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Background: Pathology-supported genetic testing (PSGT) enables transitioning of risk stratification from the study population to the individual., Research Design and Methods: We provide an overview of the translational research performed in postmenopausal breast cancer patients at increased risk of osteoporosis due to aromatase inhibitor therapy, as the indication for referral. Both tumor histopathology and blood biochemistry levels were assessed to identify actionable disease pathways using whole exome sequencing (WES)., Results: The causes and consequences of inadequate vitamin D levels as a modifiable risk factor for bone loss were highlighted in 116 patients with hormone receptor-positive breast cancer. Comparison of lifestyle factors and WES data between cases with vitamin D levels at extreme upper and lower ranges identified obesity as a major discriminating factor, with the lowest levels recorded during winter. Functional polymorphisms in the vitamin D receptor gene contributed independently to therapy-related osteoporosis risk. In a patient with invasive lobular carcinoma, genetic counseling facilitated investigation of the potential modifying effect of a rare CDH1 variant co-occurring with BRCA1 c.66dup (p.Glu23ArgfsTer18)., Conclusion: Validation of PSGT as a three-pronged pharmacodiagnostics tool for generation of adaptive reports and data reinterpretation during follow-up represents a new paradigm in personalized medicine, exposing significant limitations to overcome.

In premenopausal women, bone mineral density measurement by dual-energy X-ray absorptiometry should not be used as the sole guide for diagnosis or treatment of osteoporosis, universal screening with bone mineral density is not advised and the World Health Organization classification of bone status should not be applied. A diagnosis of premenopausal osteoporosis is reserved for those with evidence of fragility and may also be considered in women with low bone mass and an ongoing secondary cause of osteoporosis. Idiopathic osteoporosis in young women is rare. A thorough evaluation of secondary causes is indicated in all patients, with glucocorticoid treatment a common secondary cause of low bone mass and osteoporosis. Hypoestrogenism may be the primary cause of low bone mass and contribute to excessive bone loss in many conditions associated with premenopausal osteoporosis, and should be treated unless contra-indicated. The mainstay of treatment in premenopausal females with low bone mass includes risk factor reduction, advocating a healthy, active lifestyle and optimal treatment of secondary causes of bone loss. The safety of bone-specific therapy, especially long term and during pregnancy, remains uncertain. Bisphosphonates, teriparatide, denosumab and estrogen treatment increase bone density in premenopausal women with osteoporosis, but there are no study data confirming short-term fracture prevention with use of these agents.

Glucocorticoid-induced osteoporosis is characterized by decreased osteoblast numbers and a marked impairment of new bone formation. We found that, in vitro, dexamethasone inhibits both preosteoblast proliferation and mitogenic kinase activity in response to mitogens, and that inhibition of protein tyrosine phosphatases (PTPs) using sodium orthovanadate prevents this. Therefore, dexamethasone may act by either upregulating antiproliferative PTPs or downregulating promitogenic tyrosine-phosphorylated substrates. In this study, osteoporosis was induced in 3.5-month-old rats by subcutaneous injection with methylprednisolone 3.5 mg/kg per day for 9 weeks. Rats were treated with steroid alone or in combination with 0.5 mg/mL sodium orthovanadate, administered continuously in drinking water. Steroid-treated bones were significantly (p < 0.005) osteopenic (according to dual-energy X-ray absorptiometry) and physically weaker (p < 0.05) than controls. Quantitative bone histology confirmed a significant decrease in osteoid surfaces (p < 0.001), osteoblast numbers (p < 0.05), and rate of bone formation (p < 0.001). Concomitant treatment with vanadate largely prevented the densitometric, histologic, and physical abnormalities induced by prednisolone. This study supports our finding that PTPs are central to the negative regulation of osteoblast proliferation by glucocorticoids and, furthermore, suggests that PTP inhibitors such as sodium orthovanadate should be considered as novel anabolic agents for the treatment of steroid-induced osteoporosis.

Increased bone resorption is a well-described consequence of primary hyperparathyroidism (PHPT). In South Africa, little is known about the impact of PHPT on skeletal health. To determine the prevalence of decreased bone mineral density (BMD), vertebral fractures and osteitis fibrosa cystica in patients with PHPT who underwent parathyroidectomy. Retrospective study of patients who underwent parathyroidectomy for PHPT at Tygerberg Hospital in Cape Town, from January 2010 to December 2019. Clinical, biochemical and BMD parameters are described. Final analysis included 56 patients (median age 63.5 years; 80.4% female). Initial calcium, parathyroid hormone (PTH) and 25-hydroxyvitamin D (25[OH]D) levels were 2.93 mmol/l, 19.4 pmol/l and 34.0 nmol/l, respectively. Of the total cohort, 71.4% had decreased BMD. The prevalence of osteoporosis and osteopenia in postmenopausal women and men ≥ 50 years was 50.0% and 39.1% respectively; low bone mass for age in premenopausal women and men < 50 years was 20.0%. Vertebral fractures were seen in 21.2% of patients on radiography. Osteitis fibrosa cystica was present in five patients (9.6%). PTH levels were significantly elevated in patients with osteoporosis compared with those with normal BMD (36.4 vs. 16.1 pmol/l; p = 0.02). Two-thirds of patients who underwent parathyroidectomy for PHPT had decreased BMD, with osteoporosis present in 50% of postmenopausal women and older men. One in five had vertebral fractures. These findings underscore the importance of skeletal assessment in the management of PHPT. [ABSTRACT FROM AUTHOR]