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Animal models fed low calcium diets demonstrate a negative calcium balance and gross bone loss while the combination of calcium deficiency and oophorectomy enhances overall bone loss. Following oophorectomy the dietary calcium intake required to remain in balance increases some 5 fold, estimated to be approximately 1.3% dietary calcium. In the context of vitamin D and dietary calcium depletion, osteomalacia occurs only when low dietary calcium levels are combined with low vitamin D levels and osteoporosis occurs with either a low level of dietary calcium with adequate vitamin D status or when vitamin D status is low in the presence of adequate dietary calcium intake. Maximum bone architecture and strength is only achieved when an adequate vitamin D status is combined with sufficient dietary calcium to achieve a positive calcium balance. This anabolic effect occurs without a change to intestinal calcium absorption, suggesting dietary calcium and vitamin D have activities in addition to promoting a positive calcium balance. Each of the major bone cell types, osteoblasts, osteoclasts and osteocytes are capable of metabolizing 25 hydroxyvitamin D (25D) to 1,25 dihydroxyvitamin D (1,25D) to elicit biological activities including reduction of bone resorption by osteoclasts and to enhance maturation and mineralization by osteoblasts and osteocytes. Each of these activities is consistent with the actions of adequate circulating levels of 25D observed in vivo.

Background: Diagnosis of subclinical hypocalcemia in cattle is based on concentration of total Ca ([TCa]) in serum or plasma below the reference range, with [TCa] serving as proxy for the concentration of ionized Ca ([iCa]). Hypothesis/Objectives: To investigate the relation between [iCa] and [TCa] in periparturient cows over time, and its association with various metabolites. Animals: Thirty periparturient dairy cows. Methods: Prospective observational study. Blood from periparturient cows was obtained between 4 days before and 7 days after calving. Samples underwent blood gas analysis and blood biochemical analysis. The ratio of [iCa] : [TCa] was computed. Repeated measures linear regression analyses, spearman correlation‐, Deming regression‐ and receiver operating characteristic (ROC) analyses were conducted. Results: Correlations between [iCa] and [TCa] ranged from r = 0.55 to r = 0.84. The diagnostic value of [TCa] to identify cows with [iCa] below the arbitrary cut‐off of 1.1 mmol/L was weak in particular during the first 24 hours of lactation, but continuously improved toward the end of the study with areas under the ROC curve increasing from 0.64 at d 0 to 0.93 at d +4 after calving. Strongest association with [iCa] : [TCa] were found for albumin (r2 = 0.58, P <.0001), pCO2 (r2 = 0.45, P =.0003), the standard [HCO3] (r2 = 0.22, P =.01), lactate (r2 = 0.16, P =.04) and [NEFA] (r2 = 0.15, P =.05). Conclusion and Clinical Importance: The [TCa] is of limited value to identify cows with subnormal [iCa] in the first hours and days of lactation, a finding apparently attributable to the increased variation of a number of metabolic variables that affect the ratio of [iCa] : [TCa]. [ABSTRACT FROM AUTHOR]

The mitochondrial calcium uniporter (MCU) is a transmembrane protein facilitating the entry of calcium ions into mitochondria from the cell cytosol. Maintaining calcium balance is crucial for enhancing cellular energy supply and regulating cell death. The interplay of calcium balance through MCU and the sodium-calcium exchanger is known, but its regulation in the breast cancer tumor microenvironment remains elusive. Further investigations are warranted to explore MCU's potential in BRCA clinical pathology, tumor immune microenvironment, and precision oncology. Our study, employing a multi-omics approach, identifies MCU as an independent diagnostic biomarker for breast cancer (BRCA), correlated with advanced clinical status and poor overall survival. Utilizing public datasets from GEO and TCGA, we discern differentially expressed genes in BRCA and examine their associations with immune gene expression, overall survival, tumor stage, gene mutation status, and infiltrating immune cells. Spatial transcriptomics is employed to investigate MCU gene expression in various regions of BRCA, while spatial transcriptomics and single-cell RNA-sequencing methods explore the correlation between MCUs and immune cells. Our findings are validated through the analysis of 59 BRCA patient samples, utilizing immunohistochemistry and bioinformatics to examine the relationship between MCU expression, clinicopathological features, and prognosis. The study uncovers the expression of key gene regulators in BRCA associated with genetic variations, deletions, and the tumor microenvironment. Mutations in these regulators positively correlate with different immune cells in six immune datasets, playing a pivotal role in immune cell infiltration in BRCA. Notably, high MCU performance is linked to CD8 + T cells infiltration in BRCA. Furthermore, pharmacogenomic analysis of BRCA cell lines indicates that MCU inactivation is associated with increased sensitivity to specific small molecule drugs. Our findings suggest that MCU alterations may be linked to BRCA progression, unveiling new diagnostic and prognostic implications for MCU in BRCA. The study underscores MCU's role in the tumor immune microenvironment and cell cycle progression, positioning it as a potential tool for BRCA precision medicine and drug screening. [ABSTRACT FROM AUTHOR]

Individuals diagnosed with Parkinson's disease (PD) often exhibit heightened susceptibility to cardiac dysfunction, reflecting a complex interaction between these conditions. The involvement of mitochondrial dysfunction in the development and progression of cardiac dysfunction and PD suggests a plausible commonality in some aspects of their molecular pathogenesis, potentially contributing to the prevalence of cardiac issues in PD. Mitochondria, crucial organelles responsible for energy production and cellular regulation, play important roles in tissues with high energetic demands, such as neurons and cardiac cells. Mitochondrial dysfunction can occur in different and non-mutually exclusive ways; however, some mechanisms include alterations in mitochondrial dynamics, compromised bioenergetics, biogenesis deficits, oxidative stress, impaired mitophagy, and disrupted calcium balance. It is plausible that these factors contribute to the increased prevalence of cardiac dysfunction in PD, suggesting mitochondrial health as a potential target for therapeutic intervention. This review provides an overview of the physiological mechanisms underlying mitochondrial quality control systems. It summarises the diverse roles of mitochondria in brain and heart function, highlighting shared pathways potentially exhibiting dysfunction and driving cardiac comorbidities in PD. By highlighting strategies to mitigate dysfunction associated with mitochondrial impairment in cardiac and neural tissues, our review aims to provide new perspectives on therapeutic approaches. [ABSTRACT FROM AUTHOR]

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1. We have examined the relation between the rate of cortical bone loss and other measured variables in 108 women, untreated and on various therapies, observed for nearly 300 patient years. The majority of the subjects were postmenopausal women with various degrees of simple osteoporosis, but a few cases of hyperparathyroidism and other calcium disorders were included. 2. Calcium balance, bone resorption rats, urinary hydroxyproline and plasma alkaline phosphatase were shown to be related to the rate of bone loss; patients with the more negative balance or the higher values of the other variables had significantly higher rates of loss. The rate of bone loss was independent of the rate of bone formation.

Six women, aged 38 to 62 yr, participated in a 40-day metabolic study to investigate the effect of level of protein intake and of sodium bicarbonate ingestion on urinary calcium, net calcium balance, net renal acid excretion, and arterialized venous blood pH and bicarbonate ion concentration. The diet contained 44 g protein during the first 16 days and 102 g during the remaining 24 days. During the last 10 days of the study, 5.85 g of sodium bicarbonate was ingested concomitantly with the higher protein intake. Calcium, phosphorus, and magnesium intakes were held constant at 500, 900, and 300 mg, respectively. The increase in protein intake significantly increased urinary calcium and net renal acid excretion and the mean net calcium balance became negative. The ingestion of sodium bicarbonate alkalinized the urine and reversed the increase in urinary calcium associated with the higher protein intake; the mean net calcium balance became positive. The arterialized venous blood pH and bicarbonate ion concentrations were not significantly affected by dietary treatments. The results suggest that the ingestion of a small amount of sodium bicarbonate may be an effective way to increase calcium retention in women with protein-induced hypercalciuria.

Urinary adenosine 3',5'-monophosphate (cyclic AMP, cAMP) has been determined in 84 males. Two protein-binding assays were used: the method of Gilman and the Amersham assay kit. The results were in close agreement. The excretion of cAMP was nor correlated to urinary calcium or to estimated calcium intake.

1. Chromium sesquioxide (Cr2O3; 1.5 g/day) and [51Cr]chromic chloride [51CrCl3 (0.3 muCi/day)] were compared as continuously administered non-absorbed markers for the correction of faecal recoveries in 14 calcium balance studies each lasting at least 18 days. 2. The mean recoveries of each, 98.4% for Cr2O3 and 101.9% for 51CrCl3, were not significantly different from 100%. 3. The two markers reduced the uncertainity in a typical 3 x 6 day calcium balance study to a similar extent (SD = 1.4 mmol/day for Cr2O3 and SD = 1.5 mmol/day for 51CrCl3. 4. 51CrCl3 is a convenient and satisfactorily alternative to Cr2O3 when the laboratory hazards associated with estimating the latter cannot easily be eliminated.

Citrinin and ochratoxin A disrupt renal function in many animal species. The mechanism(s) underlying these actions is (are) unclear. Although citrinin has been shown to bind covalently to renal tissue, there also is evidence that it is active in the unmetabolized form. Altered calcium homeostasis has been suggested as an event which might mediate cell injury and/or death; a possible role for calcium in citrinin- or ochratoxin A-induced nephrotoxicity is reported here. Renal cortical slice calcium balance was monitored by the uptake of 45Ca. Either ochratoxin A or citrinin added to fresh renal cortex slices enhanced 45Ca accumulation. These effects were evident as early as 5 min after addition of the toxins. Greater 45Ca uptake occurred with bathing solution calcium concentration of 1.1 mM than in the absence of added carrier calcium. Finally, the effect of citrinin to reduce p-aminohippurate accumulation by renal cortical slices was greater in the presence of calcium than in its absence.

Serial mineral balances have been obtained in 3 children undergoing therapy with EHDP (ethane-1-hydroxy-1, 1-diphosphonate) for diseases involving ectopic calcification. Although clinical outcome was not uniformly satisfactory, all cases showed an overall reduction in calcium balance. This was due to increased faecal excretion of calcium and was most marked after a long duration of therapy. Although these results conflict with reported experience in adults, they are in agreement with published observations of the effects of EHDP on calcium absorption in experimental animals.

Negative calcium balance and bone loss occurring with immobilization and hypokinesia have been attributed to a lack of weight bearing on bones. The effects of weight-bearing exercise for promotion of calcium balance after hypokinesia were examined. Rats were randomly assigned to either hypokinetic suspension for 28 d or to a control sedentary group, free to move about their cages at will. After 28 d, the rats in each group were randomly subdivided to either post-hypokinetic forced running (HR), post-hypokinetic sedentary (HS), control forced running (CR), or control sedentary (CS) groups. Net calcium balance was then determined for 25 consecutive days. Net calcium balance of HR was negative for the first 5-d period of recovery and then became positive; that of HS was negative for 25 d; that of CR and CS remained essentially positive. Net calcium absorption paralleled net calcium balance. Forced running was effective in reestablishment of positive net calcium balance after 28 d of decreased weight bearing.

The effects of different levels of nitrogen, phosphorus, and caffeine intake on calcium balance and on certain of its components were assessed in 170 studies in normal middle-aged, but still premenopausal women. Statistically significant negative associations with calcium balance were found for nitrogen and for caffeine, but no effect could be found for phosphorus. Higher nitrogen intakes were associated with proportionately higher levels of urinary calcium; higher phosphorus intake was associated with slightly lower levels of urinary calcium but also with slightly more intestinal secretion of calcium. Since these two effects were opposite in direction, there was no net association of different phosphorus intakes with calcium balance. Caffeine intake was associated with higher levels of both urinary calcium and intestinal calcium secretion. None of the three intake variables was associated with differences in calcium absorption efficiency. Both the nitrogen and the caffeine effects were proportional to intake. The magnitude of the effects observed was such that a 50% increase in intake of nitrogen above the group mean intake value would be predicted to result in calcium balance shift of -0.032 gm/day. For caffeine, the corresponding calcium balance shift would be predicted to be -0.006 gm/day.

Calcium metabolic balance determinations, which have been done in various clinical and experimental conditions, were applied to the study of 8 spinal cord injured patients receiving a diet with 1600 mg calcium and 85 to 120 gm protein daily. All of the patients had hypercalciuria prior to ambulation. Those with spinal cord injuries of less than 3 months duration (early group) had a calcium balance of -27 mg before ambulation and 235 mg after ambulation. Patients with spinal cord injuries of 6 months or more duration (late group) had calcium balances of 55 mg before ambulation and 175 mg after ambulation. Ambulation significantly decreased the hypercalciuria and modified the calcium balance in a positive direction. Smaller changes were noted in the responses of the late group than in those of the early group. Early ambulation will probably prevent bone loss, calcium stones in the genitourinary tract, and other sequellae of negative calcium balance.

Recent investigations in human and experimental hypertension have characterized previously unrecognized abnormalities of calcium homeostasis. Data from human and animal studies have indicated that adequate dietary calcium intake may be an important determinant for the development of high blood pressure. Since dietary calcium supplementation has been shown to attenuate the hypertension of the spontaneously hypertensive rat (SHR), the present study was undertaken to assess the effect of dietary calcium intake on the blood pressure of the Wistar-Kyoto rat (WKY), the normotensive genetic control for the SHR. One of three levels of dietary calcium was fed to 36 WKYs beginning at eight to 10 weeks of age (WOA) through 34 WOA. Throughout the period of observation, the WKYs stratified inversely with their level os dietary calcium (p less than .001), i.e. rats fed the lowest level of calcium had the highest blood pressure. WKYs on the high calcium diet experienced an attenuation of their blood pressure with increasing age and dietary calcium intake. These salutary blood pressure effects of dietary calcium were independent of growth and urinary sodium excretion of the rats. Serum ionized calcium (Ca++) increased in the high calcium diet WKYs and appeared to be associated with the blood pressure reduction. The results suggest that calcium intake must be assessed in experimental models of hypertension and that the state of calcium balance is a possibly important determinant of blood pressure regulation.

Previous studies demonstrated that the administration of NaHCO3 or sodium citrate had either only a small effect to reduce urinary Ca excretion or no effect, but that potassium citrate significantly reduced urinary Ca excretion. In order to further evaluate and compare the effects of NaHCO3 and of KHCO3, we performed ten metabolic balances in healthy men during 18 control days, 12 days of NaHCO3, 60 mmol/day and 12 days of KHCO3, 60 mmol/day. Six subjects were fed a low Ca diet (5.2 +/- 0.7 SD mmol/day) and three of these were also given calcitriol (0.5 microgram 6-hourly). Four subjects ate a normal Ca diet (19.5 +/- 1.3 mmol/day). For all 10 subjects, KHCO3 administration reduced urinary Ca excretion from control by -0.9 +/- 0.7 mmol/day, P less than 0.001. Net intestinal Ca absorption did not change detectably so that Ca balances became less negative by a +0.9 +/- 0.9 mmol/day; P = 0.01. KHCO3 administration was also accompanied by more positive PO4 and Mg balances. NaHCO3 administration had no significant effect on urinary Ca excretion or Ca balance. NaHCO3 and KHCO3 administration were accompanied by equivalently more positive Na or K balances, respectively and equivalently more negative acid balances (HCO3 retention). Neither NaHCO3 or KHCO3 altered fasting serum HCO3 concentrations, blood pH, serum 1,25-(OH)2-D or PTH concentrations. We conclude that KHCO3 promotes more positive Ca balances by either enhancing renal Ca retention or skeletal Ca retention or both.

Calcium balance as a function of both intake and absorption of calcium fromthe diet was measured 274 times in 168 normal perimenopausal women, and comparisons made between groups of women segregated according to menopausal and estrogen therapy status. As previously reported, there is a statistically significant positive correlation between calcium balance and both calcium intake and calcium absorption. In 207 studies in premenopausal women calcium balance averaged -0.0199 gm/day, whereas in 41 studies in postmenopausal women untreated with estrogen, calcium balance averaged -0.043 gm/day (p less than 0.02). The balance difference was due approximately equally to decreased absorption from the diet and to increased urinary excretion. Twenty-six estrogen-treated postmenopausal women exhibited balance performance indistinguishable from that of the premenopausal group. In 16 women who were studied twice, 5 years apart, and who went through menopause between studies, calcium balance shifted by -0.0307 gm/day (p less than 0.05) as compared with 72 women also studied twice, but without change in menstrual status, in whom mean balance did not change significantly. Calcium intake requirement for zero balance was calculated for both the estrogen-replete and estrogen-deprived groups. Premenopausal and treated postmenopausal women exhibited an intake requirement of 0.990 gm/day Ca, whereas the untreated postmenopausal women had an apparent requirement of 1.504 gm/day (p less than 0.01). We conclude that there is a specific, estrogen-related shift in calcium performance across menopause and that the reason for the positive effect of estrogen on balance and intake requirement is a combination of enhancement of intestinal absorption efficiency and improved renal calcium conservation.

When rats are fed a selenium-deficient diet, the glutathione peroxidase activity in liver mitochondria decreases within 5 weeks to 0-6% of that of control animals fed on a diet supplemented with 0.5 ppm of selenium as sodium selenite. Analysis of the temperature dependence of energy-linked Ca(2+) uptake by means of Arrhenius plots reveals two breaks (at around 11 degrees C and 24 degrees C) in mitochondria isolated from selenium-supplemented animals, whereas in selenium-deficient rats the break at 11 degrees C is absent. Ca(2+)-loaded mitochondria of selenium-supplemented rats-i.e., with active glutathione peroxidase in the matrix-lose Ca(2+) rapidly, with a concomitant oxidation of endogenous NAD(P)H, when exposed to t-butyl hydroperoxide or H(2)O(2). In contrast, in selenium deficiency, t-butyl hydroperoxide and H(2)O(2) induce neither a release of Ca(2+) nor an oxidation of NAD(P)H. The peroxide-induced oxidation of NAD(P)H is reversible in the presence of succinate when no Ca(2+) has been taken up. When Ca(2+) has previously been accumulated, however, the oxidation of NAD(P)H is irreversible. Enzymatic analysis of mitochondrial pyridine nucleotides reveals that the peroxide-induced oxidation of NAD(P)H in Ca(2+)-loaded mitochondria leads to a loss of NAD(+) and NADP(+). It is proposed that the redox state of mitochondrial pyridine nucleotides can be or is in part controlled by glutathione peroxidase and glutathione reductase and is a factor in the balance of Ca(2+) between mitochondria and medium.

The influence of acute diuresis on calcium balance induced by furosemide (FM) and azosemide (AM) was observed and compared in the human body. The treatment resulted in significant diuresis (FM: 2488 +/- 163 ml; AM: 2930 +/- 109 ml for 6 hours) and calciuresis (FM: 132.0 +/- 15.2 mg; AM: 181.0 +/- 16.6 mg for 6 hours). In spite of the urinary calcium loss, the serum calcium concentrations were elevated by both drugs. The elevation was also found even when the correction to serum protein concentrations was performed, and the magnitude of this change was less by AM than by FM. Plasma parathyroid hormone (PTH) concentrations were slightly elevated by AM only at 6 hours, but they remained unchanged by FM. This mild elevation of PTH could not be explained sufficiently by the concentration changes of serum calcium as noted above, and might be caused by factors other than serum calcium. The alkaline phosphatase concentrations corrected by means of serum protein concentrations were unchanged in both drugs, and it was suggested that the calciuresis may not extend to bone calcium remodeling at least in such a short-term experiment.

Mean linear attenuation coefficients for trabecular bone (T) in the distal radius and total absorption coefficients (TA) in the radial mid-shafts of 22 patients with crush fracture osteoporosis were measured serially for a year by using computed tomography. After approximately 6 months, each patient was admitted to a metabolic ward for an 18-day calcium balance study. The rate of change (trend) in trabecular bone (T) in the distal radius was a better predictor of calcium balance than the trend in mid-shaft cortical bone (TA). The scatter in the regressions of the trends of T and TA on calcium balance could be accounted for by known methodological uncertainties.

Bone resorption and formation rates were evaluated at the organ level using calcium kinetic methods and at the trabecular bone tissue level using dynamic histomorphometry in 20 patients with various metabolic bone diseases (primary hyperparathyroidism (N = 9), hyperthyroidism (N = 6), and hypothyroidism (N = 5). Highly significant correlations were demonstrated between resorption and formation rates at organ level (r = .90, P less than .001) and at tissue level (volume referent) (r = .93, P less than .001), indicating a high degree of coupling between resorption and formation within the three disease states. Tissue level resorption rates (surface referent, as well as volume referent) both correlated significantly (P less than .01) to organ level resorption rate (r = .60 and r = .63, respectively). Fractional active resorption surface and cellular level resorption rate did not reveal significant correlations to calcium kinetic estimates. No correlation could be demonstrated between organ level mineralization rate and formative or labeled trabecular surfaces. However, all tetracycline based tissue level formation rates revealed highly significant correlations (P less than .01) to organ level mineralization rate (calcification rate, r = .71; surface referent bone formation rate, r = .59; volume referent bone formation rate, r = .68). Based on histomorphometric parameters for resorption and formation, actual and predicted tissue level trabecular bone balances were calculated. Both the actual and predicted bone balance correlated significantly to the organ level calcium balance (P less than .05). Correction for skeletal size based on BMC measurements did not improve any of the correlations significantly.(ABSTRACT TRUNCATED AT 250 WORDS)

The day-to-day variations in stool calcium content during calcium balance studies are usually corrected for by adjusting for the recovery of an orally administered nonabsorbable stool marker. We describe here a simple method for making this correction using chromium-51 chloride hexahydrate (51Cr) in balance studies. This approach was developed because of difficulties encountered with the more widely used marker, polyethylene glycol (PEG). With one batch of PEG, the stool recovery was only 81% (whereas with 51Cr it was 95%). The reason for this poor recovery was contamination of the PEG 4000 with a high molecular weight species (10-15%, wt/wt). Because others have also reported low PEG recoveries and because we found that the chemical abnormality in the PEG was very difficult to detect, we believe that 51Cr is more reliable and should be the preferred stool marker for the calcium balance studies.

Balance studies were performed in thirty-three post-menopausal women (all but five having vertebral crush fractures or femoral neck fractures) in the basal state and on treatment with 1alpha-hydroxyvitamin D3 and/or oestrogenic hormones. The results suggest that the effectiveness of oestrogen therapy is limited by calcium malabsorption and the effectiveness of 1alpha-hydroxyvitamin D3 is limited by oestrogen deficiency. The best results were obtained with combined therapy to remedy what appears to be two distinct deficiencies. To minimize the risks of hypercalcaemia and the possible risks of hormone therapy, we suggest that the treatment of choice in post-menopausal osteoporosis may be 1alpha-hydroxyvitamin D3 1microgram daily and ethinyloestrodiol 25 microgram daily for 3 weeks in every 4. Patients on a low dietary intake of calcium should probably be given calcium supplements. With this regimen, it should not be necessary to screen patients initially for calcium malabsorption or oestrogen deficiency because the majority of patients present with a combination of the two factors.

Twenty-two healthy postmenopausal women were divided into two groups, one group of 13 received milk supplementation of 24 oz per day and the other group of 9 controls received no intervention during two years of observation. Extensive inpatient metabolic balance and radiocalcium kinetic studies were performed at the beginning and at the end of one year of observation. In the milk supplement group, fractional calcium absorption (x +/- SD) decreased from .243 +/- .058 to .176 +/- .058, absorbed calcium increased from .159 +/- .052 gm/d to .248 +/- .063 gm/d, urine calcium increased from .117 +/- .034 gm/d to .146 +/- .027 gm/d, bone accretion decreased from .385 +/- .079 gm/d to .326 +/- .063 gm/d, bone resorption decreased from .446 +/- .098 gm/d to .342 +/- .106 gm/d and endogenous fecal calcium increased from .105 +/- .023 gm/d to .120 +/- .021 gm/d. All these changes were significant within the group and the mean changes were significantly different from the mean changes observed in the control group. Calcium balance in the milk supplemented group improved from -.061 +/- .056 gm/d to -.017 gm/d +/- .073 gm/d. Predicted changes in calcium and bone metabolism held true except that the suppression of bone remodeling was less than previously found using calcium carbonate supplements. We conclude that milk and milk products can be recommended as sources of calcium, that data on the effects of increasing calcium intake from other sources can be applied to milk and that milk may offer an advantage because it does not suppress bone remodeling as severely as calcium carbonate.

Platelets were stimulated in vitro by different ADP concentration (10(-7)--10(-9) M). Scanning electron microscopy, light transmission recording and the Ca-sensitive fluorescent probe, chlortetracycline, were used to study the time course of changes in the shape, aggregation and the amount of membrane-bound calcium during ADP activation. It was found that ADP (10(-7)--10(-8)M) causes reversible changes in the shape of platelets without disturbing their aggregation. The changes in question were accompanied by phasic alterations of the amount of membrane-bound calcium.

The effects of the (3-amino-1-hydroxypropylidene)-1,1-bisphosphonate (APD) in osteoporosis were investigated in a series of open studies. Seven patients received a high dose of 600 mg/day of APD orally and showed an increase in calcium balance of 5.5 mmol/day (P less than 0.01) within a period of 10 days. In a group of 14 patients with osteoporosis, receiving a low dose of 150 mg/day of APD continuously, the mean calcium balance rose from -0.72 +/- 0.59 mmol/day before treatment to 1.33 +/- 0.87 mmol/day (P less than 0.005) after 1 year. In 24 patients treated with APD 150 mg/day for a mean period of 3.7 years (range 1.4-6.2) repeated dual photon absorptiometry measurements of the lumbar spine showed a mean rate of increase in bone mineral content of 3.1 +/- 1.0% per year (P less than 0.005). This yearly gain in bone mineral content appeared continuous for several years of treatment. In a comparable group of 19 patients with osteoporosis who also received conventional care and treatment but no APD, no significant changes in bone mineral content were found. Addition of a low dose of APD to conventional treatment of osteoporosis does not only prevent bone loss but induces a continuous gain in bone mass. These results justify long-term prospective studies with uninterrupted low dose APD treatment in osteoporosis.

1. The effect of a high calcium intake (1 mmol day-1 kg-1) alone or with the concomitant administration of oestradiol and testosterone derivatives was monitored by serial calcium balances in 48 patients with osteoporosis of various types. 2. On high calcium alone there was an increase (P less than 0.001) in both total calcium balance and net calcium absorption as compared with values on a simulated home intake. This effect was sustained for periods up to 10 years (mean 3.5 years) by the addition of the hormones. 3. Discontinuation of the hormones (only) produced a significant decrease in both calcium balance and nett absorption but both were still increased when compared with the initial values under simulated home calcium intake. 4. No significant change in the urinary calcium output was observed under any of the regimens.