A moderately low phosphate intake may provide health benefits analogous to those conferred by UV light - a further advantage of vegan diets

Although exposure to ultraviolet light is often viewed as pathogenic owing to its role in the genesis of skin cancer and skin aging, there is growing epidemiological evidence that such exposure may decrease risk for a number of more serious cancers, may have a favorable impact on blood pressure and vascular health, and may help to prevent certain autoimmune disorders - in addition to its well-known influence on bone density. Most likely, these health benefits are reflective of improved vitamin D status. Increased synthesis or intake of vitamin D can be expected to down-regulate parathyroid hormone (PTH), and to increase autocrine synthesis of its active metabolite calcitriol in certain tissues; these effects, in turn, may impact cancer risk, vascular health, immune regulation, and bone density through a variety of mechanisms. Presumably, a truly adequate supplemental intake of vitamin D - manyfold higher than the grossly inadequate current RDA - could replicate the benefits of optimal UV exposure, without however damaging the skin. Diets moderately low in bioavailable phosphate - like many vegan diets - might be expected to have a complementary impact on disease risks, inasmuch as serum phosphate suppresses renal calcitriol synthesis while up-regulating that of PTH. A proviso is that the impact of dietary phosphorus on bone health is more equivocal than that of vitamin D. Increased intakes of calcium, on the other hand, down-regulate the production of both PTH and calcitriol - the latter effect may explain why the impact of dietary calcium on cancer risk (excepting colon cancer), hypertension, and autoimmunity is not clearly positive. An overview suggests that a vegan diet supplemented with high-dose vitamin D should increase both systemic and autocrine calcitriol production while suppressing PTH secretion, and thus should represent a highly effective way to achieve the wide-ranging health protection conferred by optimal UV exposure.     

Intravenous 1α, 25[OH]2 vitamin D3 (calcitriol) pulse therapy for bone lesions in a murine model of chronic cadmium toxicosis

The aim of the present study was to clarify the therapeutic effects of 1alpha, 25[OH]2 vitamin D3 (calcitriol) pulse injection on bone lesions induced in a rat model of chronic cadmium toxicosis. Ovariectomized (OVX) and control-operated (sham-OVX) rats were given repeated intravenous injections of 0.5 mg/kg/day CdCl2 for 70 weeks. The rats were then treated intravenously with 0.02 microg/kg/day calcitriol 3 days per week for 8 weeks. CdCl2 treatment induced increases in osteoid volumes of the femur cortex and trabecula. This change was accompanied by an increase in the volume of iron deposition at the mineralization front of the trabeculae and a reduction in mineral density. Abnormalities of bone metabolic parameters, which were increases in the blood calcium, inorganic phosphorous, bone-specific alkaline phosphatase, parathyroid hormone (PTH) and osteocalcin levels, and in the urine deoxypyridinoline (D-PYR) level, were also induced. Calcitriol treatment increased the blood calcium and inorganic phosphorous levels, and reduced the blood PTH level. Decreases in blood tartrate-resistant acid phosphatase and urine d-PYR levels were also induced indicating that bone resorption was suppressed. The findings indicated that the increased osteoid volume of the cortex and Fe-deposition volume of the trabecula were improved. These effects or improvements were observed in the sham-OVX rats but not in the OVX rats.     

Regulation of cytokine production in human peripheral blood mononuclear cells and allergen-specific th cell clones by 1alpha,25-dihydroxyvitamin D3

BACKGROUND: The steroid hormone 1alpha,25-dihydroxyvitamin D3 (calcitriol), in addition to its crucial role in calcium homeostasis, exerts several effects on the immune system by regulating cell proliferation, differentiation, and maturation. These effects may be exerted through the control of protooncogenes and the regulation of cytokine production. METHODS: The influence of calcitriol on cytokines secretion by human peripheral blood mononuclear cells (PBMC) isolated from healthy donors, and by allergen-specific T helper (Th) cell clones was studied. PBMC were cultured for 48 h with phorbol myristate acetate (PMA) and ionomycin in the presence or absence of calcitriol. Human Th cell clones were stimulated with either Bet v 1 allergen or anti-CD3 antibodies and PMA. Cytokines were measured in the supernatants by ELISA, and at single-cell level by FACS. RESULTS: Calcitriol significantly inhibited the production of IL-2, IFN-gamma and IL-12 by PBMC, as well as the percentage of CD4+ T cells containing intracytoplasmic IL-2 and IFN-gamma. Interestingly, calcitriol-treated PBMC induced the production of IL-10 and IL-5, but not of IL-4. The effect of calcitriol was maximal at 10(-7) to 10(-9) and noneffective at 10(-11) M. Calcitriol diminished the secretion of IL-1, TNF-alpha, and MG-CSF in PBMC. Furthermore, calcitriol also decreased the secretion of IL-2 and IFN-gamma by Th1 clones, and of IL-4 by Th2 clones. CONCLUSIONS: Our data strongly support the notion that calcitriol modulates the production of cytokines in a time- and concentration-dependent manner, and suggest that nonhypercalcemic derivatives of 1alpha,25-dihydroxyvitamin D(3) may be used for new immunosuppressive therapies.     

Effect of estrogen replacement therapy on parathyroid hormone secretion in elderly postmenopausal women

OBJECTIVE: Women undergo two phases of involutional bone loss that have opposing effects on parathyroid hormone (PTH) secretion. During the early phase, the loss of the direct restraining effect of estrogen on bone resorption causes an outflow of skeletal calcium into the extracellular fluid. This causes a compensatory decrease in PTH secretion. In the late phase, loss of extraskeletal effects of estrogen (on intestinal and renal calcium handling) leads to increases in whole body losses of calcium and a compensatory increase in PTH secretion. Moreover, long-term estrogen replacement therapy (ERT) suppresses both basal and stimulated PTH secretion in these women. Whereas the effects of estrogen on PTH secretion have been assumed to be due to its extraskeletal actions, estrogen may also have direct effects on the parathyroid glands. The goal of the present study was to test for these possible direct effects of estrogen on PTH secretion. DESIGN: Basal and ethylenediaminetetraacetic acid (EDTA)-stimulated PTH secretion was assessed in 10 elderly postmenopausal women (mean age, 76.4 years) before and after acute (3 days) estrogen replacement with transdermal estradiol, 0.1 mg/day. In addition, similar studies were performed in 10 age-matched women (mean age, 74.5 years) who had been on long-term ERT. These women were studied before and after 3 days of estrogen withdrawal. RESULTS: Estrogen treatment or withdrawal had no significant effect on either basal or stimulated PTH secretion. CONCLUSIONS: These data provide evidence that, in elderly postmenopausal women, estrogen does not have significant direct effects on PTH secretion and point to the importance of the actions of estrogen on intestinal and renal calcium handling as the major mechanisms for its effects on modulating calcium homeostasis and, indirectly, PTH secretion.     

Calcitriol and alendronate combination treatment in menopausal women with low bone mass

Serum calcitriol levels decrease with advancing age in relation to reduced dietary intake or poor intestinal absorption of vitamin D. These decreased levels affect the development of senile osteopenia, which can be effectively prevented by the administration of alendronate and calcium. To evaluate the effect of a combined treatment with alendronate and calcitriol on bone mineral density (BMD), we followed 152 osteopenic postmenopausal women, aged 55-75 years, for 9 months. They were divided into three groups. The first group was treated every other day with 0.25 microgram of synthetic 1,25-dihydroxyvitamin D3 plus 10 mg alendronate. The second group received the same dose of alendronate plus calcium (500 mg/day). The third group received only calcium (500 mg/day). BMD measurements were made at the level of the lumbar spine and the femoral neck. At the beginning and at the end of the period of treatment the same biochemical analyses of bone metabolism were made. There were no significant differences in the baseline values of the three groups in the biological parameters. Alendronate plus calcium treatment led to a significant reduction in total alkaline phosphatase and hydroxy prolinuria as well as to a significant increase in lumbar and femoral bone density. The same changes were observed in the group treated with alendronate plus calcitriol except that femoral BMD did not significantly improve. These results show that continuous treatment for 9 months with calcitriol or calcium in combination with alendronate significantly increases both vertebral and femoral neck density (from 3.8% to 4.5% and from 0.61% to 2.36% respectively) in osteopenic postmenopausal women. The effects of both combinations on bone mass are clearly greater than those achieved by calcium monotherapy.     

Regulation of calcitonin and parathyroid hormone secretion by oestrogens

Calcitonin is a peptide hormone secreted by C-cells which, in humans, are found mainly in the thyroid gland. It now seems that a major physiological function of this hormone in man is the long-term maintenance of the skeleton achieved by control of bone resorption. A marked sex difference in circulating calcitonin levels normally exists, with a relative deficiency in women as compared to men.It has now been found that oestrogens regulate calcitonin secretion and it appears likely that the loss of ovarian function at the menopause accelerates the natural decline in calcitonin secretion which occurs with age. Thus, post-menopausal women are more markedly calcitonin-deficient.Levels of the bone-resorbing hormones, parathyroid hormone (PTH) and 1,25 dihydroxyvitamin D are not elevated post-menopausally and it seems likely that the increased bone resorption which leads to post-menopausal bone loss is due mainly to the loss of oestrogen and calcitonin secretion.     

Effects of hyperoncotic albumin and parathyroid hormone infusion on jejunal electrolyte and water absorption in the rat

Preferential plasma volume expansion by infusion of hyperoncotic albumin solution dialyzed against distilled water (calcium-poor albumin) decreases sodium reabsorption in the dog proximal renal tubule during hydropenia. No such decrease is observed when infusing a calcium-rich hyperoncotic albumin solution. A possible role of parathyroid hormone (PTH) has been postulated. To investigate whether similar changes could be observed in intestinal electrolyte and water absorption, the effects of systemic hyperoncotic albumin infusion on jejunal transport of water, sodium, and calcium were studied in hydropenic rats by perfusing proximal jejunum in situ. It was further sought whether PTH could play a direct role in jejunal electrolyte and water transfer.Following infusion of calcium-poor, sodium-poor hyperoncotic albumin solution (group I), net jejunal absorption of water, sodium, and calcium decreased significantly when compared to control. Concurrently, lumen-to-mucosa (1-m) calcium flux, measured using 45 Ca, diminished significantly. Following infusion of calcium-rich, sodium-poor hyperoncotic albumin solution (group II), no changes in net or unidirectional fluxes were observed. After infusion of calcium-rich, sodium-rich hyperoncotic albumin solution (group III), net jejunal absorption of water and sodium, but not of calcium, were found significantly decreased when compared to control.Plasma ionized calcium increased 10 min after calcium-rich hyperoncotic albumin loading, but decreased significantly at that time when the calcium-poor hyperoncotic albumin solution was infused. However, 30 min after each of the calcium-rich and calcium-poor albumin infusion, plasma ionized calcium was increased in both groups of rats. Plasma immunoreactive PTH was unchanged 30 min after expansion with the calcium-rich solution but it increased significantly after expansion with the calcium-poor solution.Intravenous infusion of bovine PTH (group IV) resulted in a decrease of net jejunal water, sodium, and calcium flux. The decrease in net calcium transport was accompanied by a decrease in 1-m calcium flux. No such changes were observed when PTH was replaced by vehicle (group V).It is concluded that: (1) hyperoncotic albumin infusion induces jejunal water, sodium, and calcium flux changes dependent on the calcium and sodium content of the infused solution: calcium-poor, sodium-poor hyperoncotic albumin infusion leads to a decrease in net jejunal electrolyte and water absorption possibly via stimulation of PTH secretion; (2) sodium-poor hyperoncotic albumin infusion does not modify per se these fluxes in the hydropenic rat; (3) exogenous PTH infusion as well as endogenous stimulation of PTH secretion results in a comparable decrease of jejunal water, sodium, and calcium absorption.     

Effects of prolonged adrenaline infusion and of mental stress on plasma minerals and parathyroid hormone

The role of the sympatho-adrenal system for the secretion of PTH in humans is not established. Previous studies on the effects of adrenaline on plasma mineral homeostasis have focused on injections or short-term infusions of adrenaline, and conflicting results concerning calcium and parathyroid hormone (PTH) responses have been reported. We therefore infused adrenaline or placebo continuously for 3 h to 10 healthy volunteers and studied several plasma minerals, as well as PTH levels. Venous plasma adrenaline concentrations increased to the upper physiological range (5 nmol l-1) during adrenaline infusion. Another nine volunteers were exposed for 25 min to mental stress (a colour word conflict test; CWT), which causes marked circulatory changes and raises plasma catecholamine concentrations. Plasma ionized and total calcium, and magnesium concentrations were slowly and gradually reduced during infusion of adrenaline, but there was only a small increase in PTH. Plasma potassium was decreased by adrenaline within 30 min and thereafter did not change further during infusion. There was a marked but transient increase in the plasma free fatty acids concentration, which were not related to the reduction of the calcium or magnesium levels. The adrenaline-induced decrements in calcium, magnesium and potassium, and increases in heart rates persisted 30 min after the infusion, despite a rapid decrease in plasma adrenaline concentrations within 5 min of termination of the infusion. Plasma phosphate concentrations were lowered during the first 90 min of adrenaline infusion, but after 3 h they had returned to baseline despite continued infusion. CWT induced small increments of the plasma ionized calcium and PTH concentrations. Plasma potassium levels were raised despite increases in plasma adrenaline at the beginning of the stress test, while phosphate values were reduced at the end of the test. Thus, long-lasting elevations of circulating adrenaline lower plasma ionized and total calcium, phosphate, magnesium and potassium, but the time courses for these changes differed markedly. Despite the reduction of plasma ionized calcium there was only little increase in PTH and thus no indication that sustained elevations of circulating adrenaline stimulates the secretion of PTH in vivo in humans. Responses to acute mental stress and adrenaline infusion differed qualitatively, indicating that adrenaline responses to stress are of minor importance in this respect.     

Role of parathyroid hormone (PTH) and PTH-related protein (PTHrP) in regulating mineral homeostasis during fetal development

Parathyroid hormone (PTH) and PTH-related protein (PTHrP) play complementary and overlapping roles in regulating fetal mineral homeostasis. PTHrP is expressed within the growth plate, directs endochondral bone formation, and determines the fate of chondrocytes before bone formation can be initiated. It is expressed in placenta and is present at high levels in the fetal circulation. It stimulates placental calcium (and possibly magnesium) transfer and raises blood mineral levels above ambient maternal values in order to effect mineralization of the skeleton. It does not upregulate in response to absence of PTH or hypocalcemia, and thus, its secretion may be regulated autonomously or in response to placental signals. PTH is expressed in fetal parathyroids and placenta. Despite circulating at low levels, it has a more dominant effect than PTHrP in regulating the blood calcium and ensuring adequate mineralization of the skeleton. It may also have effects on bone formation in the steps that occur after apoptosis of hypertrophic chondrocytes. Unlike PTHrP, it increases with fetal hypocalcemia, but its secretion is constrained by the calcium-sensing receptor to maintain the adult calcium level, well below what the fetus normally achieves. PTH also stimulates placental calcium transfer, and its absence disrupts placental expression of calciotropic and cation transporter genes.     

Effects of acute hypercalcaemia on blood pressure in subjects with and without parathyroid hormone secretion

AIM: Acute hypercalcaemia increases the blood pressure, but the mechanism is uncertain. It may partly be the result of the concomitant fall in parathyroid hormone (PTH) secretion as PTH has been reported to have a vasodilator effect. To elucidate this, we infused calcium intravenously in subjects with and without PTH secretion. METHODS: Seven thyroparathyroidectomized subjects with undetectable PTH levels and 10 controls were studied twice, once with a calcium clamp technique that increased plasma ionized calcium in two steps of 0.1 mmol L(-1), each step lasting 60 min, and once with a placebo infusion. RESULTS: On the placebo day, blood pressure and all other variables were unaffected in both groups. On the calcium day, systolic blood pressure increased gradually and significantly from end of baseline till end of the calcium infusion in the controls (123.5 +/- 19.8 and 134.2 +/- 17.6 mmHg, P < 0.004) but not in the thyroparathyroidectomized subjects (124.9 +/- 15.7 and 126.0 +/- 20.6 mmHg, P = ns). Serum PTH levels fell promptly in the controls, and in both groups there was a significant increase in serum phosphate. The diastolic blood pressure and pulse rate, and the plasma adrenaline and noradrenaline, plasma renin activity, and serum aldosterone levels were unaffected by the calcium infusion. CONCLUSION: During acute hypercalcaemia the blood pressure increase appears unrelated to catecholamine secretion and the renin-aldosterone system, whereas the fall in PTH secretion may play a contributory role.     

Intravenous calcitriol in the treatment of refractory osteitis fibrosa of chronic renal failure

Osteitis fibrosa, a frequent complication of chronic renal failure, is characterized by increased rates of bone formation and bone resorption due to increased secretion of parathyroid hormone (PTH). Effective treatment with oral calcitriol is often impossible in patients with osteitis fibrosa, because low doses may cause hypercalcemia. Because short-term infusions of intravenous calcitriol are capable of suppressing the secretion of parathyroid hormone in patients with uremia without causing hypercalcemia, we evaluated the effectiveness of long-term intermittent calcitriol infusions (1.0 to 2.5 micrograms three times weekly, during dialysis) in treating severe osteitis fibrosa in 12 consecutive patients on hemodialysis whose disease was refractory to conventional therapy. After a mean (+/- SE) treatment period of 11.5 +/- 1.4 months, the mean bone-formation rate declined from 1642 +/- 277 to 676 +/- 106 microns 2 per square millimeter per day (P less than 0.01) in the 11 patients who successfully completed the study. Similar reductions occurred in the osteoblastic osteoid (18 +/- 3 to 9 +/- 2 percent; P less than 0.01) and the degree of marrow fibrosis (6.2 +/- 1.7 to 3.5 +/- 1.3 percent; P = 0.01). Concomitant serum biochemical changes included increased calcium levels (2.55 +/- 0.03 to 2.67 +/- 0.05 mmol per liter; P less than 0.01), decreased alkaline phosphatase levels (489 +/- 77 to 184 +/- 32 U per liter; P less than 0.001), and decreased levels of PTH (amino-terminal, 172 +/- 34 to 69 +/- 16 ng per liter in five patients, P less than 0.03; and carboxy-terminal, 1468 +/- 467 to 1083 +/- 402 ml-eq per liter in six patients, P not significant). Although the majority of the patients had transient episodes of asymptomatic hypercalcemia, this complication could be quickly reversed by temporarily halting treatment or decreasing the dose of calcitriol. We conclude that long-term intermittent infusions of intravenous calcitriol are effective in ameliorating osteitis fibrosa in patients on dialysis. Patients whose osteitis fibrosa is refractory to oral calcitriol and who are candidates for parathyroidectomy should be considered first for intravenous calcitriol therapy.     

Hormonal control of fracture healing in a dog with chorea

An experimental fracture in a dog with chorea was found to heal faster, and with a larger callus, than normal. Serum levels of parathormone (PTH), calcitonin (CT) and vitamin D metabolities were determined during callus formation. Serum concentrations of vitamin D metabolites were lower from the beginning while serum CT levels were higher compared to normal dogs. A massive increase in serum levels of 24,25-dihydroxyvitamin D was noted during the healing period. These results and observations suggest the existence of some disturbances in the secretion of hormones regulating calcium metabolism during bone repair where a nervous system lesion exists.     

Calcium-regulating system in bronchial asthma

Calcium homeostasis was determined from ionized calcium (Ca2+), total calcium (Cat) and bound calcium (Cab) levels, content of calcium-regulating hormones: calcitonin (CT) and parathyroid hormone (PTH). Lipid peroxidation (LPO) intensity was assessed from the blood plasma hydroperoxide level in 71 patients with bronchial asthma and chronic asthmatic bronchitis. The findings evidence that high blood serum levels of Ca2+ and Cab and a tendency to reduction of PTH content are characteristic of nonsevere and medium-severity atopic asthma. In bacterial asthma Ca2+ level increases at the expense of Cab, that is parallelled by elevation of CT content, as the disease progresses in severity. Blood CT level gradually decreases until it disappears completely in Stage III bacterial asthma, whereas PTH level grows. CT/PTH ratio may be an indicator of disturbed equilibrium in the CT-PTH hormonal system. In the course of treatment Ca2+ binding, most manifest in bacterial asthma, increases, CT level grows and PTH one reduces. A tendency to normalization of hormonal levels resultant from therapy does not eventuate in their complete recovery; hormonal levels remain shifted, this pointing to the essential contribution of endocrine mechanisms to calcium homeostasis disorders in asthma.     

Effect of low calcium diet on the ultrastructure of the rat parathyroid gland

Young female rats were fed with normal (1.18%) or low (0.05%) calcium diet for 3, 7, 15 or 30 days. The morphology of the parathyroid glands was studied together with serum calcium, parathyroid hormone (PTH), calcitonin and bone mineral density (BMD). As compared to the animals fed with the normal calcium diet, BMD of whole body of the rats fed with the low calcium diet was significantly decreased, whereas the serum PTH level was increased. The parathyroid glands in the rats fed with the low calcium diet were markedly enlarged. In the parathyroid chief cells of the rats fed with the low calcium diet, the Golgi complexes and the cisternae of the granular endoplasmic reticulum were well developed, while the large granules and large vacuolar bodies decreased. Some secretory granules located near the plasma membrane. A proportionally larger increase of the cytoplasm was estimated in the rats fed with the low calcium diet for three and seven days. Enlargement of the cytoplasm and rather frequent mitoses of the chief cells were observed in the rats fed with the low calcium diet for 15 and 30 days. These findings suggest that the rapid bone loss in young rats induced by the low calcium diet is essentially due to stimulated activity of the parathyroid gland. The stimulated gland may be a result of hypertrophy at the early stage and a combination of hypertrophy and hyperplasia at the later stage of calcium deficiency.     

Modulation of ovariectomy-related bone loss by parathyroid hormone in rats

Studies were carried out to examine whether parathyroid hormone (PTH) will prevent the age-related bone loss that results from ovarian hormone deficiency and to explore the mechanism of its action. Ovariectomy caused a significant decrease in bone density in the distal metaphysis and mid-diaphysis, but not in the vertebra and proximal metaphysis. The decrease was prevented by PTH injection and in all the bones examined PTH administration increased bone density and bone calcium content above the levels in sham-operated controls. Similar findings were made in bone hydroxyproline levels. PTH treated ovariectomized animals had lower serum 25(OH)vitamin D and higher 1,25(OH)2 vitamin D levels than ovariectomized and sham operated animals that received solvent vehicle. Compared to the sham operated controls, ovariectomy caused a 4.5-fold increase in the number of tartrate resistant acid phosphatase (TRAP) positive multinuclear cells. This increase did not occur in PTH-treated animals. We conclude that PTH is effective in preventing ovarian hormone deficiency bone loss in rats. PTH may mediate this effect partly by stimulating osteoblastic bone formation and partly by increasing 1,25(OH)2 vitamin D-mediated calcium absorption. The data from TRAP positive multinuclear cells indicate that an etiologic component of ovarian hormone deficiency bone loss is the expansion of a pool of osteoclast progenitors and that the bone anabolic action of PTH involves, in part, a decrease in bone resorption as a result of the suppression of the proliferation of osteoclast progenitors.     

Calcium homeostasis,and clinical or subclinical vitamin D deficiency – Can a hypothesis of “intestinal calcistat” explain it all?

The main physiological function of vitamin D is maintenance of calcium homeostasis by its effect on calcium absorption, and bone health in association with parathyroid gland. Vitamin D deficiency (VDD) is defined as serum 25-hydroxy vitamin D (25OHD) levels <20 ng/ml. Vitamin D insufficiency is called when serum 25OHD levels are between 20–29 ng/ml, though existence of this entity has been questioned. Do all subjects with VDD have clinical disease according to this definition? Analysis of published studies suggests that calcium absorption in inversely correlated with serum 25OHD levels and calcium intake. We hypothesize that there exist an intestinal calcistat, which controls the calcium absorption independent of PTH levels. It consists of calcium sensing receptor (CaSR) on intestinal brush border, which senses calcium in intestinal cells and vitamin D system in intestinal cells. CaSR dampens the generation of active vitamin D metabolite in intestinal cells and decrease active transcellular calcium transport. It also facilitates passive paracellular diffusion of calcium in intestine. This local adaptation adjusts the fractional calcium absorption according the body requirement. Failure of local adaptation due to decreased calcium intake, decreased supply of 25OHD, mutation in CaSR or vitamin D system decreases systemic calcium levels and systemic adaptations comes into the play. Systemic adaptations consist of rise in PTH and increase in active vitamin D metabolites. These adaptations lead to bone resorption and maintenance of calcium homeostasis. Not all subjects with varying levels of VDD manifest with secondary hyperparathyroidism and decreased in bone mineral density. We suggest that rise in PTH is first indicator of VDD is rise in PTH along with decrease in BMD depending on duration of VDD. Hence, subjects with any degree of VDD with normal PTH and BMD should not be labeled as vitamin D deficient. These subjects can be called subclinical VDD, and further studies are required to assess beneficial effect of vitamin D supplementation in this subset of population. This hypothesis further highlights pitfalls in treatment of hypoparathyroidism.     

Osteopetrosis

Congenital osteopetrosis is a group of disorders resulting in decreased osteoclastic function and hence decreased bone resorption. Various medical treatments have been attempted to ameliorate the osteopetrotic condition. A calcium-deficient diet has limited further sclerosis in some patients. Prednisone therapy has improved haematological function in some patients, but has not resulted in a reduction in bone mass. Calcitrophic hormones, such as parathyroid hormone (PTH) infusions and oral calcitriol, stimulate osteoclastic activity, and calcitriol in particular has stimulated osteoclastic bone resorption in some patients with osteopetrosis. Bone marrow transplantation, although curative, is limited by paucity of donors, risk of graft-versus-host disease and relapse of the disease. The demonstration of defective leucocyte superoxide production in osteopetrotic patients and the premise that osteoclasts appear to arise from the granulocyte macrophage lineage have led to attempts at treating osteopetrosis with immunomodulators. Since treatment with recombinant interferon-γ-1b (interferon γ-1b, IFNγ-1b) has resulted in increased level of superoxide generation and clinical improvement in chronic granulomatous disease, a similar strategy has been employed using IFNγ-1b to treat patients with osteopetrosis. IFNγ-1b has been demonstrated to increase osteoclastic bone resorption and leucocytic function. Long term therapy with IFNγ-1b by subcutaneous injection 3 times weekly resulted in marked clinical improvement, a decreased incidence of infections, a decreased trabecular bone mass, and an increased marrow space resulting in improved haemopoiesis. The therapy has been associated with few adverse effects, mainly fever and diarrhoea which have been managed with a reduction in IFNγ-1b dosage. The low-calcium diet occasionally results in hypocalcaemic tetany, which may be corrected by increased dietary calcium intake. Thus, IFNγ-1b has a distinct place in the therapeutic armamentarium for patients with osteopetrosis and is a feasible treatment option in such patients.     

Ethinyl estradiol and norethindrone in the treatment of primary hyperparathyroidism in postmenopausal women

Treatment with ethinyl estradiol or norethindrone reduces the bone-turnover rate and plasma calcium levels in normal postmenopausal women, without affecting the secretion of calcium-regulating hormones. To assess the effect of these sex steroids in patients with primary hyperparathyroidism, we treated postmenopausal women who had hyperparathyroidism with either ethinyl estradiol (n = 6) or norethindrone (n = 11). After three weeks of treatment, the bone-turnover rate declined and plasma calcium fell from a mean (+/- 1 SE) of 2.77 +/- 0.07 mmol per liter (11.1 +/- 0.3 mg per deciliter) to 2.58 +/- 0.05 mmol per liter (10.3 +/- 0.2 mg per deciliter; P less than 0.01) in the group treated with ethinyl estradiol, and from 2.93 +/- 0.08 mmol per liter (11.7 +/- 0.3 mg per deciliter) to 2.84 +/- 0.08 mmol per liter (11.4 +/- 0.3 per deciliter; P less than 0.05) in the patients who received norethindrone. No significant changes in the plasma levels of parathyroid hormone, calcitonin, or calcitriol were observed after the estrogen-induced increases in vitamin D-binding protein had been taken into account. Since the decline in plasma calcium levels did not stimulate secretion of parathyroid hormone, we conclude that treatment with either sex steroid resets the threshold for secretion of parathyroid hormone. Thus, although the reductions in plasma calcium levels were moderate, sex-hormone therapy may be useful in the treatment of mild hyperparathyroidism in postmenopausal women.     

Prevention of postmenopausal bone loss by low and conventional doses of calcitriol or conjugated equine estrogen

OBJECTIVES: Estrogen deficiency is the most common cause of postmenopausal osteoporosis and estrogen replacement is well known to retard postmenopausal bone loss. Calcium supplement alone is generally considered to be insufficient for the prevention of bone loss associated with estrogen deficiency while the role of calcitriol is unclear. In the present study we examined the efficacy different doses of estrogen or calcitriol in the prevention of postmenopausal bone loss in Thais. METHODS: The subjects consisted of 146 Thai women no more than 6 years postmenopausal. The subjects were randomly allocated to receive 750 mg supplemental calcium alone, calcium and conjugated equine estrogen (CEE) at 0.3 or 0.625 mg, calcium and calcitriol at 0.25 or 0.5 microg daily. Those receiving CEE also took 5 mg medrogestone for 12 days each month. BMD at L2-4 and femoral neck were measured at baseline 1 year and 2 years after treatments. Data were expressed as mean +/- S.E. RESULTS: Subjects on supplemental calcium alone had approximately 2.5% decreases in L2-4 (P < 0.05) and femoral BMD (P < 0.01) at 2 years. CEE (0.3 mg) resulted in 3.20 +/- 1.2% increase in vertebral BMD (P < 0.05) while no significant change in BMD was demonstrated at the femoral neck. Likewise, 0.625 mg of CEE induced 5.4 +/- 1.4% increase in vertebral BMD at 2 years (P < 0.001) without change in the femoral BMD. In regard to calcitriol, no significant change in vertebral or femoral BMD was demonstrated with either 0.25 or 0.5 microg calcitriol. CONCLUSION: We concluded that calcitriol is effective in the prevention of early postmenopausal bone loss in Thais. It represents an option for the prevention of osteoporosis in postmenopausal women who are contraindicated for estrogen replacement.