Reduced bone formation and relatively increased bone resorption in absorptive hypercalciuria.

Absorptive hypercalciuria (AH), a common stone-forming condition characterized biochemically by intestinal hyperabsorption of calcium and hypercalciuria may be associated with bone loss. In AH type I (AH-1), hypercalciuria persists despite restriction in dietary calcium intake. We therefore hypothesized that the skeleton may contribute to the hypercalciuria in this subgroup of patients. Histomorphometric analysis of iliac crest biopsies were performed on nine stone-formers with AH-1 and on nine matched normal subjects. After stabilization on a stone-prevention diet, calcium homeostasis in the stone formers was then evaluated on inpatient constant metabolic diet before and after short-term blockade of bone resorption by alendronate (10 mg daily, 17 days total). Compared with controls, the stone-formers had lower indices of bone formation (osteoblast surface/bone surface 1.8+/-2.1 vs 3.0+/-1.5%, P=0.04; wall thickness 35.8+/-6.9 vs 47.2+/-7.6%, P=0.001) and relatively higher bone resorption (osteoclast surface/bone surface 0.4+/-0.2 vs 0.2+/-0.2%, P=0.05). In the stone-formers, a short-term course of alendronate treatment corrected fasting urinary calcium (0.14+/-0.06 to 0.06+/-0.04 mg Ca/mg Cr, P=0.001) and marginally reduced 24-h urinary calcium by 48 mg/day (P=0.06). Increased intestinal calcium absorption and hypercalciuria persisted, but estimated calcium balance improved (P=0.007). Our results suggest that the hypercalciuria of AH-1 originates primarily from intestinal hyperabsorption of calcium, but bone resorption in excess of bone formation may contribute.

Expression of aromatase in the human growth plate.

Aromatase catalyzes the synthesis of estrogen from its androgen precursors. Estrogen is known to be important in regulating long bone growth and epiphyseal plate closure. To assess whether there may be growth plate-specific production of estrogen, we performed reverse transcriptase polymerase chain reaction (RT-PCR) to determine whether aromatase transcripts are present in the human growth plate. Immunohistochemistry was also employed to identify the specific sites of expression. Growth plates were obtained from an adolescent male and female undergoing ephysectomy to counter premature growth plate closure in the opposite leg. Aromatase transcripts were detected in RNA preparations from both growth plates. The aromatase protein was mainly expressed in the zone of maturation and the hypertrophic zone, with greatest expression in the latter. Since estrogen receptors are known to be expressed in chondrocytes, this data is consistent with a role for local estrogen production in the autocrine/paracrine control of long bone growth and growth plate maturation.

Cardiac atrophy after bed rest and spaceflight.

Cardiac muscle adapts well to changes in loading conditions. For example, left ventricular (LV) hypertrophy may be induced physiologically (via exercise training) or pathologically (via hypertension or valvular heart disease). If hypertension is treated, LV hypertrophy regresses, suggesting a sensitivity to LV work. However, whether physical inactivity in nonathletic populations causes adaptive changes in LV mass or even frank atrophy is not clear. We exposed previously sedentary men to 6 (n = 5) and 12 (n = 3) wk of horizontal bed rest. LV and right ventricular (RV) mass and end-diastolic volume were measured using cine magnetic resonance imaging (MRI) at 2, 6, and 12 wk of bed rest; five healthy men were also studied before and after at least 6 wk of routine daily activities as controls. In addition, four astronauts were exposed to the complete elimination of hydrostatic gradients during a spaceflight of 10 days. During bed rest, LV mass decreased by 8.0 +/- 2.2% (P = 0.005) after 6 wk with an additional atrophy of 7.6 +/- 2.3% in the subjects who remained in bed for 12 wk; there was no change in LV mass for the control subjects (153.0 +/- 12.2 vs. 153.4 +/- 12.1 g, P = 0.81). Mean wall thickness decreased (4 +/- 2.5%, P = 0.01) after 6 wk of bed rest associated with the decrease in LV mass, suggesting a physiological remodeling with respect to altered load. LV end-diastolic volume decreased by 14 +/- 1.7% (P = 0.002) after 2 wk of bed rest and changed minimally thereafter. After 6 wk of bed rest, RV free wall mass decreased by 10 +/- 2.7% (P = 0.06) and RV end-diastolic volume by 16 +/- 7.9% (P = 0.06). After spaceflight, LV mass decreased by 12 +/- 6.9% (P = 0.07). In conclusion, cardiac atrophy occurs during prolonged (6 wk) horizontal bed rest and may also occur after short-term spaceflight. We suggest that cardiac atrophy is due to a physiological adaptation to reduced myocardial load and work in real or simulated microgravity and demonstrates the plasticity of cardiac muscle under different loading conditions.

Bone phenotype of the aromatase deficient mouse.

Estrogens are important for normal bone growth and metabolism. The mechanisms are incompletely understood. Thus, we have undertaken characterization of the skeletal phenotype of aromatase (ArKO) deficient mice. No abnormalities have been noted in skeletal patterning in newborns. Adult ArKO mice show decreased femur length and decreased peak Bone Mineral Density (BMD) with accelerated bone loss by 7 months of age in females. Magnetic resonance microscopy (MR) and microCT (microCT) imaging disclosed decreased cancellous connectivity and reduced cancellous bone volume in ArKO females. Bone formation rate (BFR) is increased in ArKO females and decreased in ArKO males. Estradiol therapy reverses these changes. This anabolic effect of estradiol in the male skeleton is supported by 18-F- Positron Emission Tomography (PET) imaging, which clearly demonstrates decreased spinal uptake, but marked increase after estradiol therapy. Serum IGF-1 levels are high in young female ArKO mice but low in young ArKO males. The reduced BMD in ArKO females, despite the presence of elevated serum IGF 1, suggests that other mechanism(s) are operative. There is increased B-cell lymphopoiesis in adult female ArKO bone marrow cells. These results show that ArKO mice show the effects of estrogen deficiency on bone growth, mass, metabolism, microarchitecture and the hematopoietic microenvironment.

Bone has a sexually dimorphic response to aromatase deficiency.

Aromatase synthesizes estrogen from androgen precursors. To better understand the role of estrogen in skeletal metabolism and growth, we have assessed long bone growth and histomorphometry in aromatase-deficient (ArKO) mice. The age range for the animals was 5-7 months. At this age mice have already achieved peak bone density but continue slow bone growth. Femur length, an index of long bone growth, showed decreased growth in ArKO males compared with wild-type (wt) littermates but no significant difference in females. Radiographically, compared with age- and sex- matched littermates both ArKO males and females showed osteopenia in the lumbar spine. Histologically, both ArKO males and females showed an osteoporotic-type picture, characterized by significant decreases in trabecular bone volume and trabecular thickness. However, compared with wt littermates female ArKO animals showed a bone remodeling picture consistent with increased bone turnover, much like early postmenopausal osteoporosis in humans. On the other hand, male ArKO animals showed decreases in both osteoblastic and osteoclastic surfaces compared with wt littermates, similar to age-related osteopenia. These findings suggest that osteoporosis seen in aromatase-deficient mice may arise from different bone remodeling activities between males and females. These results also show that the ArKO model exhibits the expected results of estrogen deficiency and may be a good model for investigating sex-specific responses to estrogen deficiency. Furthermore, they imply that estrogen is important for attaining peak bone mass in male as well as in female mice.

Single-monthly-dose vitamin D supplementation in elderly patients.

OBJECTIVE: To determine the serum levels of calcidiol and calcitriol in 2 men and in 21 postmenopausal, primarily elderly women receiving hormone replacement therapy, orally administered calcium citrate, and an additional supplement of 50,000 IU of vitamin D (1.25 mg of cholecalciferol) once monthly for various periods. METHODS: We determined plasma calcidiol and calcitriol levels at various times, ranging from -1 to +60 days after intake of a single dose of 1.25 mg of vitamin D in 10 initial or short-term users (1 to 6 months) and in 13 women who had been using this monthly regimen for several years. The primary concerns were the safety and adequacy of the blood levels achieved with a regimen that encouraged compliance. RESULTS: In long-term users of monthly vitamin D regimens, calcidiol levels were usually slightly in excess of the upper limit of normal (that is, >52 ng/mL [>130 nmol/L]) at all times throughout the month; in contrast, calcitriol levels exceeded the normal range (8 to 52 pg/mL [19 to 125 pmol/L]) only once in 18 samplings. In short-term users, calcidiol levels exceeded the normal range only once shortly after intake, and no calcitriol level exceeded the normal range. CONCLUSION: Once-a-month dosage of 50,000 IU (1.25 mg) of vitamin D in elderly women receiving hormone replacement therapy plus supplemental calcium and uncontrolled generic multivitamin intake yields calcitriol levels within the normal range, even after years of use of this regimen. Calcidiol levels exceeded the normal range at all times in long-term users but only once in short-term users. Calcidiol concentrations, however, were found to be far below levels (>150 ng/mL [>375 nmol/L]) that might produce hypercalciuria or hypercalcemia.

The effects of twelve weeks of bed rest on bone histology, biochemical markers of bone turnover, and calcium homeostasis in eleven normal subjects.

This study was undertaken to examine the effects of 12 weeks of skeletal unloading on parameters of calcium homeostasis, calcitropic hormones, bone histology, and biochemical markers of bone turnover in 11 normal subjects (9 men, 2 women; 34 +/- 11 years of age). Following an ambulatory control evaluation, all subjects underwent 12 weeks of bed rest. An additional metabolic evaluation was performed after 12 days of reambulation. Bone mineral density declined at the spine (-2.9%, p = 0.092) and at the hip (-3.8%, p = 0.002 for the trochanter). Bed rest prompted a rapid, sustained, significant increase in urinary calcium and phosphorus as well as a significant increase in serum calcium. Urinary calcium increased from a pre-bed rest value of 5.3 mmol/day to values as high as 73 mmol/day during bed rest. Immunoreactive parathyroid hormone and serum 1,25-dihydroxyvitamin D declined significantly during bed rest, although the mean values remained within normal limits. Significant changes in bone histology included a suppression of osteoblastic surface for cancellous bone (3.1 +/- 1.3% to 1.9 +/- 1.5%, p = 0.0142) and increased bone resorption for both cancellous and cortical bone. Cortical eroded surface increased from 3.5 +/- 1.1% to 7.3 +/- 4.0% (p = 0.018) as did active osteoclastic surface (0.2 +/- 0.3% to 0.7 +/- 0.7%, p = 0.021). Cancellous eroded surface increased from 2.1 +/- 1.1% to 4.7 +/- 2.2% (p = 0.002), while mean active osteoclastic surface doubled (0.2 +/- 0.2% to 0.4 +/- 0.3%, p = 0.020). Serum biochemical markers of bone formation (osteocalcin, bone-specific alkaline phosphatase, and type I procollagen extension peptide) did not change significantly during bed rest. Urinary biochemical markers of bone resorption (hydroxyproline, deoxypyridinoline, and N-telopeptide of type I collagen) as well as a serum marker of bone resorption (type I collagen carboxytelopeptide) all demonstrated significant increases during bed rest which declined toward normal during reambulation. Thus, under the conditions of this study, the human skeleton appears to respond to unloading by a rapid and sustained increase in bone resorption and a more subtle decrease in bone formation.

Normal vitamin D receptor concentration and responsiveness to 1, 25-dihydroxyvitamin D3 in skin fibroblasts from patients with absorptive hypercalciuria.

To evaluate whether there is an increase in vitamin D receptor (VDR) concentration which could raise intestinal calcium absorption in absorptive hypercalciuric (AH) patients and promote hypercalciuria, we measured VDR concentration and VDR mRNA levels in skin fibroblasts from 16 patients with AH and 17 age-matched normal subjects before and following a 16-hour incubation in the presence of 10(-8) M 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]. There were no significant differences in VDR concentration between normal subjects and AH patients in the basal state (30 +/- 11 vs. 30 +/- 15 ng/mg protein, respectively) or following 1,25(OH)2D3-mediated upregulation (43 +/- 18 vs. 42 +/- 16 ng/mg protein) as measured by immunoblot methodology. Analysis of VDR mRNA/beta-actin mRNA ratios demonstrated no significant differences between normal subjects and AH patients prior to (2.1 +/- 1.7 vs. 1.8 +/- 2.4) or following (2.7 +/- 2.8 vs. 1.9 +/- 1.8) 1,25(OH)2D3 exposure. As a measure of VDR bioactivity, we quantitated 1,25(OH)2D3-mediated induction of 25-hydroxyvitamin D3-24-hydroxylase. Again, no significant differences were observed between normal subjects and all patients (2.1 +/- 1.6 vs. 1.9 +/- 1.6 pmol/mg/30 min, respectively). These findings indicate that there is neither an increase in VDR concentration in skin fibroblasts, a recognized vitamin D responsive cell, nor increased sensitivity to upregulation of VDR numbers by 1, 25(OH)2D3 in patients with AH. This suggests an alternative cause of intestinal hyperabsorption of calcium in AH other than alteration of the VDR number.

The effect of intermittent slow-release sodium fluoride and continuous calcium citrate therapy on calcitropic hormones, biochemical markers of bone metabolism, and blood chemistry in postmenopausal osteoporosis.

A detailed examination of calcitropic hormones and biochemical markers of bone turnover, serum chemistry, and blood hematology was performed in 75 postmenopausal women allocated to two groups: placebo plus calcium citrate (400 mg Ca B.I.D.) (n = 36) or intermittent slow-release sodium fluoride (SRNaF, 25 mg B.I.D.) plus calcium citrate (n = 39). After 2 years of therapy, a significant reduction in serum immunoreactive parathyroid hormone (PTH) was seen for both groups (43 +/- 18 SD-30 +/- 11 ng/liter, in placebo and 46 +/- 24-36 +/- 10, in SRNaF P < 0.0001 for both groups). Serum 1, 25(OH)2D significantly fell in placebo-treated patients (91 +/- 31-75 +/- 34 pmol/liter, P = 0.001) but did not change for SRNaF-treated patients. This difference in response between placebo and SRNaF-treated groups was significant, P = 0.005. Urinary hydroxyproline significantly declined during treatment in both groups (130 +/- 61-76 +/- 38 micromol/day, for placebo and 138 +/- 84-84 +/- 38 for SRNaF, P = 0.001). Similar decreases in urinary N-telopeptide of type I collagen were also observed for both groups (305 +/- 192-252 +/- 197 nmoles BCE/day for placebo and 356 +/- 230-220 +/- 197, P = 0.0001 for SRNaF). Serum carboxyterminal propeptide of type I collagen (PICP) declined significantly in both the placebo and SRNaF groups (118 +/- 38-101 +/- 36 microg/liter, and 116 +/- 47-105 +/- 39, P = 0.0027). Serum osteocalcin did not change significantly for either group, but bone-specific alkaline phosphatase (BS-ALPase), another marker of bone formation, demonstrated a significant fall in the placebo group at 2 years of therapy (16.2 +/- 6.7 U/liter-12.1 +/- 3.5, P = 0.009) and a small increase in the SRNaF-treated patients (13.0 +/- 4.1-15.0 +/- 4.5). The observed difference in response of BS-ALPase between the placebo and treated groups was significant (P = 0.007). There were no significant changes within or between treatment groups for blood hematology or serum chemistries. Mean values for all parameters remained within established normal ranges. These findings suggest that administration of calcium citrate inhibited PTH secretion and thereby reduced bone resorption in both groups, indicated by a decline in serum PTH, urinary hydroxyproline, and N-telopeptide. A low turnover state of bone may have been produced in the placebo group taking calcium citrate alone, since serum PICP, BS-ALPase, and 1,25(OH)2D also decreased. The addition of SRNaF prevented serum 1, 25(OH)2D from falling by an unknown mechanism. However, its anabolic action on the skeleton was best reflected by changes in BS-ALPase. Moreover, SRNaF appeared to exert no deleterious effects on blood chemistries or hematology during 2 years of administration.

Connectivity in human cancellous bone by three-dimensional magnetic resonance imaging.

Bone architecture affects strength and resistance to fracture. Trabecular connectivity is now recognized as an important measure of bone quality, and could be useful as an indicator of the osteoporotic condition, as well as a tool for measuring the effectiveness of therapies. We have applied three-dimensional magnetic resonance imaging microscopy to human cancellous bone biopsies, and report the results of connectivity measurements. Sample heterogeneity was examined on the basis of connectivity density for subvolumes. The choice of examination volume had a significant effect on connectivity density measurements, but sample volumes greater than 100 mm3 were found to give stable results. Connectivity density was strongly correlated with nodal density, and two-dimensional estimates of connectivity, but not bone volume fraction. Repeat measurement at constant resolution (69 x 138 x 109 microns, signal-to-noise ratio of about 35) showed reproducibility of about 5% for connectivity density. Our most recent results have significantly enhanced resolution (69 x 69 x 43 microns); bone fraction remained constant, but apparent connectivity density is greater.

Reflection ultrasound velocities and histomorphometric and connectivity analyses: correlations and effect of slow-release sodium fluoride.

To better understand how structural and functional bone properties contribute to the changes in bone biomechanical properties revealed by ultrasound critical angle reflectometry (UCR) analysis, we measured both UCR velocities and histomorphometric properties in bone biopsy specimens from 33 osteoporotic patients before and following intermittent slow-release sodium fluoride (SRNaF) and continuous calcium citrate administration. Mean skeletal fluoride exposure was 17 months, and mean skeletal fluoride content was 0.203 +/- 0.088 SD% bone ash. Intermittent SRNaF and continuous calcium citrate promoted significant increases in trabecular thickness (122 +/- 18 SD microm to 131 +/- 20, p = 0.020), mineral apposition rate (0.79 +/- 0.26 to 1.05 +/- 0.40 microm/day, p = 0.014), and a significant decline in eroded surface (3.9 +/- 1.6 to 2.8 +/- 1.4%, p = 0.002). There were also significant increases in node number (0.193 +/- 0.100 to 0.368 +/- 0.245, p < 0.01) and node-to-node strut length (0.076 +/- 0.087 to 0.191 +/- 0.173, p < 0.01) relative to total cancellous area. Cortical UCR velocity did not change but cancellous velocity significantly increased by 97 m/s following therapy (p = 0.0005). When compared against the significant changes in bone histomorphometry and connectivity, the sum of both cancellous and cortical ultrasound velocities was significantly correlated with node number/area (R2 = 0.305, p < 0.0001) and node-to-node strut length/area (R2 = 0.372, p < 0.0001) and to a lesser extent with mineral apposition rate (R2 = 0.106, p = 0.032). Multiple regression analysis demonstrated that 40% of the variance in the sum of the UCR velocities can be accounted for by the variability in these histomorphometric and connectivity parameters. There were no significant correlations between the sum of cortical and cancellous ultrasound velocities and cancellous bone volume (R2 = 0.014, p = 0533), trabecular thickness (R2 = 0.012, p = 0.47), or bone mineral density (R2 = 0.003, p = 0.80). These observations indicate that velocity measurements with the UCR methodology show an improvement in bone elasticity associated, in part, with an improvement in the rate of bone mineralization and an improvement in bone quality at the structural level as shown by microarchitecture.

Vitamin D receptors from patients with resistance to 1,25-dihydroxyvitamin D3: point mutations confer reduced transactivation in response to ligand and impaired interaction with the retinoid X receptor heterodimeric partner.

Hereditary hypocalcemic vitamin D-resistant rickets is attributable to defects in the nuclear receptor for 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3]. Two novel point mutations (I314S and R391C) identified in the hormone-binding domain of the human vitamin D receptor (VDR) from patients with hereditary hypocalcemic vitamin D-resistant rickets confer the receptor with sharply reduced 1,25-(OH)2D3-dependent transactivation. These natural mutations, especially R391C, also lead to a second specific consequence, namely impaired heterodimeric interaction with retinoid X receptor (RXR). While the transactivation ability of the I314S mutant can be largely restored by providing excess 1,25-(OH)2D3, R391C activity is more effectively restored with exogenous RXR. These observations are reflected also in the clinical course of each patient: the patient bearing the I314S mutation showed a nearly complete cure with pharmacological doses of a vitamin D derivative, whereas the patient bearing R391C responded only partially to such therapy. Further tests with patient fibroblasts and transfected cells show that the activity of the I314S VDR mutant is augmented somewhat by added RXR, while transactivation by the R391C mutant is best corrected by RXR in the presence of excess hormone. Thus, the effects of hormone vs. RXR in bolstering these mutant VDRs, such that they mediate efficient transactivation, are not entirely separable. The unique properties of these genetically altered receptors establish a new subclass of natural human VDR mutants that illustrate, in vivo, the importance of both 1,25-(OH)2D3 binding and heterodimerization with RXR in VDR action.

Disruption of cholesterol 7alpha-hydroxylase gene in mice. II. Bile acid deficiency is overcome by induction of oxysterol 7alpha-hydroxylase.

Past experiments and current paradigms of cholesterol homeostasis suggest that cholesterol 7alpha-hydroxylase plays a crucial role in sterol metabolism by controlling the conversion of cholesterol into bile acids. Consistent with this conclusion, we show in the accompanying paper that mice deficient in cholesterol 7alpha-hydroxylase (Cyp7-/- mice) exhibit a complex phenotype consisting of abnormal lipid excretion, skin pathologies, and behavioral irregularities (Ishibashi, S., Schwarz, M., Frykman, P. K. , Herz, J., and Russell, D. W.(1996) J. Biol. Chem. 261, 18017-18023). Aspects of lipid metabolism in the Cyp7-/- mice are characterized here to deduce the physiological basis of this phenotype. Serum lipid, cholesterol, and lipoprotein contents are indistinguishable between wild-type and Cyp7-/- mice. Vitamin D3 and E levels are low to undetectable in knockout animals. Stool fat content is significantly elevated in newborn Cyp7-/- mice and gradually declines to wild-type levels at 28 days of age. Several species of 7alpha-hydroxylated bile acids are detected in the bile and stool of adult Cyp7-/- animals. A hepatic oxysterol 7alpha-hydroxylase enzyme activity that may account for the 7alpha-hydroxylated bile acids is induced between days 21 and 30 in both wild-type and deficient mice. An anomalous oily coat in the Cyp7-/- animals is due to the presence of excess monoglyceride esters in the fur. These data show that 7alpha-hydroxylase and the pathway of bile acid synthesis initiated by this enzyme are essential for proper absorption of dietary lipids and fat-soluble vitamins in newborn mice, but not for the maintenance of serum cholesterol and lipid levels. In older animals, an alternate pathway of bile acid synthesis involving an inducible oxysterol 7alpha-hydroxylase plays a crucial role in lipid and bile acid metabolism.

Evidence for normal vitamin D receptor messenger ribonucleic acid and genotype in absorptive hypercalciuria.

Absorptive hypercalciuria (a stone-forming condition) is characterized by gut hyperabsorption of calcium, hypercalciuria, and reduced bone density. Inasmuch as these features implicate enhanced calcitriol action in gut and bone, we analyzed the vitamin D receptor (VDR) gene to ascertain whether an abnormality of this gene marks patients with intestinal hyperabsorption of calcium. We have compared the frequency of a restriction fragment length polymorphism (Bsm I) associated with different alleles of the VDR gene in a group of 33 well characterized absorptive hypercalciuric patients and a group of 36 normal race- and age-matched control subjects. There was no difference between the distribution of the VDR alleles in the patient population when compared with the normal population. The coding region of VDR messenger RNA was also normal, as determined by both DNA sequence analysis and chemical mismatch cleavage analysis of copy DNA from 11 index absorptive hypercalciuric patients. On the basis of these results, we propose that the enhanced intestinal calcium absorption invariably seen in absorptive hypercalciuria and attendant symptoms of this disorder are not attributable to mutations of the VDR and are not linked to a common VDR genotype.

Anabolic effects of fluoride on bone.

Fluoride exerts a biphasic action at the level of osteoblasts, on bone mineral, on bone structure and function, and in the treatment of osteoporosis. At low circulating concentrations, skeletal uptake of fluoride is limited and the effects are beneficial. At higher concentrations and greater skeletal uptake, fluoride may cause the formation of abnormally mineralized bone of impaired quality. A new treatment program entailing intermittent slow release sodium fluoride (SR-NaF) with continuous calcium citrate may capture desirable qualities of fluoride without toxic effects, and be therapeutically efficacious in postmenopausal osteoporosis.

Serum IGF 1 is low and correlated with osteoblastic surface in idiopathic osteoporosis.

We have previously reported that bone formation is impaired on histomorphometric analysis of bone in patients with idiopathic osteoporosis. In the present study, 30 patients with idiopathic osteoporosis (18 men and 12 women mean age 44 +/- 12 years) and spinal and/or appendicular fractures were studied. Compared with control values, bone biopsy analysis demonstrated reduced bone volume (13.0 +/- 4.4 vs. 23.2 +/- 4.4, p < 0.0001), osteoid volume (0.13 +/- 0.13 vs. 0.32 +/- 0.19, p = 0.001), osteoid surface (5.9 +/- 4.3 vs. 12.1 +/- 4.6, p = 0.0004), and diminished double-labeled mineralizing surface (MS/BS 2.0 +/- 2.1 vs. 5.1 +/- 2.7%, p = 0.0001) in the patients. Since insulin-like growth factor 1 (IGF-1) is one of the major determinants of bone growth and remodeling, we measured the circulating level of this growth factor in these patients. The mean serum IGF-1 concentration was lower in patients as compared with 33 healthy age-matched controls (193 +/- 59 SD ng/ml vs. 232 +/- 79). A significant difference was noted between the two groups only in subjects younger than 36 years. In patients with idiopathic osteoporosis, regression analysis of serum IGF-1 against the various histological parameters measured from the bone biopsy disclosed significant correlation's between serum IGF-1 and osteoblastic surface (r = 0.429, p = 0.032), mineralizing bone surface with a double label (r = 0.480, p = 0.015), and the bone formation rate (r = 0.457, p = 0.021). These findings suggest that in young eugonadal individuals with idiopathic osteoporosis, reduced IGF-1 concentrations may have an etiological role in the development of this disease.

Regulation of mineral homeostasis in osteopetrotic (op) rats.

The osteopetrotic (op) rat is a lethal mutation characterized by severe skeletal sclerosis resulting from reduced bone resorption. Although the skeletal manifestations have been studied extensively, little is known about mineral homeostasis in this mutation. This paucity of data prompted us to undertake this study quantitating circulating levels of calcium, phosphorus, 1,25-dihydroxyvitamin D [1,25(OH)2D] and parathyroid hormone (PTH) in op mutants and normal rats between 2 and 8 wk of age. Calcium and phosphorus levels were significantly lower in op mutants at younger ages; both parameters normalized by 6 wk. Serum levels of 1,25(OH)2D were markedly elevated in op rats at all ages and showed no signs of normalization. Serum PTH levels were also elevated at most ages, with the greatest increase occurring when op mutants were severely hypocalcemic. These results demonstrate that, in op mutants, changes in circulating PTH and calcium levels were interdependent; however, levels of 1,25(OH)2D did not change despite normalization of serum calcium and phosphorus. The latter deserves further investigation and supports the hypothesis of a localized (skeletal) resistance to 1,25(OH)2D.