The data indicate a relation between the serum concentration of iPLP and the presence of hypercalcemia in solid malignancies. The results support a role for PLP as a humoral mediator of hypercalcemia in most patients with solid tumors. Measurement of iPLP should be useful in the differential diagnosis of hypercalcemia.

Expression of a parathyroid hormone-like protein (PLP), which is associated with hypercalcemia in malignancy, has recently been localized to normal lactating mammary tissue. We examined the possibility of an extramammary role of PLP by measuring its levels in serum and milk of lactating women. The levels of PLP by radioimmunoassay in serum of lactating and nonlactating women were indistnguishable [4.2 ± 1.8 and 3.6 ± 1.0 pg equivalents (eq) of PLP-(1-34) amide per ml, respectively]. As PLP was undetectable in some serum samples, this result does not exclude the possibility that lactation results in a small increase in serum levels of PLP. In contrast, high concentrations of immunoreactive PLP [40,,000 pg eq of PLP-(1-34) amide per ml] and correspondingly high concentrations ofbioactive PLP were found in human, rat, and bovine milk. A variety of processed bovine milk products had a PLP content similar to that of fresh bovine milk, whereas infant formulas had lower concentrations, ranging down to undetectable. Although the physiological role of PLP in lactation is unknown, the data establish the presence of PLP in milk and suggest the possibility that PLP may be important in neonatal calcium homeostasis.Parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D are considered to be the major regulators of extracellular calcium homeostasis in humans. Recently, a variety of human tumors have been shown to secrete a 16-kDa protein (1-3) that has amino-terminal sequence homology with PTH (4-6). Synthetic peptides of this PTH-like protein (PLP) corresponding to PLP-(1-34) reproduce all of the major physiologic effects of PTH, including PTH receptor binding (7,8), accelerated bone resorption, phosphaturia, and hypocalciuria (9-11). Secretion of PLP probably accounts for most instances of hypercalcemia associated with solid malignancies. The Radioimmunoassay of PLP. Details of the RIA methodology will be described elsewhere. Briefly, the RIA used rabbit antiserum to synthetic PLP-(1-34) (provided by M. Shimizu, Peninsula Laboratories) with 125I-labeled PLP-(1-34) amide as radioligand and PLP-(1-34) amide as standard. Immunoreactive PLP (iPLP) in serum was measured after partial purification and concentration (15-to 25-fold) by immunoaffinity chromatography with a polyclonal rabbit antibody to synthetic PLP-(1-37) bound to Sepharose. When tumorderived PLP was added to normal serum to give 48 pg equivalents (eq) of PLP per ml, 58 ± 13% (mean ± SD) of iPLP was recovered in the immunoextracts. The within-assay coefficient of variation was 7.5%, and the between-assay coefficient of variation was 19%. No cross-reactivity was seen with human PTH or PTH fragments. Normal serum contained <10 pg eq of PLP-(1-34) amide per ml, and hypercalcemic patients with cancer had levels up to 100 pg eq/ml (unpublished data). The limit of detection was 5 pg of PLP-(1-34) amide per tube, or 50 pg eq of PLP(1-34) amide per ml in unextracted milk (to convert to pM, multiply by 0.25). The limit of detection in serum varied with the fold conce...

Purpose Several epidemiologic studies suggest that compared to white women, Asians have a greater propensity to suffer an atypical femur fracture (AFF) while taking bisphosphonate therapy. This study examines the relative risk of AFF following bisphosphonate initiation for Asian compared to white women. Methods Using data from a large integrated northern California healthcare delivery system, we examined diaphyseal femur fracture outcomes among women age ≥50 years old who initiated oral bisphosphonate therapy during 2002–2007. An AFF was defined by the 2013 American Society of Bone and Mineral Research Task Force criteria. The risk of radiographically-confirmed AFF was examined for Asian compared to white women, adjusting for differences in bisphosphonate exposure and other potential risk factors. Results Among 48,390 women (65.3% white, 17.1% Asian) who newly initiated bisphosphonate therapy and were followed for a median of 7.7 years, 68 women experienced an AFF. The rate of AFF was 18.7 per 100,000 person-years overall and eight-fold higher among Asian compared to white women (64.2 versus 7.6 per 100,000 person-years). Asians were also more likely to have longer bisphosphonate treatment duration compared to whites (median 3.8 versus 2.7 years). The age-adjusted relative hazard for AFF was 8.5 (95% confidence interval 4.9–14.9) comparing Asian to white women, and was only modestly reduced to 6.6 (3.7–11.5) after adjusting for bisphosphonate duration and current use. Conclusions Our study confirms marked racial disparity in AFF risk that should be further investigated, particularly the mechanisms accounting for this difference. These findings also underscore the need to further examine the association of bisphosphonate duration and AFF in women of Asian race, as well as differential risk across Asian subgroups. In the interim, counseling of Asian women about osteoporosis drug continuation should include consideration of their potentially higher AFF risk.

A lactating 31-year-old woman who developed four vertebral fractures 1-2 months after the delivery of her first child is described. She was hypercalcaemic (serum calcium up to 2.99 mmol/l), and urinary excretion of both calcium and hydroxyproline (an index of bone resorption) were markedly elevated. Serum levels of parathyroid hormone and 1,25-dihydroxyvitamin D were suppressed, but parathyroid hormone-related peptide was above normal. There was severe axial osteopenia, as assessed by dual-energy X-ray absorptiometry. The biochemical abnormalities were reversed within 2 weeks of weaning, with the exception of the parathyroid hormone-related peptide concentration, which declined more gradually. This appears to be the first description of the abnormalities in calcium metabolism and bone density from early in the course of post-pregnancy osteoporosis and it indicates that this condition is associated with high levels of osteolysis which return to normal after weaning. This rapid reversal of the metabolic abnormalities accounts for the inconclusive nature of previous descriptions of post-pregnancy osteoporosis, in which investigations were more delayed. It also emphasizes the importance of weaning in the management of women presenting with this condition. A possible aetiological role for parathyroid hormone-related peptide is discussed.

During 2006 to 2012, hip fracture rates declined, but diaphyseal fracture rates increased, particularly among Asian women. The association of diaphyseal fracture and bisphosphonate therapy should be further investigated with examination of fracture pattern.