Joseph E Zerwekh

PhD
Medical City Hospital, Dallas · Director, Clinical Research

Publications

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    ABSTRACT: This cross-sectional study was performed to characterize the factors affecting bone mass in male hemodialysis subjects. We found that of all the factors analyzed, the strongest correlation was with body mass index. In fact, after adjusting for body weight, the correlations with bone turnover markers and sex hormones were no longer significant. PURPOSE: Abnormalities in bone and mineral metabolism are commonly seen in patients with end-stage renal disease, reducing bone quality and raising the risk of fracture. This cross-sectional study was performed to characterize risk factors affecting bone mass among male hemodialysis subjects. METHODS: For this cross-sectional study, we recruited 66 men from three local hemodialysis units. Subjects received dual emission X-ray absorptiometry assessment of three sites (lumbar spine, hip, and distal radius) and the values were correlated with the levels of sex hormones, non-renally excreted bone turnover markers, and mineral metabolism markers. RESULTS: Subjects were found to have bone mineral density (BMD) reduced predominantly at the distal radius, with Z score < -2 seen in 15.4 % and T score < -2.5 in 21 % of men. Independent predictors of bone density included levels of bone-specific alkaline phosphatase and tartrate-resistant acid phosphatase 5b, which were inversely correlated with the femoral neck Z score. Factors positively associated with an increased Z score included body mass index at all sites and free estradiol levels at the hip and distal radius. Markers of mineral metabolism (e.g., calcium, phosphate, and 25-hydroxyvitamin D) were not correlated with Z scores of any site or with bone turnover markers. After adjusting for body weight, the associations between BMD, sex hormones, and bone turnover markers were no longer significant. CONCLUSION: We recommend that future studies seeking to assess the factors affecting bone strength among male hemodialysis subjects incorporate a weight-adjusted analysis. Additionally, dialysis-dependent men receiving dual emission X-ray absorptiometry should have the distal radius site added to the standard assessment.
    Archives of Osteoporosis 11/2012; DOI:10.1007/s11657-012-0110-3
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    ABSTRACT: Wnt/β-catenin signaling is a critical regulator of skeletal physiology. However, previous studies have mainly focused on its roles in osteoblasts, while its specific function in osteoclasts is unknown. This is a clinically important question because neutralizing antibodies against Wnt antagonists are promising new drugs for bone diseases. Here, we show that in osteoclastogenesis, β-catenin is induced during the macrophage colony-stimulating factor (M-CSF)-mediated quiescence-to-proliferation switch but suppressed during the RANKL-mediated proliferation-to-differentiation switch. Genetically, β-catenin deletion blocks osteoclast precursor proliferation, while β-catenin constitutive activation sustains proliferation but prevents osteoclast differentiation, both causing osteopetrosis. In contrast, β-catenin heterozygosity enhances osteoclast differentiation, causing osteoporosis. Biochemically, Wnt activation attenuates whereas Wnt inhibition stimulates osteoclastogenesis. Mechanistically, β-catenin activation increases GATA2/Evi1 expression but abolishes RANKL-induced c-Jun phosphorylation. Therefore, β-catenin exerts a pivotal biphasic and dosage-dependent regulation of osteoclastogenesis. Importantly, these findings suggest that Wnt activation is a more effective treatment for skeletal fragility than previously recognized that confers dual anabolic and anti-catabolic benefits.
    Molecular and Cellular Biology 08/2011; 31(23):4706-19. DOI:10.1128/MCB.05980-11 · 5.04 Impact Factor
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    ABSTRACT: The classic definition of hypercalciuria, an upper normal limit of 200  mg/day, is based on a constant diet restricted in calcium, sodium, and animal protein; however, random diet data challenge this. Here our retrospective study determined the validity of the classic definition of hypercalciuria by comparing data from 39 publications analyzing urinary calcium excretion on a constant restricted diet and testing whether hypercalciuria could be defined when extraneous dietary influences were controlled. These papers encompassed 300 non-stone-forming patients, 208 patients with absorptive hypercalciuria type I (presumed due to high intestinal calcium absorption), and 234 stone formers without absorptive hypercalciuria; all evaluated on a constant restricted diet. In non-stone formers, the mean urinary calcium was well below 200  mg/day, and the mean for all patients was 127±46  mg/day with an upper limit of 219  mg/day. In absorptive hypercalciuria type I, the mean urinary calcium significantly exceeded 200  mg/day in all studies with a combined mean of 259±55  mg/day. Receiver operating characteristic curve analysis showed the optimal cutoff point for urinary calcium excretion was 172  mg/day on a restricted diet, a value that approximates the traditional limit of 200  mg/day. Thus, on a restricted diet, a clear demarcation was seen between urinary calcium excretion of kidney stone formers with absorptive hypercalciuria type I and normal individuals. When dietary variables are controlled, the classic definition of hypercalciuria of nephrolithiasis appears valid.
    Kidney International 07/2011; 80(7):777-82. DOI:10.1038/ki.2011.227 · 8.52 Impact Factor
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    Bone 05/2011; 48. DOI:10.1016/j.bone.2011.03.353 · 4.46 Impact Factor
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    ABSTRACT: Hyperoxaluria is a major risk factor for kidney stone formation. Although urinary oxalate measurement is part of all basic stone risk assessment, there is no standardized method for this measurement. Urine samples from 24-h urine collection covering a broad range of oxalate concentrations were aliquoted and sent, in duplicates, to six blinded international laboratories for oxalate, sodium and creatinine measurement. In a second set of experiments, ten pairs of native urine and urine spiked with 10 mg/L of oxalate were sent for oxalate measurement. Three laboratories used a commercially available oxalate oxidase kit, two laboratories used a high-performance liquid chromatography (HPLC)-based method and one laboratory used both methods. Intra-laboratory reliability for oxalate measurement expressed as intraclass correlation coefficient (ICC) varied between 0.808 [95% confidence interval (CI): 0.427-0.948] and 0.998 (95% CI: 0.994-1.000), with lower values for HPLC-based methods. Acidification of urine samples prior to analysis led to significantly higher oxalate concentrations. ICC for inter-laboratory reliability varied between 0.745 (95% CI: 0.468-0.890) and 0.986 (95% CI: 0.967-0.995). Recovery of the 10 mg/L oxalate-spiked samples varied between 8.7 ± 2.3 and 10.7 ± 0.5 mg/L. Overall, HPLC-based methods showed more variability compared to the oxalate oxidase kit-based methods. Significant variability was noted in the quantification of urinary oxalate concentration by different laboratories, which may partially explain the differences of hyperoxaluria prevalence reported in the literature. Our data stress the need for a standardization of the method of oxalate measurement.
    Nephrology Dialysis Transplantation 03/2011; 26(12):3954-9. DOI:10.1093/ndt/gfr147 · 3.37 Impact Factor
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    ABSTRACT: Estrogen regulation of the male skeleton was first clearly demonstrated in patients with aromatase deficiency or a mutation in the ERα gene. Estrogen action on the skeleton is thought to occur mainly through the action of the nuclear receptors ERα and ERβ. Recently, in vitro studies have shown that the G protein-coupled receptor GPR30 is a functional estrogen receptor (ER). GPR30-deficient mouse models have been generated to study the in vivo function of this protein; however, its in vivo role in the male skeleton remains underexplored. We have characterized size, body composition, and bone mass in adult male Gpr30 knockout (KO) mice and their wild-type (WT) littermates. Gpr30 KO mice weighed more and had greater nasal-anal length (p < .001). Both lean mass and percent body fat were increased in the KO mice. Femur length was greater in Gpr30 KO mice, as was whole-body, spine, and femoral areal bone mineral density (p < .01). Gpr30 KO mice showed increased trabecular bone volume (p < .01) and cortical thickness (p < .001). Mineralized surface was increased in Gpr30 KO mice (p < .05). Bromodeoxyuridine (BrdU) labeling showed greater proliferation in the growth plate of Gpr30 KO mice (p < .05). Under osteogenic culture conditions, Gpr30 KO femoral bone marrow cells produced fewer alkaline phosphatase-positive colonies in early differentiating osteoblast cultures but showed increased mineralized nodule deposition in mature osteoblast cultures. Serum insulin-like growth factor 1 (IGF-1) levels were not different. These data suggest that in male mice, GPR30 action contributes to regulation of bone mass, size, and microarchitecture by a mechanism that does not require changes in circulating IGF-1.
    Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 02/2011; 26(2):298-307. DOI:10.1002/jbmr.209 · 6.04 Impact Factor
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    ABSTRACT: We examined the effect of fluoride (F) on intracellular ionic calcium [Ca2+]i in normal human osteoblasts maintained in culture. Cells were grown on glass coverslips to near-confluency and loaded with the Ca-sensitive dye, fura-2AM. Fluorescence changes were monitored in single cells using an inverted microscope coupled by fiberoptic to a microspectrofluorometer. The addition of F (100 ng/mL) to the medium promoted a rapid and significant increase in free [Ca2+]i from a resting level of 245 +/- 36 SE nM to a peak concentration of 440 +/- 51 nM (p less than 0.04). This increase in [Ca2+]i began at 10-20 s after addition of F and was maximal by 30 s. Intracellular [Ca2+]i levels then returned to near resting values by 60-80 s after F addition. This response was evident with as little as 25 ng/ml of fluoride and was dose dependent up to 500 ng/ml. At concentrations greater than 500 ng/ml, there appeared to be an attenuation of the rise in [Ca2+]i. The observed rise in [Ca2+]i was dependent on extracellular calcium since lowering extracellular calcium concentration or incubation with calcium channel blockers abolished the response. This observation supports a role of increased [Ca2+]i as one of the initial events of fluoride on action osteoblasts.
    Journal of Bone and Mineral Research 03/2010; 5 Suppl 1(S1):S131-6. DOI:10.1002/jbmr.5650051320 · 6.59 Impact Factor
  • Charles Y. C. Pak, Khashayar Sakhaee, Joseph E. Zerwekh
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    ABSTRACT: Long-term clinical effects of intermittent sodium fluoride (slow-release) therapy were assessed in 71 patients with primary osteoporosis. In Group I (receiving 1,25-(OH)2D3 2 micrograms/day for 2 weeks before 3 months of sodium fluoride treatment 25 mg twice a day, in each 5-month cycle), vertebral (L2-L4) bone mineral content did not change significantly. However, the L2-L4 bone mineral content significantly increased by 3.1% in Group II (those who did not receive 1,25-(OH)2D3 during 5-month cycle), 3.5% per patient year in Group III (combined NaF 25 mg twice a day with 1,25-(OH)2D3 0.5 micrograms/day for 12 months in each 13-month cycle), and by 7.8% per patient year in Group IV (combined NaF with calcium citrate for 12 months in each 13-month cycle). The rise in vertebral bone mineral content was sustained, with an annual increment of 4.2% during the third year compared with 4.4% during the first year. The vertebral fracture rate declined significantly from the pretreatment value in all groups, but comparison with a placebo control group was not available. There was no significant change in the bone density of the radial shaft or of the proximal femur. The rate of hip fracture (nontraumatic) during treatment was 1.8% per patient year, the same as before treatment. The drug was well tolerated with only minor infrequent gastrointestinal and rheumatic side effects. Thus, intermittent slow-release sodium fluoride treatment with adequate calcium supplementation augments spinal bone mass and apparently inhibits vertebral fractures, with a satisfactory safety of usage; however, it has no effect on appendicular bone mass or on hip fracture rate.(ABSTRACT TRUNCATED AT 250 WORDS)
    Journal of Bone and Mineral Research 03/2010; 5 Suppl 1(S1):S149-55. DOI:10.1002/jbmr.5650051323 · 6.59 Impact Factor
  • Bone 01/2010; 47. DOI:10.1016/j.bone.2010.04.072 · 4.46 Impact Factor
  • Joseph E. Zerwekh, Peter Antich, Charles Y. C. Pak
    Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 12/2009; 11(9):1370 - 1371. DOI:10.1002/jbmr.5650110924 · 6.04 Impact Factor
  • Joseph E Zerwekh
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    ABSTRACT: There have been relatively few studies of bone mass in children with idiopathic hypercalciuria (IH). When performed, bone mineral density (BMD) measurements have consistently disclosed decreased Z-scores for children with IH at the lumbar spine and, to a lesser extent, at the femoral neck. Few investigations have delineated the nature of the mechanism(s) that may contribute to the bone loss in these children. Some studies have been consistent, showing increased bone resorption as the probable mechanism of bone loss. To date, there have been no reports regarding the assessment of biochemical markers specific for bone formation in children with IH. However, since most of the children with IH in these reports had demonstrated normal longitudinal growth, it seems less likely that there is an alteration in bone formation. The causes for increased bone resorption also are not firmly established, but genetics, dietary indiscretions, and altered cytokine production have been proposed as being contributory to the decreased BMD observed in these children with IH. Optimal bone mineral accretion during childhood and adolescence is important in attaining peak bone mass and may serve to prevent the development of osteoporosis in adulthood. Thus, a better understanding of bone loss in children with IH is warranted.
    Pediatric Nephrology 11/2009; 25(3):395-401. DOI:10.1007/s00467-009-1338-z · 2.88 Impact Factor
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    ABSTRACT: 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.
    Journal of Bone and Mineral Research 08/2009; 10(8):1218-24. DOI:10.1002/jbmr.5650100812 · 6.59 Impact Factor
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    ABSTRACT: High [HCO(3)(-)] inhibits and low [HCO(3)(-)] stimulates bone resorption, which mediates part of the effect of chronic acidosis or acid feeding on bone. Soluble adenylyl cyclase (sAC) is a bicarbonate sensor that can potentially mediate the effect of bicarbonate on osteoclasts. Osteoclasts were incubated in 0, 12, and 24 mM HCO(3)(-) at pH 7.4 for 7-8 days and assayed for tartrate-resistant acid phosphatase (TRAP) and vacuolar-ATPase expression, and H+ accumulation. Total number and area of TRAP (+) multinucleated osteoclasts was decreased by HCO(3)(-) in a dose-dependent manner. V-ATPase expression and H+ accumulation normalized to cell cross-sectional area or protein were not significantly changed. The HCO(3)(-) -induced inhibition of osteoclast growth and differentiation was blocked by either 2-hydroxyestradiol, an inhibitor of sAC or sAC knockdown by sAC specific siRNA. The model of HCO(3)(-) inhibiting osteoclast via sAC was further supported by the fact that the HCO(3)(-) dose-response on osteoclasts is flat when cells were saturated with 8-bromo-cAMP, a permeant cAMP analog downstream from sAC thus simulating sAC activation. To confirm our in vitro findings in intact bone, we developed a 1-week mouse calvaria culture system where osteoclasts were shown to be viable. Bone volume density (BV/TV) determined by micro-computed tomography (microCT), was higher in 24 mM HCO(3)(-) compared to 12 mM HCO(3)(-) treated calvaria. This HCO(3)(-) effect on BV/TV was blocked by 2-hydroxyestradiol. In summary, sAC mediates the inhibition of osteoclast function by HCO(3)(-), by acting as a HCO(3)(-) sensor.
    Journal of Cellular Physiology 08/2009; 220(2):332-40. DOI:10.1002/jcp.21767 · 3.87 Impact Factor
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    ABSTRACT: The Westernized diet is acidogenic due to the high content of sulfur-containing amino acids and relative deficiency of potassium organic anions. Chronic acid loads result in hypercalciuria and negative calcium balance often associated with loss of bone mineral. Alkali therapy tends to reverse the hypercalciuria but little is known regarding its effect on bone as assessed by bone histomorphometry. The present study utilized dynamic bone histomorphometry to evaluate the effects of alkali therapy on acid-induced changes in bone turnover. Serum and urine analyses and bone histomorphometry were assessed in adult rats after 2 months of either a low casein (LC) or high casein (HC) diet supplemented with either potassium chloride (KCl) or potassium citrate (KCit). Compared to animals on LC-KCl diet, HC-KCl diet delivered a substantial acid load as shown by significant increases in urinary sulfate, ammonium, and net acid excretion, and a lower urinary pH and citrate excretion without detectable changes in serum parameters. The acid load also resulted in hypercalciuria. Dynamic and static bone histomorphometry disclosed a significant reduction in cancellous bone volume and trabecular number associated with a 2.5-fold increase in eroded and a 3.5-fold increase in osteoclastic surfaces. There was also a near 2-fold increase in bone formation rate in rats on the HC-KCl diet. When animals on the HC diet were given KCit instead of KCl, all of the aforementioned changes in urine biochemistry and bone turnover were significantly attenuated or entirely prevented. These findings underscore the deleterious effects of high animal protein intake in promoting hypercalciuria and increasing bone turnover. Co-administration of potassium alkali attenuates or prevents these changes. In this animal model of high dietary animal protein intake, the major skeletal effect of alkali therapy is to reduce bone resorption, with little or no effect on bone formation.
    Bone 08/2009; 45(5):1004-9. DOI:10.1016/j.bone.2009.07.077 · 4.46 Impact Factor
  • J. E. Zerwekh
    Bone 06/2009; 44. DOI:10.1016/j.bone.2009.03.027 · 4.46 Impact Factor
  • Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 05/2009; 11(5):561 - 564. DOI:10.1002/jbmr.5650110502 · 6.04 Impact Factor
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    ABSTRACT: Bisphosphonates are the most commonly prescribed medications for the treatment of osteoporosis. Although existing evidence supports a good safety profile, there is concern that chronic administration of these agents could result in severe suppression of bone turnover with increased risk of nonvertebral fractures. The objective of this study was to report the clinical presentation, selected bone histomorphometry and X-ray images of patients who developed mid-shaft long bone fractures during bisphosphonate therapy, six of whom had bone biopsy for histomorphometery. Of the 13 patients who sustained atraumatic mid-shaft fractures, 10 were on alendronate and three were on risedronate therapy before the fractures. In addition to bisphosphonates, three patients were on oestrogen and two on tamoxifen concomitantly. Four patients with glucocorticoid-induced osteoporosis were on alendronate for 3-11 years along with glucocorticoid therapy. Bone histomorphometry showed severe suppression of bone turnover in five patients and low bone turnover in one patient. Long-term bisphosphonate therapy may increase the risk of unusual long bone mid-shaft fractures. This is probably due to prolonged suppression of bone turnover, which could lead to accumulation of microdamage and development of hypermineralized bone. At present, the scope of this complication in the larger context of patients receiving bisphosphonate therapy remains unknown, but appears to be small.
    Clinical Endocrinology 04/2009; 72(2):161-8. DOI:10.1111/j.1365-2265.2009.03581.x · 3.35 Impact Factor
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    ABSTRACT: The Equil 2 computer program has been questioned by the new Joint Expert Speciation System program (Mayhem Unit Trust and Council for Scientific and Industrial Research, Pretoria, South Africa) for estimating the urinary saturation of stone forming salts to gauge the propensity for stone formation. To attempt resolution the supersaturation index according to the Joint Expert Speciation System and the relative saturation ratio according to Equil 2 were compared with the semi-empirically derived concentration-to-product ratio. Data were obtained from a recent article in The Journal of Urology(R), in which pH, calcium and citrate were varied over a wide range in 72 urine samples. We calculated the relative saturation ratio and the supersaturation index of brushite, and compared them with the available concentration-to-product ratio derived from the growth or dissolution of synthetic brushite. The mean concentration-to-product ratio did not differ from the supersaturation index but the concentration-to-product ratio and the supersaturation index were significantly lower than the relative saturation ratio (p <0.004). On the saturation value and urinary variable plot the relative saturation ratio could be readily distinguished from the concentration-to-product ratio because it was consistently and significantly higher. While the supersaturation index pattern was similar to the concentration-to-product ratio, the supersaturation index was slightly lower at high urinary pH and calcium, and slightly higher at lower urinary pH and calcium (p <0.001). When the Ca(2)H(2)(PO(4))(2) complex was deleted from the Joint Expert Speciation System, the corrected supersaturation index was not significantly different from the relative saturation ratio determined by Equil 2. The relative saturation ratio overestimates brushite saturation by about 80%. The supersaturation index yields a good approximation of brushite saturation at modest degrees of saturation but it overestimates saturation at low pH or calcium (low saturation) and underestimates it at high pH or calcium (high saturation).
    The Journal of urology 03/2009; 181(3):1423-8. DOI:10.1016/j.juro.2008.10.141 · 3.75 Impact Factor
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    ABSTRACT: It has been suggested that fluoride therapy, while increasing bone mass, produces bone with inferior mechanical properties. In the present report this hypothesis was tested using a novel reflection ultrasound technique. Transiliac crest bone biopsies were obtained from 16 patients with osteoporosis and vertebral compression fractures (12 women and 4 men, mean age 56 years) before and after approximately 2 years of intermittent slow-release sodium fluoride therapy (25 mg twice a day) combined with continuous calcium citrate supplementation. Samples were analyzed by a reflection ultrasound method, which analyzes ultrasound velocity with a sample site resolution of 200 microns and thus provides a measure of the mechanical property of single trabeculae (material). For the group, mean fractional change in velocity increased 6.1 +/- 2.3% (SEM) from a mean value of 3303 +/- 80 to 3484 +/- 55 m/s (p = 0.028). A total of 13 patients (81%) demonstrated higher velocities after treatment. Thus reflection ultrasound analysis of bone appears to provide a sensitive means of assessing changes in the material property of bone. Furthermore, these results suggest that the treatment regimen utilized in these patients improves strength of bone at the material or trabecular level largely independently of change in bone mass. The combination therapy also increased spinal (L2-L4) bone density for the group as assessed by dual-photon absorptiometry (5.3 +/- 2.0%). There was no significant correlation between the change in ultrasound velocity and bone density (r = 0.0026, p = 0.996).(ABSTRACT TRUNCATED AT 250 WORDS)
    Journal of Bone and Mineral Research 03/2009; 6(3):239-44. DOI:10.1002/jbmr.5650060305 · 6.59 Impact Factor
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    ABSTRACT: Osteopetrosis is a congenital metabolic bone disease characterized by skeletal sclerosis resulting from defective osteoclast-mediated bone resorption. Osteopetrosis has been described in several animal species (mouse, rat, and rabbit) and in children. Bone marrow transplantation, originally shown to reverse the skeletal sclerosis in some animal mutations, has been effective in curing osteopetrosis in some children. Unfortunately, not all children with osteopetrosis are candidates for or respond to bone marrow transplantation. Recent studies have shown that several animal mutations and some children inheriting osteopetrosis have significantly elevated serum levels of 1,25-(OH)2D. Based on the possibility that there may be a resistance to 1,25-(OH)2D, high-dose calcitriol therapy has been used to treat some children and stimulated some parameters of resorption. In this study, we have examined the effects of high-dose calcitriol therapy on various serum and skeletal parameters in the osteopetrotic rabbit. Mutant rabbits and normal littermates were given continuous infusions of calcitriol via subcutaneously implanted osmotic minipumps for 2 weeks at a dose of 0.5, 2.5, or 25 micrograms/kg/per day. Untreated mutant rabbits are hypocalcemic and hypophosphatemic in the presence of elevated serum 1,25-(OH)2 levels in comparison with their normal littermates. Calcitriol infusions resulted in dose-dependent increases in circulating 1,25-(OH)2D levels in both normal and mutant rabbits. However, evaluation of other serum parameters and the skeletal response demonstrated significant differences between osteopetrotic and normal rabbits. At the highest dose, normal animals rapidly became hypercalcemic and osteoporotic, accompanied by weight loss and a failure to thrive; mutants remained hypocalcemic and osteopetrotic but did not exhibit the deleterious physical effects seen in treated normal littermates. Although the number of osteoclasts increased in both mutants and normals, osteoclast phenotype in the former remained abnormal. These data indicate that although very high levels of circulating 1,25-(OH)2D were achieved in osteopetrotic mutants, activation of osteoclast-mediated bone resorption with subsequent improvement of skeletal sclerosis was not observed.
    Journal of Bone and Mineral Research 02/2009; 4(1):57-67. DOI:10.1002/jbmr.5650040109 · 6.59 Impact Factor

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