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Bone turnover markers (BTMs) are used widely, in both research and clinical practice. In the last 20 years, much experience has been gained in measurement and interpretation of these markers, which include commonly used bone formation markers (bone alkaline phosphatase, osteocalcin, and procollagen I N-propeptide); and commonly used resorption markers (serum C-telopeptides of type I collagen, urinary N-telopeptides of type I collagen, and tartrate-resistant acid phosphatase type 5b). BTMs are usually measured by enzyme-linked immunosorbent assay or automated immunoassay. Sources contributing to BTM variability include uncontrollable factors (eg, age, gender, ethnicity) and controllable factors, particularly relating to collection conditions (eg, fasting/feeding state, and timing relative to circadian rhythms, menstrual cycling, and exercise). Pregnancy, season, drugs, and recent fracture(s) can also affect BTMs. BTMs correlate with other methods of assessing bone turnover, such as bone biopsies and radiotracer kinetics, and can usefully contribute to diagnosis and management of several diseases such as osteoporosis, osteomalacia, Paget’s disease, fibrous dysplasia, hypophosphatasia, primary hyperparathyroidism, and chronic kidney disease–mineral bone disorder.

Treatment of postmenopausal osteoporosis with teriparatide parathyroid hormone amino terminal 1-34 increases bone formation and improves bone microarchitecture. A possible modulator of action is periostin. In vitro experiments have shown that periostin might regulate osteoblast differentiation and bone formation through Wnt signaling. The effect of teriparatide on periostin is not currently known.

Senescent cells and senescence-associated secretory phenotype (SASP) proteins are involved in age-related bone loss. Growth differentiation factor 15 (GDF 15), a stress-responsive cytokine member of the transforming growth factor-β (TGF-β) superfamily, is one of the key SASP proteins. It is strongly associated with age and higher levels correlate with frailty and are detected in several conditions and diseases. It also modulates appetite and body weight through the binding to its receptor glial cell- derived neurotrophic factor family receptor alpha- like (GFRAL) in the brainstem. The GDF 15 involvement in bone metabolism has been studied in several murine models, however, it is still unclear in humans. Therefore, this study aims to determine whether GDF 15 is associated with bone mineral density (BMD) and bone turnover, and to establish the effect of age and gender on its levels. Serum GDF 15 was measured with an ELISA from R&D Systems in 180 healthy women and men from the “XtremeCT study”, divided into three age groups which represent different stages of skeletal development (16–18, 30–32, over 70 years). We also measured bone resorption marker C-terminal telopeptide of type I collagen (CTX) and bone formation markers N-terminal propeptide of type I collagen (PINP), osteocalcin (OC) and bone alkaline phosphatase (BAP) using iSYS-IDS analyser. Parathyroid hormone (PTH), 25hydroxyvitamin D (25OH-vitamin D), Insulin-like Growth Factor I (IGF-1), estradiol and testosterone were measured using the Cobas automated analyser (Roche Diagnostics). We assessed BMD at spine and total hip by dual-energy x-ray absorptiometry (DXA) and high resolution peripheral quantitative computed tomography (HRpQCT) of the radius and tibia. Univariate analysis of variance with the post-hoc Sheffe test and multiple linear regression has been used to assess the effect of age and gender. Spearman's rank correlation was used to evaluate the associations between GDF 15 and the other variables. We found GDF 15 levels significantly associated with age (p < 0.001) and gender (p = 0.008), with a significant gender ∗ age interaction (p < 0.001). Significantly higher levels of GDF 15 were found in subjects aged over 70 compared with the younger people (p < 0.001) and significantly higher levels were detected in men. We did not find any significant correlation between GDF 15 and bone turnover markers (BTMs), BMD, HRpQCT measures and hormones in any of the age groups. In conclusion, age and gender are determinants of GDF15 and much higher levels are found in older people and in men. Since no association was found between GDF 15 and bone health measures, we hypothesize that the effect of GDF 15 on bone might be exert by other tissue, such as muscle.

Aseptic loosening is the most common cause of prosthesis failure after total hip arthroplasty (THA). We measured serum cross-linked carboxyterminal telopeptide of type I collagen (ICTP), tartrate-resistant acid phosphatase 5b (TRAP5b), dickkopf-1 (dkk-1) and sclerostin; and urinary α isomer of C-terminal cross-linked telopeptide of type I collagen (αCTX-I) to investigate their potential diagnostic value detecting aseptic loosening after THA. Biomarkers were measured in 24 subjects with aseptic loosening of THA versus 26 control subjects without loosening after THA. Serum ICTP in the loose group (7.04 ng/mL) was higher than controls (5.15 ng/mL), (p = 0.0007). ROC analysis demonstrated that a serum ICTP >5.5 ng/L had a sensitivity of 91% and specificity of 69% for detecting aseptic loosening (area under ROC curve = 0.77, p = 0.0001), resulting in a positive predictive value (PPV) of 73% and a negative predictive value (NPV) of 90%. Serum TRAP5b in the aseptic loosening group (4.17U/L) was higher than controls (3.44 U/L), (p = 0.03). A serum TRAP5b >2.46 U/L had sensitivity of 100% and a specificity of 31% to detect aseptic loosening (AUC 0.67, p = 0.031), resulting in a PPV of 57% and a NPV of 100%. Serum dkk-1, serum sclerostin and urinary αCTX-I were not elevated in subjects with aseptic loosening (p>0.05).Serum ICTP and TRAP5b show potential utility as screening biomarkers for excluding aseptic loosening, because of their ability to discriminate individuals without disease. Our finding of elevated ICTP, generated by the action of matrix metalloproteinases, suggests a role for this group of endopeptidases in aseptic loosening.

Skin graft contraction leading to loss of joint mobility and cosmetic deformity remains a major clinical problem. In this study we used a tissue-engineered model of human skin, based on sterilized human adult dermis seeded with keratinocytes and fibroblasts, which contracts by up to 60% over 28 days in vitro, as a model to investigate the mechanism of skin contraction. Pharmacologic agents modifying collagen synthesis, degradation, and cross-linking were examined for their effect on contraction. Collagen synthesis and degradation were determined using immunoassay techniques. The results show that skin contraction was not dependent on inhibition of collagen synthesis or stimulation of collagen degradation, but was related to collagen remodelling. Thus, reducing dermal pliability with glutaraldehyde inhibited the ability of cells to contract the dermis. So did inhibition of matrix metalloproteinases and inhibition of lysyl oxidase-mediated collagen cross-linking, but not transglutaminase-mediated cross-linking. In summary, this in vitro model of human skin has allowed us to identify specific cross-linking pathways as possible pharmacologic targets for prevention of graft contracture in vivo.

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

There is debate about the possible deleterious effect of excessive vitamin A exposure on fracture risk. In this nested case control study in older women (312 cases and 934 controls), serum retinol, retinyl palmitate, and β‐carotene were not associated with fracture risk, and there was no evidence of excess risk with multivitamin or cod liver oil supplementation.Introduction:Recent studies have suggested that higher vitamin A intake may account for a component of fracture risk within the general population and that supplemental vitamin A may be harmful even within recommended limits. No studies have examined the relationship between biochemical retinol status and fracture in older women.Materials and Methods:We examined serum retinol, retinyl palmitate, and β‐carotene as predictors of incident hip and other fractures in a large prospective study of British women over the age of 75 years (n= 2606, 312 incident osteoporotic fractures, 92 incident hip fractures; mean follow‐up duration, 3.7 years). Fasting blood samples (9:00‐11:00 a.m.) were collected at baseline. Using a case‐control design (three controls per case), serum retinol, retinyl palmitate, and β‐carotene were assessed as univariate predictors of incident osteoporotic fracture or hip fracture. Baseline BMD at the total hip, age, 25(OH)D, serum β Crosslaps, bone‐specific alkaline phosphatase, weight, height, and smoking were considered as covariates in a multivariate model.Results:Serum retinol, retinyl palmitate, and β‐carotene were not significant univariate predictors of either hip fracture or any fracture (all p> 0.05; Cox proportional hazards regression). For all osteoporotic fractures, the hazard ratio (HR) was 0.92 (95% CI, 0.81‐1.05) per 1 SD increase in serum retinol. Risk of any osteoporotic fracture was slightly less in the highest quartile of serum retinol compared with the lowest quartile (HR, 0.85; 95% CI, 0.69‐1.05; p= 0.132) There was a tendency for increased serum retinol to predict benefit rather than harm in terms of BMD (r= 0.09, p= 0.002). Multivitamin or cod liver oil supplementation was associated with a significantly lower risk of any fracture (HR, 0.76; 95% CI, 0.60‐0.96; p= 0.021). In multivariate analysis, only age, total hip BMD, and weight were associated with fracture risk (p< 0.05).Conclusions:We found no evidence to support any skeletal harm associated with increased serum indices of retinol exposure or modest retinol supplementation in this population.