C.H. Søgaard

PTH has a more pronounced effect on vertebral bone mass and biomechanical competence than antiresorptive agents (estrogen and bisphosphonate)—assessed in sexually mature, ovariectomized rats

The aim of the study was to determine the effect of PTH, the antiresorptive agents estrogen and bisphosphonate (Risedronate), and also the combination of PTH with the antiresorptive drugs on vertebral bone mass and biomechanical competence in a sexually mature, ovariectomized rat model. A total of 138 3-month-old Sprague-Dawley rats were randomized into seven groups: (1) sham operated (control); (2) ovariectomized (OVX); (3) OVX plus estrogen; (4) OVX plus bisphosphonate [Risedronate (NE)]; (5) OVX plus hPTH (1-34); (6) OVX plus hPTH (1-34) and estrogen; and, finally, (7) OVX plus hPTH (1-34) and Risedronate. Treatment regimens were initiated 4 weeks after OVX and were continued for 5 and 15 weeks for each treatment group. Changes in bone mass (ash content) and biomechanical competence were assessed on lumbar vertebral body L4. The results revealed that the Risedronate-treated OVX animals had a higher vertebral bone mass than the OVX group. hPTH (1-34) on its own had a pronounced anabolic effect and increased bone mass 20-25% and bone strength 70-80% over control levels. Neither combination therapy with estrogen nor with Risedronate provided any further advantage. The combination of PTH with Risedronate, though, seemed to allow a continued increase in both bone mass and strength during the whole treatment period.(ABSTRACT TRUNCATED AT 250 WORDS)

The anabolic effects of parathyroid hormone on cortical bone mass, dimensions and strength—assessed in a sexually mature, ovariectomized rat model

The aim of the study was to determine the effect of parathyroid hormone (PTH), the antiresorptive agents estrogen and bisphosphonate (risedronate), and also the combination of PTH with these antiresorptive drugs on femoral cortical bone mass, dimensions and strength in a sexually mature, ovariectomized rat model. A total of 138, 3-month-old Sprague-Dawley rats were randomized into seven groups: 1--sham operated (control); 2--ovariectomized (OVX); 3--OVX plus estrogen; 4--OVX plus bisphosphonate (risedronate [NE]; 5--OVX plus hPTH (1-34); 6--OVX plus hPTH (1-34) and estrogen; 7--OVX plus hPTH (1-34) and risedronate. Treatment regimens were initiated 4 weeks after OVX and were continued for 5 and 15 weeks for each treatment group. Changes in bone mass (ash content), cross-sectional area, cortical thickness and dimensions and bone strength were assessed in middiaphyseal, femoral specimens. The results revealed that ovariectomy had no effect on cortical bone mass and biomechanical competence. OVX rats treated with estrogen and also OVX rats treated with risedronate showed no significant difference from either OVX or control groups. After only 5 weeks of treatment, hPTH monotherapy increased ash content, cross-sectional area, cortical thickness and compressive bone strength (load) significantly. After 15 weeks of treatment, OVX rats treated with PTH monotherapy or PTH in combination with risedronate showed identical load-values. These values were significantly higher than those seen in both control and OVX rats. However, PTH in combination with estrogen failed to augment cortical bone strength over control or OVX levels after therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Parathyroid hormone monotherapy and cotherapy with antiresorptive agents restore vertebral bone mass and strength in aged ovariectomized rats

Previous studies have shown that parathyroid hormone (PTH) monotherapy and cotherapy with estrogen or risedronate augment vertebral bone mass and bone strength in young, ovariectomized (OVX) rats. The current study was designed to determine whether PTH has similar bone anabolic effects in aged OVX rats at a much later stage of estrogen depletion. Female Sprague Dawley rats were subjected to sham surgery or bilateral ovariectomy at three months of age and maintained untreated for one year after surgery to allow for the development of vertebral osteopenia in OVX rats. Groups of baseline control and OVX rats were sacrificed at the end of this pretreatment period. The remaining OVX rats were then treated for ten weeks with vehicle, antiresorptive agents alone (estrogen, risedronate, or calcitonin), or PTH alone. Other groups of OVX rats were treated concurrently with PTH and each of the antiresorptive agents. The first and fourth lumbar vertebral bodies were processed undecalcified for quantitative bone histomorphometry and biomechanical testing, respectively. As expected, bone mass and compressive strength were decreased in the lumbar vertebral body of baseline OVX rats compared to baseline control rats. This bone loss was associated with decreases in trabecular number and width and an increase in trabecular separation. Treatment with estrogen, risedronate, or calcitonin alone failed to reverse the changes in bone mass, structure, and strength induced by ovariectomy. In contrast, treatment of OVX rats with PTH alone restored vertebral cancellous bone volume and ash density to the level of vehicle-treated control rats and increased vertebral maximum load, stress, and normalized load to well above this level.(ABSTRACT TRUNCATED AT 250 WORDS)

Marked decrease in trabecular bone quality after five years of sodium fluoride therapy; assessed by biomechanical testing of iliac crest bone biopsies in osteoporotic patients

Sodium fluoride has for more than 2 decades been a commonly used therapeutic agent for established osteoporosis because of a repeatedly documented anabolic effect on trabecular bone mass. Recently, however, three controlled trials have failed to demonstrate any therapeutic advantage of NaF over placebo with respect to vertebral fracture rate. Also, there have been several reports of an increased incidence of nonvertebral fractures during fluoride administration. Thus, the efficacy of fluoride therapy remains a controversial issue. The aim of this longitudinal study was to investigate the effect of sodium fluoride (40-60 mg per day), calcium (45 mmol), and vitamin D2 (18,000 IU) on trabecular bone strength, assessed before and after 1 or 5 years of treatment for osteoporosis. Iliac crest biopsies were taken before and after 1 year of treatment in 12 patients, and before and after 5 years of treatment in 14 patients. Measurements were made of biomechanical competence, ash content, and bone fluoride content, and bone strength parameters were normalized for ash content, thereby obtaining a measure of trabecular bone quality. Bone fluoride content was significantly increased after both 1 and 5 years of treatment, indicating that the administered fluoride had been ingested. After 1 year of treatment, no difference was observed in iliac crest trabecular bone ash content. A general trend for decreased bone strength and bone quality was observed, but this was insignificant. After 5 years of fluoride treatment, an insignificant decrease in iliac crest trabecular bone ash content was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Calcium-restricted ovariectomized sinclair s-1 minipigs: An animal model of osteopenia and trabecular plate perforation

The ovariectomized rat model has now been generally accepted as a useful model for screening different therapeutic agents, but there is a major requirement to identify reliable large animal models for osteoporosis research. In this study, the calcium restricted, ovariectomized minipig has been thoroughly investigated in order to define a large animal model with trabecular and cortical bone remodeling which would be reliable for further testing of agents that had shown promise of efficacy during the screening procedure. Twenty six female, 4-month old minipigs were randomized into four groups and fed either normal diet (0.90% calcium (Ca.)) or diet with restricted calcium content (0.75%, 0.50%). At the age of ten months, 3 groups were ovariectomized (OVX) while one group on normal diet was shamoperated. The groups were followed for six months after the operation. At death, bone mass was determined by densitometry and by ashing. Additionally, biomechanical competence was assessed in trabecular bone cores from the vertebral bodies. Finally, histomorphometry (static and dynamic parameters) and structural analyses (star volume) were performed on the vertebral bodies. The study revealed an OVX-related decline of 6% in vertebral bone mineral density (BMD) and a decline of 15% in trabecular bone volume (BV/TV). In contrast, a 15% increase in mean trabecular plate separation (Tb.Sp.) and a small increase in marrow space star volume (Ma. Star V.) were detected. The structural changes became more pronounced when OVX was combined with mild Ca. restriction (0.75% Ca.) with an increase in Ma. Star V. to 164%.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of fluoride on rat vertebral body biomechanical competence and bone mass

For more than 30 years, sodium fluoride has been a commonly used therapeutic agent for established osteoporosis because of its repeatedly documented anabolic effect on trabecular bone mass. Recent clinical and experimental studies have, however, indicated a possible detrimental effect of fluoride on bone strength. Thus, the efficacy of fluoride therapy remains a controversial issue. The aim of this study was to investigate the effect of fluoride on both vertebral bone mass and quality in rats. Twenty-nine 3-month-old, female rats were randomized into three groups. One group served as a control group, and the other two groups received fluoridated water at different doses (100 ppm and 150 ppm). The rats were followed for 90 days. Three lumbar vertebrae were obtained from each rat, and changes in bone fluoride content, bone mass and biomechanical competence were assessed. The results revealed a significant increase in bone fluoride content, ash density and trabecular bone volume after fluoride treatment. Directly obtained load values and load corrected for cross-sectional area were constant. Load corrected for ash content, which is a measure of bone quality, decreased significantly after fluoride therapy. It is concluded that the increase in bone mass during fluoride treatment does not translate into an improved bone strength and that the bone quality declines. This investigation thereby supports the hypothesis of a possible negative effect of fluoride on bone quality.

A comparison of the effects of two anabolic agents (fluoride and PTH) on ash density and bone strength assessed in an osteopenic rat model

The aim of this investigation was to compare the effects of sodium fluoride (NaF) and parathyroid hormone (PTH) on ash density and strength in an osteopenic rat model. The study comprised 66 female virgin rats divided into the following 11 groups, each comprising six animals: baseline controls; baseline ovariectomized (ovx); intact controls (5 and 16 weeks), ovx controls (5 and 16 weeks); ovx-treated with PTH (0.02 mg/kg per day, 5 and 16 weeks); ovx treated with NaF (10 mg/kg per day, 5 and 16 weeks); ovx-treated with NaF (1.0 mg/kg per day, 16 weeks). Ovariectomy was performed at 12 weeks of age, 14 weeks prior to start of treatment. Ash density, bone fluoride content, and biomechanical analyses were performed on femoral cortical bone, the right femoral neck, and the sixth lumbar vertebral body. ovx had no effect on cortical bone, whereas the femoral neck displayed a significantly lower bone strength in ovx baseline animals compared with intact baseline rats (p < 0.05). Vertebral ash density was found to be significantly decreased in ovx rats after 5 and 16 weeks (p < 0.05). Treatment with fluoride had little effect on the osteopenic rat skeleton. Cortical ash density was significantly lower than ovx and intact groups in the high-dose-treated rats after 5 (p < 0.01) but not after 16 weeks. High doses of fluoride for 16 weeks induced a significant increase in maximum load and normalized strength in cortical bone when compared with intact animals (p < 0.05), but not at the other bone sites. Cortical bone strength was not different from the ovx animals at either timepoint. In fluoride-treated animals, femoral neck bone strength, vertebral body bone strength, bone quality, and ash density were found to be at about ovx levels and, in the vertebral body, significantly lower than intact animals (p < 0.05, p < 0.01). In contrast, treatment with PTH increased ash density, bone strength, and bone quality to above ovx levels (p < 0.01), and above the level of the intact animals also, although significant values were reached for cortical bone strength only (p < 0.01). Additionally, biomechanical competence and ash density measurements were significantly higher in PTH-treated rats compared with fluoride-treated rats. In conclusion, this study has shown that PTH has a highly anabolic effect and is capable of effectively restoring ovx-induced loss of bone mass and biomechanical competence. In addition, in this osteopenic rat model, PTH proved much more advantageous than treatment with fluoride, which failed to restore the ovx-induced loss of bone strength.

Normal age-related changes in fluoride content of vertebral trabecular bone—Relation to bone quality

In several clinical osteoporosis studies, fluoride treatment has been shown to have a positive effect on bone mass but without a concomitant decrease in vertebral fracture rate. In contrast, some studies have shown that increases in spinal BMD are also paralleled by decreased vertebral fracture incidence. We have previously demonstrated, in a pig model, that 6-month treatment with fluoride increased bone mass but decreased bone quality. The aim of the present study was to elucidate whether normal age-related fluoride accumulation in human bone per se influences bone quality. From 73 normal individuals, aged 20-91 years (36 females, 37 males) two trabecular bone cylinders were obtained from the central part of L3. Biomechanical competence, ash density, and fluoride content were assessed in one cylinder, and trabecular bone volume was determined in the other. The results showed an age-related decrease in bone mass for both men and women. Bone strength normalized for bone mass (bone quality also identical with bone material strength) also showed an age-related decrease in men and women. Bone fluoride concentration increased significantly in both sexes (range 463-4000 ppm). Multiple regression analyses disclosed that fluoride by itself had no influence on bone quality, in this study with a limited number of cases, when the influence of sex and age were taken into account. It is concluded that normal age-related accumulation of fluoride in vertebral trabecular bone does not seem to affect the quality of bone. Whether this is also the case during fluoride therapy has to be assessed.

Computerized determination of 3-D connectivity density in human iliac crest bone biopsies

The aim of the present study was to design a computer program for direct measurement of 3-D connectivity density in iliac crest bone sections, as used for conventional histomorphometry. We used the physical disector principle and developed an algorithm for non-linear alignment of the disector pairs. The method was applied on biopsies from 14 non-selected autopsy cases: 7 men (age range 20–84 yr) and 7 women (age range 20–86 yr). Connectivity density was measured using the ConnEulor principle. The study indicated decreases in trabecular bone mass (BV/TV, %) and connectivity density with age in women. However, connectivity density measurements and BV/TV showed no significant age-related changes in either men or women. The designed computer program aligns the disector pairs and depicts the differences between images automatically, thereby making correct, direct connectivity density measurements available for conventional bone research.

Spine deformity index in osteoporotic women: Relations to forearm and vertebral bone mineral measurements and to iliac crest ash density

Bone densitometric measurements are widely used for monitoring therapeutic regimens for osteoporosis. However, it is a matter of debate which measurement site is most appropriate for prediction of individual fracture risk. The aim of this cross-sectional study was to investigate the relationship between bone mineral measurements at various sites and spine deformity index (SDI) in osteoporotic women. The SDI was determined in 37 osteoporotic women aged 56–87 years (mean 70.9 years). Peripheral (single-photon absorptiometry of the distal forearm, and iliac crest ash content) and axial (dual-photon absorptiometry of the lumbar spine) bone mass measurements were obtained. SDI increased with age (r=0.34,p<0.05), whereas forearm BMC (r=−0.52,p<0.002) and forearm BMD (r=−0.62,p<0.0001) decreased. No significant age-related changes were observed in lumbar BMC or iliac crest ash content in these osteoporotic women. A highly significant correlation was found between SDI and lumbar BMC(r=−0.60,p<0.01). A significant, but less pronounced correlation was found between SDI and forearm BMC (r=−0.37,p<0.05), whereas no relation was revealed between SDI and forearm BMD or iliac crest ash content. In a multiple regression model, the relationship between lumbar BMC and SDI remained significant after adjusting for the influence of age, whereas the relationship to forearm BMC disappeared. Furthermore, a multiple regression analysis was performed in order to evaluate the ability of all four bone mass measurements and age to predict variations in SDI. Lumbar BMC was the single significant predictor of SDI in this model (r=−0.68,p<0.01). This study indicates that the risk of vertebral fracture is best estimated by bone mass determined in the spine.