Mary Beth Tedesco

Continuous PTH and PTHrP Infusion Causes Suppression of Bone Formation and Discordant Effects on 1,25(OH)2Vitamin D

Osteoblast activity and plasma 1,25(OH)2vitamin D are increased in HPT but suppressed in HHM. To model HPT and HHM, we directly compared multiday continuous infusions of PTH versus PTHrP in humans. Continuous infusion of both PTH and PTHrP results in marked and prolonged suppression of bone formation; renal 1,25(OH)2D synthesis was stimulated effectively by PTH but poorly by PTHrP.

Parathyroid Hormone-Related Protein for the Treatment of Postmenopausal Osteoporosis: Defining the Maximal Tolerable Dose

CONTEXT PTH is the only approved skeletal anabolic agent for the treatment of human osteoporosis. Unlike PTH, which is a mixed anabolic and catabolic agent, PTHrP displays features suggesting that it may be a pure anabolic agent when intermittently administered. The full dose range of PTHrP is unknown. OBJECTIVES The primary objective of the study was to define the complete therapeutic window and dose-limiting toxicities of PTHrP. The secondary objective was to determine whether PTHrP retains a pure anabolic profile at the highest usable doses. DESIGN This was a single-blinded, two-part, dose-escalating clinical trial. SETTING The study was conducted in a university academic setting. PATIENTS OR OTHER PARTICIPANTS Participants included 41 healthy postmenopausal women between the ages of 45 and 75 yr. INTERVENTION INTERVENTIONs included PTHrP(1-36) or placebo in a dose-escalating design for 3 wk. MAIN OUTCOME MEASURES Safety measures (hypercalcemia, nausea, vomiting, hemodynamics, flushing, miscellaneous) and bone turnover markers were measured. RESULTS Intermittent PTHrP was administered safely and without serious adverse events in subjects receiving 500 and 625 microg/d for 3 wk. Subjects receiving 750 microg/d developed mild hypercalcemia. Bone turnover markers suggested that even at the highest doses, daily sc PTHrP may not activate bone resorption, i.e. may be purely anabolic. Interestingly, when hypercalcemia occurred, it may have resulted not from bone resorption but from activation of intestinal calcium absorption by 1,25 dihydroxyvitamin D. CONCLUSIONS In doses as high as 750 microg/d, in contrast to PTH, intermittently administered PTHrP appears to act as a pure skeletal anabolic agent. Surprisingly, PTHrP in the high doses studied activates 1,25 dihydroxyvitamin D production. Dosing information obtained herein can be used to design a longer term head-to-head comparative efficacy trial of PTHrP vs. PTH.

A Comparison of Parathyroid Hormone‐Related Protein (1–36) and Parathyroid Hormone (1–34) on Markers of Bone Turnover and Bone Density in Postmenopausal Women: The PrOP Study

Parathyroid hormone‐related protein (PTHrP)(1‐36) increases lumbar spine (LS) bone mineral density (BMD), acting as an anabolic agent when injected intermittently, but it has not been directly compared with parathyroid hormone (PTH)(1‐34). We performed a 3‐month randomized, prospective study in 105 postmenopausal women with low bone density or osteoporosis, comparing daily subcutaneous injections of PTHrP(1‐36) to PTH(1‐34). Thirty‐five women were randomized to each of three groups: PTHrP(1‐36) 400 µg/day; PTHrP(1‐36) 600 µg/day; and PTH(1‐34) 20 µg/day. The primary outcome measures were changes in amino‐terminal telopeptides of procollagen 1 (PINP) and carboxy‐terminal telopeptides of collagen 1 (CTX). Secondary measures included safety parameters, 1,25(OH)2 vitamin D, and BMD. The increase in bone resorption (CTX) by PTH(1‐34) (92%) (p < 0.005) was greater than for PTHrP(1‐36) (30%) (p < 0.05). PTH(1‐34) also increased bone formation (PINP) (171%) (p < 0.0005) more than either dose of PTHrP(1‐36) (46% and 87%). The increase in PINP was earlier (day 15) and greater than the increase in CTX for all three groups. LS BMD increased equivalently in each group (p < 0.05 for all). Total hip (TH) and femoral neck (FN) BMD increased equivalently in each group but were only significant for the two doses of PTHrP(1‐36) (p < 0.05) at the TH and for PTHrP(1‐36) 400 (p < 0.05) at the FN. PTHrP(1‐36) 400 induced mild, transient (day 15) hypercalcemia. PTHrP(1‐36) 600 required a dose reduction for hypercalcemia in three subjects. PTH(1‐34) was not associated with hypercalcemia. Each peptide induced a marked biphasic increase in 1,25(OH)2D. Adverse events (AE) were similar among the three groups. This study demonstrates that PTHrP(1‐36) and PTH(1‐34) cause similar increases in LS BMD. PTHrP(1‐36) also increased hip BMD. PTH(1‐34) induced greater changes in bone turnover than PTHrP(1‐36). PTHrP(1‐36) was associated with mild transient hypercalcemia. Longer‐term studies using lower doses of PTHrP(1‐36) are needed to define both the optimal dose and full clinical benefits of PTHrP.

Lactation and Bone Turnover: A Conundrum of Marked Bone Loss in the Setting of Coupled Bone Turnover

CONTEXT Mothers who exclusively breastfeed lose up to 10% of their bone mass. This is primarily mediated by PTHrP, in combination with low estrogen levels. The mechanisms underlying this marked bone loss are unknown. Uncoupling of bone turnover, which is seen in other prototypical states of bone loss, would seem the likely explanation. However, the most current markers of bone turnover have not been studied in human lactation. OBJECTIVES The purpose of this study was to assess bone formation in lactating humans using the most current bone turnover markers. DESIGN AND PARTICIPANTS We conducted a prospective cohort study with repeated measures of bone metabolism in a volunteer sample of 49 women, recruited into three study groups: lactating, bottle feeding, and healthy controls. The postpartum women were studied at 6-8 and 12-14 wk postpartum, whereas the controls were studied at the follicular phase of their menstrual cycles. OUTCOME MEASURES Biochemical markers of bone turnover were assessed. RESULTS Mean serum C-telopeptide of type I collagen, a sensitive marker of bone resorption, was approximately 2-fold higher in lactating women as compared with bottle-feeding and healthy controls (P = 0.037 and P < 0.001, respectively). Surprisingly, amino-terminal telopeptides of procollagen 1, the most current marker of bone formation, bone-specific alkaline phosphatase, and osteocalcin were all significantly higher in the lactating group as compared with controls (P < 0.001, P = 0.002, and P < 0.001, respectively). CONCLUSIONS In contrast to prototypical states of rapid bone loss (myeloma, cancer, and immobilization) in which markers of bone turnover display marked uncoupling, lactational bone loss, as assessed in this small exploratory study, is distinct, showing comparably rapid bone loss in the face of apparent osteoclast-osteoblast coupling.

A 7-day continuous infusion of PTH or PTHrP suppresses bone formation and uncouples bone turnover

Human in vivo models of primary hyperparathyroidism (HPT), humoral hypercalcemia of malignancy (HHM), or lactational bone mobilization for more than 48 hours have not been described previously. We therefore developed 7‐day continuous‐infusion models using human parathyroid hormone(1–34) [hPTH(1–34)] and human parathyroid hormone–related protein(1–36) [hPTHrP(1–36)] in healthy human adult volunteers. Study subjects developed sustained mild increases in serum calcium (10.0 mg/dL), with marked suppression of endogenous PTH(1–84). The maximal tolerated infused doses over a 7‐day period (2 and 4 pmol/kg/h for PTH and PTHrP, respectively) were far lower than in prior, briefer human studies (8 to 28 pmol/kg/h). In contrast to prior reports using higher PTH and PTHrP doses, both 1,25‐dihydroxyvitamin D3 [1,25(OH)2D3] and tubular maximum for phosphorus (TmP/GFR) remained unaltered with these low doses despite achievement of hypercalcemia and hypercalciuria. As expected, bone resorption increased rapidly and reversed promptly with cessation of the infusion. However, in contrast to events in primary HPT, bone formation was suppressed by 30% to 40% for the 7 days of the infusions. With cessation of PTH and PTHrP infusion, bone‐formation markers abruptly rebounded upward, confirming that bone formation is suppressed by continuous PTH or PTHrP infusion. These studies demonstrate that continuous exposure of the human skeleton to PTH or PTHrP in vivo recruits and activates the bone‐resorption program but causes sustained arrest in the osteoblast maturation program. These events would most closely mimic and model events in HHM. Although not a perfect model for lactation, the increase in resorption and the rebound increase in formation with cessation of the infusions are reminiscent of the maternal skeletal calcium mobilization and reversal that occur following lactation. The findings also highlight similarities and differences between the model and HPT.

Evaluation of Markers of Bone Turnover During Lactation in African-Americans: A Comparison With Caucasian Lactation

CONTEXT The African-American skeleton is resistant to PTH; whether it is also resistant to PTHrP and the hormonal milieu of lactation is unknown. OBJECTIVES The objective of the study was to assess bone turnover markers in African-Americans during lactation vs Caucasians. DESIGN AND PARTICIPANTS A prospective cohort study with repeated measures of markers of bone turnover in 60 African-American women (3 groups of 20: lactating, bottle feeding, and healthy controls), compared with historic Caucasian women. SETTING The study was conducted at a university medical center. OUTCOME MEASURES Biochemical markers of bone turnover and calcium metabolism were measured. RESULTS 25-Hydroxyvitamin D (25-OHD) and PTH were similar among all 3 African-American groups, but 25-OHD was 30%-50% lower and PTH 2-fold higher compared with Caucasians (P < .001, P < .002), with similar 1,25 dihydroxyvitamin D [1,25(OH)(2)D] values. Formation markers [amino-terminal telopeptide of procollagen-1 (P1NP) and bone-specific alkaline phosphatase (BSAP)] increased significantly (2- to 3-fold) in lactating and bottle-feeding African-American women (P1NP, P < .001; BSAP, P < .001), as did resorption [carboxy-terminal telopeptide of collagen-1 (CTX) and serum amino-terminal telopeptide of collagen 1 (NTX), both P < .001]. P1NP and BSAP were comparable in African-American and Caucasian controls, but CTX and NTX were lower in African-American vs Caucasian controls. African-American lactating mothers displayed quantitatively similar increases in markers of bone formation but slightly lower increases in markers of resorption vs Caucasians (P = .036). CONCLUSIONS Despite reported resistance to PTH, lactating African-American women have a significant increase in markers of bone resorption and formation in response the hormonal milieu of lactation. This response is similar to that reported in Caucasian women despite racial differences in 25-OHD and PTH. Whether this is associated with similar bone loss in African-Americans as in Caucasians during lactation is unknown and requires further study.

MENSTRUAL AND REPRODUCTIVE FUNCTION IN WOMEN WITH TYPE 1 DIABETES.

OBJECTIVE Menstrual irregularities, reproductive abnormalities, and androgen excess are reported to be more prevalent in women with type 1 diabetes (T1D). The objective of this study was to investigate the prevalence of menstrual irregularities, reproductive abnormalities, and androgen excess among women with T1D and their age-matched controls. METHODS A survey requesting information regarding menstrual and reproductive histories was administered to all participants. Results were stratified according to age (18 to 40, 40 to 50, and >50 years). RESULTS There were no significant differences between women with and without diabetes in age at menarche, cycle length, or androgen excess in any group. Women who self-reported difficulty with glycemic control were more likely to report irregular menses than controls (P = .04). Among women who reported ever being pregnant, there were fewer pregnancies (P = .02) and live births (P = .002) in women with T1D. Women with T1D reported a lower frequency of oral contraceptive use (P = .003), despite being less likely to smoke (P = .016). CONCLUSION Menstrual and reproductive abnormalities were not observed more frequently in women with T1D in this study. Subtle but measurable differences in menstrual and reproductive function were confined to the subgroup of women who perceived poor control of their diabetes. Additional prospective studies of T1D and menstrual and reproductive function would be useful.