Markus J. Seibel

The Use of Biochemical Markers of Bone Turnover in Osteoporosis

The assay features of biochemical markers of bone turnover have markedly improved in the past few years. The most sensitive and specific markers of bone formation include serum bone alkaline phosphatase, total osteocalcin (including the intact molecule and the large N-Mid fragment) and the N extension peptide of type I collagen (PINP) measured with a recently developed radioimmunoassay. Among the various markers of bone resorption, measurements of the urinary excretion of the (deoxy) pyridinoline crosslinks and of N- and C- related telopeptides (NTX and CTX respectively) are the most sensitive and specific ones. In addition, a two-site immunoassay of serum CTX is now widely available. Bone markers can be used to predict the rate of bone loss in postmenopausal women. Three independent studies have shown that high bone turnover is associated with increased bone loss over 4 to 15 years in women aged 50 to 70 years. In addition, we have shown in elderly women that increased bone resorption, i.e. above the premenopausal range, is associated with a two-fold increase in the risk of hip fractures and that those with both a low BMD (T score < -2.5) and increased bone resorption have a 4- to 5- fold increase in hip fracture risk. We have recently confirmed that increased bone turnover predicts the risk of fragility fractures in a younger cohort of postmenopausal women followed for an average of 5 years. The mechanisms underlying the increased bone turnover in some (but not all) postmenopausal women are unknown. The increase appears to be independent from the residual secretion of 17 s estradiol (E2), assessed by a highly sensitive radioimmunoassay. Indeed, we found that a low serum E2 predicts the risk of fragility fractures in late postmenopausal women (but not in the elderly) independently of the rate of bone turnover. Bone markers can be used to monitor the efficacy of antiresorptive therapy such as hormone replacement therapy, raloxifene and bisphosphonates. We and others have shown that the short-term (3 to 6 months) decrease of bone turnover is significantly correlated with the long-term (2 years) increase in BMD of the spine. In addition, the decrease of serum osteocalcin is associated with the risk of vertebral fractures in osteoporotic women treated with raloxifene. Similar studies in patients using alendronate or risedronate show that the short-term decrease of bone turnover markers is correlated with the risk of subsequent fractures. Thus, with adequate cut-offs, individual patients can be monitored with bone markers earlier than with DXA. It remains to be assessed if such a monitoring can improve long-term compliance with therapy.

Polypharmacy cutoff and outcomes: five or more medicines were used to identify community-dwelling older men at risk of different adverse outcomes

OBJECTIVE This study aimed to determine an optimal discriminating number of concomitant medications associated with geriatric syndromes, functional outcomes, and mortality in community-dwelling older men. STUDY DESIGN AND SETTING Older men aged ≥ 70 years (n=1,705), enrolled in the Concord Health and Aging in Men Project were studied. Receiver operating characteristic curve analysis using the Youden Index and the area under the curve was performed to determine discriminating number of medications in relation to each outcome. RESULTS The highest value of the Youden Index for frailty was obtained for a cutoff point of 6.5 medications compared with a cutoff of 5.5 for disability and 3.5 for cognitive impairment. For mortality and incident falls, the highest value of Youden Index was obtained for a cutoff of 4.5 medications. For every one increase in number of medications, the adjusted odds ratios were 1.13 (95% confidence interval [CI]=1.06-1.21) for frailty, 1.08 (95% CI=1.00-1.15) for disability, 1.09 (95% CI=1.04-1.15) for mortality, and 1.07 (95% CI=1.03-1.12) for incident falls. There was no association between increasing number of medications and cognitive impairment. CONCLUSION The study supports the use of five or more medications in the current definition of polypharmacy to estimate the medication-related adverse effects for frailty, disability, mortality, and falls.

Bone mass, vitamin D deficiency, and hyperparathyroidism in congestive heart failure.

PURPOSE In contrast to renal and hepatic failure, congestive heart failure (CHF) has not been associated with a defined metabolic bone disorder. However, low bone mass has been reported in patients with CHF who receive a cardiac transplant. Both the pathophysiology and therapy of CHF may influence bone and mineral homeostasis and evidence that calciotropic hormones may affect cardiovascular function is accumulating. Therefore, we evaluated patients with severe CHF to determine the prevalence of osteoporosis and to characterize relationships between mineral homeostasis, bone turnover, bone mass, and severity of CHF. PATIENTS AND METHODS One hundred one patients (79 men and 22 women, aged 25 to 70 years) with severe CHF (New York Heart Association functional class III or IV) referred for consideration for cardiac transplantation were evaluated with measurements of serum 25-hydroxyvitamin D (25-OHD), 1,25 dihydroxyvitamin D [1,25(OH)2D], intact parathyroid hormone (PTH), markers of bone turnover (serum osteocalcin, urinary hydroxyproline, and pyridinium crosslinks); bone mineral density (BMD) by dual energy x-ray absorptiometry was measured in 91 patients. Left ventricular ejection fraction (LVEF) and resting cardiac output (CO) were determined in 88 and maximal treadmill exercise testing and peak oxygen consumption were performed in 45 patients. RESULTS Osteoporosis (T score < or = -2.5) was present in 7% at the lumbar spine, 6% at the total hip, and 19% at the femoral neck. Osteopenia (T scores between -1.0 and -2.5) was present in 43% at the lumbar spine, 47% at the total hip, and 42% at the femoral neck. Women were more severely affected (P = 0.007). Frankly low serum 25-OHD (< or = 9 pg/mL) and 1,25(OH)2D (< or = 15 pg/mL) levels were found in 17% and 26% of the patients, respectively, and elevated serum PTH (> or = 65 pg/mL) in 30%. Both low serum 1,25(OH)2D and increased serum PTH were associated with prerenal azotemia. Low serum vitamin D metabolites were associated with biochemical evidence of increased bone turnover, but BMD did not differ by vitamin D or PTH status. Patients with more severe CHF had significantly lower vitamin D metabolites and higher bone turnover, whereas elevated PTH was associated with better LVEF (21 +/- 1 versus 18 +/- 1%; P = 0.05) and correlated positively with resting CO (R = 0.220; P = 0.04). CONCLUSIONS Osteopenia or osteoporosis were observed in approximately half of these patients with severe CHF. Abnormal calciotropic hormone concentrations, also common, were associated with evidence of increased bone resorption but were not related to BMD in this cross-sectional study. Abnormal concentrations of calciotropic hormones were related to the severity of cardiovascular compromise. Because both low BMD and low serum concentrations of 25-OHD in patients with CHF are associated with higher rates of bone loss and fracture after cardiac transplantation, patients should be evaluated for and receive appropriate therapy for these disorders.

Loss of muscle strength, mass (sarcopenia), and quality (specific force) and its relationship with functional limitation and physical disability: the Concord Health and Ageing in Men Project.

OBJECTIVES: To determine the association between loss of muscle strength, mass, and quality and functional limitation and physical disability in older men.

Endogenous sex hormones and incident fracture risk in older men: the dubbo osteoporosis epidemiology study.

BACKGROUND Data on the influence of gonadal hormones on incident fracture risk in elderly men are limited. We prospectively examined the relationship between serum levels of testosterone and estradiol and future fracture risk in community-dwelling men. METHODS A total of 609 men older than 60 years had been observed between January 1989 and December 2005, with the median duration being 5.8 years (up to 13 years). Clinical risk factors, including bone mineral density and lifestyle factors, were assessed at baseline. Serum testosterone and estradiol levels were measured by tandem mass spectrometry. The incidence of a low-trauma fracture was ascertained during follow-up. RESULTS During follow-up, 113 men had at least 1 low-trauma fracture. The risk of fracture was significantly increased in men with reduced testosterone levels (hazard ratio [HR], 1.33; 95% confidence interval [CI], 1.09-1.62). After adjustment for sex hormone-binding globulin, serum testosterone (HR, 1.48; 95% CI, 1.22-1.78) and serum estradiol (HR, 1.21; 95% CI, 1.00-1.47) levels were associated with overall fracture risk. After further adjustment for major risk factors of fractures (age, weight or bone mineral density, fracture history, smoking status, calcium intake, and sex hormone-binding globulin), lower testosterone was still associated with increased risk of fracture, particularly with hip (HR, 1.88; 95% CI, 1.24-2.82) and nonvertebral (HR, 1.32; 95% CI, 1.03-1.68) fractures. CONCLUSION In community-dwelling men older than 60 years, serum testosterone is independently associated with the risk of osteoporotic fracture and its measurement may provide additional clinical information for the assessment of fracture risk in elderly men.

Case-control analysis of bone resorption markers, disability, and hip fracture risk: the Rotterdam study

Several factors besides bone mineral mass have been related to the risk of hip fracture. Bone quality, the rate of bone loss, and non-skeletal factors have been identified as important.1 2 High rates of bone resorption may be associated with disruption of the trabecular network as well as with an increased rate of bone loss. Furthermore, immobility associated with disability induces bone resorption not followed by increased bone formation.3 Urinary pyridinium crosslinks are markers of bone resorption. We investigated whether these were associated with the risk of hip fracture and also whether such an association was attributable to disability. This nested case-control analysis was conducted as part of the Rotterdam study, a prospective cohort study of the incidence of and risk factors for chronic disabling diseases.4 Briefly, all 10275 residents of a district of Rotterdam aged 55 or over were invited to participate. The study consisted of an initial home interview followed by a series …

Supplementation With Oral Vitamin D3 and Calcium During Winter Prevents Seasonal Bone Loss: A Randomized Controlled Open-Label Prospective Trial†

Bone metabolism follows a seasonal pattern with high bone turnover and bone loss during the winter. In a randomized, open‐label 2‐year sequential follow‐up study of 55 healthy adults, we found that supplementation with oral vitamin D3 and calcium during winter abolished seasonal changes in calciotropic hormones and markers of bone turnover and led to an increase in BMD. Supplementation with oral vitamin D3 and calcium during the winter months seems to counteract the effects of seasonal changes in vitamin D and thus may be beneficial as a primary prevention strategy for age‐related bone loss.

Urinary pyridinium crosslinks of collagen: specific markers of bone resorption in metabolic bone disease.

The hydroxypyridinium compounds pyridinoline and deoxypyridinoline are specific constituents of mature skeletal collagens. They are released into the circulation and excreted in the urine. Their measurement in urine is a sensitive index of the extent of ongoing bone resorption. Currently, quantification of collagen crosslinks in urine is achieved by chromatographic techniques, but more convenient immunoassays will make these measurements more widely available in the near future. Clinical applications of hydroxypyridinium markers include numerous metabolic bone disorders such as osteoporosis, primary hyperparathyroidism, Pagets disease of bone, and metastatic bone disease. Urinary pyridinium crosslinks of collagen also show great promise as markers of therapeutic efficacy in bone disorders associated with accelerated bone resorption.

Vitamin D and health in adults in Australia and New Zealand: a position statement

The prevalence of vitamin D deficiency varies, with the groups at greatest risk including housebound, community‐dwelling older and/or disabled people, those in residential care, dark‐skinned people (particularly those modestly dressed), and other people who regularly avoid sun exposure or work indoors. Most adults are unlikely to obtain more than 5%–10% of their vitamin D requirement from dietary sources. The main source of vitamin D for people residing in Australia and New Zealand is exposure to sunlight. A serum 25‐hydroxyvitamin D (25‐OHD) level of ≥ 50 nmol/L at the end of winter (10–20 nmol/L higher at the end of summer, to allow for seasonal decrease) is required for optimal musculoskeletal health. Although it is likely that higher serum 25‐OHD levels play a role in the prevention of some disease states, there is insufficient evidence from randomised controlled trials to recommend higher targets. For moderately fair‐skinned people, a walk with arms exposed for 6–7 minutes mid morning or mid afternoon in summer, and with as much bare skin exposed as feasible for 7–40 minutes (depending on latitude) at noon in winter, on most days, is likely to be helpful in maintaining adequate vitamin D levels in the body. When sun exposure is minimal, vitamin D intake from dietary sources and supplementation of at least 600 IU (15 μg) per day for people aged ≤ 70 years and 800 IU (20 μg) per day for those aged > 70 years is recommended. People in high‐risk groups may require higher doses. There is good evidence that vitamin D plus calcium supplementation effectively reduces fractures and falls in older men and women.

Bone Resorption and Osteoporotic Fractures in Elderly Men: The Dubbo Osteoporosis Epidemiology Study

Among the potential risk factors for fragility fractures, bone turnover is considered an important determinant. In a case‐cohort control study of 151 elderly men followed prospectively over 6.3 years, high bone resorption as assessed by S‐ICTP was associated with increased risk of osteoporotic fracture, independent of BMD. Combining measurements of BMD and bone turnover may improve fracture prediction in elderly men.