Associations between the metabolic syndrome and bone health in older men and women: the Rancho Bernardo Study

Summary We examined the associations of metabolic syndrome (MS) with BMD, osteoporosis, and osteoporotic fractures in 417 men and 671 women from the Rancho Bernardo Study. After adjusting for BMI, MS was associated with lower, not higher BMD. Incidence of osteoporotic non-vertebral fractures was higher in participants with MS. MS may be another risk factor for osteoporotic fractures. Introduction The metabolic syndrome (MS) is a cluster of risk factors, including abdominal obesity, high glucose, triglycerides, hypertension and low HDL levels, associated with cardiovascular disease morbidity. The association between components of the MS and bone mineral density (BMD) has been researched, but results are contradictory. Methods We used multivariate regression models to examine the cross-sectional associations of MS defined by NCEP-ATP III criteria with BMD and osteoporosis, and the longitudinal association of MS with fractures in 420 men and 676 women from the Rancho Bernardo Study. Results Prevalence of MS at baseline was 23.5% in men and 18.2% in women. In age-adjusted analyses, men and women with MS had higher BMD at total hip when compared to those without MS (p < 0.001 and p = 0.01, respectively). Men but not women with MS also had higher BMD at femoral neck (p = 0.05). After adjusting for BMI, these associations were reversed, such that MS was associated with lower and not higher BMD. Conclusion Incidence of osteoporotic non-vertebral fractures was higher in participants with MS. MS may be another risk factor for osteoporotic fractures. The association of MS with higher BMD was explained by the higher BMI in those with MS.     

Association between bone turnover rate and bone microarchitecture in men: The STRAMBO study

Few data concern the relationship between bone turnover and microarchitecture in men. We investigated the association between levels of biochemical markers of bone turnover (BTM) and bone microarchitecture in 1149 men aged 19 to 85 years. Bone microarchitecture was assessed by high‐resolution peripheral quantitative computed tomography at the distal radius and tibia. Bone formation was assessed by serum osteocalcin, bone alkaline phosphatase, and N‐terminal extension propeptide of type I collagen. Bone resorption was assessed by serum C‐terminal telopeptide of type I collagen and urinary excretion of total deoxypyridinoline. BTM levels were high in young men and decreased until age 50 years. Urinary deoxypyridinoline (DPD) increased after age 70 years, whereas other BTMs remained stable. Before 50 years of age, only cortical volumetric bone mineral density (D_cort) correlated negatively with BTM levels. Between 50 and 70 years of age, D_cort and some microarchitectural parameters correlated significantly with BTM at the radius and tibia. After 70 years of age, higher BTM levels were associated with lower cortical thickness and D_cort at both the skeletal sites. At the distal radius, men in the highest BTM quartile had lower trabecular density, number (Tb.N), and thickness (Tb.Th) and more heterogeneous trabecular distribution compared with men in the lower quartiles. At the distal tibia, higher BTM levels were associated with lower Tb.N and Tb.Th in the central but not subendocortical area. Thus, in men, bone microarchitecture depends weakly on the current bone turnover rate until age 70. Thereafter, bone turnover seems to be a significant determinant of bone microarchitecture. © 2010 American Society for Bone and Mineral Research.     

Measures of renal function, BMD, bone loss, and osteoporotic fracture in older adults: the Rancho Bernardo study.

The association between bone and renal function in healthy seniors is not well studied. In this cross-sectional and longitudinal study in 1713 older men and women, creatinine clearance was significantly associated with hip BMD. If confirmed, this may warrant adding mild to moderate renal dysfunction as an indication for osteoporosis screening. INTRODUCTION: This study determined the cross-sectional and longitudinal association between measures of renal function and BMD, bone loss, and osteoporotic fracture in older adults. It determined which measure of renal function--creatinine clearance by the Cockcroft-Gault (CG) equation, estimated glomerular filtration rate by the Modification of Diet in Renal Disease (MDRD) equation, or serum creatinine--is most strongly associated with BMD and osteoporotic fracture. MATERIALS AND METHODS: This was a cross-sectional and prospective study in older community-dwelling men and women. Between 1992 and 1995, 1713 participants (average age, 71.3 +/- 11.1 years) completed standardized questionnaires, physical examinations, laboratory testing, and bone densitometry; 1023 participants returned for a follow-up visit in 1997-1999, an average of 4.1 +/- 0.9 years later. RESULTS: Calculated renal function declined with age (p < 0.001). Renal function was categorized by Kidney Disease Outcomes Quality Initiative (K/DOQI) chronic kidney disease (CKD) stage. By the CG equation, at baseline, 5.5% of participants had stage 1 CKD (glomerular filtration rate > or = 90 ml/min/1.73 m(2)), 43.0% had stage 2 CKD (60-89 ml/min/1.73 m(2)), 48.8% had stage 3 CKD (30-59 ml/min/1.73 m(2)), and 2.7% had stages 4 and 5 CKD (<30 ml/min/1.73 m(2)). Using the MDRD equation, these percents were 7.0%, 61.7%, 30.9%, and 0.5%, respectively. In cross-sectional analyses, there was a significant linear association between creatinine clearance by CG or glomerular filtration rate by MDRD and hip BMD. In prospective analyses, there was an average annual bone loss of 0.6% and a significant association between baseline CG and 4-year hip bone loss. There was no association between baseline MDRD or serum creatinine and bone loss. At baseline, 180 of 1713 participants (11%) reported at least one clinical fracture of the hip, femur, forearm, or wrist; 79 (8%) reported new clinical fractures during follow-up. Baseline renal function by any measure was not significantly associated with prevalent or incident clinical fractures. CONCLUSIONS: Although renal function measured by both CG and MDRD was associated with BMD in cross-sectional analyses, only creatinine clearance by CG predicted 4-year bone loss. If confirmed, this should be the preferred method for assessing the association between renal function and BMD. Cross-sectional associations between renal function and BMD were strongest at higher CKD stage. None of the baseline renal function estimates was associated with prevalent or incident fractures, perhaps reflecting the multifactorial etiology of fractures beyond BMD. If further studies in the elderly confirm renal function as an important predictor of bone loss and fracture, this may warrant adding mild to moderate renal dysfunction as an indication for osteoporosis screening.     

Four-month treatment with GLP-2 significantly increases hip BMD: A randomized, placebo-controlled, dose-ranging study in postmenopausal women with low BMD

We have previously shown that repeated dosing of glucagon-like peptide-2 (GLP-2) at 10 p.m. in postmenopausal women for 14 days results in a dose-dependent decrease in the nocturnal bone resorption, as assessed by s-CTX. In contrast, bone formation, as assessed by serum osteocalcin, appeared to be unaffected by treatment with exogenous GLP-2, at least over 14 days.The present study extends the observation period to four months. The study was a double-blind placebo-controlled dose-ranging trial comparing three different doses of GLP-2 (0.4 mg, 1.6 mg and 3.2 mg GLP-2, administered nightly) against a saline control injection. We examined safety and tolerability, and the effects on biochemical markers of bone turnover and the effect on bone mineral density.Injection of 0.4 mg, 1.6 mg and 3.2 mg GLP-2 resulted in similar reduction in the nocturnal rise of s-CTX, at Treatment Day 120 the mean difference to placebo was approximately − 150%  h at AUC_0–10H (P < 0.01). Osteocalcin levels were unaffected in the 10-hour period after injection indicating that injections of 0.4 mg, 1.6 mg and 3.2 mg GLP-2 do not exert any acute stimulatory or inhibitory effect on bone formation.Treatment with GLP-2 resulted in a significant dose-dependent increase in total hip BMD over the course of the study that for the 3.2 mg GLP-2 group reached 1.1% (P = 0.007) from baseline.The overall rates of adverse events in the 4 treatment groups were similar and there were no signs of tachyphylaxis or antibodies against GLP-2.The results indicate that GLP-2 produces a substantial decrease in bone resorption without suppression of bone formation thereby changing the bone remodeling balance in favor of bone formation, particularly at the hip.     

Ghrelin and bone: is there an association in older adults?: the Rancho Bernardo study.

Laboratory studies suggest that ghrelin is involved in bone metabolism, but studies of ghrelin and bone in humans are limited. We studied sex-specific associations of ghrelin with BMD, NTX, and bone loss. Ghrelin was not associated with BMD or bone loss in either sex. There was a significant inverse association with NTX in men but not in women. INTRODUCTION: Ghrelin is a gastric hormone recently shown to be associated with bone metabolism in animal and in vitro studies. Studies in humans are limited. We investigated the association of ghrelin with BMD, the bone resorption marker N-telopeptide (NTX), and bone loss in older men and women. MATERIALS AND METHODS: Participants were 977 community-dwelling men and non-estrogen-using postmenopausal women, 50-91 years of age. Plasma ghrelin was measured by radioimmunoassay from blood obtained between 1984 and 1987. Between 1988 and 1991, BMD was measured at the midshaft radius by single photon absorptiometry and at the femoral neck, total hip, and lumbar spine by DXA. Axial BMD measurements were repeated an average of 4 years later in 544 participants. Bone turnover was assessed by NTX in urine obtained at the same time as the initial BMD. Multiple regression analyses were used to test sex-specific associations of ghrelin with BMD, NTX, and bone loss in both sexes. RESULTS: No significant ghrelin-BMD or ghrelin-bone loss associations were observed in either sex, after adjusting for age and body mass index (BMI). Ghrelin was inversely associated with NTX in men and positively associated with NTX in women, independent of age. After adjusting for both age and BMI, this association reached statistical significance in men and was weakened in women. CONCLUSIONS: Ghrelin may be associated with bone turnover, but there is no evidence for an association with BMD or short-term change in BMD in older adults.     

Race and ethnic variation in proximal femur structure and BMD among older men.

Femoral neck dimensions and vBMD from QCT were compared among 3,305 black, Asian, Hispanic, and white men >or=65 yr of age. All had similar stature-adjusted mean femoral neck volume, but black and Asian men had thicker cortices and higher trabecular vBMD, which may increase bone strength. INTRODUCTION: Hip fracture rates among elderly U.S. black and Asian men are lower than rates among white men. Structural characteristics or volumetric BMD (vBMD), which confer advantages for femoral neck bone strength, may vary by race/ethnicity. However, this topic has not been studied in detail. MATERIALS AND METHODS: In a cross-sectional study, dimensions and vBMD in the femoral neck and shaft were obtained from QCT scans among 3,305 men >or=65 yr of age in the Osteoporotic Fractures in Men (MrOS) study. Femoral neck measures were cross-sectional area; integral, cortical, and medullary volumes and integral, cortical, and trabecular vBMD. Shaft measures were cross-sectional, cortical, and medullary areas and cortical vBMD. Self-reported race/ethnicity was classified as black, Asian, Hispanic, or white. We used multivariable linear regression models with adjustment for age, height, and body mass index to compare means of the outcome measures in black, Asian, and Hispanic men to those in whites. RESULTS: All groups had similar femoral neck integral volume. Among black and Asian men, mean cortical volume as a percent of integral volume was 6% greater, integral vBMD was 6-10% greater, and trabecular vBMD was 33-36% greater than means among whites. Shaft cross-sectional area was similar among blacks, but smaller among Asians, compared with whites. However, mean shaft cortical area was greater among blacks but similar among Asians and whites, resulting in mean cortical thickness being 5% greater among black and Asian men. Blacks also had greater mean cortical vBMD in both the femoral neck and shaft. CONCLUSIONS: Black and Asian men >or=65 yr of age have features in the proximal femur that may confer advantages for bone strength. Specifically, greater cortical thickness and higher trabecular vBMD among black and Asian men could help explain the lower hip fracture rates in these populations. Discerning the mechanisms underlying these differences could provide advances for the prevention and treatment of osteoporosis.     

骨转换标志物与骨密度预测老年女性骨质疏松性骨折的对比研究

目的探讨骨密度与骨转换标志物(bone turnover markers,BTMs)在老年女性骨质疏松患者中的检测意义,对比两者对骨质疏松性骨折(osteoporotic fracture,OF)的预测能力。方法收集2017年10月至2019年2月于成都医学院第一附属医院骨科住院的OF患者96例和骨质疏松患者107例,分为骨折组和非骨折组。通过双能X线吸收仪(DXA)测定骨密度,电化学发光检测BTMs:I型前胶原N端前肽(PINP)、I型胶原β-异构化C末端肽(β-CTX)、骨钙素N端分子片段(N-MID),同时测定骨代谢相关指标:碱性磷酸酶(alkaline phosphatase,ALP)、钙(Ca)、磷(P),t检验对比两组间的计量资料,采用二分类Logistic回归分析骨密度和BTMs与OF的相关性。结果骨折组的骨密度低于非骨折组,差异有统计学意义(P 0. 05);PINP、β-CTX高于非骨折组,70～90岁患者N-MID低于非骨折组,差异均有统计学意义(P0. 05);而ALP、P、Ca在两组之间相比,差异无统计学意义(P0. 05)。二分类Logistic回归分析提示腰椎及髋部骨密度、β-CTX与OF具有显著相关性,OR分别为-4. 182、-6. 929和7. 572,差异均有统计学意义(P0. 05)。PINP、N-MID与OF呈正相关,OR分别为4. 213和2. 510,差异均无统计学意义(P0. 05)。结论低骨密度、高β-CTX的骨质疏松老年女性更容易发生OF,β-CTX比骨密度预测OF的能力更强,可适时对高危人群进行相关干预管理。     

Lumbar spine peak bone mass and bone turnover in men and women: a longitudinal study

Summary  Peak bone mass is an important determinant of bone mass in later life, but the age of peak bone mass is still unclear. We found that bone size and density increase and bone turnover decreases until age 25. It may be possible to influence bone accrual into the third decade. Introduction  Peak bone mass is a major determinant of bone mass in later life. Bone growth and maturation is site-specific, and the age of peak bone mass is still unclear. It is important to know the age to which bone accrual continues so strategies to maximise bone mass can be targeted appropriately. This study aims to ascertain the age of lumbar spine peak bone mass. Methods  We measured lumbar spine BMC, estimated volume and BMAD by DXA and biochemical markers of bone turnover in 116 healthy males and females ages 11 to 40, followed up at an interval of five to nine years. Results  The majority of peak bone mass was attained by the mid-twenties. Increases in BMC in adolescents and young adults were mostly due to increases in bone size. Bone turnover markers decreased through adolescence and the third decade and the decreasing rate of change in bone turnover corresponded with the decreasing rate of change in lumbar spine measurements. Conclusions  Skeletal maturation and bone mineral accrual at the lumbar spine continues into the third decade.     

Axial BMD, change in BMD and bone turnover do not predict breast cancer incidence in early postmenopausal women

Previous studies have indicated a relationship between bone mineral density and the incidence of breast cancer in middle-aged and elderly women, with women with higher BMD being at significant increased risk. We investigated whether there was such a relationship in younger women who were perimenopausal or in their early postmenopausal years. As part of a population-screening program for osteoporosis, 5,119 women aged between 45 and 54 years were scanned between 1990–1994 at the Osteoporosis Research Unit. In 1997–2001, 3,884 returned for follow-up scans and questionnaires, and 3,144 returned a postal questionnaire in 2002. All cases of incident breast cancer were noted. One hundred sixty-six women indicated that they had suffered from breast cancer, of which 87 were incident cases (59 had prevalent breast cancer at baseline and 20 had benign or unconfirmed diagnosis and were excluded because of the use of agents that may interfere with BMD, e.g., tamoxifen). We compared therefore the incident breast cancer group (BC group; n =87) with a control group (C group; n =3,013). There were no significant differences using a t -test between the BC group and C group for baseline DXA of the spine or femoral neck. Further changes in BMD over a mean period of 6.9 years demonstrated no significant hazard ratio for the lumbar spine or femoral neck. No relationship was seen between the bone turnover markers pyridinoline/creatinine or deoxypyridinoline/creatinine assessed at their second study visit and incidence of breast cancer. In conclusion, in perimenopausal or early postmenopausal women there is no relationship between the incidence of breast cancer and BMD, change in BMD or bone turnover.     

Hormonal profiles and biochemical indices of bone turnover in Indian women

Summary The study establishes Indian referent database for bone turnover markers. The levels of markers decreased across the four quartiles of BMD showing a negative correlation with BMD. The study depicts that levels of hormones and bone turnover makers can aid in identifying women at risk for osteoporosis. Introduction Biochemical markers of bone turnover reflect changes in bone metabolism earlier and aid in the management of osteoporosis. Since a referent database for Indian women is lacking, the study was initiated to establish the same and suggest that hormonal profiles and markers of bone turnover can aid in identifying women at risk for osteoporosis. Methods Osteocalcin (OC), bone specific alkaline phosphatase ((BSAP), C-terminal crosslinking telopeptide of type-I collagen (CTX-I), deoxypyridinoline (DPD), follicle-stimulating hormone (FSH) and estrone glucuronide (E₁G) were measured in 365 Indian women (20–70 years) and correlated with BMD measurements by dual energy absorptiometry (DXA) using one way analysis of variance (ANOVA). Results The mean levels of bone resorption markers; CTX-I and DPD increased significantly across the age showing a negative correlation with BMD. The increase in levels of CTX-I and DPD was significantly higher (p < 0.0001) as compared to the femoral and spinal BMD, which dropped only 30–36%. The levels of bone turnover markers and FSH decreased across the four quartiles of spinal and femoral BMD showing a negative correlation whereas E₁G levels increased across the four quartiles. Conclusion The bone turnover markers were comparatively low in cohort of Indian women studied.     

Comparison of the Effect of Denosumab and Alendronate on BMD and Biochemical Markers of Bone Turnover in Postmenopausal Women With Low Bone Mass: A Randomized,Blinded, Phase 3 Trial

Denosumab is a fully human monoclonal antibody that inhibits bone resorption by neutralizing RANKL, a key mediator of osteoclast formation, function, and survival. This phase 3, multicenter, double‐blind study compared the efficacy and safety of denosumab with alendronate in postmenopausal women with low bone mass. One thousand one hundred eighty‐nine postmenopausal women with a T‐score ≤ ?2.0 at the lumbar spine or total hip were randomized 1:1 to receive subcutaneous denosumab injections (60 mg every 6 mo [Q6M]) plus oral placebo weekly (n = 594) or oral alendronate weekly (70 mg) plus subcutaneous placebo injections Q6M (n = 595). Changes in BMD were assessed at the total hip, femoral neck, trochanter, lumbar spine, and one‐third radius at 6 and 12 mo and in bone turnover markers at months 1, 3, 6, 9, and 12. Safety was evaluated by monitoring adverse events and laboratory values. At the total hip, denosumab significantly increased BMD compared with alendronate at month 12 (3.5% versus 2.6%; p < 0.0001). Furthermore, significantly greater increases in BMD were observed with denosumab treatment at all measured skeletal sites (12‐mo treatment difference: 0.6%, femoral neck; 1.0%, trochanter; 1.1%, lumbar spine; 0.6%, one‐third radius; p ≤ 0.0002 all sites). Denosumab treatment led to significantly greater reduction of bone turnover markers compared with alendronate therapy. Adverse events and laboratory values were similar for denosumab‐ and alendronate‐treated subjects. Denosumab showed significantly larger gains in BMD and greater reduction in bone turnover markers compared with alendronate. The overall safety profile was similar for both treatments.     

Serum insulin-like growth factor binding protein-1 levels and bone mineral density in older adults: The Rancho Bernardo Study

Insulin-like growth factor-I (IGF-I) stimulates osteoblast function, inhibits collagen matrix degradation, and is positively associated with bone mineral density in most but not all studies. We previously reported that IGF-I was positively associated with BMD at the spine and hip in women but not men. Insulin-like growth factor binding protein-1 (IGFBP-1), a potent modulator of IGF-I, is expressed in normal osteoblasts and inhibits collagen gene expression in bone, but little is known about the relationship between IGFBP-1 and bone mineral density (BMD). We report a cross-sectional study of serum IGFBP-1 levels and BMD in 1,139 community-dwelling men and postmenopausal women (not using estrogen), aged 44–98. In both sexes, IGFBP-1 levels increased linearly with age (p<0.001) and decreased with body mass index (BMI) quartile (p<0.001). After adjusting for age and BMI, there was no significant association between IGFBP-1 and BMD at the hip or spine. IGF-I and IGFBP-1 were weakly and inversely associated with each other. These findings suggest that if there is an important role for IGFBP-1 in bone metabolism, it is mediated or confounded by weight. Studies are needed to further investigate the relationship between inhibitory components of IGF-1 and bone loss.     

Vitamin D, parathyroid hormone levels and bone mineral density in community-dwelling older women: The Rancho Bernardo Study

Vitamin D (25(OH)D) increases the efficiency of intestinal calcium absorption. Low levels of serum calcium stimulate the secretion of parathyroid hormone (PTH), which maintains serum calcium levels at the expense of increased bone turnover, bone loss and increased risk of fractures. We studied the association between 25(OH)D and PTH levels, and their associations with bone mineral density (BMD), bone loss, and prevalence of hip fractures in 615 community-dwelling postmenopausal aged 50–97 years. Mean level of 25(OH)D and PTH were 102.0 nmol/l±35.0 nmol/l and 49.4 ng/l±23.2 nmol/l, respectively; 49% of women were current hormone therapy users. The overall prevalence of vitamin D insufficiency (25(OH)D<50 nmol/l) was 2%, and prevalence of high PTH levels (>65 ng/l) was 17.4%. In multiple linear regression analyses hip BMD was negatively and independently associated with PTH levels ( p =0.04), and positively and independently associated with 25(OH)D levels ( p =0.03). There were only 23 women (3.7%) who experienced a hip fracture. In age-adjusted analyses there were no significant differences of 25(OH)D and PTH levels by hip fracture status. Across the entire range of values, the overall correlation between 25(OH)D and PTH was moderate ( r =–0.20). However, after the threshold vitamin D level of 120 nmol/l, all PTH values were below 65 ng/l. Further studies are necessary to identify the optimal vitamin D levels necessary to prevent secondary hyperparathyroidism.     

Effect of combined exercise training on bone,body balance,and gait ability: a randomized controlled study in community-dwelling elderly women

The purpose of this study was to investigate whether a 48-week multicomponent exercise program could improve the risk factors for fall and hip fracture. Fifty elderly women 65–70 years of age participated. These participants were divided into an exercise group (25 subjects) that attended an exercise program and a control group (25 subjects) that did not. The exercise program included stretching for 9 min, strength training for 10 min followed by 23 min of weight-bearing exercise at an intensity above 65%–75% of the maximal heart rate, and 18 min of balance and posture correction training. The program was conducted three times per week for 48 weeks. The 10-m maximal walk time, maximal step length, and eyes-open-one-legged-stand time in the exercise group improved significantly (P < 0.05). Concerning deoxypyridinoline, the exercise group achieved a significant improvement (P < 0.05) after the 48 weeks. Bone mineral density (BMD) of the femoral neck and trochanter in the exercise group was significantly increased after the exercise program; also body sway was significantly improved (P < 0.05). In conclusion, a multi-component exercise program with weight-bearing exercise at a moderate intensity and gait training may be effective in offsetting a decline in BMD and improving aggravation of bone resorption in this population. In addition, this program has a positive effect on postural stability and gait ability.     

Genetic variation in the RANKL/RANK/OPG signaling pathway is associated with bone turnover and bone mineral density in men

The aim of this study was to determine if single‐nucleotide polymorphisms (SNPs) in RANKL, RANK, and OPG influence bone turnover and bone mineral density (BMD) in men. Pairwise tag SNPs (r² ≥ 0.8) were selected for RANKL, RANK, and OPG and their 10‐kb flanking regions. Selected tag SNPs plus five SNPs near RANKL and OPG, associated with BMD in published genome‐wide association studies (GWAS), were genotyped in 2653 men aged 40 to 79 years of age recruited for participation in a population‐based study of male aging, the European Male Ageing Study (EMAS). N‐terminal propeptide of type I procollagen (PINP) and C‐terminal cross‐linked telopeptide of type I collagen (CTX‐I) serum levels were measured in all men. BMD at the calcaneus was estimated by quantitative ultrasound (QUS) in all men. Lumbar spine and total‐hip areal BMD (BMD_a) was measured by dual‐energy X‐ray absorptiometry (DXA) in a subsample of 620 men. Multiple OPG, RANK, and RANKL SNPs were associated with bone turnover markers. We also identified a number of SNPs associated with BMD, including rs2073618 in OPG and rs9594759 near RANKL. The minor allele of rs2073618 (C) was associated with higher levels of both PINP (β = 1.83, p = .004) and CTX‐I (β = 17.59, p = 4.74 × 10^?4), and lower lumbar spine BMD_a (β = ?0.02, p = .026). The minor allele of rs9594759 (C) was associated with lower PINP (β = ?1.84, p = .003) and CTX‐I (β = ?27.02, p = 6.06 × 10^?8) and higher ultrasound BMD at the calcaneus (β = 0.01, p = .037). Our findings suggest that genetic variation in the RANKL/RANK/OPG signaling pathway influences bone turnover and BMD in European men. © 2010 American Society for Bone and Mineral Research     

The effects of calcitonin on bone resorption in hyperthyroidism: a placebo-controlled clinical study

The effects of intranasal calcitonin on bone metabolism were investigated in patients with hyperthyroidism. Urinary deoxypyridinoline (uDPD) levels were measured as a bone turnover marker and lumbar spine (L2) bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry (DEXA) in 7 patients who were given only antithyroid drug (group 1), in 10 patients who were given antithyroid drug plus intranasal calcitonin (group 2), and in 10 healthy subjects who were given placebo (group 3) at the beginning and at the end of the study. The study continued until the patients with hyperthyroidism became euthyroidic according to the laboratory values. This period was approximately 3 months in groups 1 and 2. At the beginning of the study, uDPD was 21.5 ± 2.6nM DPD/mM creatinine in group 1, 23.3 ± 3.6nM DPD/mM creatinine in group 2, and 4.3 ± 1.2nM DPD/mM creatinine in group 3. uDPD levels measured in groups 1 and 2 were significantly higher than those in group 3 (P 0.001). Area BMD Z scores of the patients in groups 1 and 2 were significantly lower than the healthy controls (P 0.01, for both). At the end of the study, uDPD was 11.5 ± 1.6nM DPD/mM creatinine in group 1, 5.3 ± 0.6nM DPD/mM creatinine in group 2, and 4.4 ± 1.3nM DPD/mM creatinine in group 3. The levels of uDPD obtained in group 1 were significantly higher than those obtained in groups 2 and 3 (P 0.05, for both). The difference between groups 2 and 3 was not significant. Area BMD Z scores measured at the end of the study were found to be increased in groups 1 and 2 compared to early values, but the values were slightly lower than the normal values. In comparison of early and late uDPD values, the decrease in late period was statistically significant in groups 1 (P 0.05) and 2 (P 0.001). We concluded that bone turnover is high in hyperthyroidism. The treatment of hyperthyroidism decreases the rate of bone turnover, but it is not sufficient to prevent the degradation of bone in hyperthyroidism. The addition of intranasal calcitonin to the treatment of hyperthyroidism prevents the degradation of bone.     

Serum 25-hydroxyvitamin D, parathyroid hormone, and bone mineral density in men: the Rancho Bernardo study

Introduction This study examined the distribution and determinants of serum 25-hydroxyvitamin D (25OHD) and parathyroid hormone (PTH) and their associations with bone mineral density (BMD) at the hip and spine in 414 older men (mean age 74 years) living in southern California.Methods At a clinic visit (1997–2000), demographic and lifestyle information, fracture history, and medication use were recorded; venous blood for serum 25OHD and PTH was obtained; and BMD was measured at the hip and spine.Results Only one man had vitamin D deficiency (25OHD <20 nmol/l), but 15.5% of the men had high parathyroid levels (PTH ≥65 pg/ml). The mean 25OHD and PTH levels were 109.0 nmol/l and 50.3 pg/ml, respectively. Overall, 21.5% used calcium and 9.7% used vitamin D supplements. Serum 25OHD decreased with age and was lowest in the winter; levels were higher in supplement users (vitamin D and/or calcium; p<0.01). Serum PTH did not vary by age or season, and it was lower in supplement users (p<0.01). After excluding 12 men who were outliers for serum 25OHD and PTH, there was no significant correlation between serum 25OHD and PTH (r=−0.05, p=0.3). In multiple adjusted models, serum 25OHD was positively associated with BMD at the hip (p=0.01) and spine (p=0.001). Serum PTH was moderately and inversely associated with BMD at the hip (p=0.04) but not at the spine (p=0.77).Conclusion We conclude that serum 25OHD is associated with bone health in older, community-dwelling men.     

Increased bone resorption in HD patients: is it caused by elevated RANKL synthesis?

BACKGROUND: The receptor activator of nuclear factor kappaB ligand (RANKL), produced by osteoblasts/stromal cells, is a member of the RANK/RANKL/OPG system, which regulates bone resorption by osteoclasts. Since RANKL and osteoprotegerin (OPG) production in bone is influenced by parathyroid hormone (PTH), we measured serum RANKL and OPG concentrations in haemodialysis (HD) patients, who commonly hypersecrete PTH. We aimed to determine if clinically demonstrated PTH-enhanced bone resorption is a consequence of increased RANKL synthesis. METHODS: RANKL, OPG, osteocalcin, intact PTH, bone-specific alkaline phosphatase, tartrate-resistant acid phosphatase 5b and beta-CrossLaps (CTx) were measured in blood samples from 80 HD patients and 50 age-matched controls. HD patients were stratified to tertiles according to their serum PTH levels: 29.3-103.0, 109.7-263.0 and 262.0-1700.0 pg/ml in the first, second and third tertiles, respectively. RESULTS: Mean serum RANKL levels were 1.6 times higher in HD patients than in age-matched controls (1.36+/-0.39 vs 0.83+/-0.70 pmol/l; P<0.001). All the measured bone markers significantly differed between patients and controls (P<0.001). Spearman's tests of correlation showed a statistically significant association of RANKL with PTH, osteocalcin and CTx (r=0.322, P=0.004; r=0.231, P=0.039; and r=0.230, P=0.040, respectively). Mean serum RANKL levels were significantly different between PTH tertiles (P = 0.003), but serum OPG levels were not (P=0.144). The highest RANKL levels were measured in the upper PTH tertile (1.54+/-0.39 pmol/l) and were significantly higher than in the middle or lower tertiles (1.27+/-0.42 and 1.23+/-0.26 pmol/l, respectively; P=0.003). Both of the measured bone-resorption markers, tartarate-resistant acid phosphatase 5b and CTx, as well as both bone formation markers, osteocalcin and bone-specific alkaline phosphatase were also significantly higher in the upper tertile, indicating that whole-bone remodelling is activated at high PTH and RANKL levels. CONCLUSIONS: Serum RANKL levels were significantly higher in HD patients than in healthy age-matched controls. Moreover, RANKL levels were significantly higher in the upper PTH tertile, indicating enhanced RANKL synthesis in a PTH-dependent fashion. Thus, our clinical findings clearly support published in vitro studies that demonstrated a stimulating effect of PTH on RANKL synthesis. Therefore, the hypothesis that PTH increases bone resorption in HD patients through RANKL appears valid.     

Age-related changes in bone biochemical markers and their relationship with bone mineral density in normal Chinese women

Measurements of bone biochemical markers are increasingly being used to evaluate the state of bone turnover in the management of bone metabolic diseases, especially osteoporosis. However, changes in the bone turnover rate vary with age. The aim of this study was to establish the laboratory reference range of serum bone-specific alkaline phosphatase (sBAP), serum type I collagen cross-linked C-terminal telopeptide (sCTx), and urine CTx (uCTx), based on values from 665 healthy Chinese women aged 20–80 years. We measured the levels of sBAP, sCTx, serum alkaline phosphatase (sALP), and uCTx and evaluated the age-related changes and their relationship with bone mineral density (BMD) in the anteroposterior (AP) lumbar spine, hip, and left forearm. We found significant correlations between biochemical markers and age, with coefficients of determination (R ²) of 0.358 for sBAP, 0.126 for sCTx, 0.125 for uCTx, and 0.336 for sALP. The net changes in different biochemical markers were inversely correlated with the rates of BMD loss in the AP lumbar spine. After correction for age, body weight, and height, the levels of the markers had significant negative correlations with the BMD of the AP lumbar spine, femoral neck, and ultradistal forearm. All four biochemical markers had the highest negative correlation with BMD of the AP lumbar spine (partial correlation coefficients of −0.366, −0.296, −0.290, and −0.258 for sBAP, sCTx, uCTx, and sALP, respectively). The mean and SD values of these markers in premenopausal and postmenopausal women with normal BMD values were used as the normal reference ranges. The reference ranges of sBAP, sCTx, and uCTx for pre- vs postmenopausal women were 17.3 ± 6.23 vs 18.9 ± 7.52 U/l, 3.18 ± 1.49 vs 3.23 ± 1.57 nmol/l, and 15.5 ± 11.4 vs 16.2 ± 12.4 nM bone collagen equivalents/mM urinary creatinine, respectively. Levels of the bone formation marker (sBAP) and bone resorption markers (sCTx, uCTx) increased rapidly in women with osteopenia or osteoporosis, indicating that they may be sensitive markers to determine the bone turnover rate in healthy Chinese women.     

Vitamin D Status,Parathyroid Function,Bone Turnover,and BMD in Postmenopausal Women With Osteoporosis: Global Perspective

Poor vitamin D status is common in the elderly and is associated with bone loss and fractures. The aim was to assess worldwide vitamin D status in postmenopausal women with osteoporosis according to latitude and economic status, in relation to parathyroid function, bone turnover markers, and BMD. The study was performed in 7441 postmenopausal women from 29 countries participating in a clinical trial on bazedoxifene (selective estrogen receptor modulator), with BMD T‐score at the femoral neck or lumbar spine ≤ ?2.5 or one to five mild or moderate vertebral fractures. Serum 25(OH)D, PTH, alkaline phosphatase (ALP), bone turnover markers osteocalcin (OC) and C‐terminal cross‐linked telopeptides of type I collagen (CTX), and BMD of the lumbar spine, total hip, femoral neck, and trochanter were measured. The mean serum 25(OH)D level was 61.2 ± 22.4 nM. The prevalence of 25(OH)D <25, 25–50, 50–75, and >75 nM was 5.9%, 29.4%, 43.5%, and 21.2%, respectively, in winter and 3.0%, 22.2%, 47.2%, and 27.5% in summer. Worldwide, a negative correlation between 25(OH)D and latitude was observed. With increasing 25(OH)D categories of <25, 25–50, 50–75, and >75 nM, mean PTH, OC, and CTX were decreasing (p < 0.001), whereas BMD of all sites was increasing (p < 0.001). A threshold in the positive relationship between 25(OH)D and different BMD parameters was visible at a 25(OH)D level of 50 nM. Our study showed a high prevalence of low 25(OH)D in postmenopausal women with osteoporosis worldwide. Along with latitude, affluence seems to be an important factor for serum 25(OH)D level, especially in Europe, where it is strongly correlated with latitude.