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Programmed Administration of Parathyroid Hormone Increases Bone Formation and Reduces Bone Loss in Hindlimb-Unloaded Ovariectomized Rats¹

Departments of Orthopedics and Biochemistry and Molecular Biology (R.T.T., G.L.E., J.M.C.), Mayo Foundation, Rochester, Minnesota 55905; Veterans Administration Medical Center (B.H.), San Francisco, California 94121; and National Air and Space Administration, Ames Research Center (E.M.-H.), Moffett Field, California 94035

Address all correspondence and requests for reprints to: Russell T. Turner, Ph.D., Orthopedic Research, Room 3-69 Medical Science Building, Mayo Foundation, 200 First Street SW, Rochester, Minnesota 55905.

	Abstract

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Gonadal insufficiency and reduced mechanical usage are two important risk factors for osteoporosis. The beneficial effects of PTH therapy to reverse the estrogen deficiency-induced bone loss in the laboratory rat are well known, but the influence of mechanical usage in this response has not been established. In this study, the effects of programed administration of PTH on cancellous bone volume and turnover at the proximal tibial metaphysis were determined in hindlimb-unloaded, ovariectomized (OVX), 3-month-old Sprague-Dawley rats. PTH was administered to weight-bearing and hindlimb-unloaded OVX rats with osmotic pumps programed to deliver 20 µg human PTH (80 µg/kg·day) during a daily 1-h infusion for 7 days. Compared with sham-operated rats, OVX increased longitudinal and radial bone growth, increased indexes of cancellous bone turnover, and resulted in net resorption of cancellous bone. Hindlimb unloading of OVX rats decreased longitudinal and radial bone growth, decreased osteoblast number, increased osteoclast number, and resulted in a further decrease in cancellous bone volume compared with those in weight-bearing OVX rats. Programed administration of PTH had no effect on either radial or longitudinal bone growth in weight-bearing and hindlimb-unloaded OVX rats. PTH treatment had dramatic effects on selected cancellous bone measurements; PTH maintained cancellous bone volume in OVX weight-bearing rats and greatly reduced cancellous bone loss in OVX hindlimb-unloaded rats. In the latter animals, PTH treatment prevented the hindlimb unloading-induced reduction in trabecular thickness, but the hormone was ineffective in preventing either the increase in osteoclast number or the loss of trabecular plates. Importantly, PTH treatment increased the retention of a baseline flurochrome label, osteoblast number, and bone formation in the proximal tibial metaphysis regardless of the level of mechanical usage. These findings demonstrate that programed administration of PTH is effective in increasing osteoblast number and bone formation and has beneficial effects on bone volume in the absence of weight-bearing and gonadal hormones. We conclude that the actions of PTH on cancellous bone are independent of the level of mechanical usage.

	Introduction

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THE SKELETAL effects of ovarian hormone deficiency have been well characterized in the rat (1, 2, 3). Ovariectomy (OVX) results in increases in radial and longitudinal bone growth and cancellous osteopenia, changes that can be prevented by estrogen replacement. This bone loss is due to a net increase in bone resorption and is similar to postmenopausal bone loss (4). As a consequence, the ovariectomized (OVX) rat has proven to be a very useful laboratory animal model for the pathogenesis, prevention, and treatment of postmenopausal osteoporosis. Although estrogen deficiency is the most important risk factor for osteoporosis, not all postmenopausal women develop fractures, so it is likely that there are additional contributing risk factors. One of these risk factors may be an age-related reduction in mechanical usage. In this regard, spaceflight was recently shown to result in a decrease in cancellous bone volume in OVX rats over and above that caused by ovarian hormone deficiency (5). Interestingly, the additional bone loss was due to a further increase in bone resorption. This finding was a surprise because disuse osteopenia in male rats with normal gonadal function is primarily due to a decrease in bone formation; bone resorption is either transiently increased or not increased (6, 7, 8, 9, 10, 11, 12, 13). These results suggest that the cellular mechanism for skeletal adaptation to changes in mechanical usage is influenced by gonadal hormones. This conclusion is further supported by studies demonstrating that mechanical loading reduces ovariectomy-induced cancellous bone loss (14). Additional supporting evidence is derived from studies showing that the pattern of bone loss in OVX rats is related to mechanical strain energy density (15).

PTH is being investigated for treatment of postmenopausal osteoporosis (16). PTH treatment is effective in preventing OVX-induced bone loss in rats (17, 18) and can restore normal bone volume in the laboratory animal model if the bone loss is not extreme (19, 20). PTH treatment can also prevent bone loss in immobilized (21) and hindlimb-unloaded rats (22) with normal gonadal function. The efficacy of PTH treatment to prevent bone loss in gonadal hormone-deficient rats with reduced mechanical usage is unknown and is the principal question to be answered in this investigation.

	Materials and Methods

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The animal protocols were approved by the institutional animal welfare committees at the Mayo Foundation (Rochester, MN) and NASA Ames Research Center (Moffett Field, CA).

A total of 60 3-month-old Sprague-Dawley rats, weighing about 250 g, were obtained from Simonson Laboratories (Gilroy, CA) 3 days after surgery. Fifty of the rats were OVX and the remaining 10 rats were sham operated.

Two weeks after surgery, the OVX rats were randomly divided into 5 groups of 10 animals. One group of OVX rats (basal control) were killed at the start of hindlimb elevation to provide baseline measurements. Two groups of OVX rats were hindlimb elevated as previously described (23). The remaining 2 groups of OVX rats were used as weight-bearing controls. An additional sham-operated group of rats was used as a weight-bearing control group with normal ovarian function.

One group of hindlimb-elevated OVX rats was treated with recombinant human PTH-(1–34) (Bachem, Torrance, CA), and the other group was given the vehicle only. The weight-bearing OVX control groups were treated similarly. PTH was administered using sc implanted osmotic pumps (Alza, Palo Alta, CA) programmed to deliver approximately 20 µg PTH (80 µg/kg·day) during a daily 1-h infusion for 7 days as previously described (24). Programed delivery of PTH was recently shown to increase osteoblast number and bone formation as effectively as intermittent sc administration of the hormone (24, 25). The principal advantage of this method for these studies was the reduced handling of the animals compared with daily sc administration of the hormone. This was especially important for the hindlimb-elevated rats. The OVX vehicle control group received osmotic pumps loaded to deliver vehicle (150 mM NaCl, 1 mM HCl, and 2% heat-inactivated rat serum) only. The rats were double fluorochrome labeled via the tail vein with calcein (20 mg/kg) 3 days before hindlimb unloading and with tetracycline (20 mg/kg) 8 days later to label mineralizing bone matrix. The rats were killed with isoflorene. The right tibia was quickly excised and placed in 70% ethanol.

Bone histomorphometry
Histomorphometric measurements were performed with the SMI-Microcomp-P.M. semiautomatic image analysis system (Southern Micro Instruments, Atlanta, GA) as previously described (5).

Cortical bone measurements
Ground transverse sections, cut at a site just proximal to the tibia-fibula synostosis, were prepared for histomorphometric analysis of cortical bone as previously described (5). The following values were obtained as previously described (21): 1) cross-sectional bone area, 2) medullary area, 3) cortical bone area, 4) periosteal perimeter, 5) endocortical perimeter, 6) periosteal bone formation rate (calculated as the area of bone between the calcein label given at the start of the experiment and periosteal perimeter divided by the postlabeling period of 8 days), 7) periosteal mineral apposition rate (an index of osteoblast activity, which is calculated as the periosteal bone formation rate divided by the label perimeter), and 8) periosteal label perimeter (an index of osteoblast number, defined as the periosteal perimeter labeled with calcein).

Cancellous bone measurements made on stained sections
The metaphysis was dehydrated in a series of increasing concentrations of ethanol, embedded without demineralization in a mixture of methylmethacrylate-2-hydroxyethyl and methacrylate (12.5:1) to retain the fluorochrome labels, and sectioned at a thickness of 5 µm (model 2065 microtome, Reichert-Jung, Heidelberg, Germany) as previously described (5). The sections were stained with toluidine blue. A standard sampling site was established in the secondary spongiosa of the metaphysis, 1 mm distal to the calcein label that was deposited at the metaphyseal growth plate, its center perpendicular to the long axis of each bone and extending 2.0 mm distal to the starting point. This modified method, which has been described in detail previously (26), adjusts for longitudinal growth such that only the portion of the secondary spongiosa present throughout the experiment is sampled. A total metaphyseal area of 2.88 mm² was sampled for each section.

Bone volume measurements
Cancellous bone area and cancellous perimeter were determined as previously described (5). The following indexes of trabecular architecture were calculated as described: 1) trabecular thickness, 2) trabecular number, and 3) trabecular separation (27).

Bone cell measurements
The cancellous bone lined by osteoblasts and osteoclasts (perimeter referent) were measured and expressed as percentages (24). Briefly, undemineralized 5-µm thick sections were stained with toluidine blue. Osteoclast perimeter was determined as the cancellous perimeter lined by multinucleated cells. These cells usually had other characteristics of osteoclasts, including a foamy cytoplasm and location in a pronounced lacuna. Osteoblasts were identified as a palisade of large basophilic cuboidal cells directly lining a bone perimeter.

Bone formation measurements and calculations
The bone formation rate (tissue area referent) was calculated as the double labeled perimeter (microns) multiplied by the mineral apposition rate (microns per day) and divided by the tissue area (square millimeters per mm²), bone formation rate (perimeter referent) was calculated as the double labeled perimeter (microns) multiplied by the mineral apposition rate (microns per day) and divided by the total bone perimeter (millimeters per mm²), mineral apposition rate was calculated as the mean distance between the calcein label and the bone perimeter lined by osteoblasts divided by the postlabel time interval (8 days), and double labeled perimeter (tissue area referent) was measured as the length with tetracycline and calcein labels (millimeters per mm² of cancellous tissue area).

Statistical analyses
One-factor ANOVA was performed on all groups with Fisher’s protected least significant difference post-hoc multiple comparison tests to establish significance. The posttreatment OVX groups were compared with the basal OVX group to determine the effects of time. The sham-operated group was compared with the other posttreatment groups to determine the effects of OVX. Two-factor ANOVA was performed to establish the respective effects of PTH and weight bearing.

	Results

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No interactions between weight bearing and PTH treatment were observed for any of the measurements performed in this study.

The effects of OVX, hindlimb unloading, and PTH treatment on body weight, weight gain, and uterine weight are shown in Table 1. OVX increased body weight and resulted in uterine atrophy. Neither body nor uterine weight was influenced by PTH treatment or hindlimb unloading.

View larger version (35K): [in this window] [in a new window]   Figure 1. Hindlimb unloading decreases and PTH treatment increases osteoblast perimeter at the proximal tibial metaphysis in OVX rats. The values are the mean ± SE (n = 8–9). Two-factor ANOVA revealed significant effects of PTH (P = 0.0004) and loading (P = 0.049) and a nonsignificant interaction term.

View larger version (36K): [in this window] [in a new window]   Figure 2. Hindlimb unloading increases and PTH treatment has no effect on osteoclast perimeter at the proximal tibial metaphysis in OVX rats. The values are the mean ± SE (n = 8–9). Two-factor ANOVA revealed a nonsignificant effect of PTH, a significant effect of loading (P = 0.046), and a nonsignificant interaction term.

View larger version (38K): [in this window] [in a new window]   Figure 3. Hindlimb unloading had no effect on and PTH treatment increased retention of the calcein label at a growth-adjusted site at the proximal tibial metaphysis in OVX rats. The values are the mean ± SE (n = 8–9). Two-factor ANOVA revealed significant effects of PTH (P = 0.002), a nonsignificnat effect of loading, and a nonsignificant interaction term.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

The skeletal effects of hindlimb unloading in OVX rats in this study were similar to those following spaceflight (5). Both models for decreased mechanical usage resulted in reduced radial bone growth and cancellous osteopenia. Interestingly, neither spaceflight nor hindlimb unloading reduced the OVX-induced increase in bone formation at the proximal tibial metaphysis, suggesting that reduced weight bearing results in an increase in bone resorption over and above that caused by gonadal hormone insufficiency. The additional bone resorption in unweighted OVX rats is probably due to small increases in osteoclast number and activity. An increase in number is supported by the increase in osteoclast perimeter observed in the present study. There was no change in the retention of the calcein label that had been deposited into cancellous bone before launch, indicating that unloading had no effect on bone surfaces that were undergoing bone formation.

Two-factor (with or without PTH treatment and with or without weight bearing) ANOVA revealed that hindlimb unloading results in a small but significant decrease in osteoblast perimeter. Weight bearing had no effect on other indexes of bone formation, including fluorochrome-labeled perimeter, mineral apposition rate, and calculated bone formation rate. Additionally, spaceflight had no effect on steady state messenger RNA levels for bone matrix proteins, which were greatly increased by OVX (5). Thus, several independent indexes of osteoblast number and activity indicate that skeletal unloading leads to either a mild retardation or no effect on the greatly elevated cancellous bone formation in the proximal tibial metaphysis of estrogen-deficient rats.

Reduced mechanical usage also results in cancellous bone loss in male and female rats with intact gonadal function (9, 28). However, the cellular mechanism for the bone loss in normal male and female rats appears to differ from that in OVX rats. Unloading bone in males, whether due to spaceflight, sciatic neurotomy, or hindlimb elevation, results in dramatic, chronic decreases in bone formation, with either brief increases or no change in bone resorption (10, 11, 12, 13). Fewer studies have been performed in normal female rats, but these limited data suggest a similar skeletal response (29, 30).

Hindlimb unloading resulted in a decrease in the longitudinal growth rate compared with that in weight-bearing OVX rats. Abnormalities in the histology of the growth plate have been observed in rat long bones after spaceflight (31). Additionally, we have detected decreases in steady state messenger RNA levels for type 2 collagen and aggrecan in growth plate from the proximal tibia after spaceflight (Sibonga, J., and R. T. Turner, unpublished). These results suggest that weight bearing is essential for normal bone elongation. In contrast, PTH treatment had no effect on longitudinal bone growth in either hindlimb-unloaded or weight-bearing OVX rats.

PTH treatment had no short term effect on cortical bone histomorphometry. This finding is in agreement with previous short term studies in skeletally mature male and female rats (32). Other studies have revealed that long term treatment with PTH increases periosteal bone formation in OVX rats (33).

PTH treatment resulted in dramatic increases in cancellous bone formation in tibia from unweighted as well as weight-bearing rats. The increased bone formation was primarily due to an increase in osteoblast number; the small increase in the mineral apposition rate suggests that an increase in osteoblastic activity may have also contributed to the increase in bone formation.

PTH treatment of rats has been shown to prevent as well as correct established osteopenia in the OVX rat model for postmenopausal bone loss (17, 18, 19, 20). Additionally, PTH treatment can prevent cancellous osteopenia in hindlimb-unloaded male rats (7). The present study evaluated the efficacy of PTH treatment to prevent the combined effects of OVX and hindlimb unloading on rat bone. As expected, programed administration of PTH was effective in preventing cancellous bone loss in OVX weight-bearing rats. In contrast, PTH treatment reduced but did not completely prevent bone loss in hindlimb-unloaded OVX rats. Unloading, but not PTH treatment, increased osteoclast number, suggesting that PTH-stimulated bone formation was insufficient to completely compensate for the excessive bone resorption caused by the additive effects of gonadal hormone deficiency and decreased mechanical usage.

We have not ruled out the possibility that higher doses of PTH might be more effective in preventing bone loss in OVX rats with reduced mechanical usage. However, clearance studies have shown that the 80 µg/kg dose results in serum PTH levels sufficient to saturate PTH receptors (24). Dose-response studies have verified that this is a near-optimal dose for OVX rats; higher doses of the hormone result in progressively severe side-effects (34, 35, 36).

The inability of PTH to completely prevent cancellous bone loss in OVX rats with reduced mechanical usage is probably related to the mechanism of action of the hormone. The principal action of intermittent PTH treatment appears to be activation of bone lining cells to express the osteoblast phenotype (37). This action results in the addition of bone onto trabecular surfaces, causing an increase in trabecular thickness. However, the bone loss that follows OVX and skeletal unloading consists predominantly of osteoclast-mediated destruction of trabecular plates (34, 38). PTH does not antagonize this process, and as a result, the hormone-induced bone does not completely compensate for the skeletal changes. Indeed, PTH results in abnormalities in bone architecture.

One of the potentially serious limitations of PTH therapy for postmenopausal osteoporosis is the parenteral mode of administration of the drug. PTH therapy may be further limited by the narrow therapeutic window by which extending exposure to elevated circulating levels of the hormone for more than 1 h at a time results in progressively severe undesirable side-effects, including hypercalcemia, marrow fibrosis, and focal bone resorption (24). The present studies, however, demonstrate the feasibility of programed administration of implanted PTH to stimulate bone formation to reverse osteopenia.

In summary, gonadal hormone insufficiency combined with decreased mechanical usage, independent risk factors for osteoporosis that are probably present simultaneously in the elderly, did not prevent the pronounced stimulatory effects of intermittent PTH therapy on osteoblast number and bone formation in a rat model. We conclude that the actions of PTH on cancellous bone are independent of mechanical usage. PTH treatment did not, however, prevent the accelerated loss of trabeculae in the rat model. These findings suggest that PTH therapy, although clearly beneficial, is inadequate to completely protect cancellous architecture in these animals.

	Acknowledgments

 
The authors thank Ms. Lori Rolbiecki for editorial assistance.

	Footnotes

 
¹ This work was supported by NASA Grants NAGW-4963 and NCC-2–589. Additional support was obtained from NIH Grants AR-35651 and AR-41418, and the Mayo Foundation.

Received February 20, 1998.

	References

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