Osteoporosis management.
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Estrogen Replacement Therapy↗
Biomedical subjects
I R Reid
Publications and source records attributed to I R Reid.
Leukaemia inhibitory factor and bone cell function.
A bone-resorbing product of mouse spleen cells found to have differentiation-inducing activity was most probably leukaemia inhibitory factor (LIF). This revealed that LIF is a cytokine active on bone, in addition to its several other sites of action. In organ culture of newborn mouse bone, recombinant LIF promoted bone resorption by a prostaglandin-dependent process. Resorption by isolated rat osteoclasts was also promoted by LIF through an initial action on osteoblasts which was receptor-mediated. Incorporation of [3H]thymidine into DNA was increased by LIF in cells (most probably osteoblasts) of the newborn mouse bones. Osteoblasts have been shown to produce LIF, and the amount is increased by treatment with retinoic acid or TNF-alpha. LIF also acts directly on osteoblasts to inhibit plasminogen activator activity, by stimulating the synthesis of plasminogen activator inhibitor 1 mRNA and protein. The latter actions are very similar to those of TGF-beta. Again like TGF-beta, LIF was ineffective in promoting bone resorption in vitro in fetal rat long bones. These results, together with the in vivo data showing that high circulating levels of LIF in the mouse are accompanied by a substantial increase in trabecular bone mass, indicate that LIF is another cytokine with potent actions on bone and potentially important interactions with other osteotrophic factors.
Animals↗
Lateral spine densitometry is a more sensitive indicator of glucocorticoid-induced bone loss.
Osteoporosis is a common complication of glucocorticoid therapy. Bone density measurement is now commonly used in assessing which steroid-treated patients require specific interventions to reduce fracture risk. The recently developed techniques for the measurement of bone mineral density (BMD) of the vertebral body alone, by dual-energy x-ray absorptiometry (DXA) in the lateral projection, may be particularly useful in this context since steroid-induced bone loss is most marked in trabecular-rich regions like the vertebral body. This possibility has been assessed in the present study by the measurement of BMD in the lateral and anterioposterior (AP) projections in 28 women receiving chronic glucocorticoid treatment. The two BMD measurements were significantly related (r = 0.62, p < 0.001). When expressed in relation to age-appropriate normal values, lateral BMDs were lower than AP BMDs both in percentage terms (70.8 +/- 4.4 versus 90.3 +/- 2.6%, p < 0.001) and in terms of Z scores (-1.42 +/- 0.22 versus -0.91 +/- 0.24, p = 0.027). AP BMD Z scores classified 12 patients as osteopenic, whereas a further 7 were so categorized by lateral BMD Z score. It is concluded that lateral DXA scanning is a more sensitive indicator of glucocorticoid-induced osteopenia than conventional BMD measurement in the AP projection.
Absorptiometry, Photon↗
Serum blocks the osteolytic effect of cortisol in neonatal mouse calvaria.
Chronic glucocorticoid excess is associated with the development of osteoporosis and, in human subjects, there is histomorphometric evidence of increased bone resorption. Paradoxically, most in vitro studies have suggested that glucocorticoids inhibit bone resorption but recently two groups have demonstrated increased osteolysis in glucocorticoid-treated bone organ cultures. The present study reexamines the effect of cortisol on basal bone resorption in neonatal mouse calvaria with particular emphasis on the effect of serum supplementation of the media. In the absence of serum, 45Ca release was significantly stimulated by 10(-7) M cortisol (treatment/control 1.37 +/- 0.06, P less than 0.005) and by 10(-6) M cortisol (treatment/control 1.27 +/- 0.08, P less than 0.005). The stimulation of resorption by 10(-7) M hydrocortisone was progressive from 24 to 96 hours of incubation. In contrast, when calvaria were incubated in the presence of 5% serum, bone resorption was not increased by cortisol (10(-8) M-10(-6) M). In the presence of 5% charcoal-stripped, heat-inactivated serum, there was a small stimulation of 45Ca release at 10(-6) M hydrocortisone only (treatment/control 1.19 +/- 0.06, P less than 0.01). Incubation of bones with indomethacin did not modify the effect of cortisol in either the presence or absence of serum. In serum-free conditions, cortisol 10(-8) M significantly inhibited the rate of thymidine incorporation, though at higher concentrations this effect was not seen. Cortisol produced a dose-related inhibition of serum-stimulated thymidine incorporation. It is concluded that the presence of serum substantially modifies the effect of cortisol on basal bone resorption.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Bone mineral density of the proximal femur and lumbar spine in glucocorticoid-treated asthmatic patients.
The importance of the proximal femur as a site of osteoporotic fractures, the development of techniques for bone mineral density (BMD) measurement at this site and the apparent selectivity of the osteopenic effects of glucocorticoids have focused attention on the assessment of proximal femoral BMD in steroid-treated subjects. We have, therefore, measured BMD (Lunar DPX) in the lumbar spine and proximal femur of 31 asthmatic patients receiving long-term glucocorticoid therapy (mean +/- SEM dose 16 +/- 1 mg prednisone/day, mean duration 10 +/- 2 years). BMD values expressed as the percentage of normal age- and sex-appropriate mean values, after weight adjustment, were as follows: lumbar spine 80 +/- 2%, femoral neck 83 +/- 2%, Ward's triangle 78 +/- 3% and trochanter 86 +/- 2%. All these values were significantly less than control (p less than 0.0001) and the decrement in BMD was more marked in Ward's triangle than at the other two femoral sites (p less than 0.05). In all regions BMD was unrelated to dose or duration of steroid treatment. It is concluded that there are reductions in the BMD of the lumbar spine and proximal femur in glucocorticoid-treated asthmatics, probably reflecting the mixed cortical/trabecular make-up of both regions.
Adult↗
Relationships between upper-arm anthropometry and soft-tissue composition in postmenopausal women.
The value of upper-arm anthropometry as a measure of lean- and fat-tissue masses in 140 normal postmenopausal white women was assessed by studying the relationships of these measures to total and regional fat, and lean masses measured by dual-energy x-ray absorptiometry. Midarm circumference (MAC) was highly correlated with total and regional fat masses (r = 0.85-0.89, P less than 0.0001) but less so with lean-tissue masses (r = 0.26-0.34). Triceps-skinfold thickness was also correlated with fat masses (r = 0.70-0.74, P less than 0.0001) but not with lean mass (r = 0.02-0.09). The derived index, arm muscle area (AMA), was less closely correlated with fat mass than was MAC (r = 0.59-0.61), but its correlation with lean-tissue mass was comparable to that for MAC (r = 0.37-0.43). Multiple-regression analysis confirmed that the anthropometric indices were more closely correlated with fat than with lean mass. It is concluded that all these indices are useful measures of fat mass but that none, including AMA, is a specific index of lean-tissue mass in normal postmenopausal women.
Adipose Tissue↗
Normal bone mineral density following cure of Cushing's syndrome.
OBJECTIVE: Both endogenous and exogenous glucocorticoid excess are well established as causes of osteoporosis. However, there are few data describing bone mineral density in these subjects following the restoration of normal steroid levels. The present study addresses this issue. DESIGN: A cross-sectional assessment of bone mineral density in patients cured of Cushing's syndrome, and comparison of each with four normal subjects matched by age, sex, weight, menopausal status and race, was used. PATIENTS: Seventeen adults cured of Cushing's syndrome 8.6 +/- 1.6 years (mean +/- SEM) took part. MEASUREMENTS: The bone mineral density of the lumbar spine and proximal femur was measured by dual energy X-ray absorptiometry. RESULTS: Bone mineral densities, relative to control, were 100 +/- 16, 98 +/- 14, 97 +/- 19 and 98 +/- 16% (mean +/- SD), in the lumbar spine, femoral neck, Ward's triangle and trochanteric regions, respectively. There was a positive relationship between bone density and time since cure (r = 0.24-0.59, in the four regions). In contrast, bone density was significantly reduced in five subjects with active Cushing's disease when similarly matched (BMD = 87 +/- 4, 83 +/- 4, 75 +/- 6 and 82 +/- 6%, in the respective regions; 0.01 less than P less than 0.05). CONCLUSIONS: Bone density is reduced in subjects with Cushing's syndrome but not in those having undergone cure some years previously. This implies that steroid-induced osteoporosis is substantially reversible, though long-term prospective studies will be necessary to establish this definitively.
Adrenalectomy↗
Post-pregnancy osteoporosis associated with hypercalcaemia.
A lactating 31-year-old woman who developed four vertebral fractures 1-2 months after the delivery of her first child is described. She was hypercalcaemic (serum calcium up to 2.99 mmol/l), and urinary excretion of both calcium and hydroxyproline (an index of bone resorption) were markedly elevated. Serum levels of parathyroid hormone and 1,25-dihydroxyvitamin D were suppressed, but parathyroid hormone-related peptide was above normal. There was severe axial osteopenia, as assessed by dual-energy X-ray absorptiometry. The biochemical abnormalities were reversed within 2 weeks of weaning, with the exception of the parathyroid hormone-related peptide concentration, which declined more gradually. This appears to be the first description of the abnormalities in calcium metabolism and bone density from early in the course of post-pregnancy osteoporosis and it indicates that this condition is associated with high levels of osteolysis which return to normal after weaning. This rapid reversal of the metabolic abnormalities accounts for the inconclusive nature of previous descriptions of post-pregnancy osteoporosis, in which investigations were more delayed. It also emphasizes the importance of weaning in the management of women presenting with this condition. A possible aetiological role for parathyroid hormone-related peptide is discussed.
Adult↗
Determinants of total body and regional bone mineral density in normal postmenopausal women--a key role for fat mass.
In order to determine which clinical, anthropometric, dietary, and biochemical variables are independent predictors of total and regional bone mineral density (BMD) in normal postmenopausal women, a cross-sectional study of 140 normal postmenopausal women has been carried out. Subjects were white, aged 45-71 yr (mean 58 yr), and had no history of disorders or medication use likely to influence bone or calcium metabolism. Multiple regression analysis was used to derive models for total and regional BMD in terms of the other variables measured. The analysis indicated that total body BMD was positively related to fat mass (P less than 0.0001), serum estrone (P = 0.0095) and age at menopause (P = 0.0165), and negatively related to age (P less than 0.0001), 24-h urine calcium (P = 0.0002), sex hormone-binding globulin (P = 0.0003), and serum alkaline phosphatase activity (P = 0.0029) (R2 = 0.61). Similar relationships were found in the subregions of the total body scans and in the lumbar spine and proximal femur, with insulin-like growth factor-1, parity, and age at menarche also being related to BMD at at least two of these sites. Lean body mass was not an independent correlate of BMD at any site once fat mass was taken into account. Muscle strength, physical activity, alcohol intake, and dietary intakes of calcium, sodium and protein did not emerge as significant predictors of BMD in this homogeneous group of postmenopausal women. We conclude that total body fat is the most significant predictor of BMD throughout the skeleton and this relationship is not explicable in terms of either estrone production in fat tissue or the dependence of skeletal load-bearing on fat mass. The mechanism underlying this relationship is an important question to be addressed in bone biology.
Aged↗
Fat mass is an important determinant of whole body bone density in premenopausal women but not in men.
We recently reported that total body fat mass is the principal determinant of bone density in normal postmenopausal women. We have now reexamined the relationships among these variables and lean mass in 68 healthy premenopausal women and 51 men. Areal bone density (BMD), fat mass, and lean mass were measured in total body scans by dual-energy, x-ray absorptiometry. In women, BMD was correlated with weight (r = 0.69), fat mass (r = 0.60), and lean mass (r = 0.55). In men, the respective correlations were 0.56, 0.26 (NS), and 0.51. Multiple regression analysis confirmed a codependence of female BMD on fat and lean masses, whereas male BMD was related only to lean mass. Because BMD is an areal not volumetric density, it is dependent on body size. The analysis was therefore repeated using BMD/height as an index of "true" density. Correlations with fat mass were little changed but those with lean mass were reduced (women) or eliminated (men). By multiple regression, female BMD/height was related to fat mass alone, and in men there was a borderline effect of fat (P = 0.05) but none of lean mass. As a second method to exclude a scale artifact, fat mass was expressed as percent body weight. It was related to BMD (r = 0.48) only in women. It is concluded that bone density is closely related to fat mass in premenopausal women, but less so in men. In both sexes, apparent relationships between BMD and lean mass are artifacts attributable to the use of areal density (which is dependent on body size) as a surrogate for volumetric density. The mechanism of this fat-bone density relationship is an important question to be addressed in bone biology.
Adipose Tissue↗
Bone density in women receiving depot medroxyprogesterone acetate for contraception.
OBJECTIVE: To determine if the use of the injectable contraceptive depot medroxyprogesterone (DMPA), which reduces ovarian oestrogen production, is associated with changes in bone density. DESIGN: Population study. DMPA users were compared with two control groups selected from larger population studies and individually matched for several putative determinants of bone density (age, race, body mass index, and years of oestrogen deficiency). Controls and DMPA users were matched without prior knowledge of their bone density measurements. SETTING: Teaching hospital and community family planning clinics. SUBJECTS: 30 current users of DMPA with a minimum five years' previous use, 30 premenopausal controls, and 30 postmenopausal controls. MAIN OUTCOME MEASURE: Lumbar spine and femoral neck bone mineral density assessed by dual energy x ray absorptiometry. RESULTS: Compared with premenopausal controls matched for age, race, and body mass index, DMPA users had significantly reduced bone density in the lumbar spine (mean difference 7.5% (95% confidence interval 1.9% to 13.1%), p = 0.002) and in the femoral neck (6.6%, (0.8% to 12.3%), p = 0.007). Compared with postmenopausal controls matched for body mass index and duration of oestrogen deficiency, DMPA users had greater bone density in the lumbar spine (8.9% (4.3% to 13.5%), p = 0.001), but in the femoral neck the difference in bone density was less (4.0% (-0.4% to 8.5%), p = 0.04). CONCLUSIONS: Women using DMPA have bone density values intermediate between those of normal premenopausal and postmenopausal controls; thus, the degree of oestrogen deficiency induced by DMPA may have an adverse effect on bone density.
Absorptiometry, Photon↗
Regulation of osteoblast proliferation by leukemia inhibitory factor.
We recently showed that leukemia inhibitory factor (LIF) stimulates 45Ca release from neonatal mouse calvariae in vitro and that it increases DNA and protein synthesis in this model. To elucidate further the actions of LIF on bone we now report the effects of this cytokine on DNA synthesis and cell proliferation in isolated fetal rat osteoblasts and in the osteogenic sarcoma cell line, UMR-106. In both actively growing and growth-arrested rat osteoblasts, LIF stimulated [3H]thymidine incorporation in a dose-dependent manner. The increase in DNA synthesis was time dependent, was associated with an increase in the number of osteoblasts, and was not blocked by indomethacin. LIF-treated cells showed reduced [3H]thymidine incorporation in comparison with control, as they approached confluence, possibly because of the increased cell density in the LIF-treated cultures. In UMR-106 cells, treatment with LIF inhibited [3H]thymidine incorporation in both actively growing and growth-arrested cultures. The effect was dose dependent and sustained with time. There was a corresponding decrease in cell numbers. It is concluded that although LIF causes an early stimulation of proliferation in isolated osteoblasts, it has opposing effects on UMR-106 cells. It is not possible to determine which of these effects is more relevant to the actions of LIF in vivo. The demonstration of a LIF effect on both these cell types, however, provides further evidence that this cytokine acts directly on osteoblasts.
Animals↗
Effects of leukemia inhibitory factor on bone resorption and DNA synthesis in neonatal mouse calvaria.
Leukemia inhibitory factor (LIF) is a recently characterized cytokine which has been shown to regulate cell growth and differentiation in a variety of tissues. We have shown that LIF stimulates bone resorption and DNA synthesis in bone organ culture and, in vivo, LIF has been shown to have marked effects on bone remodeling. The present study examines further the dose-response, time course and mechanisms of action of LIF in neonatal mouse calvaria. 45Ca release was significantly increased by LIF at concentrations of 10-5,000 U/ml, and its stimulation of bone resorption increased with time from 24 to 96 hours. These concentrations of LIF also increased DNA synthesis at 24 hours. At 72 hours, low concentrations of LIF produced less marked stimulation of [3H]-thymidine incorporation, and 5,000 u/ml actually inhibited DNA synthesis at both this time point and at 96 hours. The effect of LIF on 45Ca release was partially inhibited when DNA synthesis was blocked by hydroxyurea (50 microM). The resorptive effect of supramaximal concentrations of LIF was not additive to that of parathyroid hormone, 1,25-dihydroxyvitamin D3, prostaglandin E2, or transforming growth factor-beta. Although LIF-stimulated resorption is at least partially dependent on DNA synthesis, these results suggest that there are different mechanisms involved in mediating LIF's effects on bone resorption and DNA synthesis. The demonstration of effects of LIF at low concentrations indicates that this cytokine may be involved in the physiological regulation of bone metabolism in vivo.
Animals↗
X-linked hypophosphatemia: skeletal mass in adults assessed by histomorphometry, computed tomography, and absorptiometry.
PURPOSE AND PATIENTS AND METHODS: X-linked hypophosphatemia (XLH) is the most common inherited form of rickets, yet its influence on skeletal mass in adulthood is controversial and incompletely characterized. Accordingly, we measured bone mass at several skeletal sites using histomorphometric and radiographic techniques in 19 adults (four men) with XLH (age range 20 to 66 years). Most subjects had not received medical therapy for XLH since puberty. RESULTS: Eight of 14 subjects who underwent transiliac bone biopsy had an elevated cancellous bone volume (osteoid and calcified bone), and the group's mean value was supranormal (p less than 0.01). Mineralized bone volume, however, was above normal in only three subjects (NS). Another measure of trabecular bone density, vertebral mineral density by computed tomography, was elevated in three of 13 subjects, and the mean value of the group was increased (p = 0.05). Integral spine bone mineral density (BMD) assessed by dual photon absorptiometry (DPA) was elevated in six of 16 subjects, and the mean was also above normal (p less than 0.01). However, total body calcium, total body BMD (both by DPA), and forearm bone mineral content assessed by single photon absorptiometry (predominantly cortical bone) were normal in almost all subjects, as were the group means for these parameters. Mean regional BMD (by DPA) was below normal in the upper and lower limbs (p less than 0.001) and above normal in the spine (p less than 0.005) and ribs (p less than 0.01). There was no relationship between these indices of bone mass and either biochemical or clinical parameters of disease severity, although men tended to have higher z-scores for axial bone density than premenopausal women whose values, in turn, tended to be higher than those in postmenopausal women (NS). CONCLUSION: We conclude that axial bone mass tends to be increased in adults with XLH, sometimes dramatically so, and this is only partially attributable to hyperosteoidosis. Peripheral bone mass, however, tends to be diminished. Despite these group trends, most adults with untreated XLH have normal indices of bone mass as assessed by a variety of techniques at the commonly used measurement sites. These findings suggest that "osteoporotic" fractures are unlikely to develop as a late complication of XLH in adults.
Absorptiometry, Photon↗
The influence of osteophytes and aortic calcification on spinal mineral density in postmenopausal women.
The assessment of vertebral bone mineral density (BMD) in the anterio-posterior projection has become widely used in the management and prevention of osteoporosis. Recently, it has been demonstrated that the presence of spinal osteophytes has a major impact on measured BMD in men, thus casting doubt on the value of these BMD measurements. We have assessed the impact of osteophytic and aortic calcification on spinal and femoral BMD measurements in 130 normal postmenopausal women, aged 45-71 yr. Lateral lumbar spine radiographs were obtained in all subjects and graded separately (0-3) for osteophytes and aortic calcification. Both forms of calcification increased with age, and BMD of all sites was correlated positively with body weight and negatively with age. The correlation coefficients between BMD and calcification scores were nonsignificant. Multiple regression analysis, including weight, age, and calcification scores, demonstrated a small but significant effect of osteophyte score on lumbar BMD (partial r2 = 0.04; P = 0.012) and a similar trend for Ward's triangle and the trochanteric region (partial r2 = 0.02; P less than 0.06). The aortic calcification score remained nonsignificant. It is concluded that the influence of spinal osteophytes on lumbar BMD in postmenopausal women is substantially less than that in men and is, therefore, unlikely to interfere with BMD estimation in most subjects. The relationship between proximal femoral BMD and osteophyte score suggests a real relationship between skeletal density and degenerative joint disease, as has been demonstrated by others.
Aged↗
Hyperoxaluria in phosphate-treated hypophosphataemic rickets.
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Adult↗
Hypercalcaemia associated with viral hepatitis.
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Acute Disease↗
Prevention of glucocorticoid-induced osteoporosis.
There is increasing evidence that pamidronate and related compounds are effective in the prevention and treatment of osteoporosis. It is therefore of relevance to document the time course and mechanism of bisphosphonate action in this condition. To this end, the present study describes the biochemical responses to prophylactic treatment with oral pamidronate (APD, 150 mg/day) in 16 glucocorticoid-treated patients and contrasts them with those in 19 steroid-treated control subjects. Measurements were made over a period of 12 months. The treated patients showed a fall in urine hydroxyproline excretion at 6 weeks associated with a reduction in serum ionized calcium concentration, a rise in serum 1,25-(OH)2D3, and a nonsignificant rise in serum bone gla protein (BGP). In contrast to BGP, serum alkaline phosphatase activity declined at 6 weeks, falling further at 3 months. Between 3 and 12 months, BGP levels paralleled those of alkaline phosphatase and hydroxyproline, all these being significantly below their initial values, and the other parameters returned to baseline. There was a gradual increase in plasma phosphate concentrations in the treated group over the 12 month period. It is concluded that pamidronate produces an acute and sustained inhibition of bone resorption followed by a more gradual reduction in bone formation. This transient dissociation results in a reduction in serum calcium, leading to a rise in serum 1,25-(OH)2D3, which in turn stimulates BGP production. Thereafter, indices of bone turnover remain subnormal but serum calcium and 1,25-(OH)2D3 return to baseline.
Adult↗