Healing of rickets after calcium supplementation.
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Calcium↗
Biomedical subjects
M W Davie
Publications and source records attributed to M W Davie.
Age-related changes in body composition, hydroxyproline, and creatinine excretion in normal women.
We have made a cross-sectional study of relationships among age, whole body bone mineral content (WBBMC), and non-bone lean body mass (NBLBM) measured by dual energy X-ray absorptiometry (DXA), and daily excretion of hydroxyproline (OHP) and creatinine (Cr) in a group of normal women. WBBMC fell with age from the 6th decade, whereas NBLBM was almost constant. Creatinine excretion fell with age from the 5th decade until the 9th, to a much greater degree than NBLBM, reaching a nadir in the 8th decade. Daily excretion of hydroxyproline showed a peak in the 6th decade and fell moderately thereafter. The greater fall of creatinine compared with hydroxyproline resulted in rising OHP/Cr ratios with advancing age, in contrast to the pattern of hydroxyproline excretion. The use of creatinine as a correction for urine dilution or for lean body mass (LBM) in assays for markers of bone turnover must therefore be viewed with caution.
Absorptiometry, Photon↗
Bone mineral density at distal forearm can identify patients with osteoporosis at spine or femoral neck.
Forearm bone mineral density (BMD) was investigated in women to identify osteoporosis at the spine or femoral neck (or both) defined by WHO criteria (T score -2.5) without requirement for fracture. BMD was measured by single-energy X-ray absorptiometry (DTX100) and by dual-energy X-ray absorptiometry (DXA) in the lumbar spine and femoral neck in 422 subjects aged 22-90 yr. A total of 62% of subjects with osteoporosis (at the spine, femoral neck, or both sites) were detected with 89% specificity [receiver operating characteristics (ROC) analysis] and included all subjects below forearm BMD 0.34 g/cm2. Conversely, above 0.419 g/cm2, only 10% of patients had osteoporosis. A total of 71.8% of women could be assigned either to those who warranted therapy (<0.34 g/cm2) or to those who did not (>0.419 g/cm2) with 90% certainty. Subjects with forearm BMD between 0.34 and 0.419 g/cm2, who constituted 28.2% of the total group and included 31% of subjects with osteoporosis, had a 40% chance of having osteoporosis. This leads to a high identification rate on subsequent DXA scanning, which is thus used efficiently.
Absorptiometry, Photon↗
Elevated collagen turnover in Nigerian children with calcium-deficiency rickets.
Calcium deficiency is a major etiological determinant of rickets in Nigerian children and is accompanied by undermineralization of the developing bone matrix which is composed largely of type I collagen. We have assessed types I and III collagen metabolism by measuring the circulating concentrations of teh N- and C-terminal pro-peptides (intact PINP and PICP) and the C-terminal telopeptide (ICTP) of type I collagen, and the N-terminal pro-peptide (PIIINP) of type III collagen in 94 healthy Nigerian children and in 44 children aged 1-5 years with active calcium-deficiency rickets. In active rickets the mean levels of the four collagen metabolites were approximately twofold higher than in the healthy children, despite a wide variation of individual values. Mean intact PINP was 812 +/- 279 versus 403 +/- 189 microg/liter; PICP was 573 +/- 265 versus 348 +/- 299 microg/liter; PIIINP was 16.8 +/- 8.6 versus 10.8 +/- 3.6 microg/liter, and ICTP was 28.4 +/- 17.2 versus 11.9 +/- 4.1 microg/liter (all P < 0.001), in rachitic and healthy children, respectively. Healthy children younger than 3 years had higher levels of all the collagen metabolites than those between 3 and 5 years (all P < 0.05). Alkaline phosphatase was greater in rickets than in the healthy group (P < 0.001) whereas mean osteocalcin levels were slightly lower (P = 0.009). 1,25(OH)2D correlated with all the collagen propeptides, but not with ICTP in the healthy children. No such correlations were found in rickets, where there was a poor inverse correlation between 1,25(OH)2D and ICTP. These data suggest that collagen turnover is elevated in cases of calcium-deficiency rickets, where vitamin D status is adequate, possibly indicating increased turnover of undermineralized osteoid.
Bone Development↗
Structural and material mechanical properties of human vertebral cancellous bone.
The structural Young's modulus (i.e. that of the cancellous framework) was determined by non-destructive compressive mechanical testing in the three orthogonal axes of 48 vertebral bone cubes. In addition, the material Young's modulus (i.e. of the trabeculae themselves) was estimated using an ultrasonic technique. Apparent and true density were determined by direct physical measurements. Significant mechanical anisotropy was observed: mean structural Young's modulus varied from 165 MPa in the supero-inferior direction to 43 MPa in the lateral direction. Structural Young's modulus correlated with apparent density, with power-law regression models giving the best correlations (r2 = 0.52-0.88). Mechanical anisotropy increased as a function of decreasing apparent density (p < 0.001). Material Young's modulus was 10.0 +/- 1.3 GPa, and was negatively correlated with apparent density (p < 0.001). In multiple regression models, material Young's modulus was a significant independent predictor of structural Young's modulus only in the supero-inferior direction. The data suggest the presence of two effects in vertebral bone associated with decreasing apparent density and, by implication, bone loss in general: (a) increased mechanical anisotropy, such that there is relative conservation of stiffness in the axial direction compared with the transverse directions; and (b) increased stiffness of the trabeculae themselves.
Adult↗
Plasma osteocalcin in healthy Nigerian children and in children with calcium-deficiency rickets.
Osteocalcin is an osteoblast-specific protein believed to be associated with events occurring during bone mineralization, which has been widely used clinically as an indicator of osteoblast function. Plasma osteocalcin concentrations (pOC) were studied in 94 (59 male, 35 female) healthy and 44 (21 male, 23 female) rachitic Nigerian children, all one to five years of age. The study was aimed at establishing a reference range for healthy Nigerian children determining any changes in plasma osteocalcin levels occurring in children with calcium-deficiency rickets. In the controls, pOC levels ranged from 3-89 ng/ml, with a mean value of 23 +/- 19 ng/ml. The values were higher in girls (29 +/- 21 ng/ml) than in boys (21 +/- 18 ng/ml), though not significantly. The controls had values consistent with other published pediatric ranges from Europe and North America. In the younger rachitic children (under 3 years) the mean pOC was lower than in the controls (P = 0.04) despite the much elevated plasma levels of 1,25(OH)2D. In the controls, pOC correlated with 1,25(OH)2D (r = 0.59, P = 0.003), alkaline phosphatase (r = 0. 22, P = 0.03), and inorganic phosphate (r = 0.27, P = 0.01). These correlations were lost in the rickets group. The findings in the controls confirm the known association between plasma 1,25(OH)2D and circulating osteocalcin levels, whereas the findings in the rickets group suggest that the stimulatory effects of 1,25(OH)2D on osteocalcin may depend on other permissive factors, such as normal circulating levels of calcium and phosphate.
Alkaline Phosphatase↗
Inhibition of prostaglandin synthesis leads to a change in adherence of mouse osteoclasts from bone to periosteum.
When mouse parietal bones were incubated for 1 day in medium containing indomethacin (Ind), the number of tartrate-resistant acid phosphatase-positive osteoclasts (TRAP+OC) counted on the bone surface was drastically reduced. This reduction did not occur with calcitonin or if the endocranial membrane (periosteum) was removed prior to incubation with Ind. The aim of this work was to determine the mechanism involved. TRAP+OC were found to be increased on the endocranial membrane adjacent to the resorbing surface after Ind treatment, compared with cultures supplemented with parathyroid hormone (PTH) or prostaglandin E2 (PGE2). However, this increase accounted for only half of those lost from the bone surface. TRAP negative osteoclasts were also seen on the membrane and, to a lesser extent, on the bone. Increased TRAP specific activity could be extracted from the endocranial membranes of bones incubated with Ind compared with PGE2 controls. When bones that had been exposed to Ind were then cultured for 1 day in PGE2, an increase in TRAP+OC occurred. This increase was blocked by the removal of the endocranial membrane prior to incubation with PGE2. We conclude that when prostaglandin production ceases, TRAP+OC become less adherent to bone and more adherent to the endocranial membrane. Stimulators of bone resorption appear to reverse this process.
Acid Phosphatase↗
Osteoclasts are not the major source of interleukin-6 in mouse parietal bones.
Interleukin-6 (IL-6) is produced by bone cells and has been shown to stimulate the proliferation of osteoclast progenitors. Which cells in bone produce IL-6 is controversial. This article tests the hypothesis that tartrate-resistant acid phosphatase-positive osteoclasts (TRAP + OC) in neonatal mouse parietal bones are the major source of IL-6. Bones were preincubated with indomethacin to decrease the number of TRAP + OC and the amount of IL-6 produced. Incubation with parathyroid hormone or prostaglandin E2 increased the number of TRAP + OC and the amount of IL-6 produced. Calcitonin and 17 beta-estradiol inhibited this increase in TRAP + OC but had no effect on IL-6 production. 1,25-dihydroxy-vitamin D3 also stimulated an increase in TRAP + OC number but did not cause increased IL-6 production. Both the endocranial and ectocranial membranes of these bones produced large amounts of IL-6. TRAP activity in extracts of endocranial membranes was 14-fold that of the ectocranial membrane and, histochemically, some TRAP + cells could be detected here. However, the ectocranial membranes produced more IL-6 than the endocranial membranes. We conclude that TRAP + OC are not a major source of IL-6 in this system.
Acid Phosphatase↗
The relative contribution of disc and vertebral morphometry to the angle of kyphosis in asymptomatic subjects.
In order to investigate the relative contributions of vertebra and inter-vertebral disk to kyphosis, a series of 100 asymptomatic healthy women (age range 39-91 years) were studied to evaluate lateral dorsal appearances and possible related parameters of bone loss. Subjects underwent lateral dorsal spine radiography and single photon absorptiometry of the radius. There was a significant decrease in physical height in relation to age (P < 0.001) and this was directly related to an increasing thoracic kyphosis (P < 0.005). The angle of kyphosis was better related to the average anterior disc height (P < 0.001) than to average anterior vertebral height. The vertebral body ratio, however (anterior/posterior height), was more strongly related to angle of kyphosis than was disk ratio. The results also showed a fall in the proximal and distal radial bone mineral content with age (P < 0.001). These findings suggest that dorsal kyphosis as part of the ageing process may be as closely related to the physical integrity of the disc as to the vertebral body. Hence, therapy for age related bone mineral loss may have limited effect on a kyphotic deformity of the dorsal spine in otherwise asymptomatic patients.
Absorptiometry, Photon↗
Etiology of rickets in Nigerian children.
We studied 26 Nigerian children with active rickets (13 boys, 13 girls), aged 1 to 5 years, and compared results of biochemical studies with those of healthy control subjects. The plasma 1,25-dihydroxyvitamin D level was elevated (568 +/- 317 pmol/L) and the 25-hydroxyvitamin D level was (36 +/- 28 mol/L) in the children with rickets compared with the control subjects (369 +/- 134 nmol/L and 69 +/- 22 nmol/L, respectively). The results suggest that rickets in Nigeria is largely the result of calcium deficiency and that vitamin D deficiency and possibly end organ resistance may be contributory factors.
Calcium↗
Ultrasound bone densitometry and dual energy X-ray absorptiometry in patients with spinal cord injury: a cross-sectional study.
Bone is lost following spinal cord injury (SCI) and in the long-term may become osteopenic and liable to fracture. Two non-invasive techniques, ultrasound bone densitometry (USBD) and dual energy X-ray absorptiometry (DXA), have been applied to monitor bone changes after spinal injury. 31 SCI patients were scanned using an ultrasound bone densitometer, to give measurements of speed of sound (SOS), broadband ultrasound attenuation (BUA) and "stiffness'. The time since injury of these patients ranged between 5 weeks to 36 years with a mean of 5.87 +/- 10.21 years. Ultrasonic properties at the calcaneus of these patients were significantly lower than the healthy reference population, and a rapid decline in ultrasound properties occurred in the first 3 months. The fall continued up to 54 months but at a slower rate. The normal linear relationship between SOS and BUA was not altered by SCI. Eighteen patients had DXA measurements at the lumbar spine and the right proximal femur. Bone mineral density (BMD) at the femoral neck was significantly lower than the normal reference population (P < 0.05). SOS and "stiffness' correlated significantly with BMD at the lumbar spine, Ward's triangle, the femoral neck, the greater trochanter and the intertrochanteric site (P < 0.05). BUA correlated significantly at all these sites with the exception of the trochanter. A negative correlation was found between the ultrasonic properties at the calcaneus and BMD at the lumbar spine which is in contrast to the positive relationship in normal subjects. There was a tendency for BMD to increase at the lumbar spine after the first 12 months after injury, although this trend was not significant overall. The "stiffness' at the calcaneus and BMD at the femoral neck were lower than the reference population following 12 months since injury. These results show that bone deficit at the calcaneus occurs rapidly and to a severe degree after SCI, and that ultrasound has an important role to play in the assessment of bone status in these patients.
Absorptiometry, Photon↗
Low and conventional dose transdermal oestradiol are equally effective at preventing bone loss in spine and femur at all post-menopausal ages.
OBJECTIVES: We wished to appraise the effectiveness of hormone replacement therapy (HRT) in early (< 67 years) and late (> 67 years) post-menopausal women referred to a metabolic outpatient clinic for assessment of their bone status. Because older women often experience side-effects with conventional HRT, a low dose preparation (Estraderm 25) was also compared with conventional HRT (Estraderm 50). DESIGN AND SETTING: Since all patients were symptomatic, the investigation was open and not placebo controlled. Patients were offered HRT and told about the two dosages. If they wished to use HRT, allocation of dosage was made randomly unless there were reasons to use a specific dose. PATIENTS: One hundred and ninety-six women were studied over 1 or 2 years with 80 reaching 3 years of treatment. Patients were divided into those under 67 years and those over 67 years at the start of treatment. Each group was further divided into those taking Estraderm 25 and those taking Estraderm 50 with norethisterone if appropriate. MEASUREMENTS: Bone mineral density (BMD) was measured (DXA, Hologic) at the lumbar spine and femoral neck at 0 year (196 patients), at 1 year (169 patients), at 2 years (139 patients) and at 3 years (80 patients). Patients losing bone were expressed as those whose 3 year BMD was lower than initial or as those whose BMD at 3 years had fallen by more than twice the coefficient of variation for that site (non-responders). RESULTS: In lumbar spine, BMD increased maximally in the first year in all groups and the gain was maintained after 3 years. The change was similar whether patients were divided by age or dosage. For those on Estraderm 25, mean change after 3 years was 8.1 +/- 6.8% and on Estraderm 50, 9.0 +/- 8.3% (combined 8.7 +/- 7.8%). Only 3.9% of patients were non-responders at the lumbar spine after 3 years. At femoral neck, changes were significant at 3 years only in the Estraderm 25 > 67 years and Estraderm 50 < 67 years groups and averaged 2.3 +/- 5.4% for all patients. At the femoral neck, 10.4% of patients were non-responders after 3 years. Percentage change of BMD over 3 years at lumbar spine correlated with that at the femoral neck (r = 0.56). Percentage change of BMD at lumbar spine over 3 years correlated with menopausal age (r = 0.295). No relation was found between dosage of Estraderm/kg body weight and response of BMD at either site. CONCLUSIONS: Transdermal oestrogen is effective at preventing bone loss in the spine at all post-menopausal ages and is capable of doing this in low dosage. Prevention of bone loss at the femoral neck is less certain and the average change in BMD over 3 years was significantly lower (P < 0.001) than in the lumbar spine. Use of Estraderm 50 is not associated with a greater response of bone mass and there was no evidence of an increasing BMD response as oestradiol dosage/kg body weight increased.
Administration, Cutaneous↗
Effects of low- and conventional-dose transcutaneous HRT over 2 years on bone metabolism in younger and older postmenopausal women.
The minimum dosage of transcutaneous hormone replacement therapy (HRT) able to exert protective effects on postmenopausal bone mass, especially in older women, is uncertain. This study investigates the effects of transcutaneous HRT at two different doses of oestradiol [Estraderm 25 and 50 (E25, E50)] over 2 years in 44 postmenopausal women younger than 67 years and 27 of 67 years and older. Circulating biochemical markers of bone and connective tissue turnover, collagen type I (intact PINP, PICP) and type III (PIIINP) propeptides and type I telopeptide (ICTP), osteocalcin (OC) and alkaline phosphatase (AP) were measured. The responses of the biochemical markers in all the groups were very similar, and most of the observed changes occurred within the first year of treatment. E25 had an effect on the bone markers similar to that of E50, and there was little difference in response according to the patient's age. PINP fell markedly after 1 year in all groups to about half the pretreatment level, with a smaller drop in the second year. PICP responded more variably, and mean values were little changed. There was a slight fall at the higher dose in the younger women, and also in the older women (whose baseline level was higher) on the lower dose. The correlation between PINP and PICP was 0.52 at pretreatment and 0.84 after 2 years of treatment. PIIINP showed no changes. OC and AP both fell in all groups by the first year, but less markedly than PINP. Their response was slightly less pronounced in the older women. ICTP fell marginally in the younger women, and only after 2 years, regardless of dose. Postmenopausal serum oestradiol levels increased after HRT and were associated with decreased binding globulin (SHBG) levels in all groups. After E25 patch application individual serum oestradiol levels were variable and peaked between 13 and 36 h with a median value of 83.8 pmol L-1. Our data suggest that low-dose transcutaneous HRT restores circulating oestradiol levels in postmenopausal osteopenic women of all ages as effectively as conventional-dose HRT and is associated with decreased circulating markers of bone and connective tissue turnover.
Administration, Cutaneous↗
Discrepant blood concentrations of type I procollagen propeptides in active Paget disease of bone.
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Adult↗
The number of tartrate-resistant acid phosphatase-positive osteoclasts on neonatal mouse parietal bones is decreased when prostaglandin synthesis is inhibited and increased in response to prostaglandin E2, parathyroid hormone, and 1,25 dihydroxyvitamin D3.
The culture of parietal bones from 4-day old mice in indomethacin (Ind) for 1 day caused a large reduction in the number of tartrate-resistant acid phosphatase positive osteoclasts (TRAP + OC) relative to both control bones and to freshly isolated bones. This reduction did not occur if prostaglandin E2 (PGE2) was present. When 5-bromo-2'-deoxyuridine (BDU) was injected into 4-day old mice, newly formed TRAP + OC nuclei became labeled 1 day later; these bones were then cultured with Ind for 1 day. TRAP + OC and newly labeled TRAP+OC nuclei were commensurately decreased in number. This suggests an active down-regulation rather than merely the inhibition of new TRAP+OC formation. Incubation of bones with Ind and either PGE2, parathyroid hormone, or 1,25 dihydroxyvitamin D3 for 6 hours following a 1-day preincubation in Ind, resulted in an increase in TRAP + OC compared with Ind alone. Using BDU labeling in vitro and in vivo, we show that this increase in number of TRAP+OC is not the result of cell proliferation, but rather differentiation of postmitotic precursors.
Acid Phosphatase↗
Interleukin-6 does not mediate the stimulation by prostaglandin E2, parathyroid hormone, or 1,25 dihydroxyvitamin D3 of osteoclast differentiation and bone resorption in neonatal mouse parietal bones.
The cytokine interleukin-6 (IL-6) was produced by neonatal mouse parietal bones during a 6- or 48-hour culture period in response to prostaglandin E2 (PGE2) and bovine parathyroid hormone (PTH) 1-34 fragment but not 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]. At the same time there was an increase in tartrate-resistant, acid phosphatase-positive osteoclasts (TRAP+OC) with all three osteotropic effectors over 6 hours, and an increase in 45Ca release over 48 hours. TRAP+OC numbers on PGE2-stimulated bones were positively correlated with IL-6 concentration. Our aim was to determine if IL-6 mediated this response. Recombinant human IL-6 (rhIL-6) was added to parietal bones in culture at concentrations within the range that PGE2 or PTH would produce during incubation. However, over 6 or 48 hours, rhIL-6 did not stimulate TRAP+OC to increase in number nor did it cause an increase in calcium release over 48 hours. Adding an antibody against mouse IL-6 to bone cultures stimulated with PTH or PGE2 neutralized the resulting IL-6 bioactivity by up to 92% but did not inhibit TRAP+OC formation. We conclude that although IL-6 is produced in response to two important stimulators of bone resorption, it does not mediate osteoclast differentiation or bone resorption in this model.
Acid Phosphatase↗
Response of biochemical markers of bone turnover to pamidronate infusion in Paget's disease of bone.
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Adult↗
Pamidronate stimulates recruitment and decreases longevity of osteoclast nuclei in mice.
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Animals↗