Familial benign hypercalcemia (FBH) and neonatal hyperparathyroidism (NHPT) are disorders of calcium homeostasis that are associated with missense mutations of the calcium-sensing receptor (CaR). We have undertaken studies to characterize such CaR mutations in FBH and NHPT and to explore methods for their more rapid detection. Nine unrelated kindreds (39 affected, 32 unaffected members) with FBH and three unrelated children with sporadic NHPT were investigated for mutations in the 3,234-bp coding region of the CaR gene by DNA sequencing. Six novel heterozygous (one nonsense and five missense) mutations were identified in six of the nine FBH kindreds, and two de novo heterozygous missense mutations and one homozygous frame-shift mutation were identified in the three children with NHPT. Our results expand the phenotypes associated with CaR mutations to include sporadic NHPT. Single-stranded conformational polymorphism analysis was found to be a sensitive and specific mutational screening method that detected > 85% of these CaR gene mutations. The single-stranded conformational polymorphism identification of CaR mutations may help in the distinction of FBH from mild primary hyperparathyroidism which can be clinically difficult. Thus, the results of our study will help to supplement the clinical evaluation of some hypercalcemic patients and to elucidate further the structure-function relationships of the CaR.

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Calcium-sensing receptor mutations in familial benign hypercalcemia and neonatal hyperparathyroidism.

Physical exercise induces adaptations in metabolism considered beneficial for health. Athletic performance is linked to adaptations, training, and correct nutrition in individuals with genetic traits that can facilitate such adaptations. Intense and continuous exercise, training, and competitions, however, can induce changes in the serum concentrations of numerous laboratory parameters. When these modifications, especially elevated laboratory levels, result outside the reference range, further examinations are ordered or participation in training and competition is discontinued or sports practice loses its appeal. In order to correctly interpret commonly used laboratory data, laboratory professionals and sport physicians need to know the behavior of laboratory parameters during and after practice and competition. We reviewed the literature on liver, kidney, muscle, heart, energy, and bone parameters in athletes with a view to increase the knowledge about clinical chemistry applied to sport and to stimulate studies in this field. In liver metabolism, the interpretation of serum aminotransferases concentration in athletes should consider the release of aspartate aminotransferase (AST) from muscle and of alanine aminotransferase (ALT) mainly from the liver, when bilirubin can be elevated because of continuous hemolysis, which is typical of exercise. Muscle metabolism parameters such as creatine kinase (CK) are typically increased after exercise. This parameter can be used to interpret the physiological release of CK from muscle, its altered release due to rhabdomyolysis, or incomplete recovery due to overreaching or trauma. Cardiac markers are released during exercise, and especially endurance training. Increases in these markers should not simply be interpreted as a signal of cardiac damage or wall stress but rather as a sign of regulation of myocardial adaptation. Renal function can be followed in athletes by measuring serum creatinine concentration, but it should be interpreted considering the athlete's body-mass index (BMI) and phase of the competitive season; use of cystatin C could be a reliable alternative to creatinine. Exercise and training induce adaptations in glucose metabolism which improve glucose utilization in athletes and are beneficial for reducing insulin insensitivity in nonathletes. Glucose metabolism differs slightly for different sports disciplines, as revealed in laboratory levels. Sport activities induce a blood lipid profile superior to that of sedentary subjects. There are few reports for a definitive conclusion, however. The differences between athletes and sedentary subjects are mainly due to high-density lipoprotein cholesterol (HDLC) concentrations in physically active individuals, although some differences among sport disciplines exist. The effect of sports on serum and urinary markers for bone metabolism is not univocal; further studies are needed to establish the real and effective influence of sport on bone turnover and especially to establish its beneficial effect.

Metabolic markers in sports medicine.

Bone mass and bone turnover in power athletes, endurance athletes, and controls: a 12-month longitudinal study

To examine the interactions between acute exercise and GH on markers of bone and collagen turnover and to assess the potential for detecting GH abuse in athletes using these markers, we studied 17 aerobically trained males (age, 26.9+/-1.5 yr). Sequential studies of exercise, GH administration, and GH withdrawal were undertaken. A randomized, controlled study of rest vs. exercise showed that exercise did not change serum osteocalcin; other markers of formation increased transiently (each P<0.001): bone-specific alkaline phosphatase (+16.1%), carboxyterminal propeptide of type I procollagen (+14.1%), and procollagen III N-terminal extension peptide (+5.0%). The carboxyterminal cross-linked telopeptide of type I collagen, a bone resorption marker, increased 9.7% (P = 0.018) in response to exercise. A randomized, double blind, placebo-controlled, parallel study of recombinant human GH treatment (0.15 IU/kg x day) for 1 week increased serum osteocalcin (net increase preexercise, +/-10.0%; P = 0.017), carboxyterminal propeptide of type I procollagen (+17.6%; P = 0.002), procollagen III N-terminal extension peptide (+48.4%; P = 0.001), and carboxyterminal cross-linked telopeptide of type I collagen (53.3%; P = 0.009). Disappearance half-times after cessation of recombinant human GH for pre- and postexercise markers ranged from 248-770 h. We conclude 1) endurance exercise transiently activates bone and collagen turnover; 2) brief GH administration results in similar but quantitatively greater augmentation; and 3) these data will assist in designing a GH detection strategy.

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Responses of Markers of Bone and Collagen Turnover to Exercise, Growth Hormone (GH) Administration, and GH Withdrawal in Trained Adult Males

The effect of exercise on bone mass is unclear. To determine the skeletal effect of weight-bearing exercise in premenopausal women, we prospectively evaluated the effects of a weight-training program on lumbar spine bone mass in 10 women (mean +/- SEM, 36.2 +/- 1.3 yr) and compared the results with those in 7 sedentary women (40.4 +/- 1.6 yr). None of the women had previously participated in a weight-training program, and all ingested a 500-mg calcium supplement each day throughout the study. Axial loading and balance of large muscle groups were emphasized. Individual strength increased by 57 +/- 8% over 9 months. Despite the increase in muscle strength, lumbar spine bone density in the exercising women decreased by 2.90% at 4.5 months and 3.96% at 9 months (P = 0.01). In contrast, there was no change in lumbar density in the controls over the 9-month period. We conclude that short term weight training at this frequency and intensity decreases vertebral bone mass in premenopausal women.

Weight training decreases vertebral bone density in premenopausal women: a prospective study.

The levels of serum osteocalcin, in addition to other parameters, were monitored in athletic (N = 9) and nonathletic (N = 10) university male students before, immediately after, and 60 min after 30 min of exercise on a running ergometer and at a constant workload of approximately 50% of their maximum capacity; there was adequate replenishment of drinking water. In both groups, the increase in serum parathyroid hormone levels observed immediately after exercise correlated well with a decrease in ionized calcium as well as the total calcium, and also with an increase in serum phosphorus, whereas the concentration of serum albumin remained stable. The response of serum osteocalcin differed between the two groups, in that (1) the concentration before exercise was significantly higher in athletic than in nonathletic students (P less than 0.001), and (2) the maximum level was evident in the former group 60 min after exercise, whereas it was present in the latter group immediately after exercise. We speculate that athletic subjects have a higher turnover of bone status compared with nonathletic subjects.

Differences in basal and postexercise osteocalcin levels in athletic and nonathletic humans

Three siblings with neonatal familial hyperparathyroidism diagnosed at age 4 months, 2 months, and 5 days, respectively, were treated. Hypercalciuria, nephrocalcinosis, and renal tubular acidosis were present in each child. In all three, there were higher responses of serum parathyroid hormone to serum calcium and higher elevation of serum calcium with oral calcium loading. The metabolism of vitamin D and calcitonin seemed to be intact. Hypercalcemia associated with the abnormal response of parathyroid hormone secretion disappeared when the children passed the age of approximately 2 years, although renal tubular acidosis and nephrocalcinosis remained. An autosomal recessive inheritance seems likely.

Self-limited neonatal familial hyperparathyroidism associated with hypercalciuria and renal tubular acidosis in three siblings.

We investigated if renal handling of phosphate could predict height velocity in 28 normal variant short children (16 boys and 12 girls). Before and after human growth hormone was given for four consecutive days, the ratio of maximum tubular reabsorption rate for phosphorus to glomerular filtration rate (TmP/GFR) was calculated. Based on increments in TmP/GFR (delta TmP/GFR) with growth hormone administration, the patients were divided into two groups; children in whom the levels of delta TmP/GFR were 0.8 mg/dl GF or more (group A, n = 7) and those with levels less than 0.8 mg/dl GF (group B, n = 21). All children in group A and some in group B (n = 9) were injected with 0.5 IU/kg/week of recombinant human growth hormone for over one year. Height velocity during therapy was significantly greater in treated children in group A than in group B and was similar among treated (n = 9) and untreated (n = 12) children in group B. The present study suggests that change in renal handling of phosphate during short-term growth hormone administration can serve to select normal variant short children who will respond well to growth hormone therapy.

Shinichi Tomoeda

Papers

Differences in basal and postexercise osteocalcin levels in athletic and nonathletic humans

Self-limited neonatal familial hyperparathyroidism associated with hypercalciuria and renal tubular acidosis in three siblings.

Can renal handling of phosphate predict response to growth hormone therapy in normal variant short children by short-term treatment?