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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 2 569-575
Copyright © 2003 by The Endocrine Society

Short-Term, High-Dose Parathyroid Hormone-Related Protein as a Skeletal Anabolic Agent for the Treatment of Postmenopausal Osteoporosis

Mara J. Horwitz, Mary Beth Tedesco, Caren Gundberg, Adolfo Garcia-Ocana and Andrew F. Stewart

Division of Endocrinology (M.J.H., M.B.T., A.G.-O., A.F.S.), The University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213; and Department of Orthopedics (C.G.), Yale University School of Medicine, New Haven, Connecticut 06520

Address all correspondence and requests for reprints to: Andrew F. Stewart, M.D., Division of Endocrinology, BST E-1140, University of Pittsburgh School of Medicine, 3550 Terrace Street, Pittsburgh, Pennsylvania 15213. E-mail: stewart{at}msx.dept-med.pitt.edu.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
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 µg/kg·d, or approximately 400 µg/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.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
OSTEOPOROSIS RESULTS FROM an imbalance between two physiological processes: bone resorption by osteoclasts and bone formation by osteoblasts. For example, accelerated osteoclastic bone resorption contributes in an important way to the bone loss that accompanies estrogen loss at menopause. Conversely, osteoporosis associated with glucocorticoid use has been ascribed principally to failure of bone formation by osteoblasts. From a therapeutic standpoint, osteoporosis therefore could be treated either by agents that diminish osteoclastic bone resorption, agents that increase osteoblastic bone formation, or both. In practice, however, the treatment of osteoporosis at present is limited to agents that diminish osteoclastic activity, the so-called antiresorptive agents. Although these agents are attractive from the standpoints of increasing bone mineral density (BMD) and reducing skeletal fractures by approximately 50% (1, 2, 3, 4, 5, 6, 7), the increase in BMD produced by these agents is generally reported to be in the range of 2–10% over 1–7 yr (1, 2, 3, 4, 5). Although this is a very significant improvement, it is far below the increments required to restore BMD to premenopausal levels, and large numbers of skeletal fractures still occur in women treated with antiresorptive therapy (1, 2, 3, 4, 5).

These considerations have prompted a search for agents that can induce new bone formation, so-called skeletal anabolic agents, with the hope of increasing BMD and reducing fractures beyond levels achievable using antiresorptives. One such agent is PTH. PTH not only induces new bone formation but also stimulates osteoclastic bone resorption. PTH is therefore anabolic in net terms (8, 9). PTH has been shown in several studies to increase bone mineral density in postmenopausal osteoporosis, senile osteoporosis in men, and glucocorticoid-induced osteoporosis (10, 11, 12, 13, 14, 15, 16, 17, 18). PTH acts via the PTH-1 receptor on osteoblasts and bone marrow stromal cells to induce osteoblastic bone formation, i.e. osteoid synthesis and accelerated mineralization (8, 9). This in turn results in reductions in skeletal fractures to levels equivalent to, or beyond, those obtained using antiresorptive agents (17). The magnitude of the increase in BMD induced by PTH is large, with increases of 10–15% over 2–3 yr in most studies (10, 11, 12, 13, 14, 15, 16, 17, 18). Moreover, PTH may offer synergistic or additive effects when used in combination with antiresorptive agents (11, 15, 19, 20).

PTH-related protein (PTHrP) is the quintessential skeletal catabolic agent. It was initially discovered as the cause of the common lethal paraneoplastic syndrome, humoral hypercalcemia of malignancy (21, 22, 23, 24). Hypercalcemia occurring among patients with humoral hypercalcemia of malignancy results principally from a striking activation of osteoclastic bone resorption (21, 22, 23, 24). Thus, PTHrP would seem an unlikely candidate as a skeletal anabolic agent, a conclusion supported by the observation that although PTHrP has been in the public domain for 15 yr, it has not been used to treat human osteoporosis.

However, PTHrP binds with equal potency to the PTH-1 receptor, also called the PTH-PTHrP receptor, and activates signal transduction pathways with equivalent potency (24, 25, 26, 27, 28). PTHrP also has been shown to increase BMD in an estrogen-deficient postmenopausal model in rats (29) and to improve biomechanical properties of the femur and vertebral body in the rat (29). PTHrP is critical to normal skeletal development in both rodents and humans because disruption of the PTHrP gene causes severe skeletal developmental abnormalities (30). We have also shown that PTHrP and PTH are equipotent when administered to humans with respect to induction of hypercalcemia, phosphaturia, nephrogenous cAMP production, and stimulation of renal tubular calcium reabsorption (28, 31). In addition, PTHrP and PTH have similar metabolic clearance rates because the T1/2 of iv infused PTHrP (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36) is 6 min (32), which is indistinguishable from the 5–6 min reported for hPTH (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34) (Refs. 33, 34).

In this study, we examined the possibility that PTHrP might be an effective skeletal anabolic agent in women with postmenopausal osteoporosis. Reasoning that PTH can cause demonstrable increases in BMD and changes in markers of bone turnover within 3 months of treatment (10, 17) and PTHrP would need to be at least as effective as PTH in increasing bone mass to be useful therapeutically, we performed a brief, 3-month double-blinded, randomized, placebo-controlled clinical pilot study in which PTHrP was compared with placebo treatment.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Preparation of PTHrP

Synthetic human PTHrP (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36), referred to hereafter as PTHrP, was synthesized as previously described in detail (25, 28, 29, 31, 35). Briefly, the peptide was synthesized using solid-phase techniques, and purity and peptide content were assessed using analytical scale reversed-phase HPLC and laser desorption mass spectroscopy. The peptide was aliquotted and packaged into sterile vials, and aliquots were examined for pyrogenicity (limulus amebocyte assay) and sterility (routine aerobic and anaerobic culture), and peptide content of the vials was confirmed using amino acid analysis. Prior studies had demonstrated that the peptide was equivalent to hPTH (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34) in both binding to the PTH receptor in SaOS-2 osteosarcoma cells and in stimulating adenylyl cyclase in these cells (25, 28). Use was approved by the Food and Drug Administration (Investigative New Drug no. 49175).

Study subjects

Sixteen consecutive healthy postmenopausal women with osteoporosis were identified for this study. Inclusion criteria included a T-score of less than -2.5 at the lumbar spine or hip, being more than 3 yr postmenopausal, being on hormone replacement for at least 3 yr, and being in generally excellent health. Exclusion criteria included use in the past of any other osteoporosis medication, including bisphosphonates, calcitonin, or selective estrogen receptor modulators. Current use of medications or agents that might influence calcium or bone metabolism (e.g. thiazides, nonphysiologic doses of thyroid hormone, glucocorticoids, lithium, alcohol, etc.) was also an exclusion criterion. All study subjects provided informed consent. The protocol was approved by the University of Pittsburgh Institutional Review Board.

Study design

This was a randomized, double-blinded, placebo-controlled clinical trial. The primary outcome measure was lumbar spine BMD. Secondary outcome measures were hip and femoral neck BMD, markers of bone turnover, serum calcium, serum creatinine, renal phosphorus handling, and adverse events. The 16 subjects were randomized to receive 3 months of treatment with either PTHrP or placebo (identically prepared empty vials containing no PTHrP). Each subject also received 400 IU vitamin D and 1000 mg calcium as calcium carbonate (Os-Cal, Glaxo-SmithKline Beecham Foods International, King of Prussia, PA) per day, and this was started 2 wk before the initiation of the PTHrP or placebo. Subjects were taught in the home the storage at -20 C, reconstitution, and self-injection of the PTHrP or placebo. Vials were reconstituted by the study subjects in 1.0 ml sterile bacteriostatic saline immediately before use, and the appropriate dose of PTHrP, 6.56 µg/kg, or saline placebo was self-administered into the abdominal sc fat. The dose used in these studies, 6.56 µg/kg·d given sc, was derived from prior dose escalation studies (32, 36) in which we demonstrated that this dose was both safe and effective in stimulating markers of bone formation over a 2-wk period. Subjects returned for blood and urine studies at 0, 14, 30, 60, and 90 d of the study and were questioned regarding adverse events at each visit. A final bone density study was performed on d 90 of the study.

Serum and urine biochemistries

Blood was analyzed for routine chemistry and hematology studies in the University of Pittsburgh Medical Center Clinical Chemistry Laboratory, as were plasma 25-vitamin D concentrations. Osteocalcin and bone-specific alkaline phosphatase were measured as described previously (36, 37). Serum collagen-1 propeptide (P1CP), serum N-telopeptide (NTX) (Osteomark), and urinary deoxypyridinoline (DPD) (Pyrilinks-D) were measured using commercial kits from DiaSorin, Inc. (Stillwater, MN), Ostex International, Inc. (Seattle, WA), and Quidel Corp. (Santa Clara, CA), respectively.

Bone densitometry

Bone densitometry at the spine and hip was measured blindly by Dr. Jane Cauley using a model 2000 densitometer (Hologic, Inc., Bedford, MA). The results were blindly and independently reviewed by Dr. Susan Greenspan and one of the authors (M.J.H.). All are experienced bone densitometrists.

Statistics

Statistical analysis was performed using a t test and ANOVA for repeated measures. A P value less than 0.05 was considered to be significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Baseline demographics

The baseline demographics in the two groups are shown in Table 1Go. The subjects were of similar age, weight, height, body mass index, years since menopause, years on estrogen, and calcium intake and had similar plasma 25 vitamin D concentrations. In the placebo group, two were smokers and one was on a normal replacement dose of thyroid hormone for hypothyroidism. Both groups displayed osteoporosis at the lumbar spine.


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  		Table 1. Baseline demographics

 
Study compliance

One patient in the placebo group dropped out of the study after 3 d because of shortness of breath and chest tightness after a sc injection. The remaining subjects in each group completed the study without event. The data analysis that follows includes all 16 patients at baseline and the eight PTHrP and seven placebo subjects who completed the 3 months of the study.

Primary outcome: lumbar spine BMD

The baseline values and changes in BMD at the lumbar spine over the 3 months of the study are shown in Fig. 1Go, left. As can be seen in the figure, the increase in BMD at the lumbar spine in the PTHrP group was 4.72% over 3 months (P = 0.025). In contrast, the change in the placebo group was 1.4%. Similar results were obtained when the results are expressed as absolute changes in BMD in grams per square centimeter (Fig. 1Go, right), with the increment in the PTHrP group being 0.0375 gm/cm2, and 0.011 gm/cm2 in the placebo group (P = 0.022). These results indicate that PTHrP can increase BMD very significantly in the lumbar spine in 3 months.



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  		Figure 1. BMD at the lumbar spine. The left panel shows the changes in BMD as measured by dual-energy x-ray absorptiometry as percentage changes from baseline. The right panel shows the same data as absolute changes in BMD from baseline in grams per square centimeter. In each panel, the bold line represents the subjects treated with PTHrP (n = 8), and the dotted line those receiving placebo (n = 7). The error bars represent SEM. P values were determined using Student’s paired t test. There is a marked increase in BMD at the lumber spine in response to PTHrP.

 
Secondary outcomes: femoral neck and total hip BMD

The changes in BMD expressed as percentage change from baseline at the total hip and femoral neck are shown in Fig. 2Go and are compared with the changes at the lumbar spine. As can be seen in the figure, although there was an approximate 1% increase in hip BMD at both sites over 3 months, there was no significant difference between the PTHrP or placebo groups at either hip site during the study.



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  		Figure 2. BMD at all three sites examined. The sites include the lumbar spine (L/S), the femoral neck (FN), and the total hip (TH). Results are expressed as percentage change from baseline. The light gray bars indicate the placebo group and the black bars the PTHrP group. The L/S data are the same as those presented in Fig. 1Go. The error bars indicate SEM, and P values were determined using Student’s paired t test.

 
Bone turnover markers

Serum bone-specific alkaline phosphatase did not change in either group during the study [baseline, 14 d, 30 d, 60 d, and 90 d values were 17.19 ± 1.68, 17.83 ± 1.65, 18.43 ± 2.21, and 16.52 ± 1.79 U/liter in the PTHrP group and 21.10 ± 2.76, 19.65 ± 2.45, 19.54 ± 2.02, 17.02 ± 1.77, and 18.8 ± 1.97 U/liter in the placebo group, P = not significant (NS)]. Similarly, serum PICP, a second marker of bone formation, was unchanged during the study (baseline, 14 d, 30 d, 60 d, and 90 d values were 118.37 ± 13.95, 140.5 ± 17.94, 167.75 ± 34.74, 112.25 ± 14.54, and 98.75 ± 11.80 ng/ml in the PTHrP group and 129.42 ± 9.15, 117.14 ± 8.54, 116.57 ± 13.55, 122.00 ± 12.06, and 115.7 ± 8.18 ng/ml in the placebo group, P = NS). However, as shown in Fig. 3AGo, serum osteocalcin, a sensitive marker of bone formation, increased in a statistically significant fashion during the study in the PTHrP-treated subjects but not the placebo controls.



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  		Figure 3. Bone turnover markers in the placebo and PTHrP-treated subjects. A, Serum osteocalcin results expressed as change from baseline. The dotted line indicates the placebo group and the solid line the PTHrP group. The error bars indicate SEM, and the P values were determined using ANOVA for repeated measures. B, Serum NTX values in the two groups. C, Urinary deoxypyridinolines in the two groups. The symbols, lines, and statistical analysis are the same as that shown in A. PTHrP stimulates serum osteocalcin and, by inference, bone formation but not bone resorption.

 
With respect to bone resorption, serum NTX (Fig. 3BGo) remained unchanged during the study in the PTHrP-treated subjects, as it did in the placebo controls. Urinary DPD excretion, a second marker of bone resorption, was also unchanged (Fig. 3CGo). These findings suggest that PTHrP may selectively stimulate bone formation without further stimulating normal rates of bone resorption, at least at these early time points.

Serum and urine chemistries

Serum total and ionized serum calcium (Fig. 4Go) remained normal and constant in both the PTHrP-treated subjects as well as in the placebo controls. No subject developed a significant increase in serum total or ionized calcium. These values were obtained 24 h after the last dose of PTHrP. Pilot studies in three subjects also showed no change in normal serum calcium at 0, 1, 3, 5, 7, and 9 h after the 6.56 µg/kg dose. Serum creatinine remained normal as well in both the PTHrP and placebo subjects (mean serum creatinine, ± SEM, on d 90 = 73.38 ± 0.05 µmol/liter in the PTHrP group vs. 74.26 ± 0.06 µmol/liter in the placebo group, P = NS). Serum phosphorus was also similar in both groups throughout the study (1.05 ± 0.18 mmol/liter in the PTHrP group vs. 0.95 ± 0.17 mmol/liter in the placebo group, P = NS), as was the tubular maximum for phosphorus (1.06 ± 0.27 mmol/liter in the PTHrP group vs. 0.84 ± 0.24 mmol/liter in the placebo group, P = NS).



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  		Figure 4. Serum total calcium (left) and ionized calcium (right) in the two groups. The symbols, error bars, and statistical analyses are the same as those in Fig. 3Go. When the error bars are not visible, they are smaller than the symbol at that time point. There is no difference in serum total or ionized calcium between the PTHrP and placebo groups, and no patient in either group developed hypercalcemia as measured by total or ionized serum calcium. Despite the very high doses of PTHrP, hypercalcemia was not observed.

 
Adverse events

No subject in the PTHrP group experienced weakness, nausea, vomiting, diarrhea, constipation, flushing, muscle cramps, or allergic phenomena. One PTHrP subject experienced 30 sec of heart palpitations with standing after the third injection, which did not recur with subsequent injections. All PTHrP subjects completed the study. In contrast, one subject in the placebo group experienced shortness of breath and chest tightness after her injection on d 3 of the study, and this subject withdrew from the study.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The results of this small, brief pilot study indicate that PTHrP administered sc in large doses over 3 months can induce statistically and biologically important increments in spine bone density in postmenopausal women with osteoporosis. The results are surprising for two reasons. First, PTHrP was originally identified as a result of its skeletal catabolic actions in humoral hypercalcemia of malignancy (1, 2, 3, 4). Second, the rate and absolute increment in spine BMD, almost 5% in 3 months, is larger than those observed using many currently available antiresorptive osteoporosis medications (1, 2, 3, 4, 5, 6, 7). Indeed, mean increments of this magnitude have not been reported using calcitonin (3) or raloxifene (4), even when these agents are given for as long as 3 yr. Estrogen causes similar increments in spine BMD, but a change of 5% requires years of treatment (1). The changes observed using some bisphosphonates, including etidronate, alendronate, risedronate, and zoledronate, may equal or exceed 5% but require far longer than 3 months, typically 1 yr or more (2, 5, 6, 7). Viewed from the perspective of available antiresorptive therapies, the effects of short-term high-dose PTHrP are striking. Indeed, the changes observed with PTHrP at 3 months are similar to those observed in studies reported, to date, using PTH over a 3-month period (10, 17). Of course, this is a small study, and such indirect comparisons are fraught with potential errors. Much larger studies will need to be performed to determine whether this preliminary apparent efficacy is reproducible.

The doses of PTHrP used in this study were large, compared with those used in similar PTH studies. Subjects in this study received 6.56 µg/kg·d, which on average was 410.25 µg/d in the eight subjects who received PTHrP. This is some 10- to 20-fold larger than doses of hPTH(1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34) (20–40 µg/d) commonly used in osteoporosis studies (8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20). Doses of PTH in excess of 20 µg/d are associated with hypercalcemia and other adverse effects in humans (17). It is surprising, therefore, that healthy subjects would tolerate doses of this magnitude without developing hypercalcemia, postural hypotension, nausea, flushing, or other adverse effects. The differences cannot be ascribed to differences in molar amounts of the two peptides used because PTHrP(1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36) is very close in molecular weight to PTH(1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34) (approximately 4200 Mr). The differences also cannot be ascribed to different interactions with the common PTH/PTHrP receptor: Both hPTH(1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34) and hPTHrP(1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36) display similar or identical binding kinetics and signal transduction activation characteristics (25, 26, 27, 28). Selection of a bad batch of PTHrP for these studies cannot be the explanation because we have performed many studies with multiple synthetic lots of PTHrP and have confirmed the biological and structural properties of these batches (28, 29, 31, 32, 35, 36, 38). Importantly, in head-to-head comparison with hPTH(1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34) in vitro (25, 26, 27, 28) and also in vivo given iv to human volunteers (28, 31), PTHrP(1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36) is equal in potency to hPTH(1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34). Different serum metabolic clearance rates are an unlikely explanation as well, for we have demonstrated that the T1/2 of iv infused PTHrP(1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36) is 6 min (33), indistinguishable from the 5–6 min reported for hPTH(1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34) (33, 34).

We therefore hypothesize that the differences in skeletal effects of the two peptides relate to differing pharmacokinetic characteristics of PTH and PTHrP after sc injection (32, 39, 40). Human PTH(1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34) has been reported in two studies to reach peak plasma levels at 30–45 min after injection (39, 40), whereas we have reported that peak plasma levels of PTHrP occur at or before 15 min after a sc dose (32). Indeed, because the 15-min time point was the first we examined, and because circulating PTHrP values appeared to be in a sharp decline at this initial 15-min time point, it is very likely that the peak occurs much earlier, perhaps at 5–10 min. Thus, hPTHrP(1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36) is absorbed more rapidly than PTH after sc injection, and plasma levels of PTHrP reach their peak and therefore decline more rapidly than those of PTH (32, 39, 40).

We believe that the different absorption and clearance kinetics of PTHrP vs. PTH underlie the requirement for large doses of PTHrP as well as the lack of hypercalcemia and other toxicities observed in the patients studied despite these large doses. This apparent safety is supported by our prior studies (36) in which an additional seven subjects received the same 6.56 µg/kg·d dose for 2 wk with no adverse events, and another study in which this dose was administered as a single dose to three healthy individuals (Plotkin, H., and A. F. Stewart, unpublished observations). Thus, no adverse events have been encountered in a total of 18 healthy human subjects receiving these large doses of PTHrP for periods of 1 d, 2 wk, or 3 months.

The osteocalcin results suggest that PTHrP may have purely anabolic effects on the skeleton, without the accompanying increase in bone resorption observed using PTH. In contrast to PTH, which displays both formation- and resorption-stimulating properties (8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20), PTHrP appears to have selective osteoblastic or anabolic effects, without concomitant resorption-stimulating effects. This apparent selective anabolic effect is reproducible because we have observed the same dissociation of bone formation and bone resorption in a previous shorter-term (2-wk) study: in that study PTHrP also stimulated an osteocalcin increment but decreased urinary NTX and urinary deoxypyridinolines (36). Moreover, we have also demonstrated an anabolic effect of PTHrP at the histomorphometric level in rats (29). The fact that the PTHrP caused an increase only in osteocalcin and not in bone-specific alkaline phosphatase or P1CP would appear to support the hypothesis that PTHrP is a relatively mild anabolic agent. In addition, the observation that BMD increased by 4.7% in the absence of a resorptive response provides further support for the anabolic actions of PTHrP.

The lack of a resorptive effect is not likely due to the brief duration (3 months) of administration of PTHrP because prior studies have shown that PTH increases bone resorption significantly at or well before 3 months. For example, in the Lindsay et al. study (11), resorption as assessed using urinary NTX was already elevated at 2 wk and was increased by 25% at 3 months. Finkelstein et al. (10) demonstrated that urinary hydroxyproline and pyridinoline, two different markers of bone resorption, were increased by approximately 200% at 3 months after treatment with PTH. Similarly, Hodsman et al. (13) have demonstrated that both urinary hydroxyproline and NTX are significantly increased by only 4 wk of treatment using PTH.

Similarly, the lack of a resorptive effect is unlikely to be due to concomitant estrogen use. First, the same type of dissociation was observed in our earlier study in postmenopausal women without estrogen use (36). Second, the resorptive response to PTH is easily apparent in estrogenized women in both the Roe et al. (15) and the Lindsay et al. (11) studies at 3 months. Thus, from the data available, to date, it can be cautiously concluded that PTHrP, in the doses used thus far and for the duration observed, to date, may be different from PTH and display purely anabolic affects. Future studies will be needed to determine whether this apparent pure anabolic effect persists over longer periods of PTHrP administration, whether it is present in longer studies in the absence of estrogen treatment, and whether it can be confirmed using skeletal biopsies and quantitative bone histomorphometry.

Assuming that the selective anabolic effect is reproducible in longer and larger studies as described above, we hypothesize that the differences in bone formation and resorption between PTH and PTHrP also may result from their different pharmacokinetics after sc absorption as described above. It is well known that longer exposure of osteoblasts or their precursors in vitro or in vivo to PTH diminishes the anabolic response, whereas it augments the osteoclastic resorptive response (8, 9, 41). By serendipity, the accelerated absorption and clearance of PTHrP after sc injection, compared with those of PTH, may further favor the formation vs. resorption balance. Again, experimental confirmation of this hypothesis is required.

This study has a number of weaknesses. First, it is a very small study. This is because it was designed as a pilot study to determine whether PTHrP might have any efficacy whatsoever in treating osteoporosis, and the results are surprisingly more favorable than anticipated. Yet the small size of the study is particularly troubling with regard to the control group. The seven subjects who completed the study displayed a 1.4% increase in spine BMD. Post hoc analysis indicated that this large mean increase was due to one subject who had a 6.5% increase in spine BMD. The increase in this subject was not due to artifacts of positioning or vascular or ligamentous calcification and was not observed in other sites (total hip, femoral neck) in this subject. This subject had one of the lowest plasma 25 vitamin D concentrations (39.9 nmol/liter) in the cohort, and the BMD changes may therefore reflect an increase in BMD resulting from calcium and vitamin D replacement in a subject with vitamin D deficiency. Subanalysis of the control group with this outlier excluded indicated a mean increase in spine BMD of 0.6% (n = 6, P = 0.003 vs. the PTHrP group), comparable with larger clinical trials for osteoporosis using calcium and vitamin D supplements in the placebo arm. Thus, we believe that these preliminary observations underscore the need for PTHrP trials involving larger numbers of subjects.

Second, no fracture data are available for PTHrP in humans. In this regard, it is noteworthy that 6 months of PTHrP administration to estrogen-deficient Sprague Dawley rats improves skeletal biomechanical properties, not only compared with estrogen-deficient rats but also compared with sham-ovariectomized, normal rats (29). It seems reasonable to conclude that because PTH and PTHrP act via comparable skeletal pathways, the antifracture efficacy of PTH may also apply to PTHrP. Again, much larger and longer studies will be needed to address this issue.

Third, no effects on hip BMD were observed. This was expected in this small brief pilot study and is similar to results reported at early time points for PTH and bisphosphonates. Increments in hip BMD in response to PTHrP may or may not be observed in longer and larger studies.

Fourth, the optimal dose of PTHrP remains to be determined. We selected the 6.56 µg/kg·d dose based on our prior 2-wk pilot study (36). Indeed, it may be possible to attain even greater BMD efficacy using doses of PTHrP larger than those used herein. Of course, greater toxicity also may be observed using larger doses. Further studies are needed to address this issue.

In summary, short-term, high-dose treatment with PTHrP(1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36) causes a remarkable increase in spine BMD. In contrast to the combined or net resorptive and anabolic skeletal effects of intermittently administered PTH over the same time period, PTHrP may have predominantly anabolic effects with little resorptive component. The differences between PTH and PTHrP are not likely to reflect differences in receptor interactions or signaling between the two molecules but likely reside in the differing pharmacokinetic properties of the two molecules after sc administration. Despite the very high doses of PTHrP used, adverse events have not been observed in 18 human subjects. The availability of a purely or predominantly anabolic agent, in addition to PTH, may permit additional combined approaches to treating osteoporosis using concomitant, intermittent, or sequential regimens with antiresorptive agents. Larger studies designed to examine optimal dosing, duration, requirement for estrogen, antifracture efficacy, safety, and combination therapy with other antiresorptive agents are warranted.


   Acknowledgments
 
We thank Drs. Jane Cauley, David Roodman, and Susan Greenspan for advice during this study and help in critiquing this manuscript. We thank Dr. Mushtaq A. Syed for his assistance in the early phases of this study. We thank Dr. Gary Marshall for the NTX and DPD measurements. We thank Glaxo-SmithKline Beecham Foods International Pharmaceuticals for providing the calcium carbonate and vitamin D supplements. We also thank the patients and their families who participated in this study.


   Footnotes
 
This work was supported by NIH Grants DK 55081 and AR 38460.

Abbreviations: BMD, Bone mineral density; DPD, deoxypyridinoline; NS, not significant; NTX, N-telopeptide; P1CP, collagen-1 propeptide; PTHrP, PTH-related protein.

Received July 18, 2002.

Accepted October 17, 2002.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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