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[A 63-year-old patient with worsening general condition, bone demineralization, hypocalcemia and excess parathyroid hormone: late manifestations of pseudohypohyperparathyroidism].

HISTORY AND CLINICAL FINDINGS: A 63-year-old man was hospitalized because of his worsening general condition and weight loss. Physical examination revealed marked thoracic kyphosis with impaired mobility of his back and restricted walking because of pain in the right hip. He also had other bone pains. INVESTIGATIONS: Serum calcium was reduced (1.60 mmol/l) and there was generalized bone demineralization. Subsequently an increased parathormone (PTH) level was noted (499.0 ng/l) as well as markedly increased activity of enzymes involved in bone metabolism, decreased renal excretion of phosphates (4.76 mmol/24 h) and multiple pathological fractures. TREATMENT AND COURSE: The listed abnormalities indicated the diagnosis of pseudohypoparathyroidism (PHP), type 1 b. After treatment had been started with vitamin D (calcitriol 2 x 0.25 micrograms/d) and calcium (calcium gluconate, 3 x 500 mg/d), the levels of calcium, PTH and enzymes in bone metabolism gradually became normal. A cataract operation had to be performed because of calcification of the lens. CONCLUSION: The level of PTH should be determined in patients with extensive bone demineralization and hypocalcaemia. If PTH is raised, PHP should be included in the differential diagnosis. Normalization of serum calcium by calcium substitution and vitamin D administration will normalize PTH and improve mineralization of the skeleton. In this way the debilitating effects of osteodystrophia cystica generalisata (OCG) (Engel von Recklinghausen syndrome) can be prevented. Also, the consequences of extraosseous calcification, such as extrapyramidal symptoms of calcification of the brain-stem ganglia can be avoided if treated in time.

Bone Demineralization, Pathologic↗

An unexpected outcome during testing of commercially available demineralized bone graft materials: how safe are the nonallograft components?

STUDY DESIGN: Radiographic and histologic analyses of commercially available bone graft materials were performed. OBJECTIVE: To compare the osteoinductive efficacy of commercially available demineralized bone matrix material. SUMMARY OF BACKGROUND DATA: The relative in vivo bone formation and toxicology of the nonallograft components the make up various commercially available demineralized bone matrix products are not known. METHODS: An in vivo bone formation model was used in 30 athymic rats. Six different bone grafting materials were tested in subcutaneous and intermuscular locations. After 4 weeks, radiographic and histologic testing of bone formation was performed. RESULTS: Eight of nine rats implanted with Grafton demineralized bone matrix products died 1 to 4 days after implantation of the bone graft material. None of the remaining 10 animals implanted with the four other grafting materials died. The experiment was modified and completed with a lower dose of bone graft material. Pathologic analysis indicated that the cause of death was hemorrhagic necrosis of the kidneys, most likely caused by a toxic effect on the glomeruli and tubules. A possible causative factor may have been the glycerol in the graft material. CONCLUSIONS: Although the volume of Grafton product per kilogram of body weight used in this study was approximately eight times the maximum volume used in humans, the authors believe that this data must be reported because this product is used substantially in clinical settings. In addition, the osteoinductive performance and relative safety of the nonallograft components in all commercially available demineralized bone grafts are not known.

Animals↗

[Bone mass evolution in patients with precocious and advanced puberty treated with LHRH analogs].

OBJECTIVE: Our aim was to know the long-term effects of treatment with LHRH analogs on the bone mass of patients with precocious or advanced puberty. PATIENTS AND METHODS: Forty-six patients (11 boys and 35 girls) received a-LHRH throughout a 2-year period. The diagnoses were precocious or advance puberty alone or associated to other pathologies. The bone mass was indirectly estimated by measuring the cortical thickness (CT) and the metacarpal diameter (BD) of the 2nd, 3rd, and 4th metacarpals, taking as a reference values the results of the longitudinal Aragonese study of the "Andrea Prader" Center. RESULTS: The CT was 1.3 SD at the beginning and decreased to 0.3 SD (p < 0.002) by the end of therapy and continuing losing to reach 0.1 SD after withdrawal. The BA decreased from 0.8 SD to 0.7 SD (p < 0.0002) and continued decreasing to reach 0.5 SD after withdrawal (p < 0.05). The BD went from -0.64 to -0.62 and to -0.9 SD (p < 0.04) after withdrawal. The longitudinal study of the same 18 cases gave similar results. No significant difference was found between sexes. CONCLUSIONS: In precocious or advance puberty, the bone age and the cortical thickness are increased. After two years of treatment with a-LHRH both decreased significantly and stabilized one year after its suppression. The BD does not change during the treatment, but continues losing value thereafter. This loss of bone mass, not well known in this pediatric situation, is probably related to estrogen deprivation and needs the attention of the physician in order to take possible preventative measures.

Adolescent↗

Reduced bone mineral density and unbalanced bone metabolism in patients with inflammatory bowel disease.

Patients with chronic inflammatory bowel diseases (IBD) are at increased risk to develop osteopenia and osteoporosis. New parameters for the assessment of bone formation and especially bone resorption have significantly improved the diagnostic procedures to characterize bone metabolism. Biochemical characterization of bone turnover in IBD patients may provide important information about the pathogenesis of osteoporosis in this patient population. A cross-sectional study was performed. One hundred forty-nine patients (77 men, 52 premenopausal, and 20 postmenopausal women) with IBD (104 with Crohn's disease [CD] and 45 with ulcerative colitis [UC]) underwent clinical, osteodensitometric, and metabolic bone assessment. Bone mineral density was determined by dual energy X-ray absorptiometry. Bone formation (bone alkaline phosphatase), bone resorption (N-terminal telopeptide of type-I collagen, free desoxypyridinoline, total pyridinoline, and desoxypyridinoline), vitamin D, and parathyroid hormone were assessed. Thirty-six percent of patients with CD and 32% with UC showed osteopenia, 15% with CD and 7% with UC showed osteoporosis. Bone resorption was significantly increased in IBD patients compared to normal controls, whereas bone formation did not show a compensatory increase. Bone formation was even more suppressed in the subset of patients currently treated with corticosteroids. Our data confirm the high prevalence of osteopenia and osteoporosis reported in IBD patients. Furthermore, we provide evidence for an increased bone resorption accompanied by low bone formation in IBD patients. This imbalance of bone metabolism is likely to be one of the reasons for increased bone loss in IBD patients.

Absorptiometry, Photon↗

Bone metabolism in orthotopic liver transplantation: a prospective study.

Bone mineral density (BMD) and mineral metabolism were assessed in 54 patients with end-stage liver disease who were evaluated for orthotopic liver transplantation (OLT) and assessed 3, 6, and 12 months after surgery in 26 patients who underwent OLT. Serum and urinary electrolyte and mineral levels, serum liver function test results, and parathyroid hormone (PTH), osteocalcin (BGP), 25-hydroxyvitamin D, and urinary hydroxyproline levels were assessed. BMD of the lumbar spine was measured at baseline and 3, 6, and 12 months after OLT. At baseline, 40.7% of patients had BMD below the fracture threshold (0.800 g/cm2). Using multiple stepwise regression analysis, we found that BMD was significantly (P < .0001) affected by age, serum creatinine level, and PTH level but not by indices of cholestasis or liver function. In the patients who underwent OLT, a 1.4% reduction (P < .006) was observed in BMD 3 months after OLT. Thereafter, BMD returned to pretransplant values. A significant increase in serum BGP was observed after 6 (P < .02) and 12 (P < . 005) months. PTH levels increased progressively 3 (P < .02), 6 (P < . 001), and 12 (P < .0001) months after OLT. This increase did not seem to be caused by cyclosporine-induced nephropathy. It was concluded that osteopenia is a major complication in hepatic cirrhosis, regardless of its causes. The increase in serum BGP levels 6 and 12 months after OLT indicates metabolic activation of osteoblasts. The increase in PTH levels after OLT warrants further investigation.

Absorptiometry, Photon↗

Spinal bone mineral loss in estrogen-replete, calcium-replete premenopausal women.

After peak bone mass in women is attained, the benefits of increased dietary calcium or supplemental calcium are uncertain. In a longitudinal, 4-year study we have investigated the effect of calcium intake on bone mineral in a group of 41 premenopausal women, aged 38-42 years at entry. Skeletal density was measured four times during the 4-year follow-up; spinal trabecular bone density (STBD) was measured by quantitative computed tomography, and midradius bone mineral density (RBMD) was measured by single photon absorptiometry. At baseline, no differences in bone density were observed among subjects in the highest and lowest quartiles of habitual dietary intake. Overall, STBD declined -0.86 +/- 0.15% per year (p < 0.001), but RBMD did not decline. Total calcium intake (dietary calcium plus supplemental calcium) did not correlate with the rate of STBD loss. Serum estradiol level did not decrease during the study, and bone loss did not correlate with the mean estradiol level. We conclude that premenopausal women in the fifth decade lose about 1% of spinal trabecular mineral yearly, in spite of a normal serum estradiol level and ample calcium intake.

Adult↗

Histomorphological confirmation of bone loss in the femoral-metaphyseal tissues of rats with skeletal unloading.

The alteration of mineral content in the femoral metaphysis of rats with skeletal unloading was investigated using a model of hindlimb suspension. Animals were fed for 4 days during the unloading. The femoral length, femoral dry weight and femoral mineral density were significantly decreased by the unloading. The calcium, phosphorus and zinc contents in the femoral metaphysis were appreciably reduced by the unloading, although, except for zinc, similar decreases were not seen in the femoral diaphysis. Moreover, the trabecular bone at the femoral metaphysis was clearly reduced by the unloading. Skeletal unloading caused a decrease in osteoid tissue in the primary and secondary spongiosa, indicating that osteoblastic bone formation may be inhibited. The present results clearly demonstrate that skeletal unloading can induce bone loss in the femoral metaphysis.

Animals↗

Kinetics of elemental content changes of bone tissue of mice during evolution under hypokinetic stress.

Concentration of 13 elements in bone tissue of mice held in tightly spaced cages for 3 wk, which caused an acute stress reaction, was determined by means of neutron activation analysis. Functionally different bone tissues of mice skeletons--the femur, accomplishing both supporting and dynamic functions; the parietal bone, being practically immovable; and the ectopic bone, newly formed under kidney capsule in the place of syngeneic bone marrow implantation--were analyzed. Similar dynamics of the elemental composition of investigated bones was found: the progressive demineralization owing to the loss of Ca, P, Mg, and Fe is accompanied by the compensatory inclusion of Sr in the bone tissues. In the ectopic bone, it was not as high. During evolution under hypokinetic stress, the microelement concentrations (Zn, Cr, Rb, Ru, Br, Co, Sb) change significantly. Results obtained form the evidence for some system character of osteoporosis at limited mobility.

Animals↗

[Bone regeneration stimulated by bone substitute materials].

Prompted by severe problems in autogeneic and allogeneic bone transplantation, intensive efforts were made to find sufficient substitutes. A main demand on these materials, especially in healing of osseous defects, is to achieve results comparable to those of auto- or allografts. These must be related to their biomechanical and particularly to their biological properties, i.e. the ability to form new bone, osseous integration and physiological remodeling. Within different trials in the tibiae of sheep we investigated bone substitutes like hydroxyapatite ceramics (HA) or partially demineralized bone matrix (pDBM) and compared them to the gold standards of autogeneic and allogeneic bone transplantation. Therefore we used two different models: the drill hole model with small size defects of 6 mm in diameter and the shaft defect model as a true-to-life defect with a 5 cm large diaphyseal defect. Evaluation was done by X-rays, histology, microradiography, fluorescent microscopy and morphometry of the small size defects. HA showed only small effects on new bone formation and works merely as an osteoconductor. However, excellent new bone formation was regularly achieved by pDBM in the small defects, whereas it was limited in the large size defects. But considering their mechanism of action, it is possible to bridge large bone defects by pDBM.

Bone Demineralization, Pathologic↗

Continuous loss of bone during chronic immobilization: a monozygotic twin study.

Acute immobilization is associated with rapid loss of bone. Prevailing opinion, based on population cross-sectional data, assumes that bone mass stabilizes thereafter. In order to address whole-body and regional skeletal mass in long-term immobilization, monozygotic twins were studied, one of each twin pair having chronic spinal cord injury (SCI) of a duration ranging from 3 to 26 years. The research design consisted of the co-twin control method using 8 pairs of identical male twins (mean +/- SD age, 40 +/- 10 years; range 25-58 years), one of each set with SCI. The twins were compared by paired t-tests for total and regional bone mineral content (BMC) and bone mineral density (BMD) measured by dual-energy X-ray absorptiometry. Linear regression analyses were performed to determine the associations of age or duration of injury with the differences between twin pairs for total and regional skeletal bone values. In the SCI twins, total-body BMC was significantly reduced (22% +/- 9%, p<0.001), with the predominant sites of reduction for BMC and BMD being the legs (42% +/- 14% 35% +/- 10%, p<0.0001), and pelvis (50% +/- 10% and 29% +/- 9%, p<0.0001). Duration of SCI, not age, was found to be linearly related to the degree of leg bone loss in SCI twins (BMC: r(2) = 0.60, p<0.05; BMD: r(2) = 0.70, p<0.01). Our findings suggest that pelvic and leg bone mass continues to decline throughout the chronic phase of immobilization in the individual with SCI, and this bone loss appears to be independent of age.

Absorptiometry, Photon↗

Bone density, vitamin D status, and disordered bone remodeling in end-stage chronic liver disease.

Hepatic osteodystrophy occurs in up to 50% of patients with chronic liver disease (CLD). The aim of this study was to determine the relative contribution of increased resorption and decreased formation to hepatic osteodystrophy by measuring biochemical markers. Twenty-seven patients with advanced CLD (14 female, 13 male) were enrolled. Bone mineral density (BMD), measured at the lumbar spine, and femoral neck, were measured by dual energy X-ray absorptiometry (DXA); bone turnover was assessed using biochemical markers of bone formation and resorption. Based on WHO criteria, osteoporosis and osteopenia were present in 41% and 18% of patients, respectively. All three markers of bone resorption (free deoxypyridinoline, pyridinoline, and hydroxyproline) were increased significantly in patients with CLD. There was a less marked change in the markers of bone formation (osteocalcin, procollagen type 1 peptide, and bone alkaline phosphatase), resulting in a negative uncoupling index in 23/27 (85%) of the patients. Only two (7%) patients had biochemical changes consistent with osteomalacia. The results suggest that increased bone resorption is the predominant cause of hepatic osteodystrophy and therapeutic strategies should be designed to suppress bone resorption, especially in preparation for liver transplantation. Bone biomarkers may be useful alternatives to bone biopsy in evaluating hepatic osteodystrophy.

Absorptiometry, Photon↗

Bone mineral density of the proximal femur after unilateral cementless total hip replacement.

It was the aim of this study to examine bone mineral density changes in the non-operated contralateral femur of patients undergoing total hip replacement. Bone density in the contralateral femur of 45 patients with an average age of 54 years was measured with the aid of the DEXA technique at one week, 3 and 6 months after total hip replacement. Within the first 3 months there was an average reduction of bone density of 3.9% (3.0%-5.9%). After a further 3 months the average difference was 2.5%.

Absorptiometry, Photon↗

Factors influencing lumbar spine bone mineral density assessment by dual-energy X-ray absorptiometry: comparison with lumbar spinal radiogram.

A study was conducted to determine the effect of radiographic findings of lumbar spinal changes upon bone mineral density measurements obtained by dual energy X-ray absorptiometry (DXA). Four hundred subjects were chosen from among 1543 community residents, aged 40-79 years. Study groups of 50 subjects each were selected by sex and 10-year age groups. This study investigated 390 of the 400 subjects who agreed to the conduct of spine bone mineral density measurement and spinal radiography. Lumbar spine radiograms were examined for findings of osteophyte formation, facet joint osteoarthritis, vertebral fracture, and aortic calcification. The prevalence of osteophyte formation, facet joint osteoarthritis, vertebral fracture, and aortic calcification increased with age in both men and women. On multiple regression analysis, bone mineral density was significantly higher (P < 0.001) in subjects with osteophyte formation or facet joint osteoarthritis than in those without these conditions, while bone mineral density was significantly lower in subjects with vertebral fracture. This study demonstrated that osteophyte formation, facet joint osteoarthritis, and vertebral fracture should be taken into account in the evaluation of bone mineral density by DXA in people in older age groups, since these conditions occur at a considerable rate in such subjects.

Absorptiometry, Photon↗

The effects of hypokinesia in primates on bone strength.

A 14 days ground based primate hypokinesia investigation was conducted to determine what changes, if any, in bone strength may be demonstrated following 2 weeks cast immobilization and at 14 davs after removal from casts. Controlled compressive loads were applied to vertebral bodies excised from control, 2 weeks immobilization and 2 weeks post immobilization Rhesus monkeys. The material properties reported herein are ultimate load, displacement to ultimate load, stiffness and energy to ultimate load. These results show a decrease in bone strength following immobilization and a still further decrease in bone strength after 14 days.

Animals↗

Bone effects of space flight: analysis by quantum concept of bone remodelling.

During the manned Skylab flights mineral losses from the calcaneum and changes in external calcium balance were in the ranges found for healthy subjects at bedrest. Calcium balance reached a nadir of -200 mg/day by two months with no change thereafter; the negative balance was due to increased urinary excretion with no change in net absorption. The total calcium loss averaged 18 g in the longest flight of 84 days; the densitiometric data suggested that about two-thirds of this came from trabecular bone and about one-third from cortical bone. These data could represent reversible bone loss due to increased birth rate of normal osteoclasts and osteoblasts and consequent increase in bone turnover and in reversible mineral deficit, or irreversible bone loss due to overactive osteoclasts and/or underactive osteoblasts. If the former explanation is correct, significant bone loss is unlikely whatever the duration of future flights, except in older persons already losing bone; if the latter explanation is correct, space flights longer than six months may lead to a significant increase in fracture risk in later life. Neither terrestrial immobilization nor unwilling animals in orbit are ideal models for the effects of space flight on human bone. To choose between reversible and irreversible mechanisms of bone loss, and to determine the effects of space flight on lifelong fracture risk, future astronauts and cosmonauts must undergo adequate histologic study of bone after in vivo tetracycline labeling.

Absorptiometry, Photon↗

Mineralization of human bone tissue under hypokinesia and physical exercise with calcium supplements.

It has been suggested that physical exercise and calcium supplements may be used to prevent demineralization of bone tissue under hypokinesia (diminished muscular activity). Thus, the aim of this study was to determine mineral content of bones of 12 physically healthy men aged 19-24 years under 90 days of hypokinesia and intensive physical exercise (PE) with calcium lactate (C) supplements. They were divided into experimental and control groups with 6 men in each. The experimental group of men were subjected to hypokinesia (HK) and intensive PE and took 650 mg C 6 times per day; the control group was placed under pure HK, i.e. without the use of any preventive measures. The mineral content of different bone tissues was measured with a densitometric X-ray method in milligrams of calcium per 1 mm3 before and after exposure to HK. The level of bone density of the examined bone tissues decreased by 7-9% and 5-7% for the control and experimental groups of men, respectively. A statistical analysis revealed that the reduction of bone mineralization was significant with P < 0.01 in both groups of men. A comparison between bone density changes in the control and experimental groups of men failed to demonstrate significant differences. It was concluded that the level of mineralization of bone tissues decreased under hypokinesia and physical exercise with calcium supplements.

Adult↗

Effect of hyperhydration on bone mineralization in physically healthy subjects after prolonged restriction of motor activity.

The objective of this investigation was to evaluate the effect of a daily intake of fluid and salt supplementation (FSS) on bone mineralization in physically healthy male volunteers after exposure to hypokinesia (decreased number of steps taken/day) over a period of 364 days. The studies were performed after exposure to 364 days of hypokinesia (HK) on 18 physically healthy male volunteers who had an average VO2max of 65 ml/kg/min and were aged between 19 and 24 years. For the simulation of the hypokinetic effect the volunteers were kept under an average of 1000 steps/day. The subjects were divided into three equal groups of 6: 6 underwent a normal ambulatory life (control group), 6 were placed under HK (hypokinetic group) and the remaining 6 were subjected to HK and consumed a daily FSS (water 26 ml/kg body wt and NaCl 0.10 mg/kg body wt) (hyperhydrated group). The density of the ulnar, radius, tibia, fibular, lumbar vertebrae and calcenous was measured. Calcium and phosphorus changes, plasma volume, blood pressure and body weight were determined. Calcium content in the examined skeletal bones decreased more in the hypokinetic subjects than in the hyperhydrated subjects. Urinary calcium and phosphorus losses were more pronounced in hypokinetic than hyperhydrated subjects. Plasma volume and body weight increased in hyperhydrated subjects, while it decreased in hypokinetic subjects. It was concluded that a daily intake of FSS may be used to neutralize bone demineralization in physically healthy subjects during prolonged restriction of motor activity.

Adult↗

Effect of fluid and salt supplements in preventing the development of "osteopenia" in hypokinetic rats.

It has been suggested that a daily intake of fluid and salt supplements may be used to prevent bone demineralization in human subjects after prolonged exposure to hypokinesia (diminished muscular activity). Thus, the objective of this investigation was to evaluate the effect of fluid and salt supplementation in the prevention of development of osteoporosis in 64 Wistar rats with an initial body weight of 339-345 g, after exposure to 90 days of hypokinesia. They divided into 4 equal groups: the first group of rats placed under ordinary vivarium conditions and served as vivarium control; the second group were also placed under ordinary vivarium conditions but received daily fluid and salt supplements; the third group were subjected to pure hypokinesia, i.e. without the use of any preventive measures; and the fourth group were submitted to hypokinesia and received daily fluid and salt supplements. For the simulation of the hypokinetic effect the experimental group of rats were kept in small, individual, wooden cages. Through the experimental period the second and fourth group of rats received 8 ml/100 g body wt water and 5 ml 100 g body wt NaCl daily. By the end of the experimental period the animals were decapitated and the spongy matter of tibia and vertebrae of the rats were examined for changes referable to osteoporosis. It was found that the daily intake of fluid and salt supplements caused an increase in the volume density of primary spongiosa of bones. It was concluded that a daily intake of fluid and salt supplements may be used to prevent the development of osteoporosis in rats subjected to prolonged motor activity restriction.

Animals↗