Pawel Szulc

Biochemical measurements of bone turnover in children and adolescents

Abstract: Biochemical measurements of bone turnover are helpful in the study of the pathophysiology of skeletal metabolism and growth. However, interpretation of their results is difficult because they depend on age, pubertal stage, growth velocity, mineral accrual, hormonal regulation, nutritional status, circadian variation, day-to-day variation, method of expression of results of urinary markers, specificity for bone tissue, sensitivity and specificity of assays. Three markers of bone formation have been described including their bone specificity and age-related changes: osteocalcin, alkaline phosphatase and its skeletal isoenzyme, procollagen I extension peptides. Bone resorption markers (hydroxyproline; deoxypyridinoline; pyridinoline; peptides containing these crosslinks such as N-telopeptide to helix in urine (NTX), C-telopeptide-1 to helix in serum (ICTP) and C-telopeptide-2 in urine and serum (CTX); tartrate-resistant acid phosphatase; hydroxylysine and its glycosides) are described with special attention to methodologic issues, mainly ways of expression of their results. Changes of bone turnover during growth are described during four periods: infancy, prepubertal period, puberty and the postpubertal period. Pubertal changes of bone markers are described with special attention to gender differences and hormonal mechanisms of the growth spurt which determine differences related to the pubertal stage. Disturbances of bone turnover in four conditions are described to illustrate the impact of such diseases on growth and formation of peak bone mass: prematurity, malnutrition, growth hormone deficiency and corticosteroid-treated bronchial asthma. Available data suggest biochemical markers of bone remodeling may be useful in the clinical investigation of bone turnover in children in health and disease. However, their use in everyday clinical practice is not advised at present.

Serum undercarboxylated osteocalcin is a marker of the risk of hip fracture: A three year follow-up study

We have previously shown that elderly women with an increased serum undercarboxylated osteocalcin (ucOC) level have an increased risk of sustaining a hip fracture as compared to those with normal serum ucOC. We reassessed our findings on a larger number of hip fractures that occurred over 3 years in 183 institutionalized women (aged 70-97 years) belonging to a large prospective clinical trial. Total OC, carboxylated OC, ucOC, and alkaline phosphatase were significantly higher at baseline in those who sustained a hip fracture during the follow-up. The age-adjusted odds ratio for hip fracture was three times higher in women with increased ucOC at baseline (odds ratio = 3.1, 99.9% C.I. = 1.7-6.0, p < 0.001). In the logistic regression, ucOC was still predictive of the hip fracture when age and parathyroid hormone concentration were included into the model (odds ratio = 2.6, 95% C.I. = 1.05-6.4). These data confirm that ucOC is a marker of the increased risk of hip fracture in elderly institutionalized women. Serum ucOC may reflect some nutritional deficiency associated with increased bone fragility.

Low Skeletal Muscle Mass Is Associated With Poor Structural Parameters of Bone and Impaired Balance in Elderly Men—The MINOS Study

In 796 men, 50‐85 years of age, decreased relative skeletal muscle mass index was associated with narrower bones, thinner cortices, and a consequent decreased bending strength (lower section modulus), as well as with impaired balance and an increased risk of falls.

Bone Fragility: Failure of Periosteal Apposition to Compensate for Increased Endocortical Resorption in Postmenopausal Women

The increase in bone fragility after menopause results from reduced periosteal bone formation and increased endocortical resorption. Women with highest remodeling had greatest loss of bone mass and estimated bone strength, whereas those with low remodeling lost less bone and maintained estimated bone strength.

Biochemical markers of bone turnover: potential use in the investigation and management of postmenopausal osteoporosis

IntroductionThe aim was to analyse data on the use of biochemical bone turnover markers (BTM) in postmenopausal osteoporosis.MethodsWe carried out a comparative analysis of the most important papers concerning BTM in postmenopausal osteoporosis that have been published recently.ResultsThe BTM levels are influenced by several factors. They are moderately correlated with BMD and subsequent bone loss. Increased levels of bone resorption markers are associated with a higher risk of fracture. Changes in the BTM during the anti-osteoporotic treatment (including combination therapy) reflect the mechanisms of action of the drugs and help to establish their effective doses. Changes in the BTM during the anti-resorptive treatment are correlated with their anti-fracture efficacy.ConclusionBiological samples should be obtained in a standardised way. BTM cannot be used for prediction of the accelerated bone loss at the level of the individual. BTM help to detect postmenopausal women who are at high risk of fracture; however, adequate practical guidelines are lacking. BTM measurements taken during the anti-resorptive therapy help to identify non-compliers. They may improve adherence to the anti-resorptive therapy and the fall in the BTM levels that exceeds the predefined threshold improves patients’ persistence with the treatment. There are no guidelines concerning the use of BTM in monitoring anti-osteoporotic therapy in postmenopausal women.

Cross-sectional assessment of age-related bone loss in men: the MINOS study

There are few data on osteoporosis in men, but cross-sectional studies have shown that age-related bone loss in men is of lower magnitude than in women. To elucidate some controversies related partially to methodological aspects, we measured bone mineral density (BMD) by dual-energy X-ray absorptiometry (DEXA) at various skeletal sites (spine, hip, and whole body using a Hologic QDR-1500 device; forearm using an Osteometer DTX 100 device) in a large cohort of 1040 men, aged 19-85 years. The final investigation was performed on 934 men, aged 19-85 years, after exclusion of 106 men with disease or treatment known to affect bone metabolism. Peak BMD was achieved at 25 and 29 years at the lumbar spine and hip, respectively, but only at 40 and 37 years at the distal forearm and whole body, respectively. The magnitude of bone loss between peak bone mass and 80 years of age was linear at most sites and averaged 13%-18%; that is, SD of 1.1-1.8 from peak BMD, except for Wards triangle, which showed a marked bone loss of 43% (i.e., 2.5 SD), and for the lumbar spine. In the entire cohort, increase of the average lumbar spine BMD after the age of 55 years was related to the development of osteoarthritis, because, in men without severe arthritis, lumbar spine BMD continued to decrease. Height-adjusted partial correlations indicate that both the mineral content and the area of long bones of the limbs increased with age up to 50 years, followed by a significant decrease of BMD without change of bone surface. SD of mean BMD increased significantly with age at most skeletal sites. In summary, age-related change of BMD varied according to skeletal site in men with peak bone mass achieved earlier at sites rich in trabecular bone than at those rich in cortical bone. Bone loss varied according to skeletal site from 14% to 43%. The variability of BMD increased with age, which may reflect interindividual variability of age-related bone loss.

Contribution of Trochanteric Soft Tissues to Fall Force Estimates, the Factor of Risk, and Prediction of Hip Fracture Risk*†‡§

We compared trochanteric soft tissue thickness, femoral aBMD, and the ratio of fall force to femoral strength (i.e., factor of risk) in 21 postmenopausal women with incident hip fracture and 42 age‐matched controls. Reduced trochanteric soft tissue thickness, low femoral aBMD, and increased ratio of fall force to femoral strength (i.e., factor of risk) were associated with increased risk of hip fracture.

Cross-Sectional Evaluation of Bone Metabolism in Men*

There are relatively few data concerning age‐related changes of bone turnover in men. The aim of the study was to evaluate age‐related changes of the levels of serum and urinary biochemical markers of bone metabolism in a large cohort of 934 men aged 19–85 years and to investigate their association with bone mineral density (BMD). Bone formation was evaluated using serum levels of osteocalcin (OC), bone alkaline phosphatase (BAP), and N‐terminal extension propeptide of type I collagen (PINP). Bone resorption was evaluated by measurement of urinary excretion of β‐isomerized C‐terminal telopeptide of collagen type I (β‐CTX) of free deoxypyridinoline (fDpyr) and total Dpyr (tDPyr) and of the serum level of β‐CTX. Levels of biochemical bone markers were very high in young men and decreased rapidly until the age of 40 years and then more slowly until 60 years of age. After the age of 60 years, markers of bone formation remained stable while resorption markers showed a moderate and variable increase with aging. Serum and urinary β‐CTX levels were elevated only in about 5% of elderly men. The age‐related increase of urinary excretion of tDpyr and of its free and peptide‐bound fractions was related to the presence of elevated levels in a subgroup of about 15% of elderly men. Before 60 years of age, levels of biochemical bone markers were not correlated with BMD, whereas after 60 years of age, they were correlated negatively with BMD. After adjustment for age and body weight, BMD in men with the highest levels of biochemical bone markers (i.e., in the upper quartile) was 1.8–12.5% (i.e., 0.25–0.89 SD) lower than in men with levels of biochemical bone markers in the lowest quartile. In conclusion, bone turnover in men is high in young adults and decreases to reach a nadir at 55–60 years of age. After the age of 60 years, bone resorption markers—but not bone formation markers—increase in some men and are associated with lower BMD, suggesting that this imbalance is responsible for increasing bone loss in elderly men.

Finite element analysis performed on radius and tibia HR-pQCT images and fragility fractures at all sites in men

Few studies have investigated bone microarchitecture and biomechanical properties in men. This study assessed in vivo both aspects in a population of 185 men (aged 71 ± 10 years) with prevalent fragility fractures, compared to 185 controls matched for age, height, and weight, from the Structure of the Aging Mens Bones (STRAMBO) cohort.

Cross‐sectional analysis of the association between fragility fractures and bone microarchitecture in older men: The STRAMBO study

Areal bone mineral density (aBMD) measured by dual‐energy X‐ray absorptiometry (DXA) identifies 20% of men who will sustain fragility fractures. Thus we need better fracture predictors in men. We assessed the association between the low‐trauma prevalent fractures and bone microarchitecture assessed at the distal radius and tibia by high‐resolution peripheral quantitative computed tomography (HR‐pQCT) in 920 men aged 50 years of older. Ninety‐eight men had vertebral fractures identified on the vertebral fracture assessment software of the Hologic Discovery A device using the semiquantitative criteria, whereas 100 men reported low‐trauma peripheral fractures. Men with vertebral fractures had poor bone microarchitecture. However, in the men with vertebral fractures, only cortical volumetric density (D.cort) and cortical thickness (C.Th) remained significantly lower at both the radius and tibia after adjustment for aBMD of ultradistal radius and hip, respectively. Low D.cort and C.Th were associated with higher prevalence of vertebral fractures regardless of aBMD. Severe vertebral fractures also were associated with poor trabecular microarchitecture regardless of aBMD. Men with peripheral fractures had poor bone microarchitecture. However, after adjustment for aBMD, all microarchitectural parameters became nonsignificant. In 15 men with multiple peripheral fractures, trabecular spacing and distribution remained increased after adjustment for aBMD. Thus, in men, vertebral fractures and their severity are associated with impaired cortical bone, even after adjustment for aBMD. The association between peripheral fractures and bone microarchitecture was weaker and nonsignificant after adjustment for aBMD. Thus bone microarchitecture may be a determinant of bone fragility in men, which should be investigated in prospective studies.