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Marc K Drezner

Publications and source records attributed to Marc K Drezner.

14 recordsLinked to original sources
PubMed2006

Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism.

The osteocyte, a terminally differentiated cell comprising 90%-95% of all bone cells, may have multiple functions, including acting as a mechanosensor in bone (re)modeling. Dentin matrix protein 1 (encoded by DMP1) is highly expressed in osteocytes and, when deleted in mice, results in a hypomineralized bone phenotype. We investigated the potential for this gene not only to direct skeletal mineralization but also to regulate phosphate (P(i)) homeostasis. Both Dmp1-null mice and individuals with a newly identified disorder, autosomal recessive hypophosphatemic rickets, manifest rickets and osteomalacia with isolated renal phosphate-wasting associated with elevated fibroblast growth factor 23 (FGF23) levels and normocalciuria. Mutational analyses showed that autosomal recessive hypophosphatemic rickets family carried a mutation affecting the DMP1 start codon, and a second family carried a 7-bp deletion disrupting the highly conserved DMP1 C terminus. Mechanistic studies using Dmp1-null mice demonstrated that absence of DMP1 results in defective osteocyte maturation and increased FGF23 expression, leading to pathological changes in bone mineralization. Our findings suggest a bone-renal axis that is central to guiding proper mineral metabolism.

Adult↗
PubMed2006

HPLC method for 25-hydroxyvitamin D measurement: comparison with contemporary assays.

BACKGROUND: The concentration of 25-hydroxyvitamin D [25(OH)D] in serum has been designated the functional indicator of vitamin D (VitD) nutritional status. Unfortunately, variability among 25(OH)D assays limits clinician ability to monitor VitD status, supplementation, and toxicity. METHODS: We developed an HPLC method that selectively measures 25-hydroxyvitamin D2 [25(OH)D2] and D3 [25(OH)D3] and compared this assay with a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method, a competitive protein-binding assay (CPBA) on the Nichols Advantage platform, and an RIA from Diasorin. RESULTS: For the new HPLC assay, between-run CVs were 2.6%-4.9% for 25(OH)D3 and 3.2%-13% for 25(OH)D2; recoveries were 95%-102%; and the assay was linear from 5 microg/L to at least 200 microg/L. Comparison data were as follows: for HPLC vs LC-MS/MS, y = 1.01x - 4.82 microg/L (Sy/x = 4.93 microg/L; r = 0.996) for 25(OH)D3, and y = 0.902x - 0.566 microg/L (Sy/x = 2.56 microg/L; r = 0.9965 for 25(OH)D2; for HPLC vs Diasorin RIA, y = 0.709x - 5.86 microg/L (Sy/x = 7.35 microg/L; r = 0.7509); and for HPLC vs Nichols Advantage CPBA, y = 1.00x - 3.60 microg/L (Sy/x = 32.7 microg/L; r = 0.6823). CONCLUSIONS: The new HPLC method is reliable, robust, and has advantages compared with the Nichols Advantage CPBA and the Diasorin RIA. The Nichols Advantage CPBA overestimated or underestimated 25(OH)D concentrations predicated on the prevailing metabolite present in patients' sera.

25-Hydroxyvitamin D 2↗
PubMed2006

Intravenous ibandronate injections in postmenopausal women with osteoporosis: one-year results from the dosing intravenous administration study.

OBJECTIVE: Although oral bisphosphonates are effective treatments for postmenopausal women with osteoporosis, oral dosing may be unsuitable for some patients. An efficacious intravenously administered bisphosphonate could be beneficial for such patients. Ibandronate, a potent nitrogen-containing bisphosphonate, can be administered using extended dosing intervals, either orally or by rapid intravenous injection. The aim of this study was to identify the optimal intravenous dosing regimen for ibandronate in postmenopausal women with osteoporosis. METHODS: In a randomized, double-blind, double-dummy, phase III, noninferiority study, we compared 2 regimens of intermittent intravenous injections of ibandronate (2 mg every 2 months and 3 mg every 3 months) with a regimen of 2.5 mg of oral ibandronate daily, the latter of which has proven antifracture efficacy. The study group comprised 1,395 women (ages 55-80 years) who were at least 5 years postmenopausal. All patients had osteoporosis (lumbar spine [L2-L4] bone mineral density [BMD] T score less than -2.5). Participants also received daily calcium (500 mg) and vitamin D (400 IU). The primary end point was change from baseline in lumbar spine BMD at 1 year. Changes in hip BMD and in the level of serum C-telopeptide of type I collagen (CTX) were also measured, as were safety and tolerability. RESULTS: At 1 year, mean lumbar spine BMD increases were as follows: 5.1% among 353 patients receiving 2 mg of ibandronate every 2 months, 4.8% among 365 patients receiving 3 mg of ibandronate every 3 months, and 3.8% among 377 patients receiving 2.5 mg of oral ibandronate daily. Both of the intravenous regimens not only were noninferior, but also were superior (P < 0.001) to the oral regimen. Hip BMD increases (at all sites) were also greater in the groups receiving medication intravenously than in the group receiving ibandronate orally. Robust decreases in the serum CTX level were observed in all arms of the study. Both of the intravenous regimens were well tolerated and did not compromise renal function. CONCLUSION: As assessed by BMD, intravenous injections of ibandronate (2 mg every 2 months or 3 mg every 3 months) are at least as effective as the regimen of 2.5 mg orally daily, which has proven antifracture efficacy, and are well tolerated.

Administration, Oral↗
PubMed2004

Interobserver reproducibility of criteria for vertebral body exclusion.

UNLABELLED: We studied reproducibility of the ISCD vertebral exclusion criteria among four interpreters. Surprisingly, agreement among interpreters was only moderate, because of differences in threshold for diagnosing focal structural defects and choice of which vertebra among a pair discordant for T-score, area, or BMC to exclude. Our results suggest that reproducibility may be improved by specifically addressing the sources of interobserver disagreement. INTRODUCTION: Although DXA is widely used to measure vertebral BMD, its interpretation is subject to multiple confounders including osteoarthritis, aortic calcification, and scoliosis. In an attempt to standardize interpretation and minimize the impact of artifacts, the International Society for Clinical Densitometry (ISCD) established criteria for vertebral exclusion, including the presence of a focal structural defect (FSD), discrepancy of >1 SD in T-score between adjacent vertebrae, and a lack of increase in BMC or area from L1 to L4. Whereas the efforts of the ISCD represent an important advance in BMD interpretation, the interobserver reproducibility with application of these criteria is unknown. We hypothesized that there would be substantial agreement among four interpreters regarding application of the exclusion criteria and the final lumbar spine T-score. MATERIALS AND METHODS: Each interpreter read a set of 200 lumbar DXA scans obtained on male veterans, applying the ISCD vertebral body exclusion criteria. RESULTS: Surprisingly, agreement among interpreters was only moderate. Differences in interpretation resulted from differing thresholds for recognition of FSD and the choice of excluding the upper or lower vertebral body for the criteria requiring comparison between adjacent vertebrae. CONCLUSIONS: Despite their apparent simplicity, the ISCD vertebral exclusion criteria are difficult to apply consistently. In principle, appropriate refinement of the exclusion criteria may significantly improve interobserver agreement.

Absorptiometry, Photon↗
PubMed2004

Recalculation of the NHANES database SD improves T-score agreement and reduces osteoporosis prevalence.

UNLABELLED: In attempt to improve diagnostic agreement between manufacturers, a recent software update incorporated NHANES III data in GE Lunar densitometers. As a result, the femur neck and trochanter T-scores were lowered, and osteoporosis prevalence was increased. Use of a recalculated young-normal SD for the GE Lunar-adjusted NHANES III database improved diagnostic agreement and is recommended. INTRODUCTION: Use of manufacturer-specific normative databases for T-score derivation leads to discordance in T-score values and differences in diagnostic classification. To address this issue, the International Committee for Standards in Bone Measurement (ICSBM) recommended the NHANES III database for femur T-score derivation. Acquired on Hologic (Hol) instruments, this database requires conversion equations for application to other DXA systems. NHANES III total femur (TF) conversions for GE Lunar (GE) have previously been available, and femoral neck (FN) and trochanter (TR) equations were reported recently. Per the ICSBM recommendation, GE Lunar incorporated these values into their female database. This should produce T-score and diagnostic agreement between Hol and GE instruments; however, this has not been evaluated. MATERIALS AND METHODS: We compared GE femur scans in 115 postmenopausal women using software before and after the NHANES III software update. Subsequently, T-scores derived from femur scans obtained on GE and Hol densitometers were compared in a different group of 89 postmenopausal women. RESULTS: The NHANES III software update had no effect on measured BMD (g/cm2) at any femur region. However, because of changes in values used for T-score calculation (increase in the mean young-normal BMD at the FN and TR and a reduction in SD at the TR), the T-scores were lower (mean, 0.48 and 0.68, respectively) at the FN and TR using post-NHANES III software. Consequently, this update increased femur osteoporosis prevalence in these 115 women from 7.8% to 18.3%. Comparison of GE with Hol total proximal femur T-scores revealed a minimal difference (<0.1) and equal diagnoses of osteoporosis. FN and TR differences were larger, with mean GE T-scores lower than Hol (p < 0.001) by 0.17 and 0.50, respectively, thereby introducing osteoporosis diagnostic disagreement (13 [GE] versus 9 [Hol]). Our evaluation suggested that this disparity resulted from direct application of published NHANES III SDs at the FN and TR. As such, we applied the conversion formulae to the NHANES III published Hologic data and found the FN and TR SDs were greater than assumed by GE. Using our recalculated SD to derive T-scores reduced the mean GE/Hol T-score difference to 0.03 at the FN and 0.32 at the TR and resolved osteoporosis diagnostic disagreement. CONCLUSION: The GE NHANES III software update leads to lower FN and TR T-scores than obtained with Hol or prior GE software. Recalculation of the young-normal SD reduces this difference and is recommended. Clinicians are advised to avoid using the TR for diagnosis or, at a minimum, use caution when making treatment decisions based solely on T-score at this site.

Absorptiometry, Photon↗
PubMed2004

Evidence for abnormal translational regulation of renal 25-hydroxyvitamin D-1alpha-hydroxylase activity in the hyp-mouse.

Hyp-mice exhibit abnormal regulation of 25-hydroxyvitamin D [25(OH)D]-1alpha-hydroxylase activity. Previous observations suggest such aberrant modulation is posttranscriptional. To investigate this possibility further, we examined whether hyp-mice manifest abnormal translation of 25(OH)D-1alpha-hydroxylase mRNA. We compared phosphate, parathyroid, and calcitonin effects on renal 25(OH)D-1alpha-hydroxylase protein as well as mRNA and enzyme activity in normal and hyp-mice. We assayed protein by Western blots, mRNA by real-time RT-PCR, and enzyme activity by measuring 1,25-dihydroxyvitamin D production. Although phosphate-depleted mice exhibited enhanced enzyme function, with significantly increased mRNA and protein expression, hyp-mice comparably increased mRNA but failed to augment enzyme activity, concordant with an inability to increase protein expression. PTH stimulation increased mRNA and protein expression as well as enzyme activity in normal mice but in hyp-mice, despite effecting mRNA enhancement, did not increment enzyme function or protein. The inability of hypophosphatemia and PTH to increase 25(OH)D-1alpha-hydroxylase activity and protein expression in hyp-mice was not universal because calcitonin stimulation was normal, suggesting proximal convoluted tubule localization of the defect. These data, in accord with absent undue enhancement of protein expression in hyp-mice treated with protease inhibitors, establish that abberrant regulation of vitamin D metabolism results from abnormal translational activity.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗
PubMed2004

Treatment of anticonvulsant drug-induced bone disease.

Although the pathophysiology of bone disease in patients treated with anticonvulsant drugs may vary, most affected patients have increased bone remodeling rather than decreased mineralization. Milder cases may show high bone turnover without significant loss of cortical or trabecular bone. Cases of intermediate severity may exhibit the characteristic features of a high-turnover osteopenia/osteoporosis, but some patients with severe bone disease may manifest the features of an osteomalacic disorder. Prophylactic vitamin D supplementation at doses up to 2000 IU/day can be recommended for all patients on initiation of anticonvulsant therapy. A calcium intake of 600-1000 mg/day should also be ensured. If an osteopenic/osteoporotic disorder exists, treatment with 2000-4000 IU/day vitamin D is appropriate. Vitamin D doses of 5000-15,000 IU/day may be needed to treat osteomalacia. Conventional treatment with bisphosphonates may be needed when the response to vitamin D is inadequate. However, routine use of bisphosphonates in patients receiving long-term anticonvulsant therapy cannot at present be recommended.

Anticonvulsants↗
PubMed2004

Use of the lowest vertebral body T-score to diagnose lumbar osteoporosis in men: is "cherry picking" appropriate?

In this study, we hypothesized that use of the lowest T-score among four lumbar vertebral bodies would lessen the impact of degenerative arthritis and other artifacts on diagnostic categorization at this site and increase study sensitivity, classifying more men with prior fracture as osteoporotic than the other two methods of lumbar spine analysis. Bone density studies of 533 male veterans measured between January and October 2002 were reviewed to determine diagnostic classification using the L1-L4 average, International Society for Clinical Densitometry (ISCD)-determined, and lowest lumbar vertebral body T-score. We calculated sensitivity and specificity of the three methods of spine analysis, using spine osteoporosis to indicate a positive test and prior fracture as the true indicator of osteoporosis. The lowest lumbar T-score performed with similar sensitivity and specificity to that of the lowest hip or wrist T-score in the ability to classify men with prior fracture as osteoporotic, whereas the average L1-L4 and ISCD-determined T-scores performed with lower sensitivity, but better specificity. In conclusion, this retrospective study suggests that use of the lowest vertebral body T-score among men increases diagnostic sensitivity of lumbar spine bone mass measurement. Prospective studies are needed to determine which of these three methods of lumbar spine analysis best predicts future fragility fracture in men and women.

Absorptiometry, Photon↗
PubMed2003

Transactivation of the epidermal growth factor receptor mediates parathyroid hormone and prostaglandin F2 alpha-stimulated mitogen-activated protein kinase activation in cultured transgenic murine osteoblasts.

Recent data suggest that G protein-coupled receptors (GPCRs), including those for PTH and prostaglandins (PGs), contribute to the proliferation and differentiation of osteoblasts in vivo. To understand how these signals are transduced, we studied activation of the ERK1/2 MAPK cascade in cultures of differentiating TMOb murine osteoblasts. In TMOb cells, stimulation of endogenous Gs/Gq-coupled PTH receptors, Gq-coupled PGF2 alpha receptors, and Gi/Gq-coupled lysophosphatidic acid receptors, but not Gs-coupled PGE2 receptors, caused a rapid 5- to 10-fold increase in ERK1/2 phosphorylation. GPCR-stimulated ERK1/2 activation coincided with increased tyrosine phosphorylation of epidermal growth factor (EGF) receptors and was blocked by the EGF receptor inhibitor, tyrphostin AG1478, and the metalloprotease inhibitor, batimastat, suggesting that the response involved transactivation of EGF receptors through the proteolytic release of an EGF receptor ligand. To further examine the mechanism of PTH-stimulated EGF receptor transactivation, we employed COS-7 cells expressing the rat PTH receptor. Here, stimulation with PTH(1-34) caused proteolysis of hemagglutinin epitope-tagged heparin binding-EGF, increased tyrosine autophosphorylation of EGF receptors, and AG1478-sensitive ERK1/2 activation. When PTH receptor-expressing COS-7 cells were placed in a mixed culture with cells lacking the PTH receptor but expressing a green fluorescent protein-tagged ERK2, stimulation with PTH(1-34) induced phosphorylation of green fluorescent protein-ERK2 that was abolished by either batimastat or tyrphostin AG1478. These data suggest that autocrine/paracrine cross-talk between EGF receptors and Gi- or Gq/11-coupled GPCRs represents the predominant mechanism of GPCR-mediated activation of ERK1/2 in cultured TMOb osteoblasts.

Animals↗
PubMed2003

Abnormal regulation of renal 25-hydroxyvitamin D-1alpha-hydroxylase activity in X-linked hypophosphatemia: a translational or post-translational defect.

The hyp mouse exhibits abnormal metabolic/hormonal regulation of renal 25(OH)D-1alpha-hydroxylase activity. Whether this results from aberrant transcriptional regulation of the 1alpha-hydroxylase gene, CYP27B1, remains unknown. To investigate this possibility, we compared phosphate and parathyroid hormone effects on renal proximal convoluted tubule and thyrocalcitonin effects on proximal straight tubule enzyme activity and mRNA expression in normal and hyp mice. We assayed 25(OH)D-1alpha-hydroxylase activity by measuring 1,25(OH)2D production and mRNA by ribonuclease protection. Phosphate-depleted mice exhibited a 3-fold increment of 25(OH)D-1alpha-hydroxylase activity compared with normals, whereas hyp mice displayed no enhanced enzyme function. Phosphate-depleted mice concurrently displayed a 2-fold increase in mRNA transcripts; in contrast, despite failure to alter enzyme activity, hyp mice exhibited a similar increment in mRNA transcripts. Parathyroid hormone stimulation of normal mice increased 25(OH)D-1alpha-hydroxylase activity 10-fold, while eliciting only a 2-fold increment in hyp mouse enzyme function. This disparity occurred despite increments of mRNA transcripts to comparable levels (22.2 +/- 3.5- vs. 19.9 +/- 1.8-fold). The dissociation between phosphate- and parathyroid hormone-mediated transcriptional activity and protein function was not universal. Thus, thyrocalcitonin stimulation of normal and hyp mice resulted in comparable enhancement of mRNA transcripts and enzyme activity. These observations indicate that abnormal regulation of vitamin D metabolism in hyp mice occurs in the proximal convoluted tubule and results, not from aberrant transcriptional regulation, but from a defect in translational or post-translational activity.

Animals↗
PubMed2003

Are Wisconsin physicians knowledgeable about male osteoporosis?

It is unknown if recent research defining the relatively frequent occurrence and pathophysiology of male osteoporosis has been conveyed to clinicians. To assess if physicians have incorporated such information, 5646 licensed Wisconsin physicians received a 1-page survey consisting of 14 statements regarding general knowledge, diagnosis, and treatment of osteoporosis in men. Twenty-six percent (1488) responded; 69% (1033) were family physicians or internists, 7% (106) orthopedic surgeons, and 5% (63) endocrinologists or rheumatologists. Of these physicians, 61% to 78% recognized that osteoporosis is not rare in men. Most (68%-97%) agreed that low-trauma fracture or corticosteroid therapy initiation are indications for bone mass measurement. Treating osteoporosis at a T-score of -2.5 was accepted by 79% to 89% of responders. Overall these physicians: (1) recognize osteoporosis as an important disease in men; (2) accept corticosteroid therapy and prior low-trauma fracture as indications for bone mass measurement; and (3) utilize T-scores in treatment decisions. These data suggest that knowledge regarding male osteoporosis has been conveyed to practicing physicians. Evaluation of methods by which physicians will translate this knowledge into action, thereby optimizing patient care, are needed.

Bone Density↗
PubMedDate not supplied

Calciphylaxis in the absence of end-stage renal disease.

OBJECTIVE: To report a case of calciphylaxis in the absence of renal failure in a patient with secondary hyperparathyroidism and low calcium/phosphorus product, in whom total parathyroidectomy resulted in relief of pain and healing of ulcerations. METHODS: We present the clinical, laboratory, and pathologic findings in a 62-year-old woman with calciphylaxis in the absence of end-stage renal disease. RESULTS: A 62-year-old woman presented with painful nonhealing bilateral calf ulcerations. Pathology examination of tissue specimens from surgical débridement revealed intravascular calcification, consistent with calciphylaxis. Laboratory investigation revealed normal renal function; however, hypocalcemia and hypophosphatemia were present--a corrected serum calcium level of 7.5 mg/dL (normal, 8.5 to 10.2) and a serum phosphorus value of 1.0 mg/dL (normal, 2.5 to 4.5). These abnormalities were likely due to vitamin D deficiency, evidenced by a 25-hydroxyvitamin D level of 14 ng/mL, which provoked an elevation of the serum parathyroid hormone (PTH) concentration, documented by an intact PTH of 213 pg/mL (normal, 15 to 65) and a whole PTH (1-84 PTH) of 70.6 pg/mL (normal, 7 to 36). Her quality of life was severely impaired, not only by the ulcerations but also by intractable pain that necessitated epidural analgesia during the hospitalization. The patient underwent total parathyroidectomy and transcervical thymectomy, with cryopreservation of parathyroid tissue. One year after the parathyroidectomy, the patient had no recurrence of calciphylaxis. CONCLUSION: This case suggests that despite the potential complex pathophysiologic aspects of calciphylaxis, even in the absence of both renal failure and an elevated calcium/phosphorus product, early parathyroidectomy in patients with appreciably increased PTH levels may improve wound healing and diminish pain.

Calciphylaxis↗