The concentration of free calcium in plasma is set by the extracellular action of noncollagenous proteins and hydroxyapatite.

The late Wm. F. Neuman frequently included the following statement in his speeches: "Plasma calcium is undersaturated in respect to itself, but supersaturated in respect to bone". As a physical chemist he knew that if plasma or extracellular fluid came in direct contact with bone surfaces plasma calcium level should fall to the saturated solubility of hydroxyapatite. How could the condition given in the quote exist? He answered this question by laboratory experiments but unfortunately died before he could explain it scientifically. In the current perspective article we feel that we cannot only explain Neuman's riddle but also use the answer to describe a revised premise for extracellular control of calcium concentrations in body fluids. The answer lies in the solubility of hydroxyapatite. A simple contact of bone mineral surface with body fluids should lead to a calcium concentration in plasma too low to support life. The evolutionary process prevented this by adding one or more noncollagenous proteins at the surface of hydroxyapatite. These proteins elevated the saturated solubility of the crystal latticework sufficiently to provide a calcium concentration that would sustain life. This report explains the solubility process in as much detail as our scientific information will permit and also includes the role of parathyroid hormone in the process. We hope that serious study of our article will permit acceptance of our premise for calcium control and induce further study that should demonstrate its importance in all aspects of bone metabolism.

Calcium homeostasis: how bone solubility relates to all aspects of bone physiology.

This perspective challenges the bone research community to study a new concept of calcium homeostasis and determine how it affects all aspects of bone physiology and disease. The concept started with Neuman's discovery that the apparent supersaturation of calcium in the extracellular fluid (ECF) could be explained by the presence of non-collagenous proteins on the surfaces of bone. His discovery opens the door to a new field of bone research and raises the question of how his result affects other aspects of bone physiology and pathology? The purpose of this perspective is to challenge the bone field to determine the significance of these findings. The report lists a few areas that need inquiry and supplies premises that need to be tested.

Calcium homeostasis: solving the solubility problem.

This report summarizes the evidence that the control of the concentration of free calcium ions in body fluids is centered at mineralized bone surfaces. This process involves an increase in the solubility of bone mineral produced by the non-collagenous proteins existing in the bone extracellular fluid (ECF) and on the adjacent surfaces of bone. The result is a basic equilibrium level produced in the absence of parathyroid hormone (PTH), which is well above the solubility of bone mineral. The effect of PTH is to increase the solubility of bone mineral still further, but the mechanism by which the hormone acts is unknown. The lining cells of the bone contain receptors for PTH and can be observed to respond to this hormone, but the relationship between this response and the increased solubility of bone remains to be discovered. Further research in this field is strongly urged.

Calcium homeostasis and bone surface proteins, a postulated vital process for plasma calcium control.

This report is a more in-depth explanation of a recently reported hypothesis for controlling the ionic calcium content of plasma and extracellular fluids (ECF). The hypothesis proposes a two-step process for returning calcium to the ECF against the established gradient continuously moving calcium from plasma to bone surfaces. The first step in this process is the predicted transfer of calcium directly from bone surfaces to the non-collagenous proteins, which are in contact with bone mineral. This calcium would be complexed to existing proteins and a portion would automatically become available for equilibration with ionic calcium in the ECF. The basis of the hypothesis is that the equilibration level helps to set the ionic calcium concentration of plasma. The gradient toward bone and the proposed two-step return occur in the ECF of bone and would be considered normal physiochemical processes. Thus, these processes are critical for mineral ion homeostasis in mammals. In this hypothesis, parathyroid hormone (PTH) is not required for the basic process. However, PTH works within the process to raise and set a precise plasma calcium concentration. The report to follow describes the process and discusses its relationship to normal and pathological conditions affecting human health.

Inclusion of a competency-based curriculum in medical pharmacology.

Medical education programs have emphasized the acquisition of basic scientific knowledge and practical skills in well-defined subject areas using lecture and role modeling as the principle means of instruction. The need to address changes in the practice environment, the recognition that alternative instructional models may be desirable in some cases, and the fact that instruction in the traditional subject areas does not prepare students for all aspects of medical practice have driven recent curricular changes at many schools. Indiana University School of Medicine, with multiple instructional sites distributed throughout the state, has adopted a school-wide plan that specifies desired educational outcomes and provides an instrument for rating student achievement. In this report we describe the implementation of new media and pedagogical methods in a two-semester medical pharmacology course with the goal of fostering and assessing competency in the nine areas outlined in this educational plan. The general conclusion is that these changes not only furthered the broader educational goals of the competency-based curriculum, but also may exert a positive influence on student learning of discipline-specific material.

Computerized controlled-substance surveillance: application involving automated storage and distribution cabinets.

A secondary data-reporting system used to scan the archives of a hospital's automated storage and distribution cabinets (ASDCs) for indications of controlled-substance diversion is described. ASDCs, which allow access to multiple doses of the same medication at one time, use drug count verification to ensure complete audits and disposition tracking. Because an ASDC may interpret inappropriate removal of a medication as a normal transaction, users of ASDCs should have a comprehensive plan for detecting and investigating controlled-substance diversion. Monitoring for and detecting diversion can be difficult and time-consuming, given the limited report-generating features of many ASDCs. Managers at an 800-bed hospital used report-writing software to address these problems. This application interfaces with the hospital's computer system and generates customized reports. The monthly activity recapitulation report lists each user of the ASDCs and gives a summary of all the controlled-substance transactions for those users for the time period specified. The monthly summary report provides the backbone of the surveillance system and identifies situations that require further audit and review. This report provides a summary of each user's activity for a specific medication for the time period specified. The detailed summary report allows for efficient review of specific transactions before there is a decision to conduct a chart review. This report identifies all ASDC controlled-substance transactions associated with a user. A computerized report-generating system identifies instances of inappropriate removal of controlled substances from a hospital's ASDCs.

Calcitonin, an enigmatic hormone: does it have a function?

This editorial presents our view of the status of thyroidal calcitonin (TCT) in mammalian physiology. The discovery of calcitonin (CT) enabled the development of a valuable therapeutic agent but the early experiments most likely misled us with regard to its physiological significance. These early purported roles for TCT, first as an agent important in blood calcium regulation and later as an agent to prevent hypercalcemia, are no longer considered as physiological functions. While large supraphysiological doses of CT have an effect on the morphology and function of osteoclasts, it is unlikely that these effects of CT are important in the normal physiology of osteoclasts or bone remodeling. It is surprising that 38 years after the discovery of TCT there is no consensus as to its role in normal mammalian physiology. This editorial concerns three possibilities with respect to TCT: 1) the hormone is vestigial; 2) the hormone plays a role in water metabolism, ionic concentrations, and/or acid-base balance, actions that may not involve calcium metabolism at all; and 3) TCT acts to store phosphate postprandially on bone surfaces as a labile calcium-phosphate colloid, an action that may provide calcium needed for use in non-feeding periods or to reduce postprandial loss of phosphate when dietary phosphate is limited. Also discussed are recent publications indicating that CT synthesized in non-thyroidal tissues (NTCT) may have paracrine actions.

Parathyroid hormone and plasma calcium control: an editorial.

The purpose of this report is to examine the various processes by which parathyroid hormone might control the ionic calcium concentration of plasma and extracellular fluid, and to emphasize the need for study of the maintenance of plasma calcium in the absence of the parathyroid glands. The report discusses mechanisms to explain the control of extracellular calcium and proposes new approaches to the study of calcium homeostasis.

Bone mineral density and history of oral contraceptive use.

To examine the relationship between oral contraceptive (OC) use and bone mineral density (BMD), we conducted a cross-sectional study on 352 white, nonsmoking, perimenopausal women aged 40-54 years. We measured bone mineral density of lumbar vertebrae 2-4 with dual photon absorptiometry and mid-radius and distal radius with single photon absorptiometry. After controlling for age, body mass, current physical activity, current calcium intake and history of breastfeeding, our analysis did not find substantial differences in BMD at any site between OC ever users and never users. However, OC ever users had slightly higher lumbar BMD among premenopausal women. No significant association was identified between recency of OC use and BMD. The results of our study suggest that when other factors are accounted for, OC use is not strongly associated with BMD among perimenopausal women, although we cannot exclude a slight beneficial effect.

PIP: This document reports the findings of a cross-sectional study in which the relationship between oral contraceptive (OC) use and bone mineral density (BMD) was examined. In postmenopausal women the loss of bone density and mass is well documented. This situation, if left unchecked, could lead to osteoporosis, and the financial impact on the U.S. public health system could range from $2 to $6.1 billion per year. This study controlled for the variables of age, body mass, current physical activity, current calcium intake, and history of breast feeding, all of which affect BMD. Of the 352 women in the study, 7 currently used OCs, 92 women had never used OCs, and 253 women were former OC users. These women were subdivided into 2 groups based on OC usage. These were the never users group and the ever users group. Bone mineral density was measured using dual photon absorptionmetry (Norland Duel 2600) on the 2nd, 3rd, and 4th lumbar vertebrae and single photon absorptionmetry on the midradius and distal radius (5-mm site). Separate analyses were conducted for premenopausal and postmenopausal women. It was found that in the premenopausal group, with increasing OC involvement, that the BMD increased slightly but was not considered statistically significant (P = 0.21). After adjusting for the variables of age, breastfeeding, body mass, physical activity, and calcium intake, no dose-effect relationship could be found between premenopausal and postmenopausal women. Women considered recent OC users were associated with an increase in BMD, though overall this was not statistically significant. The results of this study suggest that when variables are statistically adjusted for OC use is not strongly associated with BMD in perimenopausal women.

Lactation history and bone mineral density among perimenopausal women.

To examine the relation between lactation and bone mineral density, we conducted a cross-sectional study among white, nonsmoking, perimenopausal women age 40-54. Three hundred fifty-two women completed a questionnaire covering medical and reproductive histories, physical activity, and diet. We measured the bone density of lumbar vertebrae 2-4 with dual photon absorptiometry, and the midradius and distal radius with single photon absorptiometry. Women with a history of lactation had 41 mg per cm2 higher lumbar bone mineral density than women with no lactation (95% confidence interval = 8-74 mg per cm2), controlling for parity, body mass, physical activity, and menopausal status. We found no important increase at mid- or distal radius.

PIP: Reproductive health specialists used a personal activity computer to measure current physical activity of 352 White women aged 40-54 from central North Carolina. They distributed a questionnaire and simple life calendar to the women to gather information on past physical activity, menopause status, food intake, and health, reproductive, and contraceptive histories. They used dual photon absorptiometry at the second to fourth lumbar vertebrae and single photon absorptiometry at the midradius and the distal radius to measure bone mineral density (BMD). They studied the association between lactation and BMD. 58% of the women had ever breast fed (mean: 14 lifetime months; median: 9 lifetime months). The breast feeding group showed a higher parity, less current physical activity, and less physical activity in high school than their non-breast feeding counterparts. They were similar in education, calcium intake, menopausal status, and history of oral contraceptive use. When the researchers controlled for parity, body mass, current physical activity, and menopausal status, breast feeding women had 41 mg/sq. cm higher lumbar BMD than non-breast feeding women. BMD also increased at the distal radius (10 mg/sq. cm) and midradius (5 mg/sq. cm), albeit more modestly. These findings suggest that lactation has a beneficial effect on calcium homeostasis and BMD.

Are calcium intakes and physical activity patterns during adolescence related to radial bone mass of white college-age females?

The determinants of bone mass, i.e., size and density, in young adult women after cessation of growth in length of the bones are not well understood. Usual dietary calcium (Ca) intakes and physical activity (PA) patterns during the post-pubertal half-decade have been considered as two important factors contributing to bone mass. In the present hypothesis-generating cross-sectional study, radial bone mineral content and density were measured by single-photon absorptiometry at two sites containing different proportions of trabecular and cortical bone tissue in 705 healthy, Caucasian college women (18-22 years). Ca intake during high school and college, as estimated by milk and cheese intake only, was categorized into low, moderate and high groups; and physical activity, estimated during the same time frame, was also categorized into low, moderate and high groups. Bone measurements were related to both long-term dietary Ca intake from milk and cheese and long-term PA in sports, dance or other exercises, as assessed by recall. By univariate analyses, both distal and mid-radial bone mineral content (BMC) and areal bone mineral density (BMD) were found to be positively related to gynecological age (GA) (p less than 0.01). Also, independent effects of long-term Ca intake (p less than 0.05) on distal BMC and BMD, and of long-term PA (p less than 0.05) on distal and mid-BMC and BMD were observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Bone mineral content at three sites in normal perimenopausal women.

Bone mineral content (BMC) in 217 healthy white women between the ages of 40 and 55 years was measured using single- and dual-photon absorptiometry. The sites measured included the distal radius, midradius, proximal femur, and lumbar spine. The relationship between BMC and age was constant over the age range studied when the confounding effect of menopause was controlled. Women with low body mass indices (BMIs) had significantly lower BMC than women with average or greater than average BMIs. More active women had higher BMC than less active women at both appendicular and axial sites. A trend suggesting that women with higher calcium intake may have higher BMC was statistically significant only at the midradial site. A trend of postmenopausal women having lower BMC than pre- or perimenopausal women was also statistically significant only at the midradial site. Only modest correlations were found between the various sites. These correlations are too weak to allow accurate clinical predictions of BMC at axial sites from the BMC at an appendicular site in individual patients.

Monocytic origin of fibroblasts: spontaneous transformation of blood monocytes into neo-fibroblastic structures in osteomyelosclerosis and Engelmann's disease.

We describe here two pathological situations, osteomyelosclerosis and Engelmann's disease, in which HLA-DR blood monocytes modulate to the fibroblastic class, in long-term culture. Monocytes/macrophages were identified by immunofluorescence, using monoclonal antibodies against surface markers (Leu M3, CD 68, and HLA-DR) and the neo-fibroblasts by electron microscopy and immunofluorescence using monoclonal antibodies against a cytoplasmic enzyme specifically involved in the synthesis of collagen (5B5). Macrophages makers were found on the neo-fibroblasts, whereas HLA-DR macrophages expressed the cytoplasmic marker 5B5. Since osteoblasts are classically derived from fibroblasts, the significance of the in vitro differentiation of monocytes/macrophages into fibroblasts to the in vivo mechanism leading to excessive osteoblastic proliferation in both osteomyelosclerosis and Engelmann's disease, is discussed. The possible involvement of this pathway leading from monocytes to fibroblasts and osteoblasts in the normal process of bone modeling and remodeling in questioned.

Update on the use of distal radial bone density measurements in prediction of hip and Colles' fracture risk.

A controversy has developed around the question as to whether bone density values from the distal radius can be used to accurately predict risk of future fractures. To address this question, two separate studies were undertaken: (a) Bone density was measured in 460 healthy ambulatory women living in retirement centers in the state of North Carolina; 83% of these women were followed for up to 60 months for occurrence of minimal trauma hip and wrist fractures. Thirty-one minimal trauma fractures were reported in our study population, representing 8% of those followed. The fracture incidence density rate showed a close inverse relationship with incremental changes in bone density at the distal site. Twenty-eight of the 31 fractures were reported in women with bone density values below the 325-mg/cm2 "at risk" value. (b) Bone density values of the distal radius and the lumbar spine from 360 women (aged 18-85 years) from the Chapel Hill area were used to analyze the error in predicting individual spinal density from the distal radial density. Although the overall correlation was high (r = 0.67) and the confidence intervals were narrow, the prediction intervals were quite wide. Thus, prediction of an individual value of spine density from the distal radius density would result in a value with a range too wide to be clinically useful. We conclude that single-photon absorptiometry appears to be a useful tool for screening normal populations of asymptomatic women for prediction of hip or Colles' fracture risk even though it has limited usefulness in prediction of spinal fracture risk or individual values for spinal density.

Spinal bone density following spinal fusion.

Spinal bone densities were assessed in 25 patients following lumbar fusion and bracing, in an attempt to study bone remodeling by noninvasive methods. Dual-photon densitometry was used to study specific areas of autologous bone grafts and adjacent vertebrae above the fusion mass. Measurements were made preoperatively and at 6-week intervals postoperatively. The data for the first 12 months postoperatively are reported here. In all patients there was at first a consistent loss in density in the vertebrae above the fusion mass, averaging 15.7%. This was followed by a gradual density increase such that by 1 year postoperatively, in 60% of the subjects, the density of these vertebrae was higher than the preoperative level. In the grafted areas, bone changes were cyclical, demonstrating a remodeling pattern consistent with that described in animal literature for graft healing and also consistent with modern bone remodeling theory. There was a general tendency toward a gradual increase in the density of the fusion mass.

The late effect of subtotal thyroidectomy and radioactive iodine therapy on calcitonin secretion and bone mineral density in women treated for Graves' disease.

This study was designed to evaluate the effect of subtotal thyroidectomy and/or radioactive iodine therapy on plasma immunocalcitonin (iCT) levels and bone densities in patients treated for Graves' disease. Forty-eight women whose ages ranged from 29 to 79 years (mean, 55 years) were evaluated. All were at least 10 years beyond treatment. Fourteen patients had undergone subtotal thyroidectomy, 22 had received radioactive iodine therapy, and 12 had received both. Serum calcitonin levels were measured with the patient fasting and at 30 minutes and 2 hours after the ingestion of 15 mg of calcium in orange juice. Single photon absorptiometry was used to measure bone mineral density of the middle and distal radius. The mean fasting plasma levels of iCT for patients undergoing subtotal thyroidectomy was 27 +/- 2 mumol/L; women treated with radioactive iodine, 26 +/- 2; women undergoing subtotal thyroidectomy followed by radioactive iodine, 24 +/- 2, and for normal control women, 48.5 +/- 4.7. The mean stimulated iCT level of each of the patient groups was significantly lower than that of the normal controls (p = 0.01). There were no significant differences among the groups. Although there was an increased loss of bone mineral density in postmenopausal patients, with age and race as covariates, the bone densities of the distal radius in women undergoing subtotal thyroidectomy and/or receiving radioactive iodine were not significantly lower than those of normal control subjects (p greater than 0.05). These findings are consistent with other observations that patients treated by thyroidectomy and/or radioactive iodine for Graves' disease have lower basal levels of calcitonin and decreased calcitonin response to a provocative stimulus. Whether this loss of calcitonin reserve is a significant factor in development of postmenopausal osteoporosis remains unanswered.