PTH-related peptide (PTHrP) can be found in high concentrations in human breast milk and has been implicated in material calcium regulation postpartum. We studied the relationship of plasma PTHrP levels of serum markers of bone turnover and selective cancellous bone density in 35 women (age, 25 +/- 3 yr) 2-3 days postpartum and after 3 and 6 months of lactation. The mean postpartum plasma PTHrP levels measured by immunoradiometric assay was 2.64 +/- 0.19 pmol/L (mean +/- SE) and were elevated compared to that in 35 age- and sex-matched controls (1.34 +/- 0.14; P < 0.0001). PTHrP remained significantly elevated, but decreased during the lactation period of 6 +/- 1 months. Immediately postpartum, serum protein levels were lowest, and serum ionized calcium levels highest. At that time, PTH was suppressed to 50% of control values (P < 0.001). Two or 3 days postpartum, serum ionized calcium was negatively correlated with total serum protein (r = -0.47; P < 0.0001) and positively correlated with plasma PTHrP (r = -0.32; P < 0.008). PTH was inversely correlated with ionized calcium (r = -0.24; P = 0.03) and PTHrP (r = -0.31; P < 0.01). Three and 6 months postpartum, serum protein and PTH levels had returned to normal, and ionized calcium concentrations decreased. There was no indication that PTHrP may have any significant systemic effect after 3 and 6 months of lactation. Long term lactation led to a significant decrease in radial cancellous bone density (-4.5%; P < 0.05) at 6 months and to elevations in serum markers of bone resorption (2- to 3-fold for serum carboxy-terminal telopeptide of type I collagen) and formation (1- to 2-fold for osteocalcin and serum carboxy-terminal propeptide of type I procollagen). Bone turnover balance was clearly negative after 3 months of lactation compared to the control value and indicated net bone loss at a time when estrogen levels were low. With ongoing lactation, estrogen levels increased, and bone turnover balance improved significantly and independently of PTHrP levels. We interpret these results as evidence that PTHrP is elevated during the postgestational period and has a weak and temporary effect on calcium metabolism when serum protein levels are reduced. PTHrP does not seem to participate significantly in the regulation of bone turnover during lactation. Normalization of bone turnover balance at 6 months of lactation suggests that further cancellous bone loss is most likely minimal when breast-feeding is extended beyond that time.