Rise In Serum Alkaline Phosphatase Research Articles

Pattern of Liver Function Tests in Spectrum of Acute Viral Hepatitis

Objective: To find out the pattern of Liver Function tests (LFTs) in different spectrums of Acute Viral Hepatitis (AVH).Study Design: Cross sectional.Place and Duration of Study: The study was conducted at Pathology Department of Combined Military Hospital, Malir Karachi from March 2017 to August 2017.Materials and Methods: A total of 360 subjects of all age groups, both male and female, with biochemical features of acute viral hepatitis (AVH) were included. After clinical history and examination, liver function tests (LFTs) were performed that included total bilirubin, alanine amino transferases (ALT), alkaline phosphatase (ALP), followed by viral markers for hepatitis A virus (HAV), hepatitis B virus (HBV) hepatitis C virus (HCV) and hepatitis E virus (HEV).Results: Among the 360 patients studied, males (n=308, 86%) outnumbered females (n=52, 14%). Biochemical pattern showed ALT value reaching >75 times the upper limit of normal (ULN). Similarly rise of serum total bilirubin was up to 30 times of ULN while rise of serum ALP was not more than 5 times of ULN. HEV was found to be the most common (28%) in seropositive AVH in the study group. Highest number (24.4%) of HEV infection was found among males in the age group of 20-30 years. ALT and bilirubin were significantly raised in patients with HEV as compared to other causes of AVH.Conclusion: Pattern of LFTs varies in spectrum of AVH. Highest rise of ALT indicates extensive liver damage in HEV infection.
 How to cite this: Yousaf S, Younas M, Murtaza M, Akhtar F, Jaffar SR, Ijaz A. Pattern of Liver Function Test in Spectrum of Acute Viral Hepatitis. Life and Science. 2020; 1(1): 29-33. doi: http://doi.org/10.37185/L&S.1.1.38

Disulfiram and Its Copper Chelate Attenuate Cisplatin-Induced Acute Nephrotoxicity in Rats Via Reduction of Oxidative Stress and Inflammation.

The use of cisplatin (CP) in chemotherapy of resistant cancers is limited due to its dose-dependent nephrotoxicity. Disulfiram (DSF), the aversion therapy for alcoholism, has recently emerged as an anticancer and chemopreventive agent. Its anticancer activity is potentiated in the presence of copper. However, such use of copper leads to several adverse effects. In the present study, the protective effect of DSF and its copper chelate (Cu-DEDC) against CP-induced nephrotoxicity in rats was evaluated. Nephrotoxicity was induced by a single intraperitoneal injection of CP (5mg/kg). The treatment groups included control (vehicle treated), CP (CP-treated), CP + DSF (CP followed by DSF), CP + DSF + Cu (CP followed by DSF and CuCl2), CP + Cu-DEDC (CP followed by Cu-DEDC), and CP + AMF (amifostine pre-treated and CP-treated). The DSF, Cu-DEDC, and CuCl2 were administered orally at 50mM/kg/day dose for 5days post CP injection. AMF served as a standard chemo protectant, administered intravenously 30min prior to CP. The markers of oxidative stress, inflammation, and kidney function estimated on the 6th day revealed that both DSF and Cu-DEDC significantly attenuated the CP-induced rise in the serum/urine creatinine and blood urea nitrogen (BUN). The CP-induced rise in serum alkaline phosphatase (ALPase) was reversed by these drugs. Both drugs reduced the levels of malondialdehyde and nitric oxide (NO) in kidney tissues. These drugs reversed CP-induced depletion of SOD, catalase, and GSH in the kidneys. There was a significant reduction in the CP-induced TNF-α and IL-1β production along with prevention of histological alterations. Above observations indicate that DSF and Cu-DEDC may have significance as adjuvants to protect against CP-induced nephrotoxicity.

Towards the revival of alkaline phosphatase for the management of bone disease, mortality and hip fractures

The story of alkaline phosphatase in the management of mineral and bone disorder (MBD) in patients with chronic kidney disease (CKD) is an interesting and educational part of the history of nephrology. Circulating alkaline phosphatase, a marker of bone turnover, was among the first bone markers used for the detection and management of ‘renal osteodystrophy’, a term previously used by clinicians and researchers since the 1970s. However, by the mid-1990s and early 2000s alkaline phosphatase fell out of favor, when commercial parathyroid hormone (PTH) assays become available. At the same time, the first Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines on CKD–MBD chose not to mention alkaline phosphatase, as target ranges were uncertain [1]. A rise in serum alkaline phosphatase, known as hyperphosphatasemia or hyperphosphatasia, is an expected finding in progressive CKD with worsening kidney function [2]. Elevated serum alkaline phosphatase concentrations in CKD patients with otherwise intact liver and biliary systems usually result from excess of the bone isoforms of the enzyme [3–5]. Specific detection of the bone isoform may not have clinical utility, since it was found not to correlate with inflammation or mortality risk [6]. The recent data suggest that a rise in alkaline phosphatase in dialysis patients is associated with worsening bone mineral density [7], and worse responsiveness to erythropoiesis stimulating agents [8].

Evidence for circulating tumor cell (CTC) alkaline phosphatase (AP) expression in men with bone-metastatic castration-resistant prostate cancer (CRPC) during abiraterone acetate treatment.

178 Background: Serum alkaline phosphatase (AP) changes in men with metastatic prostate cancer have been described since the Nobel Prize winning discovery of the hormonal dependence of PC. High serum AP is independently associated with mortality in men with castration-resistant prostate cancer (CRPC) and reductions in AP with treatment are favorably prognostic. Transient rises in AP may occur during treatment initiation and reflect bone remodeling/healing. The source of serum AP in men with metastatic prostate cancer, however, remains unclear. We hypothesize that cancer cell osteomimicry and epithelial plasticity may contribute to serum AP elevations in these men. Methods: We examined the expression of AP in the circulating tumor cells (CTCs) of men with metastice CRPC on abiraterone acetate who had elevated serum AP to determine if one possible source of serum AP may be tumor-derived rather than host/bone derived. CTCs were isolated using the CellSearch method and EpCAM ferromagnetic capture, and only CD45 negative cells were considered CTCs. AP was evaluated using immunofluorescence and real time positive and negative controls. Liver function was evaluated to ensure lack of confounding with liver-derived AP. Results: We identified AP to be commonly expressed in the CTCs of men with CRPC who had high serum AP, with no expression in patient leukocytes. One patient had a transient rise in serum AP with no change in other liver enzymes during a dramatic response to abiraterone acetate while his prostate-specific antigen and CTC declined. AP expression was evident and common in his CTCs during this serum AP flare. A second patient was found to have common CTC AP expression in both CK+ and CK- CTCs. This patient had evidence of AR amplification, PTEN loss, and TMPRSS2-ERG fusion in his CK- and CK+ CTCs, accompanied by a high number of OB-cadherin + CTCs, indicating likely osteomimicry and plasticity of these clonal epithelial tumor cells. Conclusions: We provide clinical evidence that PC CTCs express AP, supporting the hypothesis that AP expression is associated with osteomimicry as part of the biology of epithelial plasticity in prostate cancer. These findings support the existence of multiple CTC phenotypes, the clinical significance of which is unknown.

Dietary free fatty acids form alkaline phosphatase-enriched microdomains in the intestinal brush border membrane

Free fatty acids released during intralumenal digestion of dietary fat must pass through the enterocyte brush border membrane before triacylglycerol reassembly and subsequent chylomicron delivery to the lymph system. In the present work fluorescent BODIPY fatty acid analogs were used to study this membrane passage in organ cultured intestinal mucosal explants. We found that in addition to a rapid uptake into the cytoplasm, a fraction of the fatty acid analogs were inserted directly into the brush border membrane. Furthermore, a brief exposure of microvillar membrane vesicles to a fat mixture mimicking a physiological solution of dietary mixed micelles, rearranged the lipid raft microdomain organization of the membranes. Thus, the fat mixture generated a low-density subpopulation of microvillar detergent resistant membranes (DRMs) highly enriched in alkaline phosphatase (AP). Since this GPI-linked enzyme is the membrane protein in the brush border with the highest affinity for lipid rafts, this implies that free fatty acids selectively insert stably into these membrane microdomains. We have previously shown that absorption of dietary lipids transiently induce a selective endocytosis of AP from the brush border, and from work by others it is known that fat absorption is accompanied by a rise in serum AP and secretion of surfactant-like particles from enterocytes. We propose that these physiological processes may be triggered by the sequestering of dietary free fatty acids in lipid raft microdomains of the brush border.

Changes in alkaline phosphatase levels in patients with prostate cancer receiving degarelix or leuprolide: results from a 12‐month, comparative, phase III study

Study Type - Therapy (RCT) Level of Evidence 1b OBJECTIVE To compare the activity of degarelix, a new gonadotrophin-releasing hormone (GnRH) blocker, with leuprolide depot 7.5 mg in the control of total serum alkaline phosphatase (S-ALP) levels in patients with prostate cancer. PATIENTS AND METHODS In the randomized, phase III trial (CS21), patients with histologically confirmed prostate cancer (all stages), were randomized to one of three regimens: degarelix subcutaneous 240 mg for 1 month followed by monthly maintenance doses of 80 mg or 160 mg, or intramuscular leuprolide 7.5 mg/month. Patients receiving leuprolide could also receive antiandrogens for flare protection. We report exploratory S-ALP analyses from CS21, focusing on the comparison of degarelix 240/80 mg with leuprolide 7.5 mg, in line with the recent approvals of this dose by the USA Food and Drug Administration and the European Medicines Agency. RESULTS Overall, 610 patients were included, with a median age of 73 years and median prostate-specific antigen (PSA) level of 19.0 ng/mL. Baseline S-ALP levels were high in metastatic patients and highest in patients with metastatic disease and a haemoglobin level of <13 g/dL. In metastatic disease, after initial peaks in both groups, S-ALP levels were suppressed below baseline with degarelix but were maintained around baseline with leuprolide. The late rise in S-ALP seen with leuprolide was not apparent with degarelix. The pattern of S-ALP response was similar in patients with a baseline PSA level of > or =50 ng/mL. Between-treatment differences in patients with metastatic disease and those with a PSA level of > or =50 ng/mL were significant at day 364 (P = 0.014 and 0.007, respectively). CONCLUSION Patients with metastatic disease or those with PSA levels of > or =50 ng/mL at baseline had greater reductions in S-ALP levels with degarelix than with leuprolide. Patients in the degarelix group maintained S-ALP suppression throughout the study, in contrast to those in the leuprolide group. This suggests that degarelix might offer better S-ALP control than leuprolide and might prolong control of skeletal metastases, compared with GnRH agonists, over a 1-year treatment period.

Elevated serum alkaline phosphatase levels in a renal transplant patient precede colitis

An asymptomatic, but highly significant, rise in serum alkaline phosphatase (AP) levels developed in a renal transplant recipient. Investigations ruled out bony or hepatobiliary disease. Subsequent diarrhea and weight loss led to a diagnosis of cytomegalovirus (CMV) colitis, which was confirmed with a positive CMV pp65 antigenemia test and an endoscopic finding of multiple colonic erosions. Intravenous ganciclovir led to complete patient recovery and a swift reduction of serum AP levels to normal. Normally, intestinal AP isoenzymes are cleared quickly from the circulation. However, acute bowel diseases, especially when inflammatory in origin, can produce high serum AP levels. In this presented patient, the rise in serum AP levels preceded symptomatic manifestations of CMV colitis, and fell with successful therapy. Acute CMV disease in solid organ transplant recipients is common, can take many shapes, and needs to be diagnosed quickly. An unexplained rise in serum AP levels should lead to a search for inflammatory bowel disease, specifically CMV colitis, in transplanted patients.

Time-evolution and reversibility of strontium-induced osteomalacia in chronic renal failure rats

Patients with impaired renal function can accumulate strontium in the bone, which has been associated with the development of osteomalacia. A causal role for strontium in the development of the disease was presented in chronic renal failure (CRF) rats. Strontium-ranelate has been put forward as a therapeutic agent in the treatment of osteoporosis. Since the target population for strontium treatment consists mainly in postmenopausal osteoporotic women, who may have a reduced renal function, the risk for osteomalacia should be considered. To determine the time evolution and reversibility of the strontium-induced mineralization defect, CRF rats were loaded with strontium (2 g/L) (+/- 200 mg/kg/day) during 2, 6, and 12 weeks, followed by a washout period of 0, 2, 4, or 8 weeks. Histologic examination of the bone of the animals treated with strontium revealed signs of osteomalacia already after 2 weeks. Animals that received strontium during 6 and 12 weeks had a significantly higher osteoid perimeter, area and thickness as compared to CRF controls. After 12 weeks, the mineralization was significantly affected, as evidenced by a lower double-labeled surface, mineral apposition and bone formation rate in combination with an increased osteoid maturation time and mineralization lag time. The osteoblast perimeter was significantly lower in the strontium-treated animals. After the washout periods, these effects were reversed and the bone lesions evolved to the values of CRF controls. This went along with an 18% reduction of the bone strontium content. A significant rise in serum alkaline phosphatase (ALP) activity was apparent in the strontium-treated animals as compared to CRF controls. This was not only due to higher levels of the bone ALP but also to those of the liver and the intestinal isoenzymes. Serum parathyroid hormone (PTH) levels decreased during strontium treatment. After cessation of the treatment, the serum ALP activity and PTH concentration reversed to control levels. In this study evidence is provided for the rapid development of a mineralization defect in strontium-loaded CRF rats, accompanied by a reduced osteoblast number, reduced PTH synthesis or secretion, and increased serum ALP levels. These effects can be rapidly reversed after withdrawal of the compound.

Studies on the antihypertensive, antispasmodic, bronchodilator and hepatoprotective activities of the Carum copticum seed extract

This study describes the antihypertensive, antispasmodic, bronchodilator and hepatoprotective activities of the aqueous-methanolic extract of Carum copticum Benth. seeds (CSE) to rationalize some of its traditional uses. CSE (3–100 mg/kg) caused a dose-dependent fall in arterial blood pressure in anaesthetized rats. In isolated rabbit aorta and jejunum preparations, CSE (0.1–3.0 mg/ml) caused an inhibitory effect on the K +-induced contractions. The calcium channel blocking (CCB) effect was confirmed when CSE shifted the Ca 2+ dose–response curves (DRCs) to right similar to verapamil. In isolated guinea-pig tracheal preparations, it caused inhibition of carbachol and K +-induced bronchoconstriction at 0.1–1.0 mg/ml as well as shifted the dose–response curves (DRCs) of carbachol and histamine to the right with suppression of maximum response suggestive of non-specific bronchodilator effect mediated possibly through CCB. Pretreatment of rats with CSE (500 mg/kg orally for 2 days at 12 h intervals) prevented paracetamol (640 mg/kg) and CCl 4 (150 ml/kg)-induced rise in serum alkaline phosphatase (ALP) and aminotransferases (AST and ALT). The same dose of CSE was able to prevent the CCl 4-induced prolongation in pentobarbital-induced sleeping time in mice confirming its hepatoprotectivity. These results indicate the presence of calcium antagonist(s) in Carum copticum seeds and thus provides sound mechanistic basis for some of their folkloric uses.

Enzyme polymorphisms, smoking, and human reproduction. A study of human placental alkaline phosphatase.

We investigated the possible effects of placental alkaline phosphatase (PLAP) genotype on the deleterious action of maternal smoke on intrauterine survival and birthweight. PLAP is a highly polymorphic enzyme with several alleles associated with different enzymatic activities. PLAP is produced by the embryo and is found in maternal blood, where it is responsible for the rise of serum alkaline phosphatase during pregnancy. Two hundred and fourteen Caucasian consecutive newborn infants delivered in the Maternity Department of the University of Rome La Sapienza Hospital were studied. Infants from smoking women 28 years or older show a strong decrease of both PLAP*1/*1 and *2/*2 homozygous types and a marked deviation from Hardy-Weinberg expectation, thus suggesting a different lethal effect of smoke depending on PLAP genotype and maternal age. In infants from smoking mothers there is a decrease of birthweight that is much less evident and statistically not significant in infants carrying the PLAP*1/*1 genotype as compared to other genotypes. The difference between PLAP genotypes concerning birthweight is more marked in women older than 28 years than in younger ones. This suggests that the effects of smoke on birthweight are also dependent on PLAP and maternal age.

Some biochemical markers in various neoplasms: A multivariate analysis

The analysis of biochemical parameters in 162 patients with various neoplastic disorders along with 50 normal subjects showed significant rise in serum alkaline phosphatase and lactate dehydrogenase as compared to normal subjects. 21 patients with other monoclonal gammopathies which include infection and immunological diseases were also studied. Parameters such as serum calcium, uric acid, total protein, albumin and globulin were also analyzed in 42 (26%) cases of multiple myeloma, 27 (17%) cases of gastro-intestinal malignancies, 22 (14%) cases of urogenital malignancies, 11 (6%) cases of carcinoma breast, 4 (2%) cases of bone tumors, 21 (12%) cases of other monoclonal gammopathies, including 7 (4%) cases of infection and 14 (8%) cases of immunological diseases. The results indicate use of enzymes alkaline phosphatase and lactate dehydrogenase in neoplastic disorders.

Serum Alkaline Phosphatase as an Indicator of Heterotopic Bone Formation Following Total Hip Arthroplasty

Serum alkaline phosphatase (SAP) was analyzed in 193 patients treated with total hip arthroplasty (THA) and correlated with the degree of heterotopic bone formation (HBF) one year after surgery. The influence of indomethacin on changes in SAP related to the development of heterotopic bone was studied. Ninety-eight patients received 25 mg of indomethacin three times daily for the first six postoperative weeks; the remaining 95 patients received a placebo treatment. No further anti-inflammatory drugs were allowed during the six weeks. SAP was measured preoperatively and six weeks and 12 weeks after surgery. No patients at risk for developing heterotopic bone after THA could be identified from the preoperative level of SAP. The level of SAP six weeks after THA gradually increased with the amount of HBF. A rise in SAP above 250 IU/liter 12 weeks after surgery was associated with the development of severe heterotopic bone in 13 of 17 patients. Indomethacin inhibited the development of heterotopic bone associated with a rise in SAP following THA. Future studies on HBF and SAP following THA should include information on patient use of anti-inflammatory drugs in the early postoperative period.

Ultrasonic demonstration of anicteric biliary obstruction.

ABSTRACT25 non jaundiced patients with dilatation of the biliary tree are presented. In 22 of these cases the cause of obstruction was shown either by ultrasound alone, on radionuclide (RN) study or at endoscopic retrograde cholangiography (ERCP) and was subsequently proven at surgery. In 2 cases ultrasound showed dilatation of the common duct, which was proved to be non‐obstructive dilatation on ERCP. One patient had multiple benign hepatic cysts with intrahepatic biliary dilatation and was not subjected to surgery. Twenty out of 23 patients with obstructive dilatation showed a variable rise in serum alkaline phosphatase. Bile duct size did not show any correlation with serum alkaline phosphatase levels. It is stressed that ultrasound is a more sensitive indicator of obstructive biliary disease than clinical and biochemical parameters.

Metronidazole prevention of serum liver enzyme abnormalities during total parenteral nutrition.

Abnormal serum liver enzymes are common in adults receiving total parenteral nutrition (TPN). The mechanism(s) responsible for these changes is unclear. One hypothesis is that there is overgrowth of intestinal anaerobic bacteria with subsequent toxic effects on the liver from endotoxins and/or bile acids. A retrospective survey of patients receiving TPN was undertaken. The patients were divided into two matched groups. One group had received metronidazole, a drug that suppresses anaerobic bacteria, while the other group had not. The administration of metronidazole during TPN was associated with prevention of the expected rise of serum alkaline phosphatase, gamma glutamyl transpeptidase, and aspartate amino-transferase. This study supports the concept that anerobic intestinal bacteria may be involved in the pathogenesis of liver changes commonly observed during TPN.

Liver procollagen prolyl hydroxylase in Opisthorchis viverrini infected hamsters after praziquantel administration

Infection of hamsters by the human liver fluke Opisthorchis viverrini elevated liver procollagen prolyl hydroxylase activity, reflecting increased collagen biosynthesis. The increase was proportional to the intensity of infection. However, the infected liver procollagen prolyl hydroxylase activity decreased after administration of praziquantel 300 mg kg −1 body weight, and approached normal levels two weeks after treatment. In the infected hamsters, praziquantel, at a curative dose, caused a transient increase in serum aminotransferase levels and a small but persistent rise in serum alkaline phosphatase. The drug, however, did not cause changes in these enzyme activities in the uninfected hamsters.

The use of dichloromethylene diphosphonate for the management of hypercalcaemia in multiple myeloma.

We have assessed the effects of the diphosphonate, dichloromethylene diphosphonate (Cl2MDP), in 19 patients with hypercalcaemia and increased bone resorption due to myeloma. Cl2MDP (800-3200 mg daily by mouth or 300 mg daily by intravenous infusion) decreased plasma calcium and biochemical indices of increased bone resorption in 16 of 19 patients. This effect persisted for the duration of treatment (up to 14 weeks). Prolonged treatment was associated with a progressive rise in serum alkaline phosphatase and only a transient fall in hydroxyproline suggesting the stimulation of bone repair. Since myeloma is associated with significant morbidity and mortality due to progressive bone loss, these results suggest that long-term treatment of myeloma with Cl2MDP is worthy of further study.

Retained biliary tract stones. Nonsurgical treatment with capmul 8210, a new cholesterol gallstone dissolution agent.

The ability of Capmul 8210, a commercial solvent that predominantly consists of glyceryl 1-mono-octanoate, to dissolve retained common duct stones by direct infusion into the T-tube was tested in 20 patients with a total of 43 stones. Of 19 patients who completed their infusion, stone disappearance was observed in 15, giving a success rate of 79%. The dissolution time for a single stone averaged four days. A slight rise in serum alkaline phosphatase and amylase levels occurred in some patients, and rapidly returned to normal when treatment was concluded. Other side effects, such as nausea and vomiting epigastric discomfort, or diarrhea, occurred occasionally but were easily controlled medically. We believe that this agent is a useful adjunct in the management of postoperative choledocholithiasis in the patient with an indwelling T-tube.

5 Nutritional osteomalacia and late Rickets in Greater London, 1974–1979: Clinical and metabolic studies in 45 patients

Summary Despite a century of scientific study and of socioeconomic advance classical rickets and osteomalacia are as apparent in England today as in the developing world. Forty-five patients with overt classical late rickets and osteomalacia presenting over a five-year period provided the basis for a study of age, sex and race distribution, symptoms and their onset, clinical signs, radiology and response to treatment. Results, together with measurements of plasma 250HD among newly arrived emigrants from Uganda, suggest that residence in England is a significant factor in the production of disease among Asian patients originating from East Africa. Biochemical abnormalities were quantitated. Fifty per cent of patients with overt disease were normocalcaemic. Serum alkaline phosphatase may be unequivocally normal in severe disease. Human requirement for oral 1,25(OH) 2 D 3 when replacing outside sources of vitamin D was close to 7 ng/kg/day. 24,25(OH) 2 D 3 was neither effective nor necessary for the apparent cure of osteomalacia. 1,25(OH) 2 D 3 was no more than 10 to 40 times more effective than 25(OH)D 3 on a weight basis. Both 1,25(OH) 2 D 3 and 25(OH)D 3 effectively increased renal tubular phosphate reabsorption. Serum phosphorus showed a highly significant biphasic response during long-term treatment, elevated levels being recorded during most of the period of bone remineralization (up to four months). The extent and frequency of a rise in serum alkaline phosphatase during treatment was quantitated.

Occult Anticonvulsant Osteomalacia in North India

Serum calcium, inorganic phosphate and alkaline phosphatase, tubular reabsorption of phosphate (TRP) estimation and radiological examination of the skeleton were conducted in 40 cases (18-50 years of age) on anticonvulsant therapy and 20 controls. The epileptic group showed a statistically significant rise in serum alkaline phosphatase and a fall in TRP. In none of the cases, however, was there clinical or radiological evidence of osteomalacia. Biochemical abnormalities were seen mainly in the youngest individuals. It seems that the critical factor for the development of anticonvulsant osteomalacia is the lack of dietary vitamin D/solar exposure or increased body requirement of the vitamin.

Vitamin D metabolites and bone mineralization in man.

A comparison was made of the biochemical and osseous effects of 25-hydroxyvitamin D3 [25(OH)D3], 1 alpha-25-hydroxyvitamin D3 [1 alpha, 25(OH)2D3], and 24,25-dihydroxyvitamin D3 [24,25(OH)2D3] in adult vitamin D-deficient man. Administration of 50 micrograms/d of 25(OH)D3 for 8 weeks led to a return of the mineralization front to normal associated with a return of TmPO4/GFR to normal, an increase in serum phosphate and calcium concentrations, a fall in serum IPTH, and a rise in serum alkaline phosphatase activity. Giving 2.5 micrograms/d of 1 alpha,25(OH)2D3 did not produce these effects. Administration of 1 alpha, 25 (OH)2D3 caused an increase in intestinal calcium absorption, and a rise in serum calcium associated with a fall in serum immunoreactive parathormone (IPTH) concentrations but no sustained rise in either alkaline phosphatase, serum phosphate concentration, nor in TmPO4/GFR. Its administration caused an increase in the extent of the osteoclastic bone resorption surface but the extent of the mineralization front remained subnormal. Administration of 20 micrograms/d of 24,25(OH)2D3 caused a fall in urinary calcium excretion and in serum IPTH, and a rise in serum alkaline phosphatase, but no change in TmPO4/GFR or serum phosphate, and only a slight increase in the extent of the mineralization front. Combined treatment with 1 alpha, 25(OH)2D3 and 24,25(OH)2D3 led to a return of the mineralization front of normal even though both TmPO4/GFR and serum phosphate concentration remained low. It is concluded that 1alpha,25(OH)2D3 is not the sole biologically active metabolite of vitamin D in man. It is apparent that either 25(OH)D3 or some as yet unidentified metabolite of 25(OH)D3 stimulates the renal tubular reabsorption of calcium and phosphate, and that the subsequent rise in serum phosphate concentrations along with the direct actions of 1 alpha-25(OH)2D3, 24,25(OH)2D3, and possibly 25(OH)D3 on bone cells all participate in the restoration of normal bone formation and bone mineralization in vitamin D-deficient man.