PTH-related protein (PTHrP) is homologous with PTH. PTH, an effective anabolic agent for treating osteoporosis, has been shown to stimulate both bone resorption by osteoclasts and bone formation by osteoblasts. We examined whether PTHrP might share anabolic properties in osteoporosis. A 3-month double-blind, prospective, placebo-controlled, randomized clinical trial was performed in 16 healthy postmenopausal women with osteoporosis. All received calcium and vitamin D, and all continued their prior hormone replacement therapy. One group also received daily sc PTHrP (6.56 microg/kg x d, or approximately 400 microg/d), and the other group received placebo injections. The PTHrP group displayed a 4.7% increase in lumbar spine bone mineral density (BMD) and also demonstrated an increase in osteoblastic bone formation, as assessed using serum osteocalcin measurements. In contrast, there was no increase in bone-specific alkaline phosphatase and collagen-1 propeptide or either of two markers of osteoclastic bone resorption, N-telopeptide, or deoxypyridinoline. One subject in the placebo group withdrew from the study, but there were no significant adverse events in the PTHrP group. PTHrP administered sc in high doses for only 3 months appears to be a potent anabolic agent, producing a 4.7% increase in lumbar spine BMD. This compares very favorably to available antiresorptive drugs for osteoporosis and is similar to the increases in BMD at this early time point reported for PTH. Despite the high doses, PTHrP was well tolerated. Larger clinical trials are required to confirm these results and fully assess the anabolic potential of PTHrP in osteoporosis.
PTH and PTH-related protein (PTHrP) cause primary hyperparathyroidism and humoral hypercalcemia of malignancy (HHM), respectively. These syndromes are similar in several important ways, but differ in several characteristic, yet unexplained, ways. Two of the unresolved questions in HHM and hyperparathyroidism involve renal physiology. 1) Why does renal proximal tubular production of 1,25-dihydroxyvitamin D [1,25-(OH)(2)D] differ between the two syndromes? 2) Do distal tubular calcium responses to PTH and PTHrP differ in the two syndromes? To address these questions, we compared the two peptides, human PTH-(1-34) and PTHrP-(1-36), in a direct, head to head study using a continuous, steady state infusion of each peptide at the same dose in normal human volunteers for 46 h. We had previously described such methods as applied to PTHrP, but a direct multiday comparison of PTHrP to PTH has not previously been reported. In two groups (seven subjects each) of healthy young (25- to 35-yr-old) normal volunteers, PTH and PTHrP infused at 8 pmol/kg.h displayed similar calcemic effects, although PTH was slightly more potent in this regard. Both peptides also displayed similar phosphaturic effects. In addition, both peptides had similar effects on renal tubular calcium handling, yielding fractional calcium excretion values of approximately 3.5%, some 50% below the values (6.5%) observed in subjects rendered similarly hypercalcemic by the infusion of calcium. In contrast to these several quantitatively similar effects of PTH and PTHrP, PTH tended to be selectively more effective than PTHrP in stimulating renal production of 1,25-(OH)(2)D. These studies indicate that renal tubular calcium reabsorption is likely to contribute to hypercalcemia in patients with HHM. In addition, PTH may be selectively more effective than PTHrP in stimulating 1,25-(OH)(2)D production, in contrast to its phosphaturic, calcemic effects and its effects to stimulate nephrogenous cAMP excretion and renal tubular calcium reabsorption.
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
Introduction: PTH and PTH-related protein (PTHrP) cause primary hyperparathyroidism (HPT) and humoral hypercalcemia of malignancy (HHM), respectively. Whereas HHM and HPT resemble one another in many respects, osteoblastic bone formation and plasma 1,25(OH) 2 vitamin D are increased in HPT but reduced in HHM. Materials and Methods:We performed 2-to 4-day continuous infusions of escalating doses of PTH and PTHrP in 61 healthy young adults, comparing the effects on serum calcium and phosphorus, renal calcium and phosphorus handling, 1,25(OH) 2 vitamin D, endogenous PTH(1-84) concentrations, and plasma IGF-1 and markers of bone turnover. Results: PTH and PTHrP induced comparable effects on renal calcium and phosphorus handling, and both stimulated IGF-1 and bone resorption similarly. Surprisingly, PTH was consistently more calcemic, reflecting a selectively greater increase in renal 1,25(OH) 2 vitamin D production by PTH. Equally surprisingly, continuous infusion of both peptides markedly, continuously, and equivalently suppressed bone formation. Conclusions: PTHrP and PTH produce markedly different effects on 1,25(OH) 2 vitamin D homeostasis in humans, leading to different calcemic responses. Moreover, both peptides produce profound suppression of bone formation over multiple days, contrasting with events in HPT, but mimicking HHM. These findings underscore the facts that the mechanisms underlying the anabolic skeletal response to PTH and PTHrP in humans is poorly understood, as are the signal transduction mechanisms that link the renal PTH receptor to 1,25(OH) 2 vitamin D synthesis. These studies emphasize that much remains to be learned regarding the normal regulation of vitamin D metabolism and bone formation in response to PTH and PTHrP in humans.
Parathyroid hormone-related protein (PTHrP)(1–36) increases lumbar spine (LS) bone mineral density (BMD), acting as an anabolic agent when injected intermittently, but has not been directly compared to parathyroid hormone (PTH)(1–34). We performed a three 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/d; PTHrP(1–36) 600 μg/d; and PTH(1–34) 20 μg/d. The primary outcomes 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)2vitamin 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 & 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.
OBJECTIVE -The purpose of this study was to assess the effect of glimepiride on insulin sensitivity and secretion in subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS-After a 2-week washout from prior sulfonylurea therapy, 11 obese subjects with type 2 diabetes underwent euglycemic and hyperglycemic clamp studies before and during glimepiride therapy.RESULTS -Glimepiride resulted in a 2.4-mmol/l decrease in fasting plasma glucose (P ϭ 0.04) that was correlated with reductions in postabsorptive endogenous glucose production (EGP) (16.4 Ϯ 0.6 vs. 13.5 Ϯ 0.5 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 , P ϭ 0.01) (r ϭ 0.21, P ϭ 0.01). Postabsorptive EGP on glimepiride was similar to that of control subjects (12.8 Ϯ 0.9 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 , NS). Fasting plasma insulin (66 Ϯ 18 vs. 84 Ϯ 48 pmol/l, P ϭ 0.05), and first-phase (19 Ϯ 8 vs. 32 Ϯ 11 pmol/l, P ϭ 0.04) and second-phase incremental insulin responses to glucose (48 Ϯ 23 vs. 72 Ϯ 32 pmol/l, P ϭ 0.02) improved with glimepiride therapy. Insulin sensitivity did not change with treatment (4.6 Ϯ 0.7 vs. 4.3 Ϯ 0.7 mol ⅐ kg Ϫ1 ⅐ min Ϫ1⅐ pmol Ϫ1 ) and remained below that of control subjects (8.1CONCLUSIONS -The current study demonstrates that glimepiride improves both first and second phases of insulin secretion, but not insulin sensitivity, in individuals with type 2 diabetes.
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.
Parathyroid hormone-related protein (PTHrP) is an anabolic skeletal agent in mice, rats and humans. In previous studies, we have demonstrated that PTHrP can be administered to osteoporotic postmenopausal women at a dose of 6.56 microg/kg/day (or approximately 400 microg/day) for 3 months to yield a 4.7% increase in lumbar spine BMD. This regimen was free of hypercalcemia or adverse effects. Moreover, PTHrP appeared to stimulate bone formation selectively, without stimulating bone resorption. This efficacy in the absence of adverse effects, as well as the apparent "pure anabolic" action of PTHrP, prompted us to attempt to define the complete therapeutic window for PTHrP. In this study, we gradually escalated the dose of PTHrP(1-36) from 9 to 28 microg/kg (or approximately 570 microg to 1,946 microg) administered as a single subcutaneous dose to 22 healthy young adult subjects. PTHrP(1-36) was well tolerated even at the highest dose, just under 2.0 mg, some five times higher than we have previously demonstrated to be effective in increasing bone mass, and some 100 times higher than the maximal approved dose of PTH(1-34). Despite the large dose of PTHrP, the highest serum calcium achieved was 10.6 mg/dl, and this was observed in only one subject at the highest dose. The mean serum calcium in subjects receiving the highest dose was 9.6 mg/dl. Only one subject experienced adverse symptoms/signs, and this was at the highest dose. We conclude that subcutaneous PTHrP(1-36) is safe when administered in single doses approaching 2.0 mg. These findings indicate that the therapeutic window for PTHrP(1-36) in humans is wide and permit the design and implementation of longer safety and efficacy trials.
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