Calcium metabolism and vitamin D in the extreme longevity

Skeletal remodelling is a continuous process during life and is still active also in extreme senescence. In the elderly, bone resorption often prevails over bone formation, causing bone loss and fragility. Elderly subjects are exposed to the risk of fractures, and loss of self-sufficiency, if considering that the proximal femur is the most frequently involved site. Bone remodelling can maintain circulating calcium within physiological ranges, at the expense of a substantial loss of this ion from the skeleton, particularly during senescence. Calcium metabolism is regulated at cellular/molecular level by a network of cytokines, growth factors, systemic hormones that act on bone in paracrine/autocrine/systemic fashion. Among the molecules involved in bone metabolism, parathyroid hormone (PTH) and vitamin D present some peculiar aspects during senescence. The osteometabolic features in a consistent group of centenarians have been evaluated. It results that a severe hypovitaminosis D was present in 99 out of 104 centenarians (25-OH vitamin D below 5 nmol/L), and that it plays an important role as a factor inducing a vicious circle involving hypocalcemia, secondary hyperparathyroidism, together with biochemical features indicating a consistent bone loss. Serum C-terminal cross-linking telopeptide, a specific marker of bone resorption was elevated in 92% of these subjects. Moreover, it has been found that several femoral fractures had occurred after 90 years of age. These data offer a rational for the possible prevention of elevated bone turnover, bone loss and consequently the reduction of osteoporotic fractures and fractures-induced disability, in the oldest olds, through the simple supplementation with calcium and vitamin D.     

Serum Sclerostin Increases in Healthy Adult Men during Bed Rest

Context: Animal models and human studies suggest that osteocytes regulate the skeleton's response to mechanical unloading in part by an increase in sclerostin. However, few studies have reported changes in serum sclerostin in humans exposed to reduced mechanical loading. Objective: We determined changes in serum sclerostin and bone turnover markers in healthy adult men undergoing controlled bed rest. Design, Setting, and Participants: Seven healthy adult men (31 ± 3 yr old) underwent 90 d of 6° head down tilt bed rest at the University of Texas Medical Branch Institute for Translational Sciences-Clinical Research Center. Outcomes: Serum sclerostin, PTH, vitamin D, bone resorption and formation markers, urinary calcium and phosphorus excretion, and 24-h pooled urinary markers of bone resorption were evaluated before bed rest [baseline (BL)] and at bed rest d 28 (BR-28), d 60 (BR-60), and d 90 (BR-90). Bone mineral density was measured at BL, BR-60, and 5 d after the end of the study (BR+5). Data are reported as mean ± sd. Results: Consistent with prior reports, bone mineral density declined significantly (1-2% per month) at weight-bearing skeletal sites. Serum sclerostin was elevated above BL at BR-28 (+29 ± 20%; P = 0.003) and BR-60 (+42 ± 31%; P < 0.001), with a lesser increase at BR-90 (+22 ± 21%; P = 0.07). Serum PTH levels were reduced at BR-28 (-17 ± 16%; P = 0.02) and BR-60 (-24 ± 14%; P = 0.03) and remained lower than BL at BR-90 (-21 ± 21%; P = 0.14), but did not reach statistical significance. Serum bone turnover markers were unchanged; however, urinary bone resorption markers and calcium were significantly elevated at all time points after bed rest (P < 0.01). Conclusions: In healthy men subjected to controlled bed rest for 90 d, serum sclerostin increased, with a peak at 60, whereas serum PTH declined, and urinary calcium and bone resorption markers increased.     

Pattern of bone mineral density in idiopathic male osteoporosis

The mechanisms of male idiopathic osteoporosis are little known. We evaluated bone mineral loss by dual-energy X-ray absorptiometry and determined its cortical or trabecular nature in a cohort of men with idiopathic osteoporosis with fractures. Thirty-nine men (mean age 60?±?13?years), with negative investigations for the cause of osteoporosis, were studied. All had fragility fractures: vertebral 51%, peripheral 25%, and both types 24%. Bone density was measured at the lumbar spine (L2-L4), total hip and whole body. The limb/axial skeleton (spine?+?hips) and hip/L2-L4 BMD ratios were calculated. Serum 25-hydroxy-vitamin D, PTH, bone alkaline phosphatase and CTX were measured. Bone mineral loss predominated at the lumbar spine (mean L2-L4 T-score -3?±?0.93, mean total hip T-score -1.87?±?0.75). Limb/axial skeleton and total hip/L2-L4 BMD were strongly correlated, but not hip and spine BMD. The ratio values were widely scattered, indicating markedly heterogeneous bone loss. Vitamin D, PTH, bone alkaline phosphatase and CTX levels did not differ between predominantly trabecular and cortical osteoporosis. Bone mineral density measurement in male idiopathic osteoporosis with fractures demonstrated that bone loss predominated in the spine and that it was very heterogeneous, principally affecting cortical or trabecular bone depending on the patient.     

Pegvisomant-induced serum insulin-like growth factor-I normalization in patients with acromegaly returns elevated markers of bone turnover to normal

Active acromegaly is associated with increased biochemical markers of bone turnover. Pegvisomant is a GH receptor antagonist that normalizes serum IGF-I in 97% of patients with active acromegaly. We evaluated the effects of pegvisomant-induced serum IGF-I normalization on biochemical markers of bone and soft tissue turnover, as well as levels of PTH and vitamin D metabolites, in 16 patients (nine males; median age, 52 yr; range, 28-78 yr) with active acromegaly (serum IGF-I at least 30% above upper limit of an age-related reference range). Serum procollagen III amino-terminal propeptide (PIIINP) and type I procollagen amino-terminal propeptide, osteocalcin (OC), bone-related alkaline phosphatase, C-terminal cross-linked telopeptide of type I collagen (CTx), albumin-corrected calcium, intact PTH, 25-hydroxy vitamin D, 1,25-dihydroxy vitamin D [1,25-(OH)(2) vit D], urinary type 1 collagen cross-linked N-telopeptide/creatinine ratio, and urinary calcium (24 h collection) were measured (single-batch analysis) at study entry and after IGF-I normalization, along with sera from 32 age- and sex-matched controls. Compared with controls, PIIINP, OC, and CTx were significantly elevated in patients at baseline. Pegvisomant-induced serum IGF-I normalization (699 +/- 76 to 242 +/- 28 micro g/liter, P < 0.001) was associated with a significant decrease in PIIINP, markers of bone formation (type I procollagen amino-terminal propeptide, OC, and bone-related alkaline phosphatase), and resorption (CTx and urinary type 1 collagen cross-linked N-telopeptide/creatinine ratio). 1,25-(OH)(2) vit D decreased and intact PTH increased significantly, but 25-hydroxy vitamin D was unaffected. A significant decline in calculated calcium clearance was observed. The decrease in serum IGF-I correlated positively with the decrease of serum PIIINP (r = 0.7, P < 0.01). After normalization of serum IGF-I, there was no statistical difference between patients and controls for any parameters for which control data were available. In conclusion, GH excess is associated with increased bone and soft tissue turnover. Pegvisomant-induced normalization of serum IGF-I results in a decrease in markers of bone and soft tissue turnover to levels observed in age-matched controls, and these changes are accompanied by an increase in PTH and a decrease in 1,25-(OH)(2) vit D. These data provide further evidence of the effectiveness of pegvisomant in normalizing the altered biological effects of GH hypersecretion.     

Pathophysiology of bone metabolism

Osteoporosis is a multifactorial disease entailing a high risk to sustain fragility fractures. Its susceptibility is determined by genetic and environmental factors and underlying diseases. Bone is rebuilt and regenerated by osteoclasts, osteoblasts and osteocytes. Local and systemic growth and differentiation factors such as Insulin-like growth factors, bone morphogenetic proteins and wnt-proteins confer anabolic signals, while the RANK/RANK-Ligand and Osteoprotegerin (OPG) system regulates bone resorption. The ratio of osteoclast stimulating RANKL and its soluble decoy receptor OPG is modulated by sex hormones, vitamin D, parathyroid hormone, local growth factors and mechanical loading. Osteocytes regulate bone mass via the bone formation inhibitor sclerostin. Bone is tightly interconnected with and regulated by the calcium/phosphate/vitamin D system via the parathyroid gland, the gut, liver and kidneys. Sex hormones are important for bone formation during adolescence and their loss in menopause/andropause exaggerates bone resorption. Basically over-activity of osteoclasts and/or functional deficits of osteoblasts can cause negative bone balance and favor osteoporosis.     

Insulin-like growth factors I and II: aging and bone density in women

Serum concentrations of insulin-like growth factors (IGF) were measured by RIA in 57 normal women, ages 30 - 90 yr, and in 29 untreated women with postmenopausal osteoporosis and vertebral compression fractures, ages 55 - 75 yr. These values were correlated with bone mineral density (BMD) of the distal and midradius assessed by single photon absorptiometry and of the lumbar spine assessed by dual photon absorptiometry as well as serum and urinary calcium, phosphorus, creatinine, alkaline phosphatase, immunoreactive PTH, urinary hydroxyproline, and creatinine clearance. Serum IGF-I levels declined markedly with age (r = -0.47, P less than 0.001). Serum IGF-II levels decreased only slightly with age, and this decrease was not statistically significant. Although BMD at all three scanning sites also declined significantly with age, neither serum IGF-I nor II concentrations correlated with BMD when age was held constant. In women with postmenopausal osteoporosis, serum IGF-I and II did not differ from the concentrations in normal women of similar age and did not correlate with BMD. In neither group was a correlation between serum IGF-I or II and serum or urinary proteins or cations found. Thus, there was no evidence that impaired synthesis of IGF-I and II contributes to pathogenesis of the syndrome of Type I (postmenopausal) osteoporosis, which is characterized by accelerated loss of trabecular bone and vertebral compression fractures. The possibility remains, however, that decreasing concentrations of serum IGF-I play a role in the more gradual loss of bone with aging (Type II osteoporosis) in which impared bone formation at the cellular level has been demonstrated.     

Prediction of bone mass density variation by bone remodeling markers in postmenopausal women with vitamin D insufficiency treated with calcium and vitamin D supplementation

The aim of this study was to determine whether early changes in bone markers could predict long-term response in bone mineral density (BMD) after calcium (500 mg) and vitamin D (400 IU) supplementation twice daily in ambulatory elderly women with vitamin D insufficiency (25-hydroxyvitamin D, <12 ng/ml). One hundred and ninety-two women (mean age, 75 +/- 7 yr) were randomized to receive either the supplementation (n = 95) or a placebo (n = 97) in a double-blind, controlled clinical trial for 1 yr. In comparison with the placebo group, supplementation significantly increased BMD, normalized 25-hydroxyvitamin D and significantly decreased intact PTH and bone remodeling markers. The initial values of telopeptide cross-links were correlated with improvement in total body BMD [urinary N-telopeptides (NTX), r = 0.38; C-telopeptides (CTX), r = 0.32; serum CTX, r = 0.28], and the 3-month changes in the same markers were correlated with improvement in total body (urinary N-telopeptides, r = -0.29; serum CTX, r = -0.26) and vertebral BMD (CTX, r = -0.26; all P < 0.05). We concluded that short-term changes in bone resorption markers can predict long-term variations in BMD in elderly women with vitamin D insufficiency receiving calcium and vitamin D supplementation.     

Parathormone, calcitonin, 25-hydroxycalciferol and bone histology in patients with chronic renal insufficiency

In 18 patients with chronic renal failure the parathormone (PTH), calcitonin (CT) and 25-OH-D blood levels were estimated before and after an intravenous calcium load. In ten patients the above mentioned biochemical parametres were confronted with histological findings obtained in bone biopsy material. Significantly elevated levels of PTH and CT were found while those of 25-OH-D were normal. Serum PTH decreased after a calcium load. In contrast to healthy persons no increase of serum CT was stated. Significant positive correlations were found between PTH and CT levels in blood serum as well as between the mineralized bone volume and 25-OH-D levels in serum. In addition a significant negative correlation was stated between the osteoid volume and 25-OH-D levels in blood serum. From the results obtained it is concluded, that from estimations of PTH, CT and 25-OH-D in blood serum histological alterations in bone biopsy material from chronic uremic patients can not be predicted. Beside secondary hyperparathyreoidism, relative deficiency of CT and active vitamin D metabolites other factors are also involved in the pathogenesis of renal osteodystrophy.     

Evidence of altered bone turnover,vitamin D and calcium regulation with knee osteoarthritis in female twins

BACKGROUND: Osteoarthritis (OA) is a disorder of the whole synovial joint organ. There is growing evidence of the importance of bone turnover in OA, and human studies have demonstrated that the subchondral bone is metabolically active in OA. The aim of this study was to assess the relationships of radiographic knee OA with altered bone turnover and calcium regulation. METHODS: We performed a matched and unmatched case-control study using twins assessed for OA. The subjects were 1644 female Caucasian twin pairs (266 monozygotic and 556 dizygotic) aged 24-79 yr from the St Thomas' UK Adult Twin Registry. Assays for measures of bone turnover [bone-specific alkaline phosphatase, osteocalcin and urinary deoxypyridinoline (DPD)] and calcium regulation [serum parathyroid hormone (PTH), 25-hydroxyvitamin D, serum calcium, serum magnesium and serum phosphate] were performed. The radiological features of knee OA were graded on a four-point scale (0-3) for osteophytes and a five-point scale (0-4) for Kellgren and Lawrence classification. Adjustment for age, body mass index (BMI) and relatedness was made. Conditional logistic regression analysis was also used to estimate the odds ratio (OR) and 95% confidence intervals (CI) for having radiological features of knee OA per standardized unit difference of serum variable between twins. RESULTS: Of the 1644 women studied, 474 (28.8%) had radiological evidence of knee osteophytes. There was evidence of increased bone turnover, increased PTH levels and decreased vitamin D levels in this group compared with those without osteophytes. No association was seen with joint space loss. After adjusting for age, BMI and relatedness, all of the differences disappeared except for a significant increase 10% in urinary DPD (P = 0.04). Discordant twin pair analysis (performed on a subgroup of 229 pairs) confirmed modest increases in bone resorption indicated by urinary DPD (OR 1.67, 95% CI 0.88-3.16) and a significant decrease in serum magnesium (OR 0.65, 95% CI 0.46-0.92) in the co-twins with OA. CONCLUSION: Bone resorption is increased in women with knee OA, consistent with metabolically active subchondral bone. However, bone formation, vitamin D and calcium regulation were not different after adjusting for age and BMI. The results suggest that bone resorption is increased in the presence of OA. Although we cannot clearly differentiate a cause or effect relationship, these results suggest that this is related to disease mechanisms and point to potential diagnostic or therapeutic avenues for bone resorption in OA.     

Age-related changes in bone density, serum parathyroid hormone, calcium absorption and other indices of bone metabolism in Chinese women

OBJECTIVE--To study the age-related changes in bone density, serum parathyroid hormone, calcium absorption and other indices of calcium metabolism in Chinese women who habitually have a low calcium intake. DESIGN--Cross-sectional study. SUBJECTS--One hundred and fifty-six healthy Chinese women aged 20-83 years. None were on any medication or vitamin supplements. Subjects over the age of 60 years were all living in a hostel; younger subjects were nurses or subjects attending a family clinic for minor illnesses. MEASUREMENTS--Fasting blood and urine samples were collected for biochemical measurements and calcium absorption was measured using 45Ca by the method of Marshall and Nordin. Bone density was measured by dual energy X-ray densitometry (Norland X R20 X-ray bone densitometer) at the left hip and lumbar spine. Serum parathyroid hormone was measured by a chemiluminometric assay. RESULTS--Plasma ionized calcium concentration, alkaline phosphatase, bicarbonate, plasma creatinine and serum B2 microglobulin were significantly higher in the elderly than in the young, whereas plasma phosphate and the anion gap were higher in the young. Urinary excretion of calcium, phosphate and hydroxyproline were all higher in older women. Plasma parathyroid hormone concentration was positively correlated with age even after taking into account the decline in renal function (as indicated by the rise in B2 microglobulin (r = 0.506, P less than 0.001). Serum concentrations of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D were not lower in the older women. Fractional calcium absorption from an oral load of radiolabelled calcium was significantly lower in the older women and 37% of the older women were below the 2.5 percentile found in the younger women. Bone density measured by dual energy X-ray densitometry was also significantly lower in the elderly. CONCLUSION--In Chinese women there is an increase in PTH and a decrease in calcium absorption with age in spite of the presence of normal vitamin D metabolites.     

Seasonal changes in calciotropic hormones, bone markers, and bone mineral density in elderly women

Seasonal variation of serum vitamin D metabolites, PTH, bone turnover markers, and bone mineral density (BMD), adjusted for confounding variables, was studied in a cross-sectional population of 251 ambulatory elderly women aged 65-77 yr. A significant (P < 0.05) seasonal change was observed in serum 25 hydroxyvitamin D (25OHD), bone resorption marker (urine N-telopeptide), and BMD of the spine, total body, and mid-radius. Serum 25OHD was significantly lower (P < 0.05) in winter (December, January, February, March) compared with summer (June, July, August, September), with the nadir in February (68.4 +/- 6.74 nmol/liter) and the zenith in August (85.6 +/- 5.12 nmol/liter). Mean serum PTH levels were higher in winter when serum 25OHD was low, and mean serum PTH was lower in summer when serum 25OHD was high, although the seasonal change in serum PTH was not significant. The change in serum 1,25-dihydroxy vitamin D(3) paralleled that of serum 25OHD levels, but the seasonal effect was not significant. Mean 24-h urine N-telopeptide showed a significant seasonal change (P < 0.05); it was about 24% higher in February (zenith) compared with that in August (nadir). The zenith month of urine N-telopeptide levels corresponded to the nadir month of serum 25OHD levels and vice versa. A significant (P < 0.05) inverse correlation was observed between 24-h urine N-telopeptides and serum 25OHD levels. There was a significant (P < 0.05) seasonal change in mean BMD of spine, total body, and mid-radius. These changes paralleled those in serum 25OHD levels. Spine BMD was 8.4% higher in August (zenith) compared with that in February (nadir), whereas total body BMD and mid-radius BMD were 6.1 and 7.6% higher, respectively, in July (zenith) compared with that in January (nadir). There was a nonsignificant increase of 3.6% in total hip BMD. In summary (see Fig. 5), the seasonal changes in vitamin D metabolism in elderly women are closely associated with small changes in serum PTH, changes in bone resorption, and BMD.     

The course of biochemical parameters of bone turnover during treatment with corticosteroids

The mechanisms by which glucocorticoids cause osteopenia are incompletely understood. It is generally accepted that bone formation is depressed during corticosteroid treatment, but the cause of the ongoing bone resorption is less clear. Secondary hyperparathyroidism and changes in vitamin D metabolism are thought to play a role. This is based mostly on data from cross-sectional studies in heterogeneous patient groups. We, therefore, studied longitudinally the course of biochemical parameters and the hormones influencing bone turnover in a homogeneous group of 10 euthyroid patients with Graves' ophthalmopathy, all euthyroid for at least 1 yr before, during, and after a 12-week course of prednisone. Bone formation was depressed as reflected by a fall in serum osteocalcin (3.0 +/- 2.1, 1.7 +/- 1.1, and 2.4 +/- 1.9 micrograms/L at weeks 0, 4, and 12, respectively; P = 0.02) and in total alkaline phosphatase (1.15 +/- 0.33, 0.83 +/- 0.22, and 0.88 +/- 0.40 mukat/L; P = 0.001). Parameters of bone resorption (urinary hydroxyproline/creatinine ratio, serum acid phosphatase) and the levels of vitamin D metabolites remained unchanged. Serum intact PTH seemed to decrease slightly. Our findings suggest that glucocorticoid induced osteopenia is caused by a depressed bone formation in the presence of an unaltered but ongoing bone resorption. Secondary hyperparathyroidism and changes in vitamin D metabolism are apparently not involved.     

Abnormalities in circadian patterns of bone resorption and renal calcium conservation in type I osteoporosis.

We compared changes over 24 h in 15 postmenopausal normal women (mean [+/- SD] age, 64 +/- 7 yr) with those in 15 postmenopausal women with type I osteoporosis and vertebral fractures (mean age, 64 +/- 5 yr). The serum osteocalcin concentration, a sensitive index of bone formation, increased by about 5% at night in both groups. Urinary deoxypyridinoline excretion, a sensitive index of bone resorption, increased by 48% at night (P less than 0.01) in the normal women, whereas in the osteoporotic women it was 62% higher overall (P less than 0.05), and the increase persisted into the morning. At night, urinary fractional excretion of calcium decreased by 20% (P less than 0.001) in the normal women, but was unchanged in the osteoporotic women; this circadian pattern differed between groups (P less than 0.05). The serum ionized calcium concentration did not change at night in either group. There was a trend (P = 0.07) for blunting of the nocturnal increase in the serum intact PTH level in osteoporotic women. Thus, the nocturnal serum ionized calcium level is maintained by decreased urinary calcium excretion and increased bone resorption in postmenopausal normal women, but almost entirely by increased resorption in postmenopausal osteoporotic women. This greater dependence on bone resorption during the nocturnal fast may account in part for the greater bone loss in osteoporotic women.     

Changes in calcium and bone metabolism during treatment with low dose prednisone in young,healthy, male volunteers

Summary The effect of low dose prednisone on calcium and bone metabolism was evaluated in 8 healthy, young, male volunteers. Sodium and calcium intake were kept stable during the whole study period of 7 weeks. Week 0 was the baseline period; during week 1, 3 and 5 prednisone (10 mg/day) was given, during week 3 together with 500 mg elementary calcium and during week 5 with 4000 IU vitamin D on alternate days. During week 2, 4 and 6 no medication was given. No changes occurred in fasting urinary excretion of calcium or hydroxyproline, nor in serum levels of alkaline phosphatase, 25-Vitamin D, PTH, creatinine and inorganic phosphorus. A rapid decrease of serum osteocalcin during prednisone intake was found (p<0.01). This dip also occurred during prednisone and vitamin D treatment, but did not occur when calcium was added to prednisone, although the baseline value was lower at the start of combined treatment with prednisone and calcium. Serum calcium decreased during prednisone (p<0.05), but when prednisone was given together with calcium, an increase of serum calcium was found. (p<0.05).It is concluded that 10 mg prednisone/day decreases bone formation, as shown by its effect on osteocalcin, while no influence is seen on bone resorption. Thus, prednisone, even when used in low doses, influences bone metabolism by uncoupling bone formation (decreased) and bone resorption (unchanged). These data suggest that the Cs-associated decrease in serum osteocalcin and in serum calcium does not occur during calcium suppletion.     

Physiologic fluctuations of serum estradiol levels influence biochemical markers of bone resorption in young women

We investigated the effect of physiologic variations in sex hormone levels during the menstrual cycle on biomarkers of bone turnover. Blood and 24-h and fasting urine samples were obtained in nine women (age, 25.1+/-3.0 yr) with regular menstrual cycles during the early follicular period (t1), 3 days before ovulation (t2), 3 days after ovulation (t3), at the midluteal period (t4) and again during the early follicular period of the next cycle (t5). All subjects had a calcium intake covering current dietary recommendations (above 1,000 mg/day, standardized food record). Serum calcium, phosphorus, calcitriol, 24-h and 2-h fasting urinary calcium, and phosphorus excretion remained constant during the menstrual cycle. Serum 25-hydroxyvitamin D3 levels decreased slightly from the beginning until the end of the study (P<0.05), indicating low cutaneous vitamin D synthesis during wintertime. The serum levels of sex hormones showed typical monthly variations, with the lowest estradiol (E2) levels at t1 and t5. Fasting 2-h pyridinoline (Pyd) concentrations (a marker of bone resorption) fell from t1 to t3 and rose again at t5 (P<0.01). Similar variations were observed for the resorption marker deoxypyridinoline (Dpd; P<0.05). The amplitude of the two biomarkers was 32% and 33%, respectively. The serum levels of the carboxyterminal propeptide of type I collagen (a marker of bone formation) showed an inverse cyclic pattern, as compared with the pyridinium cross-links. Low concentrations were observed at t1; a rise occurred until t3 and was followed by a decrease until t5 (P<0.05). A similar cyclic pattern was observed for serum PTH levels, with the highest concentrations at t3 (P<0.05). Dpd and Pyd values were significantly correlated with serum E2 levels (r = 0.52; P<0.0001 and r = 0.50; P<0.001, respectively). Neither progesterone nor LH nor FSH was correlated with Pyd or Dpd levels. The data suggest that normal menstrual cycling in young women is associated with monthly fluctuations in bone turnover. This physiological effect of the menstrual cycle is most probably related to variations in serum E2 concentrations.     

Development and Treatment of Tertiary Hyperparathyroidism in Patients with Pseudohypoparathyroidism Type 1B

Context: Pseudohypoparathyroidism type 1B (PHP1B) patients have PTH resistance at the renal proximal tubule and develop hypocalcemia and secondary hyperparathyroidism. Hyperparathyroid bone disease also develops in some patients. PHP1B patients are at theoretical risk of developing tertiary hyperparathyroidism. Setting: Patients were studied in a clinical research center. Patients: Five female PHP1B patients presented with hypercalcemia and elevated PTH. Intervention: Patients either underwent parathyroidectomy (n = 4) or received cinacalcet (n = 1). Main Outcome Measures: Serum calcium and PTH were serially measured before and after intervention. Results: Five PHP1B patients developed concomitantly elevated serum calcium and PTH levels (range, 235-864 ng/liter) requiring termination of calcium and vitamin D therapy (time after diagnosis, 21-42 yr; median, 34 yr), consistent with tertiary hyperparathyroidism. Four patients underwent parathyroidectomy with removal of one (n = 2) or two (n = 2) enlarged parathyroid glands. Calcium and vitamin D therapy was reinstituted postoperatively, and at 93-month median follow-up, PTH levels ranged between 56 and 182 (normal, <87) ng/liter. One patient was treated with cinacalcet, resulting in resolution of hypercalcemia. Conclusions: PHP1B patients are at risk of developing tertiary hyperparathyroidism and/or hyperparathyroid bone disease and should therefore be treated with sufficient doses of calcium and vitamin D to achieve serum calcium and PTH levels within or as close to the normal range as possible. Surgery is the treatment of choice in this setting. Cinacalcet may be a useful alternative in those who do not undergo surgery.     

Effects of calcitriol or calcium on bone mineral density, bone turnover, and fractures in men with primary osteoporosis: a two-year randomized, double blind, double placebo study.

Osteoporosis in men is an emerging public health problem. As calcitriol reduces the rate of vertebral fractures in osteoporotic postmenopausal women, we conducted a prospective study of this treatment in men with primary osteoporosis. Our study was a 2-yr, randomized, double masked, double placebo-controlled trial of calcitriol (0.25 microg twice daily) or calcium (500 mg twice daily) in 41 men with primary osteoporosis and at least 1 baseline fragility fracture. Thirty-three men (85%) completed the study. There were no differences in baseline characteristics. Spinal and femoral neck bone mineral densities at 2 yr were unchanged in both groups. Serum osteocalcin decreased in both groups by 30% (P < 0.05), whereas urine N-telopeptide cross-links decreased only in the calcium group by 30% (P < 0.05). After 2 yr, fractional calcium absorption increased by 34% (P < 0.01) in the calcitriol group. Nineteen incident fragility fractures occurred (14 vertebral and 5 nonvertebral) in 7 men. Over 2 yr, the number of men with vertebral fractures (6 vs. 1; P = 0.097) was similar in both groups. In conclusion, the efficacy of calcitriol remains unproven as a single agent for the treatment of osteoporosis in men.     

Deranged bone mineral metabolism in chronic alcoholism

Chronic alcoholic subjects may suffer from osteopenia with either osteomalacia or osteoporosis as the main histologic finding. The reasons may be multifactorial, including nutrition, direct effects of alcohol on bone, and deranged liver function. Seventeen asymptomatic subjects with chronic alcoholism were studied. Serum PTH (carboxyl and midmolecule fragments), 25 hydroxyvitamin D [25(OH)D], 1-25 dihydroxyvitamin D [1-25(OH)2D], and ionized calcium were measured in each subject. In addition to these tests, we employed a sensitive technique of dual photon absorptiometry to measure vertebral bone density and a radioimmunoassay of serum bone gla protein (BGP) to estimate osteoblast function. Our results show that subjects suffering from chronic alcoholism had significantly lower serum 25(OH)D and higher ionized calcium, BGP, PTH (midmolecule) and 1,25(OH)2D while four patients had bone density values below the fracture threshold (0.96 g/cm2). These findings demonstrate that asymptomatic patients with chronic alcoholism have deranged bone mineral metabolism including abnormal BGP and some subjects may even have abnormal dual photon absorptiometry measurements. These particular subjects may be at risk in the future for developing osteopenia and consequent vertebral compression fractures.     

Lack of insulin-like growth factor I exaggerates the effect of calcium deficiency on bone accretion in mice

Recent studies provide evidence that the GH/IGF-I axis plays a critical role in the regulation of bone accretion that occurs during puberty and that the peak bone mineral density (BMD) is dependent on the amount of dietary calcium intake during the active growth phases. To evaluate whether IGF-I deficiency exaggerates the effect of calcium deficiency on bone accretion during active growth phases, IGF-I knockout (KO) and wild-type (WT) mice were fed with low calcium (0.01%) or normal calcium (0.6%) for 2 wk during the pubertal growth phase and were labeled with tetracycline. The low calcium diet caused significant decreases in endosteal bone formation parameters and a much greater increase in the resorbing surface of both the endosteum and periosteum of the tibia of IGF-I KO mice compared with WT mice. Accordingly, femur BMD measured by dual energy x-ray absorptiometry or peripheral quantitative computed tomography increased significantly in IGF-I WT mice fed the low calcium diet, but not in IGF-I KO mice. IGF-I-deficient mice fed the normal calcium diet showed elevated PTH levels, decreased serum 1,25-dihydroxyvitamin D and serum calcium levels at baseline. Serum calcium changes due to calcium deficiency were greater in IGF-I KO mice compared with WT mice. PTH levels were 7-fold higher in IGF-I KO mice fed normal calcium compared with WT mice, which was further elevated in mice fed the low calcium diet. Treatment of IGF-I-deficient lit/lit mice with GH decreased the serum PTH level by 70% (P < 0.01). Based on these and past findings, we conclude that: 1) IGF-I deficiency exaggerates the negative effects of calcium deficiency on bone accretion; and 2) IGF-I deficiency may lead to 1,25-dihydroxyvitamin D deficiency and elevated PTH levels even under normal calcium diet.     

Relation between low calcium intake, parathyroid hormone, and blood pressure

In a population health survey in 1995, serum parathyroid hormone (PTH) was measured in 1113 subjects, aged 30 to 79 years, and was found to be elevated (>6.9 pmol/L) in 118 subjects. In 1998, this group and 131 subjects with normal PTH levels were invited for reexamination, and 82 and 90 subjects from each respective group attended the follow-up. At the follow-up, 72 subjects had elevated and 100 had normal serum PTH levels. Those with elevated serum PTH levels (8 subjects with hyperparathyroidism were excluded) had significantly lower serum calcium levels and intake of calcium than those with normal PTH (2.24+/-0.09 and 2.29+/-0.10 mmol/L [mean+/-SD] and 400.3+/-227.3 and 592.1+/-459.6 mg/d, respectively; P<0.01). Serum levels or intake of vitamin D did not differ between the 2 groups. Subjects with elevated PTH in both 1995 and 1998 had significantly lower bone mineral content and bone mineral density in the lumbar spine than did those with persistently normal PTH levels (P<0.05). In the females, but not in the males, the systolic and diastolic blood pressures were significantly higher in those with elevated serum PTH (158.0+/-27.5 versus 141.5+/-19.2 mm Hg and 90. 5+/-13.6 versus 82.6+/-8.6 mm Hg, respectively; P<0.01). This difference was even more pronounced when those with persistently elevated PTH were considered separately. In conclusion, reduced intake of calcium is frequently associated with high levels of serum PTH. This is associated with moderately reduced bone mineral content and bone mineral density in the lumbar spine. In women, high levels of serum PTH are also associated with markedly increased blood pressure.