Dynamics of Bone and Cartilage Metabolism: Principles and Clinical Applications
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Explore Now. Buy As Gift. Overview This updated edition is a comprehensive treatise that spans the complete range of basic biochemistry of bone and cartilage components to the clinical evaluation of disease markers in bone and joint disorders.
Food fortification for bone health in adulthood: a scoping review
With contributions from over 75 international experts, Dynamics of Bone and Cartilage Metabolism, Second Edition , is indispensable reading for those involved in skeletal research as well as for rheumatologists, endocrinologists, clinical biochemists, and other clinical disciplines participating in the management of patients with bone and cartilage diseases.
Part I provides an up-to-date account of current knowledge of the structure, biosynthesis and molecular biology of the major tissue components Part II covers the organizational structure and cellular metabolism of bone and cartilage Part III deals with the utility of components specific to bone and cartilage as biomarkers of health and disease. His research in musculoskeletal biology covers topics such as glucocorticoid signalling in bone and its effects on bone and systemic fuel metabolism and ageing; the biology of bone metastases; and the clinical efficacy of secondary fracture prevention programs.
Prof Seibel has published over scientific papers and is the editor of 8 books. John P. Bilezikian, MD, the Dorothy L.
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He completed four years of house staff training internship, residency and Chief Residency on the Medical Service at Columbia Presbyterian Medical Center. Gerald Aurbach. Bilezikian belongs to a number of professional societies including the American Society for Bone and Mineral Research, of which he served as President, and the International Society of Clinical Densitometry, of which he served as President, He serves on the Board of Governors of the International Osteoporosis Foundation present and on its Committee of Scientific Advisors present.
He is Chair of the Endocrine Fellows Foundation. In , he received the Gideon A. In , he was made honorary member of the Brazilian Society of Endocrinology and Metabolism. His publications number over Show More.
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BTM may be useful in the assessment of fracture risk. Findings of prospective studies have shown that BTM of resorption predict fracture risk in postmenopausal women and in men Table 1 74 , 83 — An increase of these markers above the premenopausal range was associated, after adjustment for aBMD, with a twofold increase in risk for hip, vertebral and non-vertebral fractures, over a follow-up period of 1. The results for the relationship between bone formation markers and fracture risk are not consistent. In contrast, in younger healthy postmenopausal women OFELY and HOS cohorts , a significant association was found between increased BAP serum levels and risk of vertebral as well as non-vertebral fracture 74 , 83 , Table 1 Relationship between increases in bone resorption rate and fracture risk.
These results suggest that a combined approach, with both aBMD and indices of bone turnover, could improve fracture prediction in postmenopausal women. In fact, calculating the absolute risk of fracture by combining clinical risk factor i. In elderly men high bone resorption was also associated with an increased risk of osteoporotic fracture The main domain for the clinical use of BTM is the monitoring of osteoporosis therapy. The ultimate goal in treating patients with osteoporosis is to reduce their fracture risk. However, the short-term incidence of osteoporotic fractures is low, and the absence of fracture during treatment does not necessarily mean that the treatment is effective.
Consequently, serial measurements of changes in aBMD as a surrogate marker of therapeutic efficacy are currently the standard approach to monitor osteoporosis therapy. Yet, changes in aBMD occur slowly and therapeutic effects are usually not detectable before 1—2 or more years of treatment 80 , 91 — Antiresorptive treatment generates a rapid decrease in bone resorption markers after only 2—4 weeks, reaching a plateau after 3 to 6 months of treatment 80 , 95 Fig.
The decrease in bone formation markers, reflecting the physiological coupling of bone formation to bone resorption, is delayed and reaches a plateau after 6—12 months. The magnitude of the decreases varies according to the type and dose of the drug and the marker used to assess the effect Table 2.
The diagrams show the relationship between early changes 3—6 months in BTM and changes in BMD after 2 years of either bone resorption inhibition a or bone formation stimulation b. The decrease in BTM during antiresorptive treatment is inversely related to the subsequent increase in aBMD, predominantly at the lumbar spine 80 , Several studies of postmenopausal women treated with antiresorptive agents hormone replacement therapy, raloxifen, bisphosphonates have indicated that the degree of short-term reduction in BTM after 3 to 6 months correlates with the observed long-term increase in aBMD after 1 to 3 years of treatment 79 , 81 , 95 — There is also some evidence that even a modest decrease in bone mass is nevertheless associated with some fracture risk reduction There is thus substantial evidence that bone mass or changes thereof does not explain satisfactorily either the skeletal fragility of osteoporosis or the effects of bone active agents It is therefore possible that changes in other determinants of bone strength, including the rate of bone turnover, may be more predictive of anti-fracture efficacy than changes in aBMD.
In contrast to antiresorptive agents, PTH fragments administered intermittently in low doses increase bone remodelling, stimulating bone formation preferentially over bone resorption, and resulting in net gain of bone and reducing fracture risk — These data suggest that serial BTM measurements could become useful in identifying skeletal responders to an anabolic therapy with PTH.
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Based on results from clinical studies and improved technical performance on automated platforms, several national and international guidelines recommend these markers in the follow-up of patients treated for postmenopausal osteoporosis 32 , , In the process of generating scientific support for claims on foods, BTM were deemed as not sufficiently indicative of bone health to provide evidence for enhanced function or reduced osteoporosis risk However, over the last 10 years there have been improvements in analytical performance and new knowledge of how biochemical markers can be of great utility in osteoporosis management.
Because BTM measurement can assess response to anti-osteoporotic medications, the time has come to use BTM levels to reflect bone formation and resorption in response to foods and nutrients. Several studies have examined the response of BTM levels and related hormonal factors to varying food or nutrient consumption in postmenopausal women or in elderly individuals. These studies illustrate how BTM can be important in establishing food and nutrient health claims.
In a month intervention involving postmenopausal women mean age 60—62 years , the consumption of Ca- and vitamin D-fortified milk and yogurt favourably influenced vitamin D status and bone metabolism, as expressed by changes in serum 25 OH D, PTH, CTX and IGF-I, as compared with a control group maintaining their usual diet or a group receiving equivalent Ca as lactate—gluconate and bicarbonate salts Fig.
A prospective cross-over trial in postmenopausal women mean age 59 years found that supplementation with non-fortified milk for 6 weeks induced a decrease in serum PTH and BTM, including CTX, and a non-significant increase in IGF-I In a randomised study of postmenopausal women mean age 57 years , consumption of a vitamin D- and Ca-fortified soft white cheese significantly reduced the sensitive biochemical marker of bone resorption TRAP 5b and increased serum IGF-I levels Data are adapted from Manios et al.
Favourable effects of milk, fortified or not with vitamin D or Ca, on bone turnover in elderly individuals have been documented in several intervention studies 42 , , — Interventions with dairy products such as yogurts , or soft white cheese — have shown reductions in bone turnover.
Elderly patients hospitalised for an osteoporotic fracture of the proximal femur often present with signs of undernutrition, particularly protein malnutrition In a randomised study, protein repletion by the daily consumption of a 20 g casein-enriched food v. Thus, in hip fracture patients, the long-term effects of various protein preparations on IGF-I can be predicted from changes observed as early as 1 week following protein supplementation Several nutrition-related disorders can lead to bone loss and increased risk of osteoporotic fracture.
Their pathophysiology and clinical expression in relation to the application of biochemical markers are relevant to the present review. In young women with anorexia nervosa, aBMD is reduced at several skeletal sites Body weight, but not oestrogen use, is a significant predictor of aBMD in these patients. Together with low endogenous oestrogen levels and Ca deficiency, a low protein intake very probably also contributes to the bone deficit observed in anorexia nervosa.
However, low Ca intake has not been consistently reported and 25 OH D serum levels are usually normal The BTM of bone formation, serum OC and BAP, are significantly reduced in adolescents whereas in adults with anorexia nervosa, the markers of bone resorption are elevated while those of formation are suppressed , The serum level of IGF-I is low in anorexia nervosa , , an observation quite compatible with insufficient protein intake although low protein intake has not been consistently recorded.
Nutritional rehabilitation reversed the uncoupling of bone remodelling and led to a significant increase in BTM of formation followed by increases in aBMD in as little as 3 months This reversibility occurs before oestrogen levels rise and menses return, suggesting that nutritional factors are of paramount importance , The serum level of IGF-I was reported to increase rapidly after the onset of intravenous hyperalimentation, followed by a progressive elevation in serum osteocalcin IGF-I level changes were dependent on variations in the nutritional state Increased GH levels accompanied by decreased IGF-I are seen in anorexia nervosa, suggesting an acquired resistance to GH that reversed with refeeding The administration of recombinant IGF-I alone has only a small bone-sparing effect This is not surprising, since the anabolic effects of IGI-I on bone formation are tempered by poor nutrition, particularly by insufficient protein intake In female athletes or ballet dancers, intensive exercise in the absence of appropriate nutrition can lead to hypothalamic dysfunction with delayed menarche and disruption of menstrual cyclicity, bone loss and increase risk of fracture — Nutritional restriction, more common when leanness confers advantages for performance, can play an important role in the disturbance of the female reproductive system when combined with intense physical activity.
Insufficient energy intake with respect to energy expenditure impairs the secretion of gonadotropin-releasing hormone and thereby leads to a state of hypo-oestrogenism. This hormonal disturbance is reversed by nutritional rehabilitation leading to an increase in both luteinising hormone and follicle-stimulating hormone.
These changes occur well before oestrogen rises and menses return, suggesting the dominant effect of nutritional factors However, the relative contribution of insufficient protein intake with low IGF-I remains to be assessed since it is often associated with reduced energy intake. The consequence on bone metabolism of acute experimental energy restriction has been investigated in young exercising female volunteers This study indicated that severe reduction in energy availability rapidly induces a negative uncoupling between bone formation and bone resorption The resulting bone loss may become irreversible with persistence of such a negative uncoupled remodelling, explaining the increased risk of fragility fractures in anorexia nervosa , as well as in certain athletes and ballet dancers , The degree of bone loss also depends upon the kind of diet accompanying the energy restriction.
Bone mineral loss during body-weight reduction may not be fully recovered with weight regained, at least in postmenopausal women Several studies have used bone health biomarkers, particularly with the objective to identify the key implicated nutrients.
Ca intake typically decreases with energy-restriction diets. In this condition, the reduced Ca intake is associated with elevation in both serum PTH and biochemical markers of bone remodelling , Dairy products may prevent bone loss during energy restriction not only by providing Ca but also by supplying proteins.
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Weight-reducing diets that are high in dairy products can suppress the rise in bone turnover and prevent bone loss , In postmenopausal women, a randomised month controlled study showed that higher dietary protein intake 86 v. In order to provide information on medical practice, the needed evidence-based criteria differ for foods and nutrients as compared with drugs.
The development of drugs requires a very high level of rigour, more for safety concerns than for providing evidence of efficacy 18 , 24 , An RCT is the clinical study design that best permits strong causal inference between a tested drug or nutrient and a given outcome 18 , Previous reviews or position papers have emphasised the distinct differences in the evidence that can be obtained by using RCT in the context of drug testing, as compared with the development of nutrient requirement or dietary guidelines 18 , 23 , 24 , , In the nutrition field, all types of research are useful in setting dietary recommendations: observational studies, to document prevalence and generate hypotheses; preclinical experiments to identify physiological and biochemical pathways; qualitative studies to understand the human condition; and, finally, RCT, to establish a relationship of causality 18 , 24 , 25 , The demonstration that a drug is efficacious for reducing the burden of fragility fractures necessitates the design of RCT with very large sample sizes.
Moreover, a placebo-controlled trial can neither be considered ethically acceptable when the new drug is tested in patients at low risk of fractures. This study design requires a much larger number of subjects, as compared with previous RCT conducted in patients at high risk of fragility fractures Thus, proper design and execution of long-duration large RCT aimed at demonstrating the antifracture efficacy of a drug impose requirements that are difficult to meet This difficulty also encompasses both the narrow response due to the placebo effect and the non-random loss of enrolled subjects that convert a randomised trial into a cohort study It can be expected to be magnified in long-duration RCT aimed at testing the antifracture efficacy of foods or nutrients in osteoporotic patients 18 , Therefore, the development of surrogate endpoints for antifracture efficacy of new drugs has been considered not only for foods and nutrients , , but also for drugs Taking into account not only the large sample size but also the very long duration of conducting RCT with fragility fracture as the primary outcome, it is worth considering the measurement of fracture-related data that can be obtainable within a few weeks or months after the onset of the intervention.
In clinical investigation, it is recognised that the early bone remodelling response is a good predictor of fragility fracture , Effective pharmaceutical agents, whether acting via anticatabolic or anabolic mechanisms, very promptly influence bone remodelling, as biochemically expressed by measuring BTM changes These pharmoco-kinetic and -dynamic characteristics, that combine an early response to intervention with a reliable predictability of fragility fractures, make BTM tools better suited to assess the effects of foods or nutrients in clinical research on osteoporosis than the delayed changes in DXA-measured aBMD or bone mineral content.
The short duration of these RCT limits the number of non-compliant participants. Furthermore, one may also expect that few subjects will be completely lost, i.
A physiologically meaningful set of biochemical variables can be selected and assessed at several time points. For instance, when nutritional products are evaluated for their capacity to improve vitamin D status and bone metabolism, changes in serum 25 OH D, PTH, bone formation and resorption markers should provide information on the dynamic interrelationships between these variables.
Measuring the circulating level of IGF-I can assess the response to an increase in protein intake.