Risk factors in transient osteoporosis: a retrospective study on 23 cases.
Carlo Trevisan M.D., Raymond Klumpp M.D., Riccardo Compagnoni M.D.
UOC Ortopedia AO Bolognini - Seriate (BG)
Corresponding Author:
Carlo Trevisan, MD Adjunct Professor
Scuola di Specialità in Ortopedia e Traumatologia Università degli Studi Milano Bicocca
Chief Orthopedic Dept. Ospedale Bolognini – Seriate AO Bolognini (BG)
Tel +39.035.3063410 FAX 39.035.3063403 Mobile +39.338.7718886 carlo.trevisan@bolognini.bg.it
Keywords: transient osteoporosis; migratory osteoporosis; bone marrow, metabolism; bone, pathology.
Abstract
Purpose
All these conditions in which microdamage accumulation may be expected are at risk for transient osteoporosis and in this regards this disorder might be more appropriately named bone microdamage accumulation (BMA).
The purpose of this study is to verify the prevalence of risk factors for microdamage accumulation in a cohort of BMA patients.
Methods
This is a retrospective observational cohort study on outpatient data. Inclusion criteria were: 1. acute onset of pain at a lower limb joint exacerbated by weight bearing2. Presence of bone marrow edema on MRI in a weight bearing joint without signs of intraarticular lesions; Exclusion criteria were history of trauma, tumors, rheumatic diseases, infection, hyperesthesia and/or allodynia and/or abnormal sweating.. The following risk factors for BMA were searched for in all patients: 1. previous documented episodes of BMA; 2. disorders of bone metabolism; 3. cigarette smoke; 4. recent lower limb overuse; 5. presence of osteoporosis/osteopenia.
Results
Twenty-three patients (8 females,15 males; mean age 48.4 yrs) fulfilled the inclusion criteria. An average of 1,96 risk factors for BMA were present in the cohort. The most frequent risk factor was overuse (in 15 patients, 65.2%) and the second risk factor was bone metabolism disorders (in 10 patients, 43.5%). Seven patients (30.4%) were heavy smokers (more than 20 cigarettes per day) and 7 patients showed a previous episode of BMA. Six patients (26.1% of the overall cohort but 60% of those investigated with DEXA) resulted osteoporotic or osteopenic.
Conclusion
Our results suggest that there are risk factors that must be investigated in these patients. Presence of these risk factors support the thesis that their disorder is tied to a decoupling between microdamage accumulation and self-reparative ability of bone tissue. The identification of risk factors with a precise diagnostic pathway can accelerate the diagnostic process and reducerecurrences.
Introduction
In the past 40 years, over 800 cases of transient osteoporosis have been reported in the literature mainly as case reports of one single case or few cases at the time. Most of these cases share some common characteristics: pain in a weight bearing joint with no history of trauma, bone medullary oedema on magnetic resonance imaging, complete resolution of the symptoms with a complete restitutio ad integrum within a few months [1,2].
The occurrence of transitory demineralization of the hip during pregnancy was first described by Curtiss and Kincaid in 1959 [3] and subsequently self-resolving episodes of joint pain accompanied by localized osteoporosis at the lower limb have been variously labeled as regional migratory osteoporosis, transient osteoporosis, idiopathic regional osteoporosis, migratory algodystrophy.
The uncertainty about the label to be given to this disorder reflects on one hand its long debated etiology and pathogenesis and on the other hand the lack of shared criteria on which diagnosis should be based on.
Several hypotheses have been advanced about its pathogenesis. The compression of the obturator nerve by the fetal head was indicated as the main cause by Curtiss and Kincaid in their original paper [3]. Local hyperemia and increased intramedullary pressure resulting from disturbed venous return were suggested when bone marrow oedema was regularly detected on MR imaging [4] while others favoured a mechanism close to post-traumatic complex regional pain syndrome [5] or considered transient osteoporosis to be an early and potentially reversible stage of avascular necrosis of the hip [6]. One of the most likely conjectures for the pathogenesis of transient osteoporosis is that proposed by Frost [7] who stated that under noxious tissue stimuli the ordinary biological regional processes may be greatly accelerated: bone microdamage, resulting from the weight suffered by the affected skeletal region might operate as a stimulus. Therefore, it can be argued that all conditions in which microdamage accumulation may be expected are at risk for transient osteoporosis [8]. Authors suggest that this disorder should be more appropriately named bone microdamage accumulation (BMA)
The onset of BMA would take place as the final event caused by decoupling between the production of bone micro- cracks determined by cyclic loading of the body weight and the actual capacity of the BMU(significato?) to repair such injuries in a timely manner, as we have pointed out in the past [8]. There is no homogeneity in current literature and invasive treatments are still proposed for a self-resolving disease that responds adequately and with a complete recovery to conservative treatment. (LETTERATURA)Aim of this study is to identify risk factors for microdamage
accumulation in a cohort of patients affected by BMA, analyzing the prevalence of risk factors for BMA in a cohort of carefully selected patients.
The results could be useful to define more accurately the criteria for identification of the patient suffering from BMA, to strengthen the hypothesis on BMA pathogenesis and to identify risk factors for BMA and its recurrences.
Patients and Methods
This is a retrospective observational cohort study of outpatient clinical records conducted under the principles of Helsinki’s Declaration with the approval of our hospital’s ethics committee.
We revised our outpatient data from 2004 to 2014 to select all patients examined for pain in a weight bearing joint in presence of bone marrow oedema (BME) in the same joint as evidenced by magnetic resonance imaging (MRI) (Fig.1).
Inclusion criteria were: 1. acute onset of pain in a lower limb exacerbated by weight bearing 2. evidence on MRI of bone marrow oedema in a weight bearing joint without signs of intraarticular lesions; Exclusion criteria were history of trauma, tumors, rheumatic diseases, infection, hyperesthesia and/or allodynia and/or abnormal sweating.
The following demographic and clinical data were collected: age, sex, body mass index, clinical history, approximate date of the onset of symptoms, the date of the final diagnosis, assigned treatments and time to healing.
A subset of patients performed laboratory exams and/or bone densitometry based on the clinical evaluation of each case.
The following risk factors for BMA were searched in all patients: 1. previous episode of BMA; 2. disorders of bone metabolism; 3. cigarette smoke; 4. Recent lower limb overuse; 5. presence of osteoporosis/osteopenia.
The occurrence of a previous episode of BMA was considered when the patient was able to clearly recall a self-
resolving episode of pain at a lower limb exacerbated by weight bearing for no apparent reason that he considers similar to the present event in terms of intensity and duration of pain. Cigarette smoke was considered when consumption was greater than 10 cigarettes per day.
A recent lower limb overuse was registered when the patient described a steep change of activity intensity or duration either in his jobor during leisure time which led to the onset of symptoms after a few days. A patient was labeled as osteopenic when he or she had a T-score between -1 and -2.5 at dual-energy x-ray absorptiometry evaluation (DEXA) in at least one of these regions of interest: L1-L4, femoral neck or total femur; osteoporotic when the T-score was below -2.5.
Descriptive statistical analysis summarised continuous data by mean and standard deviation (SD) or minimum and maximum values. Categorical data were summarised by the number and percentage of individuals in each category.
Results
From 2004 to 2014, 55 patients were evaluated in ouroutpatient service for persistent pain in a weight bearing joint without apparent cause. Seven patients didn’t complete the diagnostic workup or were lost at follow-up, 2 had an inadequate MRI and their symptoms resolved before repeating the MRI and 13 patients didn’t fulfil the inclusion criteria and were excluded: 3 for osteochondral lesions at the knee, 2 for avascular necrosis of the femoral head, 4 for oedema associated with severe arthrosis (3 knees, 1 hip), 2 for CRPS type 1 at the foot, 1 for metatastatic dissemination, 1 for osteoid osteoma at the femoral neck.
Twenty-three patients fulfilled the inclusion criteria and were included in the study (table 1). There were 8 females and 15 males with a mean age of 48.4 yrs (range 24-75). The involved joints were: 13 hips, 6 knees, 2 ankles and 2 feet.
Seventeen patients (73.9%) performed laboratory testsfor metabolic bone disease and 10 patients (43.5%) performed a vertebral and hip bone density evaluation by dual-energy x-ray absorptiometry (DEXA).
An average of 1,96 risk factors for BMA were present in all patients: 9 patients with 1 risk factor, 7 patients with 2, 6 patients with 3 and 1 patient with 4.
The most common risk factor was overuse detected in 15 patients (65.2%). All these patients established a clear association between the change of activity and the onset of pain in their joint.
The second risk factor was bone metabolism disorders detected in 10 patients (43.5% of the overall cohort but 58.8% of those investigated with lab tests).
Seven patients (30.4%) were heavy smokers (more than 20 cigarettes per day) and 7 patients evidenced a previous episode of BMA. Finally, 6 patients (26.1% of the overall cohort but 60% of those investigated with DEXA) resulted osteoporotic or osteopenic.
The average time from onset of symptoms to final diagnosis was 2.8 months (range 1-7).
All patients were treated with varying partial weight bearing regimen of the involved lower limb related to the degree of pain and with bisphosphonates until symptoms subsided.
The average time from diagnosis to healing was 4.3 months (range 2-7) and the average duration of symptoms from onset to recovery was 7.1 months (range 3-14).
No correlation was found between the number of risk factors and duration of symptoms or between delay in the diagnosis and recovery time.
All patients had a complete recovery without any sequelae.
DiscussionWe believe that transient osteoporosis represents an acute response of bone to an accumulation of trabecular micro-cracks in a framework that becomes inadequate to withstand the cyclic loads to which it is subject.
For this reason some factors that could increase the risk for this condition were identified. Hypothesis of the study is that if the prevalence of these factors is shown in a large cohort of patients affected by transient osteoporosis assessed with specific restrictive criteriathis could be considered a strong indicator that ourpathogenic hypothesis is reasonable and that these risk factors may be useful in the diagnostic process.All patients in this cohort have shown at least one or more factors attributable to a condition of risk for a decoupling of microdamage accumulation and self-reparative ability of bone tissue; 14 of 23 (60.8%) at least two or more.
The most represented risk factor was a significant raise of the usual level of physical activity well supporting the hypothesis of an increase in the incidence of micro-cracks within the bone.
Although other factors considered by the study as the presence of osteoporosis or cigarette smoking have already been mentioned in several clinical cases as risk factors, an assessment of possible increases of physical activity in these patients has been rarely reported in the literature [9].Results of this study support the involvement of this aspect in BMA pathogenesis which in our opinion has a significant role.One of the paradigmatic models of BMA, widely reported in the literature, are women in the third trimester of pregnancy. Although not represented in our cohort drawn from a database of orthopedic outpatients clinic, they adequately represent the model of decoupling between
microdamage and healing capacity which is mentioned in this study. During pregnancy, women develop the BMA just at the moment when there is an increase in the functional demand caused by thet gain of weight, associated with weakening of the bone structure caused by the calcium imbalance due to the transfer of calcium to the fetus [10].
Disorders in bone mineral metabolism were the second risk factor for incidence and affected almost 60% of our patients undergoing laboratory tests.
Evaluation of bone mineral metabolism with laboratory tests is uncommon in these patients. In a recent review of 18 cases of transient osteoporosis of the hip, Guler and coll. have no laboratory test on bone metabolism [11]. Singh and colleagues also did not perform any examination on bone metabolism in 18 patients with bone marrow edema of the foot or ankle [12]. The high percentage of patients with disorders observed in our series leads to reconsider the need for systematic screening of bone metabolism in patients suffering from BMA.
In the cohort of this study a densitometric evaluation was performed in 10 patients, of these 6 were found to be osteoporotic or osteopenic.
In literature, a condition of low bone mass is frequently observed in patients with BMA when bone densitometry was performed. In the study of Ridge and coll., their 12 patients with transient osteoporosis were all investigated with lumbar and femoral bone densitometry: 5 resulted osteopenic and 3 resulted osteoporotic [13]. In a more recent study conducted by Klontzas and associates on transient osteoporosis of the hip, 31 patients had a lumbar densitometry evaluation, resulting in 15 patients being classified as osteopenic and 15 as osteoporotic [14].
Thus a significant proportion of these patients have a low bone mass, nevertheless evaluation with bone densitometry remains sporadic. This applies also to our series where less than half of the subjects were investigated.
About a third of our patients previously showed an episode due to BMA. This is frequently reported in the literature and confirms, as advocated by most authors, that transient osteoporosis and migratory osteoporosis are on the same side of the same coin which the term BMA brings together under a more appropriate label.
A large number of cases of transient osteoporosis reported in the literature show its true migratory nature [15]. In their study, Singh and coll. performed a short review of 15 studies collecting 203 patients: 4 studies reported a recurrence rate to the same foot and ankle between 9% and 44% and 8 studies reported a migration rate to a different anatomical site between 4% and 50% [12].
This reinforces the importance of being able to adequately identify the risk factors underlying BMA both to prevent the recurrence of analogous episodes in the future if these factors are correctable and to achieve an earlier diagnosis which in our cohort took on average nearly three months.
The study results suggest that when precise diagnostic criteria are used to identify individuals with BMA, one should proceed to a diagnostic screening that includes a densitometric assessment and laboratory tests for bone mineral metabolism in order to complete the investigation of the major risk factors.
Transient osteoporosis is a diagnosis of exclusion in most of the clinical cases reported in the literature. A BME on MRI in a weight bearing joint must be present in the absence of other detectable diseases, but precise criteria have not been clearly stated.
Therefore we elaborated specific inclusion criteria to select our cohort. In particular, since BME is a final common pathway of many diseases and since there is some nosological uncertainty about BMA, there was the risk that patients with other confounding diseases could be included in the study [16].
The fact that in all patients there was a complete recovery without sequelae within a few months with conservative therapy, supports the validity of the criteria used for selection. In fact, the complete functional recovery after
conservative treatment is widely described in the literature as one of the characteristics of the BMA [17,18]. The only exceptions are some cases of femoral neck fracture reported mainly as a complication of BMA in pregnancy [19,20]
and more rarely in other patients [21] which we believe are exactly the result of the extreme limit of accumulation of bone microlesions [22,23].
The retrospective nature is definitely the major limit of the study. The uncertainty in BMA etiology and in the diagnostic criteria are, in our series, responsible for the amount of heterogeneity in the diagnostic pathway and it is possible that if all patients had carried out a densitometric evaluation and laboratory tests for bone metabolism, the incidence of risk factors would have been better defined.
In conclusion, the investigation of this retrospective cohort of 23 individuals selected with precise clinical criteria leads us to state that there are risk factors that must be investigated in these patients. These risk factors support the thesis that their disorder is tied to a decoupling between microdamage accumulation and self-reparative ability of bone tissue.
Therefore, in our opinion, the acronym BMA is best suited to describe this disease. The identification of risk factors with a precise diagnostic pathway can further accelerate the diagnostic process and prevent recurrences.
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Figures
Figure 1. Bone marrow oedema on magnetic resonance imaging due to bone microdamage accumulation in 3 different patients . A - proximal left tibia medial plateaux; B - right femoral head and neck; C and D – right talus.
