[Current prevention and treatment strategies for osteoporosis. Fracture-oriented, effective, low side effects and inexpensive]. / Aktuelle Osteoporoseprophylaxe und -therapie. Frakturorientiert, effektiv, nebenwirkungsarm, kostengünstig.

Osteoporosis is still an underdiagnosed and insufficiently therapied widespread disease in Germany. Of the estimated 7 million osteoporosis patients only 1.5 million receive a guideline conform diagnosis and even less receive appropriate treatment. Some 90 % of patients are provided with analgesics but only 10 % receive an effective therapy, although efficacious, well-tested and affordable medications are available. In addition, approximately one half of the patients terminate treatment after only 1 year although according to the results of recent studies the duration of therapy should be at least 3-5 years. In view of the increasing average life expectancy, a consistent management for prevention of fractures associated with osteoporosis is always most important for society, even if only for reasons of costs. Achievement of this target depends on four circumstances: clarification of the origin of osteoporosis and fractures (bone consciousness), prophylaxis of bone loss and fractures (primary prevention), consistent guideline conform diagnostics and therapy (secondary and tertiary prevention) and cooperation of all disciplines in medicine (bone is everybody's business). This article describes the current state of diagnostics (bone density measurement with dual X-ray absorptiometry, FRAX®), prophylaxis of fractures (screening program) and therapy (use of economic and effective medications with low side effects). Novel medications are already undergoing clinical testing and a "healing" of bone reduction with restoration of the normal bone structure is to be expected.

[Secondary osteoporosis: pathogenesis, types, diagnostics and therapy]. / Sekundäre Osteoporosen: Pathogenese, Formen, Diagnostik und Therapie.

Due to increasing knowledge on pathogenetic factors causing osteoporosis and increasingly more detailed investigations, the diagnosis of secondary osteoporosis is being made increasingly more often. A rational search for the underlying disease or the bone-damaging medication is indicated particularly in adolescents, premenopausal women, men and postmenopausal women with rapidly decreasing bone tissue. The early detection of the causative disease in the preclinical stage of osteoporosis and the current therapeutic options allow not only normalization of the bone structure and the risk of fracture but also targeted therapy of the cause of the osteoporosis. The focal point in the diagnostics of secondary osteoporosis is still dual energy X-ray absorptiometry (DXA) measurement together with the manifold imaging procedures in radiology and additional clinical, laboratory chemical and bioptic findings.

[Drug-induced osteopathies. Drugs, pathogenesis, forms, diagnosis, prevention and therapy]. / Medikamenteninduzierte Osteopathien. Medikamente, Pathogenese, Formen, Diagnostik, Prävention und Therapie.

A number of drugs can have "side effects" on bone metabolism and formation, causing bone atrophy, impaired mineralisation, as well as osteonecrosis. In both clinical and general practitioner settings, these forms of bone damage have been hitherto considered as adverse drug side effects and have received insufficient attention; moreover, they have not been the subject of patient information. Preventive measures are not instigated prior to initiation of medication and even after onset of bone damage, therapeutic strategies are poorly implemented. Even fracture healing with its complex, staged course can be both positively and negatively influenced by a number of drugs and these effects require monitoring. Recommendations regarding practical screening and therapy of drug-induced osteopathies are presented.

[Current diagnosis and therapy of osteoporosis on the basis of "European guidance 2008"]. / Aktuelle Diagnostik und Therapie der Osteoporose auf der Basis der "European Guidance 2008".

Osteoporosis is one of the 10 most important and widespread global diseases. In Germany alone the cost of osteoporosis runs into many billions of Euros. However, it should be noted that in the past 15 years great progress has been made both in diagnosis and in the development of new medications, and this has changed the general perception of and attitude to osteoporosis. It is now taken very seriously and recognised as a national and global disorder which is both preventable and treatable. In spite of this progress, in Europe and especially in Germany, osteoporosis remains an underdiagnosed and undertreated disease. In Germany, only about 10%-15% of patients with manifest osteoporosis are properly treated. However, in addition to national guidelines, there is now a new edition of the "European Position Paper for the Diagnosis and Management of Osteoporosis". This provides physicians treating osteoporosis patients with additional information and therefore more confidence.

[Drug-induced osteopathies. Drugs, pathogenesis, forms, diagnosis, prevention and therapy]. / Medikamenteninduzierte Osteopathien: Medikamente, Pathogenese, Formen, Diagnostik, Prävention und Therapie.

A number of drugs can have "side effects" on bone metabolism and formation, causing bone atrophy, impaired mineralisation, as well as osteonecrosis. In both clinical and general practitioner settings, these forms of bone damage have been hitherto considered as adverse drug side effects and have received insufficient attention; moreover, they have not been the subject of patient information. Preventive measures are not instigated prior to initiation of medication and even after onset of bone damage, therapeutic strategies are poorly implemented. Even fracture healing with its complex, staged course can be both positively and negatively influenced by a number of drugs and these effects require monitoring. Recommendations regarding practical screening and therapy of drug-induced osteopathies are presented.

[Reduced bone density and bone pain :osteomalacia with hypophospatemia and hypophosphaturia]. / Erniedrigte Knochendichte und Knochenschmerzen : Osteomalazie mit Hypophosphatämie und Hyperphosphaturie.

Two patients aged 24 and 64 years presented at our hospital with similar symptoms including bone pain and muscle weakness. Basic laboratory tests and urinary diagnostics, bone densitometry and bone histology revealed severe osteomalacia with renal phosphate wasting. After the exclusion of other causes an extensive tumor search was performed due to suspected tumor-induced osteomalacia. In one patient a mesenchymal tumor was found in the thigh and completely resected. After surgery the patient showed a rapid recovery from osteomalacia. Because the search was unsuccessful in the other patient phosphorus supplementation in combination with calcitriol was started. Despite continuing renal phosphate wasting a significant increase in bone mineral density was observed.

Current use of bisphosphonates in oncology. International Bone and Cancer Study Group.

PURPOSE: The purpose of this article is to review the recent data on bisphosphonate use in oncology and to provide some guidelines on the indications for their use in cancer patients. DESIGN: The group consensus reached by experts on the rationale for the use of bisphosphonates in cancer patients and their current indications for the treatment of tumor-induced hypercalcemia and metastatic bone pain in advanced disease and for the prevention of the complications of multiple myeloma and of metastatic bone disease are reviewed. RESULTS: Bisphosphonates are potent inhibitors of tumor-induced osteoclast-mediated bone resorption. They now constitute the standard treatment for cancer hypercalcemia, for which we recommend a dose of 1,500 mg of clodronate or 90 mg of pamidronate; the latter compound is more potent and has a longer lasting effect. Intravenous bisphosphonates exert clinically relevant analgesic effects in patients with metastatic bone pain. Regular pamidronate infusions can also achieve a partial objective response by conventional International Union Against Cancer criteria and enhance the objective response rate to chemotherapy. In breast cancer, the prolonged administration of oral clodronate 1,600 mg daily reduces the frequency of morbid skeletal events by more than one fourth, whereas monthly pamidronate infusions of 90 mg for only 1 year in addition to chemotherapy reduce by more than one third the frequency of all skeletal-related events. The use of bisphosphonates to prevent bone metastases remains experimental. Last, bisphosphonates in addition to chemotherapy are superior to chemotherapy alone in patients with stages II and III multiple myeloma and can reduce the skeletal morbidity rate by approximately one half. CONCLUSION: Bisphosphonate use is a major therapeutic advance in the management of the skeletal morbidity caused by metastatic breast cancer or multiple myeloma, although many questions remain unanswered, notably regarding the optimal selection of patients and the duration of treatment.

An update: 12-year follow-up of patients with hairy cell leukemia following treatment with 2-chlorodeoxyadenosine.

Long-term results of both pretreated and previously untreated patients (pts) with hairy cell leukemia (HCL) using uniformly a single 7-day course of 2-chlorodeoxyadenosine (2-CdA) by continuous infusion are reported. In addition, the probability of obtaining another response with this drug in pts who relapsed after 2-CdA treatment will be addressed. A total of 44 consecutive pts (34 males, 10 females) with a median age of 57 years (range 33-77) at the time of initiation of 2-CdA treatment were analyzed. In all, 11 pts were pretreated with either splenectomy (n=6), interferon alpha (n=9) or deoxycoformycin (dCF) (n=3) or all procedures in sequence. Two pts treated with dCF did not respond to dCF, but only 2-CdA. The median time to the start of 2-CdA treatment of the 11 pretreated pts was 47 months (mo) (10-160). Out of 44, 43 (98%) achieved complete response (CR) (13 pts with residual disease-RD), one pt reached a good partial response with a single cycle of 2-CdA. Out of 44 pts, 13 had no nonhematologic toxicities at all. Toxicities (WHO grade I-IV) were mainly of grade I and II, in one pt grade IV infectious complication. Bone marrow biopsies were performed at the time of recovery of hematopoiesis, thereafter at 2-3 mo intervals, thereafter at 6 mo, and finally annually in 35 pts. The median follow-up is 8.5 years (0.1-12.2). Disease-free survival from the start of 2-CdA treatment is 36% at 12 years (median 8.4 years), 17/44 pts relapsed. Nine of these pts were treated with 2-CdA again, eight achieved a second CR (median 2.5 yrs), one pt did not respond. Eight of our cohort had a second malignancy before receiving 2-CdA. Six pts died in CR due to the second malignancy. The overall survival at 12 years after the start of 2-CdA treatment is 79%. 2-CdA is a safe and effective treatment of HCL inducing complete remissions in the majority of pts with only a single cycle of 2-CdA, and a paucity of toxicities. Responses are durable and long-lasting. Pts who relapsed following treatment with 2-CdA responded to subsequent retreatment with 2-CdA.

Correlations between karyotype and cytologic findings in multiple myeloma.

In multiple myeloma, correlations between cytogenetic and morphologic findings are hampered by the relatively scarce chromosomal data and the lack of a widely accepted morphologic classification. The aim of the analysis, comprising 111 patients with multiple myeloma, was to study possible correlations between karyotype and a morphologic classification proposed by Bartl et al. Grade of plasma cell infiltration, predominant cell types (Marschalko, small, cleaved, polymorphous, asynchronous, blastic) and grade of malignancy are the basis of this classification. A pathologic karyotype was found in the bone marrow of 39/111 patients (35%). The incidence of chromosomal anomalies closely correlated with the grade of infiltration, plasma cell type and grade of malignancy. Chromosomal anomalies were rarely detected in patients with low infiltration (16%), but they were frequently found in high-grade infiltration (69%). A low incidence was found in Marschalko (25%) or small cell type (15%); the incidence was much higher in cleaved (75%), asynchronous (65%) and basic cell types (71%). An abnormal karyotype was more frequently found in high (71%) than in intermediate (53%) or low (23%)-grade malignant multiple myeloma. The most consistent structural chromosomal aberration found in five patients was translocation t(11;14)(q13;q32). In four of the five patients small, often cleaved plasma cells were the predominant cell types. These reported correlations between morphological and cytogenetic findings must be confirmed by future studies.

[Correlation of MRI and histopathology of bone marrow in patients with multiple myeloma]. / Korrelation zwischen MRT und Histopathologie des Knochenmarks bei Patienten mit Multiplem Myelom.

PURPOSE: To compare MRI findings and histological plasmacellular infiltration of the bone marrow in patients with multiple myeloma (MM). MATERIAL AND METHODS: Twenty-four patients with different stages of MM underwent 1.5T MRI of the pelvic bone before iliac crest punch biopsy. Precontrast T1wSE and STIR and postcontrast (Gd-DTPA) T1wSE-fatsat were acquired using axial slices. Immediately after the biopsy, T1wSE was repeated to locate the biopsy canal. The corresponding region in the examination before punch biopsy was assessed for bone marrow involvement using a three-point score (0: negative, 1: suspect, 2: definite). RESULTS: Two patients were not included because the location of the biopsy canal was unclear. Of 7 patients without histological plasmacellular infiltration, MRI was false positive in one case (suspect). Of 15 patients with histological infiltration, MRI was positive in 10 cases (4 suspect, 6 definite). The T1wSE was positive in 9 cases, STIR in 8 cases, and postcontrast T1wSE-fatsat in 7 cases. In 10 of the 15 patients, the infiltration was histologically graded as low (5 - 20 % of bone marrow). In this group, MRI was only positive in 5 cases (3 suspect, 2 definite). Of five patients with the infiltration histologically graded as high (> 20 % of bone marrow), MRI was positive in all cases (1 suspect, 4 definite). CONCLUSION: Only advanced bone marrow infiltration in MM can be reliably detected by MRI. None of the used sequences proved to be significantly superior or inferior.

A comparison of polychemotherapy and melphalan/prednisone for primary remission induction, and interferon-alpha for maintenance treatment, in multiple myeloma. A prospective trial of the German Myeloma Treatment Group.

406 untreated multiple myeloma patients of stage I (n = 54), II (n = 148) and III (n = 204) were enrolled in the trial. 51/54 stage I and 60/148 stage II patients were asymptomatic and followed without treatment until disease progression (progression free survival: 60% after 4 years for stage I versus 50% after 1 year for stage II). Symptomatic patients of stage I (n = 3/54) and II (n = 88/148) presenting with tumour progression, received melphalan 15 mg/m2 intravenously (i.v.) and prednisone 60 mg/m2 oral days 1-4 (MP). Stage II disease remission rate was 59%, and 50% tumour related survival (TRS) was 59 months. Stage III patients were randomised to receive MP or VBAMDex (vincristine/BCNU/doxorubicin/melphalan/dexamethasone) treatment. 43% of MP treated patients responded compared with 64% of the VBAMDex group. 50% TRS was 36 months in both groups without a detectable difference. 117 responders of stage II and III with stable disease were randomised to receive either IFN-alpha (5 x 10(6) IU, subcutaneous (S.C.) 3 times per week) or no maintenance treatment. The relapse rate in both groups was 50% after 13 months. No survival benefit for IFN alpha treated patients was observed (50% TRS: 45 months).

Morphologic classification of the myelodysplastic syndromes (MDS): combined utilization of bone marrow aspirates and trephine biopsies.

In a retrospective and prospective follow-up study from 1975 to 1991, bone marrow biopsies, aspirates and clinical features of 495 patients with MDS were investigated. Sections of undecalcified plastic embedded biopsies and smears of bone marrow aspirates were stained according to Giemsa. Bone marrows with MDS were characterized by three main categories of morphologic alterations: (1) cellular abnormalities, (2) architectural disorganization in the bone marrow and (3) stromal changes; the combined use of aspirates and trephine biopsies enabled a more reliable and accurate diagnosis of MDS than either one alone. The bone marrow findings fell into one of 7 subtypes, with the frequencies and median survivals in brackets: (1) MDS sideroblastic (19%, 62 months), (2) MDS megaloblastoid (13%, 56 months), (3) MDS proliferative (22%, 31 months), (4) MDS blastic (15%, 9 months), (5) MDS hypoplastic (15%, 26 months), (6) MDS fibrotic (6%, 29 months), and (7) MDS inflammatory (10%, 42 months). In follow-up studies patients with secondary MDS were excluded and the prognosis and subsequent evolution for each of the morphologic subtypes were evaluated. The conclusion is drawn that aspirates and trephine biopsies are complementary procedures and both are required for diagnosis, classification and decisions on current treatment modalities of patients with MDS.

Philadelphia chromosome-negative acute hematopoietic malignancy: ultrastructural, cytochemical and immunocytochemical evidence of mast cell and basophil differentiation.

We describe a patient with fever and multiple osteolytic bone lesions accompanied by hypercalcemia, a duodenal ulcer, anemia, and thrombocytopenia. Bone marrow showed a dense infiltration by abnormal cells characterized by small basophil granula, erythrophagocytosis and nuclear atypia. These cells were positive for toluidine blue and partly for myeloperoxidase and chloroacetate esterase, expressed myeloid differentiation markers, and exhibited multiple numerical and structural chromosome aberrations. Molecular genetic analysis showed no breakpoint cluster region rearrangement. Electron microscopy demonstrated granula both of basophil and mast cell type. Concluding, in this patient an acute hematopoietic malignancy with many features of malignant mastocytosis but also with signs of a basophil differentiation. This is further support for a hematopoietic stem cell origin of human mast cells.

Histologic classification and staging of multiple myeloma. A retrospective and prospective study of 674 cases.

Bone marrow biopsies of 674 patients with multiple myeloma (MM) were processed for diagnostic evaluation. Histologic variables were correlated with the clinical features to determine factors of value in predicting prognosis. Four of these were used to classify MM into six histologic types: Marschalko type; small cell type; cleaved type; polymorphous type; asynchronous type; and blastic type. These six types were subsequently combined into three prognostic grades: low, intermediate, and high, analogous to the malignant lymphomas. The quantity of plasma cell burden in the biopsy proved to be a useful criterion for histologic staging of MM, supplementing any clinical staging system in use. Both these parameters, grade and stage, provide information required for decisions on treatment modalities, while the effects of therapy can be monitored by sequential biopsies.

Bone marrow histology in hairy cell leukemia. Identification of subtypes and their prognostic significance.

Bone marrow biopsy specimens taken on initial investigation of 134 patients with hairy cell leukemia (HCL) were processed into plastic, and sections cut at 3 microns were used for histologic and histomorphometric evaluation. Twenty-four clinical, 10 histologic, and four histomorphometric variables were tested for their prognostic significance. Bone marrow involvement was found in all cases, and on the basis of their morphology, the hairy cells were divided into three types: ovoid (47%), convoluted (37%), and indented (16%); this classification proved to be highly significant in the test statistics, with median survivals for the three groups of 56, 12, and 5 months, respectively. The characteristic nuclear features of the three types also were identified in smears of peripheral blood, in sections of spleen, and by electron microscopy. In addition, significant differences were found when the patients were grouped according to the tumor cell mass (volume %) in the biopsy sections, with median survivals of 55, 21, and 8 months noted for less than 20 vol%, 20-50 vol%, and greater than 50 vol%, respectively. Other factors with prognostic relevance were cytoplasmic inclusion bodies in the hairy cells (HC) and a number of clinical variables, including initial values of Hb and ESR, and platelets and monocytes in the peripheral blood. These results confirm that the bone marrow always is involved in HCL and its histology is diagnostic; that HCL may be classified according to the predominant neoplastic cell type; and that the patients may be staged on the basis of the tumor cell burden in the bone marrow biopsy.

Characterization of myeloma cells by means of labeling index, bone marrow histology, and serum beta 2-microglobulin.

The relationship between two cellular prognostic parameters of multiple myeloma, the plasma cell labeling index (LI%) and bone marrow histology was studied. The LI% as the percentage of monoclonal plasma cells in the S-phase was measured by bromodeoxyuridine incorporation using the anti-bromodeoxyuridine antibody BU-1. The histologic classification was based on six plasma cell types that allow prognostic grading as the Marschalko, small cell, cleaved, polymorphous, asynchronous, and blastic types. The biopsies also were used for estimating the degree of infiltration. Beta 2-microglobulin (IMx assay, Abbott, North Chicago, IL), the most significant serum parameter for myeloma also was measured for comparison. Bone marrow specimens and sera were obtained from 50 myeloma patients. Fourteen patients with smoldering myeloma were characterized by well-differentiated Marschalko or small cell type cells, a low LI% and a low beta 2-microglobulin concentration. Considering all myeloma patients, plasma cell type and degree of infiltration showed a significant correlation with LI% and beta 2-microglobulin concentration. Patients with plasma cells that were not mature cells of the Marschalko or small cell type revealed a high LI% or high beta 2-microglobulin level in 16 of 19 cases. However, a high LI% or high beta 2-microglobulin level could be detected in only 8 of 31 patients with plasma cells of the Marschalko or small cell type. Three of 21 stage I patients did not show the typical finding of a low LI%, low beta 2-microglobulin level, and a favorable grade. Stage II patients were not uniformly characterized by LI%, beta 2-microglobulin and plasma cell morphology. The percentage of nucleolated plasma cells was not associated with the LI%. Bone marrow histology, LI%, and beta 2-microglobulin concentration appear to be supplementary prognostic factors. If LI% and beta 2-microglobulin levels are not measured, a higher risk could be overlooked in cases with mature plasma cells.

Bone biopsy in haematological disorders.

Bone marrow biopsies are now widely used in the investigation and follow-up of many diseases. Semi-thin sections of 8216 undecalcified biopsies of patients with haematological disorders were studied. Observations were made on the cytopenias and the myelodysplastic syndromes, the acute leukaemias the myeloproliferative disorders, Hodgkin's disease and the malignant lymphomas including multiple myeloma, hairy cell leukaemia and angioimmunoblastic lymphadenopathy. Bone marrow biopsies are essential for the differential diagnosis of most cytopenias and for the early recognition of fibrosis which most frequently occurred as a consequence of megakaryocytic proliferation in the myeloproliferative disorders. Different patterns of bone marrow involvement were found in the lymphoproliferative disorders and both their type and extent constituted factors of prognostic significance. A survey of the literature is given and the conclusion is drawn that bone marrow biopsies provide indispensible information for the diagnostic evaluation and the follow-up of patients with haematological disorders.

Plasma cell proliferation in monoclonal gammopathies: measurement using BU-1 antibody in flow cytometry and microscopy: comparison with serum thymidine kinase.

AIMS: The labelling index as defined by the percentage of bone marrow plasma cells doubling their DNA in the S phase is a useful prognostic factor in multiple myeloma. The aim of this study was to examine the specificity and sensitivity of a new flow cytometric method for measuring the labelling index. METHODS: Bone marrow specimens from five patients with monoclonal gammopathy of undetermined significance and 61 patients with multiple myeloma were investigated. The labelling index (LI%) was determined by means of a microscopic and flow cytometric method using the antibromodeoxyuridine antibody BU-1. Serum thymidine kinase, another index of proliferation, was measured by radioimmunoassay. RESULTS: Good comparability (r = 0.83) and nearly equal imprecision (CV < 20%) were found with microscopic and flow cytometric methods of LI% measurement. However, 1000 or more cells had to be counted by microscopy around the cutoff value to avoid an unacceptable imprecision. Plasma cells with increased S phase (LI% > 1%) were characterised by their reduced light chain fluorescence intensity ratio between plasma cells and nonspecifically stained cells (7.9 v 14.8, p < 0.002), that is, by their generally lowered cytoplasmic immunoglobulin content. There was a moderate correlation between thymidine kinase and labelling index (r = 0.56, p < 0.001). At 100% specificity, myelomas with proliferating plasma cells were more sensitively detected by the labelling index than by serum thymidine kinase (55% v 32% sensitivity). CONCLUSIONS: The labelling index represents a more specific and sensitive proliferation marker than serum thymidine kinase. Flow cytometry does not result in greater precision.

Lymphoproliferations in the bone marrow: identification and evolution, classification and staging.

Bone marrow biopsies from 3229 patients with lymphoproliferative disorders and 1156 patients with benign or reactive lymphoproliferations were investigated and criteria for distinguishing between them are given. Bone marrow involvement was found in 89% of multiple myeloma, 64% of non-Hodgkin's lymphomas and 8% of Hodgkin's disease. According to the predominant proliferative cell type there were five major entities in multiple myeloma and non-Hodgkin's lymphomas: (1) plasmacytic; (2) lymphocytic; (3) hairy cell; (4) immunocytic; (5) centrocytic. These were further classified into distinct subtypes each of which had independent prognostic significance. The mode of spread of the lymphoproliferative disorders in the bone marrow showed one of six architectural patterns, which together with the quantity of infiltration in the biopsy (reflecting the tumour cell burden) had significant predictive value. These results demonstrate the value of bone marrow biopsies in the identification, classification and staging of lymphoproliferative disorders, as well as in monitoring the course of disease and the response to therapy.

Working classification of chronic myeloproliferative disorders based on histological, haematological, and clinical findings.

Bone marrow biopsies of 850 patients with chronic myeloproliferative disorders were taken at initial diagnosis; and 169 sequential biopsies over periods of one to 188 months. Three micron sections of all biopsies were evaluated semiquantitatively with reference to the proliferating cell lines, anomalies of megakaryocytes, and fibrosis or osteosclerosis. Correlations between initial histological findings, clinical, haematological, and survival data were analysed statistically. The predominant cell lines distinguished the classical entities of polycythaemia vera, primary thrombocythaemia, and chronic myeloid leukaemia and correlated with their different prognoses, while megakaryocytes characterised subgroups that were prone to fibrotic or blastic transformation. Based on the initial histological, clinical, and haematological data analysed a working classification of chronic myeloproliferative disorders was proposed that permits recognition of both typical and atypical cases of chronic myeloproliferative disorders.