanacatib: Location and timing are everything

Odanacatib: Location and timing are everything

Long-Term Effects of Neridronate and its Discontinuation in Patients with Primary Hyperparathyroidism

In patients with primary hyperparathyroidism (PHPT) not suitable for surgical correction, a skeletal protection with bisphosphonates is considered a reasonable option, but the long-term effects after treatment discontinuation are not well known. Sixty postmenopausal women with PHPT were given 400-600IU vitamin D(3) daily and 100mg neridronate IV every 2months for 2years with 2 additional years of follow-up without antiresorptive therapies. Bone mineral density (BMD) progressively rose by 6.7±7.6% (SD) and by 2.9±4.5% at the spine and femoral neck, respectively. During follow-up, mean BMD progressively fell, but after 2years it was still 3.9±5.5% higher than baseline values at the spine. Bone alkaline phosphatase and serum C-telopeptide of type I collagen decreased significantly within 6months (28 and 49% versus baseline, respectively) and rose to baseline values within 6-12months during follow-up. Serum PTH significantly rose from baseline during treatment, but it remained significantly higher than baseline during follow-up. The PTH changes were significantly correlated with serum 25-hydroxyvitamin D (25OHD) levels. In conclusion, in this study we observed that in patients with mild PHPT treatment with bisphosphonates is associated with the expected changes in bone-turnover markers and that the significant increases of both hip and spine BMD are partially maintained for at least 2years after treatment discontinuation at the vertebral site. The marked increases in serum PTH levels, particularly in subjects with low 25OHD levels, persist after treatment discontinuation and this raises the suspicion that this might reflect a worsening of PHPT.

Effects of denosumab on bone turnover markers in postmenopausal osteoporosis

Denosumab, a fully human monoclonal antibody to RANKL, decreases bone remodeling, increases bone density, and reduces fracture risk. This study evaluates the time course and determinants of bone turnover marker (BTM) response during denosumab treatment, the percentage of denosumab-treated women with BTMs below the premenopausal reference interval, and the correlations between changes in BTMs and bone mineral density (BMD). The BTM substudy of the Fracture REduction Evaulation of Denosumab in Osteoporosis every 6 Months (FREEDOM) Trial included 160 women randomized to subcutaneous denosumab (60 mg) or placebo injections every 6 months for 3 years. Biochemical markers of bone resorption (serum C-telopeptide of type I collagen [CTX] and tartrate-resistant acid phosphatise [TRACP-5b]) and bone formation (serum procollagen type I N-terminal propeptide [PINP] and bone alkaline phosphatase [BALP]) were measured at baseline and at 1, 6, 12, 24, and 36 months. Decreases in CTX were more rapid and greater than decreases in PINP and BALP. One month after injection, CTX levels in all denosumab-treated subjects decreased to levels below the premenopausal reference interval. CTX values at the end of the dosing period were influenced by baseline CTX values and the dosing interval. The percentage of subjects with CTX below the premenopausal reference interval before each subsequent injection decreased from 79% to 51% during the study. CTX and PINP remained below the premenopausal reference interval at all time points in 46% and 31% denosumab-treated subjects, respectively. With denosumab, but not placebo, there were significant correlations between CTX reduction and BMD increase (r = -0.24 to -0.44). The BTM response pattern with denosumab is unique and should be appreciated by physicians to monitor this treatment effectively.

Lactation and Bone Turnover: A Conundrum of Marked Bone Loss in the Setting of Coupled Bone Turnover

Mothers who exclusively breastfeed lose up to 10% of their bone mass. This is primarily mediated by PTHrP, in combination with low estrogen levels. The mechanisms underlying this marked bone loss are unknown. Uncoupling of bone turnover, which is seen in other prototypical states of bone loss, would seem the likely explanation. However, the most current markers of bone turnover have not been studied in human lactation. The purpose of this study was to assess bone formation in lactating humans using the most current bone turnover markers. We conducted a prospective cohort study with repeated measures of bone metabolism in a volunteer sample of 49 women, recruited into three study groups: lactating, bottle feeding, and healthy controls. The postpartum women were studied at 6-8 and 12-14 wk postpartum, whereas the controls were studied at the follicular phase of their menstrual cycles. Biochemical markers of bone turnover were assessed. Mean serum C-telopeptide of type I collagen, a sensitive marker of bone resorption, was approximately 2-fold higher in lactating women as compared with bottle-feeding and healthy controls (P = 0.037 and P < 0.001, respectively). Surprisingly, amino-terminal telopeptides of procollagen 1, the most current marker of bone formation, bone-specific alkaline phosphatase, and osteocalcin were all significantly higher in the lactating group as compared with controls (P < 0.001, P = 0.002, and P < 0.001, respectively). In contrast to prototypical states of rapid bone loss (myeloma, cancer, and immobilization) in which markers of bone turnover display marked uncoupling, lactational bone loss, as assessed in this small exploratory study, is distinct, showing comparably rapid bone loss in the face of apparent osteoclast-osteoblast coupling.

Infusion of ibandronate once every 3 months effectively decreases bone resorption markers and increases bone mineral density in Chinese postmenopausal osteoporotic women: a 1-year study

The efficacy and safety of intravenous ibandronate were evaluated in postmenopausal osteoporosis women in China. In this multicenter, positive drug-controlled study, 158 postmenopausal osteoporotic women were randomized to receive 2 mg ibandronate given intravenously once every 3 months or 70 mg alendronate given orally once per week. All women also received supplemental calcium (500 mg) and vitamin D (200 IU) daily. One hundred fifty-one patients completed the 1-year study. Ibandronate produced mean increases in bone mineral density (BMD) by 4.27% at the lumbar spine, 3.48% at the femoral neck, and 2.03% at the trochanter. Mean increases in BMD by 4.24% at the lumbar spine, 2.72% at the femoral neck, and 2.99% at the trochanter were observed in the alendronate group. No significant difference was found between the two groups in BMD in all sites measured. Significant decreases in serum c-telopeptide of type I collagen (CTX) and alkaline phosphatase (ALP) were found in the two groups after 1 and 3 months of treatment, respectively; these serum CTX and ALP levels were then maintained at the decreased levels throughout the study period (12 months). No changes of stature were found in the patients of the two groups. Adverse events were similar in the two groups, except more mild muscle pain was observed in the first month after infusion of ibandronate than with oral alendronate (P < 0.001). The results observed in Chinese patients may support the observation that intravenous ibandronate significantly reduced bone resorption and increased BMD with good tolerance in Chinese postmenopausal osteoporotic women. Use of intravenous ibandronate possibly could potentially improve compliance as compared with other oral bisphosphonates because it may avoid the peptic side effects of oral bisphosphonate.

Insulin-like growth factor-1 is associated with bone formation markers, PTH and bone mineral density in healthy premenopausal women

Bone turnover markers (BTM) progressively decrease in young adult women. This might be linked to changes in insulin-like growth factor-1 (IGF-I). Four serum BTMs [serum C-telopeptide of type 1 collagen (CTX), osteocalcin (OC), N-terminal propeptide of type 1 procollagen (P1NP), and bone alkaline phosphatase (bone AP)], serum calcium (sCa), phosphate (sPO 4), magnesium, 25-hydroxyvitamin D [25(OH)D], intact parathyroid hormone (PTH) and IGF-I were measured in 531 young healthy premenopausal women aged 20–50 years participating in the BONTURNO study. In all subjects bone mineral density (BMD) was measured at the spine and at the hip by dual-energy X-ray densitometry. Hip BMD, IGF-I, the four BTMs, sCa and sPO 4 progressively decreased with advancing age and this was associated with proportional increases in PTH. IGF-I levels were significantly and positively correlated with sCa, sPO 4, CTX, OC, P1NP, bone AP, spine BMD, femoral neck BMD and total hip BMD and negatively with age, BMI and serum PTH. When the IGF-I levels were adjusted for age and BMI, the only correlations maintaining a statistical significance were those with serum PTH, P1NP and bone AP. These associations were weak and IGF-I accounted for a only a small proportion of the BTM variance. The mean, age-adjusted IGF-I values were significantly higher in women practicing physical exercises for more then 60 min per week than in sedentary women. In conclusion, in this study we provide evidence of an association between the age-related decline in IGF-I with the progressive decrease in bone formation markers in premenopausal women.

25-hydroxy vitamin D levels in healthy premenopausal women: Association with bone turnover markers and bone mineral density

Background Vitamin D deficiency is very common in elderly people while there are very few reports on its incidence, determinants and metabolic consequences in young subjects. Results In 608 young healthy premenopausal women participating in the BONTURNO study, levels of 25-hydroxyvitamin D [25(OH)D] below 20 ng/ml were found in almost a third of the women. Its levels were inversely ( P < 0.001) related with age and body mass index (BMI kg/m 2) and directly with sunlight exposure during the summer time, and latitude: i.e. the higher the latitude over Italy, the higher the 25(OH)D level. In women on contraceptive pill the mean 25(OH)D level was significantly increased even when the data were adjusted for age, BMI and sun exposure. 25(OH)D levels, adjusted for age and BMI, were significantly and positively related with serum C-telopeptide of type 1 collagen, serum phosphate and spine bone mineral density (BMD) and negatively with serum PTH, serum magnesium, serum bone alkaline phosphatase (bone AP). Conclusion Vitamin D deficiency is rather common in young otherwise healthy Italian women and particularly among those living in the Southern part of the country. The most close determinants of vitamin D deficiency were BMI and sunlight exposure. Vitamin D insufficiency is associated with low spine BMD and increased bone AP even in young individuals.

Age-specific effects of estrogen receptors' polymorphisms on the bone traits in healthy fertile women: the BONTURNO study

BackgroundSkeletal characteristics such as height (Ht), bone mineral density (BMD) or bone turnover markers are strongly inherited. Common variants in the genes encoding for estrogen receptor alpha (ESR1) and beta (ESR2) are proposed as candidates for influencing bone phenotypes at the population level.MethodsWe studied 641 healthy premenopausal women aged 20–50 years (yrs) participating into the BONTURNO study. Exclusion criteria were irregular cyclic menses, low trauma fracture, metabolic bone or chronic diseases. Serum C-telopeptide of type I collagen (CTX), osteocalcin (OC), and N-terminal propeptide of type I procollagen (P1NP) were measured in all enrolled subjects, who underwent to lumbar spine (LS), total hip (TH) and femoral neck (FN) BMD evaluation by DXA. Five hundred seventy Caucasian women were genotyped for ESR1 rs2234693 and rs9340799 and ESR2 rs4986938 polymorphisms.ResultsAlthough no genotype differences were found in body parameters, subjects with combined ESR1 CCGG plus ESR2 AA-AG genotype were taller than those with opposite genotype (P = 0.044). Moreover, ESR1 rs2234693 genotypes correlated with family history of osteoporosis (FHO) and hip fracture (FHF) (P < 0.01), while ESR2 AA-AC genotypes were strongly associated with FHF (OR 2.387, 95% CI 1.432–3.977; P < 0.001).When clustered by age, 20–30 yrs old subjects, having at least one ESR1 rs2234693 C allele presented lower LS- (P = 0.008) and TH-BMD (P = 0.047) than TT genotypes. In 41–50 yrs age, lower FN-BMD was associated with ESR2 AA (P = 0.0180) subjects than in those with the opposite genotype. ESR1 rs2234693 and rs9340799 and ESR2 rs4986938 polymorphisms did not correlate with age-adjusted values of OC, CTX and P1NP.ConclusionThese findings support the presence of age-specific effects of ESR1 and ESR2 polymorphisms on various skeletal traits in healthy fertile women.

Physical Activity and Bone Turnover Markers: A Cross-Sectional and a Longitudinal Study

Strenuous physical activity in young individuals has an important effect on both bone mass and bone turnover but the effect of moderate physical activity in adults remains uncertain. In a large cohort (N = 530) of healthy premenopausal women, bone formation markers (osteocalcin and N-terminal propeptide of type 1 procollagen [P1NP]), but not serum C-telopeptide of type 1 collagen (sCTX), were found to be significantly associated with the level of physical activity, and this association remained significant after adjusting the data (ANCOVA) by age and body mass index. Mean spine and hip bone mineral density (BMD) values were positively associated with physical activity but this was statistically significant (P = 0.050) only for adjusted values of spine BMD. Twenty-four healthy sedentary premenopausal women, subscribing to participate in a community exercise program lasting a month, and 18 age-matched controls were included in the longitudinal study. Serum osteocalcin and P1NP, but not sCTX, rose significantly, by ca. 25%, only in the active group after a month of exercise. The changes in the two bone formation markers remained statistically significant for values adjusted for body weight, which fell significantly in the exercise group. In conclusion, both the cross-sectional and the longitudinal parts of our study demonstrate that even minor changes in physical activity are associated with a clear effect on bone formation markers.

Determinants of Bone Turnover Markers in Healthy Premenopausal Women

Bone turnover markers (BTMs) are widely used for the management of osteoporosis, and the premenopausal reference range is the target value for the treatment of postmenopausal osteoporosis with antiresorbing agents. Three serum BTMs (serum C-telopeptide of type I collagen [CTX], osteocalcin [OC], and N-terminal propeptide of type I procollagen [P1NP]), serum calcium, creatinine, phosphate, magnesium, and follicle-stimulating hormone (FSH) were measured in 638 healthy premenopausal women aged 20-50 years. In 83 women on the contraceptive pill (CP), the levels of the three BTMs adjusted for all confounding factors were 14-26% lower (P < 0.005) than in non-CP users. In 18 women considered perimenopausal for serum FSH levels >30 IU/mL despite having regular menses, BTM levels were significantly higher than in age-matched women. This group of subjects and the women on the CP were excluded from further analysis. The three BTMs significantly decreased with advancing age and were negatively and independently correlated with body mass index (P < 0.001) and serum phosphate. In conclusion, we confirm that CP use is associated with significantly lower BTM values. An increase in BTM concentrations can be observed in perimenopausal women, i.e., women with normal menses but FSH levels >30 IU/mL. BTMs decrease substantially with advancing age, and this appears to be associated with changes in body weight and serum phosphate. New normative ranges for serum OC, CTX, and P1NP were identified; and our findings in general impose a redefinition of the criteria for establishing the normal ranges for BTMs.

Once-Yearly Zoledronic Acid for Treatment of Postmenopausal Osteoporosis

Although bisphosphonates do inhibit bone resorption in postmenopausal women and lessen the risk of vertebral and hip fractures, as many as half of patients no longer adhere to prescribed oral treatment after 12 months. A single intravenous infusion of zoledronic acid reportedly decreases bone turnover and improves bone mineral density (BMD) for at least a year. In the HORIZON (Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly) Pivotal Fracture Trial, an international, randomized, double-blind, placebo-controlled study, postmenopausal women ranging in age from 65 to 89 years were assigned to receive either a 15-minute IV infusion of 5 mg of zoledronic acid or placebo at yearly intervals up to 24 months. All women received a daily supplement of 1000-1500 mg of calcium and 400-1200 IU of vitamin D. Participants had a bone mineral density (BMD) T score of -2.5 or less at the femoral neck or a score of -1.5 or less with 1 or more vertebral fractures. The efficacy analysis included 7736 patients, and the safety analysis, 7714 patients. The 3-year incidence of vertebral fracture was 10.9% in the placebo group and 3.3% in women given zoledronic acid, a 70% reduction (relative risk, 0.30; 95% confidence interval [CI], 0.24-0.38). Similar effects were noted after 1 and 2 years. Hip fractures were reduced 41% in actively treated women (hazard ratio, 0.59; 95% CI, 0.42-0.83). Nonvertebral fractures, all clinical fractures, and clinical vertebral fractures all were significantly less frequent in women given zoledronic acid-by 25%, 33%, and 77%, respectively. Actively treated women lost significantly less height than placebo recipients (-4.2 mm vs. -7.0 mm). BMD rose significantly at all measurement sites in the active treatment group compared to placebo recipients. Biochemical markers of bone turnover-including serum C-telopeptide of type I collagen, bone-specific alkaline phosphatase, and N-terminal propeptide of type I collagen-all decreased significantly with active treatment. Postdose symptoms were more frequent in actively treated women, but there were no significant group differences in numbers of deaths. Renal function was not compromised by zoledronic acid therapy. Serious atrial fibrillation was more frequent in actively treated women than in placebo patients (1.3% vs. 0.5%), as was the prevalence of inflammatory ocular disorders, mainly conjunctivitis. One patient in each group had potential osteonecrosis of the jaw. In this large-scale trial, once-a-year infusion of zoledronic acid was associated with a sustained decrease in vertebral, hip, and other fractures in postmenopausal women with osteoporosis over a 3-year period. Treatment was generally well tolerated and had a favorable safety profile.

Intravenous zoledronic acid 5 mg in the treatment of postmenopausal women with low bone density previously treated with alendronate

This randomized, double-blind, double-dummy, multicenter trial assessed safety and efficacy of a single dose of IV zoledronic acid (ZOL) 5 mg vs. oral alendronate (ALN) 70 mg weekly in postmenopausal women with low bone mineral density (BMD) who had previously been treated with ALN. Postmenopausal women who were receiving oral ALN for at least 1 year immediately prior to randomization and with lumbar spine or femoral neck BMD T-score values ≤ − 2.0 prior to initiation of ALN were randomized to one 15-min IV infusion of ZOL 5 mg plus 52 weeks of oral placebo ( n = 113) or one IV infusion of placebo plus 52 weeks of oral ALN 70 mg ( n = 112). End points included percent change in lumbar spine BMD from baseline to month 12 and relative change from baseline in urine N-telopeptide of type I collagen (NTX), serum C-telopeptide of type I collagen (CTX), amino terminal propeptides of type I collagen (PINP), and bone-specific alkaline phosphatase (bone ALP) over 12 months. Adverse events, bone histomorphometry and microscopic appearance, and patient preference for the 2 treatment regimens were also assessed. In this study, a single infusion of ZOL 5 mg maintained BMD 12 months following the switch from oral ALN in women with osteoporosis. The mean duration of prior ALN therapy at baseline was 4 years. Mean biomarker levels in the ALN 70-mg group remained at or close to baseline levels for the duration of the study. In the ZOL 5-mg group, mean biomarker levels were reduced from baseline after 3 months, returned to baseline after 6 months, and increased thereafter but remained within the premenopausal range. The overall rates of adverse events were comparable in the 2 groups (ZOL 5 mg, 86.7%; ALN 70 mg, 80.4%). Headache occurred more commonly within the first 3 days after infusion with ZOL 5 mg (12.4%) than with ALN 70 mg (6.3%). Bone biopsies indicate that both treatments decrease excessive remodeling seen in osteoporosis. The majority (78.7%) of patients expressed preference for once yearly infusion over weekly oral therapy. We conclude that patients can be switched from oral ALN to ZOL 5 mg infusion with maintenance of therapeutic effect for at least 12 months and that patients prefer a once yearly infusion to weekly oral therapy.

Changes in bone mass and bone turnover following tibial shaft fracture

Bone loss occurs in the regional bone following tibial shaft fracture. An earlier cross-sectional study showed that measurements made at the metaphyseal region of the tibia using peripheral quantitative computed tomography (pQCT) and the ultradistal region of the tibia using dual-energy X-ray absorptiometry (DXA) were the most responsive at monitoring this bone loss. Biochemical markers of bone turnover enable us to assess the activity of bone formation and resorption during fracture healing. The aim of this longitudinal study was to determine the pattern and distribution of bone loss and bone turnover following a tibial shaft fracture treated with either plaster cast or intramedullary nail. Eighteen subjects underwent bone mass measurements using DXA at the tibia and hip and quantitative ultrasound (QUS) at the tibia and calcaneus of both limbs at 2 weeks, 8 weeks, 12 weeks and 24 weeks following fracture, with hip and tibia DXA measurements also performed at 52 weeks. Nine of the patients treated with plaster cast had pQCT measurements at the tibia at 24 weeks. We measured three bone formation markers, bone alkaline phosphatase (bone ALP), osteocalcin (OC) and procollagen type 1 N-terminal peptide (PINP), a marker of bone resorption, serum C-telopeptides of type 1 collagen (beta-CTX) and a marker of collagen III turnover, procollagen type III N-terminal peptide (PIIINP) at 1 day, 3 days and 7 days and at 2, 4, 8, 12, 16 and 24 weeks following fracture. The greatest bone losses were observed at the ultradistal region of the tibia using DXA (28%, p <0.001) and the metaphyseal region of the tibia using pQCT (26-31%, p <0.001) at 24 weeks. In the hip, the greatest loss was in the trochanter region at 24 weeks (10%, p <0.001). The greatest loss at the calcaneus measured using QUS was for broadband ultrasound attenuation (BUA) measured using CUBA Clinical at 24 weeks (13%, p =0.01). At 1 year, there was a small recovery in bone loss (ultradistal tibia DXA, 20%, p <0.01; trochanter DXA 9%, p <0.001). Bone turnover increased following fracture (PINP +72+/-21%, p <0.0001, bone ALP +199+/-22%, p =0.004, beta-CTX +105+/-23%, p <0.0001, all at 24 weeks). There was a smaller +33+/-10% increase in osteocalcin at 24 weeks. PIIINP concentration peaked at week 8 (+57+/-9%, p <0.0001). The bone resorption marker beta-CTX showed an earlier rise (week 2, 139+/-33%) than the bone formation markers. We conclude that: (1) bone loss following tibial shaft fracture occurs both proximal and distal to the fracture; (2) the decreased BMD is largest for trabecular bone in the tibia with similar measurements using DXA and pQCT; (3) there is limited recovery of bone lost at the hip and tibia at 1 year; (4) tibial speed of sound (SOS) demonstrated a greater decrease than calcaneal SOS when comparing z -scores; (5) BUA is the QUS variable that shows the biggest decrease of bone mass at the calcaneus; (6) increase in bone turnover occurs following fracture with an earlier increase in bone resorption markers and a later rise in bone formation markers.