BackgroundGlucocorticoid replacement is essential in patients with primary and secondary adrenal insufficiency, but many patients remain on higher than recommended dose regimens. There is no uniformly accepted method to monitor the dose in individual patients. We have compared cortisol concentrations in plasma, saliva and urine achieved following “physiological” and “stress” doses of hydrocortisone as potential methods for monitoring glucocorticoid replacement.MethodsCortisol profiles were measured in plasma, saliva and urine following “physiological” (20 mg oral) or “stress” (50 mg intravenous) doses of hydrocortisone in dexamethasone-suppressed healthy subjects (8 in each group), compared to endogenous cortisol levels (12 subjects). Total plasma cortisol was measured half-hourly, and salivary cortisol and urinary cortisol:creatinine ratio were measured hourly from time 0 (between 0830 and 0900) to 5 h. Endogenous plasma corticosteroid-binding globulin (CBG) levels were measured at time 0 and 5 h, and hourly from time 0 to 5 h following administration of oral or intravenous hydrocortisone. Plasma free cortisol was calculated using Coolens’ equation.ResultsPlasma, salivary and urine cortisol at 2 h after oral hydrocortisone gave a good indication of peak cortisol concentrations, which were uniformly supraphysiological. Intravenous hydrocortisone administration achieved very high 30 minute cortisol concentrations. Total plasma cortisol correlated significantly with both saliva and urine cortisol after oral and intravenous hydrocortisone (P <0.0001, correlation coefficient between 0.61 and 0.94). There was no difference in CBG levels across the sampling period.ConclusionsAn oral dose of hydrocortisone 20 mg is supraphysiological for routine maintenance, while stress doses above 50 mg 6-hourly would rarely be necessary in managing acute illness. Salivary cortisol and urinary cortisol:creatinine ratio may provide useful alternatives to plasma cortisol measurements to monitor replacement doses in hypoadrenal patients.

Osteoporosis is a global public health problem, with fractures contributing to significant morbidity and mortality. Although post-menopausal osteoporosis is most common, up to 30% of post-menopausal women, &gt;50% of premenopausal women, and between 50-80% of men have secondary osteoporosis. Exclusion of secondary causes is important as treatment of such patients often commences by treating the underlying condition. These are varied but often neglected, ranging from endocrine to chronic inflammatory and genetic conditions. General screening is recommended for all patients with osteoporosis with advanced investigations reserved for premenopausal women and men aged &lt;50 years, for older patients in whom classical risk factors for osteoporosis are absent, and for all patients with the lowest bone mass (Z-score ≤-2). The response of secondary osteoporosis to conventional anti-osteoporosis therapy may be inadequate if the underlying condition is unrecognized and untreated. Bone densitometry, using dual energy x-ray absorptiometry (DXA), may underestimate fracture risk in some chronic diseases including glucocorticoid-induced osteoporosis, type 2 diabetes and obesity, and may overestimate fracture risk in others (e.g. Turner syndrome). FRAX ® and TBS may provide additional information regarding fracture risk in secondary osteoporosis, but their use is limited to adults aged ≥40 years and ≥50 years, respectively. In additional FRAX ® requires adjustment in some chronic conditions e.g. glucocorticoid dose, type 2 diabetes and HIV. In most conditions, evidence for antiresorptive or anabolic therapy is limited to increases in bone mass. Current osteoporosis management guidelines also neglect secondary osteoporosis and these existing evidence gaps are discussed.

Atypical femoral fractures (AFFs) are uncommon and have been associated particularly with long‐term antiresorptive therapy, including bisphosphonates. Although the pathogenesis of AFFs is unknown, their identification in bisphosphonate‐naïve individuals and in monogenetic bone disorders has led to the hypothesis that genetic factors predispose to AFF. Our aim was to review and summarize the evidence for genetic factors in individuals with AFF. We conducted structured literature searches and hand‐searching of conference abstracts/reference lists for key words relating to AFF and identified 2566 citations. Two individuals independently reviewed citations for (i) cases of AFF in monogenetic bone diseases and (ii) genetic studies in individuals with AFF. AFFs were reported in 23 individuals with the following 7 monogenetic bone disorders (gene): osteogenesis imperfecta (COL1A1/COL1A2), pycnodysostosis (CTSK), hypophosphatasia (ALPL), X‐linked osteoporosis (PLS3), osteopetrosis, X‐linked hypophosphatemia (PHEX), and osteoporosis pseudoglioma syndrome (LRP5). In 8 cases (35%), the monogenetic bone disorder was uncovered after the AFF occurred. Cases of bisphosphonate‐naïve AFF were reported in pycnodysostosis, hypophosphatasia, osteopetrosis, X‐linked hypophosphatemia, and osteoporosis pseudoglioma syndrome. A pilot study in 13 AFF patients and 268 controls identified a greater number of rare variants in AFF cases using exon array analysis. A whole‐exome sequencing study in 3 sisters with AFFs showed, among 37 shared genetic variants, a p.Asp188Tyr mutation in the GGPS1 gene in the mevalonate pathway, critical to osteoclast function, which is also inhibited by bisphosphonates. Two studies completed targeted ALPL gene sequencing, an ALPL heterozygous mutation was found in 1 case of a cohort of 11 AFFs, whereas the second study comprising 10 AFF cases did not find mutations in ALPL. Targeted sequencing of ALPL, COL1A1, COL1A2, and SOX9 genes in 5 cases of AFF identified a variant in COL1A2 in 1 case. These findings suggest a genetic susceptibility for AFFs. A large multicenter collaborative study of well‐phenotyped AFF cases and controls is needed to understand the role of genetics in this uncommon condition. © 2017 The Authors JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Indole-3-carbinol (I3C), a naturally occurring component of Brassica vegetables, such as broccoli, cabbage, and Brussels sprouts, induces a G 1 cell-cycle arrest of human breast cancer cells, although the direct cellular targets that mediate this process are unknown. Treatment of highly invasive MDA-MB-231 breast cancer cells with I3C shifted the stable accumulation of cyclin E protein from the hyperactive lower-molecular-mass 35-kDa form that is associated with cancer cell proliferation and poor clinical outcomes to the 50-kDa cyclin E form that typically is expressed in normal mammary tissue. An in vitro cyclin E processing assay, in combination with zymography, demonstrated that I3C, but not its natural dimer, 3,3 -diindolylmethane, disrupts proteolytic processing of the 50-kDa cyclin E into the lower-molecular-mass forms by direct inhibition of human neutrophil elastase enzymatic activity. Analysis of elastase enzyme kinetics using either cyclin E or N-methoxysuccinyl-Ala-Ala-Pro-Val-p-nitroanalide as substrates demonstrated that I3C acts as a noncompetitive inhibitor of elastase activity with an inhibitory constant of Ϸ12 M. Finally, siRNA ablation of neutrophil elastase protein production in MDA-MB-231 cells mimicked the I3C-disrupted processing of the 50-kDa cyclin E protein and the indole-induced cell-cycle arrest. Taken together, our results demonstrate that elastase is the first identified specific target protein for I3C and that the direct I3C inhibition of elastase enzymatic activity implicates the potential use of this indole, or related compounds, in targeted therapies of human breast cancers where high elastase levels are correlated with poor prognosis.A critical challenge in controlling breast cancer is the identification of therapeutic agents that can effectively control the growth of both estrogen-responsive and nonresponsive breast cancer cells with reduced side effects, especially during prolonged treatments. Epidemiological studies show that frequent consumption of certain vegetables is associated with a lower incidence of cancers at various sites (1). For example, the consumption of Brassica (cruciferous) vegetables, such as cabbage, broccoli, and Brussels sprouts, is directly associated with decreased risk of reproductive tissue cancers in humans (2, 3) and reduced tumor incidence in experimental animals (4). These studies implicate the existence of specific biologically active phytochemicals that represent a largely untapped source of potent chemotherapeutic agents. One such promising molecule is indole-3-carbinol (I3C), a natural compound derived from glycobrassicin in Brassica vegetables, which has been shown to exhibit potent anticarcinogenic properties in a wide range of cancers such as lung, liver, colon, cervical, endometrial, prostate, and breast cancer (5-7). In addition, out of broad spectrum of analyzed phytochemicals, I3C was 1 of the few that tested positive as a chemopreventative agent in a panel of short-term bioassays relevant to carcinogen-induced DNA damage, tumor initiat...

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BMD and TBS can be preserved with early initiation and continued use of ERT. TBS may provide additional fracture risk prediction to standard DXA parameters in TS and needs to be validated in larger prospective studies.

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