The mechanisms leading to increased bone loss and skeletal fragility in women with postmenopausal osteoporosis are still poorly understood. Increased bone resorption, low serum estradiol and high serum sex-hormone-binding globulin (SHBG) recently have been reported as predictors of vertebral and hip fractures in elderly women. In a cohort of healthy untreated younger postmenopausal women aged 50-89 years (mean, 64 years), we compared baseline levels of bone markers and endogenous hormones in 55 women who subsequently had a fracture (20 vertebral and 35 peripheral fractures) with levels in the 380 women who did not fracture during a mean 5 years of follow-up. Women with levels in the highest quartile of four bone resorption markers including urinary-free deoxypyridinoline (D-Pyr), urinary type I collagen N-telopeptides (NTX), and urinary and serum type I collagen C-telopeptides (CTX) had about a 2-fold increased risk of fractures compared with women with levels in the three lowest quartiles with relative risk (RR) and 95% CI of 1.8 (1.0-3.4) for free D-Pyr, 1.7 (0.9-3.2) for urinary NTX, 2.3 (1.3-4.1) for urinary CTX, and 2.1 (1.2-3.8) for serum CTX. Serum levels of bone alkaline phosphatase (BAP) in the highest quartile were associated with an RR of fracture of 2.4 (1.3-4.2). Women with serum levels of estradiol and dehydroepiandrosterone (DHEA) sulfate in the lowest quartile had an RR of fracture of 2.2 (1.2-4.0) and 2.1 (1.2-3.8), respectively. Increased levels of SHBG and intact parathyroid hormone (PTH) were moderately associated with an increased risk of fracture. Similar results were obtained when the analysis was restricted to symptomatic vertebral and nonvertebral fractures. Adjustment of biochemical markers by hormone levels did not significantly alter the results. Women with both high bone resorption markers and low estradiol (or low DHEA sulfate) had a higher risk of fracture with RRs of 3.0-3.3 (p < 0.001). After adjustment for bone mineral density (BMD) of the hip, spine, radius, or total body, bone markers and hormones were still predictive of fracture risk with similar RRs. We conclude that high levels of some biochemical markers of bone turnover, low serum estradiol, low DHEA sulfate, high SHBG, and high PTH are associated with increased risk of osteoporotic fracture in postmenopausal women, independently of each other and of BMD. The mechanism by which some postmenopausal women have an increased rate of bone turnover leading to an increased risk of fracture remains to be elucidated.

Biochemical markers of bone turnover, endogenous hormones and the risk of fractures in postmenopausal women: the OFELY study.

Cathepsin K, a cysteine protease expressed in osteoclasts, degrades type 1 collagen. Odanacatib selectively and reversibly inhibited cathepsin K and rapidly decreased bone resorption in preclinical and phase I studies. A 1-year dose-finding trial with a 1-year extension on the same treatment assignment was performed in postmenopausal women with low bone mineral density (BMD) to evaluate the safety and efficacy of weekly doses of placebo or 3, 10, 25, or 50 mg of odanacatib on BMD and biomarkers of skeletal remodeling. Women with BMD T-scores of -2.0 or less but not less than -3.5 at the lumbar spine or femoral sites were randomly assigned to receive placebo or one of four doses of odanacatib; all received vitamin D with calcium supplementation as needed. The primary endpoint was percentage change from baseline lumbar spine BMD. Other endpoints included percentage change in BMD at hip and forearm sites, as well as changes in biomarkers of skeletal remodeling. Twenty-four months of treatment produced progressive dose-related increases in BMD. With the 50-mg dose of odanacatib, lumbar spine and total-hip BMD increased 5.5% and 3.2%, respectively, whereas BMD at these sites was essentially unchanged with placebo (-0.2% and -0.9%). Biochemical markers of bone turnover exhibited dose-related changes. The safety and tolerability of odanacatib generally were similar to those of placebo, with no dose-related trends in any adverse experiences. In summary, 2 years of weekly odanacatib treatment was generally well-tolerated and increased lumbar spine and total-hip BMD in a dose-related manner in postmenopausal women with low BMD.

Odanacatib, a cathepsin-K inhibitor for osteoporosis: a two-year study in postmenopausal women with low bone density.

BACKGROUND: Disorders of bone metabolism, most notably osteoporosis, are highly prevalent and predispose to fractures, causing high patient morbidity and mortality. Diagnosis and monitoring of bone metabolic defects can present a major challenge as these disorders are largely asymptomatic and radiographic measures of bone mass respond slowly to changes in bone physiology. CONTENT: Bone turnover markers (BTMs) are a series of protein or protein derivative biomarkers released during bone remodeling by osteoblasts or osteoclasts. BTMs can offer prognostic information on fracture risk that supplements radiographic measures of bone mass, but testing using BTMs has to take into account the large number of preanalytic factors and comorbid clinical conditions influencing BTM levels. BTMs respond rapidly to changes in bone physiology, therefore, they have utility in determining patient response to and compliance with therapies for osteoporosis. SUMMARY: BTMs are a useful adjunct for the diagnosis and therapeutic monitoring of bone metabolic disorders, but their use has to be tempered by the known limitations in their clinical utility and preanalytic variables complicating interpretation.

/pdf/bone-turnover-markers-in-the-diagnosis-and-monitoring-of-18c9vblm20.pdf

Bone Turnover Markers in the Diagnosis and Monitoring of Metabolic Bone Disease.

Previous studies have shown that immunoassay of urinary NTx (cross-linked N-telopeptides of type I collagen) provides a responsive index of human bone resorption. Here we report by a sensitive immunoassay that NTx is present in serum and is suppressed appropriately in patients with Paget disease of bone by bisphosphonate antiresorptive therapy. The monoclonal antibody (1H11) developed against urinary NTx was applied in a sensitive chemiluminescence format. Results for human serum and urine showed parallel inhibition curves. The NTx concentrations in paired serum and urine samples from individual patients correlated well when urinary concentrations were normalized to creatinine concentrations (in premenopausal and postmenopausal women and Paget disease patients, r = 0.90, n = 60). The percentage of NTx suppression from baseline values for Paget disease patients on bisphosphonate therapy was similar for serum and urine. Blood samples drawn from bone marrow at the site of Pagetic lesions in three patients with active disease had as much as 10-fold higher concentrations of NTx than did peripheral blood samples drawn at the same time. The latter finding is consistent with other evidence showing that immunoreactive NTx originates directly during the proteolytic cleavage of bone collagen by osteoclasts rather than, e.g., by degradative processes occurring later in the liver and kidney.

Evidence that serum NTx (collagen-type I N-telopeptides) can act as an immunochemical marker of bone resorption

Pycnodysostosis (Pycno) is an autosomal recessive osteosclerotic skeletal dysplasia that is caused by the markedly deficient activity of cathepsin K This lysosomal cysteine protease has substantial collagenase activity, is present at high levels in osteoclasts, and is secreted into the subosteoclastic space where bone matrix is degraded In vitro studies revealed that mutant cathepsin K proteins causing Pycno did not degrade type I collagen, the protein that constitutes 95% of organic bone matrix To determine the in vivo effects of cathepsin K mutations on bone metabolism in general and osteoclast-mediated bone resorption specifically, several bone metabolism markers were assayed in serum and urine from seven Pycno patients Two markers of bone synthesis, type I collagen carboxy-terminal propeptide and osteocalcin, were normal in all Pycno patients Tartrate-resistent acid phosphatase, an osteoclast marker, was also normal in these patients Two markers that detect type I collagen telopeptide cross-links from the N and C termini, NTX and CTX, respectively, were low in Pycno A third marker which detects a more proximal portion of the C terminus of type I collagen in serum, ICTP, was elevated in Pycno, a seemingly paradoxical result The finding of decreased osteoclast-mediated type I collagen degradation as well as the use of alternative collagen cleavage sites by other proteases, and the accumulation of larger C-terminal fragments containing the ICTP epitope, established a unique biochemical phenotype for Pycno

https://asbmr.onlinelibrary.wiley.com/doi/pdf/10.1359/jbmr.1999.14.11.1902

M.Y. Lee

Papers

Osteoclasts Generate Cross-Linked Collagen N-telopeptides (NTx) but not Free Pyridinolines When Cultured on Human Bone