The gene responsible for familial hypocalciuric hypercalcemia maps to chromosome 3q in four unrelated families.

Familial hypocalciuric hypercalcemia (FHH) is an autosomal dominant syndrome of unknown aetiology characterized by lifelong elevation in serum calcium concentration and low urinary calcium excretion. These features suggest that the causal gene is important for maintenance of extracellular calcium homeostasis by the parathyroid gland and kidney. To identify the chromosomal location of FHH gene(s), we clinically evaluated 114 individuals in four unrelated affected families and performed linkage analyses. The disease gene mapped to the long arm of chromosome 3 in each family (combined maximum multipoint lod score = 20.67). We suggest that this is the predominant FHH locus and anticipate that identification of the FHH gene will improve our understanding of the molecular basis for physiologic and pathologic regulation of calcium.

Bone mineral density in normal Swedish women.

We examined 429 women, aged 20-80 years, randomly selected from the population register to establish normal values for bone mineral density (BMD) in Swedish women. BMD of the spine and hip was measured by dual-energy X-ray absorptiometry (DEXA; Hologic QDR 1000) and in the forearm by single photon absorptiometry (SPA; Molsgaard ND-1100). The recalled age of menarche was negatively correlated to BMD at all ages. There was no significant change in BMD from 20-49 years at any site except a slight decline at Ward's triangle. Bone loss was rapid at all sites during the first decade after menopause. Thereafter, BMD declined slowly in the trochanter and total hip but more rapidly in the forearm, femoral neck, and Ward's triangle. BMD in the spine even increased in the eighth decade probably due to osteoarthritis. The average change in forearm BMD during the 15 perimenopausal years comprising mean age for menopause +/- 2 SD (43-57 years) was -0.4% per year in premenopausal females and -1.6% per year in postmenopausal females. The corresponding annual percental change was, for the spine, +0.2 and -1.7; neck, -0.7 and -1.7; trochanter, +0.5 and -1.5; and Ward's triangle, -0.1% and -2.2%, respectively. Our normal values for lumbar spine BMD prior to menopause did not differ from published values or the manufacturer's normal values; however, our spine BMD values for the first decade after menopause were significantly lower (approximately 10%) than in other studies. Our femoral neck BMD values for younger women were, like those of several other groups, significantly lower than the manufacturer's normal values, but our sample of young women in this study was small. The prevalence of osteoporosis, if defined as t score < -2.5 is highly dependent on the sampling of the reference population of young adult women, and also on the choice of skeletal site. Further studies on bone mineral density in healthy young adult women are needed.

A dose titration model for recombinant GH substitution aiming at normal plasma concentrations of IGF-I in hypopituitary adults.

OBJECTIVE: To evaluate a dose titration model for recombinant human GH substitution in adult patients with GH deficiency, aiming at normal plasma levels of IGF-I. DESIGN AND METHODS: Eighteen patients participated and a start dose of 0.17 mg GH/day was used except by two men who started with 0.33 mg/day. To demonstrate a clear GH effect the patients were first titrated, with steps of 0.17 mg GH/day every 6-8 weeks, to IGF-I levels in the upper range of age-adjusted reference values. The GH dose was then reduced 1 dose step and kept for a further 6 months. For comparison we investigated 17 healthy control subjects. RESULTS: Plasma IGF-I was increased after 2 weeks on the start dose and did not increase further for up to 8 weeks. Women had significantly lower GH sensitivity than men measured as net increment of IGF-I on the start dose of GH. GH sensitivity was not changed by age. The plasma IGF-I levels increased from 76.3+/-47.0 (s.d.) to 237+/-97 microg/l at the end of the study (P<0.001), and similar IGF-I levels were obtained in both sexes. The maintenance median GH dose was 0.33 mg/day in males and 0.83 mg/day in females (P=0.017). The GH dose correlated negatively with age in both sexes. Body weight, very low density triglycerides, lipoprotein(a) (Lp(a)), and fasting insulin increased, whereas insulin sensitivity index (QUICKI) decreased significantly. In comparison with the controls, the patients had lower fasting blood glucose, fasting insulin and Lp(a) levels at baseline, but these differences disappeared after GH substitution. The two groups had equal insulin sensitivity (QUICKI), but 2 h oral glucose tolerance test values of blood glucose and insulin were significantly higher in the patients at the end of the study. CONCLUSIONS: In conclusion our data suggest that the starting dose of GH substitution and the dose titration steps should be individualised according to GH sensitivity (gender) and the IGF-I level aimed for (age). The reduced insulin sensitivity induced by GH substitution could be viewed as a normalisation if compared with control subjects.

Increased hip-fracture incidence in the county of Ostergötland, Sweden, 1940-1986, with forecasts up to the year 2000: an epidemiological study.

The incidence of hip fractures in the county of Ostergötland in Sweden has increased dramatically from 1940 to 1986, mainly due to an increase in age-specific incidence of trochanteric fractures. The increase is most pronounced in people over 80 but is present even in age groups down to 50 years. If the age-specific incidence rates continue to increase, and the population of the elderly grows in accordance with the forecast, there will be 70% more hip fractures in the year 2000 than in 1985.

Bone mineral density in diagnosis of osteoporosis: reference population, definition of peak bone mass, and measured site determine prevalence.

A population-based study was performed in order to compare different definitions of peak bone mass, and to apply the corresponding T-scores for different skeletal sites to a cohort of 70-yr-old women for studying the prevalence of osteoporosis. Bone mineral density (BMD) of the hip, lumbar spine, and forearm was measured by dual X-ray absorptiometry (Hologic 4500) in 296 women ages 16-31 yr and 210 women age 70 yr. Peak bone mass occurred in women in their early 20s at the proximal femur and at 28 and 31 yr at the spine and forearm, respectively. BMD cutoff levels were compared to machine-specific cutoff values for the different sites. When applied to our cohort of 70-yr-old women, the prevalence of osteoporosis at the total hip was 9-25%, depending on which peak bone mass the T-score of -2.5 was based. The prevalence in the spine was 28-33% and in the forearm 45-67%. Osteoporosis in at least one of the three measured sites was documented in 49-72% of the population sample. Our results show that the use of T-score to define osteoporosis results in a highly different prevalence rate in a given population depending on the reference population and the skeletal sites chosen for measurement.

Delayed hypersensitivity response and vitamin D deficiency.

The relationship between delayed hypersensitivity and serum levels of 25-hydroxyvitamin D were examined in sixty-three elderly people. After intracutaneous injection of five recall antigens (Candida, mumps, PPD, tricophyton and varidase) nineteen subjects showed no response (anergy), seven showed only a weak reaction (relative anergy), and thirty-seven a normal reaction. In the anergic group mean serum level of 25-hydroxyvitamin D was significantly lower than in the group with normal immunoreactivity. Five subjects with anergy and serum 25-hydroxyvitamin D below 20 nmol/l were treated with oral vitamin D or UV irradiation for two to three months, after which both the serum 25-hydroxyvitamin D levels and the delayed hypersensitivity were normalized. In a non-treated group anergy persisted in seven out of nine patients in a second skin test. We conclude that anergy in the delayed hypersensitivity skin test in humans may in some cases be due to vitamin D deficiency.

Periodontal conditions in 70-year-old women with osteoporosis.

The aim of the present study was to examine the periodontal conditions in an age cohort of 70-year-old women and compare an osteoporosis group with a control group with normal bone mineral density. 210 women 70 years old and randomly sampled from the population register of the community of Linköping were examined. Bone mineral density (BMD) of the hip was measured by dual energy X-ray absorptiometry. 19 women were diagnosed with osteoporosis (BMD below 0.640 g/cm2 in total hip). 15 of them accepted to participate in the study. As a control group 21 women with normal bone mineral density (BMD exceeding 0.881 g/cm2) were randomly selected from the initial population. The clinical examination included registration of the number of remaining teeth, dental plaque and periodontal conditions. The radiographic examination included a dental panorama and vertical bite-wing radiographs. The subjects also answered a questionnaire about their general health, age at menopause, concurrent medication, smoking and oral hygiene habits. The results from this study showed no statistically significant differences in gingival bleeding, probing pocket depths, gingival recession and marginal bone level between the women with osteoporosis and the women with normal bone mineral density. In conclusion, the present randomly selected and controlled study of osteoporotic and non-osteoporotic women, showed no statistically significant differences in periodontal conditions or marginal bone level. As periodontitis as well as osteoporosis are associated with age, our study of a well-defined age cohort is of interest, but the results should be interpreted with caution since the compared groups are small.

Bone mass in elderly patients with Parkinson's disease.

OBJECTIVE: The objective of the present study was to find risk factors for low bone mineral density (BMD) in patients with Parkinson's disease (PD). MATERIAL AND METHODS: Twenty-six PD patients and 26 age-and sex-matched healthy controls were assessed twice within a 1-year period. PD symptoms, body weight, body fat mass, BMD, physical activity, smoking and serum concentrations of several laboratory analyses were investigated. RESULTS: BMD in different locations was lower in PD patients compared with their controls and decreased during the investigated year. BMD was lower in PD patients with low body weight. BMD Z-score of trochanter in the PD group was directly correlated to the degree of physical activity and indirectly to the length of recumbent rest. Total body BMD Z-score in the PD group was directly correlated to the degree of rigidity. Serum 25-hydroxy-vitamin D was slightly lower in PD patients. CONCLUSION: Low body weight and low physical activity were risk factors for low BMD in PD, while rigidity seemed to be protective.

Does L-dopa treatment contribute to reduction in body weight in elderly patients with Parkinson's disease?

OBJECTIVE: Many patients with Parkinson's disease (PD) lose weight also early during the disease. The objective of the study was to investigate possible causative factors for this loss. MATERIALS AND METHODS: In this report, 28 PD patients and 28 age- and sex-matched controls were repeatedly assessed with the focus on body weight, body fat mass, dysphagia, olfaction, physical activity, PD symptomatology and drug treatment. RESULTS: Weight loss was seen in PD patients both before and during L-dopa treatment. CONCLUSION: The underlying disease could play a role, but our results also suggest that L-dopa per se could contribute to the weight loss.

Effect of calcium intake vs. other life-style factors on bone mass.

Several life-style factors are known to or have been suggested to interact with calcium metabolism and bone turnover. Immobilization or a sedentary life-style may result in substantial bone loss, and physical exercise may increase bone mass, to different extents in different parts of the skeleton. Excessive training and/or slimming may lead to amenorrhoea, which is in turn complicated by rapid bone loss. While calcium supplementation probably cannot override the negative calcium balance induced by immobilization or amenorrhoea, the calcium requirement may be enhanced during recovery from these states. A high body mass index may to some extent protect against bone loss, particularly in post-menopausal women. Tobacco smoking and high alcohol consumption are probably detrimental to bone mass. Insufficient exposure to daylight and/or insufficient vitamin D intake occur mainly in infants and elderly people, and may impair calcium balance and cause rickets, osteomalacia or osteoporosis. Whether high intake of caffeine, protein, phosphate or fibre is detrimental to the bone mass has not yet been clarified. In many populations smoking and consumption of alcohol or caffeine are negatively correlated with calcium intake, and this exemplifies a source of confounding factors. Increased attention would be paid to important life-style factors during investigations of calcium requirements in different sex and age categories.

Serum concentrations of 25-hydroxyvitamin D and vitamin D-binding protein in elderly people. Effects of institutionalization, protein-energy malnutrition and inflammation.

Serum concentrations of 25-hydroxyvitamin D (25-OH-D) and vitamin D-binding protein (DBP) were measured in institutionalized and non-institutionalized elderly people. The institutionalized subjects were found to have low serum 25-OH-D in confirmation of other studies, but their serum DBP levels were similar to those found in non-institutionalized elderly subjects. Serum DBP concentrations were slightly higher in elderly females than in males, while no age dependence was found for DBP. Elderly people with protein-energy malnutrition who lived in their own homes had slightly reduced serum DBP and 25-OH-D levels. Elderly subjects with infections or other diseases causing acute inflammation, as indicated by an elevated serum haptoglobin and C-reactive protein, had normal levels of DBP.

Serum levels of 25-hydroxyvitamin D in adults and elderly humans after a prophylactic dose of vitamin D2.

Vitamin D2 was administered orally as a single dose (2 mg) to 19 elderly subjects and 17 young adults. The maximum elevation of serum 25-hydroxyvitamin D was significantly greater in young than in elderly subjects. To evaluate intestinal absorption we also measured serum levels of vitamin D2 5 h after the given dose. A vitamin A absorption test was also performed simultaneously. Small differences between young and old subjects were seen with respect to serum vitamin D2 or vitamin A increments. In both groups the serum level of 25-hydroxyvitamin D was still elevated above initial level 60 days after a dose was given. No side effects, nor any change in serum calcium ion activity were noted during this period. These results speak in favour of the use of intermittent large doses of vitamin D2 as a prophylaxis against vitamin D deficiency in the elderly.

Vitamin D deficiency in welfare institutions for the aged.

Serum concentrations of 25-OH-D in a group of 47 elderly people (70--94 years old) living in homes for the aged were lower than those in a matched control group living in their homes. No differences between the groups were noted in serum ionized calcium, alkaline phosphatase, inorganic phosphate, magnesium or parathyroid hormone. The low serum concentration of 25-OH-D may be due to less outdoor activities and/or a smaller dietary vitamin D intake in the institutionalized group. The importance of preserving an adequate vitamin D status in geriatric patients is emphasized.

Hyperparathyroidism and long-term lithium therapy--a cross-sectional study and the effect of lithium withdrawal.

OBJECTIVES: To assess in patients with long-term lithium treatment the incidence and prevalence of hypercalcaemia and hyperparathyroidism, and to evaluate the relationship between parathyroid function and renal function: also, to examine the effect of treatment discontinuation. DESIGN: Part 1. An epidemiological cross-sectional study covering defined catchment areas. Part 2. A lithium withdrawal study in a subgroup of the patients who were examined after a mean of 8.5 (4-16) weeks off lithium. Comparisons were made with a group of psychiatric non-lithium patients matched for sex and age. SETTING: Outpatient treatment at nine psychiatric departments in southern Sweden. SUBJECTS: Inclusion criterion was 15 years or more on lithium. Excluded from Part 2 were patients with a high risk of relapse. Out of 215 identified patients. 142 (66%) entered and completed Part 1, while 13 of the latter entered and completed Part 2. RESULTS: The point prevalence of persistent hypercalcaemia was 3.6% and of surgically verified hyperparathyroidism 2.7%. The observed incidence of hyperparathyroidism over 19 years was 6.3%. It was significantly higher than expected in females. In the withdrawal group serum calcium was significantly increased compared to controls, and did not change during 8.5 weeks without lithium. Isostenuria was significantly more common among patients with than without hyperparathyroidism. CONCLUSIONS: The point prevalence, and the 19-year incidence of hyperparathyroidism, were increased. The point prevalence of hypercalcaemia was also increased, and not reversible during 8.5 weeks off lithium. The findings support the hypothesis of a causal relationship between lithium treatment and hyperparathyroidism. Hypercalcaemia and hyperparathyroidism are sometimes aetiologically related to reduced renal function in long-term lithium patients.

Reversal of osteopenia with diet in adult coeliac disease.

To evaluate the effects of a gluten free diet on bone mineral density in untreated adult patients with coeliac disease, 63 patients (17-79 years, 35 women) were examined at diagnosis and after one year taking a gluten free diet. Bone mineral density was measured in the forearm using single photo absorptiometry and in the lumbar spine, femoral neck, and trochanter using dual energy x ray absorptiometry. The values for each patient were compared with those of 25 healthy controls, matched for sex, age, and menopausal state. Before being given a gluten free diet bone mineral density in the total group was reduced at all sites (p < 0.001). Age adjusted bone mineral density was inversely correlated with age. During the first year taking a gluten free diet bone mineral density increased at all sites (p < 0.01). This was seen in patients of all ages and in patients who were without symptoms of malabsorption (weight loss or diarrhoea) before treatment. Low bone mineral density in patients with untreated coeliac disease increases rapidly when treatment with a gluten free diet is followed. These findings emphasise the importance of early diagnosis and treatment in all patients with coeliac disease.

Trivariate evaluation of a thyroid hormone panel in clinical practice compared with multiple univariate evaluation.

The results from 510 consecutive routine determinations of free thyroxine index, free triiodothyronine index and thyrotropin were evaluated using both a trivariate reference region and the combined three univariate reference intervals. The results from 109 patients were discordant when evaluated by both the trivariate and the triple univariate reference regions. In 108 of these subjects the hormone results were found to be abnormal by the triple univariate evaluation method but normal when the trivariate reference region was used. The latter evaluation was in accordance with the clinical findings of the patients, who were euthyroid as evaluated from the 105 medical records we could trace. In one subject, clinically euthyroid, trivariate evaluation misclassified the patient as abnormal in contrast to the classical univariate evaluation. We conclude that the trivariate evaluation method was in better agreement with the clinical diagnosis of the patients and should be used in the routine evaluation of trivariate data in order to diminish the number of false abnormal results.

Three years' follow-up of bone density in adult coeliac disease: significance of secondary hyperparathyroidism.

BACKGROUND: The mechanisms of disturbances in bone mineral density (BMD) in coeliac disease are not completely understood. The aim of this prospective study was to investigate the possible significance of secondary hyperparathyroidism (SHPT) with regard to BMD in patients with untreated coeliac disease. METHODS: One hundred and five adult patients with untreated coeliac disease were examined for BMD and serum parathyroid hormone (PTH) concentration. BMD in the hip, lumbar spine, and forearm were examined up to 3 years after the introduction of a gluten-free diet. RESULTS: SHPT was found in 27% (28 of 105) of the patients. In patients with SHPT serum levels of 25-hydroxy-vitamin D were lower and those of alkaline phosphatase higher than in patients with normal PTH, but ionized serum calcium did not differ between the two groups. BMD was more severely reduced in patients with SHPT. Although the BMD increment was more rapid in patients with than in those without SPTH, only in the latter group did mean BMD became normal after 1-3 years on a gluten-free diet (GFD). After 3 years on a GFD more than half of the patients with initial SHPT still had low BMD in both the hip and the forearm. Furthermore, in patients with SHPT the intestinal mucosa more often remained atrophic at the 1-year follow-up, despite good compliance with the diet. CONCLUSIONS: Low BMD in patients with untreated coeliac disease is often associated with SHPT. After 3 years on a GFD the BMD remains low only in patients with initial SHPT. We therefore suggest that PTH should be measured when the diagnosis of coeliac disease is made, as an indicator of more serious intestinal disorder and complicating bone disease.