Calcium plays important roles in bone health, muscle contraction, signal transduction, gene expression, and many other physiological processes. Calcium in circulation is primarily regulated by parathyroid hormone (PTH), calcitonin, and 1,25-dihydroxyvitamin D concentrations. In health, concentrations of calcium and PTH are inversely associated and measurement of PTH helps identify causes of hypo- and hypercalcemia. Under normal circumstances, PTH concentrations rise in response to low circulating calcium concentrations, and vice versa.
Parathyroid hormone-related peptide (PTHrP) has close homology with PTH, binds to the same receptor, and among many other functions, similarly participates in intracellular calcium regulation. In contemporary clinical practice, PTHrP measurements help determine the cause of unexplained hypercalcemia, i.e., elevated calcium in the absence of elevated PTH. Importantly, much is still unknown about the additional physiologic functions of PTHrP. A number of radioimmunoassays (RIA) have been developed using antibodies against various epitopes within the PTHrP sequence. However, none of these methods was sufficiently sensitive to measure PTHrP in plasma samples from healthy individuals, leading to an assumption that PTHrP is only present in circulating blood during illness. Because high sensitivity/high specificity methods for PTHrP were not previously available, no studies have been performed to assess the association between PTHrP and calcium/PTH concentrations in health and in pathology.
A few years ago, we developed, validated, and implemented a high sensitivity liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for the routine clinical measurement of PTHrP (1). This LC-MS/MS method is sufficiently sensitive to quantify PTHrP in samples from both healthy and diseased individuals, thereby providing new insight into the role that PTHrP may play in a variety of processes. Early studies showed that in healthy individuals, PTHrP is present in higher concentrations in women than in men overall (1), and that the highest median concentrations were found in postmenopausal women, breastfeeding women, and men over 70 years. This may be due to the role of PTHrP in mammary gland development and pregnancy, the earlier onset of osteoporosis in women than in men, etc.
Using this LC-MS/MS method we evaluated the association between concentrations of PTHrP, calcium, and PTH and between-sex and age group differences in routine clinical patient samples from adults (n=2,701; 60.5% women and 39.5% men). Overall, PTHrP concentrations were above the sex-specific reference interval in 39.1% of clinical samples and were significantly higher in men than women. Since PTHrP measurements are frequently used to assess unexplained hypercalcemia, we also looked at PTHrP concentration distributions in samples from women (n=472) and men (n=446) with elevated calcium (>10.2 mg/dL) and suppressed PTH (<15 pg/mL). Elevated PTHrP concentrations were observed in 35.0% of women and 59.4% of men from this subset; odds ratios for PTHrP as a cause of unexplained hypercalcemia were 0.7 in women and 2.2 in men. No between-sex or among age group differences were observed in distribution of calcium concentrations. These data demonstrate that in clinical samples from patients suspected of abnormal calcium regulation and from those with unexplained hypercalcemia, elevated PTHrP concentrations are observed more frequently in samples from men than women.
Higher PTH and PTHrP concentrations in older women without pathology (as compared to men), may explain the higher prevalence of osteoporosis in postmenopausal women. Our data also suggest a possible role of PTHrP in hypercalcemic conditions that have a higher prevalence in, or are specific to men (e.g., prostate cancer) (2, 3). The use of a highly sensitive and specific method for measurement of PTHrP is the key to understanding these relationships and further defining the role of PTHrP in health and disease.
- Kushnir MM, Rockwood AL, Strathmann FG, Straseski JA, Meikle AW. LC-MS/MS Measurement of Parathyroid Hormone-Related Peptide. Clin Chem. 2016; 62: 218-26.
- Cook MB, Dawsey SM, Freedman ND, Inskip PD, Wichner SM, Quraishi SM, Devesa SS, McGlynn KA. Sex disparities in cancer incidence by time period and age. Cancer Epidemiol Biomarkers Prev. 2009; 18: 1174–1182.
- Kim HI, Lim H, Moon A. Sex Differences in Cancer: Epidemiology, Genetics and Therapy. Biomol Therap. 2018; 26: 335-342.