Clin Rheumatol (2005) 25: 30–34 DOI 10.1007/s10067-005-1132-7
O R I GI N A L A R T IC L E
P.H. Kann Æ A. Pfu¨tzner Æ G. Delling G. Schulz Æ S. Meyer
Transiliac bone biopsy in osteoporosis: frequency, indications, consequences and complications. An evaluation of 99 consecutive cases over a period of 14 years Received: 7 September 2004 / Revised: 14 February 2005 / Accepted: 14 February 2005 / Published online: 25 May 2005 Ó Clinical Rheumatology 2005
Abstract Bone biopsy is a diagnostic procedure restricted to untypical, unclear and complicated cases in evidence-based guidelines on diagnosis and treatment of osteoporosis. Its relevance has been a topic of recent controversial discussion. This study was performed to evaluate its role and relevance in routine use. A total of 99 horizontal transiliac bone biopsies performed over a time period of 14 years because of an osteological indication in one single centre were analysed, which reflects that bone biopsy followed about 0.003% of patients’ consultations. Bone biopsies were indicated for osteoporotic males (n=63) and premenopausal osteoporotic females (n=18) without endocrine abnormality and normal immunofixation (serum and urine), suspected systemic/malignant disease such as mastocytosis, osteogenesis imperfecta, non-secreting plasmocytoma, metastatic infiltration (n=16) and decreasing bone mineral density under anti-osteoporotic treatment (n=2). The most frequent diagnoses besides osteoporosis were normal histology, borderline finding towards mild osteoporosis, and osteoporomalacia with relevant osteoidosis. In some cases, pathological findings in bone marrow were detected. In most cases (82/99), bone biopsy led to consequences in medical treatment. Following histopathological diagnosis, 16 patients did not receive any anti-osteoporotic treatment. In six patients, further diagnostic procedures were initiated because of bone P. Kann (&) Æ S. Meyer Division of Endocrinology and Diabetology, Philipp’s University Hospital, 35033 Marburg, Germany E-mail:
[email protected] Fax: +49-6421-2862733 P. Kann Æ A. Pfu¨tzner Æ G. Schulz Æ S. Meyer Department of Endocrinology and Metabolic Diseases, Johannes Gutenberg University Hospital, Mainz, Germany G. Delling Department of Osteopathology, Eppendorf University Hospital, Hamburg, Germany P. Kann Æ A. Pfu¨tzner Institute for Clinical Research and Development, Mainz, Germany
histology. Bone biopsy was well tolerated and complications were rare and mild. In conclusion, despite all progress in non-invasive diagnostic procedures for metabolic bone diseases such as osteoporosis, there remains a small but significant subset of patients who may benefit from inclusion of bone biopsy into the diagnostic procedure. Keywords Biopsy Æ Bone Æ Complication Æ Density Æ Histology Æ Indication Æ Osteoporosis
Introduction Originally, osteoporosis had been characterised and defined as a systemic metabolic bone disease by anatomical and histopathological means [1–3]. Common understanding of osteoporosis, however, has switched markedly during the last 2 decades. The importance of histopathological characteristics has been replaced by a clinical, phenomenological and clinical endpoint-related understanding. Non-invasive diagnostic procedures have become established and seem to make it very easy and comfortable to achieve a correct diagnosis [4–7]. Bone biopsy has been restricted to untypical, unclear and complicated cases in evidence-based guidelines on diagnosis and treatment of osteoporosis [8, 9]. Nevertheless, there has been a recent controversial discussion about performing bone biopsies and their correct interpretation to differentiate between low-turnover and high-turnover osteoporosis with impact on therapeutic decisions [10–14]. In this context, this study was performed to evaluate the role and relevance of bone biopsy in an osteological centre (Department of Endocrinology and Metabolic Diseases—Section of Osteology, Johannes Gutenberg University Hospital, Mainz in cooperation with the Department of Osteopathology, Eppendorf University Hospital, Hamburg, Germany) with a scientific and clinical focus on osteoporosis concerning frequency and
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indications for bone biopsy, quality of the specimens, histopathological diagnosis, consequences for therapeutic strategy, complications and subjective experience of the patients.
Patients and methods In the time period between April 1988 and April 2002, a total of 99 bone biopsies were performed because of an osteological indication at the Department of Endocrinology and Metabolic Diseases—Section of Osteology, Johannes Gutenberg University Hospital, Mainz, Germany. A brief characterisation of the patients is given in Table 1. In the same period, about 10–12 consultations of patients occurred daily (Monday–Friday) for osteological diseases in the outpatient and inpatient departments. The majority of bone biopsies (90%) was performed by one single investigator (PHK). Horizontal transiliac bone biopsy was performed as described by Bordier et al. [15]. This method yields a sample with cortex at both ends, which is a representative volume of iliac bone in its entirety, i.e. as an organ, and permits the measurement of trabecular and cortical parameters. On days –21/–20 and days –7/–6 before biopsy, 500 mg tetracycline were administered orally twice to visualise mineralisation. (Tetracycline double labelling was performed routinely to retain the option for a later post hoc quantitative analysis of the bone specimen. This procedure is not necessary to achieve a histopathological diagnosis.) After local anaesthesia with 10–30 ml bupivacaine 0.5%, transiliac biopsy was taken from an area situated 2 cm behind the anterosuperior iliac spine and 2 cm below the summit of the iliac crest using a manual trocar with 6-mm inner diameter. After biopsy, patients were advised to maintain bed rest with the biopsy site on a sand sack for a period of 6 h. Processing of the bone samples was performed without decalcification as described previously [16, 17]. Sections of 5-lm thickness were cut, and Goldner and Giemsa staining were performed; furthermore, demonstration of iron and enzyme histochemical demonstration of acid phosphatase for analysing osteoclasts were undertaken. Histopathological diagnosis was made by an experienced osteopathologist (GD).
The spectrum of diagnoses is represented in Table 2: histomorphometric analysis was not considered necessary in most cases by the osteopathologist to achieve diagnosis. Osteoporomalacia (osteoporosis and osteomalacia) was distinguished from high-turnover osteoporosis by quantifying and characterising osteoblasts. High-turnover osteoporosis is characterised by about 30% of osteoid surface covered with cubic osteoblasts, whereas in osteoporomalacia, by definition, low turnover is present with inactive, flat osteoblasts or lining cells, respectively, at the osteoid surface. Osteoidosis and fibro-osteoclasia may be considered as indicators for renal osteodystrophy if impaired renal function is known (this information was always provided to the osteopathologist); if this is not the case, this histological finding suggests primary hyperparathyroidism. Osteopathia antiepileptica was defined according to published criteria [18] knowing the patient’s history and medication (this information was always provided to the osteopathologist). Bone biopsy for an osteological indication was evaluated concerning six items: 1. Indications for bone biopsy as they have been raised by the staff of the department, colleagues from other departments (such as orthopaedics) and admitting physicians from other institutions as documented in the patients’ medical report 2. Quality of the bone specimens as described by the osteopathologist 3. Histopathological diagnosis as given by the osteopathologist 4. Consequences for therapeutic strategy (in this long period of time where diagnostic criteria varied, new therapeutic strategies have been developed and different recommendations have been given) as documented in the patients’ medical reports with respect to (a) changes in specific medical treatment for bone at all, (b) whether a specific anti-osteoporotic treatment (as considered appropriate at the given time) was initiated or not and (c) whether biopsy resulted in further diagnostic attempts 5. Complications of bone biopsy, as documented in the patients medical report and reported in questionnaires (see [6]) sent to the patients at the time of analysis of the whole cohort in the year 2002
Table 2 Table 1 Patients Age (mean: 44 years, median: 43 years, range: 20–75 years) 60 years n=9 Gender Female n=31 (premenopausal n=18) Male n=68
Indications for bone biopsy Osteoporotic male without endocrine abnormality and normal immunofixation in serum and urine Premenopausal osteoporotic female without endocrine abnormality and normal immunofixation in serum and urine Suspected systemic/malignant disease (such as mastocytosis, osteogenesis imperfecta, non-secreting plasmocytoma, metastatic infiltration) Decreasing bone mineral density under anti-osteoporotic treatment
n=63 n=18 n=16 n=2
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6. Subjective experiences of the patients as reported recently by the patients in a standardised questionnaire addressing the following items: – Comparing subjective experience of bone biopsy to dental treatment – Feeling of pain at bone biopsy – Subjective estimation of impact for therapeutic decision – Adverse events/complications Frequency of bone biopsies was correlated with the number of consultations because of osteological indications at the outpatient and inpatient departments.
Results 1. Documented indications for bone biopsy are given in Table 3. Osteoporosis was defined by typical fractures and/or low bone mineral density using different criteria and methods of measurement over a period of 14 years. 2. Concerning specimens’ quality, 10 of 99 specimens were reported explicitly by the osteopathologist to be excellent. In reports on another 65 specimens, no comment was given on the specimen’s quality; however, there was no problem in achieving a definite diagnosis. Sixteen specimens were reported to be not of ideal quality, five to be of poor quality and three specimens were completely unsuitable for diagnostic use. Bone biopsies’ quality improved with the osteologist’s experience with this procedure (p=0.025, Mann–Whitney U test). 3. Histopathological diagnoses (bone and bone marrow) are shown in Table 2. 4. (a) In 82 of 99 cases, consequences in medical treatment (including the decision to stop an ongoing bone treatment) following bone biopsy were documented Table 3 Histopathological diagnosis (bone) Low-turnover osteoporosis High-turnover osteoporoses Osteoporosis, not further classified Osteoporomalacia (osteoporosis and osteoidosis) Borderline finding between normal and osteoporosis Renal osteodystrophy Finding compatible with osteoporosis and osteogenesis imperfecta Fibro-osteoclasia with osteoidosis Osteopathia antiepileptica Normal/healthy bone No diagnosis Histopathological diagnosis (bone marrow) Normal/irrelevant abnormality Increased amount of plasma cells Increased amount of mast cells Definitive mastocytosis Siderosis Hemochromatosis Eosinophilia No diagnosis
36 5 14 12 15 1 3 1 1 8 3 63 1 5 1 15 1 6 7
in the patients’ reports. In 13 patients, there was no change in treatment; in 4 cases, this was not documented in the medical report. (b) Following histopathological diagnosis after bone biopsy, 16 patients did not receive any anti-osteoporotic treatment. (c) In six patients, further diagnostic procedures were indicated following bone biopsy, which were a repeated procedure of bone marrow analysis in three cases, computed tomography-guided biopsy of lumbar vertebral bodies 3 and 4 in one case, renal biopsy in one case and a repeated diagnostic procedure because of primary hyperparathyroidism resulting in parathyroidectomy in one case. 5. Complications of bone biopsy were documented in eight patients [small but symptomatic hematoma: three cases; large and symptomatic hematoma: one case; bleeding and pain: one case (patient did not maintain bed rest as recommended), pain requiring medical treatment longer than 3 days: three cases). Small hematomas, which were from the patients’ point of view considered to be irrelevant, occurred in nearly all cases. 6. Questionnaires were sent to the patients who underwent bone biopsies in the time period from 1988 to 2002 in the year 2002. A reply was received from 58 patients (59%). The answers are summarised in Table 4. The feeling of pain decreased significantly as experience with the procedure increased (p=0.048, Mann–Whitney U test). Only 2 of 58 patients subjectively reported adverse events/complications. When asked about repetition of bone biopsy if considered useful, men agreed more frequently than women (p=0.009, Mann–Whitney U test). Table 4 Patients’ subjective experience of bone biopsy (n=58) How did you experience bone biopsy compared to dental treatment? Less comfortable 17 (29%) Comparable 21 (36%) More comfortable 20 (35%) (How) did you experience pain at bone biopsy? Very painful 8 (14%) Painful 11 (19%) Only some kind of pressure 26 (45%) No pain at all 6 (10%) Pain only after the biopsy 7 (12%) Did you feel that bone biopsy was helpful to come to a definite diagnosis and plan the appropriate therapeutic strategy? Yes 43 (74%) No 13 (22%) No answer 2 (4%) Did you experience any adverse event/complication at bone biopsy? Yes 2 (4%) uncomfortable procedure: n=1 Hematoma: n=1 No 56 (96%) Would you agree to another bone biopsy if considered useful by your physician? Yes, every time 42 (72%) Maybe 9 (16%) No, not at all 6 (10%) No answer 1 (2%)
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Correlating the frequency of bone biopsy for an osteological indication to consultations because of osteological problems in general, bone biopsy was calculated to follow 0.003% of patients’ consultations.
Discussion With increasing life expectancy and consequently increasing incidence of osteoporotic fractures in the population, physicians’ perspective on osteoporosis has switched from a histopathological perspective towards a more symptomatic one and focuses on clinical endpoints. The predominant and most relevant question in evaluating diagnostic and therapeutic strategies is to predict fracture risk and to reduce it by therapeutic intervention [6, 7]. Loss of bone mass is measured as bone mineral density by absorption of X-ray energy as the golden standard, a method which is in fact only able to quantify the physical interaction between X-ray energy and calcium-containing crystalline structures under strictly defined conditions [19]. This method is unable to distinguish between different metabolic bone diseases and histopathological abnormalities influencing X-ray absorption. Other diagnostic procedures, such as taking the patient’s history, physical examination, X-ray imaging, and laboratory testing, are mandatory [5]. Measurement of bone mineral density has proven its value to predict fracture risk in statistical analyses of large cohorts and to be a good predictor of a positive outcome of medical osteoporosis treatment on the highest level of evidence [20–22]. Histomorphometry from iliac crest biopsies is not better in predicting vertebral bone strength than measurement of bone mineral density [23]. However, statistical data obtained in large cohorts do not allow the conclusion that measurement of bone mineral density can correctly identify the bone status of each individual patient—especially in untypical situations making other diagnoses more likely, such as in young women and men suspected to suffer from osteoporosis or other metabolic bone diseases. In certain cases, even the patient’s history, physical examination, X-ray and laboratory examinations may not lead to a definite diagnosis. In a period of about 14 years, covered by this evaluation, there were about 2500 consultations per year at our department for osteological diseases including of course besides new patients a majority of follow-up consultations. Nevertheless, an average of about seven bone biopsies per year indicates that this procedure was performed rarely and only following strict indication. Patients were predominantly in the age group between 30 and 60 years, and more than two-thirds were males. The majority of the females were premenopausal. Thus, the untypical cases of suspected osteoporosis/metabolic bone disease were in fact the ones selected for bone biopsy. Interestingly, in 8 of 99 patients, despite strict selection of the patients, i.e. relevant pathological findings in
non-invasive diagnostic procedures, completely normal bone was described by the osteopathologist. In another 15 cases, just borderline findings between healthy bone and mild osteoporosis were reported—an unimpressive pathological state raising the question of the usefulness of a specific anti-osteoporotic treatment. In another group of 14 patients (osteoporomalacia, fibro-osteoclasia with osteoidosis, osteopathia antiepileptica), a classic anti-osteoporotic treatment (as considered appropriate at a specific time) might not have been required for a positive clinical outcome. In conclusion, in more than one-third of our strictly selected patients, the histopathological finding induced a therapeutic strategy different from standard anti-osteoporotic treatment. Furthermore, in certain cases bone marrow analysis also revealed relevant diagnostic information with therapeutic impact. Our finding of a documented consequence in medical treatment, or change of medical treatment, respectively, in 82 of 99 cases, however, has to be considered carefully to avoid overestimating the role of bone biopsy. Usually, definitive treatment was started when the histopathological result was available, or treatment was interrupted for several months in unclear cases to minimise an artificial influence on histopathology. Only in a small minority of the patients were the specimens not useful for diagnostics because of inadequate quality. The experience of the osteologist performing bone biopsy seems to be the major predictor of the specimen’s quality. Only minor complications/adverse events were documented or reported in a small number of patients (documented: 8%, self-reported: 4%). Again, the osteologist’s experience seems to be the major predictor of procedure-related pain. Referring to their subjective experience, patients considered bone biopsy to be comparable to a dental treatment. Most of them reported bone biopsy to be helpful to come to a definite diagnosis and to plan the appropriate therapeutic strategy and would agree to another biopsy if considered necessary and useful, which corresponds very well to another report on this diagnostic procedure [24]. In medicine, the histopathological finding at the end of a patient’s history (following surgery or the patient’s death) has been accepted as the golden diagnostic standard in general where all non-invasive measures have to compare. Referring to bone histology in osteoporosis, correlations of microstructural parameters obtained from bone biopsies of osteoporotic men and women with and without vertebral fractures to fracture prevalence have been demonstrated [25, 26]. However, evidence concerning the role of histopathological analysis of bone biopsies in the therapeutic outcome of osteoporosis is missing [13]. Thus, it remains questionable whether the ubiquitously accepted principle—to take the histopathological finding as the golden diagnostic standard—is still valid in osteology, especially when discussing osteoporosis. This study has been intended to contribute to an ongoing discussion on the relevance and role of bone biopsy in osteoporosis [10–14]. Following strict selection
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for bone biopsy and avoiding bone biopsy in ‘‘typical cases’’, i.e. primary postmenopausal osteoporosis or secondary osteoporosis classified according to noninvasive diagnostic procedures, a reasonable number of patients derive a relevant benefit from this intervention as discussed above. Bone biopsy followed about 0.003% of patients’ consultations in our section for osteological diseases. This makes it clearly evident that bone biopsy was not a widely applied procedure. Taking adverse events, pain and patients’ comfort as well as the need for bone biopsies into account, it seems to be reasonable to restrict bone biopsy to specialised centres working together with an experienced osteopathologist. In conclusion, despite all progress in non-invasive diagnostic procedures for metabolic bone diseases such as osteoporosis, there remains a small but significant subset of patients who may benefit from including bone biopsy into the diagnostic procedure. These patients are the ‘‘untypical cases’’, i.e. osteoporotic males and premenopausal females in whom conventional non-invasive diagnostic procedures cannot identify the aetiology of their disease, and ‘‘non-responders’’ to treatment.
Take Home Message Usually, metabolic bone diseases can be diagnosed by non-invasive diagnostic procedures. However, some patients still benefit from bone biopsy: these are the ‘‘untypical cases’’, i.e. osteoporotic males, premenopausal females and ‘‘non-responders’’ to anti-osteoporotic treatment in whom the aetiology of their disease and the appropriate therapeutic strategy cannot be identified non-invasively. Acknowledgements This study was conducted at the Departments of Endocrinology and Metabolic Diseases, Johannes Gutenberg University Hospital, Mainz and Osteopathology, Eppendorf University Hospital, Hamburg, Germany.
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