Low Serum Alkaline Phosphatase Research Articles

Hormone Replacement Therapy and Osteoporosis: Bone Enzymes and Nutrient Imbalances

Contrary to popular belief the available published evidence suggests that osteoporosis is not primarily due to deficiencies of either calcium or oestrogen but is related to deficiencies of key nutrients. Serum bone alkaline phosphatase (ALP) activity is a measure of bone formation. Tartrate-resistant acid phosphatase (TRAP) is a measure of bone resorption. Low serum ALP activity relates to reduced zinc, magnesium and manganese concentrations. ALP activity improves when these nutrients are supplemented, both in vitro and in vivo , but it appears that copper decreases serum bone ALP activity. Among women with confirmed or suspected osteoporosis, all those taking hormone replacement therapy (HRT) had abnormally high serum copper levels. Hormone takers also had significantly lower white cell zinc, lower red cell magnesium and lower serum bone ALP concentrations, and significantly higher mean serum phosphate levels, than other women with osteoporosis. Hormone takers had lower serum manganese, TRAP and vitamin C levels, and higher urinary excretion of zinc and hydroxyproline but these did not reach statistical significance. These results suggest that taking exogenous steroid sex hormones is associated with a reduction in essential bone nutrients and reduced bone formation. International incidence data show that fractures among women aged 35-65 years have increased dramatically in hormone prescribing countries, and evidence is presented to indicate that this may be mediated by reduction in essential nutrients for bone formation. This study indicates the need for further research directed towards establishing the relationship between status of those nutrients essential for maintenance of bone integrity and the development of osteoporosis.

Bone structural and metabolic changes at the end of pregnancy and lactation in rats

OBJECTIVE: The objective of this study was to elucidate the net change of bone structure and metabolism in the lumbar trabecular bone of rats at the end of the pregnancy and lactation. STUDY DESIGN: Female virgin Sprague-Dawley rats aged 200 days were mated, and bone mineral density by dual-energy x-ray absorptiometry, bone histomorphometry, and serum bone metabolic markers were measured at the end of pregnancy (day 22 of pregnancy), after delivery (day 5 post partum), and at the end of lactation (day 21 post partum). RESULTS: At the end of pregnancy bone mineral density, bone volume, trabecular thickness, and serum calcium decreased; serum parathyroid hormone increased; and the histomorphometric parameters indicated that bone resorption were higher than those variables in nonpregnant rats; but bone formation was suppressed, as demonstrated by the low histomorphometric parameters and by the low serum alkaline phosphatase levels. After delivery the bone mineral density of nonlactating rats recovered rapidly, as in nonpregnant rats, but nonlactating rats showed more bone formation by histomorphometry than nonpregnant rats did. At the end of lactation, bone mineral density and serum calcium levels decreased considerably, and lactating rats showed substantial bone formation, bone resorption, and high serum alkaline phosphatase levels. The correlation between the number of pups ( x) of the lactating and nonlactating groups and the bone mineral density ( y, in grams per square centimeter) showed simple linear regression ( y = -0.0067 · x + 0.2517, r = 0.949, p < 0.0001). CONCLUSIONS: These results indicate that significant decreases occur in the trabecular bone of rats at the end of pregnancy and lactation and that lactational intensity is related to bone mineral density. (Am J Obstet Gynecol 1998;178:180-5.)

Low serum alkaline phosphatase activity associated with severe Wilson's disease. Is the breakdown of alkaline phosphatase molecules caused by reactive oxygen species?

Low serum alkaline phosphatase activity associated with severe Wilson's disease. Is the breakdown of alkaline phosphatase molecules caused by reactive oxygen species?

Significance of low serum alkaline phosphatase activity in a predominantly adult male population

The causes for low serum alkaline phosphatase (ALP) activity (reference range 30-115 U/L) in a large Veterans Medical Center were reviewed. Of 69,864 ALP determinations made over a 4-year period, 130 were low (< 30 U/L, 0.19%), representing 88 individual patients. Of these, 83 (primarily men, 96%) patients' charts were reviewed and classified into two groups, those with and those without conditions previously reported to be associated with decreased serum ALP activity: 47% had conditions associated with low ALP activity, the most frequent being cardiac surgery and cardiopulmonary bypass (26.5%), malnutrition (12.0%), magnesium deficiency (4.8%), hypothyroidism (2.4%), and severe anemia (1.2%); 53% of patients did not have clinical conditions previously associated with low ALP activity. No case of clinically apparent hypophosphatasia, for which low ALP activity is the defining characteristic, was found in this population of veterans. A low serum ALP may be of significance in other patient populations such as children, where it is associated with achondroplasia and cretinism, or in postmenopausal women with osteoporosis taking estrogen replacement therapy. In the predominantly adult male population in this study, low ALP activity was rare; it was seen most frequently in cardiac surgery patients postoperatively, a clinical condition heretofore not commonly associated with low serum ALP activity.

“Wavy ribs” A reversible pathologic finding in rat fetuses

A literature of 74 scientific papers addressing the occurrence of "wavy ribs" in fetuses of small rodents has been collected with the support of a computer-assisted search on MEDLINE, TOXLINE, BIOSIS and EXCERPTA MEDICA systems (1982-1993) and has been critically examined. Numerous compounds of a large variation in chemical structure and biological activity, if given to pregnant rats during the later period of organogenesis, are known to cause "wavy ribs" in their fetuses, a reversible pathologic finding which is rarely observed in untreated controls. According to literature, causative factors, like delayed development of alkaline phosphatase, decreased fetal protein, dietary contents, maternal toxicity, renal loop diuretics, myometrial constriction, endocrine disturbances and beta-adrenoceptor stimulation or blocking have been observed and discussed, but, a general explanation for the lesions is still missing. Therefore, the following hypothesis may be added: the high doses used in reproductive toxicology may induce maternal and placental circulatory disturbances leading to reductions in fetal serum proteins, with delayed development of osteoblast progenitors and low fetal serum alkaline phosphatase in the day 17-20 fetus. Normalization of the neonate's homeostasis (serum protein) leads to enhanced ossification and concomitant bone repair until weaning.

General toxicity and peripheral nerve alterations induced by chronic vincristine treatment in the rabbit

The effects of five 0.3 mg/kg intravenous administrations of vincristine (VCR) at weekly intervals were studied in the rabbit. Body weight gain was impaired starting from the first injection, while gross signs of motor paralysis and hair loss initiated from the third week. At the end of the observation period blood analysis revealed normocytic normochromic anemia, elevated serum creatine kinase, and low serum alkaline phosphatase, whereas all the tested parameters related to liver and kidney functions where within normal limits. The decreased number of red blood cells was the consequence of a complete, although reversible, blockade of staminal hematopoietic activity. Two important indexes of peripheral nerve function were clearly altered at the end of the treatment: (i) the sciatic nerve conduction velocity in vitro was 27% reduced and (ii) the latency between sciatic nerve stimulation and extensor digitorum longus (EDL) twitch in vivo was 34% prolonged. The usefulness of the rabbit as an animal model to study side-effects of VCR treatment is discussed.

POOR CRANIAL CALCIFICATION AND POSSIBLE HYPOPHOSPHATASIA IN A GIRL WITH AIDS

A 2½ y.o. girl with AIDS and growth failure was found to have widely separated sutures and open fontanels. AIDS was diagnosed at age 6 mos. Growth has been 3SD below the mean for ht. and wt., with head circumference at the 0-5%. Dentition was intact with 16 teeth present.Serum calcium (Ca) was 7.2-9.6 mg/dl, inorganic phosphorous was 3.4-6.4 mg/dl, and alkaline phosphatase (AP)was 51-102IU (nl:146-477). Total protein was 9.0-12.8 mg/dl; albumin was 2.6-3.7 mg/dl. Endocrine studies revealed:ionized Ca, 5.2 (nl:4.6-5.4 mg/dl);C-Terminal PTH, 109 pg/ml (nl:50-330 pg/ mg);Vit D25, 19ng/ml (nl:9-52);Vit D1-25, 66 pg/ml (nl:15-60) and TSH, 4.3 uu/ml (nl: 5.0). After TRH, TSU rose from 4.3-43.0 uu/ml (60 min) and GH peaked, paradoxically, at 30 min (6.0 ng/ml). Urinary phosphoethanolamine (PE) was 1 MCM/24hr (nl:26-101). Radiographic studies showed:BA 1½ yrs. vs. CA 2½ yrs, poorly formed skull bones, typical of hypophosphatasia and osteoporotic long bones without rickitic changes or metaphyseal defects. Good permanent teeth formation was present. Mother also had delayed fontanel closure, but she and three uneffected half-sibs were unavailable for study. Our patient has many features of hypophosphatasia with low serum AP and poor cranial bone formation. However, the absence of high total serum Ca, high urinary PE, poorly formed dentition and rickitic bony changes, usually seen in hypophosphatasia, might be explained by the poor growth caused by AIDS. Her clinical manifestations is best explained by a combination of AIDS and hypophosphatasia.

Cholestatic Jaundice With a Normal Serum Alkaline Phosphatase Level: Another Case of Hypophosphatasia in an Adult?

A patient with cholestatic jaundice and normal serum alkaline phosphatase was found to have low levels of the enzyme before and after this illness. It is suggested that this patient has hypophosphatasia because of the low serum alkaline phosphatase, a leukocyte alkaline phosphatase value of zero, and increased excretion of urinary phosphoethanolamine to 12 times normal. There were no bony abnormalities except for osteoporosis compatible with his age and some old rib fractures that followed trauma. His serum magnesium, B12, and thyroid function tests were normal.

Serum alkaline phosphatase and zinc undernutrition in infants with chronic diarrhea

III infants and children need zinc replacement in total parenteral nutrition solutions, but assessment of these needs and total body zinc status is difficult. Seven infants with severe diarrhea initially given 80 to 100 micrograms/kg/day of elemental zinc developed systemic zinc deficiency as indicated by an acrodermatitis-like skin rash and low serum alkaline phosphatase. Serum zinc levels were borderline low only in conjunction with hypoalbuminemia. Daily urinary zinc excretion was normal. With increased zinc supplementation of 200 to 300 micrograms/kg/day, the rash healed and serum alkaline phosphatase rose to normal levels for age. The activity of the metalloenzyme alkaline phosphatase accurately reflects total body zinc status in infants. With diarrheal illness, infants, need high doses zinc supplementation to replace considerable stool losses.

Prognostic indicators in Indian childhood cirrhosis.

Nineteen cases of Indian childhood cirrhosis (ICC) were studied for determining prognostic indicators. Lower serum bilirubin and high serum alkaline phosphatase were associated with good prognosis. Mere presence of hyaline did not influence the clinical and biochemical parameters, however excess hyaline formation was associated with rapidly deteriorating course. Extent of reticulin condensation had no specific significance, but extensive fibrosis was associated with low serum alkaline phosphatase level and shorter survival period. There were six survivors in the study with a follow up upto 26 months and repeat liver biopsies in most of them showed very little changes.

751 ALKALINE PHOSPHATASE EXPRESSION IN CULTURED HUMAN SKIN FIBROBLASTS AND SOMATIC CELL HYBRIDS

We have developed an in vitro model system for studying the human hypophosphatasias, a group of familial diseases characterized by low serum alkaline phosphatase (ALP) levels and poor bone development. ALP electrophoretic and activity patterns were studied in human fibroblasts, mouse fibroblasts, and mouse-human hybrids. On polyacrylamide gels, human fibroblast ALP is seen as two zones of activity (a fast and a slow band), while the mouse fibroblast ALP appears as only one. Studies in human fibroblasts suggest that the ALP fast band is a product of modification of the slow band. In the hybrids, ALP fast band segregates with the gene for human malate dehydrogenase (MDH) which is located on chromosome 2 (p<0.001). This association has been confirmed by concordant segregation of ALP fast band and MDH in two hybrid subclones. ALP activity profiles were studied on 37 independently isolated hybrid clones. In one group of clones, human chromosome 19 was associated with high ALP activity levels (p=0.04), while in another group, chromosome 19 was missing from clones with repressed ALP activity levels (p=0.005). These observations suggest that a gene on human chromosome 19 may be involved in the regulation of ALP activity. The identification of genes which control ALP expression in cultured cells should help us to understand the genetic mechanism operating in hypophosphatasia.

A case of primary hyperparathyroidism with low serum alkaline phosphatase levels.

A 23-year-old man with primary hyperparathyroidism which was typical except for reduced alkaline phosphatase activity is reported. Histological examination of surgical specimens revealed chief cell hyperplasia of the parathyroid glands. Systemic abnormalities of alkaline phosphatase were demonstrated, i.e., marked reduction of all isoenzymes and undetectable osseous enzyme in the serum, abnormal distribution of the enzyme in hepatocytes and diminished enzyme activities in leukocytes. In addition, diminished bone remodeling activity was revealed in a biopsy specimen of the rib. The association of hypophosphatasia is highly unlikely, because of normal urinary excretion of phosphoethanolamine, lack of osteomalacia, and no indication of an hereditary factor. The causal relationship between low remodeling activity and abnormalities in alkaline phosphatase was suggested.

537 HYPOPHOSPHATASIA (A FAMILY STUDY) AND TURNER SYNDROME

A patient with Turner Syndrome (TS) (45,X0) diagnosed by age 2 years had at age 5 years, rachitic changes on chest x-ray, a healing traumatic fracture of the left femur and metaphyseal changes consistent with hypophosphatasia (H). The diagnosis was confirmed by a low serum alkaline phosphatase (AP) (125 mu/ml) in the presence of a fracture, elevated urinary excretion of phosphoethanolamine (PEA) (33.6 mg/day) and early shedding of deciduous teeth. Malabsorption, glomerular and tubular renal diseases were excluded by appropriate investigations. Because of limited growth potential in TS and further impairment by the concommitent occurence of H, a trial of phosphate therapy was felt to be indicated. A bone biopsy after tetracycline labelling was performed prior to the initiation of therapy; biopsy will be repeated after 6 months of therapy (1/78). The clinical response to therapy suggests a nearly twofold increase in growth rate.Historically and radiologically the paternal side was free of disease; 4/7 in the mother's sibship showed radiographic evidence of bone dysplasia in childhood. Total AP was low in the mother and her affected sister, and normal in the father. PEA excretion studies and AP isoenzyme determinations are in progress.This is the first report of the simultaneous occurrence of TS and H. The family study suggests that the H is transmitted as an autosomal dominant trait.

ADULT HYPOPHOSPHATASIA

Abstract A case of adult hypophosphatasia under treatment with a high orthophosphate (Pi) intake is described. The patient is a 53‐year‐old woman. Her symptoms have progressed for seven years, and it has been necessary to perform osteosynthesis of both crura. The diagnosis rests upon a characteristic clinical picture, low serum alkaline phosphatase activity, high urinary excretion of phosphoethanolamine, and an invariably elevated concentration of inorganic pyrophosphate (PPi) in plasma accompanied by a very high excretion of this compound in the urine. An improved technique allowed specific determinations of microquantities of PPi in biologic materials. The concentrations of PPi in plasma and urine remained unchanged when the patient's intake of phosphorus was increased to 1.98 g/day. The PPi/Pi ratio in the urine was 10–20 before treatment. During treatment Pi excretion increased, PPi excretion did not change, and the ratio decreased to around 7. The renal tubular transport of PPi probably was saturated, and therefore PPi, which was circulating in abnormally high concentrations in the patient's fluids, could not be removed by loading with Pi. Four months of treatment did not benefit the patient.

Hypophosphatasia: screening and family investigations in an endogamous Hungarian village.

A screening programme for hypophosphatasia was performed in a Hungarian village where a family with the disease had previously been observed. Consanguinity was known to be common in this area.198 schoolchildren were tested. As to physical signs, low serum alkaline phosphatase activity, and phospho‐ethanolamine excretion, 3 homozygotes and 12 heterozygotes of the juvenile type of hypophosphatasia were discovered among them. The families of the positive children were investigated; thus altogether 34 subjects were found to be affected by the disease.Tubular reabsorption of phosphates proved to be decreased in the homozygotes and in about half the heterozygotes.In 4 families a transition between hypophosphatasia and pseudohypophosphatasia, i.e. the typical clinical and biochemical picture without a low serum alkaline phosphatase level, was observed. This suggests that the two conditions belong to the same entity.

Hypophosphatasia in an Adult

HYPOPHOSHATASIA is a rare, familial disease characterized clinically, by abnormalities of the skeleton and chemically, by low serum and tissue alkaline phosphatase values and the presence of excessive quantities of phosphoethanolamine in the plasma and urine. It is believed to be inherited as an autosomal recessive trait.1The disease usually makes its appearance in infancy or childhood, with skeletal abnormalities that are similar to those seen in rickets. Premature loss of deciduous teeth is common. In infancy, the bone disease is particularly severe and, in addition, there may be premature cranial synostosis, hypercalcemia, and renal damage. Relatively few cases of hypophosphatasia have been recognized in adults.2-8In these cases, the disease has been mild, and the only symptoms were the result of occasional skeletal fractures and pseudofractures. Herein we report the clinical, laboratory, and bone biopsy findings of the tenth case of hypophosphatasia in an adult.

Hypophosphatasia in an adult

HYPOPHOSHATASIA is a rare, familial disease characterized clinically, by abnormalities of the skeleton and chemically, by low serum and tissue alkaline phosphatase values and the presence of excessive quantities of phosphoethanolamine in the plasma and urine. It is believed to be inherited as an autosomal recessive trait.¹The disease usually makes its appearance in infancy or childhood, with skeletal abnormalities that are similar to those seen in rickets. Premature loss of deciduous teeth is common. In infancy, the bone disease is particularly severe and, in addition, there may be premature cranial synostosis, hypercalcemia, and renal damage. Relatively few cases of hypophosphatasia have been recognized in adults.^2-8In these cases, the disease has been mild, and the only symptoms were the result of occasional skeletal fractures and pseudofractures. Herein we report the clinical, laboratory, and bone biopsy findings of the tenth case of hypophosphatasia in an adult.

Leprechaunism in a male infant

<h2>Summary</h2> A male infant is described who had manyof the features of the syndrome "leprechaunism", previously described only in females and who exhibited a diffuse disturbance of tissues of mesenchymal derivation. Mental ability was seriously impaired. Growth, especially of the hands, feet, and facies, was markedly deranged. There was evidence of severe disturbance of collagen and osseous metabolism. Studies of carbohydrate metabolism, though inconclusive, suggested decreased homeostatic response to hypoglycemia. Although physical examination suggested endocrine disease involving androgenic substances, no data could be obtained to substantiate the presence of it. The skin over the hands and feet grossly resembled cutis gyrata. Low connective tissue phosphatase and serum alkaline phosphatase levels were present, but the clinical picture and the absence of phosphoethanolamine in the urine made a diagnosis of hypophosphatasia untenable in the light of present knowledge. Further metabolic studies and histochemicalinvestigation of the tissues of this infant are contemplated to elucidate further the basic pathology. It is hoped that the recording of this infant will contribute to further classification and investigation of these peculiar and fundamental defects.

Metabolic observations in adult hypophosphatasia

A diagnosis of hypophosphatasia of the type which occurs in adults was established in a thirty-six year old white man who suffered an incomplete femoral fracture after minimal trauma. The diagnosis was established on the basis of consistently low serum alkaline phosphatase values, apparent absence of alkaline phosphatase activity in leukocytes, and an abnormally high urinary excretion of phosphorylethanolamine. In two prolonged metabolic balance studies during healing of the fracture it was noted that the patient was retaining calcium and phosphorus. The rate of retention of these minerals was not influenced by the administration of prednisone in three dosage levels or by stilbestrol. These drugs also failed to cause elevation of the low serum alkaline phosphatase, or to induce detectable alkaline phosphatase activity in leukocytes. The nitrogen balance varied with intake and the dosage of prednisone, and did not parallel the balance of calcium or phosphorus.

Hypophosphatasia.

1. A case of hypophosphatasia in a boy who sustained a fractured left femur is described. 2. The literature is reviewed, and the reported cases are found to fall into severe, moderately severe and mild forms. 3. The diagnostic features of the disease are the radiological picture, which resembles that of rickets, very low serum alkaline phosphatase, and excessive phosphoethanolamine excretion in the urine. 4. Other clinical features may be a failure to thrive in early infancy, premature loss of deciduous teeth, hypercalcaemia and renal damage. 5. The function of alkaline phosphatase in bone metabolism in relation to this disease has been discussed.