Howard A. Morris

Markers of bone turnover for the prediction of fracture risk and monitoring of osteoporosis treatment: a need for international reference standards

SummaryThe International Osteoporosis Foundation (IOF) and the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) recommend that a marker of bone formation (serum procollagen type I N propeptide, s-PINP) and a marker of bone resorption (serum C-terminal telopeptide of type I collagen, s-CTX) are used as reference analytes for bone turnover markers in clinical studies.IntroductionBone turnover markers (BTM) predict fracture risk, and treatment-induced changes in specific markers account for a substantial proportion of fracture risk reduction. The aims of this report were to determine their clinical potential in the prediction of fracture risk and for monitoring the treatment of osteoporosis and to set an appropriate research agenda.MethodsEvidence from prospective studies was gathered through literature review of the PUBMED database between the years 2000 and 2010 and the systematic review of the Agency for Healthcare Research and Quality up to 2001.ResultsHigh levels of BTMs may predict fracture risk independently from bone mineral density in postmenopausal women. They have been used for this purpose in clinical practice for many years, but there is still a need for stronger evidence on which to base practice. BTMs provide pharmacodynamic information on the response to osteoporosis treatment, and as a result, they are widely used for monitoring treatment in the individual. However, their clinical value for monitoring is limited by inadequate appreciation of the sources of variability, by limited data for comparison of treatments using the same BTM and by inadequate quality control. IOF/IFCC recommend one bone formation marker (s-PINP) and one bone resorption marker (s-CTX) to be used as reference markers and measured by standardised assays in observational and intervention studies in order to compare the performance of alternatives and to enlarge the international experience of the application of markers to clinical medicine.ConclusionBTM hold promise in fracture risk prediction and for monitoring treatment. Uncertainties over their clinical use can be in part resolved by adopting international reference standards.

Circulating sex hormones and breast cancer risk factors in postmenopausal women: reanalysis of 13 studies.

Background:Breast cancer risk for postmenopausal women is positively associated with circulating concentrations of oestrogens and androgens, but the determinants of these hormones are not well understood.Methods:Cross-sectional analyses of breast cancer risk factors and circulating hormone concentrations in more than 6000 postmenopausal women controls in 13 prospective studies.Results:Concentrations of all hormones were lower in older than younger women, with the largest difference for dehydroepiandrosterone sulphate (DHEAS), whereas sex hormone-binding globulin (SHBG) was higher in the older women. Androgens were lower in women with bilateral ovariectomy than in naturally postmenopausal women, with the largest difference for free testosterone. All hormones were higher in obese than lean women, with the largest difference for free oestradiol, whereas SHBG was lower in obese women. Smokers of 15+ cigarettes per day had higher levels of all hormones than non-smokers, with the largest difference for testosterone. Drinkers of 20+ g alcohol per day had higher levels of all hormones, but lower SHBG, than non-drinkers, with the largest difference for DHEAS. Hormone concentrations were not strongly related to age at menarche, parity, age at first full-term pregnancy or family history of breast cancer.Conclusion:Sex hormone concentrations were strongly associated with several established or suspected risk factors for breast cancer, and may mediate the effects of these factors on breast cancer risk.

Vitamin D Metabolites and Calcium Absorption in Severe Vitamin D Deficiency

Contrary to frequent claims, vitamin D insufficiency does not generally cause malabsorption of calcium because serum 1,25(OH)2D, which is the major determinant of calcium absorption, is maintained by secondary hyperparathyroidism. Nevertheless, because malabsorption of calcium has been described in osteomalacia, there must be a 25(OH)D level below which the serum 1,25(OH)2D can no longer be sustained, although it has never been defined. This paper seeks to define it. We examined the records of 3661 patients and found 319 with a serum 25(OH)D ≤40 nM, in whom calcium absorption, serum calcium, PTH, bone markers, and vitamin D metabolites had been measured. They were grouped according to their serum 25(OH)D into four categories, 0–10, 11–20, 21–30, and 31–40 nM, and differences between the groups were tested by ANOVA. Correlations between the variables were also examined. Serum calcium, 1,25(OH)2D, and calcium absorption were significantly decreased and serum PTH and alkaline phosphatase (ALP) and urine hydroxyproline were increased in those with 25(OH)D ≤10 nM. Serum ALP and urine hydroxyproline were more strongly related, inversely, to calcium absorption than to the vitamin D metabolites. We conclude that vitamin D deficiency does not reduce serum 1,25(OH)2D, and therefore calcium absorption, until the serum 25(OH)D falls to ∼10 nM. At this level, the substrate concentration seems to be insufficient to maintain the level of the dihydroxy metabolite despite secondary hyperparathyroidism. Further studies are needed to see how these changes correlate with the histological changes of osteomalacia.

Amylin inhibits bone resorption while the calcitonin receptor controls bone formation in vivo

Amylin is a member of the calcitonin family of hormones cosecreted with insulin by pancreatic β cells. Cell culture assays suggest that amylin could affect bone formation and bone resorption, this latter function after its binding to the calcitonin receptor (CALCR). Here we show that Amylin inactivation leads to a low bone mass due to an increase in bone resorption, whereas bone formation is unaffected. In vitro, amylin inhibits fusion of mononucleated osteoclast precursors into multinucleated osteoclasts in an ERK1/2-dependent manner. Although Amylin +/− mice like Amylin-deficient mice display a low bone mass phenotype and increased bone resorption, Calcr +/− mice display a high bone mass due to an increase in bone formation. Moreover, compound heterozygote mice for Calcr and Amylin inactivation displayed bone abnormalities observed in both Calcr +/− and Amylin +/− mice, thereby ruling out that amylin uses CALCR to inhibit osteoclastogenesis in vivo. Thus, amylin is a physiological regulator of bone resorption that acts through an unidentified receptor.

Circulating steroid hormones and the risk of prostate cancer.

Epidemiologic studies have failed to support the hypothesis that circulating androgens are positively associated with prostate cancer risk and some recent studies have even suggested that high testosterone levels might be protective particularly against aggressive cancer. We tested this hypothesis by measuring total testosterone, androstanediol glucuronide, androstenedione, DHEA sulfate, estradiol, and sex hormone–binding globulin in plasma collected at baseline in a prospective cohort study of 17,049 men. We used a case-cohort design, including 524 cases diagnosed during a mean 8.7 years follow-up and a randomly sampled subcohort of 1,859 men. The association between each hormone level and prostate cancer risk was tested using Cox models adjusted for country of birth. The risk of prostate cancer was ∼30% lower for a doubling of the concentration of estradiol but the evidence was weak (Ptrend = 0.07). None of the other hormones was associated with overall prostate cancer (Ptrend ≥ 0.3). None of the hormones was associated with nonaggressive prostate cancer (all Ptrend ≥ 0.2). The hazard ratio [HR; 95% confidence interval (95% CI)] for aggressive cancer almost halved for a doubling of the concentration of testosterone (HR, 0.55; 95% CI, 0.32-0.95) and androstenedione (HR, 0.51; 95% CI, 0.31-0.83), and was 37% lower for a doubling of the concentration of DHEA sulfate (HR, 0.63; 95% CI, 0.46-0.87). Similar negative but nonsignificant linear trends in risk for aggressive cancer were obtained for free testosterone, estradiol, and sex hormone–binding globulin (Ptrend = 0.06, 0.2, and 0.1, respectively). High levels of testosterone and adrenal androgens are thus associated with reduced risk of aggressive prostate cancer but not with nonaggressive disease. (Cancer Epidemiol Biomarkers Prev 2006;15(1):86–91)

Effect of age on bone density and bone turnover in men

OBJECTIVE Little Is known about the pattern of age‐related bone loss in men, and although androgens are required for optimum bone mass it Is not clear whether the fall in bone mass with age in men is related to failing androgens.

International Osteoporosis Foundation and International Federation of Clinical Chemistry and Laboratory Medicine Position on bone marker standards in osteoporosis

Abstract The International Osteoporosis Foundation (IOF) and the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) Working Group on Bone Marker Standards (WG-BMS) has evaluated the clinical potential of bone turnover markers (BTMs) in the prediction of fracture risk and for monitoring treatment. Research evidence suggests that BTMs may provide information on fracture risk independently from BMD, so that fracture risk prediction might be enhanced by their inclusion in assessment algorithms. The potential use of BTMs to predict the response to treatments for osteoporosis in the individual patient is also of great interest. Treatment-induced changes in specific markers account for a substantial proportion of fracture risk reduction. However, there is still a need for stronger evidence on which to base practice in both situations. IOF/IFCC recommends one bone formation marker (serum procollagen type I N propeptide, s-PINP) and one bone resorption marker (serum C-terminal cross-linking telopeptide of type I collagen, s-CTX) to be used as reference markers and measured by standardised assays in observational and intervention studies in order to enlarge the international experience of the application of markers to clinical medicine and to help resolve uncertainties over their clinical use.

Calcium absorption in normal and osteoporotic postmenopausal women

SummaryHourly fractional absorption of radiocalcium (alpha), serum calcitriol, and a number of other variables were measured in 152 normal and 148 osteoporotic postmenopausal women. Alpha, body weight, and serum albumin were all significantly lower in the osteoporotic than in the normal women, and plasma alkaline phosphatase, fasting urinary calcium, sodium, and hydroxyproline were all significantly higher in the osteoporotic than in the normal group. The most significant determinant of alpha in each group was the serum calcitriol concentration, but calcium absorption relative to serum calcitriol was significantly lower in the osteoporotic than in the normal women. The serum calcitriol level was slightly but not significantly lower in the osteoporotic than in the normal group and accounted for only 20% of the difference in alpha between them. The implied “resistance” to calcitriol in the osteoporotic group was significantly related to serum albumin and body weight but independent of age. Urinary hydroxyproline was an inverse function of alpha and a positive function of fasting urinary calcium in the osteoporotic group.

Osteoporosis and Klinefelter’s Syndrome

objective We wanted to measure forearm mineral density and bone‐related biochemical variables in patients with Klinefelters syndrome.

Glycomic profiling of cells and tissues by mass spectrometry: fingerprinting and sequencing methodologies.

Over the past decade, rapid, high-sensitivity mass spectrometric strat-egies have been developed and optimized for screening for the types of N- and O-glycans present in a diverse range of biological material, including secretions, cell lines, tissues, and organs. These glycomic strategies are based on matrix-assisted laser desorption/ionization (MALDI) time-of-flight mass fingerprinting of permethylated derivatives, combined with electrospray (ES) or MALDI tandem mass spectrometry (MS/MS) sequencing and gas chromatography (GC)-MS linkage analysis, complemented by chemical and enzymatic degradations. Protocols for these methods are described in the first part of this chapter. Glycomic experiments yield large volumes of MS data, and interpretation of the resulting spectra remains a time-consuming bottleneck in the process. In the second part of this chapter, we describe the use and operation of a mass spectral viewer program capable of displaying and automatically labeling spectra arising from MALDI fingerprinting of N-glycans.