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Biomedical subjects

F R Singer

Publications and source records attributed to F R Singer.

At least 19 recordsLinked to original sources
PubMed1998

Evidence for a novel osteosarcoma tumor-suppressor gene in the chromosome 18 region genetically linked with Paget disease of bone.

Paget disease of bone, or "osteitis deformans," is a bone disorder characterized by rapid bone remodeling resulting in abnormal bone formation. It is the second most common metabolic bone disease after osteoporosis, affecting 3%-5% of subjects aged >40 years. Recent evidence suggests that predisposition to Paget disease may have a genetic component. Genetic linkage analysis of families with multigenerational Paget disease shows linkage to a region of chromosome 18q near the polymorphic locus D18S42. Approximately 1% of Paget patients develop osteosarcoma, which represents an increase in risk that is several thousandfold over that of the general population. Osteosarcoma in Paget patients is the underlying basis for a significant fraction of osteosarcomas occurring after age 60 years. Our analysis of tumor-specific loss of constitutional heterozygosity (LOH) in 96 sporadic osteosarcomas has identified a putative tumor-suppressor locus that maps to chromosome 18q. We have localized this tumor-suppressor locus between D18S60 and D18S42, a region tightly linked to familial Paget disease. Analysis of osteosarcomas from patients with Paget disease revealed that these tumors also undergo LOH in this region. These findings suggest that the association between Paget disease and osteosarcoma is the result of a single gene or two tightly linked genes on chromosome 18.

Adult↗
PubMed1998

Risedronate, a highly effective oral agent in the treatment of patients with severe Paget's disease.

Thirteen patients with severe Paget's disease of bone [mean serum alkaline phosphatase (SAP) level 17 times the upper limit of normal] were treated with 30 mg oral risedronate daily for 8 weeks. Patients were followed for 16 weeks without treatment. The change from baseline SAP was the primary end point. Those patients whose SAP levels did not reach the normal range were retreated with 30 mg for another 8 weeks. There was a mean percent decrease in SAP of 77% after the first course of risedronate treatment and 87% after the second course of treatment. All patients who completed the study had a decrease in SAP of at least 77% from the baseline. The urinary hydroxyproline/creatinine level was decreased by 64% and 79%, respectively, during the first and second treatment courses. There were transient asymptomatic decreases in serum calcium and phosphorus levels. The urinary calcium/creatinine ratio also decreased in these patients. Serum intact PTH and 1,25-dihydroxyvitamin D levels increased transiently during risedronate treatment. Oral risedronate was well tolerated by the patients. Only one patient discontinued treatment because of an adverse event (diarrhea) thought to be related to risedronate therapy.

Aged↗
PubMed1998

Risedronate in the treatment of Paget's disease of bone: an open label, multicenter study.

An open-label, multicenter study was conducted to determine the efficacy and safety of oral risedronate (a pyridinyl bisphosphonate) in 162 patients (102 men, 60 postmenopausal women; mean age, 68 years) with moderate to severe Paget's disease of bone (mean serum alkaline phosphatase [ALP] approximately seven times the upper limit of normal). Patients were treated with oral risedronate, 30 mg/day for 84 days, followed by 112 days without treatment. This 196-day cycle was repeated once if serum ALP did not normalize or increased from the nadir value by > or = 25%. At the end of the first and second cycles, the mean percentage decreases for serum ALP were 65.7% and 69.1%, and for urinary hydroxyproline/creatinine 50.4% and 66.9%, respectively. The decreases from baseline in ALP and urinary hydroxyproline/creatinine were significant (p < 0.001). Normalization of serum ALP was observed in 86 patients (53.8%): 53 during the first treatment cycle and 33 during the second. There was a significant proportion of patients reporting a decrease in the pagetic bone pain at days 84 and 196 (p < 0.001). Overall, risedronate was well tolerated. Five patients withdrew due to adverse events, none of which were considered to be drug related. In conclusion, 30 mg of oral risedronate administered daily for 84 days significantly reduced the biochemical indices of disease activity and was associated with pain reduction in patients with moderate to severe Paget's disease of bone. Normalization of ALP was observed in the majority of patients. Repeated administration of risedronate was shown to be beneficial. In general, risedronate was well tolerated and demonstrated a good safety profile.

Administration, Oral↗
PubMed1998

Pagetic osteoclasts formed in vitro: absence of paracrystalline inclusions.

In Paget's disease of bone, osteoclasts are increased in number and size and contain intracellular paramyxoviral-like inclusions which cross-react with antibody against measles, respiratory syncytial, and canine distemper viral nucleocapsid antigens. Moreover, measles virus nucleocapsid transcripts are present in pagetic osteoclasts and their mononuclear precursors formed in vitro. The present study was undertaken to morphologically assess pagetic osteoclasts formed in culture; special attention has been directed towards the ultrastructural identification of nuclear and cytoplasmic inclusions. Pagetic osteoclasts were produced in long-term cultures of non-adherent bone marrow mononuclear cells derived from involved bone of patients with Paget's disease. These cultured osteoclasts had many of the ultrastructural features of pagetic osteoclasts in vivo. Of interest, no viral-like inclusions were observed in either the multinucleated osteoclasts or mononuclear cell precursors in these cultures. These data suggest that other factors in the bone microenvironment are required for viral nucleocapsid formation in pagetic osteoclasts.

Bone Marrow Cells↗
PubMed1997

Increments in bone mineral density of the lumbar spine and hip and suppression of bone turnover are maintained after discontinuation of alendronate in postmenopausal women.

PURPOSE: Previously we have reported a significant increase in bone mineral density (BMD) of the spine and the hip and reductions in biochemical indices of bone turnover in postmenopausal women with osteoporosis treated with alendronate at various doses over 1 to 2 years. We have followed BMD and biochemical parameters in these patients for 1 or 2 years after discontinuation of alendronate to determine resolution of alendronate effects. PATIENTS AND METHODS: Participants received daily oral doses of placebo, 5 or 10 mg of alendronate for 2 years, or 20 or 40 mg of alendronate for 1 year followed by 1 year of placebo. No treatment was given in the third year of study. RESULTS: Lumbar spine BMD changes in the 5- and 10-mg groups (-1.4 and -0.4%) were similar to those in the placebo group (-1.2%) 1 year after discontinuation of drug and lumbar spine BMD changes in the 20- and 40-mg groups (-1.2% and 0.8%) were similar to those in the placebo group (-0.9%) 2 years after discontinuation of drug. BMD of the total hip followed the same pattern of resolution. The difference in BMD between alendronate and placebo groups at the end of alendronate treatment was maintained up to 2 years. Residual reductions in the bone resorption markers urinary deoxypyridinoline (D-Pyr) and collagen type 1 cross-linked N telopeptides and the bone formation markers serum bone-specific alkaline phosphatase and osteocalcin remained for 1 year after discontinuation of 5 and 10 mg of alendronate and for 2 years after discontinuation of 20 and 40 mg of alendronate, other than return of D-Pyr to baseline 1 year after cessation of treatment with the 5- and 10-mg doses. CONCLUSIONS: A residual decrease in bone turnover may be found up to 2 years after discontinuation of alendronate. Accelerated bone loss is not observed when treatment is discontinued. However, continuous therapy with alendronate is required to achieve a continuous gain in BMD.

Adult↗
PubMed1997

Genetic linkage of Paget disease of the bone to chromosome 18q.

Paget disease is a common bone disease characterized by abnormal osteoclasts that are large, multinucleated, and overactive and that contain paramyxovirus-like nuclear inclusions. There is evidence for a major genetic component to Paget disease, with up to 40% of patients having affected first-degree relatives; however, the locus (loci) and gene(s) involved are unknown. Another bone disorder, familial expansile osteolysis (FEO), although extremely rare, also is characterized by similar osteoclast abnormalities but has an earlier age at onset and a more aggressive clinical progression. The causative gene for FEO has been localized to a region of human chromosome 18q. On the basis of the presence of similar clinical findings and of viral-like nuclear inclusions in osteoclasts, we hypothesized that FEO and Paget disease are allelic versions of the same locus. Therefore, a large kindred with a high incidence of Paget disease was examined to determine if Paget disease was linked to genetic markers in the same region of chromosome 18 as that for FEO. Our analysis yielded a two-point LOD score of 3.40, with the genetic marker D18S42, a marker tightly linked to the FEO locus. This demonstrates that the gene(s) responsible for FEO and that for Paget disease are either closely linked or the same locus.

Adult↗
PubMed1997

Evidence that serum NTx (collagen-type I N-telopeptides) can act as an immunochemical marker of bone resorption.

Previous studies have shown that immunoassay of urinary NTx (cross-linked N-telopeptides of type I collagen) provides a responsive index of human bone resorption. Here we report by a sensitive immunoassay that NTx is present in serum and is suppressed appropriately in patients with Paget disease of bone by bisphosphonate antiresorptive therapy. The monoclonal antibody (1H11) developed against urinary NTx was applied in a sensitive chemiluminescence format. Results for human serum and urine showed parallel inhibition curves. The NTx concentrations in paired serum and urine samples from individual patients correlated well when urinary concentrations were normalized to creatinine concentrations (in premenopausal and postmenopausal women and Paget disease patients, r = 0.90, n = 60). The percentage of NTx suppression from baseline values for Paget disease patients on bisphosphonate therapy was similar for serum and urine. Blood samples drawn from bone marrow at the site of Pagetic lesions in three patients with active disease had as much as 10-fold higher concentrations of NTx than did peripheral blood samples drawn at the same time. The latter finding is consistent with other evidence showing that immunoreactive NTx originates directly during the proteolytic cleavage of bone collagen by osteoclasts rather than, e.g., by degradative processes occurring later in the liver and kidney.

Adult↗
PubMed1996

Detection of measles virus nucleocapsid transcripts in circulating blood cells from patients with Paget disease.

Paget disease of bone is characterized by abnormalities in all phases of bone remodeling, but the fundamental cellular abnormality resides in the osteoclast (OCL). Osteoclasts in bone involved by Paget disease contain viral-like nuclear and cytoplasmic inclusions that react with antibodies directed against paramyxovirus nucleocapsid proteins, such as measles virus, respiratory syncytial virus, or canine distemper virus. However, the identity of the virus or the mechanisms responsible for its persistence or pathologic role in Paget disease is unclear. Furthermore, although Paget disease persists for many years, it remains a highly localized process with new lesions rarely if ever developing in previously unaffected bones. Since osteoclasts are formed by fusion of mononuclear precursors derived from colony forming unit-granulocyte macrophage (CFU-GM), the granulocyte-macrophage progenitor, we used reverse transcriptase polymerase chain reaction (RT-PCR) analysis to determine if CFU-GM, more differentiated osteoclast precursors, and peripheral blood cells derived from CFU-GM express measles virus nucleocapsid (MV-N) transcripts. We found that osteoclast precursors, as well as peripheral blood mononuclear cells, express MV transcripts in 9 of 13 patients. Sequence analysis of the PCR amplified products confirmed nucleotide identity of MV-N transcripts expressed in peripheral blood and bone marrow-derived cells from the same patient. In contrast, MV-N transcripts were not detected in OCL precursors or the peripheral blood from 10 normal subjects. In situ hybridization studies using 35S-labeled antisense riboprobes to MV-N transcripts further confirmed the expression of MV transcripts in these cells. Sequence analysis of the PCR amplified product from one of these patients also identified a novel mutation that converted lysine441 to glutamic acid441 in the MV-N transcript. These data demonstrate that OCL precursors and circulating peripheral blood cells also express MV transcripts in patients with Paget disease and suggest that the pagetic marrow microenvironment plays a critical role in maintaining the highly localized nature of the lesions in Paget disease.

Aged↗
PubMed1996

Medical management of nonparathyroid hypercalcemia and hypocalcemia.

In this article the differential diagnosis and management of non-parathyroid hypercalcemia and hypocalcemia are outlined. A differentiation is made between the acute management of symptomatic hypercalcemia and hypocalcemia and the chronic control of these relatively common states of abnormal electrolyte homeostasis. The use of newer agents such as bisphosphonates for hypercalcemia and calcitrol for hypocalcemia is emphasized.

Acute Disease↗
PubMed1995

Alendronate treatment of the postmenopausal osteoporotic woman: effect of multiple dosages on bone mass and bone remodeling.

BACKGROUND: The effects of the aminobisphosphonate alendronate sodium on bone mass and markers of bone remodeling were investigated. PATIENTS AND METHODS: In a multicenter, randomized, double-blind, placebo-controlled, 2-year study, 188 postmenopausal women, aged 42 to 75 years, with low bone mineral density (BMD) of the lumbar spine were randomly assigned to 1 of 6 daily treatment groups: placebo for 2 years, alendronate 5 or 10 mg for 2 years, alendronate 20 or 40 mg for 1 year followed by placebo for 1 year, or alendronate 40 mg for 3 months followed by 2.5 mg for 21 months. All subjects were given 500 mg/d of elemental calcium as calcium carbonate. RESULTS: At each dose, alendronate produced significant reductions in markers of bone resorption and formation, and significantly increased bone mass at the lumbar spine, hip, and total body, as compared with decreases (significant at lumbar spine) in subjects receiving placebo. In the 10-mg group, mean urinary deoxypyridinoline/creatinine had declined by 47% at 3 months, and mean serum osteocalcin by 53% at 6 months. Mean changes in BMD over 24 months with 10 mg alendronate were +7.21% +/- 0.49% for the lumbar spine, +5.27% +/- 0.70% for total hip, and +2.53% +/- 0.68% for total body (each P < 0.01) compared to changes of -1.35% +/- 0.61%, -1.20% +/- 0.64% and -0.31% +/- 0.44% at these sites, respectively, with placebo treatment. Progressive increases in BMD of both lumbar spine and total hip were observed in the second year of treatment with 10 mg alendronate (both P < 0.05). CONCLUSION: Alendronate, a potent inhibitor of bone resorption, reduces markers of bone remodeling and significantly increases BMD at the lumbar spine, hip, and total body, and is well tolerated at therapeutic doses (5 or 10 mg daily) in the treatment of osteoporosis in postmenopausal women.

Adult↗
PubMed1995

Bone marrow mononuclear cells from patients with Paget's disease contain measles virus nucleocapsid messenger ribonucleic acid that has mutations in a specific region of the sequence.

Ultrastructural, immunocytochemical, and in situ hybridization studies have suggested that paramyxoviruses, such as measles virus (MV), are present in Pagetic osteoclasts and may contribute to the abnormality in osteoclast function. However, little additional information is known about potential viruses present in Pagetic osteoclasts. As there are increased numbers of osteoclast precursors among the marrow mononuclear cells of Paget's patients, we used the reverse transcriptase-polymerase chain reaction to amplify the nucleocapsid sequence of MV from freshly isolated bone marrow-derived mononuclear cells to examine the potential role of these viruses in cells in the osteoclast lineage. We detected MV nucleocapsid transcripts in 5 of 6 individual Paget's patients' marrow samples. MV transcripts were not detected in marrow samples from 10 normal subjects. Sequence analysis of the PCR products revealed that 1 patient had the same sequence as the Edmonston strain of MV. The remaining 4 patients had point mutations clustered between position 1360-1371 base pairs. Two of the patients exhibited identical mutations at this region. In total, 3 different point mutations were identified that resulted in amino acid substitutions. These data show that 1) unlike those from normal subjects, marrow mononuclear cells from Paget's patients express MV nucleocapsid messenger ribonucleic acid; and 2) mutations of a specific region of the MV nucleocapsid gene were present in 4 of 5 patients and suggest a persistent MV infection in Pagetic osteoclast precursors. These data further suggest that osteoclasts are infected by fusion with infected precursors.

Amino Acid Sequence↗
PubMed1995

Bisphosphonates in the treatment of disorders of mineral metabolism.

Bisphosphonates are analogues of inorganic pyrophosphate, a naturally occurring chemical in bone. In vitro and animal experiments demonstrated that these agents were effective inhibitors of bone resorption. Subsequently they were applied to a variety of clinical problems in which increased bone resorption was an underlying feature of the pathology. In 1971 etidronate became the first bisphosphonate shown to inhibit bone resorption in humans when it was given to patients with Paget's disease. Subsequently this agent was also found to be useful in treating the hypercalcemia of malignancy. At the present time cyclic etidronate therapy is also used for the prevention of bone loss in patients with osteoporosis and for the prevention of heterotopic ossification in spinal cord-injured patients and in patients after hip replacement. Newer bisphosphonates are generally more potent than etidronate and do not produce a severe mineralization defect as do higher doses of etidronate. Pamidronate and clodronate are highly effective in the management of Paget's disease, hypercalcemia due to malignancy and immobilization, metastatic bone disease, and hematologic malignancies affecting bone. They are also promising agents for the prevention of osteoporosis. Alendronate, risedronate, and CGP 42446 are highly potent bisphosphonates that look very promising for the treatment of all disorders of bone resorption. It is fortunate that adverse reactions are not a prominent feature of bisphosphonate use. The main side effects are nausea and abdominal discomfort, mainly with oral use, a transient increase in bone pain in patients with Paget's disease, and an acute-phase reaction (fever, myalgia, mild leukopenia) in patients receiving aminobisphosphonates. The evolution of bisphosphonate therapy should be considered one of the major therapeutic events of the past 25 years. Future research should define the optimum use of these agents.

Diphosphonates↗
PubMed1993

Abnormalities in osteoclast precursors and marrow accessory cells in Paget's disease.

Paget's disease of bone is characterized by increased numbers of abnormal osteoclasts. To determine if osteoclast precursors were increased or abnormal in this disease, we examined CFU-GM, the committed granulocyte-macrophage progenitor and the most likely precursor for osteoclasts. In cultures of unfractionated marrow mononuclear cells, CFU-GM colony formation was significantly increased in Paget's marrow cultures compared to that in normal cells (356 +/- 44 vs. 271 +/- 15/10(5) cells; P < 0.05). However, when we enriched hematopoietic precursors from Paget's and normal marrow samples using an antibody that recognizes the CD34 antigen present on most hematopoietic precursors, we found that similar numbers of CFU-GM colonies were formed (87 +/- 13/10(4) cells plated vs. 83 +/- 13). Coculture experiments with highly purified hematopoietic precursors (CD34+ cells) and nonhematopoietic marrow accessory cells (CD34- cells) revealed that the growth of Paget's precursors was significantly enhanced above expected levels by normal or Pagetic CD34- cells (P < 0.05). CFU-GM colony formation was also significantly enhanced when normal CD34+ cells were cocultured with Pagetic, but not with normal, CD34- cells. In addition, CFU-GM colony-derived cells from Paget's patients were hyperresponsive to 1,25-dihydroxyvitamin D3 and could form osteoclast-like multinucleated cells with 1,25-dihydroxyvitamin D3 concentrations one tenth of that required for normal multinucleated formation (10(-11) vs. 10(-10) M). These data suggest that osteoclast precursors may be abnormal in Paget's disease, and other cells in the Pagetic marrow microenvironment may further enhance the growth and differentiation of these abnormal precursors.

Antigens, CD↗