Diltiazem stimulates parathyroid hormone secretion in vivo whereas felodipine does not

The impact of two calcium channel blockers of different structure, diltiazem and felodipine, on PTH secretion was studied under hyper- and hypocalcemic conditions. Six healthy volunteers were investigated before and after treatment with felodipine, then after treatment with diltiazem. Under each of these three conditions, they received first a calcium infusion (0.109 mmol/kg over 130 min). Blood was drawn every 5-10 min for measurements of Ca2+ and intact PTH concentrations, and urine was collected over the infusion periods for measurements of calcium and creatinine. Basal levels of Ca2+ and intact PTH concentrations were similar under the three conditions. During calcium infusion, Ca2+ increased linearly from 1.27 to 1.51 mmol/L during the control period. Based on the whole response curve, Ca2+/time, this rise was less marked (P < 0.002) during each of the calcium channel blocker periods than under control conditions, although the three values of urinary calcium excretion were similar. In addition, PTH secretion was less suppressed on diltiazem than on felodipine therapy or during the control period (P < 0.04). During EDTA infusion, Ca2+ decreased in a linear way from 1.27 to 1.07 mmol/L during the control period. Based on the whole response curve, Ca2+/time, this decrease was more marked during felodipine than during diltiazem treatment or in the control period (P < 0.001). Although Ca2+ concentrations did not differ between the control and diltiazem periods, PTH levels were 1.3-fold higher (P < 0.0001) during diltiazem, but similar in the control and felodipine periods. These data demonstrate that diltiazem, but not felodipine, stimulates PTH secretion in vivo in man, with a maximal effect observed under hypocalcemic conditions.     

Whole-body autoradiography of 123I-labelled islet amyloid polypeptide (IAPP). Accumulation in the lung parenchyma and in the villi of the intestinal mucosa in rats

The basal levels of cytosolic calcium ([Ca2+]i) in rats and/or humans with chronic renal failure (CRF) are elevated in many cells including brain synaptosomes, pancreatic islets, polymorphonuclear leukocytes, platelets and B and T cells. This rise in [Ca2+]i has been attributed to the state of secondary hyperparathyroidism of CRF. These observations have led to the proposition that CRF is a state of cellular calcium intoxication mediated by excess parathyroid hormone (PTH). The documentation of a high basal level of [Ca2+]i in other cells is needed to provide further support for this postulate. The present study evaluated the basal levels of [Ca2+]i of thymocyte, which are targets for PTH action, in normal, CRF, and CRF parathyroidectomized (CRF-PTX) rats. We also examined whether CRF affects the phenotype expression (Thy-1, CD4 and CD8) in thymocytes. The results showed that the basal levels of [Ca2+]i in thymocytes from CRF rats (81 +/- 3.7 nM) are significantly (p < 0.01) higher than those in normal animals (60 +/- 2.9 nM). PTX of CRF animals prevented the elevation in the basal levels of [Ca2+]i of thymocytes; in these animals, the levels were 59 +/- 2.8 nM. Neither CRF nor the elevation in [Ca2+]i of thymocytes affected their phenotype expression.     

Effects of parathyroidectomy on induced renal failure in dogs

OBJECTIVE: To determine the effects of parathyroid hormone (PTH) depletion on dogs with induced chronic renal failure. ANIMALS: 2 groups of 26 mixed-breed dogs of both sexes (13 were parathyroidectomized [PTX] and 13 had sham surgery). PROCEDURE: After surgical reduction of renal mass and PTX, dogs were selected for a 24-month period of study and monitored for clinical, hematologic, blood biochemical, and organ function status. On development of uremia or after 24 months, dogs were euthanatized, and tissues were examined. RESULTS: Higher survival rate and smaller decrement in renal function (glomerular filtration rate) were observed in PTX dogs, compared with those that had sham surgery, but values did not reach statistical significance. The PTX dogs remained hypocalcemic during the study and had lower serum Ca2+ X P product values. Regardless of parathyroid state, survivors and fatalities could be separated on the basis of serum Ca2+ X P product values. Parathyroidectomy did not prevent renal deposition of calcium, and renal lesions were poorly correlated with renal cortical calcium concentration. Abnormalities reported in dogs with renal failure, which were attributed to PTH (glucose intolerance, pulmonary hypertension), were not observed in PTX dogs or those that had sham surgery. CONCLUSIONS AND CLINICAL RELEVANCE: PTX had beneficial effects, but these were mediated via changes in mineral homeostasis rather than via direct effects of PTH. Results attributable to PTX were similar to those previously obtained by dietary restriction of phosphate intake.     

Biochemical markers of calcium and bone metabolism during 18 months of lactation in Gambian women accustomed to a low calcium intake and in those consuming a calcium supplement

The effect of 18 months of lactation on indexes of calcium and bone metabolism was studied in 60 Gambian women accustomed to a very low calcium intake. Half the women consumed a calcium supplement from 10 days postpartum for 52 weeks (supplement, 714 mg Ca/day; total Ca intake, 992 +/- 114 mg/day), and half consumed placebo (total Ca intake, 288 +/- 128 mg/day). Fasting blood and 24-h urine samples were collected at 1.5, 13, 52, and 78 weeks of lactation and analyzed for calciotropic hormones (intact PTH, 1,25-dihydroxyvitamin D, and calcitonin), bone turnover markers (osteocalcin, bone alkaline phosphatase, and urinary deoxypyridinoline), and plasma minerals (calcium and phosphate). The first months of lactation were associated with increased bone turnover and plasma phosphate, and decreased PTH and 1,25-dihydroxyvitamin D. These effects diminished by 52 weeks, although breast milk volumes remained high. The Gambians had higher PTH, 1,25-dihydroxyvitamin D, and bone formation than British women with a greater customary calcium intake. None of the biochemical indexes was affected by calcium supplementation, with the possible exception of bone alkaline phosphatase (-29% at 52 weeks; P = 0.015). These data demonstrate that lactation-associated changes in calcium and bone metabolism are physiological and are independent of dietary calcium supply in women with very low calcium intakes.     

Low Ca2+ dialysate. Effects on bone metabolism in the course of paired filtration dialysis

To evaluate the 1-year effects of PFD performed with low Ca2+ dialysate (1 mmol/l) on calcium metabolism and on bone disease, the authors studied in eight patients who were previously treated with PFD performed with standard Ca2+ dialysate (1.75 mmol/l). On samples from these subjects, the following were evaluated: 1) serum Ca2+ and PO4 levels, 2) serum PTH levels, 3) serum Al levels, and 4) bone morphology. All the patients were hypercalcemic, four with high serum PTH levels (high turnover bone disease, group 1) and four with low serum PTH levels (low turnover bone disease, group 2). In both groups, a decrease in serum Ca2+ and an increase in serum PTH was observed within the third month. In group 2, PTH levels reached the normal range. Because serum Ca2+ levels decreased to normal in both groups, it was possible to administer oral CaCO3 (10.5 +/- 2 g/day) to control serum PO4 and to stop Al gels. This did not induce any increase in serum Ca2+, whereas serum Al fell significantly. In group 1, to prevent a further rise in PTH, patients were treated with intravenous calcitriol (5 +/- 2 micrograms/week). This induced a reduction in the serum PTH without increasing serum Ca2+ or PO4. Within 12 months, an improvement in bone morphology was seen in both groups. It is concluded that the use of low Ca2+ dialysate corrects hypercalcemia in patients with PFD treated with high oral doses of CaCO3, and improves low turnover bone disease. The combination of low Ca2+ dialysate and intravenous calcitriol also improves high turnover bone disease.     

Calcitonin and the bone fluid compartment: effect of calcitonin and/or parathyroid hormone on plasma radiocalcium changes

Changes in plasma calcium and 45Ca concentrations were followed after injection of calcitonin or a combination of calcitonin (CT) and parathyroid hormone (PTH) into thyroparathyroidectomized rats maintained on thyroxine. Comparison was made between rats injected with the hormone(s) after a recent feeding and after an overnight fast. Also cor (18 hr 45Ca) before, and more than 6 days (greater than 6 day 45Ca) prior to hormone administration. The following results were obtained: The action of CT predominated over that of PTH for the first few hours after injection. However, the effects of PTH were eventually manifested even when additional CT was administered. In the "greater than 6 day" 45Ca groups, PTH normally produced an increase in plasma 45Ca specific activity. However, in fasted rats, plasms 45Ca fell with total calcium with no change in specific activity following CT injection. In fed rats CT injection was followed by a decrease in plasma 45Ca specific activity. When both hormones were administered plasma 45Ca specific activity changes mimicked those produced by CT alone even after PTH plasma effects were manifested. In the "18 hr" 45Ca groups, CT produced first a drop in plasma 45Ca, followed by a reduction in the rate of its removal from plasma. It is concluded that the data can best be explained by the postulate that plasma calcium concentrations are maintained by the control of fluxes between bone fluid in the osteocyte-lining cell bone unit and the extracellular fluid. PTH increases the efflux from this bone fluid compartment while CT restricuts the source of calcium and, therefore, the efflux. Plasma 45Ca changes are due to a combination of changes in flux rates and mixing processes between the extracellular fluid compartment and the bone fluid compartment.     

Effects of calcitonin and parathyroid hormone on calcification of primary cultures of chicken growth plate chondrocytes

Few studies have been directed toward elucidating the action of calcitonin (CT) and parathyroid hormone (PTH) on growth plate chondrocytes, cells directly involved in longitudinal bone growth and provisional calcification. In this study, primary cultures of avian growth plate chondrocytes that calcify without the supplement of beta-glycerophosphate were used to investigate the effects of synthetic human CT and 1-34 bovine PTH on (1) cell division and growth; (2) the deposition of Ca2+ and inorganic phosphate (Pi); (3) the activity of alkaline phosphatase (AP), an enzyme long associated with the mineralization process; (4) the levels of proteoglycans; and (5) the synthesis of collagens. Added continually to preconfluent cultures from day 6 until harvest, CT (1-30 nM) and PTH (0.1-1.0 nM) increased mineral deposition; the maximal increase was seen between days 18-21 at 10 nM CT (175-260%) and 0.5 nM PTH (approximately 170-280%), both p < 0.001. CT had no significant effect on cellular protein, or AP-specific activity, whereas PTH increased cellular protein, DNA, proteoglycan, and collagen content of the cultures in a dosage-dependent manner. AP activity and levels of Type II and X collagens and fibronectin in the culture medium showed a biphasic response to PTH; maximal increases were seen at 0.5 nM between days 15-18. Longer exposure (days 21-27) to PTH at higher levels (5-10 nM) caused a marked decreased in AP activity but a lesser decrease in the collagens. These results indicate that CT and PTH can act directly on chondrocytes to stimulate mineralization, but that PTH specifically stimulated cell division and synthesis of cellular and extracellular proteins by growth plate chondrocytes. The implications of these findings with regard to Ca2+ homeostasis and bone formation are discussed.     

Influence of ovariectomy on bone metabolism in very old rats

Twenty-five 30-month-old Lou rats fed a diet (6 g/100 g BW/day) containing 0.9% Ca and 0.8% Pi were divided into five groups. Four groups were surgically ovariectomized. From day 2 until day 29 after ovariectomy, they were S.C. injected either with 17 beta estradiol (E2; 10 micrograms/kg BW/48 hours) or progesterone (P; 140 micrograms/kg BW/48 hours), or 17 beta estradiol + progesterone (E2P) at the same doses, or solvent alone (OVX). The fifth group was sham operated (SH) and injected with solvent. Urine was collected in metabolic cages from day 24 to 29 after ovx, and urinary pyridinoline (PYD) and deoxypyridinoline (DPD) excretion (markers of bone resorption) was measured by HPLC. All animals were killed 30 days after ovariectomy. Serum was then collected for measurement of osteocalcin (OC), alkaline phosphatase (ALP), parathyroid hormone (PTH), and calcitonin (CT). At necropsy, the success of ovariectomy was checked by marked atrophy of the uterine horns. Left and right femur were harvested for densitometric and mineral analysis, respectively. Ovariectomy had no significant effect upon plasma calcium and PTH concentrations. E2 or E2P treatment significantly increased plasma PTH and calcitonin concentrations. Plasma OC concentrations and ALP were not different in any of the groups. In contrast, urinary excretion of PYD and DPD was higher in OVX than in SH rats. Bone mineral density (BMD) of the distal femur was decreased by OVX, but was not different in the E2P and SH groups. A similar pattern was observed for the mineral or Ca content of whole femur. Thus, OVX decreased BMD and bone mineral content (BMC) in very old female rats. Plasma OC concentration and ALP activity failed to demonstrate any significant effect of OVX, whereas PYD and DPD were elevated. These results suggest that bone resorption is increased in OVX rats, even when supplemented with E2 or P alone. However, no significant difference was observed between SH and OVX rats treated with supplementation of both E2 and P. Thus, in very old rats, a combination of E2 and P is much more effective than E2 or P alone to prevent bone loss following ovariectomy.     

Influence of ovariectomy and estradiol treatment on calcium homeostasis during aging in rats

Study was carried out an Wistar female rats to evaluate the consequences of ovariectomy and 17 beta-estradiol substitutive treatment during aging on bone. Ca metabolism and calciotropic hormones. Three groups of fifteen rats, mature, old and senescent (4-, 10-, and 28 month-old) female were fed a diet (6 g/100 g BW/day) containing 0.9% Ca and 0.8% Pi, Within each group, 10 rats were surgically ovariectomized (OVX). From day 1 until day 60 after OVX, they were subcutaneously injected with either 17 beta-estradiol (E: 10 micrograms/kg BW/48 h; n = 5) or with solvent alone (OVX; n = 5). Five other rats were sham operated (SH) and received solvent alone. Animals were put in balance 1 day per week to determine Ca and Pi intestinal apparent absorption and urinary pyridinium cross-links excretion was measured by HPLC. All rats were killed by exsanguination 60 days after OVX. Plasma was collected for measurement of intact parathyroid hormone (PTH), calcitonin (CT), insulin-like growth factor-1 (IGF-1), Ca and Pi. The success of OVX was confirmed at necropsy by observation of marked atrophy of the uterine horns. The right femur was collected, cleaned from adjacent tissue and used for mineral analysis. Despite correct matching for feeding, BW was significantly larger in 6 and 12 month-old OVX rats. OVX and 17 beta-estradiol had no significant effect upon plasma Ca, Pi and CT concentrations. Aging is associated with increased circulating PTH levels (pg/ml) (SH-6 months: 50.8 +/- 12.6; 12 months: 219.1 +/- 34.9; 30 months: 158.7 +/- 23.5; P < 0.05). Urinary and fecal Ca and Pi excretion in senescent animals were higher than in adult or old rats, thus resulting in a drastic fall in both intestinal apparent absorption and retention of Ca and Pi in 30 month-old animals. In each group, urinary pyridinium cross-links excretion and plasma osteocalcin concentration were higher in the OVX animals than in the controls, consistent with increased bone turnover in the estrogen deficient state. Both biochemical turnover markers were reduced in the estrogen-treated groups. In the same way, OVX increased and estrogen decreased the plasma IGF-1 levels. We conclude that 17 beta-estradiol prevents high turnover-induced osteopenia even in 30 month-old rats.     

Parathyroid hormone raises cytosolic calcium in pancreatic islets: study on mechanisms

The pancreatic islets of Langerhans are targets for PTH and the action of the hormone on the islet is most likely mediated through the ability of PTH to increase cytosolic calcium ([Ca2+]i) of the islet cells. Although direct evidence for such an effect has been clearly demonstrated, the mechanisms through which the hormone exerts such an action are not elucidated. The present study examined these questions using pancreatic islets isolated from normal rats. Both 1-34 and 1-84 PTH produced a dose dependent increase in [Ca2+]i of the islets but the effect of the latter was significantly (P < 0.01) greater than that of the former. This action of PTH was significantly (P < 0.01) decreased by the use of PTH antagonist or by verapamil. The G protein activator (GTP gamma S) mimicked the effect of PTH while pertussis toxin and the G protein inhibitor (GDP beta S) significantly reduced the PTH-induced rise in [Ca2+]i. Dibutyryl cAMP, and phorbol ester 12-myristate 13 acetate increased [Ca2+]i of pancreatic islets in a dose dependent manner and the effect was inhibited (P < 0.01) by verapamil. Staurosporine inhibited the effect of TPA as well as of 1-84 PTH on [Ca2+]i of the islets. These data indicate that: (1) PTH increases [Ca2+]i of pancreatic islets, (2) this action is partly receptor mediated and is produced by activation of L-type calcium channels through stimulation of G protein(s), and (3) the rise in [Ca2+]i is due to both stimulation of cAMP generation and activation of protein kinase C.     

Secretion of a bone resorbing factor by chick thyroid glands in organ culture

The ability of the thyroid gland to secrete a bone resorbing factor in vitro was studied using glands obtained from 20-day-old chick embryos. The glands were incubated in a modified BGJ medium containing 1 mg/ml bovine serum albumin under 5% CO2-40% O2 at 37 C. The culture media were assayed in vitro by measuring the stimulation of the release of previously incorporated 45Ca from cultured 19-day fetal rat bone shafts over a 48 h period. The glands secreted a stimulator of bone resorption which did not appear to be parathyroid hormone (PTH). The dose-response curve for the thyroid gland factor was not parallel to that obtained using PTH and secretion was not under calcium control. Neither thyroxine (T4) nor triiodothyronine (T3) produced a marked stimulation of bone resorption over a wide range of doses. Bone resorption stimulated by the thyroid gland factor was inhibited by calcitonin (CT). Concentrations of TH and thyroid gland factor which were minimally effective when tested separately, produced a marked synergistic response when added together. This synergism was not seen when T4, T3, PGE1, or PGE2 were tested with PTH. Media obtained by culturing explants of embryonic chick liver, heart and muscle did not have bone resorbing activity. Secretion of the bone resorbing factor by thyroid glands was blocked by Indomethacin (10(-5)M) but the effects of the factor on bone were not blocked by this agent. These results suggest that the thyroid gland is capable of secreting a stimulator of bone resorption, possibly a prostaglandin, which is capable of synergizing with PTH, and which may represent a tissue factor which under certain circumstances may exert an influence on bone.     

Mineral metabolism in plasma, urine and bone of periparturient cows fed anionic diets with different calcium and phosphorous contents

The objective of this experiment was to evaluate the influences of Ca and P contents in an anionic diet on the mineral metabolism in plasma, urine and bone in periparturient diary cows. Fifteen multiparous Holstein-Friesian cows were divided into 3 dietary groups (5 cows/group) by dietary Ca and P contents and dietary cation-anion balance [(Na + K) - (Cl + S) mEq/kg DM]; diet 1 [low Ca (0.46%), low P (0.24%), cationic (+195.8 mEq/kg DM)]; diet 2 [low Ca (0.46%), low P (0.24%), anionic (-32.4 mEq/kg DM)]; and diet 3 [high Ca (0.93%), high P (0.60%), anionic (-41.0 mEq/kg DM)]. Cows were fed one of these 3 diets from approximately 4 weeks before the expected calving date to 5 days after calving. There was no outbreak of milk fever in any cows fed these 3 diets; however, plasma Ca levels at 1 and 2 days after calving tended to be higher in the cows fed diet 3 than those in the cows fed diets 1 or 2. Fractional urinary excretion of Ca in the cows fed diet 2 or 3 was higher than that in the cows fed diet 1. Fractional urinary excretion and plasma level of Pi were higher during the periparturient period in the cows fed diet 3 than those in the cows fed diets 1 or 2. There were no significant differences in plasma parathyroid hormone levels among the 3 groups. In the spongy substance of ilium at 5 days after calving, the Ca and Mg contents bone volume and trabecular thickness were the lowest, but not significant, in the cows fed diet 2. These data suggest that sufficient Ca and P contents in an anionic diet may be effective in maintaining plasma Ca and Pi levels of periparturient cows and further in preventing of potential bone damage brought about by increased urinary mineral excretion following the feeding of an anionic diet.     

A high sucrose diet decreases the mechanical strength of bones in growing rats

High sucrose diets alter mineral metabolism in humans and animals. We examined the effect of a high sucrose diet on bone growth, composition and mechanical strength in growing rats. Weanling Wistar rats received a high sucrose (43 g/100 g) diet (9 males, 11 females). In the control diet (8 males, 8 females), sucrose was replaced with potato starch, providing an equal energy value. At the onset of the experiment, bones were marked by tetracycline. After 5 wk, the tibias and femurs were weighed, and maximum breaking strengths were determined. Tibias were cut at the tibia-fibular junction; the widths of the bone at the start of the experiment, the periosteal bone formation during the experiment, the widths of the medullary cavity and the final bone width were determined from tetracycline lines. Bone ash weight, Ca and P contents were determined. The breaking strengths of both bones were significantly lower in the sucrose-fed groups of both sexes. In females, the weight of both bones and the final width of the tibias were significantly lower in the sucrose-fed group. The Ca concentration in both bones and the P concentration in tibias were significantly lower in the sucrose-fed group. It was concluded that the metabolic interference induced by sucrose was the reason for the differences. The alterations were more pronounced in females, but independent of body weight.     

Altered instantaneous and calcium-modulated oscillatory PTH secretion patterns in patients with secondary hyperparathyroidism

The relative contributions of increased parathyroid cell mass and altered control mechanisms of parathyroid hormone (PTH) secretion in secondary hyperparathyroidism are still controversial. In this study, endogenous pulsatile PTH secretion was analyzed by the multiparameter deconvolution technique to differentiate alterations in cell mass-dependent (PTH burst mass) and regulation-dependent (frequency, synchrony, calcium responsiveness) PTH release in uremic patients. PTH concentration versus time profiles were obtained in 13 uremic and 16 healthy adults under baseline conditions and during acute hypo- and hypercalcemia. Plasma PTH half-life was increased in patients compared with control subjects (4.7+/-1.9 versus 2.6+/-0.1 min, P < 0.005). The baseline PTH secretion rate was elevated eightfold in the patients as a result of an increased PTH mass secreted per burst (17.1+/-4.7 versus 2.0+/-0.4 pM, P = 0.0001), higher burst frequency (8.0+/-0.3 versus 6.8+/-0.3 h(-1), P < 0.01), and a higher tonic secretion rate (343+/-99 versus 30+/-4 pM/h, P = 0.0001). Acute hypocalcemia elicited an immediate, frequency- and amplitude-mediated selective increase in the pulsatile secretory component, which was fractionally weaker in patients (+595%) than control subjects (+1755%, P < 0.001). The acceleration and the amplification of PTH bursts were 35 and 60% lower in the patient group. Acute hypercalcemia suppressed total PTH secretion by 79% in control subjects but only by 63% in patients (P < 0.002). PTH burst frequency was reduced during hypercalcemia by 30% in control subjects, but remained unchanged in patients. In conclusion, uremic hyperparathyroidism is mediated by a marked increase in glandular secretion, but also by reduced PTH elimination. The increased spontaneous PTH burst frequency and the blunted responsiveness to changes in Ca2+ indicate partial uncoupling of hyperplastic parathyroid glands from the physiologic regulatory mechanisms that direct pulsatile PTH release.     

Compartmental shifts of calcium and magnesium as a result of swimming and swimming training in rats

To describe accurately the mineral changes (Ca and Mg) provoked by swimming, the aims of this study were to analyze those tissues that, with regard to their mineral content, can better classify individuals performing both swimming until exhaustion and swimming as training and to know the shifts of these minerals between different tissues after a single session of swimming until exhaustion and after training. Wistar rats were distributed into 12 groups, six male and six female (N = 10): 1) control rest group (CR); 2) trained rest group (TR); 3) control exercise group (CE); 4) trained exercise group (TE); 5) control recovery group (CER) and 6) trained recovery group (TER). The most informative tissues of Ca and Mg compartmental shifts during exercise have been determined. Discriminant analysis selected heart Ca, muscle Ca and bone Ca, bone Mg, erythrocyte Mg, and serum Mg as the most significant variables. The animals were classified by means of two canonical axes: the first one relates to training situation and sex, and the second one shows the special characteristics of trained male rats. Another independent discriminant analysis applied to male and female groups separately showed that the first canonical axis (control/trained) is basically defined by heart Ca, bone Ca, and erythrocyte Mg (male), and by heart Ca, bone Ca, and bone Mg (female), while the second axis, related to the exercise situations, is defined by the serum Mg levels in both sexes. We think that discriminant analysis is a statistical method capable of explaining physiological processes and classifying individuals performing exercises of different length. It suggests that the homeostasis of Ca and Mg is somewhat different for males and females. Serum magnesium must be considered to distinguish exercise situations. The analysis of these tissues could inform us about the mineral status of the rats and then we could correct possible deficiencies in our research. In this work we have only found different mineral redistributions among tissues. The trained animals have a better mineral recovery capacity than the untrained ones. Training has a different physiological repercussion in male and female rats on the basis of their respective maximal swimming times after training and their mineral behavior.     

Characterization of osteopenia in feline mucopolysaccharidosis VI and evaluation of bone marrow transplantation therapy

Studies on a feline model of MPS VI demonstrated a marked osteopenia in iliac crest bone samples from young adult animals with fewer, finer trabeculae. In the absence of significant differences in bone remodeling, this was considered due to defects in endochondral ossification and the formation of fewer trabeculae. Cell-level bone formation was normal despite the presence of vacuolated osteoblasts. Affected animals had vacuolated osteocytes in larger lacunae. Cats of the same age who had received a bone marrow transplant 12 months prior as young kittens, had significantly more trabecular bone with thicker trabeculae. The presence of smaller osteocyte lacunae in these animals as compared to their untreated MPS VI cats appeared to be a direct effect of bone marrow transplantation and a useful parameter to monitor its efficacy.     

Calcium-regulating hormones, bone mineral content, breaking load and trabecular remodeling are altered in growing pigs fed calcium-deficient diets

Studies on calcium nutrition in appropriate large animal models can be directly relevant to humans. We have examined the effect of dietary Ca deficiency on various bone and bone-related variables, including plasma markers, histomorphometry, mineral content and breaking strength in pigs. Three groups of eight 38-d-old female pigs were fed adequate (0.9%; control), low (0.4%; LCa) or very low (0.1%; VLCa) Ca diets for 32 d. Plasma Ca significantly decreased over time only in the VLCa-deficient pigs. The concentrations of the parathyroid hormones (PTH) and calcitriol increased as Ca deficiency developed, and the plasma PTH and calcitriol levels varied inversely with dietary Ca. The total bone ash contents, bending moments, trabecular bone volume and the mineral apposition rate all decreased as the calcium intake decreased. The osteoclast surface areas were greater than those of controls in both Ca-deficient groups, whereas the osteoblast surface areas were greater only in the VLCa group. The plasma osteoblast-related markers (alkaline phosphatase, carboxy-terminal propeptide of type I procollagen and osteocalcin) were either greater or unaffected in the Ca-deficient pigs. The results indicate that deficient bone mineralization combined with an increased bone resorption led to bone loss and fragility. The differences in the changes in bone cells (number and activity) between LCa and VLCa groups might be due to differences (time and extent) of circulating PTH and calcitriol. The defective mineralization in both Ca-depleted groups resulted mainly from the lack of Ca because their osteoblast activity was either maintained or stimulated. The results also underline the progressive sensitivity of pigs to Ca supply and the usefulness of this model.     

Bone hyperresorption is prevalent in chronically critically ill patients

STUDY OBJECTIVE: Chronically critically ill (CCI) patients are primarily elderly people who have survived a life-threatening episode of sepsis but remain profoundly debilitated and ventilator dependent. The objective of this study was to determine the prevalence of bone hyperresorption and parathyroid hormone (PTH)-vitamin D axis abnormalities in these patients. DESIGN: Prevalence survey. SETTING: Respiratory care step-down unit (RCU) at a tertiary care teaching hospital. PATIENTS: Forty-nine ventilator-dependent CCI patients transferred from ICUs within the same institution. INTERVENTION: None. MEASUREMENTS AND RESULTS: N-telopeptide (NTx) levels in 24-h urine collections and serum intact PTH, 25-vitamin D, and 1,25-vitamin D levels were measured within 48 h of RCU admission. Patients were hospitalized a median of 30 days before RCU admission. Four patients (9%) had normal NTx and PTH levels. Forty-five patients (92%) had elevated urine NTx levels consistent with bone hyperresorption. Nineteen patients (42% of total patients) had elevated PTH levels consistent with predominant vitamin D deficiency, 4 patients (9%) had suppressed PTH levels consistent with predominant hyperresorption from immobilization, and 22 patients (49%) had normal PTH levels consistent with an overlap of both vitamin D deficiency and immobilization. There were no differences in vitamin D metabolites among these groups. CONCLUSIONS: CCI patients have a high prevalence of bone hyperresorption in which PTH levels may clarify the cause. Further studies will determine the efficacy and cost-effectiveness of routine NTx and PTH screening in these patients and the role of vitamin D and antiresorptive therapies.     

The lack of effect of chronic metabolic acidosis on 25-OH-vitamin D metabolism and serum parathyroid hormone in humans

We evaluated the turnover of the plasma 25-OH-vitamin D pool, acid, and mineral balances in paired balance studies of 6 normal subjects during normal acid base conditions and during stable chronic metabolic acidosis induced by NH4Cl. Positive acid balances and negative Ca balances due to hypercalciuria were observed as previously reported. Plasma 25-OH-D pool turnover averaged 6.1+/-0.4 nmol/day during control and did not change during acidosis (6.5 +/- 0.5 nmol/day) nor were any significant increments in net intestinal absorption of Ca, PO4, or Mg, the physiological expression of vitamin D action, observed during acidosis. In 3 other subjects, repetitive measurements of serum iPTH during 7 control days and 24 days of stable NH4Cl acidosis showed no changes. We interpret the data to support the hypothesis that neither PTH nor vitamin D and its metabolites mediates the increase in net bone resorption that must accompany chronic metabolic acidosis.