The effects of PTH (1-34) on bone structure and strength in ovariectomized monkeys.
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Animals↗
Biomedical subjects
R Brommage
Publications and source records attributed to R Brommage.
Treatment with human parathyroid hormone (1-34) for 18 months increases cancellous bone volume and improves trabecular architecture in ovariectomized cynomolgus monkeys (Macaca fascicularis).
A key feature of postmenopausal osteoporosis is the loss of trabecular bone mass and connectivity. The current study focuses on these parameters in the assessment of long-term (12 and 18 months) parathyroid hormone (PTH) therapy and its withdrawal (6 months) in the ovariectomized cynomolgus monkey (Macaca fascicularis), a well-characterized model for bone changes associated with postmenopausal osteoporosis. We used static and dynamic histomorphometric parameters to assess the amount and architecture of cancellous bone in four clinically important sites for osteoporotic fractures, including the lumbar vertebra, femoral neck, distal radius, and iliac crest. Recombinant human PTH(1-34) was administered daily to two groups for 18 months at 1.0 microg/kg per day (n = 19) and 5.0 microg/kg per day (n = 21). To study the effects of PTH withdrawal, two groups were administered PTH(1-34) daily for 12 months at 1.0 microg/kg per day (n = 20) and 5.0 microg/kg per day (n = 20), followed by daily administration of vehicle for 6 months. Sham-ovariectomized and ovariectomized (ovx) groups each received daily injections of vehicle for 18 months. Treatment with PTH had minimal effects on bone formation rates at the timepoints studied, but markedly increased cancellous bone volume relative to ovx monkeys in iliac crest biopsies at 6 and 15 months, as well as in terminal specimens of lumbar vertebrae, femoral neck, and distal radius after 18 months. At all sites, PTH significantly improved trabecular architecture, as evidenced by increased trabecular number (Tb.N) and decreased trabecular separation (Tb.Sp), with no significant change in trabecular thickness (Tb.Th). The mechanism of these structural changes is suggested by qualitative observations of trabecular tunneling observed in the iliac crest and vertebra. Longitudinal tunneling of thickened individual trabeculae is hypothesized to convert them into multiple trabeculae, resulting in a normalization of Tb.Th, but an increase in Tb.N. A significant positive effect on cancellous bone volume was still apparent after a 3-6 month withdrawal period following 12 months of PTH treatment in the iliac crest, vertebra, and femoral neck. Corresponding increases in Tb.N and decreases in Tb.Sp also remained significant after PTH withdrawal at these three sites. The distal radius was relatively insensitive to PTH treatment or its withdrawal, compared with the other bones. In summary, PTH therapy dramatically improved cancellous bone mass and architecture in both axial and appendicular sites.
Absorptiometry, Photon↗
Levormeloxifene prevents increased bone turnover and vertebral bone loss following ovariectomy in cynomolgus monkeys.
Levormeloxifene, a nonsteroidal selective estrogen receptor modulator (SERM), has been evaluated for its effects on bone in cynomolgus monkeys (Macaca fascicularis). Adult female monkeys were imported from Indonesia and randomized into six groups of 25-28 animals each (n = 158). Animals in one group were sham ovariectomized (sham) and received vehicle. Animals in the remaining five groups were ovariectomized and received either vehicle (ovx); 17beta-estradiol at 0.016 mg/kg (est); or levormeloxifene at 0.5 (L1), 1 (L2), or 5 (L3) mg/kg. Lumbar spine and whole body bone mass were measured by dual-energy X-ray absorptiometry (DXA) pretreatment and at 6 and 12 months following the initiation of treatment. Bone mass at the femoral neck was measured by peripheral quantitative computed tomography (pQCT) at 0 and 12 months. Serum markers of bone turnover, including bone-specific alkaline phosphatase (BSAP), osteocalcin (BGP), tartrate-resistant acid phosphatase (TRAP), and urinary collagen C-terminal extension peptides (CrossLaps), were measured at 0, 6, and 12 months. Ovariectomy resulted in an increase in these markers; the increase was prevented by estradiol or levormeloxifene. Estradiol or levormeloxifene inhibited loss of lumbar spine bone mineral density (BMD) following ovariectomy compared with untreated monkeys (ovx -5.0%; sham -0.4%; est +0.2%; L1 -3.6%, L2 -2.0%, L3 -2.5%). Estradiol, but not levormeloxifene, prevented loss of BMD at the femoral neck (ovx -7.4%; sham -3.1%; est -3.6%; L1 -8.0%, L2 -6.5%, L3 -7.8%), and whole body bone mineral content (BMC) (ovx -7.6%; sham -1.9%, est -2.9%; L1 -6.2%, L2 -6.1%, L3 -6.7%). Bone loss at each site was correlated with bone turnover as measured by serum and urine biomarkers. There was no dose effect of levormeloxifene.
Animals↗
Intermittently administered human parathyroid hormone(1-34) treatment increases intracortical bone turnover and porosity without reducing bone strength in the humerus of ovariectomized cynomolgus monkeys.
Cortical porosity in patients with hyperparathyroidism has raised the concern that intermittent parathyroid hormone (PTH) given to treat osteoporotic patients may weaken cortical bone by increasing its porosity. We hypothesized that treatment of ovariectomized (OVX) cynomolgus monkeys for up to 18 months with recombinant human PTH(1-34) [hPTH(1-34)] LY333334 would significantly increase porosity in the midshaft of the humerus but would not have a significant effect on the strength or stiffness of the humerus. We also hypothesized that withdrawal of PTH for 6 months after a 12-month treatment period would return porosity to control OVX values. OVX female cynomolgus monkeys were given once daily subcutaneous (sc) injections of recombinant hPTH(1-34) LY333334 at 1.0 microg/kg (PTH1), 5.0 microg/kg (PTH5), or 0.1 ml/kg per day of phosphate-buffered saline (OVX). Sham OVX animals (sham) were also given vehicle. After 12 months, PTH treatment was withdrawn from half of the monkeys in each treatment group (PTH1-W and PTH5-W), and they were treated for the remaining 6 months with vehicle. Double calcein labels were given before death at 18 months. After death, static and dynamic histomorphometric measurements were made intracortically and on periosteal and endocortical surfaces of sections from the middiaphysis of the left humerus. Bone mechanical properties were measured in the right humeral middiaphysis. PTH dose dependently increased intracortical porosity. However, the increased porosity did not have a significant detrimental effect on the mechanical properties of the bone. Most porosity was concentrated near the endocortical surface where its mechanical effect is small. In PTH5 monkeys, cortical area (Ct.Ar) and cortical thickness (Ct.Th) increased because of a significantly increased endocortical mineralizing surface. After withdrawal of treatment, porosity in PTH1-W animals declined to sham values, but porosity in PTH5-W animals remained significantly elevated compared with OVX and sham. We conclude that intermittently administered PTH(1-34) increases intracortical porosity in a dose-dependent manner but does not reduce the strength or stiffness of cortical bone.
Animals↗
Three-dimensional modeling of the effects of parathyroid hormone on bone distribution in lumbar vertebrae of ovariectomized cynomolgus macaques.
Biomechanical and quantitative computed tomography (QCT) analyses showed beneficial effects of parathyroid hormone (PTH (1-34)) on lumbar vertebrae from ovariectomized monkeys, even after withdrawal of treatment for 6 months. Adult cynomolgus monkeys were randomized, ovariectomized (except for sham ovariectomy controls), and treated subcutaneously with vehicle (OVX) or 5 micrograms/kg per day PTH (1-34) (PTH5) for 18 months. An additional group was treated subcutaneously with 5 micrograms/kg per day PTH (1-34) (PTH5W) for 12 months and then switched to vehicle for the remaining 6 months. Lumbar vertebrae were excised at necropsy, and L5 were serially scanned by QCT, using 70 x 70 x 500 microns voxels. PTH increased volumetric bone mineral density (BMD, mg/cm3) and bone mineral content (BMC, mg) for both PTH5 and PTH5W compared with OVX and Sham without inducing hypermineralization, without stimulating periosteal expansion, and without significant constriction of the neural canal. BMD values for the voxels were then averaged to create nearly isotropic voxels of 490 x 490 x 500 microns. Serial scans were stacked and a triangular surface mesh generated for each bone, using a 'marching cubes' algorithm. A smoothed version of each surface mesh was used to generate a tetrahedral element for three-dimensional finite element modeling. An isotropic Young's modulus for each tetrahedral element was calculated as a function of the original voxel BMDs. Linear elastic stress analysis was then performed for each finite element model in which a distributed load of 100 newtons (N) was applied to the top surface of the centrum, perpendicular to the bottom surface with the bottom surface constrained in the direction of loading. Analysis of the effective strain showed considerable reduction in vertebral strain for both PTH5 and PTH5W, compared with OVX. Compression testing of the adjacent L3 and L4 confirmed that vertebral strength and stiffness for PTH5 and PTH5W were significantly greater than for OVX. Histogram and QCT analyses showed PTH conversion of low-density bone (trabecular bone) into medium-density bone (more and thicker trabeculae) by stimulating bone apposition. PTH withdrawal induced conversion of medium-density into low-density and high-density bone with the latter higher than in OVX. These data show that even transient PTH treatment improves vertebral architecture and bone quality to reduce the likelihood of fracture, and that transient treatment is better than no PTH treatment at all.
Animals↗
Rapid embedding protocol for visualizing bone mineral and matrix.
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Acetone↗
Changes in bone turnover during the menstrual cycle in cynomolgus monkeys.
It is well established that estrogen deficiency at menopause results in increased bone turnover, which is reflected in increased concentrations of markers of bone formation and bone resorption in serum and urine. Since serum 17beta-estradiol concentrations vary markedly throughout the menstrual cycle, one would expect to see changes in bone turnover as well. Studies in humans have not yielded consistent results, perhaps because of differences in diet and activity throughout the test period. Therefore, we examined changes in bone biomarkers throughout the menstrual cycle in cynomolgus macaques. Seven intact female cynomolgus macaques (Macaca fascicularis) were evaluated. Vaginal swabs for menstrual blood were performed 3 times/week to determine the stage of the reproductive cycle. Blood and urine were collected at weekly or biweekly intervals for a total of eight samples per monkey for analysis of serum 17beta-estradiol, progesterone, parathyroid hormone (PTH), osteocalcin, bone-specific alkaline phosphatase (BSAP), and urinary CrossLapstrade mark. Cycle lengths were determined, and collection days were adjusted to a standardized length of 28 days for all monkeys. Values for bone biomakers were evaluated as % mean for each monkey cycle. By fitting the data to a sine wave (cosinor analysis), serum osteocalcin, BSAP, and urinary CrossLaps demonstrated significant cycles with peaks at days 2.6, 7.3, and 27.8, respectively. Serum osteocalcin and urinary CrossLaps were inversely correlated to serum 17beta-estradiol. Urinary CrossLaps were significantly lower in the week just prior to and during ovulation when estradiol was elevated. No rhythm was detected in serum PTH. A peak in bone resorption when serum 17beta-estradiol is at its nadir is consistent with the hypothesis that estrogen decreases bone turnover.
Alkaline Phosphatase↗
Unbiased determination of cytokine localization in bone: colocalization of interleukin-6 with osteoblasts in serial sections from monkey vertebrae.
Few data are available describing the in vivo localization of cytokines in bone. The objective of this study was to describe the histological localization of interleukin-6 (IL-6) relative to osteoblasts (alkaline phosphate [ALP]-positive cells) and osteoclasts (tartrate-resistant acid phosphate [TRAP]-positive cells) in midsagittal, paraffin-embedded serial sections of thoracic 13 (T-13) vertebrae from 49 female cynomolgus monkeys. Serial sections 1 and 4 were immunostained for IL-6, section 2 was histochemically stained for TRAP, and section 3 was immunostained for ALP. Sixteen centrally located fields were measured in the cancellous compartment and grid alignment among sections was verified using image analysis. Using a Merz grid, IL-6 localized to 6% of the bone surface on sections 1 and 4, whereas TRAP localized to 8.5% and ALP to 12% of the bone surface. Colocalization was defined as positive staining within an 80 x 80 microm block in the first serial section that "overlapped" staining in either the corresponding block or its eight surrounding blocks within the second serial section. For each section, 1600 blocks were analyzed. Using Monte Carlo simulations, random colocalization was calculated to determine the statistical significance of experimental colocalizations. Colocalization of approximately 90% between the two IL-6 sections verified staining reproducibility and proper grid alignment among sections. Colocalization of TRAP and ALP was not statistically different from random (p 0.3). As identified using ALP- or TRAP-positive surfaces, there was significant IL-6 colocalization with osteoblasts (p < 0.003), but not with osteoclasts (p 0.3). These in vivo colocalization data support the hypothesis that osteoblasts produce and respond to IL-6.
Animals↗
Measurement of serum bone-specific alkaline phosphatase activity in cynomolgus macaques.
Serum levels of bone-specific alkaline phosphatase activity (B-ALP) in cynomolgus monkeys were evaluated as an index of elevated bone turnover following ovariectomy. The enzyme immunoassay 96-well microtiter plate B-ALP assay, developed by Metra Biosystems (Mountain View, CA) for human use, was employed and compared with a standard automated assay measuring total serum levels of alkaline phosphatase activity (T-ALP). The B-ALP assay was first validated for use in these monkeys. Ovariectomy led to increased bone turnover as indicated by approximately 2-fold higher activity in both assays and this elevation was inhibited by daily estradiol administration. Although both assays provided generally similar results, several monkeys were observed to have greatly elevated values of T-ALP but not B-ALP. This discrepancy is believed to result from high levels of the liver isoform of alkaline phosphatase in monkeys with hepatic dysfunction, which are not detected by the B-ALP assay.
Alkaline Phosphatase↗
Daily treatment with human recombinant parathyroid hormone-(1-34), LY333334, for 1 year increases bone mass in ovariectomized monkeys.
PTH stimulates bone formation to increase bone mass and strength in rats and humans. The aim of this study was to determine the skeletal effects of recombinant human PTH-(1-34) [rhPTH-(1-34)] in monkeys, as monkey bone remodeling and structure are similar to those in human bone. Adult female cynomolgus monkeys were divided into sham-vehicle (n = 21), ovariectomized (OVX)-vehicle (n = 20), and OVX groups given daily s.c. injections of rhPTH-(1-34) at 1 (n = 39) or 5 (n = 41) microg/kg for 12 months. Whole body bone mineral content was measured, as was bone mineral density (BMD) in the spine, proximal tibia, midshaft radius, and distal radius. Serum and urine samples were also analyzed. rhPTH-(1-34) treatment did not influence serum ionized Ca levels or urinary Ca excretion, but depressed endogenous PTH while increasing serum calcitriol levels. Compared to that in the OVX group, the higher dose of rhPTH-(1-34) increased spine BMD by 14.3%, whole body bone mineral content by 8.6%, and proximal tibia BMD by 10.8%. Subregion analyses suggested that the anabolic effect of rhPTH-(1-34) on the proximal tibia was primarily in cancellous bone. Similar, but less dramatic, effects on BMD were observed with the lower dose of rhPTH-(1-34). Daily s.c. rhPTH-(1-34) treatment for 1 yr increases BMD in ovariectomized monkeys without inducing sustained hypercalcemia or hypercalciuria.
Animals↗
The anesthetic isoflurane decreases ionized calcium and increases parathyroid hormone and osteocalcin in cynomolgus monkeys.
The effects of anesthetics on calcium metabolism in cynomolgus monkeys were studied. Eight adult female cynomolgus monkeys were used in a crossover design. Blood was collected from each of the monkeys at four timepoints: (1) while conscious; (2) following induction of anesthesia with ketamine, ketamine and atropine, isoflurane, or no anesthetic; (3) at 30 min; and (4) 120 min thereafter. Four experiments were performed with a 1 week washout period between sessions, such that each monkey received each treatment. Potassium was lower in anesthetized monkeys than in those that remained conscious. Cortisol, although high, did not differ among anesthetic treatments. Ketamine and ketamine/atropine did not consistently affect ionized calcium or parathyroid hormone (PTH) concentrations. Isoflurane decreased ionized calcium (0.05 mmol/L), and increased PTH and osteocalcin twofold. The serum inorganic fluoride concentration was higher in monkeys anesthetized with isoflurane than with ketamine/atropine, which may partially account for the decrease in ionized calcium with isoflurane. The increases in PTH and osteocalcin are presumably secondary to the decrease in ionized calcium.
Anesthetics, Inhalation↗
Genes in idiopathic calcium oxalate stone disease.
An examination of the urinary excretions of 101 normal subjects indicated that the major genetic influence on calcium excretion is a codominant pair of alleles giving rise to three phenotypes, low, intermediate and high (hypercalciuric) excretors. This inference was based on variance, Hardy-Weinberg and segregation analyses. Similar independent gene pairs also appear to influence oxalate and citrate excretion, A 3-locus Hardy-Weinberg table using estimates of gene frequencies derived from the study of normals suggests that only 3 or 4 leading genes are involved in oxalate stone disease. Strong candidate genes identified from molecular and physiological studies cannot be proposed at present, but it is assumed that they influence the transport of these ions in either the intestine, kidney or both organs. The identification of the genes involved should be facilitated by the reduction of dietary influences on urinary excretions through the use of formula diets.
Calcium Oxalate↗
Treatment of ovariectomized rats with the complex of rhIGF-I/IGFBP-3 increases cortical and cancellous bone mass and improves structure in the femoral neck.
Sixteen-week-old Sprague-Dawley rats were ovariectomized (Ovx) or sham-operated and housed for 8 weeks to develop osteopenia prior to systemic administration of rhIGF-I (0.9 and 2.6 mg/kg) alone or the rhIGF-I/IGFBP-3 (0.9, 2.6 and 7.5 mg/kg) complex. After 8 weeks of treatment, proximal femurs were fixed, embedded, and cut through the midneck region. Structural and dynamic histomorphometric analyses were performed using standard techniques. Ovx increased endocortical resorption and modeling-dependent periosteal formation which resulted in decreased cortical bone area. Despite increased bone formation, trabecular number, thickness, and area were all reduced due to increased resorption. Structural changes following Ovx included fewer struts and nodes, a higher percentage of the simpler strut forms, and reduced endocortico-trabecular connectivity. Eight weeks of treatment with rhIGF-I or rhIGF-I/IGFBP-3 promoted periosteal and endocortical bone formation and reduced the endocortical resorption induced by Ovx. Both rhIGF-I formulations stimulated bone formation on existing trabecular surfaces which increased trabecular thickness and area but not trabecular number. These treatments prevented further deterioration of the trabecular network caused by Ovx and preserved endocortico-trabecular connectivity. In summary, changes in the femoral neck following Ovx appear to be similar in rats and humans. The highest dose of rhIGF-I/IGFBP-3 used in this study showed the best results in promoting cortical and cancellous bone formation, and appears to be promising therapy for human osteopenias.
Animals↗
The cecum does not participate in the stimulation of intestinal calcium absorption by calcitriol.
Intestinal Ca absorption from the diet consumed during one night was measured in male rats fed a normal (0.5%) Ca, low fiber (3% cellulose) diet by determining the decrease in 47Ca/47Sc ratio between diet and feces. One-half of the rats had been cecectomized 9 weeks previously at 14 weeks of age. Calcitriol injections, given intraperitoneally the morning of the experiment, stimulated fractional intestinal Ca absorption 2.5-fold in intact rats (16.9 +/- 2.0% to 42.2 +/- 1.8%) and 2.3-fold in cecectomized rats (20.1 +/- 1.4% to 46.8 +/- 1.2%). Similar results were obtained when the data were calculated in terms of total Ca absorption expressed as mg/day. Thus, although the cecum can absorb Ca when diets contain large amounts of digestible fiber, cecectomy does not influence the stimulation of intestinal Ca absorption induced by calcitriol in vitamin D-replete rats fed a low fiber diet.
Animals↗
Systemic administration of rhIGF-I or rhIGF-I/IGFBP-3 increases cortical bone and lean body mass in ovariectomized rats.
The purpose of this study was to compare dose-related effects on cortical bone and lean body mass following subcutaneous administration of rhIGF-I alone, or bound to an equimolar amount of rhIGFBP-3 to adult Ovx rats. At the age of 16 weeks, rats were ovariectomized or sham-operated and were allowed 8 weeks to develop osteopenia. After being divided into control (saline treated) or treatment groups, rats were injected daily during an 8-week period with 0.9 and 2.6 mg/kg of rhIGF-I, or with 0.9, 2.6, and 7.5 mg/kg of rhIGF-I bound to rhIGFBP-3. Fluorescent bone markers were given 9 and 2 days prior to necropsy. Body weights and lean body mass were monitored throughout the experiment. Cortical bone histomorphometry was performed on tibial cross-sections at the tibiofibular junction, and endochondral bone growth was measured at the distal femoral metaphysis. All rats treated with rhIGF-I or the rhIGF-I/IGFBP-3 complex had increased body weights, corresponding to a dose-dependent increase in lean body mass. Endochondral growth was slightly increased in all experimental groups, but was not dose-dependent. A dramatic increase in periosteal, modeling-dependent formation, coupled with decreased or unchanged resorption on the endocortical envelope resulted in a dose-dependent increase in cortical thickness and cross-sectional area in groups treated with the complex of rhIGF-I/IGFBP-3. This complex appeared to be more effective in promoting positive musculoskeletal changes than rhIGF-I alone.(ABSTRACT TRUNCATED AT 250 WORDS)
Absorptiometry, Photon↗
The effect of systemically administered rhIGF-I/IGFBP-3 complex on cortical bone strength and structure in ovariectomized rats.
The action of systematically administered recombinant human insulinlike growth factor-I (rhIGF-I) complexed to its natural binding protein-3 (rhIGFBP-3) on cortical bone dynamic, structural, and mechanical properties was tested in previously ovariectomized (Ovx) rats. Bilateral ovariectomy or sham surgery was performed on 16-week-old female Sprague-Dawley rats. Eight weeks after surgery basal Sham and Ovx rats were killed to establish baseline cortical bone values before the initiation of treatment with rhIGF-I/IGFBP-3 complex. At that time, Ovx rats had increased body weight and body fat mass with reduced femoral BMC and BMD relative to basal Shams. Bone formation rates in Ovx rats were increased on both cortical envelopes relative to time-matched controls. The thickness of the inner lamellar bone layer and average cortical width were reduced due to increased endocortical erosion. A similar ratio between Sham and Ovx rats in body mass and composition and femoral BMC and BMD continued throughout the experiment. Sixteen weeks after surgery bone formation rates at both cortical envelopes in Ovx rats were reduced relative to Shams, but endocortical erosion remained high causing a further decrease in thickness of the inner lamellar layer. As a result of periosteal bone modeling. Ovx rats exhibited a larger femoral cross-sectional area and periosteal perimeter, as well as a thicker outer lamellar layer. Newly deposited periosteal bone increased ultimate torque values in the Ovx rats relative to Shams at 16 weeks. Treatment of Ovx rats with the rhIGF-I/IGFBP-3 complex increased body weight, lean body mass, and femoral BMC and BMD.(ABSTRACT TRUNCATED AT 250 WORDS)
Analysis of Variance↗
Benefit of systemically administered rhIGF-I and rhIGF-I/IGFBP-3 on cancellous bone in ovariectomized rats.
The dose-related effects of systemically administered rhIGF-I and rhIGF-I/IGFBP-3 were monitored in the osteopenic rat skeleton at three different sites with cancellous bone: distal femoral metaphysis, epiphysis, and lumbar vertebral bodies. At the age of 16 weeks, rats were bilaterally ovariectomized (OVX) or sham operated (sham) and 8 weeks later divided into the control groups (sham OVX), and OVX groups treated with different doses of rhIGF-I or rhIGF-I/IGFBP-3 for 8 weeks. Fluorescent bone markers were given 9 and 2 days before necropsy. In addition, changes in designated bone sites as a result of ovariectomy alone were evaluated 8 and 16 weeks after surgery. High bone resorption, which dominates the postovariectomy remodeling process, resulted in a loss of cancellous bone at all measured sites. The highest trabecular bone loss was measured in the metaphyses (40%), compared with 22% in the lumbar vertebrae and 16% in the epiphyses. After 8 weeks of treatment with 7.5 mg/kg of rhIGF-I/IGFBP-3, bone formation rates were increased at all sites measured. Increased trabecular thickness was observed at the epiphyses and in the lumbar vertebral bodies. Increased bone resorption was restricted to the metaphyses of the rats that received the highest dose of rhIGF-I or rhIGF-I/IGFBP-3. Both formulations of rhIGF-I increased longitudinal bone growth similarly. This experiment demonstrates site-specific differences in cancellous bone reactions following ovariectomy. Epyphyses showed some advantages for cancellous bone histomorphometry over metaphyses and lumbar vertebral bodies. The data presented confirm the potential of rhIGF-I/IGFBP-3 complex to promote the bone formation process at various bone sites in osteoporotic rat skeleton.
Animals↗
Intestinal calcium absorption in rats is stimulated by dietary lactulose and other resistant sugars.
Lactulose is a disaccharide analogue of lactose that is resistant to metabolism in the small intestine but not in the large intestine. The effects of lactulose and other sugars on intestinal Ca absorption were determined from the decrease in the 47Ca:47 Sc ratio between diet and feces after feeding male rats diets containing these sugars during a single night. Dietary lactulose was more potent than lactose in stimulating Ca absorption and was effective between 5 and 38 wk of age. The component sugars of lactulose, galactose and fructose, did not influence Ca absorption when provided together at concentrations equimolar to that of lactulose. The stimulation of Ca absorption by dietary lactulose increased as dietary Ca concentration was raised and was not influenced by prior injections of calcitriol. Lactulose must be present in the same meal as Ca to stimulate Ca absorption, but this stimulation was lost if the rats were fed lactulose continuously for 2 or 7 d prior to the test diet. Other sugars thought to be poorly absorbed in the small intestine (xylitol, lactobionate, arabinose, raffinose, pyroglutamate, sorbitol, gluconate and raftilose) stimulated Ca absorption to an identical extent as lactulose. Cecectomy did not influence the enhancement of Ca absorption by lactulose. These results indicate that sugars resistant to metabolism and absorption in the small intestine but not the large intestine stimulate Ca absorption in the small intestine.
Age Factors↗